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APPLICATIONS OF TUNGSTEN-CATALYZED OXIDATIVE CARBONYLATION OF AMINES TO UREAS
By
AMPOFO KWAME DARKO
A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT
OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY
UNIVERSITY OF FLORIDA
2010
2
© 2010 Ampofo Darko
3
To my Mom, who knows that this is all “rubbish”
4
ACKNOWLEDGMENTS
I am indebted to my advisor, Professor Lisa McElwee-White, for giving me the
freedom to make mistakes and learn from them, which for me, was the most effective
learning tool. Her patience and support as a mentor was everpresent, even in the face
of frustration. I also thank the rest of my committee, Dr. William Dolbier, Dr. Adam
Veige, Dr. Alan Katritzky, and Dr. Susan Percival for contributing to interesting
discussions and experiences that will undoubtedly shape the way I think about
Chemistry.
I must also acknowledge the support of my fellow group members, especially Dr.
Phillip Shelton, and Dr. Seth Dumbris. Sharing the common bond of graduate student
existence have brought us all closer together and will build lasting friendships. I have
also had the pleasure of mentoring intelligent undergraduates and exchange students.
F. Chris Curran, Chloé Copin, Maxime Roche, and Lily Zhang have all contributed to my
learning experience. I have learned much from them as they have from me.
Special thanks go to my beautiful wife, Megan, and my boys, Kieran-Yaw and
Brendan Osei-Akoto. They have supported me throughout my graduate career and
deserve as much of the recognition. Coming home to them was always the best part of
my day. I am grateful to my brother, Kwame, for his continued encouragement when
times were difficult. I would like to thank my sister, affectionately known as Muffet, for
being a great example of having strength in your convictions and beliefs. I would like to
thank my parents, Eva Tagoe-Darko and Charles Darko, for sacrificing so much of their
time for the education and well being of their children. They have instilled the work ethic
in me that gives me the drive to succeed.
5
I must also thank Dr. Delmy Diaz and Dr. Keisha Gay-Hylton for their previous
work on catalytic carbonylations of amines to ureas. I also thank the donors of the
American Chemical Society Petroleum Research Fund for their support of this work
through the Green Chemistry Institute. The research of F. Chris Curran was supported
by The Howard Hughes Medical Institute Science for Life program. The Ecole National
Supérieure de Chemie de Clermont Ferrand (ENSCCF) supported the research of
Chloé Copin and Maxime Roche. The China Scholarship Council funded Lily Zhang
during her exchange visit to the University of Florida.
6
TABLE OF CONTENTS page
ACKNOWLEDGMENTS .................................................................................................. 4
LIST OF TABLES ............................................................................................................ 8
LIST OF FIGURES .......................................................................................................... 9
ABSTRACT ................................................................................................................... 12
CHAPTER
1 TRANSITION METAL-CATALYZED OXIDATIVE CARBONYLATION OF AMINES TO UREAS ............................................................................................... 14
Introduction ............................................................................................................. 14
Palladium-Catalyzed Oxidative Carbonylation of Amines ....................................... 15
Homogeneous Carbonylation of Amines to Ureas ............................................ 15
Pd Catalysis in Ionic Liquids ............................................................................. 18
Electrocatalytic Carbonylation .......................................................................... 19
N-Heterocyclic Carbene-Palladium Complexes ................................................ 20
Supported Palladium Nanoparticles ................................................................. 21
Mechanistic Studies ......................................................................................... 22
Other Late Transition Metal Catalysts ..................................................................... 23
Nickel-Catalyzed Oxidative Carbonylation........................................................ 23
Ruthenium-Catalyzed Oxidative Carbonylation ................................................ 24
Cobalt- and Rhodium-Catalyzed Oxidative Carbonylation................................ 26
Gold-Catalyzed Oxidative Carbonylation .......................................................... 29
Tungsten-Catalyzed Oxidative Carbonylation of Amines ........................................ 30
Carbonylation of Primary Amines ..................................................................... 30
Carbonylation of Primary and Secondary Diamines to Cyclic Ureas ................ 33
Conclusions ............................................................................................................ 45
2 CATALYTIC CARBONYLATION OF FUNCTIONALIZED DIAMINES TO UREAS: APPLICATION TO DERIVATIVES OF DMP 450 ..................................... 46
Introduction ............................................................................................................. 46
Synthesis of DMP 323 and DMP 450 ..................................................................... 49
Synthesis of DMP Analogues by Tungsten Catalyzed Carbonylation ..................... 52
Carbonylation of Aminobutanediols .................................................................. 53
Carbonylation of Aminohexanediols ................................................................. 57
3 CATALYTIC OXIDATIVE CARBONYLATION OF ARYL AMINES TO UREAS ...... 62
Introduction ............................................................................................................. 62
Results and Discussion ........................................................................................... 63
7
Optimization of Reaction Conditions for Oxidative Carbonylation of Aniline to N,N'-Diphenylurea ..................................................................................... 64
Oxidative Carbonylation of p-Substituted Aryl Amines to Symmetrical Diarylureas .................................................................................................... 65
Oxidative Carbonylation of Aryl Amines to Unsymmetrical Diarylureas ............ 68
Conclusions ............................................................................................................ 73
4 APPLICATION OF W(CO)6/I2 CATALYZED CARBONYLATION TO THE SYNTHESIS OF THE LOPINAVIR SIDECHAIN ..................................................... 74
Introduction ............................................................................................................. 74
Literature Synthesis of the Lopinavir Sidechain ...................................................... 75
Tungsten-Catalyzed Synthesis of Lopinavir Sidechain Derivative .......................... 78
Substrate Synthesis ......................................................................................... 78
Tungsten-Catalyzed Carbonylation of N-(3-aminopropyl)glycine methyl ester 80 ......................................................................................................... 79
Conclusion .............................................................................................................. 80
5 EXPERIMENTAL PROTOCOLS ............................................................................. 81
APPENDIX
A SPECTRA OF SYNTHESIZED COMPOUNDS .................................................... 107
B TABLE OF MELTING POINTS ............................................................................. 143
LIST OF REFERENCES ............................................................................................. 146
BIOGRAPHICAL SKETCH .......................................................................................... 157
8
LIST OF TABLES
Table page 1-1 Tungsten-catalyzed oxidative carbonylation of substituted primary diamines .... 35
1-2 Tungsten-catalyzed catalytic carbonylation of substituted benzylamines to ureas .................................................................................................................. 38
1-3 Tungsten-catalyzed carbonylation of diamines 28-30 to ureas 31-33. ................ 40
1-4 Tungsten-catalyzed oxidative carbonylation of aminoalcohols to ureas and carbamates. ........................................................................................................ 42
1-5 Yields of bicyclic ureas from diamines 39a-42a .................................................. 44
2-1 Carbonylation of diamines 60a-60f ..................................................................... 56
2-2 Carbonylation of diamines 60g, 60h, 28, and 30. ............................................... 58
2-3 Conditions attempted for the carbonylation of 60j-m .......................................... 59
3-1 Optimization of the reaction conditions for the W(CO)6 /I2-catalyzed carbonylation of aniline to N,N’-diphenylurea. .................................................... 63
3-2 Oxidative carbonylation of various aryl amines to symmetrical N,N`-diarylureas using the W(CO)6 /I2 catalyst system. ............................................... 65
9
LIST OF FIGURES
Figure page 1-1 PdI2-catalyzed oxidative carbonylation of amines to ureas. ................................ 16
1-2 Proposed mechanism of the PdI2-catalyzed oxidative carbonylation of amines to ureas. ................................................................................................. 17
1-3 PdI2-catalyzed oxidative carbonylation of 1,2-benzenediamine .......................... 17
1-4 Application of PdI2-catalyzed oxidative carbonylation to the synthesis of neuropeptide Y5 receptor antagonist NPY5RA-972. .......................................... 17
1-5 Pd-catalyzed carbonylation using ionic media. ................................................... 19
1-6 Pd(II)/Cu(II)-catalyzed electrocatalytic carbonylation of aliphatic amines ........... 19
1-7 Pd-NHC catalysts. .............................................................................................. 21
1-8 Representation of the immobilized palladium nanoparticle ([Pd]-APTS-Y) catalyst. .............................................................................................................. 22
1-9 Mechanism for the Pd-catalyzed conversion of primary amines to ureas. .......... 23
1-10 Pathways for the Ni-catalyzed carbonylation of amines to ureas. ....................... 24
1-11 Mechanism of the [Ru(CO)3I3]NBu4-catalyzed carbonylation of aniline. ............. 25
1-12 Carbonylation mechanism of cobalt salen complexes. ....................................... 27
1-13 Co(salen) (15) and modified Co(salen) complexes (16-20). ............................... 27
1-14 Rhodium intercalated into titanium phosphate catalyzes the carbonylation of aniline to diphenylurea. ....................................................................................... 29
1-15 Carbonylation of aryl and aliphatic amines using a polymer supported gold catalyst ............................................................................................................... 30
1-16 Carbonylation of primary aliphatic and aromatic amines using a tungsten carbonyl complex. ............................................................................................... 32
1-17 Carbonylation of primary and secondary diamines using W(CO)6/I2 as the catalyst. .............................................................................................................. 34
1-18 Gem-dimethyl secondary diamines form ureas and tetrahydropyrimidine .......... 36
1-19 Substituent study of the W(CO)6/I2-catalyzed carbonylation of benzylamines. ... 37
10
1-20 Structures of the HIV protease inhibitors DMP 323 and DMP 450 ..................... 39
1-21 Tungsten-catalyzed carbonylation of 28-30. ....................................................... 40
1-22 Oxazolidinone formation from the tungsten-catalyzed carbonylation of diol 34. ...................................................................................................................... 41
1-23 Synthesis of biotin methyl ester (38b) using the W(CO)6/I2 catalyst system. ...... 43
1-24 Synthesis of biotin derivatives via the W(CO)6/I2 catalytic system. ..................... 44
2-1 Comparison of binding motifs of peptide-derived HIVPR inhibitors to a generic 6-membered ring cyclic NPPI. ............................................................... 47
2-2 Structures A-D show the path to the identification of the cyclic urea NPPI. ........ 47
2-3 Cyclic urea binding motif. ................................................................................... 48
2-4 Synthesis of DMP 323 and DMP 450 ................................................................. 50
2-5 Imine pathway for the synthesis of DMP 323 and DMP 450. .............................. 51
2-6 Phosphorus-tether and RCM pathway to DMP-450 analogue. ........................... 51
2-7 Synthesis of the core DMP-450 structure by tungsten-catalyzed carbonylation ...................................................................................................... 52
2-8 Unprotected amino alcohol carbonylation by tungsten hexacarbonyl. ................ 53
2-9 Synthesis of protected aminobutanediols 60a-60d. ............................................ 54
2-10 Synthesis of unprotected substrates 60e and 60f ............................................... 55
2-11 Tungsten-catalyzed catalytic carbonylation of 60a-f ........................................... 55
2-12 Synthesis of diamines 60g and 60h. .................................................................. 57
2-13 Hydrogenolysis of 44 to obtain diamine diol 34. ................................................. 58
2-14 Carbonylation of diamine 34 leads to mixed products ........................................ 59
2-15 Attempted synthesis of 63j-m. ............................................................................ 59
2-16 Conformational analysis of 7-membered cyclic ureas predicting that A is preferred when the nitrogens are not substituted, while B is preferred when the nitrogens are substituted113 .......................................................................... 60
3-1 Synthesis of N,N’-diphenylurea via W(CO)6/I2 carbonylation. ............................. 63
11
3-2 Oxidative carbonylation of various p-substituted aryl amines to symmetrical N,N’-diarylureas. ................................................................................................. 65
3-3 Iodo-deboronation of aminophenylboronic ester 67m ........................................ 67
3-4 Structure of the cancer drug sorafenib, a possible application of the tungsten-catalyzed carbonylation of aryl amines ............................................................... 70
3-5 Proposed isocyanate pathway for the tungsten-catalyzed synthesis of symmetrical and unsymmetrical aryl ureas ......................................................... 71
3-6 Attempted carbonylation of N-methylaniline ....................................................... 71
3-7 Carbonylation of aniline and N-methylaniline to provide unsymmetrical urea 69ap ................................................................................................................... 72
4-1 Structure of ritonavir ........................................................................................... 74
4-2 Structure of lopinavir. .......................................................................................... 75
4-3 Retrosynthetic strategy for the synthesis of lopinavir .......................................... 76
4-4 Synthesis of the urea moiety of lopinavir ............................................................ 76
4-5 Alternate synthesis of 70 .................................................................................... 77
4-6 Synthesis of 70 using CDI .................................................................................. 78
4-7 Retrosynthesis of compound 78 ......................................................................... 78
4-8 Preparation of N-(3-aminopropyl)glycine methyl ester 79 ................................... 79
4-9 Attempted W(CO)6/I2-catalyzed carbonylation of glycine methyl ester 79 .......... 80
12
Abstract of Dissertation Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy
APPLICATIONS OF TUNGSTEN-CATALYZED OXIDATIVE CARBONYLATION OF
AMINES TO UREAS
By
Ampofo Darko
December 2010
Chair: Lisa McElwee-White Major: Chemistry
Synthesis of ureas from amines generally involves the use of phosgene or
phosgene derivative for the installation of the urea moiety. The health and
environmental hazards associated with phosgene and its derivatives coupled with the
prevalence of ureas in various areas have prompted research on alternative methods
for the synthesis of ureas from amines. Of the alternatives, transition metal-catalyzed
oxidative carbonylation has emerged as both an effective method and an
environmentally friendly alternative, producing only protons and the reduced form of the
oxidant as byproducts. Tungsten hexacarbonyl (W(CO)6) with iodine as the oxidant as
the catalytic system was found to be successful in the catalytic carbonylation of amines
to ureas. Various primary and secondary amines have been converted to their
respective ureas in good yields. The method has been applied to the synthesis of the
core cyclic urea moiety of the HIV protease inhibitor, DMP 450. Yields of the urea from
the catalytic reaction were comparable to previously reported methods. In addition,
analogs of the core structure can be synthesized without protection of the diol
functionality. The catalytic system has also been successfully applied to the synthesis
13
of symmetrical and unsymmetrical diarlyureas. This extended scope of the system can
be applied to a new class of biologically active compounds that include aryl amines.
14
CHAPTER 1 TRANSITION METAL-CATALYZED OXIDATIVE CARBONYLATION OF AMINES TO
UREAS
Introduction
The development of new synthetic protocols for the preparation of ureas has
recently attracted interest because of the presence of this functional group in
pharmaceutical candidates,1-8 agrochemicals, resin precursors, dyes9 and additives to
petrochemicals and polymers.10 The classical syntheses of ureas from amines have
been based on the use of toxic and/or corrosive reagents, such as phosgene or
isocyanates.11,12 In recent years, however, alternative routes have been developed that
utilize phosgene derivatives, CO2, or CO itself as the source of the carbonyl moiety.13
Particularly attractive from the standpoint of atom economy14 is oxidative
carbonylation,15,16 which employs amines, carbon monoxide and an oxidant as starting
materials and produces only the reduced form of the oxidant and protons as byproducts.
In an effort to develop new methodologies for preparing moieties with carbonyl-
nitrogen bonds, metal-catalyzed carbonylation of amines has been extensively studied.
Mono- and dicarbonylations of amines catalyzed by Mn,17-19 Fe,20,21 Co,22-26 Ni,27-29
Ru,30-34 Rh,33,35,36 Pd,37-53 W,54-63 Pt,64 Ir,64 or Au65-68 have been reported, and many
different types of products, including ureas,18,22,27,33,36,51,69 urethanes,70,71 oxamides,72
formamides,73-78 and oxazolidinones,79-81 have been obtained. These carbonylations
are generally carried out at high temperatures under moderate-to-high pressures of CO
and efforts to find catalysts that are effective under mild conditions continue. This
chapter highlights some selected recent advances in the transition metal-catalyzed
oxidative carbonylation of amines to ureas.
15
Palladium-Catalyzed Oxidative Carbonylation of Amines
Carbonylation of amines using Pd catalysts has been extensively studied since
Tsuji reported the first Pd-catalyzed carbonylation of amines in 1966.47 Methods for
oxidative carbonylation using PdCl2 as catalyst with copper oxidants or O2 as the
terminal oxidant and CuX or CuX2 as a mediator have been developed for preparation
of ureas,82-84 carbamates,38,85 and oxamides.38,69,86,87 This section will highlight a few
notable examples of the Pd-catalyzed carbonylation of amines.
Homogeneous Carbonylation of Amines to Ureas
Fukuoka88 and Chaudhari89 reported the oxidative carbonylation of alkylamines
using Pd/C as catalyst and iodide salts as promoters in the presence of O2, which
afforded the corresponding ureas and/or carbamates in good yields. Related results
have been reported by Gabriele81 for the oxidative carbonylation of amines using PdI2
and O2, which led to formation of ureas, carbamates, and their cyclic derivatives in good
yields. New conditions for the PdI2-catalyzed oxidative carbonylation of amines to ureas
(Figure 1-1), afforded ureas in high yields with turnover numbers as high as 4950.41,90
Carbonylations of primary aliphatic amines (Figure 1-1, R = alkyl) were carried out at
100 °C under a mixture of CO, air, and CO2 in the presence of a simple catalytic system
consisting of PdI2 in conjunction with a KI promoter. In the absence of CO2, less
satisfactory results were obtained.90 The choice of solvent was critical to product
selectivity. Monocarbonylation to the urea was favored in dioxane or 1,2-
dimethoxyethane (DME), while double carbonylation to the oxamide predominated in
the more polar solvents N,N-dimethylacetamide (DMA) or N-methylpyrrolidinone (NMP).
The selectivity was attributed to higher nucleophilicity of the amine substrates in DMA or
NMP, which favors the formation of Pd(CONHBu)2 species that generate the oxamide
16
by reductive elimination. Primary aromatic amines (Figure 1-1, R = Ar) were generally
less reactive than primary aliphatic amines under these conditions but addition of an
electron-donating methoxy group increased the nucleophilicity of the aromatic amine
enough to improve the activity.
Figure 1-1. PdI2-catalyzed oxidative carbonylation of amines to ureas.
The mechanism for the carbonylation of primary amines was examined in more
detail after it was determined that the secondary amines diethylamine, dibutylamine,
and morpholine were unreactive under the same conditions. The difference in reactivity
was attributed to the formation of isocyanate intermediates from the primary amine, with
carbamoylpalladium complex 1 formed in preequilibrium with starting materials (Figure
1-2). In agreement with this hypothesis, isocyanates were detected (by GLC, TLC, and
GLC/MS) in the reaction mixtures in low-conversion experiments. Under these
conditions, Pd(0) is reoxidized to Pd(II) by oxidative addition of I2, which is regenerated
through oxidation of HI by oxygen.
This catalytic system proved to be effective for the synthesis of cyclic ureas from
the corresponding diamines, with 1,3-dihydrobenzoimidazol-2-one obtained in 99%
isolated yield (Figure 1-3). This particularly high reactivity was attributed to increased
nitrogen nucleophilicity and a less negative entropy of activation due to the proximity of
the ortho amino groups.41
17
Figure 1-2. Proposed mechanism of the PdI2-catalyzed oxidative carbonylation of amines to ureas.
Figure 1-3. PdI2-catalyzed oxidative carbonylation of 1,2-benzenediamine
Direct catalytic preparation of trisubstituted ureas with high selectivity (Figure 1-1)
was possible under these conditions if the primary amine were carbonylated in the
presence of an excess of a secondary amine.41 This methodology has proven to be
effective for the synthesis of several types of urea derivatives, such as cyclic ureas from
primary diamines and N,N-bis(methoxycarbonylalkyl)ureas from primary α-amino esters.
A showcase synthesis of the neuropeptide Y5 receptor antagonist NPY5RA-972 was
also reported (Figure 1-4).41
Figure 1-4. Application of PdI2-catalyzed oxidative carbonylation to the synthesis of neuropeptide Y5 receptor antagonist NPY5RA-972.
18
Pd Catalysis in Ionic Liquids
Recently, many catalytic reactions have been reported to proceed in ionic liquids
as reaction media with excellent results.91 This approach has been adapted by Deng
for Pd-catalyzed carbonylation of amines to ureas.92 A solubility study of the catalyst
Pd(phen)Cl2 established that the ionic liquids BMImBF4 (BMIm = 1-butyl-3-
methylimidazolium), BMImPF6, BMImFeCl4, and BMImCl were candidate media for the
carbonylation reaction and that catalyst solubility could be adjusted through the tuning
of either the cation or anion of the ionic liquids. Carbonylation of aniline to the
carbamate in the presence of O2 and methanol was used to demonstrate catalytic
activity and recyclability of the catalyst/ionic liquid mixture.
Subsequent work by the Deng group developed a new method using silica gel-
immobilized ionic liquids, in which a Pd complex acts as a heterogenized catalyst for the
carbonylation of amines and nitrobenzene to ureas. Heterogenization of the metal
catalyst by preparation of a silica gel confined ionic liquid was followed by the
carbonylation of amines and nitrobenzene to the corresponding ureas (Figure 1-5).93
No additional oxidant is necessary since the nitrobenzene serves as both substrate and
oxidant. In terms of green chemistry, the advantages of this method are the low
quantities of ionic liquids used and the avoidance of potentially explosive CO/O2
mixtures. The authors suggested that the enhanced catalytic activity of this system may
be derived from the high concentration of ionic liquid containing the metal complex
confined within the cavities of the silica gel matrix.93
Experiments with the ionic liquids DMImBF4 (1-decyl-3-methylimidazolium
tetrafluoroborate) and EMImBF4 (1-ethyl-3-methylimidazolium tetrafluoroborate) and the
catalysts HRu(PPh3)2Cl2, Rh(PPh3)3Cl, Pd(PPh3)2Cl2 and Co(PPh3)3Cl2 afforded good to
19
excellent yields of N,N′-diphenylurea (DPU) from nitrobenzene and aniline. The Rh-
DMImBF4/silica gel catalyst produced 93% conversion of starting materials with a
selectivity of 92% for the urea. Conversion of aliphatic amines and nitrobenzene to the
unsymmetrically substituted ureas could also be achieved with this particular catalyst.
Figure 1-5. Pd-catalyzed carbonylation using ionic media.
Electrocatalytic Carbonylation
Another method for the synthesis of alkylureas is the electrocatalytic carbonylation
of aliphatic amines, as reported by Deng.94 Electrocatalytic carbonylation of a series of
aliphatic amines to dialkylureas and isocyanates using Pd(II) complexes with a Cu(II)
cocatalyst could be achieved under mild reaction conditions, with particularly good
results for primary amines (Figure 1-6). The additional steric hindrance in secondary
amines apparently prevents the reaction, as diisopropyl amine was unreactive under the
same conditions. In addition, no conversion of primary diamines to cyclic ureas was
observed although one long chain diamine did afford a low yield of the corresponding
isocyanate.
Figure 1-6. Pd(II)/Cu(II)-catalyzed electrocatalytic carbonylation of aliphatic amines
20
Although products were obtained with a single complex as catalyst [Cu(OAc)2,
PdCl2 or Pd(OAc)2], catalytic activity and selectivity for the urea were improved when
both a Pd complex and Cu(OAc)2 were present in the reaction mixtures. Quantitative
conversion and 98% selectivity for the urea were achieved in the case of n-butylamine
with Pd(PPh3)2Cl2 and Cu(OAc)2.94 The authors suggested a synergistic effect between
Pd(II) and Cu(II), as opposed to simple mediation of electron transfer, which had been
invoked in a related case of electrocatalysis.95
N-Heterocyclic Carbene-Palladium Complexes
N-Heterocyclic carbene (NHC) complexes have been studied extensively for their
roles in carbonylation reactions.96,97 Reactions such as hydroformylations97 have
benefited from the use of NHC ligands. Realizing their potential, Xia and coworkers
used NHC ligands in a series of palladium complexes for the catalytic carbonylation of
amines to ureas (Figure 1-7).98 Using CO and O2, aliphatic and aryl amines were
converted to their corresponding ureas in good yields and high selectivity, with as low
as 0.02 mol% of catalyst. Yields of aryl ureas were greatly affected by electron-
donating or electron-withdrawing substituents at the para-position of the aniline, with the
latter hindering reaction yields. Aliphatic amines were less selective due to the
formation of formamides and oxamides as byproducts. Optimal results were obtained
for aliphatic amines when the temperature was lowered and the solvent changed from
DMF to dimethoxyethane.
21
Figure 1-7. Pd-NHC catalysts.
Supported Palladium Nanoparticles
While most palladium oxidative catalysts in carbonylation have been
homogeneous, there have been some examples of the use of supported palladium
catalysts. While testing a variety of catalysts for the oxidative carbonylation of
methylamine, Chaudhari and coworkers found that the palladium-containing ZSM-5
zeolite catalyst gave good conversion of amine with a high selectivity for the formation
of the urea over the carbamate.89 Very recently, Chaudhari has revisited the concept by
employing Pd nanoparticles as a catalyst for the oxidative carbonylation of amines.37
Palladium nanoparticles were anchored on zeolites by using 3-aminopropyl-
trimethoxysilane (APTS) as an anchoring agent (Figure 1-8). Using an 8:1 CO:O2 gas
mixture, simple aryl and aliphatic amines were converted to the corresponding ureas in
high conversion and selectivity. The authors also found that catalyst turnover frequency
(TOF) compared favorably to commercial Pd catalysts despite a previous report66 that
Pd nanoparticles were inactive for the reaction. Other parameters such as solvent,
promoters, temperature, and substrate concentration were studied to achieve optimal
conditions. Moreover, the catalyst was recycled five times without any loss of
conversion of the amine or selectivity for the urea.37
22
Figure 1-8. Representation of the immobilized palladium nanoparticle ([Pd]-APTS-Y) catalyst.
Mechanistic Studies
Progress has also been made in understanding the mechanism of the
carbonylation of amines to ureas. Shimizu and Yamamoto have reported a mechanistic
study focusing on the role of the reoxidation of Pd(0) species formed in the principal
catalytic cycle to electrophilic Pd(II) species during the selective carbonylation of amines
to oxamides and ureas.72 Their work revealed the importance of the oxidant in
selectivity as 1,4-dichloro-2-butene (DCB) afforded oxamides from primary and
secondary amines while use of I2 as the oxidizing agent resulted in formation of ureas.
Further insight was obtained through independent generation of carbamoylpalladium
complexes as models for species in the catalytic cycle.
Two possible mechanisms for the conversion of primary amines to ureas by
palladium-catalyzed carbonylation were discussed in conjunction with this study. In the
first, the critical step is reductive elimination of carbamoyl and amido ligands to generate
the urea, as previously proposed by Alper.69 The crucial step in the second possible
route involves formation of an intermediate alkyl isocyanate from an N-
23
monoalkylcarbamoylpalladium species (3, Figure 1-9). The urea product is then derived
from nucleophilic attack of a primary or secondary amine on the isocyanate to release a
symmetrically or unsymmetrically substituted urea. This second possibility is based on
an earlier proposal by Gabriele for a related system.90 Support for the isocyanate
pathway came from the inability of secondary amines to form tetrasubstituted ureas, the
presence of trisubstituted ureas upon carbonylation of mixtures of primary and
secondary amines and the kinetics of conversion of model compounds for 3 to ureas in
the presence of NEt3.72
Figure 1-9. Mechanism for the Pd-catalyzed conversion of primary amines to ureas.
Other Late Transition Metal Catalysts
Nickel-Catalyzed Oxidative Carbonylation
The extensive development of palladium-catalyzed oxidative carbonylation
reactions along with the ability of Ni complexes to undergo carbonylation and produce
stable carbamoyl derivatives suggested investigation of nickel complexes as catalysts
for the oxidative carbonylation of amines.27 Giannoccaro obtained N,N′-dialkylureas,
24
rather than the previously reported oxamides,28 by reacting aliphatic primary amines
with the nickel amine complexes NiX2(RNH2)4 (X = Cl, Br; R = alkyl). However, yields
were low, and at temperatures higher than 50˚C, side reactions became significant. At
lower temperatures the reductive step, in which amine carbonylation occurs, failed. The
product selectivity depended on the amount of water present, with anhydrous conditions
favoring the oxamide, while the presence of water promoted urea formation (Figure 1-
10). The authors suggested that water could coordinate to the nickel center, allowing
the formation of only one carbamoyl group. Under aqueous conditions, this
intermediate would then undergo nucleophilic attack by the amine to form the urea. In
the absence of water, oxamide would arise from reductive elimination of two carbamoyl
groups.27
Figure 1-10. Pathways for the Ni-catalyzed carbonylation of amines to ureas.
Ruthenium-Catalyzed Oxidative Carbonylation
Gupte utilized ruthenium catalysts for the selective formation of N,N′-diphenylurea
(DPU) from the oxidative carbonylation of aniline.33 High selectivity (99%) for the
formation of DPU was obtained with [Ru(CO)3I3]NBu4 as the catalyst and NiI as the
25
promoter. The key step in the proposed mechanism involves the formation of
carbamoyl species 8 (Figure 1-11). Loss of CO from the catalyst precursor [Ru(CO)3I3]-
generates intermediate 5, which reacts with aniline to form 6 and HI. Addition and
insertion of CO affords carbamoyl complex 8, which reacts with aniline to yield the urea
and the hydrido carbonyl species 9. Addition of aniline to form 10 is followed by
oxidation with O2 to regenerate the active species 6 (Figure 1-11).33 Related chemistry
with alkylamines has been reported by Chaudhari.89,99
Figure 1-11. Mechanism of the [Ru(CO)3I3]NBu4-catalyzed carbonylation of aniline.
26
Cobalt- and Rhodium-Catalyzed Oxidative Carbonylation
Rindone reported the synthesis of acyclic and cyclic ureas from aromatic primary
amines, using N,N′-bis(salicylidene)ethylenediaminocobalt(II) ([Co(salen)]) as the
catalyst.22 Optimal reaction conditions varied with the substrate. For example, the urea
yields from 4-methylaniline were higher at high pressure of O2, while 4-fluoroaniline
reacted better at lower O2 pressure. Substituent effects were also examined. Electron-
withdrawing groups in the para position lowered the conversion of the starting amine
while ortho-aminophenol was more reactive than the other amines. The substituent
effects were elaborated in a subsequent paper.100
The proposed mechanism involved equilibrium between planar and non-planar
salen ligands (11 and 12) on a cobalt (III) amido complex, either of which could undergo
carbon monoxide insertion to give an equilibrium mixture of carbamoyl complexes 13
and 14. Compound 13, having the planar salen ligand and a trans relationship between
the carbamoyl and amine ligands, could lead to free isocyanate or carbamate, while
complex 14, having a nonplanar salen and a cis relationship between the carbamoyl
and amine ligands, would lead to the urea (Figure 1-12).22
Claver prepared modified [Co(salen)] complexes (Figure 1-13) and utilized them
as catalysts for oxidative carbonylation of aniline.101 Results revealed that the t-butyl-
substituted catalyst 16 produced 100% selectivity for diphenylurea in the presence of
butanol, while the other complexes afforded mixtures of the urea and the corresponding
butyl carbamate. The phenanthroline derivative 19 also showed high selectivity (94%)
for the urea.
27
Figure 1-12. Carbonylation mechanism of cobalt salen complexes.
Figure 1-13. Co(salen) (15) and modified Co(salen) complexes (16-20).
28
Efforts in the rhodium-catalyzed carbonylation of amines to ureas have been
sparse. An early study by Chaudhari investigated various factors that affect activity and
selectivity of rhodium-catalyzed oxidative carbonylation.102 Although the primary
objective was the synthesis of carbamates, some conditions were found to favor the
formation of ureas. In studies focused on the oxidative carbonylation of aniline, a Rh/C-
NaI system was determined to be best for the catalytic process. Using this catalyst,
polar solvents such as acetonitrile or DMF favored formation of diphenylurea, while
most other solvents favored the carbamate. Modifying pressure, temperature, and
concentration also affected selectivity and activity.102
Giannoccaro reported preparation of Rh3+ and Rh3+-diamine complexes
intercalated into γ-titanium phosphate (TiP), and measured their activity towards
oxidative carbonylation of aniline.103 Intercalation provided a way to heterogenize an
otherwise homogeneous catalyst. Typical conditions involved acetonitrile or methanol
as the solvent, a CO/O2 mixture at atmospheric or higher pressure, temperatures
between 70-120˚C, and the presence of PhNH3+I- as a promoter. The highest catalyst
activities were obtained with increased pressure of the CO/O2 mixture, higher
temperature, and a molar ratio of co-catalyst to Rh3+(PhNH3+I-/ Rh3+) between 5 and 6.
It was found that the materials containing simple Rh3+ salts worked better than those
prepared from Rh3+-diamine complexes. The key intermediate in the postulated
reaction mechanism (Figure 1-14) is the Rh3+-carbamoyl complex 21 which reacts with
molecular iodine to form the iodoformate intermediate, ICONHPh. The latter reacts with
aniline to afford diphenylurea.103
29
Figure 1-14. Rhodium intercalated into titanium phosphate catalyzes the carbonylation of aniline to diphenylurea.
Gold-Catalyzed Oxidative Carbonylation
Deng has investigated gold compounds as catalysts for the carbonylation of
amines.66,78,104-106 Although simple Au(I) salts afforded carbamates from aniline, the
reactions of aliphatic amines also yielded the urea in some cases.104 Polymer
immobilized gold catalysts, prepared from commercially available ion exchange resins
and HAuCl4, were found to catalyze the carbonylation of aryl amines to their methyl
carbamates in the presence of methanol.66 In the absence of methanol, the diarylureas
became the major products. In contrast to previously reported gold catalysts, the
polymer immobilized variety showed enhanced catalytic efficiency, could easily be
separated from the product, and could be used in the absence of organic solvents.
Subsequent work demonstrated that use of this system with aliphatic amines and CO2
could afford symmetrical dialkylureas with high yields and turnover frequencies (Figure
1-15).106 The mechanism is unclear, but it was postulated that the high activity can be
30
attributed to some synergistic relationship between gold nanoparticles and the polymer
support.
R2NHAu/polymer
CO + O2
or CO2
R2NHCONHR2
Figure 1-15. Carbonylation of aryl and aliphatic amines using a polymer supported gold catalyst
Angelici used gold powder to convert primary amines to ureas in mild conditions
with CO and O2.68,107 With a 2.5:1 ratio of CO and O2 at approximately 1 atm in
acetonitrile at 45°C, ureas were the major products after 24 h of reaction time. Steric
bulk and nucleophilicity of the amine played a role in the yields of the ureas. Alkyl and
aryl amines were both suitable substrates, though yields were lower for aryl ureas
because of their lower nucleophilicity. The key species in the proposed mechanism is
an isocyanate, which reacts with an additional amine to form the urea product. Trace
isocyanate detected in some of the reactions support the claim. Furthermore,
secondary amines do not form tetrasubstituted ureas, which is consistent with the
isocyanate mechanism. Unsymetrical ureas were synthesized when equimolar
amounts of primary amine and secondary amine were used. Because secondary
amines are more nucleophilic towards isocyanates, unsymmetrical ureas were often the
only product.68
Tungsten-Catalyzed Oxidative Carbonylation of Amines
Carbonylation of Primary Amines
Despite extensive investigation of transition metal-catalyzed carbonylation
reactions, examples involving Group 6 metals still remain rare. During the last 15 years,
though, there have been examples of conversions of amine substrates to the
31
corresponding ureas using tungsten carbonyl complexes as the catalysts and I2 as the
oxidant.
The initial report described catalytic oxidative carbonylation of primary amines
using the iodo-bridged tungsten dimer [(CO)2W(NPh)I2]2 (22) as the precatalyst.56
During those studies, it was shown that primary aromatic and aliphatic amines could be
carbonylated to 1,3-disubstituted ureas, while secondary amines afforded formamides in
modest yields.
Mechanistic studies on this process established that primary amines reacted
stoichiometrically with dimer 22 to yield the amine complexes (CO)2I2W(NPh)(NH2R)
(23) (Figure 1-16), which undergo reaction with excess amine to afford the
corresponding ureas.58 Nucleophilic attack of the amine on a carbonyl ligand of 24,
followed by proton abstraction using a second equivalent of the amine would afford
carbamoyl complex 25. IR spectra of the reaction mixtures were consistent with the
presence of carbamoyl complexes. The intermediacy of carbamoyl complex 25 is
precedented by Angelici's work on the carbonylation of CH3NH2 by
[(ƞ5-C5H5)W(CO)4]PF6,108 for which the first step is conversion of [(ƞ5-C5H5)W(CO)4]
+ to
the carbamoyl complex (ƞ5-C5H5)W(CO)3(CONHCH3) upon reaction with 2 equiv of
CH3NH2.
Assignment of the next step as oxidation was supported by IR spectra that showed
the disappearance of the carbamoyl stretches after the reaction mixtures were exposed
to air. It is expected that following oxidation of the complex, the carbamoyl proton would
be more acidic and deprotonation of 25 with the excess amine would produce the
isocyanate complex 26. Nucleophilic attack of an amine on either coordinated or free
32
isocyanate would afford the 1,3-disubstituted urea, producing coordinatively unsaturated
complex 27, which could undergo addition of CO to regenerate cationic intermediate 24
and close the catalytic cycle (Figure 1-16).
Figure 1-16. Carbonylation of primary aliphatic and aromatic amines using a tungsten carbonyl complex.
The previous results implied that other tungsten carbonyl iodide complexes might
also serve as catalysts. The simplest choice as precatalyst was the readily available,
inexpensive, and air stable tungsten hexacarbonyl (W(CO)6). Preliminary studies were
33
carried out using W(CO)6 as catalyst for the catalytic carbonylation of n-butylamine.
Reaction of W(CO)6, 100 equiv of n-butylamine, 50 equiv of iodine, and 100 equiv of
K2CO3 in a 125 mL Parr high-pressure vessel pressurized with 100 atm CO produced
di-n-butylurea in an amount corresponding to 39 turnovers per equivalent of W(CO)6, or
80% yield with respect to amine.58
Subsequent optimization studies using n-propylamine established that N,N'-
disubstituted ureas could be obtained in good to excellent yields using the W(CO)6/I2
oxidative carbonylation system.59 Once W(CO)6 (2 mol %) was established as the
preferred catalyst, other variables were examined. Optimal conditions were 90°C, 80
atm CO, 1.5 equiv of K2CO3, and a chlorinated solvent such as CH2Cl2 or CHCl3. Using
these conditions, though, the conversion of aniline to diphenylurea failed, presumably
due to lower nucleophilicity of the aryl amine.
Carbonylation of Primary and Secondary Diamines to Cyclic Ureas
Many methods for conversion of diamines to the corresponding cyclic ureas have
been reported.11,12 Most of them are stoichiometric reactions based on nucleophilic
attack of amines on phosgene and related derivatives. Catalytic oxidative carbonylation
of diamine substrates provides an alternative route to cyclic ureas in which CO is used
as the carbonyl source. However, the synthesis of cyclic ureas via metal-catalyzed
carbonylation has received limited attention. Early reports of transition metal-catalyzed
carbonylation of diamines mentioned cyclic ureas only as very minor or side products.
In the case of Mn2(CO)10-catalyzed carbonylation of the diamines H2N(CH2)nNH2 (n = 2-
4 and 6), no cyclic products were observed when n = 2, 4, or 6 and only 6% of the six-
membered urea was observed when n = 3.109 The catalytic carbonylation of diamines to
cyclic ureas was thus explored using W(CO)6 as the catalyst, I2 as the oxidant, and CO
34
as the carbonyl source.57 Both primary and secondary ,-diamines were substrates
for the reaction, with secondary diamines being converted directly to the corresponding
N,N'-disubstituted cyclic ureas.
Synthesis of the five-, six-, and seven-membered cyclic ureas from the primary
diamines could be achieved in moderate to good yields (Figure 1-17),57 with the highest
isolated yield for the six-membered cyclic urea. Only trace amounts of the eight-
membered ring compound could be detected in the reaction mixtures, which was not
surprising as there are no reports in the literature of preparation of this compound from
1,5-pentanediamine. In addition, (+)-(1R,2R)-1,2-diphenyl-1,2-ethanediamine was
carbonylated to the 2-imidazolidinone in 46% yield with no epimerization. Reaction of
the secondary diamines RNHCH2CH2NHR (Figure 1-17, R = Me, Et, iPr, Bn) under
similar conditions resulted in conversion of the diamines to the corresponding N,N'-
disubstituted cyclic ureas. For both primary and secondary substrates, it was necessary
to employ high dilution conditions to minimize formation of oligomers, a problem also
encountered during the reactions of phosgene and its derivatives with diamines.110
Figure 1-17. Carbonylation of primary and secondary diamines using W(CO)6/I2 as the catalyst.
Steric effects on the ring closure reaction were probed by the carbonylation of
N,N'-dimethyl, diethyl, diisopropyl, and dibenzyl diamines under the standard
conditions.57 As expected, 1,3-diethyl-2-imidazolidinone and 1,3-dimethyl-2-
imidazolidinone were produced in nearly identical yields. Changing the substituents to
35
benzyl groups lowered the yield only modestly but the presence of bulky isopropyl
groups dramatically reduced the yield of the imidazolidinone to only 10%. Yields in the
sterically hindered cases could not be improved by raising the reaction temperature.
Although primary amines reacted much more readily than secondary amines, N-
methylpropanediamine reacted under the oxidative carbonylation conditions to produce
the corresponding monosubstituted N-methyl cyclic urea in preference to acyclic urea
formation through the more reactive primary amines.57
A more extensive study on the carbonylation of α,ω-diamines to cyclic ureas
involved further optimization of the conditions using propane-1,3-diamine as the test
substrate, W(CO)6 as catalyst and I2 as the oxidant.111 Effects of solvent and
temperature variation on the yields of the cyclic urea from propane-1,3-diamine were
examined. Additional experiments probed the effect of alkyl substituents in the linker of
primary diamines (Table 1-1). In the cases of simple n-alkyl substituents, the yields of
cyclic ureas are significantly higher for the 2,2-dialkyl-1,3-propanediamines than for the
parent propane-1,3-diamine as a result of the Thorpe-Ingold effect and improved
solubility in organic solvents during workup.
Table 1-1. Tungsten-catalyzed oxidative carbonylation of substituted primary diamines
Amine Product % Yield
H2N NH2 NHHN
O
52
80
NH2H2NHN NH
O
36
Table 1-1. Continued
Amine Product % Yield
70
48
50
33
38
Figure 1-18. Gem-dimethyl secondary diamines form ureas and tetrahydropyrimidine
The carbonylation of N,N'-dialkyl-2,2-dimethylpropane-1,3-diamines afforded
tetrasubstituted ureas; however, the products were obtained in modest yields, and
tetrahydropyrimidine byproducts were formed in significant amounts when the
substrates bore N-alkyl substituents larger than methyl (Figure 1-18). Comparison of
these results with the carbonylations of secondary diamines to form five-membered
NH2H2N
Bu Bu
HN NH
Bu Bu
O
H2N NH2
PhH2C CH2Ph
HN NH
PhH2C CH2Ph
O
H2N NH2 HN NH
O
H2N NH2 HN NH
O
H2N NH2
BuEtHN NH
Bu
Et
O
37
cyclic ureas suggested that the effects of ring size and N-substituent size on the
carbonylation reaction are complex.
Success with conversion of diamines to cyclic ureas suggested the use of
W(CO)6-catalyzed oxidative carbonylation in the synthesis of complex targets.
However, before considering applications in synthesis, it was necessary to evaluate the
functional group compatibility of the catalyst, often a critical issue in the use of early
metal systems. Studies of functional group compatibility using a series of substituted
benzylamines (Figure 1-19, Table 1-2) demonstrated that the oxidative carbonylation of
amines using the W(CO)6/I2 system is tolerant of a wide variety of functionality, including
halides, esters, alkenes, and nitriles. A distinguishing feature is the tolerance of
unprotected alcohols, which would be problematic with phosgene derivatives.59 A
critical result of this study is the observation that the addition of water to generate a
biphasic solvent system produced dramatic increases in the yields of functionalized
ureas. In order for the reaction to work efficiently, it is necessary to solubilize the
catalyst, the starting amine, the hydroiodide salt of the starting material which is formed
when protons are scavenged, and the base (K2CO3). The biphasic solvent system
provides phase transfer conditions in which the amine salt can be deprotonated by
aqueous carbonate and then returned to the organic phase for carbonylation.
Figure 1-19. Substituent study of the W(CO)6/I2-catalyzed carbonylation of benzylamines.
38
Table 1-2. Tungsten-catalyzed catalytic carbonylation of substituted benzylamines to ureas
Amine %Yielda,b
CH2Cl2
%Yielda,c
CH2Cl2/H2O Amine
%Yielda
CH2Cl2 %Yieldb
CH2Cl2/H2O
63 73
36 55
35 77
0 37
30 77
41 69
39 70
45 76
47 70
37 68
24 81
28 14
5 70
17 20
0 0
a Reaction conditions: amine (7.1 mmol), W(CO)6 (0.14 mmol), I2 (3.5 mmol), K2CO3 (10.7 mmol), CH2Cl2 (20 mL), 70 ˚C, 80 atm CO, 24 h.
bThe solvent was CH2Cl2 (21 mL) plus H2O (3 mL).
After broad functional group tolerance during W(CO)6/I2-catalyzed oxidative
carbonylation of amines to ureas had been established,59 use of this methodology to
install the urea moiety into the core structure of the HIV protease inhibitors DMP 323
and DMP 450 (Figure 1-20)112,113 was investigated.114 Direct comparison of the catalytic
carbonylation reaction with stoichiometric reaction of the same substrates with
phosgene derivatives was possible due to the extensive literature on the synthesis of
these targets.
39
It has been reported in the literature that the urea moiety of DMP 323 and DMP
450 was installed by reaction of phosgene or a phosgene equivalent with an O-
protected diamine diol. In the initial small-scale preparations, a primary diamine was
reacted with the phosgene derivative 1,1'-carbonyldiimidazole (CDI)113,115-117 followed by
N-alkylation as appropriate. The practical preparation of DMP 450 involves reaction of
secondary diamine with phosgene to form the cyclic urea. Since use of phosgene or
CDI requires protection of the diol, extensive protecting group studies have been carried
out.115,118 Three of the previously described O-protected diamine diols, acetonide 28,118
MEM ether 29,113,119 and SEM ether 30113 were tested in the catalytic carbonylation
reaction as representative examples containing cyclic and acyclic protecting groups,
respectively (Figure 1-21).114
Figure 1-20. Structures of the HIV protease inhibitors DMP 323 and DMP 450
40
Figure 1-21. Tungsten-catalyzed carbonylation of 28-30.
Carbonylation of diamine substrates 28-30 (Figure 1-21) to the cyclic ureas 31-33
provided a means for comparison of the W(CO)6-catalyzed process to the stoichiometric
reactions of the phosgene derivative CDI. Varying results were obtained in the yields of
the ureas from the catalytic reaction depending on the protecting group on the diol, as
was also observed for ring closure with stoichiometric CDI (Table 1-3). These results
demonstrate that the catalytic oxidative carbonylation reaction can be used to convert
diamines to cyclic ureas in examples relevant to the preparation of complex targets.
Table 1-3. Tungsten-catalyzed carbonylation of diamines 28-30 to ureas 31-33.
Diamine Reagent Solvent Urea YieldRef (%)
28 CDI CH3CN 15115
28 CDI TCE 67115
28 W(CO)6/CO CH2Cl2/H2O 38114
28 W(CO)6/CO CH2Cl2 23114
29 CDI CH2Cl2 62,76113,116,119
29 W(CO)6/CO CH2Cl2/H2O 49114
30 CDI CH2Cl2 52,93113,116
30 W(CO)6/CO CH2Cl2/H2O 75114
41
Efforts to avoid the protecting group chemistry in reported syntheses of DMP 323
and DMP 450 by carbonylating the diamine diol 34 were frustrated by the reaction of the
diol hydroxyl groups to generate oxazolidinones 35 and 36 (Figure 1-22).61
Oxazolidinone formation had also been reported as the result of reaction of 34 with CDI
and phosgene.120 The earlier functional group compatibility study had suggested that
the catalyst was tolerant of -OH groups (Figure 1-19, Table 1-2) but the test substrate in
that study was [4-(aminomethyl)phenyl]methanol, in which the -OH group is para with
respect to the amine so as to eliminate the possibility of formation of a cyclic carbamate.
For that substrate, the corresponding urea was produced without competing carbamate
or carbonate formation.59 For diamine diol 34, oxazolidinone formation had been
preferred under the reaction conditions tested.61
Figure 1-22. Oxazolidinone formation from the tungsten-catalyzed carbonylation of diol 34.
More recently, the catalytic carbonylation of a series of amino alcohols of varying
tether lengths and substitution patterns was carried out to probe the selectivity of the
W(CO)6/I2 carbonylation system for reactivity of alcohols versus amines. The phosgene
derivatives dimethyl dithiocarbamate (DMDTC) and 1,1'-carbonyldiimidazole (CDI) were
used as representative stoichiometric reagents for comparison purposes.61 A series of
1,2-, 1,3-, 1,4- and 1,5-aminoalcohol substrates was subjected to W(CO)6-catalyzed
oxidative carbonylation for evaluation of the selectivity of the W(CO)6/I2 system toward
formation of the ureas or carbamates, either cyclic or acyclic (Table 1-4). As a
42
comparison of the stoichiometric reactions of phosgene derivatives to the catalytic
W(CO)6/I2 methodology, the results of reaction of CDI and DMDTC with the amino
alcohol substrates also appear in Table 1-4.
Table 1-4. Tungsten-catalyzed oxidative carbonylation of aminoalcohols to ureas and carbamates.
Substrate Reagent Urea (%)
Cyclic Carbamate (%)
W(CO)6 /CO 64 2
CDI 80 trace
DMDTC 45 0
W(CO)6 /CO 93 0
CDI 70 trace
DMDTC 93 0
W(CO)6 /CO 95 trace
CDI 36 60
DMDTC 30 8
W(CO)6 /CO 72 14
CDI 49 30
DMDTC 34 47
W(CO)6 /CO 60 5
CDI 55 28
DMDTC 32 29
W(CO)6 /CO 78 10
CDI 18 22
DMDTC 72 trace
W(CO)6 /CO 79 14
CDI 30 52
DMDTC 73 trace
The results indicated that the W(CO)6/I2 methodology can indeed be applied to
carbonylation of amino alcohols to the ureas without protection of the hydroxyl group.
The W(CO)6-catalyzed oxidative carbonylation was consistently selective for the urea
43
over the cyclic carbamate for all tether lengths and substitution patterns studied. Acyclic
carbamates were not detected in the reaction mixtures. In contrast, reactions of the
phosgene derivatives CDI and DMDTC with 1,3- and 1,2-amino alcohol substrates
exhibited variable selectivities between ureas and cyclic carbamates. It is important to
note that the reaction conditions for these studies were not the same as for the initial
work on diamine diol 34. Optimized conditions for carbonylation of amino alcohols to
the ureas involved use of pyridine as the base, removing the necessity for the biphasic
solvent system used in the original functional group compatibility study.59
Other interesting targets that were prepared to investigate the scope of the
W(CO)6/I2 system were biotin and related heterocyclic ureas.121 Biotin (37b), also
known as Vitamin H, is produced on large scale as a feed additive for poultry and swine.
It has also been the target of more than 40 total and formal syntheses.122 One recurring
theme in these syntheses has been installation of the urea moiety by reaction of
phosgene with a diaminotetrahydrothiophene derivative.
Figure 1-23. Synthesis of biotin methyl ester (38b) using the W(CO)6/I2 catalyst system.
44
Figure 1-24. Synthesis of biotin derivatives via the W(CO)6/I2 catalytic system.
Although biotin itself could not be produced directly from carboxylic acid 37a, biotin
methyl ester (38b) was obtained in 84% yield upon W(CO)6-catalyzed oxidative
carbonylation of diamine 38a (Figure 1-23). The related heterocycles 39b-42b were
also prepared by the carbonylation procedure and the yields compared to those
obtained by reaction of the same substrates with CDI (Figure 1-24, Table 1-5). Yields of
the ureas were moderate to good and depended on the solubility of the diamine and
urea in methylene chloride.
Table 1-5. Yields of bicyclic ureas from diamines 39a-42a
Amine Urea W(CO)6/I2a
Yield CDI Yield
39a 39b Trace 20%
40a 40b 47% 67%
41a 41b 46% 37%
42a 42b 57%b 56%c
aAll reactions were carried out in CH2Cl2 (40 mL) at room temperature under 80 atm of CO. Diamine (1
mmol), W(CO)6 (4 mol%), K2CO3 (3 mmol), I2 (1 mmol). bYield based on diamine consumed (47%).
cYield based on diamine consumed (70%).
45
Conclusions
Transition metal-catalyzed carbonylation of amines offers new and efficient
methodology for the selective synthesis of ureas under relatively mild reaction
conditions. Use of CO as the carbonyl source in the presence of a catalyst and an
oxidant provides an alternative to the traditional methods for conversion of amines to
ureas, which involve stoichiometric use of phosgene and its derivatives. From the
perspective of green chemistry, the replacement of phosgene and the minimization of
the waste streams associated with phosgene derivatives would be beneficial.
Recent developments in metal-catalyzed oxidative carbonylation of amines include
new techniques such as the use of ionic liquids, microwave irradiation and
electrocatalytic carbonylation. In addition to extensive work with palladium complexes,
carbonylation reactions that utilize other late transition metals, such as Ni, Ru, Rh, Co,
Au, have also been demonstrated to afford ureas. Indications that tungsten-catalyzed
oxidative carbonylation of functionalized amines could be of use in the synthesis of
complex targets have also been reported. Given the prevalence of urea functionality in
compounds with a wide range of applications, further work in this area is no doubt
forthcoming.
46
CHAPTER 2 CATALYTIC CARBONYLATION OF FUNCTIONALIZED DIAMINES TO UREAS:
APPLICATION TO DERIVATIVES OF DMP 450
Introduction
In response to the growing global pandemic that is the Acquired Immunodeficiency
Syndrome (AIDS), considerable effort has been placed on researching novel therapy to
treat its causative agent, Human Immunodeficiency Virus (HIV). Of the various
treatment strategies under investigation, most have targeted the aspartyl protease of
the virus. As an alternative to multi-drug cocktails or the modification of existing anti-
HIV drugs, novel agents were also used to improve medicinal profiles. An example of
these novel agents were cyclic, non-peptidic HIV protease inhibitors (NPPIs).4
X-ray crystal structures of HIV protease complexed with various peptidic inhibitors
showed the presence of a tightly bound water molecule between the inhibitor molecule
and the beta strands of the HIV protease dimer (Figure 2-1). This water molecule
accepts two hydrogen bonds from amide backbone residues I1e 50 and I1e 50’ and
donates two hydrogen bonds to carbonyl groups in the inhibitor. Effective inhibition is
achieved through the interactions between the two catalytic aspartyl residues and a
hydroxyl group in the inhibitor molecule (Figure 2-1). Comparative X-ray structures of
non-peptidic protease inhibitors, however, revealed the absence of the water molecule.
These inhibitors contained an already suitable hydrogen bond acceptor, such as a
carbonyl or a sulfonyl group, which forms the necessary hydrogen bonds with the amide
flaps directly, without the need for a water molecule. These cyclic protease inhibitors
also contained hydroxyl groups in specific areas which interacted with the aspartyl
residues. It was anticipated that the entropic advantage gained by the absence of the
47
water molecule coupled with the relatively constrained cyclic structure of the inhibitors
would result in good selectivity against mammalian aspartyl proteases.4
Figure 2-1. Comparison of binding motifs of peptide-derived HIVPR inhibitors to a generic 6-membered ring cyclic NPPI.
In 1994, the DuPont-Merck group reported studies that led to the discovery of
cyclic ureas as potent inhibitors of the HIV protease enzyme.123 Using X-ray structures
and computational methods, the investigators found that a simple cyclohexanone ring A
would be a suitable synthetic scaffold (Figure 2-2). The ring was enlarged to a seven-
membered ring B and further modified to urea C. Ureas, they reasoned, were already
known as excellent hydrogen bond acceptors in nature and in other synthetic systems.
Additional studies also predicted the 4R,5S,6S,7R-stereochemistry as the optimal
configuration as shown in structure D (Figure 2-2).
Figure 2-2. Structures A-D show the path to the identification of the cyclic urea NPPI.
48
Crystallographic data for the urea bound to the active site showed that the cyclic urea
oxygen was positioned well to serve as a hydrogen bond acceptor to the
aforementioned amide flaps of the host site. The data also showed that the diol
functionality hydrogen bonds with the aspartyl residues (Figure 2-3). A factor
contributing to the potency was the preorganized, rigid conformation of the cyclic ureas,
leading to complementary binding to the HIV protease (HIV PR). The preliminary data
lead to the systematic discovery of the first generation cyclic urea compound, DMP
323.123
Figure 2-3. Cyclic urea binding motif.
DMP 323 was particularly highly pre-organized for binding at the active site of the
HIV PR and performed well in preliminary in vitro studies and in animals.113 However,
clinical trials revealed poor aqueous solubility and variable human oral bioavailability.
The compound was subsequently withdrawn from clinical trials. Continued modification
of the cyclic urea compounds focused on the N-benzyl substituents. Extensive studies
resulted in replacement of the p-hydroxymethylbenzyl groups in DMP 323, with weakly
basic m-aminobenzyl substituents. This second generation cyclic urea, DMP 450,
49
exhibited similar potency as its predecessor, while the oral availability was significantly
increased by the conversion to the bis-mesylate salt.119 Phase I clinical trials produced
promising results, although it was found that large amounts and a multiple dosing
schedule of DMP 450 were needed to reach proper levels for treatment.119 At this time
in the development of DMP 450, Avid Corporation acquired licensing rights to the drug,
re-named it Mozenavir, and continued the clinical trials after merging with Triangle
Pharmaceuticals.4,119 After concluding a phase I/II study comparing Mozenavir with
leading HIV drugs, the results suggested that Mozenavir was well tolerated with only
mild side effects. Despite the encouraging results, further studies were halted by
Triangle Pharmaceuticals.4
Synthesis of DMP 323 and DMP 450
In order to obtain the necessary stereochemistry for optimum binding (RSSR),
synthesis of DMP 323 and DMP 450 was derived from unnatural D-phenylalanine. In
the reported synthetic strategy (Figure 2-4),113 N-(benzyloxycarbonyl)-(R)-
phenylalaninol 43 was oxidized under Swern conditions to the corresponding aldehyde.
The aldehyde was then coupled using VCl3(THF)3 and zinc to give diol 44 with a high
diastereomeric purity of the RSSR product (98:2, RSSR:RRRR). The diol was
protected with (2-(trimethylsilyl)-ethoxy)methyl chloride (SEMCl) to afford 45, followed
by removal of the benzyloxycarbonyl (Cbz) groups by hydrogenolysis. The diol could be
protected with (2-methoxyethoxy)methyl chloride (MEMCl) as well. The crude diamine
was cyclized with carbonyl diimidazole (CDI) to give the cyclic urea 33. Appropriate N-
alkylation of the urea followed by further reduction and deprotection of the diol produced
the DMP compounds (Figure 2-4).
50
Figure 2-4. Synthesis of DMP 323 and DMP 450
Synthesis of the cyclic urea HIVPR inhibitors was also achieved starting from L-
(+)-tartaric acid (Figure 2-5). Starting with isopropylidene dimethyl tartrate 47, reduction
of the ester with DIBAL-H and trapping the aldehyde with 1,1-dimethylhydrazine
produced 48. Chelation controlled addition to the hydrazone gives the dihydrazine 49.
Hydrogenolysis and cyclization with CDI produced urea 31. Cyclization to the urea was
difficult when the diamine was acetonide-protected due to ring strain imposed by the
trans-fused five-membered ring. This strain makes the approach of the two amino
groups difficult. The ring strain was alleviated with the use of a six-membered ring,
trioxepane, as the protecting group.118
51
Figure 2-5. Imine pathway for the synthesis of DMP 323 and DMP 450.
A novel approach to the synthesis of the diamine precursors by Hanson and
coworkers involved the use of phosphorus tethers in conjunction with ring-closing
metathesis (RCM).124,125 Allylic amine 50 coupled with PCl3 or RP(O)Cl2 (R ≠ Cl),
followed by RCM produced the P-tethered 1,4-diamine 52. The P-tether can be
removed by treatment with HCl. Carbonylation with CDI or triphosgene and subsequent
N-benzylation afforded urea 54. Conversion of the olefin to the DMP-450 analogue 56
was accomplished via osmium-mediated dihydroxylation of 55(Figure 2-6).124
Figure 2-6. Phosphorus-tether and RCM pathway to DMP-450 analogue.
52
Synthesis of DMP Analogues by Tungsten Catalyzed Carbonylation
Although there are different synthetic pathways to the diamine precursor, the
installation of the urea moiety involved the use of phosgene, or a phosgene derivative.
This transformation, in addition to the health and environmental implications, also
required protection of the diol functionality. Prior research using tungsten hexacarbonyl
[W(CO)6] as a catalyst for the catalytic oxidative carbonylation of diamines to ureas with
iodine (I2) as the oxidant (Figure 1-17)57,111 included its application to the synthesis of
functionalized targets.61,114,121 It was fitting, then, to apply this methodology to the
synthesis of the core urea structure of the DMP compounds.113,123
Since the use of phosgene or its derivatives such as CDI requires protection of the
diol, an extensive study of protecting groups was carried out in order to find the best
conditions.115,120 Although protection of the diol functionality was integral to the success
of the catalytic carbonylation reaction using the original reaction conditions, as it had
been with stoichiometric use of phosgene and its derivatives, yields from the
carbonylation reaction were comparable to those obtained using stoichiometric methods
(Figure 2-7).114
Figure 2-7. Synthesis of the core DMP-450 structure by tungsten-catalyzed carbonylation
Subsequent modification of the reaction conditions led to the selective catalytic
oxidative carbonylation of unprotected amino alcohols to ureas.61 Using pyridine as the
53
base and changing the work-up allowed for good to excellent yields of ureas from a
series of 1,2-, 1,3-, 1,4-, and 1,5-amino alcohols. Good yields of urea 58 from the 1,2-
amino alcohol 57 (Figure 2-8)61 suggested that it could be possible to synthesize the
core structure of DMP 450 by catalytic carbonylation without protecting group chemistry.
This possibility was explored by synthesizing a variety of diamine diols and converting
them to the core structures of DMP 450 and its derivatives.
Figure 2-8. Unprotected amino alcohol carbonylation by tungsten hexacarbonyl.
Substrates for the carbonylation study were chosen from a series of primary and
secondary diamine diols that would afford the core structure of DMP 450 and its
derivatives. In order to assess the need for protecting group chemistry, the substrates
included O-protected, as well as unprotected hydroxyl substituents. All substrates were
subjected to W(CO)6/I2 catalyzed oxidative carbonylation. Depending on the substrate,
carbonylation was achieved using two sets of reaction conditions, the main differences
being in base and solvent. In one procedure, potassium carbonate was used as the
base with a biphasic solvent system (CH2Cl2/H2O), while in a second procedure, the
preferred base was pyridine with methylene chloride or dichloroethane (at 80°C) as the
solvent.
Carbonylation of Aminobutanediols
The investigation began with the carbonylation of secondary diamines to
tetrasubstituted ureas. The DuPont-Merck synthetic procedures focused on making
54
ureas from primary amines followed by alkylation of the urea. Using secondary amines
as substrates could possibly allow for a complete structure after the carbonylation step,
negating the need for N-alkylation of ureas. The synthesis of the substrates started with
amidation of the starting chiral tartrate 47a126-128 followed by reduction by lithium
aluminum hydride128,129 to afford the bis(amino)butanediols 60a-b in good yields (Figure
2-9). A similar approach can be applied to obtain SEM-protected diols 60c and
unprotected 60f (Figure 2-10) starting from the appropriate parent tartrate, however,
attempts at the reduction of 59d to provide 60d were unsuccessful. Due to purification
issues, a different route was employed to synthesize compound 60e. Starting from the
ditosylate 61, aminolytic ring opening of diepoxide 62 provided compound 60e in
quantitative yield (Figure 2-10). Results from the carbonylation of aminobutanediols
60a-f are summarized in Table 2-1.
Figure 2-9. Synthesis of protected aminobutanediols 60a-60d.
55
Figure 2-10. Synthesis of unprotected substrates 60e and 60f
Figure 2-11. Tungsten-catalyzed catalytic carbonylation of 60a-f
From Table 2-1, it is apparent that the W(CO)6/I2 catalytic carbonylation method
can be applied to secondary diamines bearing the seven-membered ring skeleton
(Figure 2-11). The ureas were obtained in good yields whether or not the diol was
protected. The method was also found to be somewhat substrate-dependent; the
unprotected N-methyl variant 60e took 48 hours to give a 42% yield of urea (Table 2-1,
entry 4). Good yields were obtained for the acetonide protected substrates (Table 2-1,
entries 1 and 2). The acetonide-protected N-methyl diamine 60a produced 58% of urea
63a and N-benzyl diamine 60c gave excellent yields of urea based on starting material
consumed. When the protecting group was the acyclic SEM group, however, the
diamine 60c did not react (Table 2-1, entry 3). The N-benzyl, free diol 60f produced
only 10% of the corresponding urea (Table 2-1, entry 5). A portion of the starting
material (25 %) was recovered in salt form, stemming from the inability of the base,
56
pyridine, to deprotonate the resulting hydroiodide salt of the substrate. Substituting
pyridine with DMAP or DBU did not increase the yield. It is important to note that the
free diol substrates 60e and 60f formed their respective ureas without competitive
formation of the cyclic carbamate. This is remarkable given the kinetic preference for
the formation of 5-membered rings over the desired 7-membered rings.
Table 2-1. Carbonylation of diamines 60a-60fa
Entry Aminobutanediol Product Yieldb
1
60a
63a
58%
2
60b
63b
99%d
3
60c
63c
0%
4
60e
63e
42%c
5
60f
63f
10%
aReagents and conditions: W(CO)6, I2, pyridine, 80 bar CO, CH2Cl2, 40°C, 24h.
bIsolated yields.
c48h.
dBased on starting material consumed.
57
Carbonylation of Aminohexanediols
Given the success of the carbonylation of secondary diamines 60a-60f, the
method was applied to primary diamines with alkylation at the carbon alpha to the
nitrogen. In order to extend the scope of the reaction methodology, the synthesis of
bis(amino)hexanediols 60g and 60h, starting from the chiral amino alcohol 64 (Figure 2-
12) was employed.113,117,130 Swern oxidation of 64 followed by vanadium-mediated
coupling affords diol 65. Protection of the diol to produce 66a-b, and hydrogenolysis
using cyclohexene as the hydrogen source gives O-protected amines 60g-h.
Unprotected diol 34 can be obtained by the direct hydrogenolysis of 44 (Figure 2-13).
Figure 2-12. Synthesis of diamines 60g and 60h.
For α-methyl diamines 60f and 60g, ureas were obtained in good yields regardless
of whether the protecting group was acetonide or SEM (Table 2-2, entries 1 and 2).
The protecting group preference was more apparent with a benzyl group in the α-
position(Table 2-2, entries 3 and 4).114 In addition, the core structure of DMP 450 could
be obtained from diamine 34 without protection of the diol (Figure 2-14), though the
reaction suffered from low conversion (54%) due to the formation of the amine salt, and
58
also oxaxolidinones 35 and 36 from participation of hydroxyl groups in the cyclization.
The quantities of urea 63i were highest after 16 hours with increased temperature
(80°C) and dichloroethane as the solvent.
Figure 2-13. Hydrogenolysis of 44 to obtain diamine diol 34.
Table 2-2. Carbonylation of diamines 60g, 60h, 28, and 30.a
Entry Amine Product Yieldb
1
60g
63g
83%
2
60h 63h
75%
3
28
31
36%114
4
30 33
75%114
aReagents and conditions: W(CO)6, I2, K2CO3, 80 bar CO, CH2Cl2/H2O, 40°C, 24h.
bIsolated yields.
59
Figure 2-14. Carbonylation of diamine 34 leads to mixed products
With the success of the carbonylation of the aminohexanediols (Table 2-2), the
methodology was applied to secondary diamines with alkylation at the α-position (Figure
2-15). N-Methylation of 66a-d followed by deprotection of the Cbz group affords 60j-m
in modest to good yields.
Figure 2-15. Attempted synthesis of 63j-m.
Table 2-3. Conditions attempted for the carbonylation of 60j-m
Entry Amine Base Solvent, Temp (°C)
1 60j Pyridine CH2Cl2, 80°C 2 60j DBU CH2Cl2, 40°C 3 60k Pyridine CH2Cl2, 40°C 4 60k Pyridine DCE, 40°C 5 60k Pyridine DCE, 80°C 6 60k DBU CH2Cl2, 40°C 7 60k DBU DCE, 80°C 8 60l Pyridine CH2Cl2, 40 9 60m Pyridine CH2Cl2, 40°C 10 60m Pyridine CH2Cl2, 80°C
60
Figure 2-16. Conformational analysis of 7-membered cyclic ureas predicting that A is preferred when the nitrogens are not substituted, while B is preferred when the nitrogens are substituted113
Attempts at the synthesis of ureas 63j-m by carbonylation were met with difficulty
(Table 2-3). The substrates did not react using standard conditions from the synthesis
of ureas 63a-f (W(CO)6/I2, pyridine, 80 bar CO, CH2Cl2, 40°C, 24h). Increasing the
temperature to 80°C, while using dichloroethane as the solvent, also proved
unsuccessful. In addition, using the stronger base DBU often resulted in decomposition
of the starting material. It seems that substitution at both the nitrogen and the α-carbon
is a detriment to the success of the reaction, possibly due to steric reasons. As seven-
membered rings, the urea products can exist in two pseudo-chair conformations.
Conformational analysis of the urea product reveals that there is a preferred
conformation (conformation B, Figure 2-16) when the nitrogens are substituted due to
allylic 1,2-strain.113 The opposite configuration (conformation A, Figure 2-16) is
preferred when the nitrogens are not substituted due to 1,3-diaxial strain. Based on the
61
analysis it can be presumed that the secondary amines are unable to adopt the
necessary configuration to form the urea when bound to the metal.
Building on previous success with the synthesis of the O-protected core structure
of DMP 450, it is shown that the W(CO)6/I2-catalyzed carbonylation reaction can be
applied to similar functionalized diamine substrates. Furthermore, the subsequent
ureas can be obtained without protection of the diol in several cases. The synthesis of
tetrasubstituted ureas can also be achieved, although steric constraints tend to lower
the yields of the ureas. The tetrasubstituted ureas cannot be synthesized, however,
with substitution at the α-carbon. Even with these limitations, the scope of the
W(CO)6/I2 catalyzed carbonylation of amines to ureas has been successfully extended
to include the synthesis of analogues of DMP 450.
62
CHAPTER 3 CATALYTIC OXIDATIVE CARBONYLATION OF ARYL AMINES TO UREAS
Introduction
N,N′-Disubstituted ureas have numerous applications in areas such as
pharmaceuticals,131-133 pesticides,1,3 and dyes.9,134 Traditional synthetic routes for the
synthesis of ureas involve the use of phosgene or phosgene derivatives. However,
phosgene poses handling issues due to its toxicity, while its derivatives produce
undesirable byproducts.13 In light of these problems, developing a less hazardous
synthetic route for ureas has attracted considerable interest over the years.37,93,135-137
Transition metal-catalysts have shown promise as an alternative route to the
synthesis of ureas from amines.138 Reaction conditions typically involve amines, an
oxidant, and CO as the carbonyl source. Catalysts including complexes of Pd,37-53 Ni,27-
29 Co,22-26 Ru,30-34 and Au65-68 have been employed for the oxidative carbonylation of
amines to ureas. For example, Pd(OAc)2 afforded good to high yields of ureas from aryl
and alkyl amines, as well as carbamates from amino alcohols.53 Other palladium
complexes, such as Pd(PPh3)2Cl293 have also been utilized. A NiI/[Ru(CO)3I3]NBu4
33
catalyst system showed excellent reactivity for the selective formation of N,N'-
diphenylurea from the oxidative carbonylation of aniline.
Previous reports have shown that W(CO)6 is a good catalyst for the oxidative
carbonylation of various aliphatic primary and secondary diamines.57,111 However, early
experiments suggested that aryl amines were not suitable substrates for this reaction,
as the oxidative carbonylation of aniline to N,N'-diphenylurea was unsuccessful when
K2CO3 was used as base.59 Manipulating reaction conditions, though, has led to the
W(CO)6/I2 catalyzed oxidative carbonylation of aniline (Figure 3-1) and other p-
63
substituted aryl amines (Figure 3-2) to their respective aromatic ureas. In addition, in
certain cases, aryl amines could be carbonylated to unsymmetrical ureas using this
catalytic system.
Results and Discussion
Initially, carbonylation reaction conditions for the conversion of aniline to N,N'-
diphenylurea were screened (Figure 3-1). Variables such as temperature, solvent, CO
pressure, and equivalents of base were examined and the results are described below
(Table 3-1).
Figure 3-1. Synthesis of N,N’-diphenylurea via W(CO)6/I2 carbonylation.
Table 3-1. Optimization of the reaction conditions for the W(CO)6 /I2-catalyzed carbonylation of aniline to N,N’-diphenylurea.
Entry Base Temp (°C) Time (h) CO (atm) Equiva
(I2:Base) Yield (%)b,c
1 DBU 40 20 80 1 : 2 Trace 2 Pyridine 40 20 80 1 : 2 Trace 3 DMAP 40 20 80 1 : 2 81 4 DMAP 40 20 80 1 : 1 52 5 DMAP 40 20 80 1 : 3 59 6 DMAP 40 20 80 0.5 : 2 79 7 DMAP 25 20 80 1 : 2 60 8 DMAP 60 20 80 1 : 2 78 9 DMAP 80 20 80 1 : 2 72 10 DMAP 40 4 80 1 : 2 39 11 DMAP 40 8 80 1 : 2 85 12 DMAP 40 8 40 1 : 2 34 13 DMAP 40 20 60 1 : 2 61
aBased on 1 equiv aniline.
b Isolated yield of diarylurea calculated per equivalent of aniline.
c Reaction
conditions: aniline (5.0 mmol), 3 mol % W(CO)6, 40 mL CH2Cl2, others as listed in table.
64
Optimization of Reaction Conditions for Oxidative Carbonylation of Aniline to N,N'-Diphenylurea
Initial experiments involved the carbonylation of aniline (0.46 g, 5 mmol) in the
presence of 1.5 mol % W(CO)6, 1.0 equiv of I2, and 2.0 equiv of base in 40 mL CH2Cl2
with 80 atm CO, stirred at 40 °C for 20 h (Table 3-1). Using
diaza(1,3)bicyclo[5.4.0]undecane (DBU) or pyridine as the base only produced trace
amounts of the desired product (Table 3-1, entries 1 and 2). Alternatively, substituting
4-dimethylaminopyridine (DMAP) as the base dramatically increased the yield to 81%
(Table 3-1, entry 3). Lowering the amount of DMAP to 1 equiv resulted in a reduced
isolated yield of 52% and observation of unreacted starting material (Table 3-1, entry 4).
Furthermore, increasing the amount of DMAP to 3 equivalents produced a similar yield
(59%, Table 3-1, entry 5). Following these experiments, 2.0 equivalents of DMAP was
chosen for further optimization studies.
Once DMAP had been established as the preferred base, the quantity of iodine
was optimized. Lowering the amount of the oxidant to 0.5 equivalents resulted in a 79%
yield (Table 3-1, entry 6). The highest activity was obtained when the mole ratio of I2 to
DMAP was 1:2. The temperature was then varied from 25 °C to 80 °C (Table 3-1
entries 7-9). When the temperature was lower than 40°C, only 60% yield was obtained.
The yield improved when the temperature was increased to 60°C, but decreased slightly
at 80°C. Further increases in the temperature caused the yields to decrease, most
likely due to degradation of the urea product at higher temperature or the appearance of
other byproducts.
The carbonylation yields were also determined as a function of time (Table 3-1
entries 10-11). At 40 °C and 4 h, the yield of N,N'-diphenylurea decreased significantly
65
to 39%, while at 8 h the urea yield was 85%, which was an improvement from previous
trials at 20 h. Therefore, the optimal time for the carbonylation was determined to be 8
h.
The CO pressure was found to be critical to the yield of urea in this reaction (Table
3-1. entries 11-12). As the CO pressure was decreased to 80 atm and 40 atm, the
yields were markedly lowered to 85% and 34%, respectively. At 60 atm of CO, the urea
was obtained in moderate yield (Table 3-1, entry 13). Therefore, the optimal conditions
for the carbonylation reaction were determined to be 40 °C, 80 atm CO, 1 equiv of I2, 2
equiv of DMAP, and CH2Cl2 as solvent. Selected primary aryl amines were then
converted into their corresponding N,N’-disubstituted ureas using these conditions.
Oxidative Carbonylation of p-Substituted Aryl Amines to Symmetrical Diarylureas
To explore the scope of the reaction for possible application in organic synthesis, a
study of functional group tolerance was undertaken. Various substituted aryl amines
(Figure 3-2) were converted to symmetrical N,N'-diarylureas under the optimized
carbonylation conditions (Table 3-2).
Figure 3-2. Oxidative carbonylation of various p-substituted aryl amines to symmetrical N,N’-diarylureas.
Table 3-2. Oxidative carbonylation of various aryl amines to symmetrical N,N`-diarylureas using the W(CO)6 /I2 catalyst system.
Entry Amine Urea Yielda,b (%)
1 67a, R = H 68a, R = H 85
2 67b, R = p-Cl 68b, R = p-Cl 68
66
Table 3-2. Continued
Entry Amine Urea Yielda,b (%)
3 67c, R = p-I 68c, R = p-I 68
4 67d, R = p-Br 68d, R= p-Br 64
5 67e, R = p-OMe 68e, R = p-OMe 38
6 67f, R = p-NO2 68f, R = p-NO2 84
7 67g, R = p-CN 68g, R = p-CN 48
8 67h, R = p-COOEt 68h, R = p-COOEt 83
9 67i 68i
41
10 67j 68j
0
11 67k, R = p-CH2OH 68k, R = p-CH2OH 0
12 67l, R = p-COOH 68l, R = p-COOH 0
a
Reaction conditions: 5.0 mmol of aryl aniline, 3mol% W(CO)6, 5.0 mmol I2, 10.0 mmol DMAP, in 40 mL CH2Cl2, 40 °C, 80 atm CO, 8 h.
bIsolated yield based on aryl amine.
The effect of halogen substituents was evaluated first. The yield of urea 68b from
4-chloroaniline 67b was good (68%, Table 3-2, entry 2). Bromo- (67c) and iodo-
substituted (67d) amines afforded their respective N,N'-disubstituted ureas in nearly
identical yields (Table 3-2, entries 3-4). In contrast to the halogenated anilines,
substitution with the electron-donating methoxy group (67e) resulted in a significant
decrease in the yield of urea (38%, Table 3-2, entry 5), while the electron poor p-
nitroaniline 67f was successfully carbonylated to its urea in 84% yield. This trend of
higher yields with electron-withdrawing substituents is followed by ethyl-aminobenzoate
67
67h (83%, Table 3-2, entry 8). An exception is 4-aminobenzonitrile 67g, which affords
just 48% of the urea (Table 3-2, entry 7), despite its electron withdrawing cyano
substituent. However, the ability of the nitrile moiety to serve as ligand for the catalyst
may be affecting the yield. In prior studies on p-substituted benzyl amines,59 amines
with coordinating substituents such as carboxylates gave poor yields under the original
reaction conditions.
Figure 3-3. Iodo-deboronation of aminophenylboronic ester 67m
In addition, we also investigated the aromatic amine 67i under the carbonylation
conditions, which formed the cyclic urea 3,4-dihydro-2-quinazolinone in 41% yield. This
result was an improvement compared to the original reaction conditions using K2CO3 as
base in which the yield of the urea was 10% yield.59 Boronic esters were also tested for
compatibility under carbonylation conditions. Interestingly, attempted catalytic
carbonylation of 4-aminophenylboronic ester 67m did not result in the formation of urea,
but rather p-iodoaniline 67c (Figure 3-3). Control experiments found that the p-
iodoaniline 67c was also formed from 67m at room temperature in the absence of CO
and the W(CO)6 catalyst. This observation is not unprecedented, as iodo-deboronation
has been observed in the reaction of alkenylboranes in the presence of I2 and sodium
68
hydroxide in ethereal solvents.139,140 Further functional group studies included 4-
aminostyrene, 4-aminobenzylalcohol, and 4-aminobenzoic acid (67j-67l). Unfortunately,
none of their corresponding ureas could be detected in the reaction mixtures (Table 3-2,
entries 10-12). These results are also consistent with the prior study on substituted
benzyl amines, where the same substituents resulted in lower yields of the dibenzyl
ureas.
Oxidative Carbonylation of Aryl Amines to Unsymmetrical Diarylureas
Catalyzed carbonylation of aryl amines with various functional groups to
symmetrical ureas suggested the possibility that unsymmetrical ureas might also be
synthesized with the same reaction conditions (Table 3-3).
Table 3-3. Synthesis of symmetrical diaryl ureas with tungsten hexacarbonyl
Entry Amines Ratio Ureas (% Yield)a,b
1
p-NO2
67f
p-CN 67g
1:1
69fg (58)
68f (0)
68g (0)
2
p-Cl 67b
p-OMe 67e
1:1
69be (12)
68b (19)
68e (24)
3
67b
67e
1:2
69be (0)
68b (0)
68e (36)
4
67b
67e
2:1
69be (43)
68b (11)
68e (0)
5
67b
67e
5:1
69be (11)
68b (14)
68e (0)
69
Table 3-3. Continued
Entry Amines Ratio Ureas (% Yield)a,b
6 p-Cl, m-CF3
67n
67e 2:1
69ne (12)
68n (0)
68e (24)
7 p-Cl 67b
p-OPh 67o
2:1
69bo (41)c
68b (4)c
68o (23)c
8 p-Cl, m-CF3
67n
p-OPh 67o
1:1
69no (12)
68n (0)
68o (41)
a Isolated yield based on aryl amine.
bThe reactions were carried out with aryl amines (1.0 mmol each,
unless otherwise noted), W(CO)6 (0.06 mmol), I2 (2.0 mmol), DMAP (4 mmol), CH2Cl2 (40 mL), 40 °C, 80 atm CO, 20 h.
cNMR yield.
To explore the feasibility of aryl amines with electron withdrawing groups
producing unsymmetrical ureas, compounds 67f (p-NO2), and 67g (p-CN) were
subjected to the same reaction conditions. This reaction provided the desired
unsymmetrical urea 69fg as the major product in 58% yield (Table 3-3, entry 1), without
formation of the symmetrical ureas 68f and 68g in the product mixture. The equimolar
pair of aryl amines 67b (p-Cl) and 67e (p-OCH3) provided the desired unsymmetrical
urea 69be in low yield (12%, Table 3-3, entry 2). The symmetrical products, 1,3-bis(4-
chlorophenyl)urea 68b and 1,3-bis(4-methoxyphenyl) urea 68e, were also detected in
the mixture. Although the yield of unsymmetrical urea 69be was low, the yields of
symmetrical ureas from electron-rich aryl amines are also low and it is possible that 67e
is just moderately unreactive. The presence of the unsymmetrical urea suggests that
manipulation of the reaction conditions could tip the product mixture in its favor. When
70
the ratio was 1:2 in favor of 67e, however, the symmetric urea 68e was formed
exclusively in 36% yield (Table 3-3, entry 3). Using more of the p-chloroaniline 67b
(2:1, Table 3-3, entry 4) resulted in 43% yield of the unsymmetrical urea 69be and 11%
of 68b (Table 3-3, entry 5). A large excess of 67b resulted the formation of its
respective symmetric urea 68b, and a low yield of the unsymmetrical urea (Table 3-3,
entry 6). Compound 69be is of particular interest because of its application to the
synthesis of sorafenib, an FDA approved drug for cancer treatment (Figure 3-4).133 As
shown in Figure 3-4, 69be represents a simplified derivative of the cancer drug. Upon
further modification of the aryl amines, the W(CO)6/I2 system was used to install a
derivative of the urea moiety of sorafenib.
Figure 3-4. Structure of the cancer drug sorafenib, a possible application of the tungsten-catalyzed carbonylation of aryl amines
Coupling of 4-chloro-3-(trifluoromethyl)aniline (67n) with anisidine (67e) produced
mixed results with a 2:1 ratio of 67n to 67e (Table 3-3, entry 6). The symmetric urea
68e was the major product (24% yield) while the unsymmetrical urea 69ne was
produced in low yield (12%). Only trace amounts of symmetric urea 68n was detected.
The electron deficiency of the parent aniline 67n in addition to added steric bulk
associated with two aryl substituents are probably the cause of the low conversion.
This inactivity is useful since it enables the possibility of increasing the amounts of 67n
without competition of its symmetric urea. When 4-phenoxyaniline (67o) and p-
71
chloroaniline (67b) were subjected to carbonylation conditions, the unsymmetrical urea
69bo was obtained as the major product (Table 3-3, entry 7). Symmetrical urea 68o
was obtained in 23% yield, while 68b was present in small quantities (4% yield). Urea
69no exemplifies the structure of sorafenib most and was obtained in 12% yield from a
1:1 ratio of 67n to 67o (Table 3-3, entry 8). Symmetric urea 68o was the major product
(41% yield). As mentioned earlier, increased amounts of 67n in the reaction could lead
to increased yields of 69no without competitive formation of 68n. After this series of
unsymmetrical amine synthesis, it seems that the electron-poor counterpart is always
the least reactive species when coupled with an electron-rich aryl amine. This pattern
possibly suggests the formation of an isocyanate intermediate which is subsequently
attacked by the more nucleophilic electon-rich aryl amine (Figure 3-5).
Figure 3-5. Proposed isocyanate pathway for the tungsten-catalyzed synthesis of symmetrical and unsymmetrical aryl ureas
Figure 3-6. Attempted carbonylation of N-methylaniline
72
To probe whether the reaction proceeds through an isocyanate pathway, N-
methylaniline (67p) was subjected to carbonylation conditions. After 20 hours under 80
atm of CO at 40°C, urea 68p was not observed in the product mixture. Most of the
starting material was recovered along with trace quantities of p-iodo-(N-methyl)aniline
(67q), a result of the electrophilic aromatic substitution of N-methylaniline with elemental
iodine (Figure 3-6). The lack of urea in the product mixture serves to further validate the
isocyanate pathway. Furthermore, when N-methylaniline (67p) and aniline (67a) were
combined under optimized conditions, the major product was unsymmetrical urea 69ap
(31% yield, Figure 3-7) when excess 67p was used. Diphenylurea (68a) was detected
in only trace amounts. Some aniline was also recovered due to incomplete conversion.
Although a modest yield, the selectivity for the unsymmetrical urea implies formation of
isocyanate from the primary aryl amine followed by attack of the more nucleophilic
secondary aryl amine.
Figure 3-7. Carbonylation of aniline and N-methylaniline to provide unsymmetrical urea 69ap
Past experiences with the carbonylation of amines to ureas led to the conclusion
that aniline did not provide N,N-diphenylurea because of its decreased nucleophilicity
compared to aliphatic substrates under the conditions studied. These recent results
have proven the contrary. From the results presented, the issue lies possibly in the
deprotonation of a metal-bound amine species in order to provide an isocyanate, which
73
is converted to the urea by nucleophilic attack of a second equivalent of amine. Aryl
amines are more acidic (pKa aniline = 4.58) than their aliphatic counterparts (pKa
methylamine = 10.62) which necessitates the use of a weaker base than previous
conditions.
Conclusions
In conclusion, we have demonstrated the catalytic carbonylation of aniline to N,N'-
diphenylurea using the W(CO)6/I2 catalyst system. After optimizing the conditions for
the carbonylation of aniline, various p-substituted aryl amines were also oxidatively
carbonylated to symmetrical and unsymmetrical diarylureas. The results demonstrate
the moderately broad tolerance of functionality during the oxidative carbonylation
reaction and provide an alternative to the reaction of amines with phosgene and
phosgene derivatives. The results of the unsymmetrical diarylureas show promise in
the synthesis of biologically important diarylureas using the W(CO)6/I2 system. Some
progress has been made in understanding the most complimentary pairing of aryl
amines to ensure maximum unsymmetrical urea formation. The results have also led to
valuable insights in the mechanistic pathway to urea formation.
74
CHAPTER 4 APPLICATION OF W(CO)6/I2 CATALYZED CARBONYLATION TO THE SYNTHESIS
OF THE LOPINAVIR SIDECHAIN
Introduction
The introduction of highly active antiretroviral therapy (HAART) in 1996 led to a
dramatic change in fighting HIV infection. The therapy involves using at least three
drugs from two different classes of antivirals. Using this strategy, a protease inhibitor
(PI) could be used in combination with two nucleoside/nucleotide reverse transcriptase
inhibitors (N(t) RTIs).141 One of the first generation of drugs approved by the Food and
Drug Administration (FDA) was ritonavir (Figure 4-1), a product of Abbott laboratories
that targeted the HIV protease. The structure of ritonavir took advantage of the C2-
symmetric nature of the HIV protease homodimer.142 Unlike most peptidomimetics
which suffered from low absorption, ritonavir showed high bioavalability due to
increased aqueous solubility in addition to high potency against HIV protease. The path
to the discovery of ritonavir started with core symmetric or pseudo-symmetric diamines.
Structure-activity studies of modifications of the core structures identified heterocyclic
side groups as a key component in increasing solubility. Incorporation of thiazoles as
the side groups led to the identification of ritonavir as a lead compound.142 After
successful clinical trials, ritonavir was licensed by the FDA and approved for use with
reverse transcriptase inhibitors (RTIs).
Figure 4-1. Structure of ritonavir
75
Although ritonavir was effective when combined with RTIs, it was affected by the
development of drug-resistance from virus mutations. Furthermore, the combination
had modest oral availability and short plasma half-life. This meant the administration of
high doses of the drug to maintain the inhibitory effects.143 This led to the search for a
second generation of drugs to overcome these drawbacks. Abbott Laboratories
addressed the shortcomings of ritonavir with the release of its next generation HIV
inhibitor, lopinavir (Figure 4-2). Lopinavir, when co-administered with small doses of
ritonavir, showed a significant increase in bioavailability and activity against wild strain
HIV-1 and other mutations.143 In contrast to rotinavir, lopinavir contained different
terminal groups; a urea moiety on one side and a dimethyl phenolic moiety on the other.
This was done in order to both decrease the molecular weight of the compound and
increase bioavailability and potency.141
Figure 4-2. Structure of lopinavir.
Literature Synthesis of the Lopinavir Sidechain
The general strategy for the synthesis of lopinavir focused on acylation of the core
diamine structure to each acid side chain (Figure 4-3). The core structure 71 was
readily available through rotinavir manufacturing starting from L-phenylalanine and side
chain 72 can be easily derived from published procedures. The synthesis of 70,
however, proved more difficult.143
76
Figure 4-3. Retrosynthetic strategy for the synthesis of lopinavir
The original synthetic route for 70 involved a low yielding six step synthesis with 3-
aminopropanol and L-valine methyl ester as starting materials. In an improved
synthesis, L-valine was converted to the carbamate 73 using phenyl chloroformate.
Control of pH was essential for the success of this reaction in order to suppress
byproduct formation. Treatment of 73 with 3-chloropropylamine hydrochloride produces
74 in situ. Crude 74 is then cyclized with potassium tert-butoxide (KOtBu) to obtain
compound 70 (Figure 4-4).143 A disadvantage of this method, however, stems from the
quality of 3-chloropropylamine hydrochloride. The reagent is prone to developing dark
colored impurities which are difficult to remove. The use of high quality amine is critical
to the success of the cyclization reaction.
Figure 4-4. Synthesis of the urea moiety of lopinavir143
77
In an alternate route, the L-valine is first reacted with acrylonitrile and methyl
chloroformate to obtain 75, which is then hydrogenated with Raney-Ni to obtain 70
(Figure 4-5). Apart from the low overall yield of this procedure, a second drawback
involves the use of Raney-Ni. The reagent is classified as potentially carcinogenic and
is also not diposed of easily.144 A slightly different route utilizes rhodium as a
hydrogenation catalyst in place of Raney-Ni, but this reaction is done in the presence of
ammomium gas.144
Figure 4-5. Alternate synthesis of 70144
The most current reported synthesis of 70 utilizes a phosgene derivative, CDI, to
install the urea from the parent amine (Figure 4-6).145 Treatment of 76 with
trifluoroacetic acid (TFA) followed by CDI affords 77. Subsequent hydrolysis of 77
provided compound 70 (Figure 4-6). Since two equivalents of imidazole are eliminated
from the stoichiometric reaction with CDI, proper disposal of the waste is an issue,
especially on the industrial scale. Using the W(CO)6/I2 catalyst system is a viable
alternative to the use of CDI since the only byproducts from the catalytic reaction are
protons and the reduced form of the oxidant.
78
Figure 4-6. Synthesis of 70 using CDI145
Tungsten-Catalyzed Synthesis of Lopinavir Sidechain Derivative
To begin the investigation on the synthesis of 70 with the W(CO)6/I2 catalyst
system, the glycine derivative of the sidechain (79) was chosen as the target
compound for steric reasons. In addition, the carboxylic acid was protected in the form
of an ester to limit any side reactions and increase solubility of the substrate.
Conditions for the carbonylation involved 5 mol % W(CO)6, 1 equiv of iodine, 4 equiv of
K2CO3, and 80 bar CO.
Substrate Synthesis
The retrosynthetic analysis of the glycine derivative of the lopinavir sidechain is
shown in Figure 4-7. Urea 78 could be obtained from diamine 79 via catalytic
carbonylation. Synthesis of the diamine could be accomplished by reacting α-
chloroacetic acid with 1,3-diaminopropane 80 (Figure 4-7).
Figure 4-7. Retrosynthesis of compound 78
Even though the N-(3-aminopropyl) glycine 81 is commercially available as an HCl
salt, it is expensive ($120 per gram). Laboratory synthesis using cheaper reagents was
deemed a better alternative. However, the coupling reaction of diamine 80 with
79
chloroacetic acid began with difficulty (Figure 4-8). The reaction was performed several
times with variations of experimental conditions. It was found that when methylene
chloride was the solvent, production of the hydrochloride salt of the diamine stopped
reaction progress. Increasing the scale of the reaction without solvent produced the
desired product 81 with 1,3-diaminopropane hydrochloride in a 2:1 ratio. Unreacted
diamine was removed by distillation and the resulting crude paste was recrystallized
using boiling acetic acid and ethanol.146 Even though the yield of 81 was low (12%), the
reagents are inexpensive and the unreacted diamine could be recycled. Esterification
of 81 was first attempted with refluxing methanol in the presence of concentrated
sulfuric acid. After the reaction, the work-up procedure was problematic due to the
affinity of the product for the aqueous layer. After many extractions with 5:2 chloroform
to ethanol, ester 79 was obtained with small amounts of unreacted starting material.
Needing a pure substrate for the upcoming carbonylation reaction, another route to
esterification was undertaken. Generation of hydrogen chloride gas in situ (by the
reaction between concentrated HCl and calcium chloride) followed by reflux in methanol
provided the glycine methyl ester 79 in 91% yield (Figure 4-8).146
Figure 4-8. Preparation of N-(3-aminopropyl)glycine methyl ester 79
Tungsten-Catalyzed Carbonylation of N-(3-aminopropyl)glycine methyl ester 80
The glycine compound 79 was subjected to W(CO)6/I2-catalyzed carbonylation
conditions. Using potassium carbonate as the base, a biphasic system (methylene
chloride and water) as the solvent, and 80 bar CO at 80°C for 24 h, preliminary results
80
indicated that the desired urea 78 was not obtained (Figure 4-9). Mass spectral
analysis of the white solid that was recovered revealed signals of 204.8310 and
234.9883 Da with the largest abundance in the spectrum. The solid was acquired from
the aqueous layer of the reaction by extraction with a 3:1 solution of chloroform and
ethanol. The expected ions of the desired product ([M + H]+ calcd, 173.0926) were not
found. More work is needed to find the appropriate conditions for the reaction. Success
with the synthesis of urea 78 could lead to the catalytic carbonylation of other
derivatives with substituents alpha to the ester, and subsequently the valine derived
lopinavir side chain 70.
Figure 4-9. Attempted W(CO)6/I2-catalyzed carbonylation of glycine methyl ester 79
Conclusion
The W(CO)6/I2 catalytic system has been applied to the synthesis of the glycine
derivative of the HIV protease inhibitor lopinavir, however, preliminary results show the
formation of an unknown product. More experimentation is needed to indentify this
product, and also to produce the desired urea. If successful, this method would provide
an alternative to the use of the phosgene derivative, CDI, in the preparation of the cyclic
urea side chain of lopinavir.
81
CHAPTER 5 EXPERIMENTAL PROTOCOLS
General Methods. All experimental procedures were carried out under nitrogen in
oven-dried glassware unless otherwise indicated. Carbonylation reactions were
conducted in a 300 mL glass liner in a Parr autoclave behind a blast shield. Solvents
and reagents were obtained from commercial sources in the appropriate grade and
used without purification unless otherwise noted. Syntheses of compounds 31,114 33,
114 , 44,113 45,113 61,147 and 66c148 were carried out according to literature procedures.
1H and 13C NMR spectra were obtained on Varian Gemini 300 MHz, VXR 300 MHz, and
Mercury 300 MHz spectrometers. Infrared spectra were measured using a Perkin-
Elmer Spectum One FTIR. High-resolution mass spectrometry was performed by the
University of Florida analytical service.
34
(2R, 3S, 4S, 5R)-2,5-Diamino-1,6-diphenyl-3,4-hexanediol (34). The procedure
was adapted from the literature.130 A mixture of 44 (1.33 g, 2.34 mmol), ammonium
formate (0.88 g, 0.014 mol), and 10% Pd/C (0.80 g) in DMF (20 mL) was heated to 120
ºC under an Ar atmosphere for 8 h. The reaction was allowed to cool and the mixture
was then filtered through Celite. The filter cake was rinsed with methanol and the
combined filtrates were concentrated into a pale yellow oil. The oil was taken up in
ethyl acetate and washed with water, saturated sodium bicarbonate, and saturated
sodium chloride, dried over magnesium sulfate, filtered, and concentrated to obtain 34
(0.40 g, 70% yield). The product was identified by comparison with literature data.130 1H
82
NMR (CDCl3) 7.39 - 7.02 (m, 10H), 3.67 (s, 2H), 3.02 (dd, J = 5.6, 8.9 Hz, 2H), 2.91
(dd, J = 5.8, 13.2 Hz, 2H), 2.71 (dd, J = 8.9, 13.1 Hz, 2H)
47b
(2R,3R)-Dimethyl 2,3-bis((2-(trimethylsilyl)ethoxy)methoxy)succinate (47b).
Under Ar and at 0 °C, SEM chloride (5.08 g, 30.5 mmol) was added dropwise to a
stirring solution of dimethyl-L-tartrate (1.81 g, 10.2 mmol) and DIPEA (3.94 g, 30.5
mmol) in dry CH2Cl2. After gas evolution ceased, the reaction was stirred at room
temperature overnight. The solution was then washed with 1 M HCl (1X) followed by
water (2X). The organic layer was dried over magnesium sulfate, filtered, and
concentrated to afford 47b as a pale yellow oil in quantitative yield (4.43 g). 1H NMR
(CDCl3) δ 4.85 - 4.66 (m, 6H), 3.74 (s, 6H), 3.67 - 3.48 (m, 4H), 1.00 - 0.77 (m, 4H), -
0.02 (s, 18H).
59a
(4R,5R)-N,N,2,2-Tetramethyl-1,3-dioxolane-4,5-dicarboxamide (59a).
Methylamine (46 mL, 2.0 M in methanol) was added to dimethyl 2,3-O-isopropylidene-L-
tartrate 47a (4.20 mL, 22.9 mmol) in methanol (15 mL) and stirred at room temperature
for 3 days. The solution was then concentrated to afford 59a as a white solid (4.93 g,
83
99% yield). The compound was identified by comparison with literature data.149 1H
NMR (CDCl3) 7.06 (br s, 2H), 4.51 (s, 2H), 2.89 (d, J = 4.9 Hz, 6H), 1.49 (s, 6H).
59b
(4R,5R)-N,N-Dibenzyl-2,2-dimethyl-1,3-dioxolane-4,5-dicarboxamide (59b). A
mixture of 47a (10.78 g, 49.40 mol), benzylamine (10.32 g, 96.30 mmol), potassium
carbonate (0.172 g, 1.24 mmol) and methanol (35 mL) was refluxed overnight. It was
then cooled to room temperature and the solvent evaporated to afford an orange oil.
The oil was purified by column chromatography (1:1 ethyl acetate/dichloromethane) to
afford 59b as a pale yellow solid (10.73 g, 67 % yield). The compound was identified by
comparison with literature data.128 1H NMR (CDCl3) 7.38 - 7.24 (m, 10H), 4.63 (s, 2H),
4.50 (d, J = 6.0 Hz, 4H), 1.46 (s, 6H).
59c
(2R,3R)-N,N-Dimethyl-2,3-bis((2 (trimethylsilyl)ethoxy)methoxy)succinamide
(59c). Using the same procedure for 59a, 59c (1.54 g, 84% yield) was obtained from
47b (1.83 g, 4.17 mmol). 1H NMR (CDCl3) δ 6.80 (d, J = 4.4 Hz, 2H), 4.85 - 4.62 (m,
6H), 3.74 - 3.52 (m, 4H), 2.86 (d, J = 5.0 Hz, 6H), 1.06 - 0.82 (m, 4H), 0.01 (s, 18H).
13C NMR (CDCl3) 170.3, 97.0, 79.5, 67.0, 26.2, 18.3, -1.2.
84
59d
(2R,3R)-N,N-Dibenzyl-2,3-bis((2-(trimethylsilyl)ethoxy)methoxy)succinamide
(59d). Compound 59d was obtained in 62% yield from 47b using the procedure for
59b. 1H NMR (CDCl3) 7.35 - 7.14 (m, 10H), 4.73 (s, 2H), 4.62 (dd, J = 6.4, 11.3 Hz,
4H), 4.45 (d, J = 5.8 Hz, 4H), 3.49 (td, J = 7.4, 10.0 Hz, 4H), 0.87 - 0.66 (m, 4H), -0.08
(s, 18H).
59e
(2R, 3R)-1,4-N,N-Dibenzylamino-2,3-dihydroxysuccinamide (59e). Using the
same procedure as for 59b, diethyl-L-tartrate (7.00 g, 0.0339 mol) was employed to
afford 59c as a white solid. The crude product was filtered, washed with water, and
recrystallized from 50% ethanol in water to obtain pure 59c (10.0 g, 90% yield). The
compound was identified by comparison with literature data.150 1H NMR (DMSO-d6)
8.25 (t, J = 6.3 Hz, 2H), 7.39 - 7.13 (m, 10H), 5.74 (d, J = 7.2 Hz, 2H), 4.48 - 4.17 (m,
6H). 13C NMR (DMSO-d6) 172.1, 139.4, 127.5, 126.5, 72.7, 41.9.
85
60a
1,1'-((4S,5S)-2,2-Dimethyl-1,3-dioxolane-4,5-diyl)bis(N-methylmethanamine)
(60a). Using a variation of the literature procedure,128 a solution of diamide tartrate 59a
(3.51 g, 0.0162 mol) in dioxane (50 mL) was added slowly to a vigorously stirring
suspension of lithium aluminum hydride (1.85 g, 0.0487 mol) in dioxane (160 mL). The
reaction was refluxed overnight after addition was complete. After the reaction mixture
cooled, it was quenched by careful addition of 3 mL water, 3 mL 15% NaOH, and 3 mL
water. The solution was filtered and the filtrate concentrated to afford crude 60a as a
pale red oil (3.01 g, 98% yield). The product was identified by comparison with
literature data.149 1H NMR (CDCl3) 3.93 - 3.88 (m, 2H), 2.76 - 2.72 (m, 4H), 2.46 (s,
6H), 1.40 (s, 6H).
60b
N,N'-(((4S,5S)-2,2-Dimethyl-1,3-dioxolane-4,5-diyl)bis(methylene))bis(1-
phenylmethanamine) (60b). The procedure used to prepare 60a was used with 59b
(4.00 g, 0.0109 mol) to obtain 60b in 71% yield (2.62 g) as a pale brown oil after
purification by column chromatography with CH3OH/CH2Cl2 as eluent. The product was
identified by comparison with literature data.128 1H NMR (CDCl3) 7.31 - 7.19 (m, 10H),
86
3.97 - 3.90 (m, 2H), 3.79 (s, 4H), 2.77 (dd, J = 2.1, 3.4 Hz, 4H), 1.66 (br s, 2H), 1.38 (s,
6H).
60c
(2S,3S)-N,N-Dimethyl-2,3-bis((2-(trimethylsilyl)ethoxy)methoxy)butane-1,4-
diamine (60c). Compound 59c (2.28 g, 5.22 mmol) afforded 60c (0.760 g, 36% yield)
using the procedure for 60a in refluxing THF (100 mL). 1H NMR (CDCl3) 4.81 - 4.67
(m, 4H), 3.89 - 3.75 (m, 2H), 3.69 - 3.54 (m, 4H), 2.82 - 2.59 (m, 4H), 2.42 (s, 6H), 1.03
- 0.85 (m, 4H), 0.00 (s, 18H). 13C NMR (CDCl3) 95.6, 78.2, 65.7, 52.2, 36.7, 18.3, -
1.2. HRMS calcd for C18H44N2O4Si2 [M + H]+ 409.2912, found 409.2918.
60e
(2S,3S)-1,4-Bis(methylamino)butane-2,3-diol (60e). Diepoxide 62 (0.232 g,
2.69 mmol) was added to methylamine (11.6 mL of a 2.0 M solution in methanol, 0.0232
mol) at 0°C and then stirred at room temperature overnight. The reaction was then
concentrated to yield 60e as a white solid (0.40 g, 99%). The product was identified by
comparison with literature data.151 1H NMR (CDCl3) 3.83 (t, J = 2.5 Hz, 2H), 3.05 (dd,
J = 3.3, 12.0 Hz, 2H), 2.65 (dd, J = 2.5, 12.0 Hz, 2H), 2.42 (s, 6H).
87
60f
(2S,3S)-1,4-Bis(benzylamino)butane-2,3-diol (60f). Diamide 59e (4.00 g,
0.0122 mol) was placed in a Soxhlet thimble and extracted into a refluxing suspension
of lithium aluminum hydride (1.20 g, 0.0316 mol) in 200 mL of tetrahydrofuran.
Refluxing was continued for 72 h and the suspension stirred at room temperature
overnight. Water (3 mL) was then added dropwise to the mixture followed by 15%
NaOH (3 mL), and additional water (3 mL). The mixture was filtered and the solids were
washed with tetrahydrofuran. The filtrate concentrated and the resulting residue was
purified by column chromatography with CH3OH/CH2Cl2 as the eluent to afford 60f (1.36
g, 37% yield) as a white solid. The product was identified by comparison with literature
data.151 1H NMR (CDCl3) 7.34 - 7.17 (m, 10H), 3.85 - 3.69 (m, 6H), 3.10 (dd, J = 3.8,
12.0 Hz, 2H), 2.72 (dd, J = 2.1, 12.0 Hz, 2H), 1.54 (br. s., 2H).
60g
(1R,1'R)-1,1'-((4S,5S)-2,2-Dimethyl-1,3-dioxolane-4,5-diyl)diethanamine (60g).
The procedure was adapted from the literature.117 Compound 66a (0.73 g, 1.6 mmol),
45 mL ethanol, Pd(OH)2/C (108 mg), and cyclohexene (45 mL) were combined and
refluxed overnight. After cooling to room temperature, the reaction was filtered through
a bed of celite and the resulting liquor was concentrated into an oil. Column
88
chromatography with CH3OH/CH2Cl2 provided 60g as a pale brown oil (0.28 g, 93%
yield). The product was identified by comparison with literature data.152 1H NMR
(CDCl3) 3.55 (d, J = 5.2 Hz, 2H), 2.86 (quin, J = 5.1 Hz, 2H), 2.64 (br s, 4H), 1.34 (s,
6H), 1.04 (d, J = 6.6 Hz, 6H).
60h
(2R,3S,4S,5R)-3,4-Bis((2-(trimethylsilyl)ethoxy)methoxy)hexane-2,5-diamine
(60h). The procedure for 60g was used to produce 60h (1.28 g, 86% yield) from 66b
(2.46 g, 3.63 mmol). The product was identified by comparison with literature data.117
1H NMR (CDCl3) δ 4.73 (d, J = 7.0 Hz, 2H), 4.62 (d, J = 7.0 Hz, 2H), 3.64 (s, 2H), 3.62 -
3.47 (m, 6H), 1.26 (d, J = 6.7 Hz, 6H), 0.85 (ddd, J = 3.4, 7.3, 9.7 Hz, 4H), 0.00 (s,
18H).
60j
(1R,1'R)-1,1'-((4S,5S)-2,2-Dimethyl-1,3-dioxolane-4,5-diyl)bis(N-
methylethanamine) (60j). Sodium hydride (0.451 g, 18.8 mmol, 60% dispersion in
mineral oil) was washed with dry hexanes. DMF (35 mL) was added, followed by the N-
protected diamine diol 66a (1.43 g, 3.13 mmol) in DMF (35 mL) via cannula. After 1
hour, methyl iodide (2.68 g, 18.8 mmol) was added and the reaction was left to stir
overnight at room temperature. The reaction was poured into cold water, then extracted
89
3 times with ethyl acetate. The combined organic layers were then washed with water 3
times, dried, and evaporated to obtain a crude residue. Flash chromatography using
mixtures of ethyl acetate/hexanes afforded N-methylated compound. 1H NMR (DMSO-
d6, 98 °C) 7.42 - 7.25 (m, 10H), 5.21 - 4.93 (m, 4H), 4.27 (br. s., 2H), 3.74 (d, J = 3.2
Hz, 2H), 2.81 (s, 6H), 1.26 (s, 6H), 1.12 (d, J = 7.0 Hz, 6H). HRMS calcd for
C27H36N2O6 [M + H]+ 485.2646, found 485.2664. The purified N-methylated compound
was then treated with .292 g of Pd(OH)2 and cyclohexene (40 mL) in refluxing ethanol
(40 mL) overnight. After cooling to room temperature, the mixture was filtered through
celite. The filtrate was concentrated to afford 60j in 70% yield (0.480 g) over the two
steps. 1H NMR (CDCl3) 3.79 (d, J = 5.3 Hz, 2H), 2.66 - 2.53 (m, 2H), 2.39 (s, 6H),
1.37 (s, 6H), 1.02 (d, J = 6.3 Hz, 6H). 13C NMR (CDCl3) 109.2, 82.5, 57.4, 33.9, 28.4,
16.4.
60k
(2R,3S,4S,5R)-N,N-Dimethyl-3,4-bis((2-
(trimethylsilyl)ethoxy)methoxy)hexane-2,5-diamine (60k). The procedure for 60j
was used to produce 60k from 66b in 60% yield over two steps. 1H NMR (CDCl3)
4.81 - 4.74 (m, 4H), 3.75 - 3.56 (m, 6H), 2.84 (br s, 2H), 2.42 (s, 6H), 1.14 (d, J = 6.6
Hz, 6H), 0.94 (t, J = 8.5 Hz, 4H), 0.02 (s, 18H). 13C NMR (CDCl3) 96.8, 82.8, 66.1,
55.4, 33.9, 18.4, 16.4, -1.2. HRMS calcd for C20H48N2O4Si2 [M + H]+ 437.3225, found
437.3241.
90
60l
(1R,1'R)-1,1'-((4S,5S)-2,2-Dimethyl-1,3-dioxolane-4,5-diyl)bis(N-methyl-2-
phenylethanamine) (60l). The procedure for 60j was used to produce 60l from 66c in
31% yield over two steps. 1H NMR (CDCl3) 7.38 - 7.08 (m, 10H), 4.05 (s, 2H), 2.80 -
2.60 (m, 6H), 2.31 (s, 6H), 2.06 (br. s., 2H), 1.41 (s, 6H)
60m
(2R,3S,4S,5R)-N,N-Dimethyl-1,6-diphenyl-3,4-bis((2-
(trimethylsilyl)ethoxy)methoxy)hexane-2,5-diamine (60m). The procedure for 60j
was used to produce 60m from 45 in 23% yield over two steps. 1H NMR (CDCl3) δ 7.39
- 7.09 (m, 10H), 4.39 (d, J = 6.9 Hz, 2H), 4.25 (d, J = 6.9 Hz, 2H), 3.77 (s, 2H), 3.56 (dt,
J = 7.1, 9.6 Hz, 2H), 3.40 - 3.10 (m, 6H), 2.73 (dd, J = 10.4, 13.6 Hz, 2H), 2.61 (s, 6H),
0.80 - 0.69 (m, 4H), -0.05 (s, 18H). 13C NMR (CDCl3) 137.4, 129.4, 129.0, 127.1,
95.1, 74.9, 66.6, 56.8, 53.6, 34.0, 31.4, 18.1, -1.2. HRMS calcd for C32H56N2O4Si2 [M +
H]+ 589.3851, found 589.3846.
62
(2S,2'S)-2,2'-Bioxirane (62). Compound 61147 (2.62 g, 6.09 mmol) was
suspended in 30 mL ether. Pulverized potassium hydroxide (0.72 g, 0.013 mol) was
91
then added and the mixture refluxed for 6 hours. The reaction was filtered, and the
filtrate concentrated into a colorless oil. The residue was purified by fractional
distillation to obtain 63 as an oil (0.231 g, 44% yield). The product was identified by
comparison with literature data.153 1H NMR (CDCl3) 2.94 - 2.88 (m, 2H), 2.87 - 2.82
(m, 2H), 2.77 - 2.73 (m, 2H).
63a
General Procedure A for Catalytic Oxidative Carbonylation of Diamine Diols
with W(CO)6/I2: (3aS,8aS)-2,2,5,7-tetramethyltetrahydro-3aH-[1,3]dioxolo[4,5-
e][1,3]diazepin-6(7H)-one (63a). To a glass-lined 300 mL Parr high-pressure vessel
containing CH2Cl2 (40 mL) was added diamine 60a (200 mg, 1.06 mmol), W(CO)6 (18.6
mg, 0.0531 mmol), I2 (270 mg, 1.06 mmol), and pyridine (336 mg, 4.25 mmol). The
vessel was then charged with 80 bar of CO and heated at 40°C for 24 h. The pressure
was released and 10 mL of CH2Cl2 was added to further dissolve any crude material.
The solution was washed with a saturated solution of Na2SO3 followed by 0.1M HCl,
then dried over MgSO4 and filtered. The solvent was removed by evaporation and the
resulting residue was purified by column chromatography using mixtures of methanol
and methylene chloride as the eluent to yield 63a as a pale brown oil (133 mg, 58%
yield). IR (neat) CO 1637 cm-1. 1H NMR (CDCl3) 3.65 - 3.54 (m, 2H), 3.32 - 3.17 (m,
4H), 2.91 (s, 6H), 1.45 (s, 6H). 13C NMR (CDCl3) 165.0, 111.5, 79.5, 51.2, 40.3, 26.9.
HRMS calcd for C10H18N2O3 [M + Na]+ 237.1210, found 237.1226.
92
63b
(3aS,8aS)-5,7-Dibenzyl-2,2-dimethyltetrahydro-3aH-[1,3]dioxolo[4,5-
e][1,3]diazepin-6(7H)-one (63b). Following Procedure A, urea 63b was obtained in
99% yield (53.2 mg) from 60b (50.0 mg, 0.147 mmol reacted) after column
chromatography on silica using ethyl acetate/methylene chloride as the eluent. IR (neat)
CO 1638 cm-1. 1H NMR (CDCl3) 7.50 - 7.14 (m, 10H), 4.52 (s, 4H), 3.46 - 3.36 (m,
2H), 3.36 - 3.29 (m, 2H), 3.21 - 3.08 (m, 2H), 1.33 (s, 6H). 13C NMR (CDCl3) 165.1,
138.3, 128.7, 128.7, 127.6, 111.5, 79.9, 55.5, 48.6, 26.8. HRMS calcd for C22H26N2O3
[M + Na]+ 389.1836, found 389.1853.
63e
(5S,6S)-5,6-Dihydroxy-1,3-dimethyl-1,3-diazepan-2-one (63e). Following
Procedure A, 63e (53.2 mg, 45 % yield) was obtained from 60e (100 mg, 0.675 mmol)
after 48 h. IR (neat) CO 1625 cm-1. 1H NMR (CDCl3, CD3OD) 3.96 (br s, 2H), 3.44 -
3.35 (m, 2H), 3.12 - 3.02 (m, 2H), 3.02 - 2.89 (m, 2H), 2.71 (s, 6H). 13C NMR (CDCl3)
166.2, 72.7, 53.8, 39.1. HRMS calcd for C7H14N2O3 [M + H]+ 175.1077, found
175.1074.
93
63f
(5S,6S)-1,3-Dibenzyl-5,6-dihydroxy-1,3-diazepan-2-one (63f). Following
Procedure A, urea 63f was obtained as a clear oil in 10% yield (40.1 mg) from 60f (370
mg, 1.23 mmol). IR (neat) CO 1622 cm-1. 1H NMR (CDCl3) 7.45 - 7.13 (m, 10H), 4.43
(dd, J = 14.9, 67.8 Hz, 4H), 3.33 - 3.25 (m, 2H), 3.21 - 3.00 (m, 4H). 13C NMR (CDCl3)
= 165.9, 138.2, 128.9, 128.7, 127.8, 73.1, 54.3, 51.2. HRMS calcd for C19H22N2O3 [M +
Na]+ 349.1523, found 349.1540.
63g
General Procedure B for Catalytic Oxidative Carbonylation of Diamine Diols
with W(CO)6/I2: (3aS,4R,8R,8aS)-2,2,4,8-tetramethyltetrahydro-3aH-
[1,3]dioxolo[4,5-e][1,3]diazepin-6(7H)-one (63g). To a glass-lined 300 mL Parr high-
pressure vessel containing 40 mL of CH2Cl2 and 10 mL of water was added diamine
60g (200 mg, 1.06 mmol), W(CO)6 (18.6 mg, 0.0531 mmol), I2 (270 mg, 1.06 mmol), and
K2CO3 (587 mg, 4.25 mmol). The vessel was then charged with 80 bar of CO and
heated at 80°C for 24 h. The pressure was released and 10 mL of water was added.
The organics were separated and washed with a saturated solution of Na2SO3 followed
by 0.1M HCl. Each of the collected aqueous layers was extracted with 3:1 CHCl3/EtOH.
94
The organic layers were combined, dried over MgSO4 and filtered. The solvents were
removed by evaporation and the residue was purified by column chromatography using
mixtures of methanol and methylene chloride as the eluent to yield 63g as a pale yellow
solid. IR (neat) CO 1639 cm-1. 1H NMR (CDCl3, CD3OD) 5.52 (d, J = 8.8 Hz, 2H),
4.09 - 3.85 (m, 2H), 3.70 (s, 2H), 1.39 (s, 6H), 1.19 (d, J = 6.7 Hz, 6H). 13C NMR
(CDCl3, CD3OD) 158.2, 108.0, 80.3, 44.1, 25.9, 18.5. HRMS calcd for C10H18N2O3 [M
+ H]+ 215.1390, found 215.1387.
63h
(4R,5S,6S,7R)-4,7-Dimethyl-5,6-bis((2-(trimethylsilyl)ethoxy)methoxy)-1,3-
diazepan-2-one (63h). Following Procedure B, 60h (400 mg, 0.979 mmol) was
converted to 63h (320 mg, 75% yield). The product was identified by comparison with
literature data.117 IR (neat) CO 1683 cm-1. 1H NMR (CDCl3) 4.81 (d, J = 7.2 Hz, 2H),
4.70 (d, J = 7.0 Hz, 2H), 4.36 (s, 2H), 3.75 (q, J = 6.6 Hz, 2H), 3.65 (dd, J = 7.3, 9.6 Hz,
4H), 3.53 (s, 2H), 1.27 (d, J = 6.9 Hz, 6H), 0.93 (dd, J = 7.6, 9.6 Hz, 4H), 0.02 (s, 18H).
13C NMR (CDCl3) 164.3, 95.7, 78.1, 65.9, 46.9, 19.4, 18.2, -1.3. HRMS calcd for
C19H42N2O5Si2 [M + Na]+ 457.2525, found 457.2536.
95
(4R,5S,6S,7R)-4,7-Dibenzyl-5,6-dihydroxy-1,3-diazepan-2-one (63i), (4R,5S)-5-
((1S,2R)-2-amino-1-hydroxy-3-phenylpropyl)-4-benzyloxazolidin-2-one (35), and
(4R,4'R,5S,5'S)-4,4'-dibenzyl-[5,5'-bioxazolidine]-2,2'-dione (36). To a glass-lined
300 mL Parr high-pressure vessel containing 1,2-dichloroethane (60 mL) was added
diamine 34 (610 mg, 2.03 mmol), W(CO)6 (71.0 mg, .203 mmol), I2 (515 mg, 2.03
mmol), and pyridine (642 mg, 8.12 mmol). The vessel was then charged with 80 bar of
CO and heated at 80°C for 16 h. The pressure was released and 10 mL of CH2Cl2 was
added to further dissolve any crude material. The solution was washed with a saturated
solution of Na2SO3 followed by 0.1M HCl, then dried over MgSO4 and filtered. The
solvent was removed by evaporation and the resulting residue was purified by column
chromatography using mixtures of methanol and methylene chloride as the eluent to
yield 63i (30 mg, 10% yield), 35 (32 mg, 11% yield), and 36 (42 mg, 13%). Urea 63i
was identified by comparison with literature data.120 IR (neat) CO 1662 cm-1. 1H NMR
(CDCl3, CD3OD) δ 7.29 - 7.08 (m, 10H), 3.82 (t, J = 7.6 Hz, 2H), 3.50 (s, 2H), 3.01 -
2.78 (m, 4H). Carbamate 35: IR (neat) CO 1736 cm-1. 1H NMR (CDCl3, CD3OD) δ 7.32
- 7.09 (m, 10H), 4.36 (d, J = 5.6 Hz, 1H), 4.24 (q, J = 6.5 Hz, 1H), 3.82 - 3.72 (m, 1H),
3.44 (br. s., 1H), 3.13 - 2.88 (m, 4H), 2.77 (dd, J = 7.4, 13.6 Hz, 2H). 13C NMR (CDCl3,
CD3OD) δ 159.4, 135.2, 134.5, 129.4, 129.3, 128.9, 127.7, 127.3, 82.5, 67.7, 55.6, 55.3,
40.9, 36.1, HRMS calcd for C19H23N3O2 [M + H]+ 327.1708, found 327.1714.
Carbamate 36 was identified by comparison with literature data.154 1H NMR (CDCl3) δ
96
7.38 - 7.18 (m, 7H), 7.06 (dd, J = 1.9, 7.5 Hz, 4H), 5.80 (s, 2H), 4.04 (q, J = 6.5 Hz, 2H),
3.93 (d, J = 5.3 Hz, 2H), 2.86 (dd, J = 6.7, 13.5 Hz, 2H), 2.70 (dd, J = 7.3, 13.5 Hz, 2H).
65
Dibenzyl ((2R,3S,4S,5R)-3,4-dihydroxyhexane-2,5-diyl)dicarbamate (65).
Preparation of 65 was adapted from a literature procedure.119 A solution of oxalyl
chloride (18.0 mL of 2.0 M solution in CH2Cl2, 0.036 mol) in CH2Cl2 (30 mL) was cooled
to -78ºC, and anhydrous dimethylsulfoxide (3.40 mL, 0.0478 mol) in CH2Cl2 (53 mL)
was added over 20 min while the temperature was kept near -78 ºC. Immediately
thereafter, a solution of N-Z-D-alaninol 64 (5.00 g, 0.0239 mol) in CH2Cl2 (70 mL) was
added over 30 min, followed by stirring at -78 ºC for 40 min. Triethylamine (9.67 g,
0.0956 mol) was added over 15 min, followed by stirring for 2 hr at -78 ºC to ensure
completion of the reaction. After 20% aqueous KHSO4 (50 mL) was added, the reaction
mixture was allowed to warm to room temperature and water (45 mL) was added. The
aqueous phase was separated and washed twice with CH2Cl2 (20 mL). The organic
layers were combined and washed with saturated sodium bicarbonate (50 mL x 2),
water (50 mL x 3), and saturated sodium chloride (50 mL x 2), dried over magnesium
sulfate, filtered, and concentrated in vacuo to afford the resulting aldehyde in
quantitative yield as an oil (4.95 g, 99% yield). The crude aldehyde was used without
further purification to prevent possible racemization. Under an inert atmosphere, Zn
dust (0.937 g, 0.0143 mol) was added to a solution of VCl3(THF)3 (9.83 g, 0.0263 mol)
97
in dry CH2Cl2 (55 mL), resulting in a color change from reddish-brown to green after
stirring for 20-30 min. A solution of the aldehyde (4.95 g, 0.0239 mol) in CH2Cl2 (55 mL)
was added via cannula, causing a color change from green to brown. After being stirred
at room temperature overnight, the reaction was opened to air and poured into 1 M HCl
(125 mL). The two phases were stirred together overnight resulting in a blue aqueous
layer and the precipitated coupling product in the organic layer. Adding CH2Cl2 and
tetrahydrofuran dissolved all solids. The phases were separated and the aqueous
phase was extracted with CH2Cl2 (85 mL). The combined organic layers were washed
with saturated sodium bicarbonate (20 mL) and saturated sodium chloride (20 mL), and
then dried, filtered, and evaporated to yield a white solid. Recrystallization from THF
and hexanes afforded diol 65 (3.92 g, 84% yield). The product was identified by
comparison with literature data.117 1H NMR (DMSO-d6) 7.38 - 7.26 (m, 10H), 6.83 (d,
J = 8.8 Hz, 2H), 5.08 - 4.93 (m, 4H), 4.37 (d, J = 5.7 Hz, 2H), 3.84 - 3.70 (m, 2H), 3.25 -
3.14 (m, 2H), 1.00 (d, J = 6.4 Hz, 6H).
66a
Dibenzyl ((1R,1'R)-((4S,5S)-2,2-dimethyl-1,3-dioxolane-4,5-diyl)bis(ethane-1,1-
diyl))dicarbamate (66a). The procedure was adapted from the literature.155 To a
suspension of diol 65 (1.14 g, 2.74 mmol) in 70 mL CH2Cl2 was added 2,2-
dimethoxypropane (1.99 g, 0.0192 mol) at 0°C. A catalytic amount of (+)-camphor-10-
sulfonic acid (50.0 mg) was added and the mixture was stirred overnight at room
98
temperature. The reaction was then concentrated into a dark oil. Column
chromatography (30% ethyl acetate/hexanes) afforded 66a as a white solid (1.18 g,
94% yield). The product was identified by comparison with literature data.152 1H NMR
(CDCl3) 7.44 - 7.27 (m, 10H), 5.19 - 5.01 (m, 4H), 4.95 (d, J = 9.5 Hz, 2H), 4.00 - 3.82
(m, 2H), 3.61 (s, 2H), 1.35 (s, 6H), 1.22 (d, J = 6.1 Hz, 6H).
66b
Dibenzyl ((2R,3S,4S,5R)-3,4-bis((2-(trimethylsilyl)ethoxy)methoxy)hexane-
2,5-diyl)dicarbamate (66b). The procedure was adapted from the literature.117 To a
suspension of diol 65 (1.58 g, 3.79 mmol) in 65 mL CH2Cl2 was added DIPEA (2.94 g,
0.0228 mol) and cooled to 0 °C. SEM chloride (2.78 g, 0.0167 mol) was then added
dropwise until gas evolution ceased. The mixture was then refluxed overnight. After
cooling to room temperature, cold water was added and the layers separated. The
aqueous layer was extracted with methylene chloride. The organic layers were
combined and washed with water, dried over magnesium sulfate, and concentrated into
a yellow oil. Column chromatography using mixtures of ethyl acetate and hexanes
afforded pure 66b as a pale yellow oil (2.52 g, 98% yield). The product was identified
by comparison with literature data.117 1H NMR (CDCl3) 7.47 - 7.28 (m, 10H), 5.22 -
4.97 (m, 6H), 4.80 - 4.62 (m, 4H), 4.09 - 3.95 (m, 2H), 3.83 - 3.67 (m, 2H), 3.58 - 3.39
(m, 4H), 1.21 (d, J = 6.6 Hz, 6H), 1.01 - 0.84 (m, 4H), 0.01 (s, 18H).
99
68a
General procedure A for the catalytic carbonylation of p-substituted aryl
amines: N,N'-diphenylurea (68a). Aniline 67a (0.46 g, 4.9 mmol) was added to a
glass-lined 300 mL Parr high-pressure vessel with W(CO)6 (0.0527 g, 0.015 mmol, I2
(1.27 g, 5.00 mmol), DMAP (1.22 g, 10.0 mmol) in CH2Cl2 (40mL). The vessel was
charged with 80 atm CO and the reaction was left to stir for 8 h at 40 °C. After that, the
autoclave was cooled, the excess CO gas was released, and the reaction mixture was
filtered and washed with saturated Na2SO3. The resulting solution was then dried with
MgSO4, filtered, and concentrated. The crude residue was purified by flash
chromatography on silica gel using mixtures of ethyl acetate and CH2Cl2 as eluent to
recover 68a in 85 % yield (0.45 g) . The product was identified by comparison with
literature data.156 IR (neat) νCO 1635 cm-1. 1H NMR (DMSO-d6) 8.60 (s, 2H,) 7.40 (d,
J = 8.5 Hz, 2H) 7.22 (t, J = 7.6 Hz, 2H) 6.84 - 6.97 (m, 1H). 13C NMR (DMSO-d6)
153.1, 140.3, 129.4, 122.4, 118.8.
68b
1,3-Bis(4-chlorophenyl)urea (68b). Procedure A afforded urea 68b from 4-
chloroaniline 67b (0.255 g, 2.00 mmol) in 68% yield (0.190 g). The product was
identified by comparison with literature data.157 IR (neat) νCO 1643 cm-1. 1H NMR
(DMSO-d6) 8.81 (s, 2H) 7.45 (d, J = 8.8 Hz, 4H) 7.30 (d, J = 8.8 Hz, 4H). 13C NMR
100
(DMSO-d6) 153.0, 139.2, 129.3, 126.2, 120.5. HRMS calcd for C13H10Cl2N2O [M + H]
+ 281.0243, found [M + H] + 281.0239.
68c
1,3-Bis(4-iodophenyl)urea (68c). Procedure A afforded urea 68c from 4-
iodoaniline 67c (0.219 g, 1.00 mmol) in 76% yield (0.176 g). IR (neat) νCO 1634 cm-1.
1H NMR (300 MHz, DMSO-d6) 8.77 (s, 2H) 7.55 (d, J = 8.5 Hz, 4H) 7.25 (d, J = 8.5
Hz, 4H). 13C NMR (DMSO-d6) 152.8, 140.1, 138.0, 121.2, 85.5. HRMS calcd for
C13H10I2N2O [M + H] + 464.8955, found [M + H] + 464.8947.
68d
1,3-Bis(4-bromophenyl)urea (68d). Procedure A afforded urea 68d from 4-
bromoaniline 67d (0.172 g, 1.00 mmol) in 64% yield (0.120 g). The compound was
identified by comparison with literature data.158 IR (neat) νCO 1644 cm-1. 1H NMR
(DMSO-d6) 8.80 (s, 1H) 7.38 (s, 4H). 13C NMR (DMSO-d6) 152.9, 139.6, 132.2,
120.9, 114.0. HRMS calcd for C13H10Br2N2O [M + H] + 370.9213, found [M + H] +
370.9238.
101
68e
1,3-Bis(4-methoxyphenyl)urea (68e). Procedure A afforded urea 68e from p-
anisidine 67e (0.615 g, 5.00 mmol) in 38% yield (0.260 g). The compound was identified
by comparison with literature data.159 IR (neat) νCO 1631 cm-1. 1H NMR (DMSO-d6)
8.31 (s, 2H) 7.28 (d, J = 9.1 Hz, 4H) 6.80 (d, J = 8.9 Hz, 4H) 3.29 (s, 2H). 13C NMR
(DMSO-d6) 154.9, 153.6, 133.6, 120.5, 115.6, 114.6, 55.8. HRMS calcd for
C15H16N2O3 [M + H] + 273.1234, found [M + H] + 273.1239.
68f
1,3-Bis(4-nitrophenyl)urea (68f). Procedure A afforded urea 68f from p-
nitroaniline 67f (0.691 g, 5.0 mmol) in 84% yield (0.638). The compound was identified
by comparison with literature data.160,161 IR (neat) νCO 1635 cm-1. 1H NMR (300 MHz,
DMSO-d6) 9.58 (br s, 2 H) 7.93 - 8.24 (m, 4 H) 7.30 - 7.79 (m, 4 H). 13C NMR (75
MHz, DMSO-d6) 125.8, 118.6. HRMS calcd for C13H10N4O5 [M + H]+ 301.0578, found
[M + H]+ 301.0579.
68g
1,3-Bis(4-cyanophenyl)urea (68g). Procedure A afforded urea 68g from 4-
aminobenzonitrile 67g (0.295 g, 2.50 mmol) in 48% yield (0.160 g). IR (neat) νCO
102
1643cm-1. 1H NMR (300 MHz, DMSO-d6) = 9.33 (s, 2 H) 7.66 - 7.78 (m, 4 H) 7.59 (d,
J = 8.76 Hz, 4 H). 13C NMR (75 MHz, DMSO-d6) 152.4, 144.3, 134.0, 119.9, 119.0,
104.5. HRMS calcd for C15H10N4O5 [M + H] + 263.0927, found [M + H] + 263.0920.
68h
Diethyl 4,4'-(carbonylbis(azanediyl))dibenzoate (68h). Procedure A afforded
urea 68h from ethyl p-aminobenzoate 67h (0.331 g, 2.00 mmol) in 74% yield (0.263 g).
IR (neat) νCO 1642cm-1. 1H NMR (CDCl3) 7.85 (d, J = 8.6 Hz, 4H) 7.41 (d, J = 8.6 Hz,
4H) 4.23 (t, J = 7.1 Hz, 4H) 3.53 (br s, 2H) 1.27 (t, J = 7.1Hz, 6H). 13C NMR (CDCl3)
170.9, 156.5, 147.5, 134.9, 128.2, 121.8, 65.0, 18.3. HRMS calcd for C19H20N2O5 [M +
H]+ 357.1445, found [M + H]+ 357.1418.
68i
3,4-Dihydroquinazolin-2(1H)-one (68i). Procedure A afforded urea 68i from 2-
aminobenzylamine 67i (0.122 g, 1.00 mmol) in 41% yield (60 mg). The product was
identified by comparison with literature data.162 IR (neat) νCO 1643cm-1. 1H NMR (300
MHz, DMSO-d6) 8.95 (br s, 2H) 6.94 - 7.15 (m, 2H) 6.64 - 6.86 (m, 2H) 4.25 (br s,
2H). HRMS calcd for C8H8N2O [M + H] + 149.0709, found [M + H] + 149.0713.
103
69fg
1-(4-Cyanophenyl)-3-(4-nitrophenyl)urea (69fg). Procedure A afforded urea
69fg from p-nitroaniline 67f (0.138 g, 1.00 mmol) and 4-aminobenzonitrile 67g (0.118g,
1.00 mmol) in 58 % yield (0.150 g). The product was identified by comparison with
literature data.163 IR (neat) νCO 1644 cm-1. 1H NMR (CDCl3) 7.90 (d, J = 9.1 Hz, 2H)
7.32 (d, J = 3.6 Hz, 4H) 7.22 (s, 4H). HRMS calcd for C14H10N4O3 [M + H] + 283.0826,
found [M + H] + 283.0755.
69be
1-(4-Chlorophenyl)-3-(4-methoxyphenyl)urea (69be). Procedure A afforded
urea 69be from 4-chloroaniline 67b (0.255 g, 2.00 mmol) and p-anisidine 67e (0.123 g,
1.00 mmol) in 43% yield (0.118 g). IR (neat) νCO 1633 cm-1. 1H NMR (DMSO-d6) 8.66
(s, 1H) 8.44 (s, 1H) 7.41 (d, J = 8.9 Hz, 4H) 7.16 - 7.34 (m, 4H) 6.81 (d, J = 8.9 Hz, 2H)
3.66 (s, 3H). HRMS calcd C14H13ClN2O2 [M + H] + 277.0738, found [M + H] + 277.0742.
69ne
1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-methoxyphenyl)urea (69ne).
Procedure A produced urea 69ne from p-anisidine 67e (.123 g, 1.00 mmol) and 4-
104
chloro-3-(trifluoromethyl) aniline 67n (.391 g, 2.00 mmol) in 12% yield (0.042 g). IR
(neat) νCO 1627 cm-1. 1H NMR (DMSO-d6) δ 9.04 (s, 1H), 8.61 (s, 1H), 8.04 (s, 1H), 7.64
- 7.48 (m, 2H), 7.31 (d, J = 8.9 Hz, 2H), 6.82 (d, J = 8.9 Hz, 2H), 3.67 (s, 3H). 13C NMR
(DMSO-d6) δ 155.4, 153.2, 140.2, 132.6, 123.5, 121.2, 117.2, 114.6, 55.8, 23.4. HRMS
calcd C15H12ClF3N2O2 [M + H] + 345.0612, found [M + H] + 345.0608.
69bo
1-(4-Chlorophenyl)-3-(4-phenoxyphenyl)urea (69bo). Procedure A afforded
69bo from 4-phenoxyaniline 67o (.185 g, .999 mmol) and 4-chloroaniline 67b (.255 g,
2.00 mmol) in 41% yield (.138 g) by NMR (see Appendix A for mixed spectrum).
69no
1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-phenoxyphenyl)urea (69no).
Procedure A afforded 69no from 4-chloro-3-(trifluoromethyl)aniline 67n (.196 g, 1.00
mmol) and 4-phenoxyaniline 67o (.185 g, 1.00 mmol) in 12% yield (0.050 g). 1H NMR
(DMSO-d6) δ 9.12 (s, 1H), 8.83 (s, 1H), 8.09 (d, J = 2.1 Hz, 1H), 7.71 - 7.53 (m, 2H),
7.46 (d, J = 9.1 Hz, 2H), 7.34 (t, J = 7.9 Hz, 2H), 7.14 - 7.03 (m, 1H), 7.01 - 6.88 (m,
3H). 13C NMR (DMSO-d6) δ 158.2, 153.2, 151.8, 140.1, 135.8, 132.6, 130.6, 123.5,
121.2, 120.4, 118.4.
105
69ap
1-Methyl-1,3-diphenylurea (69ap). Procedure A afforded 69ap from aniline 67a
(0.093 g, 1.00mmol) and N-methylaniline 67p (0.536 g, 5.00mmol) in 31% yield (0.070
g). 1H NMR (CDCl3) δ 7.56 - 7.16 (m, 9H), 7.04 - 6.94 (m, 1H), 6.25 (br. s., 1H), 3.34 (s,
3H).
79
Methyl 2-((3-aminopropyl)amino)acetate hydrochloride (79). The 2-(3-
aminopropylamino)acetic acid hydrochloride 81 (0.639g, 4.84 mmol) was suspended in
anhydrous methanol (55 mL) and hydrogen chloride gas, produced by the dropwise
addition of 37% hydrochloric acid (50 mL) to 60g of anhydrous CaCl2, was bubbled
through the reaction until complete consumption of CaCl2. The reaction mixture was
then refluxed for 3 hours, and the solvent evaporated under reduced pressure after
cooling to room tempreature to give 79 as a white solid (0.756 g, 91% yield). The
product was identified by comparison with literature data.146 1H NMR (D2O) δ 4.05 (s,
2H), 3.82 (s, 3H), 3.23 (t, J = 7.7 Hz, 2H), 3.10 (t, J = 7.8 Hz, 2H), 2.21 - 2.03 (m, 2H).
81
106
2-((3-Aminopropyl)amino)acetic acid hydrochloride (81). Neat
propylenediamine 80 (42.0 g, 0.318 mol) was rapidly stirred while being cooled in an ice
bath (4 °C). Chloroacetic acid (3.00 g, 0.0318 mol) was added portionwise, ensuring for
complete dissolution between each addition. The reaction was then stirred at room
temperature for 48 h. The unreacted propylenediamine was removed by distillation
under reduced pressure. The remaining paste was triturated with DMSO. The
precipitate was collected by filtration and washed with ethanol to give a white solid
which was subsquently dissolved in boiling acetic acid (16 mL) and precipitated with
ethanol (60 mL) with stirring at 0 °C for 2 h. The solids were filtered off, washed three
times with ethanol to give 0.640 g of 81 as a white solid (12 % yield). The product was
identified by comparison with literature data.146 1H NMR (D2O) 3.24 (s., 2H), 2.92 (dt,
J = 6.6, 24.0 Hz, 2H), 2.72 (t, J = 7.0 Hz, 2H), 1.82 (t, J = 6.7 Hz, 2H).
107
APPENDIX A SPECTRA OF SYNTHESIZED COMPOUNDS
1H NMR of (2R, 3S, 4S, 5R)-2,5-Diamino-1,6-diphenyl-3,4-hexanediol (34)
NH2NH2
OHOH
(34)diamine_columnfr33-72_082710.esp
7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0
Chemical Shift (ppm)
0
0.05
0.10
0.15
Norm
alized Inte
nsity
0.780.991.1210.00
TMS
M03(dd)
M04(dd)
M05(dd)
M02(s)
M01(m)
2.7
32.7
42.7
72.9
02.9
2
2.9
63.0
33.0
53.0
63.0
8
3.7
0
7.1
87.2
0
7.2
97.3
2
1H NMR of (2R,3R)-Dimethyl 2,3-bis((2-(trimethylsilyl)ethoxy)methoxy)succinate
(47b)
OO
OO
CH3 CH3
O O
O
Si
O
Si
CH3
CH3
CH3
CH3
CH3
CH3
(47B)AD188_H_CDCL3_CRUDEPROD_71108.ESP
5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0
Chemical Shift (ppm)
0
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
0.45
0.50
Norm
alized Inte
nsity
18.004.394.365.125.76
M06(s)
M03(s)
M04(m)
M02(m)
M05(m)
-0.0
2
0.8
30.8
60.8
90.9
10.9
43.5
23.5
53.5
83.6
1
3.7
4
4.6
9
4.7
54.7
7
108
1H NMR of (4R,5R)-N,N,2,2-Tetramethyl-1,3-dioxolane-4,5-dicarboxamide (59a)
NH NHCH3CH3
OO
CH3 CH3
O O
(59A)AD204_H_CDCL3_CRUDEPROD_9208.ESP
7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0
Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Norm
alized Inte
nsity
5.736.001.941.79
M01(s)
M04(br. s.)
M03(s)
M02(d)
1.4
9
2.8
82.8
9
4.5
1
7.0
6
1H NMR of (4R,5R)-N,N-Dibenzyl-2,2-dimethyl-1,3-dioxolane-4,5-dicarboxamide
(59b)
NH
NH
O
O
CH3
CH3
OO
(59B)CCSTEP2COLUMNPRODUCT1CHCL3.ESP
7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0
Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Norm
alized Inte
nsity
6.004.432.0711.45
M03(s)
M04(m)
M02(d)
M01(s)
1.4
6
4.4
94.5
1
4.6
3
7.2
57.2
67.2
77.3
07.3
27.3
47.3
6
109
1H NMR of (2R,3R)-N,N-Dimethyl-2,3-bis((2
(trimethylsilyl)ethoxy)methoxy)succinamide (59c)
NHNH
OO
CH3 CH3
O O
O
Si
O
Si
CH3
CH3
CH3
CH3
CH3
CH3
(59C)AD169_H_CDCL3_CRUDEPROD_52708.ESP
7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0
Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Norm
alized Inte
nsity
22.435.216.005.256.551.16
M04(d)
M06(s)
M01(d)
M03(m)M02(m)
M05(m)
0.0
1
0.9
00.9
10.9
20.9
30.9
40.9
50.9
8
2.8
52.8
7
3.5
83.5
93.6
03.6
13.6
23.6
54.6
5
4.6
94.7
34.7
54.7
8
6.8
06.8
1
13C NMR of 59c
NHNH
OO
CH3 CH3
O O
O
Si
O
Si
CH3
CH3
CH3
CH3
CH3
CH3
(59C)AD169_C_CDCL3_CRUDEPROD_52708.ESP
168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0
Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Norm
alized Inte
nsity
M07(s)
M02(s)M06(s)
M03(s)
M01(s)
M04(s)M05(s)
-1.1
8
18.3
4
26.2
2
66.9
6
77.2
379.4
5
96.9
7
170.3
2
110
1H NMR of (2R,3R)-N,N-Dibenzyl-2,3-bis((2-
(trimethylsilyl)ethoxy)methoxy)succinamide (59d)
NH
NH O
O
O
O
O
Si
OSi
CH3CH3
CH3
CH3
CH3
CH3
(59D)2CC87TUBES10-15CHCL3.ESP
7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0
Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Norm
alized Inte
nsity
18.004.905.304.945.1315.72
M02(s)
M04(d)
M03(dd)
M07(s)
M05(dt) M06(m)
M01(m)
-0.0
8
0.7
20.7
40.7
50.7
70.7
80.7
90.8
0
3.4
53.4
73.4
83.5
03.5
03.5
3
4.4
44.4
6
4.5
94.6
14.6
34.7
3
7.2
47.2
57.2
77.2
8
1H NMR of (2R, 3R)-1,4-N,N-Dibenzylamino-2,3-dihydroxysuccinamide (59e)
NHNH
O
OOH
OH
(59E)AD108_H_DMSO_RECRYSTPROD_92507.ESP
8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0
Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Norm
alized Inte
nsity
7.042.2411.102.00
M02(d)
M03(m)
M01(m)
M04(t)
0.0
0
2.4
92.5
02.5
1
3.3
53.3
6
4.3
24.3
4
4.3
74.3
7
5.7
25.7
5
7.2
17.2
37.2
47.2
97.3
0
8.2
38.2
58.2
7
111
13CNMR of 59e
NH
NH
OH
OH
OO
(59E)AD108_C_DMSO_RECRYSTPROD_92507.ESP
168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0
Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Norm
alized Inte
nsity
M03(s)
M05(s)
M06(s) M01(s)
M04(m)
M02(s)
41.8
7
72.7
4
126.5
3127.0
4128.0
6
139.4
2
172.0
9
1H NMR of 1,1'-((4S,5S)-2,2-Dimethyl-1,3-dioxolane-4,5-diyl)bis(N-
methylmethanamine) (60a)
NHNH
CH3CH3
O O
CH3 CH3
(60A)AD157_H_CDCL3_CRUDEPROD_41508.ESP
4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0
Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Norm
alized Inte
nsity
6.006.073.361.73
dioxane
M03(m)
M04(m)
M02(s)
M01(s)
1.4
0
2.4
6
2.7
32.7
32.7
42.7
52.7
5
3.8
83.8
93.9
03.9
03.9
13.9
13.9
2
112
1H NMR of N,N'-(((4S,5S)-2,2-Dimethyl-1,3-dioxolane-4,5-diyl)bis(methylene))bis(1-
phenylmethanamine) (60b)
NH NH
OO
CH3 CH3
(60B)AD134_H_CDCL3_COLUMN_123007.ESP
7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0
Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Norm
alized Inte
nsity
6.321.884.004.2810.00
methanolmethylene chloride
M05(m)
M03(dd)
M04(s)
M06(m)
M01(s)
M02(br. s.)
1.3
8
1.6
6
2.7
62.7
62.7
72.7
7
3.7
93.9
33.9
43.9
5
7.2
07.2
27.2
37.2
57.2
87.3
0
1H NMR of (2S,3S)-N,N-Dimethyl-2,3-bis((2-(trimethylsilyl)ethoxy)methoxy)butane-
1,4-diamine (60c)
NH
NH O
O
CH3
CH3
O
Si
OSi
CH3CH3
CH3
CH3
CH3
CH3
(60C)AD190_H_CDCL3_DRIFR87-102_72208.ESP
5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0
Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Norm
alized Inte
nsity
18.004.386.464.374.461.974.40
M05(s)
M07(s)
M01(m)
M02(m)
M03(m)M06(m)
M04(m)
0.0
0
0.9
00.9
20.9
30.9
30.9
5
2.4
2
2.6
82.7
02.7
32.7
42.7
72.7
8
3.5
93.6
03.6
23.6
53.6
63.8
03.8
13.8
3
4.7
14.7
34.7
44.7
6
113
13C NMR of 60c
NH
NH O
O
CH3
CH3
O
Si
OSi
CH3CH3
CH3
CH3
CH3
CH3
(60C)AD190_C_CDCL3_DRIFR87-102_72208.ESP
105 100 95 90 85 80 75 70 65 60 55 50 45 40 35 30 25 20 15 10 5 0 -5
Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Norm
alized Inte
nsity
M02(s)M06(s)
M04(s)
M05(s)
M03(s)
M07(s)
M01(s)
-1.2
3
18.3
4
36.7
3
52.2
065.7
5
78.1
8
95.5
6
1H NMR of (2S,3S)-1,4-Bis(methylamino)butane-2,3-diol (60e)
NH NH
CH3 CH3
OH OH
(60E)AD208_H_CDCL3_CRUDEPROD_9908.ESP
4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0
Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Norm
alized Inte
nsity
6.001.931.721.71
M01(s)
M04(t) M02(dd)M03(dd)
2.4
2
2.6
32.6
42.6
72.6
8
3.0
23.0
33.0
63.0
7
3.8
23.8
33.8
4
114
1H NMR of (2S,3S)-1,4-Bis(benzylamino)butane-2,3-diol (60f)
NH NH
OHOH
(60F)AD419_H_CDCL3_CRUDESOLIDAB_061410.ESP
7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0
Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Norm
alized Inte
nsity
2.901.862.005.769.50
M02(dd)M03(dd)
M01(br. s.)
M04(m)
M05(m)
1.5
42.6
92.7
02.7
32.7
43.0
73.0
83.1
13.1
2
3.7
03.7
53.7
83.8
33.8
4
7.2
17.2
17.2
27.2
47.2
87.3
07.3
17.3
3
1H NMR of (1R,1'R)-1,1'-((4S,5S)-2,2-Dimethyl-1,3-dioxolane-4,5-diyl)diethanamine
(60g)
NH2NH2
O
O
CH3
CH3
CH3
CH3
(60G)AD244_H_CDCL3_CRUDEPROD_1609.ESP
4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0
Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Norm
alized Inte
nsity
6.006.454.452.212.02
M05(d)
M01(d)
M03(br. s.)
M02(s)
M04(quin)
1.0
31.0
5
1.3
4
2.6
4
2.8
22.8
42.8
62.8
72.8
9
3.5
43.5
6
115
1H NMR of (2R,3S,4S,5R)-3,4-Bis((2-(trimethylsilyl)ethoxy)methoxy)hexane-2,5-
diamine (60h)
NH2
NH2
O
O
CH3
CH3O
Si O
Si
SiH3
SiH3SiH3
SiH3
SiH3
SiH3
(60H)AD254_H_CDCL3_FR43-120_013009.ESP
5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0
Chemical Shift (ppm)
0
0.05
0.10
0.15
Norm
alized Inte
nsity
18.004.466.746.432.71
M07(s)
M05(s)
M06(d)
M01(d)M03(d)
M02(ddd)
M04(m)
-0.0
5
0.8
20.8
30.8
40.8
50.8
50.8
60.8
70.8
9
1.2
51.2
7
3.4
93.5
13.5
33.5
43.5
73.6
03.6
4
4.6
14.6
3
4.7
24.7
4
1H NMR of (1R,1'R)-1,1'-((4S,5S)-2,2-Dimethyl-1,3-dioxolane-4,5-diyl)bis(N-
methylethanamine) (60j)
NH NH
OO
CH3CH3
CH3
CH3
CH3CH3
(60J)AD360_H_CDCL3_CRUDE_011210.ESP
4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0
Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Norm
alized Inte
nsity
6.006.145.982.271.96
M03(s)
M01(d)
M04(s)
M02(m)
M05(d)
1.0
11.0
3
1.3
72.3
9
2.5
72.5
92.6
0
3.7
83.8
0
116
13CNMR of 60j
NH NH
OO
CH3CH3
CH3
CH3
CH3CH3
(60J)AD360_C_CDCL3_CRUDE_011210.ESP
115 110 105 100 95 90 85 80 75 70 65 60 55 50 45 40 35 30 25 20 15 10 5 0
Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Norm
alized Inte
nsity
M01(s)
M05(s)
M02(s)
M04(s)
M06(s)
M03(s)
16.3
6
28.3
9
33.9
3
57.3
9
82.5
2
109.2
5
1H NMR of (2R,3S,4S,5R)-N,N-Dimethyl-3,4-bis((2-
(trimethylsilyl)ethoxy)methoxy)hexane-2,5-diamine (60k)
NH
NH
CH3
CH3
O
O
CH3
CH3O
Si
O
Si
CH3
CH3
CH3
CH3
CH3
CH3
(60K)AD363_H_CDCL3_FR47-111_020110.ESP
5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0
Chemical Shift (ppm)
0
0.05
0.10
0.15
0.20
0.25
Norm
alized Inte
nsity
18.004.485.876.272.056.664.19
M04(s)
M01(s)
M03(d)M07(m)
M02(t)
M05(br. s.)
M06(m)
0.0
2
0.9
10.9
40.9
7
1.1
31.1
5
2.4
2
2.8
4
3.5
83.6
03.6
13.6
13.6
43.6
73.6
93.7
03.7
2
4.7
54.7
74.7
84.8
0
117
13C NMR of 60k
NH
NH
CH3
CH3
O
O
CH3
CH3O
Si
O
Si
CH3
CH3
CH3
CH3
CH3
CH3
(60K)AD344_C_CDCL3_CRUDE_111109.ESP
105 100 95 90 85 80 75 70 65 60 55 50 45 40 35 30 25 20 15 10 5 0
Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Norm
alized Inte
nsity
M03(s)
M02(s)
M04(s)
M05(s)
M06(s)M07(s)M08(s)
M01(s)
-1.2
0
16.4
318.3
6
33.9
5
55.4
4
66.1
3
82.8
4
96.8
4
1H NMR of (1R,1'R)-1,1'-((4S,5S)-2,2-Dimethyl-1,3-dioxolane-4,5-diyl)bis(N-methyl-
2-phenylethanamine) (60l)
NH NH
OO
CH3 CH3
CH3 CH3
(60L)AD339_H_CDCL3_FR41-72_102409.ESP
7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0
Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Norm
alized Inte
nsity
6.002.075.875.891.8810.10
M06(s)
M04(s)
M02(s)
M05(br. s.)
M03(m)
M01(m)
1.4
1
2.0
6
2.3
1
2.6
42.6
62.6
92.7
22.7
5
4.0
5
7.1
47.1
7
7.2
77.2
9
118
1H NMR of (2R,3S,4S,5R)-N,N-Dimethyl-1,6-diphenyl-3,4-bis((2-
(trimethylsilyl)ethoxy)methoxy)hexane-2,5-diamine (60m)
NH
NH
OO
CH3
CH3
Si
SiCH3
CH3
CH3 CH3
CH3
CH3
(60M)AD394_H_CDCL3_FR31-37_040810.ESP
7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0
Chemical Shift (ppm)
0
0.05
0.10
0.15
0.20
0.25
0.30
0.35
Norm
alized Inte
nsity
21.654.556.008.493.652.712.3017.17
M08(s)
M10(s)
M09(m)
M04(s)
M03(d)
M02(d)
M05(td)
M07(dd)
M06(m)
M01(m)
-0.0
5
0.7
20.7
20.7
40.7
50.7
50.7
70.7
8
2.6
12.7
43.1
43.1
63.2
13.2
53.2
73.3
03.3
5
3.5
43.5
43.5
73.7
7
4.2
44.2
6
4.3
84.4
0
7.1
67.1
77.2
07.2
27.2
3
7.2
5
13C NMR of 60m
NH
NH
OO
CH3
CH3
Si
SiCH3
CH3
CH3 CH3
CH3
CH3
(60M)AD394_C_CDCL3_FR31-37_040810.ESP
136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0
Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Norm
alized Inte
nsity
M03(s)
M02(s)
M01(s)
M07(s)
M06(s)
M11(s)
M08(s)
M09(s)M12(s)
M10(s)
M05(s)
M13(s)
-1.1
6
18.0
9
31.4
3
34.0
2
53.6
3
56.8
266.6
2
74.8
6
95.1
0
127.1
4129.0
5129.4
0
137.3
7
119
1H NMR of (2S,2'S)-2,2'-Bioxirane (62)
O O
(62)AD205_H_CDCL3_RESIDUE_9508.ESP
3.5 3.0 2.5 2.0 1.5 1.0 0.5 0
Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Norm
alized Inte
nsity
2.002.04
M01(m)
M02(m)
M03(m)
2.7
42.7
52.7
52.7
62.8
32.8
5
2.9
02.9
12.9
12.9
22.9
2
1H NMR of (3aS,8aS)-2,2,5,7-Tetramethyltetrahydro-3aH-[1,3]dioxolo[4,5-
e][1,3]diazepin-6(7H)-one (63a)
N N
OO
CH3 CH3
CH3 CH3
O
(63A)AD162_H_CDCL3_FR27-34_5308.ESP
4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0
Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Norm
alized Inte
nsity
5.956.004.071.93
M01(s)
M02(s)
M04(m)
M03(m)
1.4
5
2.9
1
3.1
83.2
13.2
23.2
53.2
53.2
63.2
9
3.5
73.5
83.5
83.5
83.5
93.5
93.6
13.6
23.6
4
120
13C NMR of 63a
N N
OO
CH3 CH3
CH3 CH3
O
(60a)AD139_C_CDCl3_fr79-84_11108.esp
168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0
Chemical Shift (ppm)
0
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
Norm
alized Inte
nsity
M04(s)
M06(s)
M01(s)M02(s)M03(s)
M05(s)
26.9
1
40.3
0
51.2
3
76.8
077.2
377.6
579.5
5
111.5
4
165.0
3
1H NMR of (3aS,8aS)-5,7-Dibenzyl-2,2-dimethyltetrahydro-3aH-[1,3]dioxolo[4,5-
e][1,3]diazepin-6(7H)-one (63b)
N N
OO
O
CH3 CH3
(63b)AD136_H_CDCl3_drifr22-33_1408.esp
7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0
Chemical Shift (ppm)
0
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
0.45
0.50
0.55
0.60
0.65
0.70
Norm
alized Inte
nsity
6.112.001.933.9510.00
M02(m)
M01(m)
M03(m)
M06(s)
M05(s)
M04(m)
1.3
3
3.1
0
3.1
43.1
53.1
83.3
03.3
13.4
03.4
13.4
23.4
3
4.5
2
7.2
57.2
77.2
87.3
07.3
37.3
47.3
6
121
13C NMR of 63b
N N
OO
O
CH3 CH3
AD136(6c)_C_CDCl3_drifr22-33_1408.esp
160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0
Chemical Shift (ppm)
-0.05
0
0.05
0.10
0.15
0.20
0.25
0.30
0.35
Norm
alized Inte
nsity
M08(s)
M07(s)
M06(s)
M10(s)
M09(s)
M04(s)
M05(s) M02(s)
M03(s)
M01(s)
26.8
1
48.5
7
55.5
1
76.8
177.2
377.6
579.9
0
111.5
2
127.6
2128.6
5128.7
2
138.2
8
165.0
5
1H NMR of (5S,6S)-5,6-Dihydroxy-1,3-dimethyl-1,3-diazepan-2-one (63e)
NN
OHOH
CH3CH3
O
AD210(6b)_H_CDCl3_CD3OD_drifr28-46_92408.esp
5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0
Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Norm
alized Inte
nsity
6.001.711.821.846.80
M01(s)
M04(m)M03(m)
M05(br. s.)
M02(m)
2.7
12.9
22.9
52.9
7
3.0
03.0
53.0
63.1
03.1
03.3
93.4
03.4
03.4
1
3.9
6
122
13C NMR of 63e
N N
OHOH
CH3 CH3
O
AD163(6b)_C_CDCl3_fr24-38_5608.esp
168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8
Chemical Shift (ppm)
-0.1
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Norm
alized Inte
nsity
hexaneshexaneshexanes
M06(s)
M05(s)
M07(s)
M01(s)
39.0
6
53.8
2
72.7
3
166.1
7
1H NMR of (5S,6S)-1,3-Dibenzyl-5,6-dihydroxy-1,3-diazepan-2-one (63f)
N N
OHOH
O
(63f)2CC7ProductCHCL3.esp
7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0
Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Norm
alized Inte
nsity
4.542.004.5911.68
M02(m)
M01(m)
M04(m)
M03(dd)
3.1
03.1
23.1
43.1
93.2
83.2
93.3
04.2
94.3
4
4.5
24.5
7
7.2
57.2
67.2
67.2
97.2
97.3
17.3
37.3
6
123
13C NMR of 63f
N N
OHOH
O2CC7(6d)ProductCHCL3C13.esp
168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8
Chemical Shift (ppm)
0
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
0.45
0.50
Norm
alized Inte
nsity
51.2
2
54.2
8
127.7
8128.7
1128.8
9
138.2
4
165.9
0
1H NMR of (3aS,4R,8R,8aS)-2,2,4,8-tetramethyltetrahydro-3aH-[1,3]dioxolo[4,5-
e][1,3]diazepin-6(7H)-one (63g)
NHNH
O O
CH3 CH3
CH3CH3
O
AD304(6e)_H_CDCl3CD3OD_fr23-27_060209.esp
7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0
Chemical Shift (ppm)
0
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
0.45
0.50
0.55
0.60
0.65
0.70
0.75
Norm
alized Inte
nsity
6.006.291.941.900.44
M01(d)
M03(s)
M02(s)
M05(d)
M04(m)
1.1
81.2
0
1.3
9
3.7
0
3.9
63.9
84.0
0
5.5
15.5
4
124
13C NMR of 63g
NH NH
O O
CH3 CH3
CH3 CH3
O
AD304(6e)_C_CDCl3CD3OD_aqBW_080710.esp
160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8
Chemical Shift (ppm)
0
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
0.45
0.50
0.55
0.60
Norm
alized Inte
nsity
M04(s)M05(s)
M01(s)
M03(s)M06(s)
M02(s)
18.4
5
25.9
3
44.1
4
80.2
7
108.0
2
158.2
1
1H NMR of (4R,5S,6S,7R)-4,7-Dimethyl-5,6-bis((2-(trimethylsilyl)ethoxy)methoxy)-
1,3-diazepan-2-one (63h)
NH NH
OO
CH3CH3
O
O
Si
O
SiCH3
CH3
CH3CH3
CH3
CH3
AD306(6f)_H_CDCl3_fr33-40_061709.esp
5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0
Chemical Shift (ppm)
0
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
0.45
0.50
0.55
Norm
alized Inte
nsity
18.004.586.332.112.352.002.17
M09(s)
M08(d)
M01(d)
M07(s)
M04(s)
M05(dd)
M03(d)
M06(q) M02(dd)
0.0
2
0.9
00.9
30.9
30.9
6
1.2
61.2
8
3.5
33.6
23.6
43.6
53.6
7
3.7
33.7
63.7
8
4.3
6
4.6
94.7
2
4.8
04.8
2
125
13C NMR of 63h
NH NH
OO
CH3CH3
O
O
Si
O
SiCH3
CH3
CH3CH3
CH3
CH3
(63h)AD306_C_CDCl3_fr33-40_061709.esp
168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0
Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Norm
alized Inte
nsity
M06(s)M07(s)
M05(s)
M03(m)
M08(s)
M02(m)
M04(s)
M01(s)
-1.2
8
46.9
2
65.8
6
78.0
6
95.6
8
164.3
5
1H NMR of (4R,5S,6S,7R)-4,7-Dibenzyl-5,6-dihydroxy-1,3-diazepan-2-one (63i)
NHNH
O
OHOH
(63i)AD432_H_CDCl3_CD3OD_dricrude_092210.esp
7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0
Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Norm
alized Inte
nsity
3.711.961.7110.00
M03(s)
M02(t)
M01(m)
M04(m)
2.8
12.8
3
2.8
52.8
82.9
12.9
32.9
52.9
8
3.5
0
3.8
03.8
23.8
5
7.1
47.1
77.2
37.2
5
126
1H NMR of (4R,5S)-5-((1S,2R)-2-amino-1-hydroxy-3-phenylpropyl)-4-
benzyloxazolidin-2-one (35)
NH2
NH
O OHO
(35)AD431_H_CDCl3_CD3OD_rxnsolids_fr120-132_092110.esp
7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0
Chemical Shift (ppm)
0
0.05
0.10
0.15
0.20
0.25
Norm
alized Inte
nsity
1.002.660.600.911.0014.08
M07(br. s.)M02(d)
M03(q)
M04(m)
M06(dd)
M01(m)
M05(m)
2.7
62.7
82.8
12.9
12.9
42.9
83.0
43.0
63.0
93.1
13.4
4
3.7
43.7
53.7
73.8
0
4.2
14.2
34.2
5
4.3
54.3
7
7.1
57.1
67.1
67.1
77.1
87.2
7
7.2
9
1H NMR of (4R,4'R,5S,5'S)-4,4'-dibenzyl-[5,5'-bioxazolidine]-2,2'-dione (36)
NH
OO
NHO
O
(12i)AD423_H_CDCl3_fr38-50_073010.esp
7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0
Chemical Shift (ppm)
-0.05
0
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
0.45
0.50
Norm
alized Inte
nsity
2.061.961.844.007.05
M05(d)
M07(dd)
M06(dd)M03(s)
M02(dd)
M04(q)
M01(m)
2.6
72.6
92.7
12.7
42.8
32.8
52.8
72.8
9
3.9
23.9
4
4.0
34.0
54.0
7
5.8
0
7.0
57.0
57.0
77.0
87.2
67.3
07.3
2
127
1H NMR of Dibenzyl ((2R,3S,4S,5R)-3,4-dihydroxyhexane-2,5-diyl)dicarbamate (65)
NHNH
OO
OH
OHCH3
CH3
O
O
AD207(9a)_H_DMSO_recrystprod_9808.esp
7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0
Chemical Shift (ppm)
0
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
Norm
alized Inte
nsity
6.002.592.302.185.052.0211.59
Water
DMSO
M04(d)
M01(d)
M06(d)M02(m)
M07(m)
M03(m)
M05(m)
0.9
91.0
1
3.1
83.1
93.2
03.2
13.2
2
3.7
43.7
53.7
73.7
83.8
1
4.3
64.3
8
4.9
55.0
05.0
15.0
56.8
26.8
5
7.3
07.3
17.3
27.3
37.3
57.3
67.3
6
1H NMR of Dibenzyl ((1R,1'R)-((4S,5S)-2,2-dimethyl-1,3-dioxolane-4,5-
diyl)bis(ethane-1,1-diyl))dicarbamate (66a)
NH NH
OO
OO
CH3 CH3
CH3CH3
OO
(66a)AD288_H_CDCl3_fr31-46_042409.esp
7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0
Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Norm
alized Inte
nsity
5.061.971.711.659.57
M01(d)
M02(s)
M05(d)
M03(s)
M07(m)
M06(m)
M04(m)
1.2
11.2
3
1.3
5
3.6
1
3.8
83.9
13.9
44.9
34.9
65.0
55.0
95.1
05.1
4
7.3
37.3
37.3
47.3
57.3
6
128
1H NMR of Dibenzyl ((2R,3S,4S,5R)-3,4-bis((2-
(trimethylsilyl)ethoxy)methoxy)hexane-2,5-diyl)dicarbamate(66b)
NHNH
OO
CH3
CH3
O
O
O
O
O
Si
O
Si
CH3
CH3 CH
3
CH3
CH3
CH3
AD252(10b)_H_CDCl3_fr21-42_12109.esp
7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0
Chemical Shift (ppm)
0
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
0.45
0.50
Norm
alized Inte
nsity
18.007.205.955.012.972.535.327.9013.02
M01(s)
M03(d)
M06(m)
M05(m)
M02(m)
M07(m)
M09(m)
M04(m)M08(m)
0.0
1
0.8
60.8
90.9
1
0.9
40.9
61.2
01.2
2
3.4
4
3.5
13.5
23.5
5
3.7
33.7
44.0
14.0
34.0
64.0
7
4.6
74.7
04.7
44.7
65.0
35.0
75.1
15.1
5
7.3
27.3
47.3
67.3
7
129
1H NMR of N,N'-diphenylurea (68a)
NH NH
O
(68a)ZL46_MDSO_30-37_220210.esp
8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0
Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Norm
alized Inte
nsity
2.004.184.041.94
Water
M03(t)
M02(d)
M04(m)
M01(s)
6.8
96.9
16.9
37.2
07.2
27.2
57.3
87.4
1
8.6
0
13C NMR of 68a
NH NH
O
ZL46_MDSO_30-37_carbony_220210
152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0
Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Norm
alized Inte
nsity
M05(s)
M04(s)
M03(s)
M02(s)
M01(s)
118.8
2
122.4
4
129.4
2
140.3
2
153.1
5
130
1H NMR of 1,3-Bis(4-chlorophenyl)urea (68b)
NH NH
OCl Cl
(68b)ZL59_DMSO_beforeworkup_260310.esp
9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5
Chemical Shift (ppm)
0
0.05
0.10
0.15
0.20
0.25
0.30
Norm
alized Inte
nsity
4.004.231.96
DMSO
M03(d)
Water
M02(d)
M01(s)
7.2
87.3
1
7.4
47.4
7
8.8
1
13C NMR of 68b
NH NH
OCl Cl
ZL59_DMSO_beforeworkup_C_260310
152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16
Chemical Shift (ppm)
-0.05
0
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
Norm
alized Inte
nsity
120.5
2
126.1
9
129.3
1
139.2
0
153.0
2
131
1H NMR of 1,3-Bis(4-iodophenyl)urea (68c)
NH NH
OI I
(68c)ZL64_DMSO_beforeworkup_090410.esp
10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0
Chemical Shift (ppm)
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Norm
alized Inte
nsity
DMSO
Water
M02(d)
M03(d)
M01(s)
7.2
37.2
6
7.5
37.5
6
8.7
7
13C NMR of 68c
NH NH
OI I
(68c)ZL64_DMSO_beforeworkup_C_090410.esp
160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0
Chemical Shift (ppm)
-0.05
0
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
0.45
0.50
0.55
Norm
alized Inte
nsity
85.5
3
121.2
0
137.9
7140.0
6
152.8
0
132
1H NMR of 1,3-Bis(4-bromophenyl)urea (68d)
NH NH
OBr Br
(68d)ZL58_DMSO_H_240310.esp
9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5
Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Norm
alized Inte
nsity
M01(s)
M02(m)
7.3
57.3
87.4
2
8.8
0
13C NMR of 68d
NH NH
OBr Br
ZL58_DMSO_C_240310
160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0
Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Norm
alized Inte
nsity
114.0
4
120.9
0
132.1
6
139.5
8
152.8
9
133
1H NMR of 1,3-Bis(4-methoxyphenyl)urea (68e)
NH NH
OO O
CH3 CH3
ZL50_MDSO_31-32_050310
8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0
Chemical Shift (ppm)
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Norm
alized Inte
nsity
M04(s)
M02(d)M03(d)
M01(s)
3.6
5
6.7
86.8
1
7.2
77.3
0
8.3
1
13C NMR of 68e
NH NH
OO O
CH3 CH3
(68e)ZL50_MDSO_31-32_040310_carbony.esp
160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40
Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Norm
alized Inte
nsity
55.8
3
114.6
0
120.5
4
133.5
6
153.5
7154.9
5
134
1H NMR of 1,3-Bis(4-nitrophenyl)urea (68f)
NH NH
ON+
O-
O
N+
O-
O
(68f)ZL51_MDSO_22-36_050310.esp
10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0
Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Norm
alized Inte
nsity
DMSO
Water
M02(m)
M01(br. s.)
M03(m)
7.6
17.6
47.6
4
8.1
18.1
38.1
4
9.5
8
135
1H NMR of 1,3-Bis(4-cyanophenyl)urea (68g)
NH NH
O
NN
ZL53_DMSO_31-33_090310
9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0
Chemical Shift (ppm)
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Norm
alized Inte
nsity
DMSO
M03(d)
M02(m)
Water
M01(s) 7.5
87.6
17.6
97.7
2
9.3
3
13C NMR of 68g
NH NH
O
NN
ZL53_C_MDSO_100310
152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0
Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Norm
alized Inte
nsity
104.5
0
119.0
3119.8
7
133.9
9
144.3
4
152.4
4
136
1H NMR of Diethyl 4,4'-(carbonylbis(azanediyl))dibenzoate (68h)
NH NH
O
O
O CH3
O
OCH3
(68h)ZL60_CD13_48-70_290310.esp
8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0
Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Norm
alized Inte
nsity
M02(d)
M05(t)
M01(d)
M04(q)
1.2
51.2
71.3
0
4.1
94.2
24.2
44.2
6
7.3
97.4
2
7.8
47.8
6
13C NMR of 68h
NH NH
O
O
O CH3
O
OCH3
ZL60_CD13_48-70_Carbony_300310
176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0
Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Norm
alized Inte
nsity
18.3
2
65.0
1
121.8
2
128.2
4
134.8
7
147.5
3
156.5
4
170.9
5
137
1H NMR of 3,4-Dihydroquinazolin-2(1H)-one (68i)
NH
NH
O
(68i)ZL66_DMSO_91_220410.esp
9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0
Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Norm
alized Inte
nsity
Water
M04(br. s.)
M01(br. s.)
M03(m)
M02(m)
4.2
5
6.6
96.7
26.7
56.7
66.7
86.8
1
7.0
27.0
4
8.9
5
1H NMR of 1-(4-Cyanophenyl)-3-(4-nitrophenyl)urea (69fg)
NH NH
NN+
O-
O O
ZL78_DMSO_28-64_310810
9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0
Chemical Shift (ppm)
0.05
0.10
0.15
0.20
0.25
Norm
alized Inte
nsity DMSO
Water
M02(d)
M01(d) M03(dd)
M04(m)
7.6
17.6
27.6
67.6
77.6
97.7
0
8.1
58.1
58.1
88.1
8
9.3
59.4
19.5
89.6
3
138
1H NMR of 1-(4-Chlorophenyl)-3-(4-methoxyphenyl)urea (69be)
NH NH
OCl O
CH3
ZL76_DMSO_18-23_060510
9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0
Chemical Shift (ppm)
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
Norm
alized Inte
nsity
DMSO
Water
M02(s)
M04(m)
M01(s) M05(d)
M03(d)
M06(s)
3.6
6
6.8
06.8
3
7.2
47.2
77.2
8
7.4
07.4
3
8.4
4
8.6
6
1H NMR of 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-methoxyphenyl)urea (69ne)
NH NH
OCl O
CH3F
F
F
AD446_H_DMSO_fr30-48_111910
9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5
Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Norm
alized Inte
nsity
3.001.921.901.860.920.870.84
DMSO
Water
M01(s) M03(s)M02(s)
M05(d)
M07(s)
M06(d)
M04(m)
9.0
4
8.6
1
8.0
4
7.5
6 7.5
6 7.5
5
7.3
27.2
9
6.8
46.8
1
3.6
7
139
13C NMR of 69ne
NH NH
OCl O
CH3F
F
F
AD446_C_DMSO_fr30-48_111910
220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10
Chemical Shift (ppm)
0
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
0.45
0.50
0.55
0.60
0.65
0.70
Norm
alized Inte
nsity
M05(s)
M10(s)
M04(s)
M09(s)M07(s)
M06(s)
M08(s)
M03(s)
M01(s)
M02(s)
155.4
3153.1
9
140.2
2
132.5
7
123.5
2121.2
0
117.2
0114.6
2
55.8
5 23.3
7
1H NMR of 1-(4-Chlorophenyl)-3-(4-phenoxyphenyl)urea (69bo) and 68o
AD447_H_DMSO_fr61-78_111910
9.0 8.5 8.0 7.5 7.0 6.5
Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Norm
alized Inte
nsity
11.052.718.098.141.400.96
M03(s)
M02(s)
M01(s)
M06(m)
M07(t)
M04(dt)
M05(m)
8.7
4
8.6
6
8.6
1
7.4
57.4
3
7.4
27.4
07.4
0
7.3
37.3
17.2
87.2
5
7.0
67.0
37.0
1
6.9
46.9
16.8
9
NH NH
OOO
NH NH
OOCl
140
1H NMR of 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-phenoxyphenyl)urea (69no)
NH NH
OOCl
F
F
F
AD449_H_DMSO_fr33-42_120110
9.5 9.0 8.5 8.0 7.5 7.0 6.5
Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Norm
alized Inte
nsity
3.000.731.431.812.080.960.920.91
M05(d)
M03(d) M06(t)
M01(s)
M07(m)
M02(s)
M08(m)
M04(m)
9.1
2
8.8
3
8.0
98.0
9
7.6
47.6
1
7.5
97.5
6
7.4
8 7.4
5
7.3
77.3
47.3
2
7.1
07.0
77.0
5
6.9
86.9
56.9
3
13C NMR of 69no
NH NH
OOCl
F
F
F
AD449_C_DMSO_fr33-42_120110
220 200 180 160 140 120 100 80 60 40 20 0 -20
Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Norm
alized Inte
nsity
158.2
0
153.1
6151.7
8
140.1
0
135.7
8132.6
5130.6
0
123.6
9123.5
2121.1
5
118.3
9
41.0
440.7
640.4
840.2
039.9
339.6
539.3
7
141
1H NMR of 1-Methyl-1,3-diphenylurea (69ap)
N
CH3
NH
O
AD453_H_CDCl3_fr39-46_120110
8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5
Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Norm
alized Inte
nsity
3.000.820.759.00
ethyl acetate
methylene chloride
M04(s)
M02(m) M03(br. s.)
M01(m)
7.5
17.4
87.4
67.3
97.3
57.2
97.2
77.2
57.2
37.2
0
7.0
1 6.9
86.9
6 6.2
5
3.3
4
1H NMR of Methyl 2-((3-aminopropyl)amino)acetate hydrochloride (79)
O
NH NH2O
CH3
(79)MR29_H1D2O.ESP
5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0
Chemical Shift (ppm)
0
0.005
0.010
0.015
0.020
0.025
0.030
0.035
Norm
alized Inte
nsity
1.821.791.902.922.00
M02(s)
M01(s)
M04(t)
M03(t)
Water
M05(m)
2.0
62.0
92.1
02.1
2
2.1
42.1
42.1
73.0
73.1
0
3.2
03.2
33.2
6
3.8
2
4.0
5
142
1H NMR of 2-((3-Aminopropyl)amino)acetic acid hydrochloride (81)
OH
NH NH2O
(81)MR27_H1D2O.ESP
5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5
Chemical Shift (ppm)
0
0.05
0.10
0.15
0.20
Norm
alized Inte
nsity
1.661.412.001.17
M01(br. s.)
M03(t) M04(t)
Water
M02(dt)
1.8
01.8
21.8
4
2.7
02.7
22.7
52.8
82.9
12.9
42.9
62.9
9
3.2
4
143
APPENDIX B TABLE OF MELTING POINTS
Entry Compound Literature
Melting Point (°C)
Experimental Melting Point
(°C)
1
35
-- 70-74
2
36
-- 159-162
3
59a
132-134149 130-132
4
59b
83-84164 82-84
5
59c
-- 158-159
6
59d
-- 144-145
7
59e
198-200165 197-199
144
Table of Melting Points. Continued
Entry Compound Literature
Melting Point (°C)
Experimental Melting Point
(°C)
8
60f
77-79165 82-85
9
65
-- 170-173
10
68a
236-238166 238.0-238.5
11
68b
302158 295-296
12
68c
>350167 >300
13
68d
295158 293-294
14
68e
240158 233-234
15
68f
299-305160 298-300
16
68g
273168 270-271
145
Table of Melting Points. Continued
Entry Compound Literature
Melting Point (°C)
Experimental Melting Point
(°C)
17
68h
-- 219-220
18
68i
231-233169 222-224
19
69fg
>250163 277-279
20
69be
254170 250-253
21
79
-- 166-168
146
LIST OF REFERENCES
(1) Anderson, M.; Yu, H.; Penaranda, C.; Maddux, B.; Goldfine, I.; Youngren, J.; Guy, R. Journal of Combinatorial Chemistry 2006, 784-790.
(2) Drewe, W.; Nanjunda, R.; Gunaratnam, M.; Beltran, M.; Parkinson, G.; Reszka, A.;
Wilson, W.; Neidle, S. Journal of Medicinal Chemistry 2008, 7751-7767. (3) McCleland, B.; Davis, R.; Palovich, M.; Widdowson, K.; Werner, M.; Burman, M.; Foley,
J.; Schmidt, D.; Sarau, H.; Rogers, M.; Salyers, K.; Gorycki, P.; Roethke, T.; Stelman, G.; Azzarano, L.; Ward, K.; Busch-Petersen, J. Bioorganic & Medicinal Chemistry Letters 2007, 1713-1717.
(4) Chrusciel, R. A.; Strohbach, J. W. Current Topics in Medicinal Chemistry (Sharjah,
United Arab Emirates) 2004, 4, 1097-1114. (5) De Lucca, G. V.; Lam, P. Y. S. Drugs of the Future 1998, 23, 987-994. (6) Dragovich, P. S.; Barker, J. E.; French, J.; Imbacuan, M.; Kalish, V. J.; Kissinger, C. R.;
Knighton, D. R.; Lewis, C. T.; Moomaw, E. W.; Parge, H. E.; Pelletier, L. A. K.; Prins, T. J.; Showalter, R. E.; Tatlock, J. H.; Tucker, K. D.; Villafranca, J. E. Journal of Medicinal Chemistry 1996, 39, 1872-1884.
(7) Semple, G.; Ryder, H.; Rooker, D. P.; Batt, A. R.; Kendrick, D. A.; Szelke, M.; Ohta, M.;
Satoh, M.; Nishida, A.; Akuzawa, S.; Miyata, K. Journal of Medicinal Chemistry 1997, 40, 331-341.
(8) vonGeldern, T. W.; Kester, J. A.; Bal, R.; WuWong, J. R.; Chiou, W.; Dixon, D. B.;
Opgenorth, T. J. Journal of Medicinal Chemistry 1996, 39, 968-981. (9) Kumaran, R.; Ramamurthy, P. Journal of Physical Chemistry B 2006, 23783-23789. (10) Vishnyakova, T. P.; Golubeva, I. A.; Glebova, E. V. Russian Chemical Reviews (English
Translation) 1985, 54, 249-261. (11) Sartori, G.; Maggi, R. In Science of Synthesis; Ley, S. V., Knight, J. G., Eds.; Thieme:
Stuttgart, 2005; Vol. 18, p 665-758. (12) Hegarty, A. F.; Drennan, L. J. In Comprehensive Organic Functional Group
Transformations; Katritzky, A. R., Meth-Cohn, O., Rees, C. W., Eds.; Pergamon: Oxford, 1995; Vol. 6, p 499-526.
(13) Bigi, F.; Maggi, R.; Sartori, G. Green Chemistry 2000, 2, 140-148. (14) Trost, B. M. Angewandte Chemie-International Edition in English 1995, 34, 259-281.
147
(15) Klausener, A.; Jentsch, J.-D. In Applied Homogeneous Catalysis with Organometallic Compounds (2nd Edition); Cornils, B., Herrmann, W. A., Eds.; VCH: Weinheim, 2002; Vol. 1, p 164-182.
(16) Gabriele, B.; Salerno, G.; Costa, M. In Catalytic Carbonylation Reactions; Beller, M.,
Ed.; Springer: Heidelberg, 2006, p 239-272. (17) Li, K. T.; Peng, Y. J. Journal of Catalysis 1993, 143, 631-634. (18) Srivastava, S. C.; Shrimal, A. K.; Srivastava, A. Journal of Organometallic Chemistry
1991, 414, 65-69. (19) Wan, B. S.; Liao, S. J.; Yu, D. R. Applied Catalysis a-General 1999, 183, 81-84. (20) Dombek, B. D.; Angelici, R. J. Journal of Catalysis 1977, 48, 433-435. (21) Liu, C.; Lu, W.; Yan, Y. Chinese Journal of Organic Chemistry 2010, 843-848. (22) Bassoli, A.; Rindone, B.; Tollari, S.; Chioccara, F. Journal of Molecular Catalysis 1990,
60, 41-48. (23) Benedini, F.; Nali, M.; Rindone, B.; Tollari, S.; Cenini, S.; Lamonica, G.; Porta, F.
Journal of Molecular Catalysis 1986, 34, 155-161. (24) Park, J. H.; Kim, E.; Chung, Y. K. Organic Letters 2008, 10, 4719-4721. (25) Enquist, P.-A.; Nilsson, P.; Larhed, M. Abstracts of Papers, 229th ACS National
Meeting, San Diego, CA, United States, March 13-17, 2005 2005, ORGN-107. (26) Hong, F.; Huang, Y.; Chen, H. Journal of Organometallic Chemistry 2004, 689, 3449-
3460. (27) Giannoccaro, P.; Nobile, C. F.; Mastrorilli, P.; Ravasio, N. Journal of Organometallic
Chemistry 1991, 419, 251-258. (28) Hoberg, H.; Fañanás, F. J.; Riegel, H. J. Journal of Organometallic Chemistry 1983,
254, 267-271. (29) Mulla, S. A. R.; Rode, C. V.; Kelkar, A. A.; Gupte, S. P. Journal of Molecular Catalysis
a-Chemical 1997, 122, 103-109. (30) Kondo, T.; Kotachi, S.; Tsuji, Y.; Watanabe, Y.; Mitsudo, T. Organometallics 1997, 16,
2562-2570. (31) Kotachi, S.; Kondo, T.; Watanabe, Y. Catalysis Letters 1993, 19, 339-344.
148
(32) Mulla, S. A. R.; Gupte, S. P.; Chaudhari, R. V. Journal of Molecular Catalysis 1991, 67, L7-L10.
(33) Mulla, S. A. R.; Rode, C. V.; Kelkar, A. A.; Gupte, S. P. Journal of Molecular Catalysis
a-Chemical 1997, 122, 103-109. (34) Liu, G. W.; Hakimifard, M.; Garland, M. Journal of Molecular Catalysis a-Chemical 2001,
168, 33-37. (35) Durand, D.; Lassau, C. Tetrahedron Letters 1969, 2329-30. (36) Park, J.; Yoon, J.; Chung, Y. Advanced Synthesis & Catalysis 2009, 1233-1237. (37) Didgikar, M. R.; Roy, D.; Gupte, S. P.; Joshi, S. S.; Chaudhari, R. V. Industrial &
Engineering Chemistry Research 2010, 49, 1027-1032. (38) Alper, H.; Vasapollo, G.; Hartstock, F. W.; Mlekuz, M.; Smith, D. J. H.; Morris, G. E.
Organometallics 1987, 6, 2391-2393. (39) Chiarotto, I.; Feroci, M. Journal of Organic Chemistry 2003, 68, 7137-7139. (40) Choudary, B. M.; Rao, K. K.; Pirozhkov, S. D.; Lapidus, A. L. Synthetic Communications
1991, 21, 1923-1927. (41) Gabriele, B.; Salerno, G.; Mancuso, R.; Costa, M. Journal of Organic Chemistry 2004,
69, 4741-4750. (42) Imada, Y.; Mitsue, Y.; Ike, K.; Washizuka, K.; Murahashi, S. Bulletin of the Chemical
Society of Japan 1996, 69, 2079-2090. (43) Ozawa, F.; Soyama, H.; Yanagihara, H.; Aoyama, I.; Takino, H.; Izawa, K.; Yamamoto,
T.; Yamamoto, A. Journal of the American Chemical Society. 1985, 107, 3235-45. (44) Ozawa, F.; Sugimoto, T.; Yuasa, Y.; Santra, M.; Yamamoto, T.; Yamamoto, A.
Organometallics 1984, 3, 683-692. (45) Ozawa, F.; Yamamoto, A. Chemistry Letters 1982, 865-868. (46) Shi, F.; Deng, Y. Q.; SiMa, T. L.; Yang, H. Z. Tetrahedron Letters 2001, 42, 2161-2163. (47) Tsuji, J.; Iwamoto, N. Chemical Communications 1966, 380. (48) Ragaini, F.; Gasperini, M.; Cenini, S.; Arnera, L.; Caselli, A.; Macchi, P.; Casati, N.
Chemistry-a European Journal 2009, 15, 8064-8077.
149
(49) Giannoccaro, P.; Dibenedetto, A.; Gargano, M.; Quaranta, E.; Aresta, M. Organometallics 2008, 27, 967-975.
(50) Zheng, S. Z.; Peng, X. G.; Liu, J. M.; Sun, W.; Xia, C. G. Helvetica Chimica Acta 2007,
90, 1471-1476. (51) Giannoccaro, P.; Ferragina, C.; Gargano, M.; Quaranta, E. Applied Catalysis a-General
2010, 375, 78-84. (52) Orito, K.; Miyazawa, M.; Nakamura, T.; Horibata, A.; Ushito, H.; Nagasaki, H.; Yuguchi,
M.; Yamashita, S.; Yamazaki, T.; Tokuda, M. Journal of Organic Chemistry 2006, 71, 5951-5958.
(53) Peng, X.; Li, F.; Hu, X.; Xia, C.; Sandoval, C. A. Chinese Journal of Catalysis 2008, 129,
638-642. (54) Hylton, K.-G. Ph.D. Dissertation, University of Florida, 2004. (55) McCusker, J. E. Ph. D. Dissertation, University of Florida, 1999. (56) McCusker, J. E.; Abboud, K. A.; McElwee-White, L. Organometallics 1997, 16, 3863-
3866. (57) McCusker, J. E.; Grasso, C. A.; Main, A. D.; McElwee-White, L. Organic Letters 1999,
1, 961-964. (58) McCusker, J. E.; Logan, J.; McElwee-White, L. Organometallics 1998, 17, 4037-4041. (59) McCusker, J. E.; Main, A. D.; Johnson, K. S.; Grasso, C. A.; McElwee-White, L. Journal
of Organic Chemistry 2000, 65, 5216-5222. (60) McCusker, J. E.; Qian, F.; McElwee-White, L. Journal of Molecular Catalysis a-
Chemical 2000, 159, 11-17. (61) Díaz, D. J.; Hylton, K. G.; McElwee-White, L. Journal of Organic Chemistry 2006, 71,
734-738. (62) Main, A. D. Ph. D. Dissertation, University of Florida, 2000. (63) Díaz, D. J. Ph.D. Dissertation, University of Florida, 2007. (64) Fukuoka, S.; Chono, M.; Kohno, M. Journal of Organic Chemistry 1984, 49, 1458-1460. (65) Shi, F.; Deng, Y.-Q.; Sima, T.-L.; Gong, C.-K. Gaodeng Xuexiao Huaxue Xuebao 2001,
22, 645-647.
150
(66) Shi, F.; Deng, Y. Q. Journal of Catalysis 2002, 211, 548-551. (67) Angelici, R. J. Journal of Organometallic Chemistry 2008, 693, 847-856. (68) Zhu, B. L.; Angelici, R. J. Journal of the American Chemical Society 2006, 128, 14460-
14461. (69) Pri-Bar, I.; Alper, H. Canadian Journal of Chemistry-Revue Canadienne De Chimie
1990, 68, 1544-1547. (70) Waller, F. J. In Eur. Pat. Appl.; (du Pont de Nemours, E. I., and Co., USA). EP, 1986, p
31 pp. (71) McGhee, W. D.; Riley, D. P.; Christ, M. E.; Christ, K. M. Organometallics 1993, 12,
1429-1433. (72) Hiwatari, K.; Kayaki, Y.; Okita, K.; Ukai, T.; Shimizu, I.; Yamamoto, A. Bulletin of the
Chemical Society of Japan 2004, 77, 2237-2250. (73) Bitsi, G.; Jenner, G. Journal of Organometallic Chemistry 1987, 330, 429-435. (74) Byerley, J. J.; Rempel, G. L.; Takebe, N.; James, B. R. J. Chem. Soc. D. 1971, 1482-3. (75) Jenner, G.; Bitsi, G. Appl. Catal. 1987, 32, 293-304. (76) Süss-Fink, G.; Langenbahn, M.; Jenke, T. Journal of Organometallic Chemistry 1989,
368, 103-109. (77) Tsuji, Y.; Ohsumi, T.; Kondo, T.; Watanabe, Y. Journal of Organometallic Chemistry
1986, 309, 333-344. (78) Sima, T.-L.; Shi, F.; Deng, Y.-Q. Fenzi Cuihua 2001, 15, 435-437. (79) Chiusoli, G. P.; Costa, M.; Gabriele, B.; Salerno, G. Journal of Molecular Catalysis a-
Chemical 1999, 143, 297-310. (80) Peng, X. G.; Li, F. W.; Hu, X. X.; Xia, C. G.; Sandoval, C. A. Chinese Journal of
Catalysis 2008, 29, 638-642. (81) Gabriele, B.; Salerno, G.; Brindisi, D.; Costa, M.; Chiusoli, G. P. Organic Letters 2000,
2, 625-627. (82) Giannoccaro, P. Journal of Organometallic Chemistry 1987, 336, 271-278. (83) Gupte, S. P.; Chaudhari, R. V. Journal of Catalysis 1988, 114, 246-258.
151
(84) Sheludyakov, Y. L.; Golodov, V. A. 1984, 57, 251-253. (85) Alper, H.; Hartstock, F. W. Journal of the Chemical Society-Chemical Communications
1985, 1141-1142. (86) Murahashi, S.; Mitsue, Y.; Ike, K. Journal of the Chemical Society-Chemical
Communications 1987, 125-127. (87) Tam, W. Journal of Organic Chemistry 1986, 51, 2977-2981. (88) Fukuoka, S.; Chono, M.; Kohno, M. Journal of the Chemical Society-Chemical
Communications 1984, 399-400. (89) Kelkar, A. A.; Kolhe, D. S.; Kanagasabapathy, S.; Chaudhari, R. V. Industrial &
Engineering Chemistry Research 1992, 31, 172-176. (90) Gabriele, B.; Mancuso, R.; Salerno, G.; Costa, M. Chemical Communications 2003,
486-487. (91) Welton, T. Chemical Reviews 1999, 99, 2071-2083. (92) Shi, F.; Peng, J.; Deng, Y. Journal of Catalysis 2003, 219, 372-375. (93) Shi, F.; Zhang, Q.; Gu, Y.; Deng, Y. Advanced Synthesis & Catalysis 2005, 347, 225-
230. (94) Yang, H. Z.; Deng, Y. Q.; Shi, F. Journal of Molecular Catalysis a-Chemical 2001, 176,
73-78. (95) Hartstock, F. W.; Herrington, D. G.; McMahon, L. B. Tetrahedron Letters 1994, 35,
8761-8764. (96) Veige, A. S. Polyhedron 2008, 27, 3177-3189. (97) Chen, A. C.; Ren, L.; Decken, A.; Crudden, C. M. Organometallics 2000, 19, 3459-
3461. (98) Zheng, S.; Peng, X.; Liu, J.; Sun, W.; Xia, C. Helvetica Chimica Acta 2007, 1471-1476. (99) Kanagasabapathy, S.; Gupte, S. P.; Chaudhari, R. V. Industrial & Engineering
Chemistry Research 1994, 33, 1-6. (100) Bolzacchini, E.; Meinardi, S.; Orlandi, M.; Rindone, B. Journal of Molecular Catalysis a-
Chemical 1996, 111, 281-287.
152
(101) Orejón, A.; Castellanos, A.; Salagre, P.; Castillón, S.; Claver, C. Can. J. Chem. 2005, 83, 764-768.
(102) Presad, K. V.; Chaudhari, R. V. Journal of Catalysis 1994, 145, 204-215. (103) Giannoccaro, P.; De Giglio, E.; Garganno, M.; Aresta, M.; Ferragina, C. Journal of
Molecular Catalysis A: Chemical 2000, 157, 131-141. (104) Shi, F.; Deng, Y. Q. Chemical Communications 2001, 443-444. (105) Shi, F.; Deng, Y.-Q.; Gong, C.-K.; Sima, T.-L.; Yang, H.-Z. Huaxue Xuebao 2001, 59,
1330-1334. (106) Shi, F.; Zhang, Q.; Ma, Y.; He, Y.; Deng, Y. Journal of the American Chemical Society
2005, 127, 4182-4183. (107) Angelici, R. Journal of Organometallic Chemistry 2008, 847-856. (108) Jetz, W.; Angelici, R. J. Journal of the American Chemical Society 1972, 94, 3799-3802. (109) Dombek, B. D.; Angelici, R. J. Journal of Organometallic Chemistry 1977, 134, 203-217. (110) Davies, S. G.; Mortlock, A. A. Tetrahedron Letters 1991, 32, 4791-4794. (111) Qian, F.; McCusker, J. E.; Zhang, Y.; Main, A. D.; Chlebowski, M.; Kokka, M.; McElwee-
White, L. Journal of Organic Chemistry 2002, 67, 4086-4092. (112) De Lucca, G. V. Journal of Organic Chemistry 1998, 63, 4755-4766. (113) Lam, P. Y. S.; Ru, Y.; Jadhav, P. K.; Aldrich, P. E.; DeLucca, G. V.; Eyermann, C. J.;
Chang, C. H.; Emmett, G.; Holler, E. R.; Daneker, W. F.; Li, L. Z.; Confalone, P. N.; McHugh, R. J.; Han, Q.; Li, R. H.; Markwalder, J. A.; Seitz, S. P.; Sharpe, T. R.; Bacheler, L. T.; Rayner, M. M.; Klabe, R. M.; Shum, L. Y.; Winslow, D. L.; Kornhauser, D. M.; Jackson, D. A.; EricksonViitanen, S.; Hodge, C. N. Journal of Medicinal Chemistry 1996, 39, 3514-3525.
(114) Hylton, K.-G.; Main, A. D.; McElwee-White, L. Journal of Organic Chemistry 2003, 68,
1615-1617. (115) Confalone, P. N.; Waltermire, R. E. In Process Chemistry in the Pharmaceutical
Industry; Gadamasetti, K. G., Ed.; Marcel Dekker: New York, 1999, p 201-219. (116) Lam, P. Y.; Jadhav, P. K.; Eyermann, C. J.; Hodge, C. N.; De Lucca, G. V.; Rodgers, J.
D. In U.S.; (The Du Pont Merck Pharmaceutical Company, USA). US, 1997, p 198 pp., Cont.-in-part of U.S. Ser. No. 47,330, abandoned.
153
(117) Nugiel, D. A.; Jacobs, K.; Worley, T.; Patel, M.; Kaltenbach, R. F.; Meyer, D. T.; Jadhav, P. K.; DeLucca, G. V.; Smyser, T. E.; Klabe, R. M.; Bacheler, L. T.; Rayner, M. M.; Seitz, S. P. Journal of Medicinal Chemistry 1996, 39, 2156-2169.
(118) Rossano, L. T.; Lo, Y. S.; Anzalone, L.; Lee, Y. C.; Meloni, D. J.; Moore, J. R.; Gale, T.
M.; Arnett, J. F. Tetrahedron Letters 1995, 36, 4967-4970. (119) Hodge, C. N.; Aldrich, P. E.; Bacheler, L. T.; Chang, C. H.; Eyermann, C. J.; Garber, S.;
Grubb, M.; Jackson, D. A.; Jadhav, P. K.; Korant, B.; Lam, P. Y. S.; Maurin, M. B.; Meek, J. L.; Otto, M. J.; Rayner, M. M.; Reid, C.; Sharpe, T. R.; Shum, L.; Winslow, D. L.; EricksonViitanen, S. Chemistry & Biology 1996, 3, 301-314.
(120) Pierce, M. E.; Harris, G. D.; Islam, Q.; Radesca, L. A.; Storace, L.; Waltermire, R. E.;
Wat, E.; Jadhav, P. K.; Emmett, G. C. Journal of Organic Chemistry 1996, 61, 444-450. (121) Zhang, Y.; Forinash, K.; Phillips, C. R.; McElwee-White, L. Green Chemistry 2005, 7,
451-455. (122) DeClercq, P. J. Chemical Reviews 1997, 97, 1755-1792. (123) Lam, P. Y. S.; Jadhav, P. K.; Eyermann, C. J.; Hodge, C. N.; Ru, Y.; Bacheler, L. T.;
Meek, J. L.; Otto, M. J.; Rayner, M. M.; Wong, Y. N.; Chang, C. H.; Weber, P. C.; Jackson, D. A.; Sharpe, T. R.; Erickson-Viitanen, S. Science 1994, 263, 380-384.
(124) McReynolds, M. D.; Sprott, K. T.; Hanson, P. R. Organic Letters 2002, 4, 4673-4676. (125) Sprott, K. T.; McReynolds, M. D.; Hanson, P. R. Organic Letters 2001, 3, 3939-3942. (126) Briggs, M. A.; Haines, A. H.; Jones, H. F. Journal of the Chemical Society-Perkin
Transactions 1 1985, 795-798. (127) Levin, J. I.; Turos, E.; Weinreb, S. M. Synthetic Communications 1982, 12, 989-993. (128) Angelovski, G.; Keränen, M. D.; Eilbracht, P. Tetrahedron-Asymmetry 2005, 16, 1919-
1926. (129) Haines, A. H.; Morley, C.; Murrer, B. A. Journal of Medicinal Chemistry 1989, 32, 742-
745. (130) Kempf, D. J.; Sowin, T. J.; Doherty, E. M.; Hannick, S. M.; Codavoci, L.; Henry, R. F.;
Green, B. E.; Spanton, S. G.; Norbeck, D. W. Journal of Organic Chemistry 1992, 57, 5692-5700.
(131) Drewe, W. C.; Nanjunda, R.; Gunaratnam, M.; Beltran, M.; Parkinson, G. N.; Reszka, A.
P.; Wilson, W. D.; Neidle, S. Journal of Medicinal Chemistry 2008, 51, 7751-7767.
154
(132) Tao, Z. F.; Wang, L.; Stewart, K. D.; Chen, Z. H.; Gu, W.; Bui, M. H.; Merta, P.; Zhang, H. Y.; Kovar, P.; Johnson, E.; Park, C.; Judge, R.; Rosenberg, S.; Sowin, T.; Lin, N. H. Journal of Medicinal Chemistry 2007, 50, 1514-1527.
(133) Wilhelm, S.; Carter, C.; Lynch, M.; Lowinger, T.; Dumas, J.; Smith, R. A.; Schwartz, B.;
Simantov, R.; Kelley, S. Nature Reviews Drug Discovery 2006, 5, 835-844. (134) Bekiari, V.; Lianos, P. Chemistry of Materials 2006, 4142-4146. (135) Ferretti, F.; Ragaini, F.; Lariccia, R.; Gallo, E.; Cenini, S. Organometallics 2010, 29,
1465-1471. (136) Leung, M. K.; Lai, J. L.; Lau, K. H.; Yu, H. H.; Hsiao, H. J. Journal of Organic Chemistry
1996, 61, 4175-4179. (137) Pasha, M.; Reddy, M. Synthetic Communications 2009, 2928-2934. (138) Díaz, D. J.; Darko, A. K.; McElwee-White, L. European Journal of Organic Chemistry
2007, 4453-4465. (139) Brown, H. C.; Hamaoka, T.; Ravindra.N Journal of the American Chemical Society
1973, 95, 5786-5788. (140) Lightfoot, A. P.; Twiddle, S. J. R.; Whiting, A. Tetrahedron Letters 2004, 45, 8557-8561. (141) Mastrolorenzo, A.; Rusconi, S.; Scozzafava, A.; Barbaro, G.; Supuran, C. T. Current
Medicinal Chemistry 2007, 14, 2734-2748. (142) Kempf, D. J.; Sham, H. L.; Marsh, K. C.; Flentge, C. A.; Betebenner, D.; Green, B. E.;
McDonald, E.; Vasavanonda, S.; Saldivar, A.; Wideburg, N. E.; Kati, W. M.; Ruiz, L.; Zhao, C.; Fino, L. M.; Patterson, J.; Molla, A.; Plattner, J. J.; Norbeck, D. W. Journal of Medicinal Chemistry 1998, 41, 602-617.
(143) Stoner, E. J.; Cooper, A. J.; Dickman, D. A.; Kolaczkowski, L.; Lallaman, J. E.; Liu, J.
H.; Oliver-Shaffer, P. A.; Patel, K. M.; Paterson, J. B.; Plata, D. J.; Riley, D. A.; Sham, H. L.; Stengel, P. J.; Tien, J. H. J. Organic Process Research & Development 2000, 4, 264-269.
(144) Bertolini, G.; Losa, M.; Feliciotti, L.; Frigerio, M. In PCT Int. Appl.; Clariant Life Science
Molecules: Italy, 2003, p 14. (145) Sham, H. L.; Betebenner, D. A.; Rosenbrook, W.; Herrin, T.; Saldivar, A.; Vasavanonda,
S.; Plattner, J. J.; Norbeck, D. W. Bioorganic & Medicinal Chemistry Letters 2004, 14, 2643-2645.
155
(146) Hyrup, B.; Egholm, M.; Nielsen, P. E.; Wittung, P.; Norden, B.; Buchardt, O. Journal of the American Chemical Society 1994, 116, 7964-7970.
(147) Zhang, S.-q.; Zhang, S.-y. Tetrahedron: Asymmetry 1991, 2, 173-174. (148) Kaltenbach, R. F.; Nugiel, D. A.; Lam, P. Y. S.; Klabe, R. M.; Seitz, S. P. Journal of
Medicinal Chemistry 1998, 41, 5113-5117. (149) Shainyan, B. A.; Nindakova, L. O.; Ustinov, M. V.; Chipanina, N. N.; Sherstyannikova, L.
V. Russian Journal of Organic Chemistry 2002, 38, 1802-1805. (150) Chen, W.; Liu, Y.; Chen, Z. European Journal of Organic Chemistry 2005, 2005, 1665-
1668. (151) Star, A.; Goldberg, I.; Lemcoff, N. G.; Fuchs, B. European Journal of Organic Chemistry
1999, 1999, 2033-2043. (152) Shi, H.; Liu, K.; Leong, W. W. Y.; Yao, S. Q. Bioorganic & Medicinal Chemistry Letters
2009, 19, 3945-3948. (153) Robbins, M. A.; Devine, P. N.; Oh, T. Organic Syntheses 1999, 76, 101. (154) Dondoni, A.; Perrone, D.; Rinaldi, M. Journal of Organic Chemistry 1998, 63, 9252-
9264. (155) Chandrasekhar, S.; Ramachandar, T.; Reddy, M. V. Synthesis 2002, 1867-1870. (156) Capuano, B.; Crosby, I. T.; Lloyd, E. J.; Neve, J. E. Australian Journal of Chemistry
2007, 60, 214-217. (157) Lee, H. G.; Kim, M. J.; Park, S. E.; Kim, J. J.; Kim, B. R.; Lee, S. G.; Yoon, Y. J. Synlett
2009, 2809-2814. (158) Li, Z.; Wang, Z. Y.; Zhu, W.; Xing, Y. L.; Zhao, Y. L. Synthetic Communications 2005,
35, 2325-2331. (159) Mizuno, T.; Mihara, M.; Iwai, T.; Ito, T.; Ishino, Y. Synthesis-Stuttgart 2006, 2825-2830. (160) McGeary, R. R.; Bennett, A. J.; Tran, Q. B.; Prins, J.; Ross, B. P. Tetrahedron 2009, 65,
3990-3997. (161) Sarveswari, S.; Raja, T. K. Indian Journal of Chemistry Section B-Organic Chemistry
Including Medicinal Chemistry 2006, 45, 546-547. (162) Paz, J.; Perez-Balado, C.; Iglesias, B.; Munoz, L. Journal of Organic Chemistry 2010,
75, 3037-3046.
156
(163) Reddy, L. S.; Chandran, S. K.; George, S.; Babu, N. J.; Nangia, A. Crystal Growth &
Design 2007, 7, 2675-2690. (164) Choi, H. J.; Kwak, M. O.; Song, H. Synthetic Communications 1997, 27, 1273-1280. (165) Pecanha, E. P.; Figueiredo, L. J. O.; Brindeiro, R. M.; Tanuri, A.; Calazans, A.; Antunes,
O. A. C. Il Farmaco 2003, 58, 149-157. (166) Kurzer, F.; Sanderson, P. M. Journal of the Chemical Society 1962, 230-236. (167) Chattaway, F. D.; Constable, A. B. Journal of the Chemical Society 1914, 105, 124-131. (168) Bogert, M. T.; Wise, L. E. Journal of the American Chemical Society 1912, 34, 693-702. (169) Thanigaimalai, P.; Sharma, V. K.; Lee, K. C.; Yun, C. Y.; Kim, Y.; Jung, S. H. Bioorganic
& Medicinal Chemistry Letters 2010, 20, 4771-4773. (170) Fahmy, A. F. M.; Aly, N. F.; Arief, M. H. Indian Journal of Chemistry Section B-Organic
Chemistry Including Medicinal Chemistry 1978, 16, 697-701.
157
BIOGRAPHICAL SKETCH
Ampofo Darko was born in Accra, Ghana, in 1982 to Eva Tagoe-Darko and
Charles Darko. After receiving his Bachelor of Science in chemistry from Guilford
College in 2004, he worked as a research assistant in the pharmaceutical industry for a
year. Wanting to learn more about his craft of choice, Ampofo then enrolled in graduate
school at the University of Florida. Under the guidance of Professor Lisa McElwee-
White, he worked with extending the scope of of tungsten-catalyzed carbonylation
reactions to include a variety of functionalized substrates. For his efforts, Ampofo has
been the recipient of the M. A. Battiste Award for Creative Work in Synthetic Organic
Chemistry and an American Chemical Society Division of Organic Chemistry travel
award for the 238th American Chemical Society National Meeting and Exposition.
Ampofo received his Ph.D from the University of Florida in December 2010, after which
he was appointed as a postdoctoral fellow at the University of Delaware under the
direction of Professor Joseph Fox.
