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DIASTEREOSELECTIVITY AND REACTIVITY
OF OXOKETENE AND IMIDOYLKETENE:
INVESTIGATING THE PSEUDOPERICYCLIC
REACTION MECHANISM
by
WILLIAM WALTER SHUMWAY, B.S.
A DISSERTATION
IN
CHEMISTRY
Submitted to the Graduate Faculty of Texas Tech University m
Partial Fulfillment of the Requirements for
the Degree of
DOCTOR OF PHILOSOPHY
Approved
May, 2001
ACKNOWLEDGMENTS
I wish to recognize the most important acknowledgment for this work, God the
creator, from whom all things come, in whom all things are possible, and without whom
this work would not have been possible.
I want to give special recognition to my mentor. Dr. David M. Bimey. His
guidance and counsel has been invaluable, and his patience laudable. I would also like to
recognize my committee members. Dr. Allen D. Headley and Dr. Bruce Whitelsey. I
would also Hke to thank Dr. Richard A. Bartsch who served on my committee for three
years.
I would also like to recognize and thank the Robert A. Welch foundation for their
financial support of the work in this project and the Leo Adler foundation for their
financial support of my education.
I also wish to thank the following people who have provided help and made
contributions to this work; Dr. Bart Neff, Dr. Sihun Ham, Mr. David Purkiss, Robert
Valentine, Jessica Moer, and Chun Jhou. And finally, I thank friends and family members
too numerous to mention for their support over these past years.
TABLE OF CONTENTS
ACKNOWLEDGEMENTS ii
LIST OF TABLES iv
LISTS OF FIGURES v
ABBREVIATIONS USED vi
CHAPTER
1. INTRODUCTION 1
2. SURVEY OF KETENE RESEARCH 6
3. DIASTEREOSELECTIVITY IN CYCLOADDITIONS OF ACETYLKETENE; EVIDENCE FOR A CONCERTED PATHWAY. 24
4. REINVESTIGATION OF THE REACTIONS OF CAMPHORKETENE; EVIDENCE FOR A PSEUDOPERICYCLIC PATHWAY. 40
5. DIASTERIOSELECTIVITY IN TRAPPING a-OXOKETENE; EFFECTS OF POSITION OF CHIRALITY, SOLVENT, AND TEMPERATURE. 47
6. EFFORTS TOWARDS THE PRODUCTION OF IMIDOYLKETENE AND THE STUDY OF ITS
REACTIVITY 67
7. CONCLUSIONS 81
8. FUTURE RESEARCH AIMS 84
9. EXPERIMENTAL 89
REFERENCES 122
APPENDIX 127
ui
LIST OF TABLES
I. 3.1 Reaction conditions and resuhs of Scheme 3.3. 28
2 3.2 Reaction conditions and results of Scheme 3.4. 30
3. 3.3 Reaction conditions and results of Scheme 3.6. 31
4. 4.1 Reaction conditions and results of scheme 4.2 44
5. 5.1 Results of trapping studies. 56
6. 5.2 "A Values" for substituents of compounds 34a and 70. 65
7. Al Crystal data and structure refinement for 55. 130
8. A2 Atomic coordinates [ x IC*] and equivalent isotropic
displacement parameters [A x 10 ] for 55. 132
9. A3 Bond lengths [A] and angles [°] for 55. 134
10. A4 Anisotropic displacement parameters [A^x 10 ] for 55. 136
II . A5 Hydrogen coordinates [ x iC*] and isotropic displacement parameters [A x 10 ] for 55. 138
12, A6 Optimized Cartesian coordinates (B3LYP/6-31G**) of 60 and 61. 140
IV
LIST OF FIGURES
1. 1.1 General structures of ketene (5), a-oxoketene (3) and a-imidoylketene (4). 5
2. 2.1 Frontier molecular orbitals of ketene. 8
3 2.2 Comparison of pericyclic and pseudopericyclic orbital interactions. 18
4. 3.1 Chiral trapping reaction of Sato et al. 26
5. 3.2 Possible transition states in the reaction of acetylketene. 34
6. 3.3 Stepwise reaction mechanism for acetylketene with dieneophiles. 35
7. 3.4 Diels-AIder reaction mechanism transition states. 36
8. 3.5 PseudopericycHc reaction mechanism transition states. 37
9. 3.6 Proposed eight centered transiton state leading to 41. 39
10. 4.1 Geometry optimization of a-oxoketene models. 45
11. 5.1 Molecules used in trappmg reactions shown in table 5.1 56
12. 5.2 Stepwise intermediates in the reactions of 72, 74 and 76 with 63. 60
13. 5.3 FeUdn-Anh models of the effects of electronegativity on selectivity. 62
14. 5.4 Felkin-Anh models with a small electronegative group. 64
15. 8.1 Test compounds Avith known non-chelation selectivity. 85
16. 8.2 Test compounds for selectivity for small electronegative groups. 85
17. 8.3 Test compounds for selectivity with electropositive groups. 86
18. 8.4 Imine trapping molecules for torquoselectivity study. 86
19. Al X-ray structure of minor diastereomer 34b. 128
20. A2 X-ray structure of camphorketene dimer 56. 129
21. A3 Proton NMR of 55, 141
22 A4 Proton NMR expansion of 55. 142
23. A5 Proton NMR expansion two of 55. 143
24. A6 Carbon NMR of 55. 144
25. A7 DeptNMRofSS. 145
26. A8 Proton NMR of 56. 146
27. A9 Proton NMR of 57. 147
28. AIO Carbon NMR of 57. 148
29. All Dept NMR of 57. 149
30. A12 Gradient HMQC of 57. 150
31. Al3 Proton NMR of 58. 151
32. Al 4 Carbon NMR of 58. 152
33.A15 Gradient HMQC of 58. 153
34. A16 Dept NMR of 58. 154
35. Al7 Proton NMR of 59. 155
36. AI8 Carbon NMR of 59. 156
37. AI9 Proton NMR of 70. 157
38. A20 Proton NMR of diasteriomers 71. 158
39. A2I Proton NMR of 72. 159
40. A22 Proton NMR of diastereomers 73. 160
4I.A23 CarbonNMRofdiastereomer I of73. 161
42. A24 Carbon NMR of diastereomer 2 of 73. 162
vi
43. A25 Proton NMR of 74 163
44. A26 Carbon NMR of 74. 164
45. A27 Proton NMR of diastereomer I of 75. 165
46. A28 Proton NMR of diastereomers of 75. 166
47. A29 Carbon NMR of diastereomer 1 of 75. 167
48. A30 Proton NMR of diastereomers of 76. 168
49. A31 Carbon NMR of diastereomers of 76. 169
50. A32 Proton NMR of diastereomer 1 of 77. 170
51. A33 Carbon NMR of diastereomer 1 of 77. 171
52. A34 Proton NMR of diastereomer 2 of 77. 172
53. A3 5 Carbon NMR of diastereomer 2 of 77. 173
54. A36 Proton NMR of diastereomer 3 of 77. 174
5 5. A3 7 Carbon NMR of diastereomer 3 of 77. 175
56. A3 8 Proton NMR of diastereomer 4 of 77. 176
57. A39 Carbon NMR of diastereomer 4 of 77. 177
58. A40 Proton NMR of 94. 1'78
59. A41 Carbon NMR of 94. l'^^
60. A42 IR spectra of 94. 1^^
6I.A43 Proton NMR of 96. ^^^
62. A44 Carbon NMR of 96. ^ ^
63. A45 Proton NMR of 110. 1^^
64. A46 Proton NMR of 112.
vii
184
65. A47 IR spectra of 112. 185
vm
ABBREVIATIONS USED
A:
Ac:
Bn:
t-Bu:
C:
cal:
CAN:
D:
de:
DDQ:
DMSO:
Et:
FVT:
HOMO:
HPLC:
Hz:
IR:
K:
L:
LDA:
LUMO:
Angstrom
Acetate
Benzyl
Tertiary butyl
Celcius
Calorie
Ceric Anmionium Nitriate
Dextrarotatory
Diastereomeric excess
2,3-DichIoro-5,6-dicyano-1,4-benzoquinone
Dimethylsulfoxide
Ethyl
Flash Vacuum Thermolysis
Highest Occupied Molecular Orbital
High Performance Liquid Chromatography
Hertz
Infi-a Red Spectroscopy
Kelvin
Leverotatory
Lithium Diisopropyl Amide
Lowest Unoccupied Molecular Orbital
IX
Me:
NMR:
Nu:
Ph:
/•-pr:
THF:
TLC:
UV:
Methyl
Nuclear Magnetic Resonance
Nucleophile
Phenyl
Isopropyl
Tetrahydruafuran
Thin Layer Chromatography
Ultra Violet Spectroscopy
CHAPTER 1
INTRODUCTION
The reactions of organic chemistry can be divided into three broad mechanistic
categories; ionic, radical, and pericycHc. The main features of ionic and radical reactions
were relatively weU understood by the 1950's but pericyclic reactions were stiU a
mystery. Some specific examples such as the Diels-Alder reactions were known, but the
rationale for these reactions was not understood. The mystery of pericyclic reactions went
far enough for Doering to proclaim them to be the 'No mechanism reactions.' But in the
late 1960's the theoretical foundations that were later to be caUed the Woodward-
Hoffinarm rules were laid and finally gave chemists an understandmg of pericycHc
reactions. With the advent of these rules pericyclic reactions were no longer mysterious.
They became predictable, testable, and gained a whole new level of synthetic use.
The boon to the field of organic chemistry can hardly be underestimated.
PericycHc reactions are widely used m organic chemistry because of their predictabiHty.
Whole chapters of text books are dedicated to the theory and use of pericycHc reactions.
One need only browse current Hterature to find numerous examples of such reactions.
Understanding pericycHc reactions has lead to impressive work both in synthetic
application and also in theoretical aspects of organic chemistry.
PericycHc reactions are characterized by two features. First, the reactions are
concerted rather than happening in a stepwise fashion. AU electrons involved in bond
breaking and bond formation move simultaneously. Second, that the transition states of
these reactions are cycHc and conjugated, taking place around a closed loop of interacting
orbitals. These reactions tend to have characteristic features which include very high
stereospecificy and large negative entropies of activation. Further, pericycHc reactions are
often not affected by solvent.
But none of these features give predictive value to which pericyclic reactions are
"aUowed" and which are "forbidden." Woodward and Hoffinann put forth the theory of
conservation of orbital symmetry. They explained that a pericycHc reaction was allowed if
the symmetry of the orbitals of the starting material was conserved within the products.
The analysis of orbital symmetry quickly led to rules for the various pericycHc reactions.
Examples of the rules foUow.
For suprafacial cycloadditions, it was determined that a ground state pericycHc
reaction is symmetry allowed when the total number of (4q+2) and (4r) components is
odd, where q and r are integers representing the pi electrons within a given reaction. In
the reaction of a diene with a dienophile the diene contains 4 pi electrons making r = I and
the dienophile contams 2 pi electrons making q = 0. R + q = l which is odd and therefore
the reaction is aUowed. In the case of two dienes, r = 2 and therefore the reaction is
forbidden.
Likewise for sigmatropic rearrangements, rules were quickly developed that
predicted that suprafacial hydrogen shifts would be symmetry allowed for molecules
containing an even number of conjugated pi bonds and symmetry forbidden for odd
numbers of conjugated pi bonds. The [1,5] shift is allowed because it contains two
conjugated double bonds while the [1,3] shift is forbidden because it contains one double
bond.
The rules put forth by Woodward and Hofl&nann work very well for hydrocarbons
but begin to fail when heteroatoms are introduced into the reaction system. Reactions
became more complex and less predictable with the introduction of heteroatoms. Hence
research into pericycHc reactions involving heteroatoms has been slow with much work
yet to be done to produce theories that explain heteroatom behavior.*
In 1976, Lemal et al. made some interesting spectral observations of
perfluoroteteramethyl(Dewerthiophene) 1 shown in Scheme I.l. By NMR, at
temperatures as low as -100 °C, the four perfluoromethyl groups appeared as a single
signal consistent with structure 2. At temperatures below -I00°C, the signal spHt into two
signals consistent with 1. This data led them to beHeve a rapid exchange between the
sulfoxide moiety and the rest of the molecule was taking place in a degenerate
rearrangement.
3 F3C CF3 F a C ^ ^ ^ C F a FsCy^ ^ C F \ ^ _ _ P 3 C ^ C P 3 ^
1 1 2
Scheme 1.1
These observations were rationaUzed as a symmetry forbidden [1,3] sigmatropic
rearrangement. Lemal et al. proposed that the lone pan- of electrons on the sulflir would
initiate the new bond formation and that the breaking bond of the sulflir would then
become the new lone pair of electrons.' This mechanism required an orbital disconnection
not seen in other pericycHc reactions and led them to propose a new type of reaction
mechanism; the pseudopericyclic reaction mechanism. They describe a pseudopericycHc
reaction as a "concerted transformation whose primary changes in bonding compass a
cycHc array of atoms, at one (or more) of which nonbonding and bonding atomic orbitals
interchange roles" (p.4327). However the most stunning prediction of this new reaction
mechanism was that "pseudopericycHc reactions caimot be orbital symmetry
forbidden"(p.4327).' This meant that the familiar rules of Woodward and Hoffinaim could
not be appHed to predict the reaction outcome.
It would be incorrect to describe all pericycHc reactions containing heteroatoms as
pseudopericycHc. But heteroatoms provide the orbital topology that makes
pseudopericycHc reactions possible. Pseudopericyclic reactions should at least be a special
subset of pericycHc reactions; recognizable and governed by their own set of rules.
But why study pseudopericyclic reactions? The answer Hes in the value of the
predictabiHty of pericyclic reactions and the chemical variabiHty inherent in the use of
heteroatoms. UntU rules were estabHshed for pericycHc reactions they were merely a
coUection of know reactions. After the advent of Woodward and Hoffinarm, pericyclic
reactions became powerful tools in synthetic chemistry.
Much of organic synthesis attempts to mimic natural products. Nature is replete
with the use of heteroatoms which provide changes in electronic and structural properties
compared to simple hydrocarbons. Therefore there is the need to explore
pseudopericycHc reactions to determine the rules that govern their fiinction and give rise
to testable predictions in pseudopericyclic reactions. If such rules can be determined the
synthetic community can make effective use of the variety afforded in pseudopericycHc
reactions.
Our lab has focused on making predictions of the properties and outcome of
pseudopericycHc reactions based on ab inito calculations. ' ' Our lab has made three
general predictions regarding pseudopericyclic reactions based on calculations. First, that
pseudopericycHc cycloadditions of a-oxoketenes are have planar transition states. Second
that pseudopericyclic reactions that are favorable have low activation barriers. Third, that
because of the orbital disconnection of pseudopericycHc reactions, no such reaction can be
forbidden. The work reported in this dissertation in particular has attempted to test and
demonstrate experimentally the predictions put forth regarding pseudopericycHc reactions,
particularly the first prediction regarding planar transition states. The work on this project
has focused on a-oxoketene (3) and a-imidoylketene (4), shown in Figure 1.1, as reactive
intermediates that participate m pseudopericycHc reactions. We have used these species
primarily to probe the transition state structure, selectivity, and reactivity as it relates to
pseudopericycHc reactions.
«Y^ ^K. -J^v R"
R'^'"^© R ' ^ ' ^ N ' ' R" 'R'
Figure 1.1 General structures of ketene (5), a-oxoketene (3) and a-imidoyUcetene (4).
CHAPTER 2
SURVEY OF KETENE RESEARCH
2.1 Introduction
Like many great discoveries, the first ketene was initially prepared and
subsequently characterized by accident. In 1905 Hermarm Staudinger attempted to
prepare a stable diradical by treatment of 6 with Zn as shown in Scheme 3.1, and instead
produced diphenyl ketene (5a, R = R' = Ph).* Later this method was generalized to
produce ketenes firom acid chlorides by treatment with triethylamine.' Ketene displays
many interesting chemical properties including both nucleophilic and electrophilic
properties and a propensity to participate m [2+2] cycloadditions. Ketene was quickly
recognized for its chemical utility in the production of more complex molecules, and
therefore became a popular topic of research. To this day ketene stiU commands a great
deal of research interest both for its reactivity and mechanistic concerns.
CI
6 CI
CI
Ph
Ph
R
R
Zn ^
E t , N ^
1
Ph-^/^Ph 5a
0
R - ^ R
5
Scheme 2.1
The focus of this work is aimed primarily at two classes of ketenes; a-oxoketenes
(3) and a-imidoylketene (4). Both of these heteroatom conjugated ketenes display some
properties that are similar to that of ketene but they also display physical properties and
reactivities that are highly divergent fi-om simple ketene.
2.2 Ketene History
Ketene has been extensively studied and many reviews'"'*' have been written on its
characteristics and reactivity. However this forum requhes an overview of the properties
of ketene in order to adequately compare and contrast the parent ketene molecule to a-
oxoketenes and a-imidoylketenes.
2.2.1 Structure, bonding, and electronic properties of ketene
Structurally, ketene is a planar molecule. The orbital topology of ketene is its
most distinguishing feature. ' The ketene HOMO orbital resides above and below the
plane of the molecule and shows high electron density around the P-carbon of the ketene
and low electron density around the ketene a-carbon as shown in Figure 2.1. Conversely
the ketene LUMO is perpendicular to the plane of the molecule as shown in Figure 2.1.
This orbital topology places substantial negative charge on the ketene oxygen and
3-carbon with positive charge on the ketene a-carbon.'^ This gives the ketene both
nucIeophiHc and electrophiHc properties.
o oO
Ketene Homo Ketene Lumo
Figure 2.1 Frontier molecular orbhals of ketene. '
2.2.2 Synthesis of ketenes
Ketene can be prepared fi^om a variety of sources and processes'' including
chemical,' thermal,' and photochemical processes.'"* See Scheme 3.1 for the original
preparation of ketene.
Ketene dimers can often be used to produce ketene monomers thermally. This is
especially true in the case of the parent ketene (5b, R= H) which is readily produced from
diketene" (8) as seen in Scheme 2.2. The temperatures used in the production of ketenes
by this method are often very high because formally this is a forbidden retro [2+2]
cycloaddition. The high temperatures often lead to many side products and low yields
making this an undesirable method of ketene production"
^ 550^ J y^^o . ^ H
8 5b
Scheme 2.2
One of the most predominant methods of ketene production is from diazoketones.
Diazoketones such as 9 can react thermaUy, photochemically, and even catalytically'^"to
produce keto carbenes. These compounds then undergo Wolff rearrangements to produce
ketene as seen in Scheme 2.3.
R
R
Scheme 2.3
Diazo compounds have proven to be very versatile. They work equally well with
both open cham and cycHc compounds.'* There is adequate precedent for group
migratory aptitude to lead to predictable ketene products.'*
These methods are by no means comprehensive. Many additional methods have
been employed to produce ketenes and can be found in reviews on ketene.'"'"
2.2.3 Reactivity of ketenes
Owing to their unusual structural and electronic properties, ketenes participate in a
wide variety of reactions mcluding reactions with nucleophiles and electrophiles,
electrocycHzations, and fi^ee radical reactions.
2.2.3.1 Reactions of ketenes with nucleophiles and electrophiles
Nucleophiles react with the positively charged a-carbon of ketene to form addition
products. The final product depends on the form of the nucleophile. Incoming
nucleophiles would be expected to interact with the ketene LUMO perpendicular to the
plane of the molecule. NucleophUes of the form NuH tend to result in addition of
hydrogen to the ketone oxygen of the ketene. Keto-enol tautomerization follows forming
carboxylic acid derivatives 10 as seen in Scheme 2.4.'^ Conversely, nucleophiles of the
form NuX tend to produce substituted enol ester derivatives 11.'^'^" The 3-carbon of
ketene, being partially negatively charged, can undergo electophillic attack by strong
electrophiles. '
R R
5
NuH,
NuX
H p-H
Nu
Nu
R 10
R Nu 11
Scheme 2.4
2.2.3.2 Cycloadditions of ketenes
Cycloaddition reactions of ketenes remain one of the most interesting and usefiil
reactions of ketenes. It is a powerfiil method to generate four membered ring systems
including the formation of P-lactams of use in pharmaceutical chemistry. Ketenes
participate in [2+2] reactions with a wide variety of dienophiles."'^' Ketenes often
undergo dimerization by a [2+2] mechanism. Mechanistically, dienophiles approach
perpendicularly to the ketene as seen in Scheme 2.5.
The concertedness of this reaction is still in question and has been argued to be
synchronous by some ^ and stepwise by others.^ Perhaps the most stunning and useful
feature of the [2+2] additions to ketenes is the degree of stereoselectity. When
considering an unsymmetrical ketene with R groups of differing steric bulk, the largest
10
group prefers the more hindered endo position in the final product^'' as seen in Scheme
2.5.
•o Or^o r s
L = Sterically larger group S = Sterically small group
Scheme 2.5
Conjugated ketenes such as vinyl ketene 12 will also participate in [4+2] hetero
Diels-Alder reactions with dienophiles to produce the familiar six membered ring
products^' as seen in Scheme 2.6. Interestingly when the roles are reversed and ketene is
reacted with dienes it does not act as a dienophile. Instead, it prefers to react via the
[2+2] pathway.^"-^'
O
R ^ 12
O
R R 5
Scheme 2.6
R
/
2.3 a-Oxoketenes
a-Oxoketenes are highly reactive derivatives of ketene. They have long been
impHcated as intermediates in reactions but the reactive conformation, which wiU be
II
discussed below, was not observed directly until 1989. * a-Oxoketenes are often
observed directly only by matrix trapping and react quickly upon warming of the matrix."
2.3.1 Generation of a-oxoketenes
Like simple ketenes, a-oxoketenes can be generated from a variety of
sources. ' ' ' Generally, an a-oxoketene is derived from one of six general methods
shown in Scheme 2.7. Thermolysis or photolysis of 2-diazo-l,3-dicarbonyl compounds
(13) to produce a carbene that is foUowed by Wolff rearrangement is a widely used and
clean method for a-oxoketene production. The subsequent chemistry in many cases is
identical to ketene chemistry. Furan-2,3-diones (14) can also be employed to cleanly
produce 3 in the same manner as diazo compounds. A versatile method for producing 3 is
the thermolysis or photolysis of 1,3-dioxinones (15). However, this method requires a
trapping agent that is more reactive that the resultant carbonyl byproduct of 1,3-dioxinone
fragmentation. Similarly P-keto esters (16) are often readily available and can easily
produce 3 upon heating, but require trapping agents more reactive that the alcohol that is
eliminated from the P-keto ester. Meldrum's acid derivatives (17) can be easily modified,
but limit R group manipulation of the a-oxoketene produced. Just as ketene can be
prepared by the treatment of acid chlorides with base so too can treatment of the
appropriate P-ketoacid chloride (18) with base produce 3.
12
o o
o o
: ' ' > < ^ C I EtaN R' ^ H \ . or
R Y R '2 13
-N2 ^r hv
R H /f./
Scheme 2.7
2.3.2 a-Oxoketene Conformations
Because of its conjugated nature a-oxoketenes are restricted to two different low
energy conformations. These conformations shown in Scheme 2.8 are designated s-E and
s-Z'*
Scheme 2.8
Generation of formyUcetene by photolysis of diazomalonaldehyde in an argon
matrix at 10 K produces both s-Z and s-^ conformations." Calculations show that the s-Z
13
form of formylketene is lower in energy compared to the s-E form by 0.2 Kcal/mol. ' '
This result is initially somewhat surprising given that the more stable s-Z conformation
places the electronegative oxygens in closer proximity than the less stable form. However
the highly electronegative a-carbon interacts with the electronegative keto oxygen to
provide an electrostatic attraction that stabilizes the s-Z conformation Interconversion of
the s-Z and s-E forms can occur both photochemically and thermally. While both
conformations are nearly equally energetically stable, the calculated barrier to rotation
between s-Z and s-E forms is approximately 9.3 Kcal/mol.' The s-Z conformations are
observed to be the reactive conformation of a-oxoketene. ^ It has been suggested that
this conformation allows for orbital overlap between the ketene and the species it reacts
with in a concerted reaction.' Calculations mdicate that this reaction is pseudopericycHc
in nature which wiU be discussed further.
2.3.3 a-Oxoketene Reactivity
a-Oxoketenes are usuaUy highly reactive species. Like ketene, a-oxoketenes
participate in electrocycHzations, nucIeophiHc and electrophUic reactions. a-Oxoketenes
can however be stabiUzed both stericaUy and electronically.'* As mentioned in the
previous section the s-E conformation is relatively unreactive. Sterically buUcy R group
substituents on the ketene shift the s-Els-Z equilibrium of the ketene to the s-E form which
is highly persistent.
Ketenes such as compound 19 shown m Scheme 2.9 are just such stabilized
ketenes. ^ Compound 19 has been shown to react only slowly with refluxing methanol to
14
give ester 20. In contrast, a-oxoketenes in the s-Z conformation will react with
compounds such as methanol upon warming from an argon matrix; " this reaction
normally takes place in the range of-90°C to -50°C. " Electronic stabilization of a-
oxoketenes from carboxylic acid, acid chloride, and trifluoromethyl substituents can lead
to compounds stable enough to be distilled and observed without matrix trapping.'*
O
OMe
Scheme 2.9
Reactive a-oxoketenes in the absence of other compounds tend to form more
stable products rather than remain a-oxoketenes. Irradiation of 3 with broadband UV in
Ar at 10 K can cause the eHmination of carbon monoxide to give S" as seen in Scheme
2.10. In solution, 3 typically undergoes [4+2] dimerization to give 21. Several examples
of such dunerization have been demonstrated.'* While the oxetene (22) is accessible from
3, reactions of formyl ketene show no appreciable oxetene formation nor is the product
isolated. '
O
•^M^. ^v^° , - ^ ,
hvy -<6o R ^ R
21
Scheme 2.10
° ^^ R. y
R 22
15
2.3.3.1 a-Oxoketene reactivity in the presence of nucleophiles.
Like ketene, a-oxoketene reacts with nucleophiles as shown in Scheme 2.11.
However the reaction products are different from ketene. The nucleophile attacks the a-
carbon of the a-oxoketene while the accompanying hydrogen undergoes nucIeophiHc
attack by the keto moiety of the a-oxoketene. This reaction is followed by keto-enol
tautomerization.'* Alcohols and amines alike readily add to a-oxoketenes to produce P-
keto esters and amides respectively.'* a-Oxoketenes show marked chemeoselectivity
selectivity for amines over alcohols. Further a-oxoketenes tend to react with sterically
less bulky nucleophiles faster in the order of 1°>2°>3°.''' *
O O
Nu ^ V ^ Nu
R' "OH R " ' ^© r NuH R
Scheme 2.11
This chemistry is not restricted to intermolecular systems and has been employed
with intramolecular alcohols ^ as shown in Scheme 2.11. This chemistry has provided a
powerfiil ring closure reaction to produce medium-sized lactones.
16
2.3.3.2 a-Oxoketene reactivity in the presence of dieneophiles
a-Oxoketenes can be readily trapped with a large variety of dieneophiles in [4+2]
cycloadditions. Ketones, aldehydes, imines, alkenes, alkynes, and cyanides readily form
six membered ring systems'*' ' ' as seen in Scheme 2.12. While these reactions result in
products reminiscent of hetero Diels-Alder reactions, there are marked differences
between typical Diels-Alder reactions and the [4+2] reactions of a-oxoketenes. We
beHeve these reactions to be pseudopericyclic in nature which wiU be discussed flirther.
-P
Scheme 2.12
2.4 Pseudopericyclic Reactions
The now familiar rules of Woodward and Hoffinann predicted with great accuracy
for hydrocarbons which pericycHc reactions were "aUowed" and which were "forbidden."
These rules are appropriate for concerted pericycHc reactions in which bonding changes
take place around a closed loop of interacting orbitals, in a cycHc transition state. This
connected orbital topology can be seen in Figure 2.2 in the Diels-Alder reaction. Like
pericycHc reactions, pseudopericycHc reactions are concerted and have cycHc transition
states. But in contrast to pericycHc reactions, pseudopericycHc reactions do not interact
around a closed loop of orbitals and are characterized by an orbital disconnection. This
leads to the most striking difference between pericycHc and pseudopericyclic reactions.
17
that pseudopericyclic reactions are allowed regardless of the number of electrons
involved.'
Diels-Alder pericyclic reaction Pseudopericyclic reaction
/
. , , _ J Orbital
\ ) r " A A V " ' \ ^ disconnecton O S.O
T W ~ / ~ I 4. II ^ 1 1 I
Orbital disconnecton
Figure 2.2 Comparison of pericycHc and pseudopericyclic orbital interactions.
Pericyclic reactions such as the Diels-Alder reaction seen in Figure 2.2 have a
nonplanar transition state with the dienophile approaching the diene from the top or
bottom.^ In contrast, pseudopericycHc reactions as iUustrated in Figure 2.2 for as the
reaction of formylketene with formaldehyde, because of the orbital disconnection, have a
planar transition state.''^
Furthermore, although pericycHc reactions usually have lover activation barriers
than competing stepwise mechanisms (ionic or radical) these barriers are nevertheless
often substantial (>30 Kcal/mol).^ In contrast pseudopericycHc reactions may have
extremely low or even no activation barriers.''*
18
2.5 Inridovlketenes
The chemistry of imidoylketenes is far less known and explored than that of a-
oxoketene nor have imidoylketenes found the synthetic applications that a-oxoketenes
have. Nonetheless, they are closely related to a-oxoketene both structurally and
electronically.* They might therefore be expected to react very much Hke a-oxoketenes,
includmg reaction through the pseudopericyclic pathway.
2.5.1 Conformations of imidoyUcetene
ImidoyUcetenes can exist in one of the four conformations as seen below in Scheme
2.13. The anti s-Z conformation places the ketene in the reactive conformation with the
lone pah of electrons on the nitrogen toward the reaction center and therefore should be
the reactive species in a concerted, pseupopericyclic reaction.*
R " Y-V^° R. ° ^N '
R' R-Anti s-E Syn s-E Anti s-Z Syn s-Z
Scheme 2.13
2.5.2 Generation of imidoyUcetenes
Several methods exist for the generation of imidoylketenes.*' *" * The most
common methods include the foUowmg seen in Scheme 2.14; eHmination of alcohols from
enamino esters (23), thermal decarbonylations of pyrole-2-3-diones (24), and thermal
decomposition of Meldrum's acid derivatives (25). Of note is that generation of
19
imidoylketenes from diazo compounds has not been reported. This is in contrast to a-
oxoketenes which are often readily generated from diazo compounds.
O O
R 'SC^NR R H
23
R 24 R
K HN h—O
O 25
R - ^ N
Scheme 2.14
The same reaction constraints imposed by the starting materials on the production
of a-oxoketenes also exist in the production of imidoylketenes. Production of
imidoyUcetenes from enamino esters produces a by-product alcohol and so only trappmg
agents more reactive than the alcohol can be used. Meldrum's acid derivatives produce an
acetone byproduct which could compHcate trapping by weak dieneophUes. A clean source
of imidoyUcetene is the 2,3-pyroledione which produces carbon monoxide as the only by
product, which is highly unreactive.
2.5.3 Imidoylketene reactivity
Like a-oxoketenes, imidoylketenes participate m electrocycHzations, nucleophilic
and electrophiHc reactions. Imidoylketenes in the absence of other reactants will undergo
20
reactions including [4+2] dunerization as do a-oxoketenes. Unlike 3, imidoylketenes
can undergo intramolecular reaction to give rise to an appreciable amount to P-Iactam
which can be isolated.^*
One of the complicating factors with imidoylketenes, and most probably the reason
they have not enjoyed widespread synthetic utility is that the R group on the nitrogen has a
dramatic impact on the reactions. Aromatic R groups on the nitrogen such as compound
26, attack the electophihc site of the ketene resulting in cycHzation^* producing
compounds such as 27 as seen in Scheme 2.15. Aliphatic R groups as in compound 28 are
also susceptible to [1-5] hydride shifts^^*''to the electrophiHc site of the imidoyUcetene
giving rise to compounds such as 29. These [1-5] shifts are usuaUy foUowed by the
presumably forbidden [1-3] shift to produce an amine such as compound 30.
O
Scheme 2.15
21
2.5.3.1 Imidoylketene reactivity in the presence of nucleophUes and electrophiles
Imidoylketenes react in the same manner as do a-oxoketenes in the presence of
nucleophiles and electrophiles; they are readily trapped by both amines and alcohols* One
difference in the reaction outcome of reactions with hydrogen bearing nucleophUes is that
the trapped imidoyUcetene does not undergo keto-enol tautomerization and instead results
in an eneamine or eneamino esters* when reacted with an amine or alcohol respectively to
give rise to compounds of the form of 31 as seen in Scheme 2.16. Imidoylketene follows
the same pattern of chemoselectivity and steric selectivity that a-oxoketene does,
1°>2°>3°.*
.O
NuH
R^rji 4R
Scheme 2.16
2.5.3.2 Imidoylketene reactivity in the presence of dieneophUes
In contrast to a-oxoketenes, reported electrocycHc trapping reactions of
imidoylketene with dieneophiles are not weU known. However some examples do exist
where imidoylketene has been shown to trap imines as shown in Scheme 2.17.
22
Scheme 2.17
23
CPL\PTER 3
DIASTEREOSELECTIVITY IN CYCLOADDITIONS OF
ACETYLKETENE; EVIDENCE FOR A
CONCERTED PATHWAY
3.1 Introduction
a-Oxoketenes m general and acetylketene (33) in particular have been used
extensively in theoretical studies involving pseudopericyclic reactions"'* and have also
been employed synthetically as well.'*' ' ' The point of greatest mechanistic interest of a-
oxoketenes is the marked differences in their reactivity compared to ketene (5), namely
their tendency to participate in [4+2] cycloadditions'* in contrast to the [2+2]
cycloadditions preferred by 5. Qualitative predictions and quantitative molecular obrital
calculations indicate that the [4+2] reactions of acetylketene are pseudopericyclic in
„ „ . . , „ 5,7,40
nature.
As noted in Chapter 2, reactions that are pseudopericycHc are generally beHeved to
be concerted rather than stepwise and are predicted to have nearly planar transition
states.'"'''**' The cycHc array of interacting orbitals is not continuous and contains at least
one discoimection. This prediction is in stark contrast to the weU known and studied
Diels-Alder [4+2] cycloadditions that occur via:: to TI face interactions around a closed
loop of interacting orbitals.
Some efforts have previously been made to address these predictions of
pseudopericyclic reactions. Calculations of the addition of water and formaldehyde to 24
formylketene indicate a planar, concerted transition state as expected.' These calculations
also indicate that water would be significantly more reactive than formaldehyde towards
formylketene.' Subsequent trapping studies of acetylketene indeed showed remarkable
chemoselectivity.' Despite the reactive nature of acetylketene, it readily discriminates
between amines, alcohols, and carbonyl compounds. These results demonstrated that at
least part of the predictions of formylketene reactivity were correct. However these
studies did not address the questions of concerted vs. stepv dse reactions and planar vs. pi
to pi face interactions in the transition state for the reaction of a-oxoketenes with
dieneophiles.
Because of the reactive nature of acetyUcetene traditional methods of exploring
transition state geometry are hard to employ. Few researchers have attempted kmetics
studies of acetyUcetene;"*' however, Kresge has done laser flash kinetics on a-
oxoketenes. ' Problems arise with solvent studies as few solvents are Hquid at -90 K and
yet unreactive towards a-oxoketene. However stereochemical induction can be employed
and may give insights to some of the questions of transition state geometry and the
concertedness of the reaction. The reaction of acetylketene with a chiral dieneophile leads
to the formation of one new stereocenter. The type and degree of chhal induction at this
site can potentially sort out some of the mechanistic questions of these reactions including
the degree of concertedness of the reaction and the planarity of the transition state. One
such reaction had been attempted previously using a a-ketoester with a chiral menthyl
group as a trap with formylketene as seen in Figure 3.1 but no selectivity was observed 43
25
This experiment relied on a chiral a-ketoester where the chiral group was placed
far from the newly forming chiral center and therefore the lack of selectivity may not
reflect the reactivity of acetylketene.
.O o
Figure 3.1 Chiral trapping reaction of Sato et al. 42
On a practical note, a-oxoketenes have found use in synthesis.' ' '*' * Asymmetric
reactivity would only serve to increase the utility of a-oxoketenes and therefore these
resuhs could prove useflil to the synthetic community as weU.
In this work we report the reactions of chiral aldehydes and ketones with
acetylketene, the reactions of increasing sterically bulky ketones with acetyUcetene and
finally chiral a-oxoketenes with benzaldehyde. These results wiU be discussed in the
context of addressing the theoretical questions of pseudopericycHc reactivity.
3.2 Methods and Resuhs
Calculations in this lab of the reaction of formylketene with acetaldehyde indicated
a planar transition state where the hydrogen substituent of the aldehyde adopts the
pseudoaxial position, while the methyl group prefers the less hindered pseudoequatorial
26
position. Ab initio and density function theory calculations carried out on Gaussian 94"*
were used to calculate these systems. Geometries were optimized at the RHF/3-21G,
RFIF/6-3IG* levels and frequency calculations were used to provide free energy
corrections to predict the geometry of the transition states."*
We envisioned that trapping acetylketene whh a chiral aldehyde might lead to
stereoselective addition. Our original reasoning was that increasing the steric bulk of the
substituents around the carbonyl moiety would change the psuedoaxial/pseudoequatorial
position equiHbrium for each case; and if an R group that was more bulky than the chiral
group was used, the chiral group would occupy the pseudoaxial position to a greater
degree. Then the chiral group would be closer to the mcoming nucleophilic oxygen of the
acetylketene and might have a greater effect on selectivity. Indeed, FeUcin-Anh selectivity
of nucleophUic additions to related systems is enhanced by a more buUcy R group.
AcetyUcetene is readily generated by thermolysis of 2,2,2-trimethyI-4H-l,3-dioxin-
4-one (32) as shown m Scheme 3.1. Previous studies in this lab of the chemoselectivity of
O
o
o
33
*A
Scheme 3.1
acetylketene employed Flash Vacuum Thermolysis (FVT) as a means of generatmg
acetylketene with m situ trapping.' The same method was employed again m these
studies. Racimic 2-phenylpropanal (34a) was chosen as a chiral trap because it has been
27
extensively studied in diastereoselective reactions including being used in pioneering work
by Felkin thereby providing a direct method of comparison with our ketene trapping.
Racemic chiral ketones 34b-d were prepared by first treating 34a with the appropriate
Grignard reagent. The subsequent alcohols were oxidized to give the chiral ketones. This
series of reactions was carried out as seen in Scheme 3.2.
H
OH RMgBr
34a Ph
H2Cr04 »-
Swem
35b-d Ph
bR = Me cR = Et d R = t-Bu
Ph 34b-d
Scheme 3.2
Aldehyde 34a and ketones 34b-d were then subjected to FVT conditions along with
acetylketene precursor 32 as seen in Scheme 3.3. The results of these reactions are
summarized in Table 3.1. Compounds also recovered from these reactions include startmg
materials and a-oxoketene dimer. This result was also seen in each series of reactions.
Scheme 3.3
Table 3.1 Reaction conditions and resuhs of Scheme 3.3
Reactant 34a 34b 34c 34d
R H Me Et t-Bu
Product 36 2.3 6.3 2.0 no reaction
Product 37 1.0 1.0 1.0
yield 40% 11% 5.4% 0%
28
These results demonstrate that reactions of acetylketene with chiral carbonyl
compounds do indeed result in diastereoselective trapping. In the case of 34b, the
selectivity of 6.3 to 1 is high enough to be synthetically usefiil. These levels of selectivity
compare well to studies of the reduction of 34b with LiAIH* which proceeds with only 2.8
to 1 selectivity."*'
We were unable to assign the stereochemistry of the cycloadducts 36a-c and 37a-c
from NMR. However, the minor diastereomer 37b was successfuUy crystaUized. This
product was subjected to x-ray analysis and proved to be the anti FeUdn-Anh product.
Thus the major product 36b was then assigned as the Felkin-Anh product.
Stereochemistry of the other cycloadducts was assigned by analogy.
As expected the nature of the chiral group has a dramatic unpact on selectivity.
Changing the chiral group trap to compoimds 38a-b and reacting them with 32 as seen in
Scheme 3.4 resuUed in very poor selectivity as reported in Table 3.2. This resuh was not
surprising but in agreement with other studies mdicating that the similar steric bulk of the
methyl and ethyl groups leads to poor FeUdn-Anh discrimination by the incoming
nucleophile."**
38a-b 39a-b \ 32
Scheme 3.4
»*\
29
Table 3.2 Reaction conditions and resuhs of Scheme 3.4
Reactant 38a 38b
R H Me
Product 39 «1.1 1.1
Product 40 1.0 1.0
Yield 10% 22%
The reaction of ketone 34c with acetylketene (from Scheme 3.3) gave a surprising
resuU. While the FeUdn-Anh product was formed in preference to the anti-Felkin-Anh
product as expected, however the combined yield was only 5.4% and only in 2.0 to 1.0
ratio respectively, demonstrating low reactivity and poor selectivity compared to other
compounds m this series. But more mterestmgly, as shovm in Scheme 3.5 was the major
product of this reaction vinyl ester 41, in 24% yield. This reaction was repeated twice
with similar resuhs. We were curious as to the factors leadmg to the formation of this
O O O 32 + \ . / ^ ^ ^ - ^ ^ 36c + 37c + ^ A ^ / " \ ^
34c Ph 41
Scheme 3.5
unusual product. It seemed unlUcely that the enol was bemg trapped. We are able to
rationaUze this product as arriving from an eight centered pseudopericycHc elimination.
But we are unable to provide support for this mechanism. We rationalized that the
eUmmation might occur when the steric demand around the carbonyl moiety of the
trapping compound became too great for a [4+2] reaction. A series of related ketones, 42
a-f, with increasing steric bulk was reacted with acetyUcetene as seen in Scheme 3.6. See
Table 3.3 for reaction conditions. This series of reactions showed a dramatic decrease in
product yields with increasing steric bulk. However, each ketone produced the famihar
30
[4+2] cycloadducts 43a-f but no detectable amount of enol esters. While we can
rationalize the formation of 41 we have no explanation for why only 34c gives rise to this
product or what factors induce its reaction pathway.
R2 37a-f 38a-f
Scheme 3.6
Table 3.3 Reaction conditions and resuhs of Scheme 3.6.
Reactant 42a 42b 42c 42d 42e 42f
Ri Me Et Et i-Pr Et Et
R2 Et Et i-Pr i-Pr t-Bu Bn
Product 43a 43b 43c 43d 43e 43f
% Yield 58% 29% 25% 4% 0% a
Enol ester? No No No No No No
a) not determined
FmaUy m an effort to draw clear distinctions between the a-oxoketene
pseudopericyclic reaction mechanism and the Diels-Alder [4+2] cycloadditions, chhal a-
oxoketenes were generated and trapped with benzaldehyde. We reasoned that if the
proposed pseudopericycHc mechanism was correct, and the transition state planar and
concerted, then a chiral group on the ketene would be far removed from the reaction
center and have little or no effect on the newly forming bonds. If however, the transition
state was an endo Diels-Alder form, a chiral group on the ketene should have a dramatic
impact and lead to selectivity in the products.
31
The chiral a-oxoketene precursor 2-diazo-l,4-diphenyl-l,3-pentanedione (47) was
prepared as seen in Scheme 3.7 by first condensing the enolate anion of acetophenone
with 34a. The resuhant alcohol 44 was then oxidized with H2Cr04 to produce 45.
Compound 45 was treated with diazo transfer reagent 46"*' to produce 47. We knew from
Scheme 3.7 Synthesis of chiral a-oxoketene precursor,
other work m our lab that photochemical production of the ketene failed in the presence of
aromatic groups, and therefore thermal production of the ketene was chosen. The
migratory aptitude of the phenyl group is known to be greater than that of a alkyl group ui
Wolff rearrangement under thermal conditions,''''* so we hoped the phenyl group would
migrate faster. The chiral group however is much more Hke a benzyl group than an alkyl
group and thermolysis of 47 led to loss of nitrogen and rearrangement, but both groups
migrated. The ratio of migration of the chiral group to the phenyl group was 10 to 1
giving rise to 48 and 49 as seen in Scheme 3.8. This outcome proved to be fortimate as
we were able to trap both rearrangement intermediates with benzaldehyde and identify all
four products, 50-53, by NMR. The regiochemistry of 50 and 51 as well as 52 and 53
was deduced by NMR using a combination of HMBC and HMQC techniques. The
selectivity of each diastereomer pah, 50 to 51, and 52 to 53 was essentially 1.1 to 1. The
32
relative stereochemistries of these diastereomers were not determined. Resubmission of
isolated diastereomers to the reaction conditions revealed essentially no rearrangement
indicating that the 1.1 to I ratio was a kinetic product. Heating the diastereomers at
temperatures above mitial reachon conditions induced rearrangement to the
thermodynamic product in each case. Based on this information we were able to assign
the thermodynamic product as the major product in the kinetic trapping.
I F?h O Ph O
Ph- 'S^ -Benz-
^ ^ P h ^ ^ O aldehyde p ^
47 ^« O
\ P h ^ ^ ^ ° Ph T BiHT II I *
"Xp'^^O aidehydeY'^O^Ph Ph Ph Ph
49
Scheme 3.8 Chiral a-oxoketene production and trapping outcome.
These results contrast sharply with those of the chiral trapping agents 34a-c. In
the case of chiral traps, clear induction of chiraHty is seen between the reactants and
products. Where the a-oxoketene is chiral instead, virtuaUy no selectivity is observed.
3.3 Discussion
In analyzing the data these chirality studies have afforded in terms of transition
states, it is important to remember that computer modeling has aheady predicted what the
transition state of these reactions should look Hke, and how the reactions proceed. ' '
33
These models indicate a concerted pseudopericyclic transition state where the substituent
of the incommg dienophile v ll occupy pseudoaxial and pseudoequatorial positions of a
planar six membered transition state. Further the substituent with the greatest bulk wiU
prefer the pseudoequatorial position."** Does this experimental evidence support this
position?
To adequately address this question it is reasonable to consider five possible
transition states as seen in Figure 3.2. The first would be a stepwise ionic mechanism.
The second and third would be Diels-Alder type of TC to 7t face uiteractions with either
endo or exo selectivity. Finally would be the pseudopericycHc planar interaction with
either pseudo axial or pseudo equatorial selectivity.
R* = chiral group
,0 O O P
fr" -o /^:o /T '-P Ir^"? *R"^R R-^R* / 4 Endo Exo Pseudoequatorial Pseudoaxial
Figure 3.2 Possible transition states in the reaction of acetylketene.
The chiral selectivity seen in the reaction of acetyUcetene with chiral carbonyl
compounds is consistent both m structure and ratio with FeUdn-Anh selectivity. This
34
indicates that the nucleophilic oxygen of the ketene attacks the carbonyl carbon in a
manner similar to a typical incoming nucleophile. However given the strong electrophiHc
nature of the acetylketene a-carbon it might be expected that nucIeophiHc attack on this
she by the carbonyl oxygen would proceed the a-oxoketene nucleophUic attack on the
carbonyl carbon m an ionic mechanism as seen in Figure 3.3. This would lead to a
zwitterion product with a full negative charge on the acetylketene nucleophilic oxygen and
a fliU positive charge delocalized between the carbonyl carbon and oxygen. This charge
Figure 3.3 Stepwise reaction mechanism for acetylketene with dieneophiles.
separated state would then ring close to give the observed products. This ring closure
should be very fast with the six membered ring system. In order for selectivity to be seen
m this ionic mechanism, there would have to be a preference for a sense of rotation around
the partial double bond of the former carbonyl. This result seems highly unlUcely. As
mentioned eariier, competition studies between aldehydes and ketones show essentially the
same rate' which should not be the case if the ionic reaction mechanism is correct.
Therefore experimental evidence of Felkin-Anh selectivity provides no support for the
ionic mechanism.
35
The Diels-Alder transition state model is probably the reaction mechanism most
often mvoked in [4+2] cycloadditions. The Diels-Alder mechanism has the two possible
configurations for the chiral substituent, endo and exo as seen m Figure 3.4. It has been
r ~o F' ~o
*R R R^^R* Endo Exo
Figure 3.4 Diels-Alder reaction mechanism transition states.
shown that Diels-Alder reactions with chiral groups in the exo position of the incoming
dienophile do show selectivity."*^ However this selectivity has been demonstrated to often
be anti-Felkin-Anh."*' This selectivity is not consistent with our observed Felkm-Anh
selectivity and the complete lack of selectivity m the work of Sato. Therefore the
demonstration of selectivity m our trapping reactions can rule out the Diels-Alder exo
transition state model. But what about the endo transition state? Diels Alder reactions
are often highly endo selective.'" If the reaction proceeds through the endo Diels-Alder
transition state the selectivity of chiral traps with acetylketene can be explained. In direct
contrast is the poor selectivity seen with the chiral a-oxoketenes 48 and 49. If the
reaction proceeds with endo selectivity the phenyl ring of the benzaldehyde trap must be
placed in close proximity to the chiral group of the ketene particularly m compound 49.
This lack of selectivity argues agamst the endo Diels-Alder transhion state. Further,
placement of the chiral group in either position on the a-oxoketene has no discemable
36
effect on selectivity. If the transition state was that of an endo Diels-Alder, one would
expect different selectivity when the phenyl ring of the benzaldehyde is closer to the chiral
group as in 49 than when h is flirther away as in 48. These results provide no evidence to
support a Diels- Alder transition state.
It can therefore be concluded that the diastereoselectivity data points directly to
and supports the computer model of the planar pseudopericycHc transition state as seen m
Figure 3.5. The planar concerted transhion state should give Felkin-Anh selectivity as the
O o
^ O - X R * / ^ - X R
R *R Pseudoequatorial Pseudoaxial
Figure 3.5 Pseudopericyclic reaction mechanism transition states.
nucIeophiHc oxygen of the ketene approaches the chiral dieneophile. The planar transition
state should place the dieneophUe far away from any chirality on the a-oxoketene and
therefore show poor selectivity.
However, these results do not however directly address the difference between the
pseudoaxial and pseudoequatorial transition states of the pseudopericycHc model. But
insight can be gamed by lookmg at the series of varied steric ketones trapped by
acetylketene. One comparison that can be made in the series of ketones reacted with
acetylketene are entries 42a, through 42d from Table 3.3. There is a dramatic decrease in
37
yield from 42a to 42b; however, very little change in yield from 42b to 42c. And then
once again a large decrease in yield from 42c to 42d. These resuhs indicate that the total
amount of steric bulk has only a small impact on the yield but when the steric bulk of the
smaller group changes the reaction yield changes dramaticaUy. This resuh is consistent
with the model because changing the steric bulk of the pseudoaxial group will place the
bulk closer to the reaction center and have a large impact on the reaction. Changmg the
steric bulk of the pseudoaxial group would have only a minor unpact on the reaction
center because the steric bulk would be facing away from the newly forming bond. Once
again the experimental work provides no rebuttal of the computer model and in contrast
only serves to strengthen the proposed reaction mechanism.
In regards to the formation of enol-ester 41 we have been unable to provide a
satisfactory answer for this unusual product. OriginaUy, we had thought that the reason
for the formation of 41 was a function of steric bulk. We proposed that as the steric buUc
around the carbonyl became larger it be came more difficult for the incommg nucleophile
to react with the carbonyl carbon. As the steric demands became too great, the ketene
would then abstract an adjacent unhmdered a-hydrogen giving rise to product 41. This
proposed eight centered transition state is shown in Figure 3.6. However, this proposal
was ruled out after the series of reactions m Scheme 3.6 with increasing steric bulk faUed
to produce any enol-ester product. We then proposed that ketone 34c was producmg
large quanthies of enol that was trappmg acetylketene leading to the formation of product
41. However, experimental data indicated that compounds Hke 34c would preferentially
form enols at the more substituted C2 position rather than the less substituted C4
38
position." This should have led to a mixture of enols-esters arising from two different
enols, however the isolation of 41 was consistent with only enol formation at the less
hindered C4 position and therefore trapping of the enol was also ruled out.
Figure 3.6 Proposed eight centered transkon state leading to 41.
3.4 Conclusions
We have demonstrated chirality induction in the cycloadducts of acetylketene with
chiral aldehydes and ketones. The selectivity of these reactions is consistent whh FeUdn-
Anh selectivity. In some cases the selectivity is high enough to be usefiil syntheticaUy.
We have also shown that chiral a-oxoketenes do not provide selectivity in trapping
benzaldehyde.
These results are consistent with the proposed pseudopericycHc reaction
mechanism. Conversely, these experimental resuhs are not consistent with ehher a
stepwise mechanism or with Diels-Alder pathways.
39
CHAPTER 4
REINVESTIGATION OF THE REACTIONS OF
CAMPHORKETENE; EVIDENCE FOR A
PSEUDOPERICYCLIC PATHWAY
4.1 Introduction
As part of our study of reactions of a-oxoketenes in general and of their
stereoselectivity in particular,''"*"* we became interested in camphorketene (54). Camphor is
a readily avaUable chiral compound and its derivatives often give excellent facial
selectivity. As noted Chapter 2, a-oxoketenes exhibh unusual reactivity as compared to
unsubstituted ketenes.'* This work was undertaken to explore the unpact of the camphor
on a-oxoketene m the reactivity of 54.
Staudinger first generated camphorketene by the treatment of acid chloride 53
with triethylamine as in Scheme 4.1.'^ Two dimers were isolated in 45% and 21% yields.
Later, Yates and Chandross deduced the general structures of dimers 55 and 56 resulting
from [4+2] cycloadditons but did not assign the relative stereochemistry of the dimers.'
Subsequently Wentrup directly observed 54 by IR not only in argon matricies but also at
room temperature m solution. " Wentrup was able to trap 54 with methanol yielding the
esters 57. " In contrast to other P-keto esters, the back reaction producing 54 from 56
was seen only at very high temperatures and m low yeild. " Wentrup attributed this to a
lack of the more reactive enol tautomer.
40
5 3 °
Et,N
MeOH
O 57
O
54
<700°C
56
Scheme 4.1
We first sought to verify the structures, assign the sterochemistry of 55 and 56,
and mvestigate the apparent lack of diastereoselectivity in the dimerization of 54. Further
we reasoned that 54 might be trapped with other alcohols and whh unsymmetrical
dieneophUes. These reactions could provide msights regarding the reaction mechanism
and the effects of chirality transfer from the camphor moiety to the newly forming bonds
of the cycloadduct.
4.2 Resuhs and Discussion
Using Staudmger's general method, acid chloride 53 was readUy prepared by first
carboxylatmg D-(+)-camphor and subsequently treating the resuhant camphor-3-
carboxyUc acid (59) with SOCI2. The camphorketene dhners were easily obtained upon
treatment of 53 with triethylamme (Scheme 4.1). Successive recrystallization from diethyl
ether yielded pure crystals of 55 and 56. The optical rotations of the dhners compare well
41
with those originally reported by Staudinger. X-ray analysis of the minor dimer confirmed
the structure as 55.'"* The major product is assigned as structure 56 by analogy and
comparison of the NMR spectra. These results are consistent with the expected [4+2]
dimerization of 54 '
Camphor derivatives often show remarkable facial selectivities, even at fairiy
remote sites. For example, camphor sultam acrylates give high facial selectivities in Diels-
Alder reactions, giving 100% de after reystalization.'**'' How can it then be that this [4+2]
dimerization forming a new sterogenic center at the core of the camphor skeleton,
proceeds with only 2:1 selectivity? This seems unlikely to be a concerted Diels-Alder
reaction with bond formation between the two K faces.
We would suggest that in the transition state both molecules of 54 are bonding in
ways that mmunize the diasteroselectivity. The four atom component is expected to react
in a pseudopericycHc fashion whh bonds forming in the plane of the a-oxoketene. We
have previously shown that there is essentiaUy no diastereoselectivity in [4+2] reactions of
chiral a-oxoketenes."*^ Furthermore, the two atom component is reacting as a ketene.
Initial bond formation here again is expected to occur in the plane of the ketene, not at one
at the extended K faces."
We anticipated that a [4+2] cycloaddhion with a trap other than a ketene might
lead to higher diastereoselectivity, as observed for other a-oxoketenes. WhUe
benzaldehyde has been shown to trap a-oxoketenes,"*^ addhion of benzaldehyde to the
reaction sequence m Scheme 4.1 faUed to produce any cycloadduct. The only products
were those of camphor ketene dimerization. Imines are more reactive than aldehydes m
42
trapping with other a-oxoketenes '*'" so N-propylbenzaldhnine was substituted in place
of benzaldehyde m the previous reaction. This again gave dimers 55 and 56 but no
evidence for reaction between 54 and the imine.
Ketenes can react through multiple pathways. a-Oxoketenes are weU known to
react rapidly with alcohols to produce P-keto esters.'* Indeed, when 54 is generated as
seen in Scheme 4.2 in the presence of isopropanol, the isopropyl ester 54 is formed. In 20
minutes this gave complete conversion to the isopropyl-3-camphor ester 54, entry la in
Table 4.1. However, in this reaction sequence the precursor 53 can m principle be
esterifed directly by the alcohol to give the same product. In order to test the mechanism
of reactivity of 53, a competition reaction was set up using isopropanol and methanol as
trapping molecules. A control reaction of 53 with an isopropanol/methanol mixture (entry
b m Table 4.1) and was run in paraUel with a reaction of 53 with the same
isopropanol/methanol mixture and triethylamine (entry c in Table 4.1) under condhions
used to generate the ketene. Both reactions were quenched with water after 20 minutes,
at which tune any unreacted 53 or 54 were converted to the acid 59.
EtaN MeOH/ /-PrOH
»-H,0
57 R = Me 58 R = /-Pr
OR 5 9 R = H
Scheme 4.2
43
Table 4.1 Reaction condhions and resuhs of Scheme 4.2
entry
a b c
Et3N; MeOH: i-PrOH 5 : 0 - 2 0 : 5 : 2 5 : 5 : 2
%57
0 30 79
endo: exo
1.9: 1 4 : 1
%58
100 13 21
endo: exo
4.4: 1 3.3 : 1 6. 1
%59
0 56 0
The control reaction, entry b in Table 4.1, produced isopropyl-3-camphor ester 58,
methyl-3-camphor ester 57, and camphor-3-carboxylic acid 59, indicating an incomplete
reaction after 20 minutes. Entries a and c both show complete conversion in the same
time indicating a far faster reaction than entry b. Furthermore, the product ratio of esters
57 to 58 and the endo:exo ratio of products for entry b are different than for entry c.
These resuhs argue for two hnportant pomts. First, the two reactions must proceed by
different mechanisms in the presence and absence of triethylamine, the former bemg much
faster. Differing product and endo: exo ratios of 57 and 58 m entries b and c indicate that
the two reactions do not share a common reaction intermediate. These resuhs are
consistent with a ketene intermediate for entries a and c and not a direct esterification of
the acid. The second point is the surprising resuh that the more reactive a-oxoketene 54
(entry c) shows higher selectivity for methanol than does the acid chloride 53 (entry b).
However, this selectivity is consistent with that observed m reactions of acetylketene.
The NMR spectra of both esters 57 and 58 show a mixtiare of endo and exo
products but also show no appreciable enol formation. This resuh was consistent with the
findmgs of Wentrup. " Given that P-keto esters are often primarily enols, lack of enol
formation is surprisuig and wUl be discussed below.
44
The reactivity of a-oxocamphorketene is apparently unique. Despite being
constrained to the reactive s-Z conformation'* it does not participate in [4+2] trapping
reactions observed with other a-oxoketenes.'*' ^" ' However, it reacts similarly to as other
a-oxoketenes in the presence of alcohols'' " and it dhnerizes through a [4+2] pathway.
We reasoned that the strain of the camphor moiety of 52 inight puU the ketene and ketone
fimctionalhies fitrther apart than m the corresponding formyl ketene 58 and thus reduce hs
reactivity, particularly towards carbonyl compounds and imines. Geometry optimization of
60 and 61 (the latter as a des-methyl model of 54) as seen in Figure 4.1 were performed at
the B3LYP density function level'* with the 6-3IG* basis set using Gaussian 94."*
1.168
1.332
1.467 > 2.846
i . > ^
60
3.015
1.213
61
Figure 4.1 Geometry optimization of a-oxoketene models.
The distances given m Figure 4.1 are m angstroms. The distance between the
reactive centers (05 and the ketene carbon C2) was calculated to be approxunately 0.17 A
longer for 61 compared to 60. A larger gap in camphorketene 54 may make h more
difficuh for typical dieneophile traps to bond in a [4+2] pathway. The dunerization may
45
be favored due to the longer bond length of the carbon carbon double bond of the ketene
compared to that of the carbonyl moiety. (0.1 A, Figure 4.1) This steric constraint may
also account for the lack of enol formation in the P-keto esters 57 and 58. The ester-enol
distance may be too great for the effective hydrogen bonding that usuaUy stabilizes the
enol tautomers of P-keto esters.
4.3 Conclusions
The stereochemistries of the camphorketene (54) dimers 55 and 56, first
synthesized in 1920 by Staudinger, have finally been determined. The surprising lack of
diastereoselectivity in the [4+2] dimerization of 54 is consistent v dth a planar,
pseudopericycHc transhion state on the four atom component. Trapping 54 with alcohols
shows chemoselectivity compatible to other a-oxoketenes. However, 54 does not display
typical a-oxoketene reactivity towards benzaldehyde, or benzaldimine, desphe being
constrained to the reactive s-Z conformation. Camphorketene has been investigated for
over 80 years. While some aspects of its chemistry had been elucidated, very little
understanding of its reactivity m term of structure and function existed before this study.
46
CHAPTER 5
DIASTERIOSELECTIVITY IN TRAPPING
a-OXOKETENE; EFFECTS OF POSITION
OF CHIRALITY, SOLVENT, AND
TEMPERATURE
5.1 Introduction
As has been noted in previous chapters, a-oxoketenes have been extensively
studied m terms of reactivity and mechanism.''''"''* In our work elucidatmg
pseudopericycHc reaction mechanisms we trapped acetylketene with chiral aldehydes and
ketones. These reactions demonstrated Felkin-Anh selectivity of acetylketene towards
chiral dienophiles and provided experimental evidence to support the proposed planar
pseudopericycHc reaction mechanism of a-oxoketenes."*"*
WhUe this work answered many questions regardmg the mechanism of a-
oxoketene reactivity, the demonstrated selectivity of these reactions served to raise flirther
questions about the reactivity of a-oxoketenes. As part of our ongoing studies we began
to explore the nature of the diastereoselectivity of a-oxoketenes in greater detaU. Sato et
al. had trapped acetylketene with a chiral ester but no selectivity was observed. Why
had these reactions failed to produce selectivity? Was the reason simply the remote nature
of the chhal group? How would moving the chiral group relative to the newly formmg
47
stereogenic center affect selectivity, such as trapping with an imine whh a chiral group on
the nitrogen?
The selectivity observed in trapping acylketene was consistent with the Felkin-Ahn
model."* Was the differentiation by the ketene due purely to steric effects of the chiral
group, or do electronics play a role in selectivity? Cram,'' Felkin,"*' and Conforth*" have
argued that a strongly electronegative substituent will interact with the carbonyl oxygen
and the incommg nucleophUe. What selectivity might be afforded by usmg a chhal
trapping compound with an electronegative or electroposhive substituent that could
interact with the mcoming nucleophile?
FmaUy, if we could show selectivity with a remote chiral center placed on an hnine
nitrogen, could double diastereoselectivity of two chiral groups afford higher selectivity
than the two groups independently. And of course, what could this data further reveal
about the nature of the reaction mechanism of a-oxoketenes? These were the questions
we sought to answer.
5.2 Resuhs
In our work to generate imidoylketene we explored the use of 3-diazo-2,4-
pentanedione (62) as a precursor to a-oxoketene. Our interest m this compound stemmed
from the abiUty to generate a-oxoketene photochemicaUy' from a diazo compound in
order to compare trapping of a-oxoketene m solution at room temperature to our FVT
studies from Chapter 3. However, attempted photolysis of 62 m the presence of carbonyl
48
compounds failed to produce any cycloadduct. Primarily starting material was recovered
from these reactions along whh degradation products. Longer irradiation resuhed only in
higher levels of degradation as the NMR revealed loss of starting material, but no peaks
characteristic of the desired cycloadduct. As a control reaction, 62 was photolized in
ethanol as shown in Scheme 5.1. Compound 64 was readily produced with complete
conversion of 62 within 30 minutes, presumably through the ketene intermediate 63.
O
When h became clear that the a-oxoketene could not be generated photolytically
in the presence of carbonyl compounds, we began to explore generation of the a-
oxoketene by thermal means. Generally loss of nitrogen is initiated in a high boihng point
solvent. ' ' However kinetics studies have shown that deazatization could be hiitiated
as low as 80°C when using unstabiUzed 3-diazo-2,4-diketones' such as 62. It is generaUy
found that higher levels of selectivity can be achieved at lower temperatures. This a
natural outcome of the Arrhenius equation where k = Ae"^^^ The rate of a reaction is
slower with lower temperature thereby favoring low energy pathways. Therefore, a series
of reactions were run shown in Scheme 5.2 usmg 62 with 2-phenylpropanal (34a) as a trap
m solvents of differing boUing points.
49
Scheme 5.2
This reaction series would allow us to compare selectivity of thermally solution
generated a-oxoketene with the resuhs from our FVT studies. The benefits of such
thermal solution phase generation include lower solution temperature as compared to FVT
which would reduce the degradation of heat senshive aldehydes used as trappmg
molecules. Higher yields with fewer side products, and simpler reaction conditions as
compared to FVT would also serve to enhance the synthetic usefulness of these reactions.
Initially, to compare the selectivity at different temperatures, these reactions were run in
benzene (bp 80°C), heptane (bp 97°C), toluene (bp 111°C), and octane (bp I26°C). AU
reactions were refluxed for two hours. Diastereoselectivity ratios were determined by
NMR of the crude reaction mixtures. The resuhs of these experiments are summarized m
Table 5.1. WhUe the selectivity was indeed better at lower temperature, we were
surprised that aromatic solvents showed lower selectivity at a given temperature than the
corresponding aliphatic solvent.
Reactmg 62 with imme 67 as shown m Scheme 5.3 resuhed in complete
conversion to cycloadduct 68 within two hours. Submission of the product to refluxmg
benzene with acetone faUed to produce any of the acetone trapped cycloadduct. As a
further control reaction a-oxoketene precursor 33 was reacted with 67 m refluxmg
50
benzene for two hours. No product was observed and only starting materials recovered.
These experiments established that the ketene cycloadduct is stable in refluxing benzene
indicating that at least the trapping reactions at lower temperatures represent kinetic
trapping ratios and not thermodynamic equilibrium.
O O
\.X ^Ph
N A ^AN
62 H Ph
67
*A
II Ph
68
SOX
80°C
N. R.
N. R.
Scheme 5.3
These prehminary resuhs led to flirther studies vnth a series of chiral dienophUes to
trap the a-oxoketene. In each case a series of flve solvent systems was employed; heptane
at 85°C and the original four solvents from the first series, refluxing benzene, heptane,
toluene, and octane. Because the loss of nitrogen could not be initiated below 80°C, an
oU bath was employed to run the reaction in heptane at the temperature range of 80-85°C.
Heptane was chosen because of our desire to use an aliphatic solvent for better selectivity.
Interestingly, we were unable to observe any product at 80°C in heptane in contrast to
51
benzene and the temperature had to be increased slightly to 85°C for even slight
deazatization to occur.
The second chiral trap used was 2-methoxy-2-phenylpropanal (70) which was
prepared as seen in Scheme 5.4. Aldehyde 34a was brominated giving rise to aldehyde 69
which was converted into 70 by treatment whh a solution of silver nitrate in methanol.
O O MeOH/
H V - ^ H^3, — Ph Ph
34a 69
Scheme 5.4
O x^ ^ I^OMe
70 P^
Compound 70 was purified by column chromatography and reacted whh 70 as shown in
Scheme 5.5. The same procedure used in trapping 34a was employed with the five chosen
solvents. The results of these reactions are summarized m table 5.1.
0 O
O ^ V ^ ?
° n l h o M e ° ft i;OMe 71 Ph 71 ^^
Scheme 5.5
The selectivity of these reaction showed the same temperature dependence and
solvent effects that had been demonstrated whh 34a but the selectivity of 70 was
dramaticaUy lower.
We wanted to make comparisons of the diastereoselectivity of imines with chiral
groups on the hmne nitrogen to that of aldehydes 34a and 70. However a direct
52
comparison would not be acceptable because the effects of the imine function group and
the more remote chiral center would be combined in the same reaction. To deconvolute
these effects we prepared chiral imine 72 by treating 70 with propyl amine. Aldehyde 70
was used to generate 72 in place of aldehyde 34a desphe lower selectivity because 70
contains no a-hydrogens. Reactions of aldehydes containing a-hydrogens with amines
produce eneamines. Of course, eneamines contain muhiple flinctionalitys which would
most probably result m trapping of the a-oxoketene with the amine fiinctionaUty. Imine
72 was subjected to the famihar reaction condhions as shown in Scheme 5.6 and whose
resuhs are shown in Table 5.1.
•V -A^ N2 ^^ H i^OMe H J^OMe
62 72 73 Ph 73 P"
Scheme 5.6
The effect of the hnine was readily apparent and surprismg as the
diastereoselectivity was decreased even flirther than with aldehyde 70. These effects were
hritiaUy attributed to the imine bemg more reactive than the corresponding aldehyde. A
compethion reaction trapping ketene 63 with imme 72 and aldehyde 70 was set up to test
this hypothesis. The ratio of hnine to aldehyde was approxunately 1:3 yet the ratio of
cycloadduct arismg form 72 to 70 was approximately 95:5 demonstratmg that the hnine
effectively out-competed the aldehyde.
53
Having tested the effect of the imine on diasterioselectivity the next step was to
test the effect of placing the chirality remotely on the nitrogen of an imine. Racimic chiral
imine 74 was prepared by reacting benazaldehyde whh DL-a-methylbenzylamine. Imine
74 was then reacted with 62 as seen in Scheme 5.7 as was done in the previous trap
I O Ph O Ph
62 74 75 75
Scheme 5.7
studies with the same series of solvents. Resuhs of these reactions are summarized in
Table 5.1. The diastereoselectivity of cycloadducts 75 was lower than 65 and 66 which
was expected due to the more remote nature of the chhal group. However the
diastereoselectivity was much higher than expected based on the trapping resuhs of hnine
72. The solvent effect was once again pronounced in contrast to 72 as well.
Finally in an effort to explore the effect of multiple stereocenters to produce double
diastereoselectuty in the reactions of a-oxoketene with chiral dienophiles. Diastereomeric
imines 76 were prepared by reacting aldehyde 70 with DL-a-methylbenzylamine. Colunm
chromatography of hnines 76 resulted m an approximately 1:1 ratio of the two
diastereomers. This mixture of diastereomers was then reacted with 62 in a simUar fashion
to the previous trapping reactions as shovra m Scheme 5.8, giving rise to the four
cycloadduct diasteriomers 77. Separation of the diastereomers was accomplished by
HPLC giving all four compounds. The relative stereochemistries of these four compounds
54
was not determined. Analysis of the crude NMR gave the diastereoselectivity ratios.
These results are summarized in Table 5.1. The results were surprising. We expected the
effects of two chiral centers to at least be additive and expected selectivity better than the
reactions of 70 and 74. However the selectivity closely paralleled that of imine 74 with
only a slightly increase in diastereoselectivity and with the same solvent effect.
O O 76 Pli
62 N2 . X
H OME
76 Ph
Scheme 5.8
55
OMe H
N ^ ^ P h N^ Ph N ' ^ ^ P f i .X. II
OMe H Ph H
74
OME H
76 Ph
OME
76 Ph
Figure 5.1 Molecules used in trapping reactions shown in Table 5.1
Table 5.1 Results of trappmg studies.
Entry a b c d e f
g h J k m n o
P q r s t u V
w X
y
Trap 34a 34a 34a 34a 70 70 70 70 70 72 72 72 72 72 74 74 74 74 74 76 76 76 76
Solvent Benzene Heptane Toluene Octane Heptane 85°C Benzene Heptane Toluene Octane Heptane 85°C Benzene Heptane Toluene Octane Heptane 85°C Benzene Heptane Toluene Octane Benzene Heptane Toluene Octane
cycloadduct 63:64 63:64 63:64 63:64 71 71 71 71 71 73 73 73 73 73 75 75 75 75 75 77 77 77 77
Product ratios 47:100 43:100 59:100 58:100 65:100 70:100 68:100 76:100 70:100 88:100 90:100 90:100 89:100 89:100 68:100 78:100 73:100 82:100 73:100 80:102:93:100 64:94:84:100 76:103:98:100 66:95:91:100
56
5.3 Discussion
The use of thermally generated a-oxoketenes from diazo compounds has inherent
limitations when studying stereochemical phenomena. These Hmitations include the use of
higher temperatures which most likely provide lower selectivity. Obviously higher
selectivities are desirable from a yield, cost, and purification standpoint. Thermal
generation can also lead to ahemate reaction pathways not accessible at lower
temperatures which can cause more side products. However, if this chemistry is to be
utilized syntheticaUy, the trade off in ease of set up, higher yield, and potentially simpler
separation depending on the reaction, may easily overcome these Umhations.
But of greater mterest to our studies are the implications of the selectivity as well
as the thermal and solvent effects on the reaction mechanism. In order to analyze this
series of reactions m terms of mechanistic hnpHcations h is helpful to first break the
reaction down mto hs component parts. The first step in these reactions is the loss of
nitrogen from compound 62. The loss of nitrogen is foUowed by Wolff rearrangement to
give the a-oxoketene mtermediate 63. Given the reactive nature of a-oxoketene, this first
step is the rate determining step. The second step of the reaction is the product
determining step of the reaction where intermediate 63 reacts with the dienophile leading
to the cycloadduct product. Because the observed trappmg ratio is manifested in the form
of the cycloadduct that arises from the product forming step of the reaction, and the
ketene is a common mtermediate m each of these reactions, we can effectively ignore the
first rate determining step and focus on the product forming step. This is convenient since
57
we wish to investigate the reaction of the ketene with the dienophile and not the
deazatization.
It is first important to compare the resuhs of the thermal solution phase work whh
our original studies of chirality induction by FVT."*"* Comparing the resuhs of solution
trapping of 62 with 34a to the FVT study in Chapter 3, trapping 34a with acetyUcetene
shows that at moderate temperatures the resuhs correlate well. In heptane the ratio of the
products of this reaction (Scheme 5.2) is 43:100. This is nearly identical to the ratio of
products from the reaction of acetylketene (33) with 34a (Scheme 3.3) of 44:100. This
indicates that the thermal trappmg resuhs can give a good measure of the selectivity
possible in these reactions.
Before discussing the solvent effect h would be helpful to analyze the reactions of
the chiral hnines 72 and 74 with 62 as h wiU have a bearing on the discussion regardmg
the solvent effect. On the surface these two reactions appear quhe different with 72
providmg very low selectivity despite the proximity of the chhal group to the newly
forming stereogenic center and 74 providing modest selectivity v^th a more remote
stereocenter. Further the reaction with 72 shows very little solvent effect while 74 shows
a much larger solvent effect. However these reactions can be explained with a common
mechanism. Unpublished computational resuhs from this lab* mdicate that the reaction of
a-oxoketenes with hnines is stepv^se as shown m Scheme 5.9.
58
N'
H
-R'
We have argued that a stepwise mechanism would lead to lower selectivity."*' That
appears to be the case in the reaction of 72. But what about the reaction of 74? How is h
that if this mechanism is correct that selectivity and a solvent effect is observed. These
observations can be rationalized with the stepwise mechanism. In the case of 72, the R
group on the nitrogen is a propyl group which should not bias the conformation of the
chiral group on the imine carbon to any extent as shown m Figure 5.1. This lack of bias is
also the basis for the lack of solvent effect which will be cUscussed later. The closing
reaction should be fast and the incoming nucleophUe will not be able to discrimmate weU
between the conformations of the chiral group, and lead to low selectivity. However m
the reaction of 74 the chiral group on the nitrogen wUl interact vAth the phenyl ring on the
imine carbon and bias hs conformation before the addition of the nucleophile as shown m
Figure 5.2. This wiU lead to rotational selectivity in the intermediate as the phenyl ring
and the hydrogen wiU have different propensities to move away from the chhal group.
When the cycloadduct is formed torquoselectivity wiU then be observed.
59
I II / Ph II /^Ph ©. . _ . . _ . .
CH3 1PCH3 Y l ' ^ ' " ' Y^ f^ '
79 80 Ph
OCH3 CH3
Figure 5.2 Stepwise intermediates in the reactions of 72, 74 and 76 with 63.
The selectivity of diastereomers 76 was nearly identical to that of imine 74. If the
reaction is stepwise, this is not a surprising result as the initial reaction creates the
zwitterion 80 which looks very simUar to that of 79. The incommg nucleophile then has
very Uttle discrimination for the second chiral center just as seen with imine 70. Therefore
otUy a sHght increase in selectivity for imines 76 over imine 74 can be rationalized.
What was far more surprismg was the solvent effect of the aromatic solvents on
these reactions. When a change to a more polar solvent effects the rate of reaction, h is
generaUy considered evidence of a stepwise mechanism. However in this case we have
not measured the rate of reaction, only the stereochemcial outcome of the products.
Lower selectivity is indicative of a change m activation energy barriers. This raises the
question how is the solvent impactmg the reaction?
The first possibility is an interaction whh the ketene intermediate. If the aromatic
solvent mteracts with the ketene intermediate 63 it could unpact the outcome of the
reaction. However for lower selectivity to be observed the intermediate would have to be
destabUized m aromatic solvents. The ketene is expected to have poshive and negative
charge buUd up at different poshions on the ketene. The ketene is also conjugated and
60
contains several pi bonds. It seem highly unlikely that more polar aromatic solvents would
destabilize the intermediate and in contrast, would most likely stabilize the intermediate
through charge charge interactions or pi-stacking.
The second possibility is a lowering of the transition state energy in the product
forming step. This rationalization seems much more acceptable except that each reaction
series shows an almost identical solvent effect with the exception of trapping whh 72.
Why would reactions that are stepwise be stabilized to the same degree that concerted
reactions are stabiHzed? One would expect that the stepwise imine reactions would be
stabUized by more polar solvent. But if the zwitterionic intermediate is stabiHzed, ring
closure should be slower aUowing for greater discrimination by the incoming nucleophile
and selectivity should be higher in polar solvents, not lower. It is possible that aromatic
solvents stabiHze the transition state in the product forming step and the observed
decrease in selectivity is therefore a function of temperature, but once agam h is hard to
rationalize why stepwdse and concerted reactions should be impacted the same way.
There may however be another answer in this case. The chiral trap 2-
phenylpropanal (34a) was used by FeUdn et al. in their original studies."*' The authors
noted the importance of electronegative substituents, particularly the phenyl ring, in
selectivity. They were able to demonstrate greater diastereoselectivity for 2-
phenylpropanal (34a) vs 2-cyclohexylpropanaI.'*' This difference is clearly due to the
electronegativity of the phenyl ring as the phenyl ring and the cyclohexyl ring are sterically
equivalent. FeUdn et al. attributed the greater selectivity of the 2-phenylpropanal to the
mteraction of the electronegative group with the mcommg nucleophile and the carbonyl
61
carbon. The authors argued that if the large group was electronegative h would
reinforce the selectivity as shown in Figure 5.3 A. However if the medium group was
electronegative, selectivity would be reversed as seen whh 2-chloropropanal,'''''*^ as
shown in Figure 5.3B.
Leiec
u S \
nu
Melee
B
O
u S \
L = large group M = medium group S = Small group elec = electronegative group
nu
Figure 5.3 FeUdn-Anh models of the effects of electronegativity on selectivity.
In the studies reported here nearly every reaction series with the exception of the
reaction series of Scheme 5.6 with imine 72 show a loss of selectivity in aromatic solvents.
This effect is hard to explain given the current data. However h might prove helpful to
propose two possible hypotheses to explain this data.
AU the chiral groups used in these trappmg studies contam a phenyl substituent.
The solvent would surround the cMral group. In the case of hydrocarbon solvents, the
phenyl group would be expected to exhibh a strong interaction with the carbonyl oxygen
and the incoming nucleophile. However m the case of aromatic solvents, this same
interaction would be minimized because the carbonyl oxygen and mcommg nucleophile see
the same electronegativity aU around them. Therefore the discrimination of the incoming
62
nucleophile in aromatic solvents would be purely steric in nature whhout the reinforcing
eflfects of the phenyl groups electronegative interaction. Therefore the solvent effect seen
in each series of these reactions is a measure of the reinforcing effects of the phenyl
groups electronegativity on the overall selectivity.
Another possible explanation is a more traditional view of the solvent effect. The
reactions of a-oxoketene whh aldehydes are expected to be concerted but asynchronus.
Since the aromatic solvent is more easily polarizible than the correspondmg ahphatic
solvent, the aromatic solvent would be expected to stabiUze a charged transition state.
The reactions of the aldehydes being asynchronous would show some charge buUd up in
the transition state which would be better stabilized by the aromatic solvents. This m turn
would give rise to a transhion state that becomes more stepAvise in nature. Reactivity data
from the hnine reactions show that stepwise reactions show poor selectivity and therefore
the reduction m selectivity seen v^th the aldehydes is due to the transition state becoming
more stepwise. The hnine reactions are most likely stiU affected by the electronic
mteractions discussed above. The reactions of the hnines are stepwise and their selectivity
is not based on FeUdn-Anh discrimination, rather torquoselectiviy and therefore
stabUization of the charged mtermediate should not impact selectivity.
FeUcm at al. failed to address the eflfects of electronegativity when the most
electronegative group is the small group as seen m Figure 5.4. Does the smaU
electronegative group assume the dhecting role or do sterics overcome the electronegative
eflfects?
63
B
Selec
L = large group M = medium group S = Small group elec = electronegative group
Figure 5.4 Felkin-Anh models with a small electronegative group.
Cram has shown selectivity when reacting phenyl Gringard with 3-phenyl-2-
butanone (81), as shown m Scheme 5.10. The major product is 82, the minor 83 in a ratio
of 86:14, but this selectivity is a product of chelation control.' '*'**' To the best of our
knowledge no one has addressed the question of the selectivity from Figure 5.4 without
chelation control.
Mg - ^
Pti"' V CH3 CH3
81
H3CO OH H3CO OH
"'Ph*'"/ V"CH3 Ph' ' ; / V!'Ph H3C
"CH3 Ph" ; Ph H3C CH,
82 83
Scheme 5.10
The reaction of aldehyde 70 with 62 is unique in that the configuration of the chhal
center is that seen in Figure 5.4, and the reaction of the ketene with 70 is not under
chelation control. WhUe we have no concrete evidence of the conformation of the chhal
group, some conclusions can be drawn. The solvent effect of the reactions of Scheme 5.4
is very similar to that of the other reactions. This suggests that a large change in
64
configuration with the addition of aromatic solvents does not occur. If the conformation
of the aldehyde is dictated by steric interactions, model B of figure 5.4 should be the most
important. Comparisons of the steric bulk of the substituents of 34a and 70 can then be
compared.
"A values"*' are often used as a measure of the steric bulk around a reactive
center. Since the A value is actually an equilibrium constant of endo-exo ratios of
cyclohexanes it is not a perfect measure of steric bulk but is a convenient relative measure.
The A values of the substituents of 34a and 70 appear below in Table 5.6. '
Table 5.2 "A Values" for substituents of compounds 34a and 70.
Substituent H OCH3 CH3 Ph
A Value 0 0.8 1.8 3.0
In the case of 34a the incoming nucleophile must discriminate between groups
with an A value difference of 1.8 while the A value difference is only 1.0 in the case of 70,
just less than half of the steric discrimmation of 34a. If the basis of selectivity of 70 is
purely steric mteractions the selectivity of 70 should be expected to be just under half of
the selectivity obtained with 34a. The selectivity of 34a at 85°C is 44:100 while the
selectivity of 70 at 85°C is 68:100. This data does not conclusively rule out an electronic
mteraction as the selectivity of 70 is better than half that of 34a but h does lend support to
65
the argument that electronic interactions with the small electronegative group do not play
a vital role in the discrimination of the incoming nucleophile in this case.
5.4 Conclusions
In continuing our studies of a-oxoketene diastereoselectivity we have
demonstrated chiral selectivity from a variety of chiral aldehydes and imines. Most
importantly we have given evidence that the reaction of a-oxoketenes with inunes is
stepwise in nature as opposed to the concerted reactions of aldehydes and ketones. We
have demonstrated a solvent effect in these trapping reactions but this is most likely a
fimction of solvent mteraction with the chhal group and not an implication of the
mechanism of a-oxoketene reactivity Avith chhal dienophiles.
66
CHAPTER 6
EFFORTS TOWARDS THE PRODUCTION OF
IMIDOYLKETENE AND THE STUDY
OF ITS REACTIVITY
6.1 Introduction
While a-oxoketenes have been extensively studied and has found utiHzation in
synthetic chemistry,''''"''* relatively littie is known about a-imidoylketenes. In many ways
a-imidoylketenes are expected to be very similar to a-oxoketenes,* bemg generated in
similar ways *" * and reacting through the same pseudopericycHc reaction mechanism.''*
Just as a-imidoylketenes are expected to be similar to a-oxoketenes in some respects, h is
expected to be strikingly different m others. Primarily the difference is expected to be
manifested electronically because the nitrogen an of a-imidoylketene is expected to be
more nucIeophiHc than the corresponding oxygen of an a-oxoketene. The fhst question
that arises is what impact might this change in electronics have on the mechanistic aspects
of a-hnidoylketene reactivity? Addressmg some of these questions a-imidoylketenes have
been shown to behave shnilarly to a-oxoketene towards amines and alcohols, showing
selectivity for less hindered nucleophies and ammes in preference to alcohols. As noted m
Chapter 2, a-hnidoylketenes have also shovra shnUar reactivity towards imines and have
been shown to dhnerize. **
67
A question that has not been addressed is the impact of the electronic differences
of a-imidoylketenes on reactions with dieneophiles. The greater nucleophilicity of the
nitrogen an of a-imidoylketene as compared to the corresponding a-oxoketene may effect
the concertedness of the reaction making it more ionic in character. Do the electronic
differences have an impact on the chemo-, regio-, or stereoselectivity as compared to a-
oxoketenes in reactions with dienophiles?
The greater nucleophilicity of an a-imidoylketene should lead to faster reactions.
a-Oxoketenes can be stabiHzed effectively by adding steric bulk forcing them into a non-
reactive conformation.^^ Can the same principle be applied to synthesize a stabilized a-
imidoyUcetene that can be observed and characterized at room temperature?
The synthetic ability to easily and reliably introduce nitrogen mto heterocyclic
molecules is deshable. Can a general method of producing a-hnidoyUcetene cleanly in
order to better utilize them syntheticaUy be developed? Eneamino esters have prove an
effective means of generatmg a-imidoylketene.' However trapping the ketene requires
that a agent more reactive than the by-product alcohol. Meldrum's acid derivatives and
2,3-pyrolediones can be thermoHzed to give a-hnidoylketenes.^''^* However thermal
methods Hmit the selection of R groups that can be placed on the a-imidoylketene
nitrogen because this molecule is highly susceptible to 1,5 hydride shifts as seen in Scheme
2.15."* ' *
68
These studies focus on the production of a-imidoylketene, the comparison of hs
reactivity to that of a-oxoketene. Our studies have then attempted to focus on the
implications of the mechanism of a-imidoylketene reactivity.
6.2 Resuhs
This research started with the goal of synthesizing a hmdered imidoylketene that
would be stable at room temperature. It was thought that the way to achieve this
molecule was to use the build an imidoylketene analog of 19 with large stericaUy bulky t-
butyl groups. Like 19 the steric bulk would push imidoyUcetene 84 to adopt the unreactive
s-E conformation and prohibit rotation mto the reactive s-Z conformation. This
compound would then be stable at room temperature and could be easUy characterized.
Scheme 6.1 represents a retrosynthetic analysis of the production of 84.
O
l y ' ^ ^ " \ / \ - - 5 . 0 Chloride ^c"'^— amine Oxalyl l ^ .Bu
N A f-Bu^
85 86
yr =^ •,! > ^ t-Bw ^Bu
84 Q O
87 88 89
Scheme 6.1
This Scheme was modifled as shown in Scheme 6.2 to overcome difficulties in the
retrosynthetic approach.
69
Scheme 6.2
The addition of the Grignard reagent 89 to the acid chloride 88 resuhed m a
complex reaction mixture that was not only difficuh to separate but also difficuh to
reproduce. The synthesis was then changed to produce the Hthium Grignard in situ from
90 foUowed by addhion of ^butyl aldehyde to give the alcohol 91 which was then oxidized
by the Swem reaction to give 87. However addition of/-butyl amine to 87 gave none of
the deshed product 86. After several attempts to produce 86, model reactions were run
reacting acetophenone (92) with propylamine and aniline as shown m Scheme 6.3 to
produce hnines 93 and 94. Once the methodology for hnine generation was developed,
reaction of/-butyl amine with 92 was attempted to test the reactivity of/-butyl amine. No
product was obtained indicating that t-butyl amme is quite uru-eactive. The most probable
explanation for this lack of reactivity is that the large steric buUc of the /-butyl moiety
decreasmg the abUity of the nucIeophiHc nitrogen to attack moderately hindered
electrophiles.
70
Propyl amine
aniline
f-Bu amine ., »- No reaction
Scheme 6.3
Whh the production of the model imines 93 and 67 complete, but Imgering
problems with the /-butylamine it was decided to go forward and use the model imines 93
and 67. These imines were cyclized as shown in Scheme 6.4 with oxalyl chloride to
produce the brightly red colored pyrole-2,3-diones 94 and 95.
71
cr CI
cr CI
67 V ^
Scheme 6.4
With the production of 94 and 95 h was decided to use these compounds to
develop methodology to produce imidoylketene. The use of photolysis to open 2,3-
flirandiones has been well documented, however exhaustive attempts to open 94
photoIyticaUy as shown in Scheme 6.5 returned only starting material. Another problem
became evident as it was found that 94 and 95 would react whh nucleophUes wdth only
mUd heating to open the 2,3-pyroledione resulting in a-ketoesters** such as compound 96.
These results showed that solution phase generation of the ketene with nucleophilic
trapping compounds would not be practical.
72
350 nm •'O . trapping rayonet
\ \ / compound *- No Reaction -N Hanovia
lamp
94 + Eton
94 +
N - " " ^ ^ ^
Scheme 6.5
Since 94 was on hand, h was subjected to FVT conditions to create the a-
imidoyUcetene thermaUy. While this procedure apparently did produce the ketene
intermediate, the temperature required to thermolize 94 was high enough to cause the
formation of 98. Presumably 98 is formed from 94 by a [1,5] hydride shift of the ketene
mtermediate to give mtermediate 97 which then gives rise to compound 98 through a [1,3]
hydride shift.
Because of the propensity of the R group on the nitrogen to give up p-hydrogens
in [1,5] hydride shifts we reasoned that if a precursor could be produced with R groups
that did not contain P-hydrogens, the ketene could then be produced and trapped without
the [1,5] hydride shift destroying the ketene. The best choice was considered to be a
hydrogen substituent as h would fulfUl the above requirement as well as aUow for
modification of the amme after the ketene reaction was complete. As shown in Scheme
73
6.6 we first tried to produce a hydrogen bearing imine directly that could then be cyclized
with oxalyl chloride. The reaction of acetonitrile with phenyl Grignard reagent resuhed in
consumption of the Grignard but only degradation products were formed. A second
method was tried to generate the imine by reacting 92 whh both ammonia and
ammoniumacetate. Neither reaction resulted in the desired imine.
N / = + (s V - M g B r ^ Degradation
92 \ ^
a:NH3 ,, „ ^ No Reaction
b: NH40AC
Scheme 6.6
A second approach was tried which used a protected amine m the synthesis an
imine which could be deprotected after cycHzation to give the 2,3-pyroledione bearing a
hydrogen substituent on the nitrogen. /7-Methoxybenzylamme (99) was reacted with 92 to
give imine 100 which was then cyclized with oxalyl chloride to give 2,3-pyroledione 101
as seen in Scheme 6.7. However reaction of 101 with ceric ammonium nitrate (CAN), the
standard oxidative deprotecting agent for the para methoxybenzyl protecting group faUed
to remove the protecting group. Reaction of 101 with DDQ as well as lead subacetate,
with a higher oxidation potential,** also faUed to remove the protectmg group.
74
H,N
Me CI CI
O
No Reaction DDQ
Pb(0Ac)4
101
Scheme 6.7
Two more strategies as shown in Scheme 6.8 were employed to generate a-
hnidoyUcetene thermally. Isatoic anhydride (102) was subjected to FVT conditions to
produce a-hnidoylketene. However the solubihty of 102 was so poor that virtually none
of the material went through the thermolysis tube m the FVT reactor. The smaU amount
of solid that did go through remained unchanged by the reaction.
O
-O FVT No Reaction
No Reaction
103
Scheme 6.8
75
Meldrum's acid derivative 103 was then tried as a means (Scheme 6.8) of
generating a-imidoylketene. This compound in particular was appealing because the ring
system would confine the a-imidoylketene to the reactive s-Z conformation while keeping
the R group attached to the nitrogen out of proximity of the a-carbon of the ketene thus
not allowing the [1,5] shift to occur. While 103 proved to be readily soluble h was not
thermoHzed on exposure to FVT condhions. Even temperatures above 800°C failed to
give anything but recovered starting material.
Our final attempt to produce a-imidoyUcetene revolved around the use of diazo
compoimds. Diazo compounds are often an excellent source of a-oxoketene'^''^but
because of theh toxicity and lack of precedent in producing a-imidoylketenes we had
avoided theh use. As seen in Scheme 6.9 diazo compound 105 was readily generated
from p-ketoester 104 by standard procedures. However treatment of 105 with
propylamme to produce the imine resuhed instead in amidation of the ester moiety of 105
to give 106. Reaction of 106 with excess amme also faUed to produce the hnine. This
result is not enthely surprisuig given that amides are more stable than esters.
76
?\ ?\ o o o o
104 105 ^2 106 , 2
AJ^ph PTS0N3 A ^ p , 107 108
P P O
Ph
109 N2
PTSON3 ^ ^ > l ^ ^ p h
O O ' ^ - - ^ ' ^ N H O J ^ 111 ^2
/J^Aph HNPr, A A F Ph -^ ^ ^ ^ ^ ^ Ph 107 ^^0
Scheme 6.9
Reaction of P-ketoester 107 with the diazo transfer reagent"*'readily facilhated
production of diazo compound 108. Treatment of 108 with propylamine resuhed in
cleavage of ketoeneamine and resuhed only in diazoketone 109.
It was thought that perhaps the order of addition of the components would make a
difference in preparing the diazo precursor and so compound 107 was reacted with propyl
amine to generate hnine 110. This reaction showed remarkable regioselectivity, only the
ketone moiety bearing the methyl group reacted to form an eneamine product. No
evidence of amine reaction at the other ketone was observed. However treatment of 110
with the diazo transfer reagent resulted m a compound with 'H and ' C NMR spectra
77
consistent with 111. What was thought to be compound 111 was subjected to photolytic
conditions with a trapping agent but formed only a white solid with a similar but shifted
NMR pattern. IR spectroscopy of compound 111 revealed the absence of any diazo
stretch and so the structure of 111 could not be what was originally proposed. The result
of the reaction of 110 with the diazotransfer reagent is most likely structure 112.
6.3 Discussion
Production of a-imidoylketene has proved to be more difficult than originally
anticipated. The use of 2,3-furandiones in the production of oxoketenes is versatile based
on its response to both thermal and photochemical means of opening. The by-product of
this ring opening is carbon monoxide making this reaction virtually hreversible. However
2,3-pyroledione has not proved to be as versatUe. We have been unable to photolyticUy
open 2,3-pyroledione with a variety of solution phase and matrix isolation experiments. It
may be possible that the choice of substituents on the 2,3-pyrolediones tested precluded
the photolytic activity. The common trah between aU of the pyrolediones tested was the
hydrogen and phenyl substituents in the C4 and C5 poshions of the 2,3-pyrolediones
respectively. Perhaps the phenyl ring is hnparting excess stabilization via resonance
through the pi bonding system or perhaps h is serving to quench the exerted state of the
molecule and thereby precluding photolytic activity.
As expected, thermal generation of a-imidoyUcetenes is possible form 2,3-
pyrolediones however the temperatures necessary for the thermolysis provide the energy
78
necessary for side reactions of the reactive ketene moiety with the substituent on the
nitrogen of the imidoylketene precluding intermolecular reactions. This problem might be
surmounted as we suggest by placing a hydrogen substituent on the nhrogen of the a-
imidoylketene. We have as yet been unable to test this theory.
The use of diazo compounds to produce ketene and a-oxoketene has provided a
reliable method to access several ketene species. From the series of reactions involving
compounds 104 to 112 it is evident that the standard methods for producing a diazo
precursor to a-imidoylketene do not resuh in the desired products. This is unfortunate
given the versatile nature of the diazo compounds and what seems a major source of a-
imidoylketene now seems inaccessible due to functional group incompatibility that has
plagued other aspects of this research.
6.4 Conclusions
The analogy of a-imidoylketene to a-oxoketene may be difficuh to explore
because of severe differences imposed on the production and reactivity of a-imidoylketene
by the nature of the nitrogen herteroatom. The reactivity is greatly impacted by the
substituent on the nitrogen. What one might originaUy consider a minor perturbation or
even a potential she for modification has proved to be a major stumbling block to utUizing
a-hnidoylketenes. Even precursors are hnpacted by this change and therefore h is proving
difficuh to apply the analogous a-oxoketene chemistry to produce a-imidoylketene.
While h may stiU be possible to exploh some of the a-oxoketene precursors through the
79
use of protecting groups on the nitrogen, rt has not as yet proved that simple. It is likely
that new methodology will have to be developed for a general method of a-imidoylketene
production.
80
CHAPTER 7
CONCLUSIONS
The work in this dissertation has focused on the reactivity of a-oxoketenes and
provided experimental evidence for the pseudopericyclic reaction mechanism. We have
demonstrated that a-oxoketenes react with chhal dienophiles in a stereoselective manner.
This diastereoselectivity is in accordance whh the Felkin-Anh model. Conversely, the
reactions of chiral a-oxoketenes have been shown to be nonstereoselective. This data
provides exceptional evidence to confirm that a-oxoketenes react through a
pseudopericycHc reaction mechanism as opposed to a pericycHc reaction mechanism. This
impHes that the transition state is planar and means that Felkin-Anh selectivity can be
expected with these systems. We further went on to demonstrate that the reactivity of a-
oxoketenes are highly sensitive to the steric bulk of the dienophUe. This data could prove
useful in synthetic appHcations.
Camphorketene is an a-oxoketene that has been investigated since 1920. We have
proved the structures of the camphorketene dimers first proposed by Yates and
Chandross, confirming the [4+2] dimerization mechanism. However we have also
discovered that unlike other a-oxoketenes, camphorketene faUs to react with aldehydes.
In contrast, camphorketene reacts as a typical a-oxoketene is expected to towards
alcohols. We have also demonstrated that P-ketoesters of camphorketene show no enol
tautomerization. AU of these observations are rationaUzed by the stram hnposed on the a-
oxoketene moiety by the camphor structure. This strahi forces the ketene and ketone
81
flinctionaHties further apart as compared to formylketene. This data may also explain
other experiments where strained P-ketoester systems show no appreciable enol
formation. One other interesting observation was noted. a-Oxoketenes have been
shown to react selectively with alcohols of decreasing steric bulk. In this reaction
sequence we were able to dhectly compare the P-ketoacid chloride of camphor to
camphorketene. Desphe bemg significantly more reactive, the a-oxoketene displays
higher levels of selectivity.
In an effort to enhance our understanding of the selectivity of a-oxoketene we
ttapped methylacetylketene with various chiral aldehydes and imines. These results
proved interesting as a solvent effect was noted as well as an apparent change in
mechanism depending on the dienophUe. Based on the selectivity we beHeve that the
reactions of a-oxoketenes with hnines is stepwise and therefore not pseudopericycHc,
opposed to the concerted mechanism in reactions with aldehydes and ketones. This is
perhaps the most mteresting resuh of this work providmg evidence that ahemate reaction
pathways are accessible by choice of dienophile. Dienophiles with strong nucleophilic
shes may be expected to react in stepwise fashion. Even though the stepwise mechanism
is invoked, moderate levels of selectivity can stiU be achieved by using chhal groups on the
hnine nitrogen. This selectivity is most Hkely a product of torquoselectivity of the R
group on the imme carbon respondmg to steric and electronic interactions v^th the chiral
group on the imine nitrogen rather than discrimination of the nucleophile.
In this series of reactions we observed a solvent effect on selectivity. Selectivity
was consistently lower m aromatic solvents than aliphatic solvents at similar temperatures.
82
This solvent effect may be attributed to electronic affects of the chiral group or possibly a
change in the mechanism of reaction.
These resuhs have given experimental evidence to support the computer models of
a-oxoketene reactivity. While the experiments have affirmed much of what we believed
to be true regarding a-oxoketene reactivity they have also created new questions yet to be
answered.
83
CHAPTER 8
FUTURE RESEARCH AIMS
8.2 Introduction
As often occurs in science, the pursuit to answer a question only raises others, as
has often occurred in the course of this work. While we have answered many of the
questions that were proposed, new questions have arose which beg experimental work to
answer.
8.2 Solvent effect studies
In the trapping studies of Chapter 5 we observed a pronounced solvent effect. The
proposed reason for these solvent effects is as least provocative given that solvent effects
are normally attributed to intermediate or transition state electronic effects, as opposed to
nucleophilic discrimination. This theory demands to be tested. In Felkin's original work,
ketone 34b was employed along with 3-cycIohexylpropanal (113)."*' FeUcin's work
pomted out the importance of the electronegativity of the phenyl ring. The trapping
experiments of Chapter 5 should be repeated using 113 as seen in Scheme 8.1. If the
solvent effect is as proposed, a product of nucleophilic discrimination, no solvent effect
should be seen in trappmg 113. This would serve as an effective test of this theory.
Further, if a solvent effect is observed h would support an mcreased stepvdse component
of the reaction mechanism.
84
113
Scheme 8.1
8.3 Electronegativity effects
Selectivity has been shown to be greatly impacted by electronegative substituents
as noted in Chapter 5. Our reaction system gives a unique opportunity to study
stereoselectivity in the absence of a chelating agent. WhUe this particular area of study has
aheady been explored,*" selectivity based on non-chelation control has relied on hindered
Lewis acids mstead of the absence of any chelating agents. Our trappmg reaction have
aheady shown Felkm-Anh selectivity, and contam no chelating agents, giving a very clear
picture of electronic effects. A series of trapping reactions could be designed to try to
quantify the importance of electronegative groups on stereoselectivity, particularly what is
the effect if the stericaUy smaU group is the electronegative group. The first series of
reactions that could be run would be trapping 63 with compounds aheady studied
including those shovm in Figure 8.1.
85
OCH, H
OCH.
~H H
CH3
H
Figure 8.1 Test compounds with known non-chelation selectivity.
In each of these compounds the most electronegative group is the sterically
medium sized group which should provide the primary discrimmation in the Felkm-Anh
model. The results of trapping with these compounds can then be compared whh the
resuhs of previous non-chelation experiments. Once these comparisons are made, further
trapping could be done with compounds where electronegative substituents are sterically
small to answer questions about the importance of electronic mteractions vs. steric
mteractions. Possible trappmg compounds include the following compounds shown in
Figure 8.2
HV CH-;
' ^ ^
CH3 H ^ '
,F
XH3
Figure 8.2 Test compounds for selectivity for smaU electronegative groups.
Another possible trappmg experiment of interest m this series would be to use an
electropositive group to see if hs effects would be opposhe that of electronegative groups
86
and then if these effects could be additive. Such compounds might include the following
shown in Figure 8.3.
H CH3
SiMe3
SlMeq HV_ PCH-,
I SiMcs H
OCH3
H SiMe3
Figure 8.3 Test compounds for selectivity with electroposhive groups.
Also in Chapter 5 we asserted that the imine reactions with 63 are stepwise and
that the selectivity seen was based on torquoselectivity of groups on the imine carbon in
spatial relation to the group on the imine nitrogen. To test this theory a series of trappmg
molecules could be tested with mcreasing steric bulk on the imine carbon. These
molecules could include the foUowing as shown in Figure 8.4
Ph Ph
N'
H
N
Ph
H'
N
Figure 8.4 Imine trapping molecules for torquoselectivity study.
If torquoselectivity of groups on the hnine carbon is the basis of selectivity, higher
levels of selectivity should be seen with larger groups.
87
Finally we would like to find a method to produce imidoylketene that could be
used in our trapping studies. With the change in electronegative effects of a-
imidoylketene compared to a-oxoketene, would reaction with aldehydes and ketones be
stepwise? Could the reaction of a-imidoylketene with imines be concerted? To this end a
hydrogen bearing pyrroledione could be produced by the following retrosynthetic analysis
as shown in Scheme 8.2
R ^ X S ^ ° (COCO2 ^/SiMea
" yl =^ ..X. :>
Ph SiMe3 H ^^
O y + H2NSiMe3
H - ^ P h
Scheme 8.2
This compound could give access to hydrogen bearing a-imidoylketenes which we
propose would not rearrange, and allow trapping of the a-imidoylketene with various
dienophUes.
88
CHAPTER 9
EXPERIMENTAL
9.1 Solvent and Chemical Procedures
Reaction solvents used were freshly distilled or recently distilled and stored over
drying agent unless noted. THF was distilled from, either sodium or NaK.
Dichloromethane, triethylamine, acetonitrile, were distiUed from calcium hydride. Ether,
Benzene, toluene, heptane, and octane were distUled from sodium. Chloroform was
distiUed from calcium chloride. Acetone, ethanol and methanol were used as received or
dried over 4A molecular sives. 2,2,6-TrimethyI-4H-l,3-dioxm-4-one (32) was purified by
passing h through a plug of siUca gel and eluting with ether or ether/hexane mixtures.
Other reagents were used as received.
9.2 Spectroscopy
NMR Spectra were obtained m ehher CDCI3 or (CD3)2CO. Proton NMR spectra
were obtained at 500MHz, 300MHz and 200MHz. Carbon NMR spectra were obtained
at 125MHz, 75MHz and 50Mhz. These spectra were recorded on the foUowing NMR
mstruments; Varian INOVA 500MHz; Varian UNITY 300MHz, Burker 300MHz and
Bruker 200MHz NMRs. IR spectra were recorded on Perkin-Elmer 1600 and 1650 FTIR
histmments. These spectra were obtained usmg sodium chloride salt plates. Uv-Vis
spectroscopy was done on a Shimadzu UV-265 using acetonitrile or cholorform as
solvents.
89
9.3 Chromatography
Flash chromatography was done using 230-400 mesh 60A flash grade silica gel.
Chromatography solvents were not distilled prior to use. HPLC separations were
performed using a 19 mm x 30 cm 60A, 60 pm silica gel column with a tunable
absorbance detector at 260 nm. HPLC grade solvents were degassed prior to use in
HPLC.
9.4 Flash Vacuum Thermolysis (FVT)
All FVT experiments were carried out in the following manner unless otherwise
noted. AU FVT experiments were done with a quartz tube approximately 50 cm in length,
placed vertically, and heated by a tube furnace to approximately 400°C as measured with a
thermocouple. A trap placed at the receiving end of the quartz tube used with liquid
nitrogen as the trappmg agent. An addhion furmel was placed on the top of the quartz
tube and used for sample deHvery into the heated tube. The apparatus was evacuated by a
rough pump which provided approximately 0.25 torr vacuum. In each experiment the
vacuum and tube furnace were allowed at least two hours to warm up and equUibrate
before samples were introduced. After each experiment the apparatus was flUed with
heHum, the tube furnace cooled and the trap warmed to room temperature.
90
9.5 Synthetic Procedures
3-Phenyl-2-butanol (35b). In a 100 mL round bottom flask, THF (20 mL) and 2-
phenylpropanal (1.8 mL, 14.9 mmol) were cooled to -78°C. To this reaction mixture
methyllithium solution (10.0 mL, 16.4 mmol, 1.4 M) was slowly added. After addition
was complete the reaction was warmed to room temperature. The reaction was worked
up m cHethyl ether then washed successively whh sodium bicarbonate and brine solutions.
99% yield. These compounds were prepared and characterized previously by Kingsbury
et. al.
Kingsbury, C. A.; Thorton, W. B. J. Org Chem., 1966, 31, 1000-1004.
3-Phenyl-2-butanone (34b). In a 100 mL round bottom flask with
dichloromethane (20 mL) and DMSO (2.50 mL, 25.6 mmol) were cooled to -78°C.
Oxalylchloride (1.70 mL, 19.2 mmol) was added and allowed to sth for 30 minutes. To
this solution a mixture of 3-phenyl-2-butanol (1.90 mL, 12.8 mmol) and dichlormethane (5
mL) was added and aUowed to stir for 30 minutes. To this reaction mixtiare EtsN (8.9
mL, 64 mmol) was added, aUowed to sth 10 minutes and then warmed to room
temperature. The reaction was worked up in diethyl ether and washed with sodium
bicarbonate and brine solutions. Evaporation of solvent foUowed by siHca gel
chromatography (Hexane/EtOAc, 95/5, 200 mL) produced a 58% yield. This compound
has been previously prepared by Aranda et. al.
Aranda, A.; Diaz, A.; Diez-Barra, E.; de la Hoz, A.; Moreno, A.; Sanchez-Verdu, P. J. Chem. Soc. Perkin Trans 1., 1992,2427.
91
2-Phenyl-3-pentanol (35c). In a 100 mL round bottom flask fltted with a reflux
condenser, magnesium tumings (0.38 g, 12.2 mmol), THF (20 mL), and bromoethane
(I.14mL, 15.3 mmol) were added and stirred. After 2 hours the consumption of
magnesium stopped and the reaction cooled indication completion of reaction. The
resuhant Grignard was transferred slowly via canula to a 250 mL three neck flask fitted
with a reflux condenser and containing THF (20 mL) and 2-phenylpropanal (1.61 mL,
12.2 mmol). The reaction was monitored by TLC and worked up after 2 hours by
extraction with diethyl ether and washed with sodium bicarbonate and brine solutions.
Evaporation of solvent foUowed by silica gel chromatography (hexane/EtOAc, 95/5, 500
mL) produced a 36% yield of a mixture of diastereomers. These compounds were
previously prepared by Jones et. al.
Jones, P.; Goller, E. J.; Kauflftnan, W. J. J. Org. Chem., 1971, 36, 3311-3315.
2-Phenyl-3-pentanone (34c). This reaction was carried out in a simUar maimer to
the reaction producmg 3-phenyl-2-butanone (34b). Changes mclude using 0.69 mL of
DMSO (7.6 mmol), 0.50 mL of oxalylchloride (5.7mmol), 0.63 g of 2- phenyl-3-pentanol
(35c) (3.8 mmol), and 2.65 mL of EtsN (19.0 mmol). Puriflcation by sUica gel
chromatography (hexane/EtOAc, 9/1, 100 mL, hexane/EtOAc, 8/2, 100 mL) produced an
80% yield. This compound was prepared previously by Rathke et al.
Rathke, M. W.; Vigiazoglou, D. J. Org. Chem. 1987,52, 3697-3698.
92
2,2-Diniethyl-4-phenyl-3-peiitanol (35d). In a 100 mL round bottom flask,
hexane ( 25 mL), diethyl ether (15 mL) and 2-phenylpropanal (1.4 mL, 10.4 mmol) were
cooled to -5°C and /-butyl Hthium (12.3 mL, 20.9 mmol, 1.7 M) was added slowly. The
reaction was allowed to stir 30 minutes and monitored by TLC. The reaction was worked
up in diethyl ether and washed whh sodium bicarbonate and brine solutions. Evaporation
of the solvent followed by sUica gel chromatography (hexane/EtOAc, 9/1, 200 mL,
hexane/EtOAc, 8/2, 200 mL) produced a 50% yield. These compounds were produced
previously by Zioudrou et. al.
Zioudrou, C; Moastakali-Mavridis, M, Chrysuchou, P; Kurabatsos, G. J. Tetrahedron, 1978, 5-/, 3181-3186.
2,2-Dimethyl-4-phenyl-3-pentanone (34d). This reaction was carried out in a
simUar maimer to the reaction producmg 3-phenyl-2-butanone (34b). Changes mclude
usmg 0.37 mL of DMSO (4.0 mmol), 0.32 mL of oxalylchloride (3.6 mmol), 0.39 g of
2,2-dimethyl-4-phenyl-3-pentanol (35d) (2.0 mmol), and 1.42 mL of EtsN (10.0 mmol).
Purification by sUica gel chromatography (hexane/EtOAc, 95/5, 100 mL) produced a 57%
yield. This compound was prepared previously by Zioudrou et. at.
Zioudrou, C; MoastakaH-Mavridis, M; Chrysuchou, P; Kurobatsos, G. J. Tetrahedron, 1978,54,3181-3186.
2,2-Dimethyl-3-pentanone (42e). In a 50 mL round bottom flask, 2,2-dimethyl-
3-pentanol (1.0 mL, 7.1 mmol)) obtamed from Acros was subjected to oxidation by Jones
reagent. The reaction separated into two layers and Jones reagent was added untU the top
93
layer stayed presistently orange. The reaction was worked up m diethylether washing v^th
successive brine and sodium bicarbonate solutions. Solvent was evaporated by fractional
distillation.
90% yield. This compound was produced previously by Whitmore et. al. However using
their method failed to produce any product.
'H NMR (300MHz in CDCI3) 5 0.97 (t, 3H, J = 7.2Hz), 1.10 (s, 9H), 1.48 (q, 2H, J =
7.2Hz).
' C NMR (75MHz in CDCI3) 5 8.13, 26.50, 29.55, 43.98, 216.70.
2-Ethyl-2,6-diinethyl-4H-l,3-dioxin-4-one (43a) A mixture of 2-butanone (32)
(2.0 mL, 22.3 mmol) obtamed from Aldrich and 2,2,6-trimethyI-4H-l,3-dioxin-4-one (32)
(3.0 mL, 22.3 mmol) were subjected to FVP condhions. The resuhant liquid was
rotovaped. Purification was accompHshed by silica gel chromatography (hexane/EtOAc,
24:1, 200 mL, hexane/EtOAc, 95:5, 200 mL). Crude yield by NMR was 58%. This
compound has been prepared previously by CoreU et. al.
' H NMR (200MHz in CDCI3) 6 0.96 (t, 3H, J = 7.42Hz), 1.57 (s, 3H), 1.92 (q, 2H, J =
7.16Hz), 1.93 (s, 3H), 5.16 (q, IH, J = 0.82Hz).
'^C NMR (50MHz m CDCIs) 6 7.35,19.73, 21.94,31.19, 93.55,108.15,161.10,
168.48.
CoreU, M. F.; Bader, A. R. J. Am. Chem. Sac, 1953, 75, 5400.
94
2,2-Diethyl-6-methyl-4H-l,3-dioxin-4-one (43b). A mixture of 2,2,6-trimethyl-
4H-I,-dioxin-4-one (32) (1.3 mL, 10.0 mmol) and 3-propanone (4.0 mL, 39.6 mmol)
obtained from Aldrich were subjected to FVT conditions. The resultant liquid was
rotovaped and components separated by silica gel chromatography (hexane/EtOAc, 24:1,
250 mL, hexane/EtOAc, 9/1, 400 mL). The crude yield by NMR was 29%. This
compound has been prepared previously by Dehmolow et. al.
Dehmolow, E. V.; Shamout, A. R. Liebigs. Ann. Chem., 1982, 1753-1755.
2-Ethyl-2-isopropyl-6-methyl-4H-l,3-dioxin-4-one (43c). A mixture of 2-
methyl-3-pentanone (1.9 mL, 15.3 mmol) obtained from Aldrich, 2,2,6-trimethyl-4H-l,3-
dioxin-4-one (32) (1.0 mL, 7.7 mmol) and dichloromethane (2.0 mL) were subjected to
FVP conditions. The resultant liquid was rotovaped and products were separated by siHca
gel chromatography (hexane/EtOAc, 24/1, 250 mL, hexane,/EtOAc, 23/2,250 mL
hexane/EtOAc, 22:3, 250 mL. Crude yield based on NMR was 25%.
'H NMR (300 MHz m CDCls) 5 0.92 (t, 3H, J = 7.4 Hz), 0.96 (d, 3H, J = 5.1 Hz), 0.98
(d, 3H, J = 5.1 Hz), 1.94 (dq, 2H), 1.95 (s, 3H), 2.30 (dq, IH), 5.12 (s, IH).
'^C NMR (75 MHz in CDCI3) 6 7.1, 16.0, 16.3, 19.7, 25.0, 32.7, 93.3, 112.2, 161.1,
168.4.
Anal Calcd CioHieOs; C, 65.19; H, 8.76. Found; C, 64.80; H, 9.06.
2,2-Diisopropyl-6-inethyl-4H-l,3-dioxin-4-one (43d). A mixture of dusopropyl
ketone (5.0 mL, 35.2 mmol) obtained from Aldrich, 2,2,6-trimethyl-4H-l,3-dioxin-4-one
95
(32) (2.0 mL, 15.3 mmol) and dichloromethane (2.0 mL) were subjected to FVT
conditions. The resuhant liquid was rotovaped and components separated by siHca gel
chromatography (hexane/EtOAc, 95/5, 250 mL, hexane/EtOAc, 9/1, 250 mL). Crude
yield by NMR was 4%.
' H NMR (200 MHz in CDCls) 6 0.96 (d, 12H, J = 6.9 Hz), 1.92 (s, 3H), 2.13 (sep, 2H,
J - 7.3 Hz), 4.96 (s, IH).
' C NMR (75 MHz in CDCls) 5 16.2, 19.7, 35.0, 91.1,114.0, 160.6, 169.0.
Anal Calcd for Ci iHigOs: C, 66.63; H, 9.15. Found: C, 66.51; H, 8.99.
6-Methyl-2-(l-phenylethyl)-4H-l,3-dioxin-4-one (36a,37a) A mixture of 2-
phenyl-3-propanal (34a) (2.03 mL, 15.4 mmol), 2,2,6-trimethyl-4H-l,3-dioxin-4-one (32),
(I.O mL, 7.7 mmol) and dichloromethane (2 mL) were subjected to FVT condhions. The
resuhant Hquid was rotovaped and products separated by siUca gel chromatography
(hexane/EtOAc, 24/1, 250 mL, hexane/EtOAc, 95:5,400 mL). Further separation was
accompHshed by successive HPLC (hexane/EtOAc, 95/5).
Diastereomer I (36a)
' H NMR (200 MHz in CDCls) 8 1.46 (d, 3H, J = 7.2 Hz), 1.97 (s, 3H), 3.30 (m, IH),
5.26 (s, IH), 5.50 (d, IH, J = 5.0), 7.32 (m, 5H).
'^C NMR (50 MHz in CDCls) 6 14.41, 14.90, 19.34, 42.63, 42.78, 95.94, 102.80,
102.92, 127.26, 128.46, 139.55, 162.54, 172.02.
Anal Calcd C13H14OS; C, 71.54; H, 6.47. Found; C, 71.24; H, 6.38.
96
2,6-Dimethyl-2-(l-phenylethyl)-4U-l,3-dioxin-4-one (36b, 37b). A mixture of
3-phenyl-2-butanone (34b) (1.08 g, 7.4 nunol), 2,2,6-trimethyl-4H-l,3-dioxin-4-one (32),
(0.97 mL, 7.4 nmiol) and dichloromethane (2 mL) were subjected to FVT conditions.
The resultant liquid was rotovaped and products separated by silica gel chromatography
(hexane/EtOAc, 98/2, 200 mL, hexane/EtOAc, 95:5, 400 mL). Further separation of
diastereomers was accomplished by HPLC (hexane/EtOAc, 95/5).
Diastereomer 1 (36b)
'H NMR (200 MHz in CDCls) 6 1.44 (d, 3H, J = 7.23 Hz), 1.48 (s, 3H), 1.96 (s, 3H),
3.30 (q, IH, J = 7.13 Hz), 5.20 (s, IH), 7.27 (m, 5H).
'^C NMR (50 MHz in CDCls) 5 15.4, 19.9,20.6,47.5,93.7, 109.3, 127.2, 128.2, 129.1,
140.7, 160.9, 168.6.
Anal. Calcd for C14H1603: C, 72.39; H, 6.94. Found: C, 72.42; H, 7.05.
Diastereomer 2 (37b)
'H NMR (200 MHz in CDCls) 6 1.44 (d, 3H, J = 7.13 Hz), 1.49 (s, 3H), 1.96 (s, 3H),
3.25 (q, IH, j = 7.12 Hz), 5.18 (s, IH), 7.27 (m, 5H).
"C NMR (50 MHz in CDCls) 6 15.4, 19.9,20.9,47.9,93.8, 109.1, 127.2, 128.2, 129.1,
140.2, 161.0, 168.5.
X-ray data available in supportmg information, Shumway, W.; Ham, S.; Moer, J.; Whittlesey, B. R.; Bhney, D. M. J. Org. Chem. 2000, 65, 7731-7739.
2-Ethyl-6-methyl-2-(l-phenylethyl)-4H-l,3-dioxin-4-one (36c, 37c). A nuxture
of 2-phenyl-3-pentanone (34c) (1.02 g, 5.8 mmol), 2,2,6-trimethyl-4H-l,3-dioxin-4-one
97
(32) (0.82 ml, 5.8 mmol) and dichloromethane (3.0 mL) were subjected to FVT
condhions. The resultant liquid was rotovaped and products separated by silica gel
chromatography (hexane/EtOAc, 24/1, 250 mL, hexane/EtOAc, 95/5, 200 mL). Further
separation of diastereomers was accomplished by HPLC (hexane/EtOAc, 95/5).
Diastereomer 1 (36c)
'H NMR (300 MHz in CDCls) 6 0.89 (t, 3H, J = 7.5 Hz), 1.40 (d, 3H, J = 7.2 Hz), 1.66
(m, IH), 1.97 (s, 3H), 2.06 (m, IH), 3.42 (q, IH, J = 7.1 Hz), 5.14 (s, IH), 7.26 (m, 5H).
' C NMR (50 MHz in CDCls) 6 7.3, 15.6, 19.9,26.4,44.9,93.4, 111.5, 127.1, 128.3,
129.0, 140.3, 163 (tentative assignment), 168.5.
Diastereomer 2 (37c)
'H NMR (300 MHz in CDCls) 6 0.92 (t, 3H, J = 7.2 Hz), 1.40 (d, 3H, J = 7.2 Hz), 1.67
(m, IH), 1.94 (s, 3H), 2.0 (m, IH), 3.37 (q, IH, J = 7.1 Hz), 5.07 (s, IH), 7.26 (m, 5H).
'^C NMR (50 MHz in CDCls) 6 7.3 15.5, 19.9,26.9,45.2,93.4, 111.3, 127.1, 128.2,
129.2, 140.2, 161 (tentative assignment), 168.4.
l-(l-PhenyIethyI)-l-propenyl 3-oxobutanoic ester (41). Procedure is identical
to preparation of 2-Ethyl-6-methyl-2-(I-phenylethyl)-4H-I,3-dioxm-4-one (36c, 37c)
except that flirther purification was done by HPLC (hexane/Et20, 3/1). NMR data is
presented as a mixture of cis and trans products in an approximately 4:1 ratio.
' H NMR (300 MHz m CDCls) 6 1.04 (d, 3H, J = 6.2), 1.19 (d, 0.7H, J = 6.2), 1.28 (d,
3.7H, J - 6.3), 2.0 (s, 0.6H), 2.22 (s, 3H), 2.85 (m, 1.4H), 3.26 (s 0.4H), 3.43 (s, 2H)
5.07(1.4H),7.25(m, 6.1H).
98
"C NMR (50 MHz in CDCls) 6 16.94, 17.42, 17.53, 17.77, 18.14, 18.28,21.23,21.95,
29.72, 30.16, 44.53, 45.01, 45.30, 50.37, 50.45, 75.69, 76.17, 90.02, 126.15, 126.6,
126.64, 127.82, 127.87, 128.05, 128.13, 128.18, 128.31, 128.43, 128.49, 128.56, 142.83,
142.93, 166.49, 166.72, 175.49,200.61.
Anal Calcd CisHisOs; C, 73.10; H, 7.37. Found; C, 71.80; H, 7.55.
2-Ethyl-6-methyl-2-(phenylmethyl)-4H-l,3-dioxin-4-one (430. A mixture of
2,2,6-trhnethyl-4H-l,3-dioxm-4-one (32) (1.0 mL, 7.7 mmol) and l-phenyl-2-butanone
(42f) (2.27 mL, 15.3 mmol) were transfered to the FVP apparatus and washed with
cHchlormethane (2 mL). The solution was subjected to FVP condhions. The resuhant
Hquid was rotovaped and products separated by siHca gel chromatography
(hexane/EtOAc, 24/1, 250 mL, hexane/EtOAc, 95/5, 200 mL). Further separation of
diastereomers was accompHshed by HPLC (hexane/EtOAc, 95/5).
Major Product
' H NMR (200 MHz in CDCls) 6 0.99 (t, 3H, J = 7.3 Hz), 1.86 (q, 2H, J = 7.3 Hz), 1.98
(s, 3H), 3.23 (pseudo q, 2H), 5.16 (s, IH), 7.26 (m, 5H).
'^C NMR (50 MHz m CDCls) 6 7.1, 19.9, 29.2, 41.3, 93.8, 109.3, 127.2, 128.3, 130.5,
134.2, 160.9, 169.6
Anal Calcd for C14H16O3: C, 72.39; H, 6.94. Found: C, 72.27; H, 7.21.
2-(l-Methylpropyl)-6-methyI-4H-l,3-dioxin-4-one (39a, 40a). A mixtiire of
2,2,6-trimethyl-4H-I,3-dioxin-4-one (32) (1.0 mL, 7.7 mmol) and sec-butyl aldehyde
99
(38a) obtained from Aldrich (1.52 mL, 15.3 mmol) were transfered to the FVT apparatus
and washed with dichloromethane (2 mL). The solution was subjected to FVT conditions.
The products were allowed to warm slowly by allowing Hquid nitrogen to evaporate from
the trap while leaving the sample in the trap. The resuhant Hquid was rotovaped and
products separated by silica gel chromatography (hexane/EtOAc, 24/1, 1000 mL,
hexane/EtOAc, 9/1, 200 mL). Further separation was accompHshed by HPLC
(hexane/EtOAc, 95/5). Cmde yield based on NMR was 10%. The diastereomers proved
too difficult to separate and therefore NMR data is presented as a mixture of
diastereomers. The ratio of diastereomers as determined by NMR was found to be
85:100.
Major Product
'H NMR (300 MHz in CDCls) 6 0.94 (t, 3H, J = 7.5 Hz), 1.02 (d, 3H, J = 6.9 Hz), 1.32
(m, IH), 1.60 (m, IH), 1.88 (m, IH), 2.01 (s, 3H), 5.26 (s, IH), 5.29 (dd, IH).
"C NMR (75 MHz m CDCls) 6 11.44, 11.48, 12.88, 12.91, 19.52, 23.49, 37.85, 37.89,
95.94, 103.46, 103.50, 163.19, 172.23.
2-(l-methyipropyl)-2,6-dimethyl-4H-l,3-dioxin-4-one (39b, 40b). A mixhire of
2,2,6-trimethyl-4H-I,3-dioxin-4-one (32) (1.0 mL, 7.7 mmol) and 3-methyl-2-pentanone
(38b) obtamed from Aldrich (1.88 mL, 15.3 mmol) were transfered to the FVP apparattis
and washed with dichlormethane (2 mL). The solution was subjected to FVP conditions.
The products were aUowed to warm slowly by aUowmg liquid nitrogen to evaporate from
the trap whUe leaving the sample in the trap. The resultant Hquid was rotovaped and
100
products separated by silica gel chromatography (hexane/EtOAc, 24/1, 500 mL,
hexane/EtOAc, 8/2, 200 mL). Further separation was accomplished by HPLC
(hexane/EtOAc, 95/5). Crude yield based on NMR was 22%. The diastereomers proved
too difficult to separate and therefore NMR data is presented as a mixture of
diastereomers. The ratio of diastereomers as determined by NMR was found to be
90:100.
'H NMR (300 MHz in CDCls) 6 0.91 (t, 6H, J = 7.4 Hz), 0.98 (d, 3H, J = 5.7 Hz), 1.07
(d, 3H, J = 5.7), 1.14 (m, 2H), 1.54 (m, 2H), 1.69 (s, 6H), 1.93 (m, 2H), 1.94 (s, 6H),
5.18 (s,2H).
' C NMR (75 MHz in CDCls) 6 12.08, 12.91, 13.14, 19.15, 19.96,23.15,23.42,42.33,
42.88, 93.68, 93.69, 110.36, 110.38, 161.28, 161.32, 168.49, 168.51.
Anal Calcd CioHi60s; C, 65.19; H, 8.75. Found; C, 65.39; H, 8.91.
3-Hydroxy-l,4-diphenylpentan-2-one (44). In a 100 mL round bottom flask,
THF (25 mL) and acetophenone (1.0 mL, 8.5mmol) were cooled to -78°C. To this
reaction mixture LDA solution (8.7mL, 9.4 mmol, 2.0 M) was added and the resuhant
solution stirred for 20 mineuts at -78°C, then allowed to warm to room temperature
foUowed by cooHng to -78°C. This solution was then transferred to a 250 mL round
bottom flask containing THF (25mL) and 2-phenylpropanal (34a) (1.2 mL, 8.5 mmol)
which was cooled to -78°C. The resultant solution was solution stirred for 20 minutes at -
78°C, then allowed to warm to room temperature. The reaction was quenched with
ammonium chloride solution (5 mL). The reaction was worked up in diethyl ether then
101
washed successively with sodium bicarbonate and brine solutions. Evaporation of the
solvent followed by silica gel chromatography (hexane/EtOAc, 95/5, 1000 mL) gave the
product as a mixture of diastereomers in 63% yield.
l,4-Diphenyl-l,3-pentanedione (45). This reaction was carried out in a similar
manner to the reaction producing 3-phenyl-2-butanone. Changes include using 0.55 mL
of DMSO (7.7 mmol), 0.50 mL of oxalylchloride (5.7mmol), 0.93 mL of 3-hydroxy-1,4-
diphenylpentanone (3.9 mmol), and 2.68 mL of EtsN (19.2 mmol).
Bahgrie, L, M; Leung-Toung, R; TidweU, T, T. Tetrahedron Lett. 1988, 29(14), 1673-1676.
/7-ToluenesuIfonyl azide (46). In a 100 mL round bottom flask, water (4 mL),
ethanol (6 mL), and sodium azide (0.74 g, 11.4 mmol) were added. To this solution a
solution of ethanol (18 mL) and p-toluene sulfonyl chloride (2.0 g, 10.5 mmol) was added
and allowed to sth at room temperature for 4 hours. The reaction was worked up in
diethyl ether and washed successively with brine and sodium bicarbonate solutions.
Quantative yield.
Regitz, M.; Hocker, J.; Liedhegener, A. Organic Synthesis, John WUey: New York, 1973; CoUect. Vol. V,pp 179-183.
2-Diazo-l,4-diphenyH,3-pentanedione (47). In a 100 mL round bottom flask
acetonitrile (15 mL), l,4-diphenyl-I,3-pentanedione (45) (1.04 mL, 4.1 mmol) were mbced
and cooled to -4°C. Triethylamme (0.58 mL, 4.2 mmol) was added foUowed hyp-
102
toluenesulfonyl azide (0.69 g, 4.51 mmol). The reaction was stirred at -4°C for 2 hours.
The reaction was worked up in dichloromethane and successively washed with brine and
sodium bicarbonate solutions. Evaporation of the solvent followed by by silica gel
chromatography (hexane/EtOAc, 12/238, 250 mL, hexane/EtOAc, 12/188, 200 mL) gave
the product in 51% yield.
'H NMR (500 MHz in CDCls) 6 1.43 (d, 3H, J = 7.0 Hz), 4.84 (q, IH, J = 7.0 Hz), 7.33
(m, lOH).
' C NMR (125 MHz in CDCI3) 5 18.94, 48.72, 83.21, 127.34, 128.21, 128.24, 128.50,
128.63, 132.54, 137.37, 140.12, 184.85, 193.64.
Trap products (50-53).
Typical procedure. In a 50mL round bottom flask heptane (15ml), 2-diazo-l,4-
diphenyI-I,3-pentanedione (47) (0.10 g), and benzaldehyde (0.10 mL) were mixed and
heated to reflux for 2 hours. Solvent was then evaporated via vacuum pump at room
temperatures. Separation of products by chromatography (hexane/EtOAc) have the
products m the foUowing ratios.
Spectroscopy data for the major product, thermodynamic diastereomer. 5-(l-
Phenylethyl)-2,6-diphenyl-4H-l,3-dioxin-4-one (either 50, or 51).
'H NMR (500 MHz m CDCls) 6 1.87 (d, 3H, J = 7.0 Hz), 4.05 (q, IH, J = 7.0 Hz), 6.40
(s, IH), 7.41 (m, I5H).
103
"C NMR (125 MHz in CDCls) 6 17.94, 37.08, 99.28, 113.34, 126.26, 126.69, 127.56,
128.17, 128.57, 128.72, 129.12, 130.29, 131.25, 131.74, 133.80, 148.83, 162.37, 164.87.
Diagnostic peak used for diastereomer ratio determination in Major product; 5 6.58 (s,
IH).
Spectroscopy data for the minor product thermodynamic diastereomer. 6-(l-
Phenylethyl)-2,5-diphenyl-4H-l,3-dioxin-4-one (either 52, or 53).
'H NMR (500 MHz in CDCI3) 6 1.50 (d, 3H, J = 7.0 Hz), 4.09 (q, IH, J = 7.0 Hz), 6.55
(s, IH), 7.35 (m, I5H).
'^CNMR(125MHzinCDCl3) 6 18.63,40.91,99.84, 110.16, 126.76, 127.52, 127.70,
128.12, 128.51, 128.87, 130.06, 130.51, 130.96, 132.04, 134.04, 140.49, 162.89, 172.58
Diagnostic peak used for diastereomer ratio determination m Minor product; 6 6.37 (s,
IH).
D-(+)-Camphor-3-Carboxylic Acid (59). In a 250 mL three neck flask toluene
(25 mL) and D-(+) Camphor (2.0 g, 1.3 mmol) were cooled to -78°C. LDA (16.0 mL,
2.6 mmol, 2M) was added and sthred at -78°C for 15 mmutes. The resuhant solution was
then allowed to warm to room temperature and then poured into an excess of dry ice and
stirred until all dry ice disappeared. The reaction was then worked up by adding water (35
mL) and extracting with ether. The basic aqueous layer was acidified with dUute HCl and
reextracted with ether. The organic layer was dried over MgS04 and the excess solvent
evaporated. Yield = 96% mixture of endo and exo.
104
Staudinger, H.; Scholtz, S. Ber. Dtsch. Chem. Ger. 1920, 53, 1105-21.
Major product
' H NMR (300 MHz in CDCb) 6 0.86 (s, 3H), 0.93 (s, 3H), 1.00 (s, 3H), 1.48 (m, IH),
1.56 (m, IH), 1.71 (m, IH), 1.89 (m,lH), 2.46 (t, IH, J = 4.5Hz), 3.30 (m, IH), 9.07
(S,1H).
"C NMR (125 MHz in CDCI3) 6 9.34, 18.61, 19.57, 22.34, 29.96, 45.63, 46.58, 55.52,
58.49, 173.17,213.39.
D-(+)-3-Camphoryl Chloride (53). In a 100 mL round bottom flask camphor
carboxyHc acid (2.3 g 1.17 mmol) was placed and the flask cooled to -4°C in an ice bath.
Thionyl chloride (10 mL) was added. The reaction was stirred at -4°C for 12 hours.
Excess thionyl chloride was evaporated with a vacuum pump. The resuhant yeUow oU
was washed with petroleum ether. The petroleum ether was subsequently removed by
rotary evaporation. Yield = 95% mbcture of endo and exo.
Staudmger, H.; Scholtz, S. Ber. Dtsch. Chem. Ger. 1920, 53,1105-21.
a-Oxocamphorketene dimers (55,56). In a 100 mL round bottom flask diethyl
ether (20 mL) and triethyl amine (2.5 mL, 1.8 mmol) were placed. Camphoryl chloride
(53) (2.0 g, 0.93 mmol) was added and the resuhant reaction stirred for 30 minutes. The
reaction was worked up m diethyl ether and washed successively whh sodium bicarbonate
and brine solutions. The organic layer was dried over MgS04 and the excess solvent
105
evaporated. The cmde product was repeatedly recrystalized from diethyl ether. Yield =
20%.
Staudinger, H.; Schohz, S. Ber. Dtsch. Chem. Ger. 1920, 53, 1105-21.
Dimer 1 (minor) (55)
Optical rotation ao = + 135° (in CHCI3) (ao = + 126° in EtOAc)
' H NMR (500 MHz in CDCI3) 6 0.91 (s, 3H), 1.03 (s, 3H), 1.06 (s, 9H), 1.17 (s, 3H)
1.23 (m,2H), 1.60 (m, IH), 1.80 (m,3H), 1.78 (m, IH), 2.13(m, IH), 2.71 (d, IH, J = 6
Hz), 2.83 (d, IH, J = 6.0 Hz).
'^CNMR(125MHzinCDCl3) 6 8.74,9.68, 18.61, 19.45,21.01,21.90,25.86,26.64,
29.77, 32.92, 47.52, 48.17, 54.13, 54.49, 55.13, 58.59, 74.70, 120.04, 168.79, 173.14,
185.81,206.89.
See Appendix P 129 for x-ray data.
Dimer 2 (major) (56) RecrystaHzed from MeOH, decomposed on standmg.
'H NMR (300 MHz in CDCI3) 6 0.85 (s, 3H), 0.94 (s, 3H), 0.94 (s, 3H), 0.97 (s, 3H),
0.99 (s, 3H) 1.04 (s, 3H) 1.48 (m, 2H), 1.72 (m, 3H), 1.81 (m, 3H), 2.00 (m, IH), 2.28
(d, IH, J = 3.9 Hz), 2.47 (d, IH, J = 3.6 Hz), 3.26 (dd, IH).
Attempted reaction of D-(+)-3-CamphoryI Chloride and benzaldehyde. In a
100 mL round bottom flask diethyl ether (25 mL), benzaldehyde (0.24 mL, 0.18 mmol),
and triethyl amme (0.50 mL, 3.4 mmol) were placed. Camphoryl chloride (53) (0.38 mL,
0.18 mmol) was added. The resuhant solution was sthred for 30 minutes. The reaction
106
was worked up with diethyl ether and washed successively with sodium bicarbonate and
brine solutions. Yield = 0% cycloadduct. Quantative dimer yield.
Attempted reaction of D-(+)-3-Camphoryl Chloride and N-
Propylbenzaldimine. In a 100 mL round bottom flask diethyl ether (25 mL), N-
propylbenzaldimine (147 mg, 0.10 nunol), and triethyl amine (0.25 mL, 1.9 mmol) were
placed. Camphoryl chloride (0.21 mL, 0,10 mmol) was added. The resuhant solution was
sthred for 30 minutes. The reaction was worked up with diethyl ether and washed
successively whh sodium bicarbonate and brine solutions. Yield = 0% cycloadduct.
Quantative dimer yield.
D-(+)-Isopropyl-3-camphor ester. (58) In a 100 mL round bottom flask
camphoryl chloride (53) (0.14 g, 0.07 mmol), and diethyl ether (20 mL) were placed. To
this solution isopropanol (O.IO mL, 0.13 mmol) and triethylamine (0.46 mL, 3.3 mmol)
were added simuhaneously. The resuhant reaction was stirred for 20 minutes and then
quenched with water. The reaction was worked up v^th diethyl ether and washed
successively v^th sodium bicarbonate and brine solutions. The organic layer was dried
over MgS04 and the excess solvent evaporated.
D-(+)-Isopropyl-3-camphor ester (58) and D-(+)-Methyl-3-camphor ester
(57). See table 4.1 for product ratios and yields. Method 1 for synthesis. In a 100 mL
round bottom flask camphoryl chloride (53) (0.14 g, 0.07 mmol), and diethyl ether (20
107
mL) were placed. To this solution isopropanol (0.36 mL, 0.47 mmol), methanol (0.76
mL, 1.9 mmol), and triethylamine (0.46 mL, 3.3 nunol) were added simultaneously. The
resuhant reaction was stirred for 20 minutes and then quenched with water. The reaction
was worked up with diethyl ether and washed successively with sodium bicarbonate and
brine solutions. The organic layer was dried over MgS04 and the excess solvent
evaporated. Method 2 for synthesis. In a 100 mL round bottom flask camphoryl chloride
(53) (0.10 g, 0.05 mmol), and diethyl ether (20 mL) were placed. To this solution
isopropanol (0.025 mL, 0.36 mmol) and methanol (0.045mL, 1.1 mmol) was added. The
resultant reaction was sthred for 20 minutes and then quenched with water. The reaction
was worked up with diethyl ether and washed successively with sodium bicarbonate and
brine solutions. The organic layer was dried over MgS04 and the excess solvent
evaporated. Method 3 for synthesis. Usmg a modiflcation of method 1,
isopropanol/methanol mixture m the molar ratio of 1:3.23 was used as the solvent in place
of diethyl ether. Yield = 96% based on cmde NMR.
Spectroscopy data for D-(+)-Isopropyl camphor ester (58).
endo product
' H NMR (500 MHz in CDCI3) 6 0.87 (s, 3H), 0.95 (s, 3H), 1.02 (s, 3H), 1.25 (d, 3H, J =
6Hz) 1.26 (d, 3H, J = 6Hz), 1.55 (m, 2H), 1.69 (m, IH), 1.71 (m, IH), 2.43 (t, IH, J =
4.5Hz), 3.30 (m, IH), 5.07 (sept, IH, J = 6Hz).
"CNMR(125MHzinCDCl3) 6 9.52, 18.81, 19.48,21.77,21.80,22.35,29.36,45.70,
47.05, 55.73, 55.49, 68.42, 169.20, 211.57.
108
endo assignment based on 6 3.30 muhiplet.
exo product
' H NMR (500 MHz in CDCI3) 6 0.80 (s, 3H), 0.96 (s, 3H), 0.98 (s, 3H), 1.26 (d, 3H, J =
6Hz) 1.28 (d, 3H, J = 6Hz), 1,40 (m, IH), 1.55 (m, IH), 1.71 (m, IH), 2.03 (m, IH), 2.63
(t, IH, J = 4.5Hz), 2.84 (s, IH), 5.03 (sept, IH, J = 6Hz)
'-'C NMR (125 MHz in CDCI3) 6 9.46, 19.44, 20.81, 21.62, 21.65, 27.38, 30.11, 45.99,
46.75, 57.58, 58.74, 68.74, 167.25, 211.1
exo assignment based on 6 2.84 singlet.
Spectroscopy data for D-(+)-Methyl camphor ester (57).
endo product
'H NMR (500 MHz in CDCI3) 6 0.85(s, 3H), 0.91 (s, 3H), 0.99 (s, 3H), 1.51 (m, 2H),
1.67 (m, IH), 1.84 (m, IH), 2.40 (t, IH, J = 4.5Hz), 3.31 (m, IH), 3.69 (s,3H).
'^C NMR (125 MHz in CDCI3) 6 9.42, 18.69, 19.41, 22.39, 29.30, 45.60, 46.95, 55.43,
58.49,68.42, 169.20,211.57.
endo assignment based on 6 3.31 muhiplet.
exo product
'H NMR (500 MHz in CDCI3) 6 0.75(s, 3H), 0.92 (s, 3H), 0.95 (s, 3H), 1.37 (m, IH),
1.51 (m, IH), 1.67 (m, IH), 2.02 (m, IH), 2.62 (d, IH, J = 4.5Hz), 2.85 (s, IH), 3.71 (s,
3H).
109
"C NMR (125 MHz in CDCI3) 6 9.37, 19.30, 20.63, 27.21, 30.01, 45.89, 46.67, 57.70,
57.48,68.5, 168.20,210.8.
exo assignment based on 6 2.85 singlet.
3-Diazo-2,4-pentanedione (62). In a 50 mL round bottom flask, acetonitrile (7
mL), 2,4-pentanedione (0.48 mL, 4.7 mmol) and triethylamine (0.65 mL, 4.7 mmol) were
placed and cooled to 0°C. p-Toluenesulfonylazide (0.92 g, 4.7 mmol) was dripped in
slowly. Reaction was allowed to sth 3 hours. The reaction was worked up m diethylether
and washed successively v^th brine and sodium bicarbonate solutions. The excess solvent
was evaporated under reduced pressure and siHca gel column chromatography
(hexane:EtOAc, 9:1, 300 mL) gave the product in 53% yield.
Regitz, M.;Maas, G. Diazo Compounds Properties and Synthesis. Harcourt Brace Jovanovich, Orlando, 1986, p 81.
N-Phenyl-5,6-dimethyl-2-phenyl-4H-3-amino-l-oxin-4-one (68). In a 25 mL
round bottom flask benzene (10 mL), 3-Diazo-2,4-pentanedione (60 mg, 0.48 mmol) and
N-phenylmethylphenylimine (86 mg, 0.48 mmol) were placed and brought to reflux for 2
hours. Excess solvent was evaporated and column chromatography on sihca gel
(hexane: EtO Ac, 95:5,400m mL, hexane:EtOAc, 9:1, 100m mL, hexane:EtOAc, 8:2,
100m mL) gave the product m 88 % yield.
' H NMR (300 MHz in CDCI3) 6 1.73 (s, 3H), 1.90 (s, 3H), 6.49 (s, IH) 7.30 (m, lOH).
110
2-Bromo-2-phenylpropanal (69). In a 50 mL round bottom flask
dichloromethane (20 mL), 2-phenylpropanal (34a) (1.0 mL, 7.5 mmol), and a drop of
bromine were mixed together. When the red color disappeared, the mixture was cooled to
0°C and the reminder of bromine (0.39 mL, 7.5 mmol) was added. The resuhant mixtiare
was stirred 2 hours. The reaction was worked up whh diethyl ether and washed whh brine
solution. Evaporation of the solvent followed by silica gel chromatography
(hexane/EtOAc, 95:5, 200 mL), gave the product m 93% yield.
Reuss, R. H. et. al., J. Org. Chem. 1974, 39, 1785.
2-Methoxy-2-phenylpropanal (70). In a 100 mL round bottom flask, methanol
(25 mL) and sUver nitrate (0.40 g, 2. Immol) was placed. Once the sUver nitrate was
dissolved, 2-bromo-2-phenylpropanal (69) (0.43 g, 2.0 mmol) was added dropwise and
aUowed to stir 15 minutes. The reaction was worked up with diethyl ether and washed
with brine solution. Evaporation of the solvent followed by siHca gel chromatography (2 X
hexane/EtOAc, 98:2, 200 mL), gave the product in 60% yield.
' H NMR (300 MHz m CDCI3) 6 1.65 (s, 3H), 3.28 (s, 3H), 7.38 (m, 5H), 9.4 (s, IH).
N-Propyl-(2-methoxy-l-phenyl-l-ethyl)imine (72). In a 50 mL round bottom
flask, dichlormethane, (20 mL), 4A molecular sives, 2-methoxy-2-phenylpropanal (70)
(0.11 g, 0.68 mmol) and propylamme, (0.11 mL, 1.4 mmol) were mixed and put under
reflux condhions for 10 hours. The resuhant mixtiare was fihered through celhe and
excess solvent evaporated. Yield = 88%.
I l l
' H NMR (300 MHz in CDCI3) 6 0.83 (t, 3H, J = 7 Hz), 1.60 (sext, 2H, J = 7 Hz), 1.65 (s,
3H), 3.34 (s, 3H), 7.41 (m, lOH), 7.91 (s, IH).
N-(l-Phenylethyl)-phenylimine (74). This reaction was carried out in a similar
manner as N-propyl(l-methoxy-l-phenyl)imine (72). Changes include the foUowing; 0.5
mL benzaldehyde (4.9 mmol), 0.63 mL DL-a-methylbenzylamine (4.9 mmol)
Quanthative yield.
'H NMR (300 MHz in CDCI3) 6 1.63 (d, 3H, J = 7 Hz), 4.57 (q, IH, J = 7 Hz), 5.27 (s,
IH), 7.40 (m, 8H), 7.83 (m, 2H), 8.41 (s, IH).
'^C NMR (75 MHz in CDCI3) 6 20.5, 56, 118, 122.0, 122.5, 125.0, 125.5, 128, 137, 143,
159.
N-(l-Pheylethyl)(l-methoxy-l-phenylethyl)imine (76). This reaction was
carried out m a shnilar manner as N-propyl-(2-methoxy-l-phenylethyl)imine (72).
Changes include the foUowing; 0.49 g 2-bromo-2-phenylpropanaI (0.30 mmol), 0.58 mL
DL-a-methylbenzylamme (4.5 mmol). Puriflcation by sUica gel chromatography
(hexane/Ether, 9:1, 350 mL) gave a 1:1 mixture of the two diastereomers m a yield of
92%. Note, very dry hexane and ether must be used for chromatography.
'H NMR (500 MHz in CDCI3) 6 1.48 (d, SH J = 7 Hz), 1.53 (d, 3H J = 7 Hz), 1.72, (s,
3H), 1.73 (s, 3H), 3.25 (s, 3H), 3.32 (s, 3H), 4.40, (m 2H), 7.15 (m, lOH), 7.74 (s, 2H).
112
'-'C NMR (125 MHz inCDCb) 6 21.42, 21.66, 24.58, 50.95, 51.07, 68.78, 80.31, 80.41,
126.03, 126.40, 126.66, 126.70, 127.20, 128.24, 18.25, 128.26, 128.31, 142.69, 142.73,
144.69, 144.94, 164.73, 164.91.
Cycloadducts 63,64, 71, 73, 75,77. All the previous cycloadducts were made by the
same general procedure. A typical procedure follows. This procedure uses excess 2-
diazo-l,3-pentanedione (62).
In a 50mL round bottom flask heptane (15ml), 2-diazo-l,3-pentanedione (0.10 g, 0.8
mmol), and 2-phenyIpropanal (34a) (0.10 mL,) were mixed and heated to reflux for 2
hours. Solvent was then evaporated via vacuum pump at room temperatures. Separation
of products was done by column by chromatography (hexane/EtOAc 95:5,200 mL)
foUowed by HPLC (Hexane/EtOAc 95:5, I L)
Spectroscopy data for N-propyl-5,6-dimethyl-2-(l-methoxy-l-phenyIethyl)-
4H-3-amino-l-oxin-4-one (73).
Diastereomer 1
"C NMR (75 MHz m CDCI3) 6 9.37, 11.24, 16.85, 19.43, 20.85, 48.39, 49.51, 82.56,
91.95, 105.66, 127.45, 127.91 139.05, 155.83, 162.60.
Diastereomer 2
' 'CNMR(75MHzinCDCl3) 6 9.72, 11.18, 16.83, 17.81,20.81,48.52,49.86,83.88,
92.53, 104.87, 126.91, 127.67, 128.21, 140.45, 157.31, 163.12.
113
Spectroscopy data for N-(l-Phenylethyl)-5,6-dimethyl-2-phenyl-4H-3-amino-
l-oxin-4-one (75).
'H NMR (500 MHz in CDCI3) 6 1.36 (d, 3H, J = 7 Hz), 1.68 (s, 3H), 1.72 (s, 3H), 5.96,
(s, IH), 6.01 (q, IH J = 7 Hz), 7.32 (m, lOH)
mix of diastereomers
' C NMR (125MHz in CDCls) 6 10.24, 10.28, 17.20, 17.27, 17.53, 17.71, 50.43, 51.94,
83.05, 83.48, 106.61, 107.19, 126.81, 126.96, 127.07, 127.43, 127.51, 127.54, 127.98,
128.13, 128.16, 128.24, 128.53, 128.77, 137.52, 138.60, 139.38, 141.31, 157.04, 157.27,
163.53, 163.75.
Spectroscopy data for N-(l-Phenylethyl)-5,6-dimethyl-2-(l-methoxy-
lphenylethyl)-4H-3-amino-l-oxin-4-one(77).
Diastereomer I
' H NMR (500 MHz m CDCI3) 6 0.92 (d, 3H, J =lHz), 1.57 (d, 3H, J = 1 Hz), 1.70 (s,
3H), 2.05 (d, 3H, J = 7 Hz), 3.03 (s, 3H), 4.63 (q, IH, J = 7 Hz), 5.22 (s, IH), 7.25 (m,
lOH).
' C NMR (125MHz m CDCI3) 6 9.25, 16.83, 18.20, 20.43, 49.50, 61.54, 81.46, 94.60,
106.79, 126.70, 126.90, 127.44, 127.91, 127.94, 128.11, 139.07, 142.41, 155.69, 163.11.
Diastereomer 2
' H NMR (500 MHz in CDCI3) 6 0.96 (d, 3H, J =lHz), 1.54 (s,3H), 1.56 (d, 3H, J = 1
Hz), 1.78 (d, 3H, J = 7 Hz), 3.02 (s, 3H), 4.72 (s,lH), 5.70 (q, IH, J = 7 Hz), 7.25 (m,
I OH).
114
"C NMR (125MHz in CDCI3) 6 9.54, 16.85, 18.29, 20.28, 49.05, 55.20, 79.80, 89.82,
106.92, 127.34, 127.47, 127.76, 127.88, 128.29, 128.66, 139.93, 140.69, 155.83, 163.97.
Diastereomer 3
'H NMR (500 MHz in CDCI3) 6 1.53 (s,3H), 1.55 (d, 3H, J =lHz), 1.65 (d, 3H, J = 1
Hz), 1.92 (d, 3H, J = 7 Hz), 2.97 (s, 3H), 4.86 (q, IH, J - 7 Hz), 5.28 (s, IH), 7.15 (m,
lOH).
'-'C NMR (125MHz in CDCI3) 6 9.76, 16.81, 17.12, 17.80,49.57,59.56,83.44,93.99,
105.84, 126.82, 127.00, 127.69, 128.13, 128.26, 141.04, 142.07, 157.34, 163.50.
Diastereomer 4
'H NMR (500 MHz m CDCI3) 6 1.52 (d, 3H, J =lHz), 1.64 (s,3H), 1.68 (d, 3H, J = 7
Hz), 1.71 (d, 3H, J = I Hz), 2.99 (s, 3H), 4.85 (s, IH), 5.68 (q, IH, J = 7 Hz), 7.15 (m,
lOH).
'^C NMR (125MHz in CDCI3) 6 10.07, 16.69, 17.97, 18.04,49.19, 54.95, 82.72, 90.20,
105.63, 126.81, 127.44, 127.54, 128.15, 128.28, 125.50, 140.43, 141.43, 157.55, 164.07.
2,2,5,5-Tetramethyl-3-hexanol (91). In a 100 mL round bottom flask, THF (30
mL) and neopentyl iodide (0.67 mL, 5.0 mmol) were cooled to -78°C. /-ButyUithium
(4,45 mL, 7.6 mmol, 1.7 M) was added slowly and allowed to stir 15 mmutes at -78°C
then warmed to room temperature. The solution was recooled to -78°C and /-butyl
aldehyde (0.82 mL, 7.6 mmol) was added, sthred for 10 mmutes. The reaction was
worked up with diethyl ether and washed successively with sodium bicarbonate and brine
115
solutions. Evaporation of the solvent foUowed by silica gel chromatography
(hexane/EtOAc, 95:5, 350 mL), gave the product in 93% yield.
'H NMR (200 MHz in CDCI3) 6 0.86 (s, 9H), 0.93 (s, 9H), 1.08 (dd, IH J = 10, 20 Hz),
1.48 (d, IH J = 20 Hz), 3.30 (d, IH, J = 10 Hz).
2,2,5,5-Tetramethyl-3-hexanone (87). This reaction was carried out in a simUar
manner to the reaction producing 3-phenyl-2-butanone (34b). Changes include using 0.90
mL of DMSO (9.9 mmol), 0.66 mL of oxalyl chloride (7.4 mmol), 0.075 g of 2,2,5,5-
Tetramethyl-S-hexanol (91) (4.9 mmol), and 3.4 mL of EtsN (24.7 mmol). Purification
by sUica gel chromatography (hexane/EtOAc, 98/2, 500 mL) produced an 32% yield.
' H NMR (300 MHz in CDCI3) 6 0.99 (s, 9H), 1.07 (s, 9H), 2.34 (s, 2H)
'^C NMR (75 MHz in CDCls) 6 26.3, 29.7, 30.5, 44.6, 47.9, 215.47.
N-Propylmethylphenylimine (93). In a 100 mL round bottom flask,
dicholormethane (30 mL) was added whh activated 4 A molecular sives, acetophenone
(0.33 mL, 2.7 mmol) and propylamine (0.23 mL, 2.7 mmol). The resuhant solution was
refluxed for 12 hours then fihered through celhe. Excess solvent was evaporated under
reduced pressure. No purification yielded 81% product.
'H NMR (200 MHz in CDCI3) 6 0.97 (t, 3H, J = 7 Hz), 1.74 (sext, 2H, J = 7 Hz), 2.21
(s, 3H), 3.4 (t, 2H, J = 7 Hz), 7.35 (m, 3H), 7.78 (m 2H).
116
N-Phenylmethylphenylimine (67). This reaction was carried out in a similar
manner to the reaction producing N-propylmethylphenylimine. Changes include 1.19 mL
of acetophenone (10 mmol), 0.93ml analine (10 mmol), 18 hours reflux time. Yield =
70%.
N-(p-methoxybenzyl)methylphenylimine (99). This reaction was carried out in
a simUar manner to the reaction producing N-propylmethylphenylimine. Changes include
0.35 mL of acetophenone (3.0 mmol), 0.39ml analine (3.0 mmol), 12 hours reflux time.
Yield = 81%.
N-Propyl-4-phenyI-l,2-pyroledione (95). In a 100 mL round bottom flask,
dichloromethane (40 mL) was added v^th oxalyl chloride (0.70 mL, 8.0 mmol) and cooled
to -78°C. N-PropylmethylphenyHmine (93) (1.30g, 7.3mmol) was mixed with
dichlormethane (2 mL) and added to the above mixture and sthred 10 minutes.
Triethylamine (2.04 mL, 14.6 mmol) was added and aUowed to sth an additional 10
minutes then warmed to room temperature. The reaction was worked up in ethylacetate
and washed successively with sodium bicarbonate and brine solutions. Evaporation of the
solvent foUowed by sUica gel chromatography (hexane/EtOAc, 9:1, 600 mL,
hexane/EtOAc, 8:2, 500 mL) gave the product in 52% yield.
' H NMR (200 MHz in CDCI3) 6 0.75 (t, SH, J = 7 Hz), 1.40 (sext, 2H, J = 7 Hz), 3.57
(dd, 2H), 5.45 (s, IH), 7.51 (m 5H).
117
'^C NMR (75 MHz in CDCls) 6 10.99, 22.12, 42.93, 100.73, 127.20, 129.73, 129.32,
129.43, 132.08, 160.0, 173.58, 183.33.
N-Phenyl-4-phenyl-l,2-pyroledione (94). This reaction was carried out in a
similar manner to the reaction producing N-propyl-5-phenyl-l,2-pyrolecHone. Changes
include 0.68 mL oxalyl chloride (7.7 mmol), 1.38 g N-phenylmethylphenylimine (67), (7.0
mmol) and 1.97 mL of triethylamine (14 mmol). Yield = 74%.
N-(p-Methoxybenzyl)-5-phenyl-l,2-pyroledione (101). This reaction was
carried out in a simUar manner to the reaction producing N-propyl-5-phenyl-l,2-
pyroledione. Changes include 0.31 mL oxalyl chloride (3.5 mmol), 0.61 g N-(p-
methoxybenzyI)methylphenyHmine (99), (2.5 mmol) and 0.71 mL of trietylamine (5.1
mmol). Yield = 63%.
Ethyl 4-(propylamine)-2-oxo-4-phenyl-3-butenoate (96). In a 25 mL test tube
N-PropyI-5-phenyl-l,2-pyroledione (94), (100 mg 0.46 mmol) was added with ethanol (10
mL). The resuhant solution was heated in an oil bath at 55°C for I hour. Excess solvent
was evaporated under reduced pressure. Quantative yield.
' H NMR (200 MHz in CDCI3) 6 0.85 (t, 3H, J = 7 Hz), 1.30 (t, 3H, J = 7 Hz), 2.02 (sext,
2H, J = 7 Hz), 3.21 (t, 2H, J = 7 Hz), 4.22 (t, 2H J = 7 Hz), 5.27 (s, IH), 5.89 (s, IH),
7.41 (m5H).
118
^^C NMR (75 MHz in CDCls) 6 11.73, 14.17,23.63,46.92,49.38,94.33, 127.52,
128.63, 130.03, 134.50, 147.94, 170.05, 176.45.
Ethyl 2-diazo-3-oxo-3-phenylpropanoate (105). In a 25 mL beaker, p-
toluenesulfonylazide (0.45 g, 2.3 mmol), ethyl-3-oxo-3-phenylpropanoate (0.4 mL, 2.3
nrniol) were added with HPLC grade acetonitrile (2 mL). Triethylamine (0.32 mL, 2.3
mmol) was added. The reaction was stirred 5 hours then worked up in diethylether. The
organic layer was washed flrst with 16% KOH foUowed by washing whh 4% KOH then
water. Excess solvent was removed under reduced pressure. Yield = 73%.
'H NMR (300 MHz in CDCb) 6 1.20 (t, 3H, J = 7 Hz), 4.21 (q, 2H, J = 7 Hz), 7.25 (m,
2H), 7.45 (m, IH), 7.6 (m, 2H).
Propyl 2-diazo-3-oxo-3-phenylpropanamide (106). In a 10 ml round bottom
flask dichlormethane (5 mL), 4A molecular sives, ethyl 2-diazo3-oxo-3-phenylpropanoate
(87 mg, 0.40 mol), and propylamme (0.25 mL, 3.0 mmol) were placed. The flask was
fltted with a reflux condenser and subjected to reflux condhions for 12 hours. The
resuhant mixture was flhered through celhe and excess solvent removed under reduced
pressure.
2-Diazo-l-phenyl-l,3-butanedione (108). In a 50 mL round bottom flask/;-
toluenesulfonylazide (46), (0.56 g, 2.8 mmol), I-phenyl-l,3-butanedione (0.46, 2.8 mmol),
and acetonitrile (20 mL). Triethylamine (0.40 mL, 2.8mmol) was added and the reaction
119
stirred 2 hour then worked up in diethylether. The organic layer was washed flrst whh
16% KOH followed by washing with 4% KOH then water. Excess solvent was removed
under reduced pressure. Purification by silica gel chromatography (hexane/EtOAc, 95:5,
300 mL) Yield = 65%.
Regitz, M.; Maas, G. Diazo Compounds Properties and Synthesis. Harcourt Brace Jovanovich, Orlando, 1986, p 81.
Diazoacetophenone (109). This reaction was carried out in a similar manner to
the reaction producing propyl 2-diazo-3-oxo-3-phenylpropanamide. Changes include 0.11
g of 2-diazo-I-phenyl-l,3-butanedione (108) (0.55 mmol), 0.14 ml propylamine (1.7
mmol), 12 hours reflux time. Yield = 72%.
Regitz, M ; Maas, G. Diazo Compounds Properties and Synthesis. Harcourt Brace Jovanovich, Orlando, 1986, p 48.
N-propyl-3-amino-l-phenyl-2-buten-l-one (110). This reaction was carried out
in a simUar manner to the reaction producing propyl 2-diazo-3-oxo-3-phenylpropanamide.
Changes include 0.83 g of I-phenyl-l,3-butanedione (5.2 mmol), 1.2 ml propylamine
(14.5 mmol), 12 hours reflux time. Product is a yeUow liquid in a yield of 81%.
' H NMR (300 MHz in CDCI3) 6 1.0 (t, 3H, J = 7 Hz), 1.65 (sext, 2H, J = 7 Hz), 2.05 (s,
3H), 3.28 (q, 2H, J = 7 Hz), 5.65 (s, IH), 7.41 (m 5H), 11.45 (s, IH).
Attempted production of Compound 111, (112). This reaction was carried out
m a shnilar manner to the reaction producmg 2-diazo-l-phenyl-1,3-butandione (108).
120
Changes include 0.97 g N-propyl-3-amino-I-phenyl-2-buten-l-one (110), (4.7 mmol),
0.93 g p-toluenesulfonylazide (4.7 mmol), 0.66 mL triethylamine (4.7 mmol). Gave white
soHd in a yield of 85%.
' H NMR (300 MHz in CDCI3) 6 1.0 (t, 3H, J = 7 Hz), 1.91 (sext, 2H, J = 7 Hz), 2.61 (s,
3H), 4.28 (dd, 2H), 7.51 (m 3H), 8.29 (m, 2H)
IR in cm'' (w, 3100), (m, 2900), (s, 1650), (s, 1450), (m, 1150), (s, 950), (m, 875),
(s,850).
121
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(11) TidweU, T. T. Ketenes. John Wiley and Sons, Inc., New York, 1995.
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122
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123
(36) (A) Crabtree, H. E., Smalley, R. K., Suschitzky, H. J. Chem. Soc C 1968, 2730-2733. (B) Smalley, R. K. Suschitzky, H. Tetrahedron Lett. 1966, 29, 3465-3469. (C) Burgess, E.; Milne, G. Tetrehedron Lett. 1966, 29, 93-96. (D) Kretschmer, G.; Warrener, R. N. Tetrehedron Lett. 1975,16, 1335-1338. (E) Olofson, R. A.; Meer, R. K.; Hoskin, D. H.; Bemheim, M. Y.; Stoumas, S.; Morrison, D. S. J. Org. Chem. 1984, 49, 3367-3372.
(37) (A) Briehl, H.; Lukosch, A., Wentmp, C; J. Org Chem. 1984, 49, 2772-2779. (B) Cheikh, A. B.; Chuche, J., Manisse,;N., Pommelet, J. C ; Netsch, K. P.; Lorencak, P.; Wentmp, C. J. Org. Chem. 1991, 56, 970-975. (C) FuUon, B. E.; Wentmp, C. J. Org Chem. 1996, 61, 1363-1368.
(38) (A) Fulloon, B.; El-Nabi, H. A.; KoUenz, G.; Wntmp, C. Tetrahedron Lett. 1995, 36, 6547-6550. (B) Kappe, C. O.; KoUenz, G.; Toung. R. L.; Wentmp, C ; J. Chem. Soc, Chem. Commun. 1992, 487-488. (C) Kappe, C. O.; KoUenz, G.; Netsch, K.; Toung. R. L.; Wentmp, C ; J. Chem. Soc, Chem. Commun. 1992, 488-490.
(39) Boger, D. L.; Weinreb, S. N. Hetero Diels-Alder Methodology in Organic Synthesis. Harcourt Brace Jovanovich 1987, p 254.
(40) WagenseUer, P. E.; Bimey, D. M.; Roy. D. J. Org Chem. 1995, 60, 2853-2859.
(41) (A) Witzeman, J. S. Tetrahedron Lett. 1990, 37, 1401-1404. (B) Witzeman, J. S.; Clemens, R. J. J. Am. Chem. Soc 1989, 777,2186-2193.
(42) Sato, M.; Murakami, M.; Kaneko, C. Tetrahedron 1993, 32, 1582-1584.
(43) Frisch, M. J.; Tmcks, G. W.; Schlegel, H. B.; GUI, P. M. W.; Johnson, B. G.; Robb, M. A.; Cheeseman, J. R.; Kehh, T.; Petersson, G. A.; Montgomery, J. A.; Raghavachari, K.; Al-Laham, M. A.; Zakrzewski, V. G.; Ortiz, J. V.; Foresman, J. B.; Peng, C. Y., Ayala, P. Y.; Chen, W.; Wong, M. W.; Andres, J. L.; Replogle, E. S.; Gomperts, R.; Martm, R. L.; Fox, D. J.; Bmkley, J. S.; Defrees, D. J.; Baker, J.; Stewart, J. P.; Head-Gordon, M.; Gonzalez, C ; Pople, J.A. Gaussian 94, Revision B.3; Gaussian, Inc.: Pittsburgh PA, 1995.
(44) Shumway, W.; Ham, S.; Moer, J.; Whittlesey, B. R.; Bhney, D. M. J. Org Chem. 2Qm, 65,7731-7729.
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(46) Smith, M, B. Organic Synthesis McGraw-HUl, Inc., New York, 1994, pp 400-413.
(47) Regitz, M.; Hocker, J.; Liedhegener, A. Organic Synthesis, John WUey: New York, 1973; .Collect. Vol. V, pp 179-183.
124
(48) (A) Appolzer, W. Pure &App. Chem 1990, 62, 1241-50. (B) Busacca, C. A.; Campbell, S ; Dong, Y.; Grossbach, D.; Ridges, M.; Smit, L.; Spinelli, E. J. Org. Chem. 2000, 65,4753-55.
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(51) Lowry, T. H.; Richardson, K. S. Mechanism and Theory in Organic Chemistry Harper and Row, New York, 1987, pp 723-731.
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(53) Yates, P.; Chandross, E. A.; Tetrahedron Lett. 1959, 1-6.
(54) See supporting mformation for x-ray data
(55) Wang, X.; Haulk, K. N. J. Am. Chem. Soc 1994, 772, 1754-1756.
(56) UnpubHshed resuhs from this lab. See Chapter 5.
(57) Sato, M; Ogasawara. H, Yoshizumi, E.; Kato, T. Chem. Pharm. Bull. 1983, 31, 1902-1909.
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(59) (A) Cram, D. J.; Elhafez, F. A. A. J. Am. Chem. Soc 1952, 74, 5828-5835. (B) Cram, D. J.; Kopecky, K. R. J. Am. Chem. Soc 1959, 81, 2748-2755.
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(61) Meier, H.; Zeller, K. Angew. Chem. Int. Ed. Engl. 1975,14, 32-43.
(62) Calculations from our research group of a-oxoketene reactivity with immes by Chun Zhou.
(63) Anh, N. T. Top. Curr Chem. 1980,88,145-162.
(64) Corey, E. J.; Femer, N. F. J. Org. Chem. 1980, 45, 765-780.
125
(65) Wienstein, S.; Holness, N. J. J. Am. Chem. Soc 1955, 77, 5562-5578.
(66) Kappe, C. O., Terpetschnig, E.; Penn, G.; KoUenz, G.; Peters, K.; Peters, E. M.; Schmering, H. G. Liebigs Ann. 1995,537-543.
(67) Greene, T. W. Protective Groups in Organic Synthesis John WUey and Sons, New York, 1981, p. 241.
(68) The standard reduction potential of Pb(IV) to Pb (III) is 1.69 vohs and Ce "* to Ce ^ is 1.443 vohs. In general the larger the reduction potential, the greater the oxidizing power of the reagent. Smith, M. B. Organic Synthesis. McGraw-HiU, New York, 1994, pp. 218-219.
126
APPENDLX
X-RAY DATA; ' H NMR, ' C NMR AND IR SPECTROSCOPY
127
t-l u s o u u
O a
'^-l
O
o
128
l-H
s o u u
+-» U)
o a
o u
s 3 ; - i
V.I
; - i
129
Table Al Crystal data and structure refinement for 55.
Identification code
Empirical formula
Formula weight
Temperature
Wavelength
Crystal system
Space group
U n i t c e l l d i m e n s i o n s
VoliiTie, Z
Density (calculated)
Absorption coefficient
F(OOO)
Crystal size
0 range for data collection
Limiting indices
Reflections collected
Independent reflections
Refinement method
Data / restraints / parameters
2 G o o d n e s s - o f - f i t on F
F i n a l R i n d i c e s [ I > 2 a ( I ) ]
dmb2
S2"2a°4
3 5 6 . 4 4
2 9 3 ( 2 ) K
0 . 7 1 0 7 3 k
Monoclinic
' \ . o
a = 11.549(3) A alpha = 9 0
b = 13.860(3) A beta = 98.97(2) o
c = 12.352(2) A gamma = 90
1952.8(7) A , 4
, 3 1.212 Mg/m
-1 0.082 mm
768
0.40 X 0.35 X 0.25 mm
2.22 to 27.50
-15 < h < 0, -18 < ;< < 0, -15 < I £ 16
4876
4652 (R. ^ = 0.0317) int
2 Full-matrix least-squares on F
4652 / 1 / 470
1.030
Rl = 0.0529, wR2 = 0.1019
130
Table Al Contmued.
R indices (all data) Rl = 0.1053, wR2 = 0.1240
fiisolute structure parameter 0.4(14)
Extinction coefficient 0.0060(8)
• -3 Largest diff. peak and hole 0.148 and -0.140 eA
131
Table A2 Atomic coordmates [ x 10*] and equivalent isotropic displacement parameters [A x lO''] for 55.
0(1)
C(l)
C(2)
0(3)
0(4)
C(5)
C(6)
C(7)
0(8)
0(9) C(10)
0(11)
0(12)
0(13)
0(13)
0(14)
C(15)
C(16)
0(17)
C(18)
C(19)
C(20)
0(21)
C(22)
C(23)
C(24)
0(31)
C(31)
C(32)
C(33)
C(34)
0(35)
C(36)
C(37)
0(38)
C(39)
C(40)
C(41)
0(42)
C(43)
0(43)
8242(2)
8920(3)
9560(4)
9708(4)
8718(4)
9076(4)
10265(4)
10975(5)
9892(4)
10798(4)
11925(4)
11051(5)
9713(2)
9101(3)
8645(3)
9157(3)
10349(3)
10601(3)
9635(4)
8999(3)
8296(4) 8287(3)
7237(2)
10011(4)
11018(4)
9620(4)
6269(3)
5879(3)
5374(4)
5127(4)
6244(4)
6241(4)
5094(3)
4696(5)
5366(3)
4268(4)
3088(4)
4021(4)
5781(2)
6299(4)
7003(3)
7439(2)
6772(3)
6531(3)
7036(3)
6628(4)
5566(4)
5489(3)
4610(4)
5622(3)
6512(3)
6697(4)
6722(4)
4855(2)
5034(3)
4362(2)
6049(3)
6218(3)
5293(4)
5320(3)
6291(3)
6641(4)
6147(3)
6117(2)
6928(3]
7081(4
7923(3
5595 (2
4829(3
4634(3
5290(3
5244(3
4196(3
3752(3
2822(3
3750(3
4655(3
4475(4
5032(4
2934(2
3068(3
2487 (2
8171(2)
8342(3)
9392(3)
10490(3)
11063(4)
11266(4)
10827(3)
11199(4)
9615(3)
11101(3)
10627(4) 12337(4)
8923(2)
7879(3)
7392(2)
7441(3)
6997(3)
6380(3)
5370(3) 5448(3)
4386(3) 6358(3)
6286(2)
6031(3)
53S8(4)
) 6336(4)
) 1751(2)
) 1398(3)
) 282(3)
) -717(3)
) -1245(3)
) -1656(3)
) -1348(3)
) -1907(4)
) -125(3)
) -1493(3)
) -1115(4)
) -2669(3)
) 430(2)
) 1513(3)
) 1891(2)
51
41
42
50
64
62(
47(
74<
42(
51< 76(
72(
51( 43 (
60(
38(
46(
54(
54( 44(
65( 39(
49(
46(
69
65
58
40
43
47 54
50
42
64
38
49
74
64
45
42
58
1)
1)
1)
1)
1)
1)
1)
2) 1)
1)
2)
2) 1)
1)
1)
1)
1)
1)
1)
1)
1) 1)
1)
1)
>1)
il) (1)
(1)
(1)
(1) (1) (1)
(1)
(1)
(1)
(1) (2)
(1)
(1)
(1)
(1)
132
Table A2 Conthiued.
U(eq)
C ( 4 4 ) 5 8 5 6 ( 3 ) 3 9 1 3 ( 3 ) 2 1 1 3 ( 3 ) 3 7 ( 1 ) 0 ( 4 5 ) 4 6 1 2 ( 3 ) 3 6 9 2 ( 3 ) 2 4 0 0 ( 3 ) 4 3 ( 1 ) C ( 4 6 ) 4 6 0 2 ( 4 ) 2 6 3 2 ( 3 ) 2 7 3 0 ( 3 ) 4 9 ( 1 ) C ( 4 7 ) 5 4 6 2 ( 4 ) 2 6 1 0 ( 3 ) 3 8 2 3 ( 3 ) 5 3 ( 1 ) C ( 4 9 ) 6 2 5 2 ( 4 ) 3 8 9 3 ( 4 ) 5 2 5 5 ( 3 ) 7 2 ( 2 ) C ( 4 8 ) 5 7 7 1 ( 3 ) 3 6 8 3 ( 3 ) 4 0 6 8 ( 3 ) 4 6 ( 1 ) C ( 5 0 ) 6 5 7 8 ( 3 ) 3 9 6 2 ( 3 ) 3 2 6 9 ( 3 ) 4 0 ( 1 )
0 ( 5 1 ) 7 5 9 6 ( 2 ) 4 1 9 2 ( 2 ) 3 4 7 6 ( 2 ) 5 7 ( 1 ) C ( 5 2 ) 4 6 3 3 ( 4 ) 4 2 0 0 ( 3 ) 3 5 3 0 ( 3 ) 4 8 ( 1 ) C ( 5 3 ) 3 5 5 0 ( 4 ) 3 9 6 0 ( 5 ) 4 0 6 3 ( 4 ) 7 3 ( 2 ) C ( 5 4 ) 4 7 4 8 ( 4 ) 5 3 0 3 ( 4 ) 3 5 2 8 ( 4 ) 6 8 ( 1 )
133
Table A3 bond lengths [A] and angles [°] for 55.
0 ( 1 ) - C ( 1 )
C ( l ) - C ( 1 4 )
C ( 2 ) - C ( 3 )
C ( 3 ) - C ( 9 )
C ( 5 ) - C ( 6 )
C ( 6 ) - C ( 8 )
C ( 8 ) - 0 ( 1 2 )
C ( 9 ) - C ( l l )
C ( 1 3 ) - 0 ( 1 3 )
C ( 1 4 ) - C ( 2 0 )
C ( 1 5 ) - C ( 1 6 )
C ( 1 6 ) - C ( 1 7 )
C ( 1 8 ) - C ( 2 0 )
C ( 1 8 ) - C ( 2 2 )
C ( 2 2 ) - C ( 2 4 )
0 ( 3 1 ) - C ( 3 1 )
C ( 3 1 ) - C ( 4 4 )
C ( 3 2 ) - C ( 3 3 )
C ( 3 3 ) - C ( 3 9 )
C ( 3 5 ) - C ( 3 6 )
C ( 3 6 ) - C ( 3 7 )
C ( 3 8 ) - 0 ( 4 2 )
C ( 3 9 ) - C ( 4 0 )
C ( 4 3 ) - 0 ( 4 3 )
C ( 4 4 ) - C ( 5 0 )
C ( 4 5 ) - C ( 4 6 )
C ( 4 6 ) - C ( 4 7 )
C ( 4 9 ) - C ( 4 8 )
C ( 4 8 ) - C ( 5 2 )
C ( 5 2 ) - C ( 5 4 )
0 ( 1 ) - C ( 1 ) - C
C ( 2 ) - C ( l ) - C
C ( 8 ) - C ( 2 ) - C
C ( 2 ) - C ( 3 ) - C
C ( 4 ) - C ( 3 ) - C
C ( 4 ) - C ( 5 ) - C
C ( 7 ) - C ( 6 ) - C
C ( 7 ) - C ( 6 ) - C
C ( 5 ) - C ( 6 ) - C
C ( 2 ) - C ( 8 ) - C
C ( 1 0 ) - C ( 9 ) -
C ( l l ) - C ( 9 ) -
C ( l l ) - C ( 9 ) -
C ( B ) - 0 ( 1 2 ) -
( 2 )
( 1 4 )
( 3 )
( 4 )
( 9 )
( 6 )
( 5 )
( 9 )
( 9 )
( 6 )
C ( l l )
C ( 3 )
C ( 6 )
C ( 1 3 )
1 . 2 0 8 ( 5 )
1 . 5 5 3 ( 6 )
1 . 5 1 2 ( 5 )
1 . 5 4 4 ( 6 )
1 . 5 5 6 ( 6 )
1 . 5 0 3 ( 5 )
1 . 3 6 1 ( 5 )
1 . 5 3 6 ( 6 )
1 . 1 8 6 ( 5 )
1 . 5 4 9 ( 5 )
1 . 5 4 2 ( 6 )
1 . 5 3 9 ( 6 )
1 . 5 0 6 ( 5 )
1 . 5 5 0 ( 5 )
1 . 5 1 7 ( 6 )
1 . 2 0 9 ( 5 )
1 . 5 4 9 ( 5 )
1 . 5 2 3 ( 5 )
1 . 5 4 3 ( 6 )
1 . 5 6 0 ( 6 )
1 . 5 0 0 ( 6 )
1 . 3 6 9 ( 4 )
1 . 5 2 8 ( 6 )
1 . 1 8 7 ( 5 )
1 . 5 3 8 ( 5 )
1 . 5 2 5 ( 6 )
1 . 5 4 6 ( 5 )
1 . 5 1 3 ( 5 )
1 . 5 5 3 ( 6 )
1 . 5 3 4 ( 7 )
1 2 4 .
1 1 2 .
1 0 5 .
1 0 4 .
1 0 2 .
1 0 3 .
1 1 4 .
1 1 9 .
1 0 1 .
1 1 0 .
1 0 7 .
1 1 4 .
1 1 3 .
1 1 6
6 ( 4 )
0 ( 3 )
3 ( 3 )
7 ( 4 )
1 ( 3 )
7 ( 4 )
8 ( 4 )
5 ( 4 )
7 ( 4 )
5 ( 4 )
9 ( 4 )
3 ( 4 )
2 ( 4 )
6 ( 3 )
C ( l ) - C ( 2 )
C ( 2 ) - C ( 8 )
C ( 3 ) - C ( 4 )
C ( 4 ) - C ( 5 )
C ( 6 ) - C ( 7 )
C ( 6 ) - C ( 9 )
C ( 9 ) - C ( 1 0 )
0 ( 1 2 ) - C ( 1 3 )
C ( 1 3 ) - C ( 1 4 )
C ( 1 4 ) - C ( 1 5 )
C ( 1 5 ) - C ( 2 2 )
C ( 1 7 ) - C ( 1 8 )
C ( 1 8 ) - C ( 1 9 )
C ( 2 0 ) - O ( 2 1 )
C ( 2 2 ) - C ( 2 3 )
C ( 3 1 ) - C ( 3 2 )
C ( 3 2 ) - C ( 3 8 )
C ( 3 3 ) - C ( 3 4 )
C ( 3 4 ) - C ( 3 5 )
C ( 3 6 ) - C ( 3 8 )
C ( 3 6 ) - C ( 3 9 )
C ( 3 9 ) - C ( 4 1 )
0 ( 4 2 ) - C ( 4 3 )
C ( 4 3 ) - C ( 4 4 )
C ( 4 4 ) - C ( 4 5 )
C ( 4 5 ) - C ( 5 2 )
C ( 4 7 ) - C ( 4 8 )
C ( 4 8 ) - C ( 5 0 )
C ( 5 0 ) - O ( 5 1 )
C ( 5 2 ) - C ( 5 3 )
0 ( 1 ) - C ( 1 ) - C
C ( a ) - C ( 2 ) - C
C ( l ) - C ( 2 ) - C
C ( 2 ) - C ( 3 ) - C
C ( 5 ) - C ( 4 ) - C
C ( 7 ) - C ( 6 ) - C
C ( 8 ) - C ( 6 ) - C
C ( 8 ) - C ( 6 ) - C
C ( 2 ) - C ( 8 ) - 0
0 ( 1 2 ) - C ( 8 ) -
C ( 1 0 ) - C ( 9 ) -
C ( 1 0 ) - C ( 9 ) -
C ( 3 ) - C ( 9 ) - C
0 ( 1 3 ) - C ( 1 3 )
( 1 4 )
( 1 )
( 3 )
( 9 )
( 3 )
( 8 )
( 5 )
( 9 ) ( 1 2 )
C ( 6 )
C ( 3 )
C ( 6 )
( 6 ) - 0 ( 1 2 )
1 . 4 2 9 ( 5 )
1 . 3 3 2 ( 5 )
1 . 5 4 2 ( 6 )
1 . 5 3 9 ( 7 )
1 . 5 0 0 ( 6 )
1 . 5 6 2 ( 6 )
1 . 5 3 0 ( 6 )
1 . 3 9 2 ( 5 )
1 . 5 1 2 ( 6 )
1 . 5 7 7 ( 5 )
1 . 5 5 0 ( 6 )
1 . 5 4 4 ( 6 )
1 . 5 1 1 ( 6 )
1 . 2 0 3 ( 4 )
1 . 5 3 7 ( 6 )
1 . 4 3 6 ( 5 )
1 . 3 2 5 ( 5 )
1 . 5 3 6 ( 6 )
1 . 5 3 8 ( 6 )
1 . 4 9 4 ( 5 )
1 . 5 6 8 ( 6 )
1 . 5 2 8 ( 6 )
1 . 3 9 0 ( 5 )
1 . 5 1 6 ( 5 )
1 . 5 6 3 ( 5 )
1 . 5 6 0 ( 5 )
1 . 5 4 8 ( 6 )
1 . 5 1 0 ( 5 )
1 . 2 0 7 ( 4 )
1 . 5 3 7 ( 5 )
1 2 3 . 3 ( 3 )
1 2 0 . 0 ( 4 )
1 3 2 . 5 ( 4 )
1 0 1 . 0 ( 3 )
1 0 3 . 0 ( 4 )
1 1 7 . 5 ( 4 )
1 0 2 . 0 ( 3 )
9 8 . 4 ( 3 )
1 2 6 . 8 ( 4 )
1 2 1 . 5 ( 3 )
1 1 4 . 3 ( 4 )
1 1 3 . 5 ( 4 )
9 3 . 2 ( 3 )
1 1 6 . 7 ( 4 )
134
Table A3 Contmued.
0 ( 1 3
C ( 1 3 C ( 2 0 C ( 2 0
0 ( 1 6 C ( 2 2 C ( 1 6 0 ( 2 0 0 ( 2 0 C(17
0 ( 2 1 )
0 ( 2 4 ) 0 ( 2 3 ) 0 ( 2 3 ) 0 ( 3 1 0 ( 3 2 0 ( 3 8 0 ( 3 2 0 ( 3 4 0 ( 3 4 0 ( 3 8 C ( 3 3 C ( 3 5 0 ( 3 2 ,
C ( 4 1 C ( 4 0
C ( 4 0 C ( 3 8
0 ( 4 3 0 ( 4 3 C ( 5 0 C ( 5 0 0 ( 4 6 0 ( 5 2 0 ( 4 6 0 ( 5 0 C ( 5 0 0 ( 4 7 0 ( 5 1 0 ( 5 4 . 0 ( 5 3 C ( 5 3
) - C ( 1 3 ) - 0 ( 1 4 ) - C ( 1 4 ) - C ( 1 4
) - 0 ( 1 5 ) - 0 ( 1 5 ) - 0 ( 1 7 ) - C ( 1 8 ) - C ( 1 8 ) - C ( 1 8
- 0 ( 2 0 ]
- 0 ( 2 2 ] - 0 ( 2 2 ] - 0 ( 2 2 )
) - C ( 3 1 ) - C ( 3 1 ) - C ( 3 2 ) - C ( 3 3 ) - C ( 3 3 ) - C ( 3 5 ) - 0 ( 3 6 ) - C ( 3 6 ) - C ( 3 6
- 0 ( 3 8 - 0 ( 3 9
- 0 ( 3 9 - 0 ( 3 9
) - 0 ( 4 2 ) - 0 ( 4 3 ) - C ( 4 4 ) - C ( 4 4 ) - C ( 4 4 ) - C ( 4 5 ) - C ( 4 5 ) - 0 ( 4 7 ) - 0 ( 4 8 ) - C ( 4 8 ) - C ( 4 8 ) - C ( 5 0 ) - C ( 5 2 > - C ( 5 2 ) - C ( 5 2
) - 0 ( 1 4
) - 0 ( 2 0
) - c ( i ) ) - C ( 1 5
) - 0 ( 2 2 ) - 0 ( 1 4 ) - C ( 1 8 ) - C ( 1 7 ) - 0 ( 2 2 ) - 0 ( 2 2
- 0 ( 1 4 ]
- 0 ( 2 3 ] - 0 ( 1 5 ) - 0 ( 1 8 )
) - 0 ( 3 2 ) - 0 ( 4 4 ) - 0 ( 3 3 ) - C ( 3 4 ) - 0 ( 3 9 ) - 0 ( 3 6 ) - 0 ( 3 5
- 0 ( 3 9 > - C ( 3 9 ; - 0 ( 3 6 , - 0 ( 4 0 ] - 0 ( 3 3 ]
) - 0 ( 3 6 ^ ) - 0 ( 4 3 ) - 0 ( 4 4 ) - O ( 5 0 ) - 0 ( 3 1 ) - 0 ( 4 5 ) - 0 ( 5 2 ) - 0 ( 4 4 ) - C ( 4 8 ) - 0 ( 4 7 ) - C ( 5 2 ) - 0 ( 5 2 ) - C ( 4 4 ) - C ( 5 3 ) - 0 ( 4 8 ) - C ( 4 5 ,
) 1 2 6 . 1 ( 4 ) 1 0 9 . 4 ( 3
1 1 3 . 5 ( 3 ) 9 9 . 8 ( 3 ) 1 0 1 . 1 ( 3 ) 1 0 3 . 5 ( 3 ) 1 0 5 . 2 ( 3 ) 1 0 4 . 6 ( 3 ) 1 0 0 . 9 ( 3 ) 1 0 1 . 2 ( 3
1 2 4 . 8 ( 3 1 0 6 . 7 ( 4 1 1 2 . 2 ( 4 1 1 4 . 1 ( 3 ]
) 1 2 5 . 7 ( 4 ) 1 1 0 . 7 ( 3 ) 1 0 4 . 8 ( 3 ) 1 0 4 . 8 ( 3 ) 1 0 2 . 3 ( 3 ) 1 0 4 . 6 ( 3 ) 1 0 1 . 2 ( 3 > 9 8 . 4 ( 3 ,
1 0 0 . 4 ( 3 , 1 1 1 . 7 ( 3 ,
1 0 7 . 6 ( 4 ] 1 1 4 . 9 ( 4 ] 1 1 3 . 0 ( 4 ] 1 1 5 . 9 ( 3 ]
) 1 2 6 . 4 ( 4 , ) 1 0 8 . 2 ( 3 ' ) 1 1 6 . 0 ( 3 ' ) 1 0 0 . 5 ( 3 ) 1 0 1 . 3 ( 3 ) 1 0 3 . 2 ( 3
1 0 4 . 5 ( 3 1 0 5 . 4 ( 3
9 9 . 7 (3 1 0 1 . 8 ( 3 1 2 5 . 3 ( 4 ] 1 0 7 . 0 ( 4 ] 1 1 4 . 1 ( 4 ] 1 1 2 . 7 ( 4 1
) 0 ( 1 2 ) C ( 1 3 ) C ( 1 3 ) C ( l ) -
) C(16 ) C (17 ) C ( 2 0 ) C ( 1 9 ) C ( 1 9 ) 0 ( 2 1
0 ( 1 8 0 ( 2 4 ] 0 ( 2 4 ] 0 ( 1 5 ]
) 0 ( 3 1 ) C ( 3 8 > C ( 3 1 ) C ( 3 2 > C ( 3 3 ) C ( 3 8 » C ( 3 7 , 1 C ( 3 7 ,
C ( 3 2 ] 0 ( 4 2 ] 0 ( 4 1 ) 0 ( 4 1 ) 0 ( 3 3 ] 0 ( 4 3 ] 0 ( 4 2 ] C ( 4 3 ] C ( 4 3 ] C ( 3 1 ] C ( 4 6 ] 0 ( 4 5 ] C ( 5 0 ] 0 ( 4 9 ] 0 ( 4 9 ] 0 ( 5 1 ] 0 ( 4 8 ) 0 ( 5 4 ) 0 ( 5 4 ) 0 ( 4 8 )
) - C ( 1 3 ) - C ( 1 4 ) - C ( 1 4 - C ( 1 4 ) ) - C ( 1 5 ) - 0 ( 1 6 ) - o ( i a > - 0 ( 1 8 ) - 0 ( 1 8 ) - C ( 2 0
- 0 ( 2 0 - 0 ( 2 2 - C ( 2 2 - C ( 2 2
) - C ( 3 1 ) - 0 ( 3 2 ) - 0 ( 3 2 ) - 0 ( 3 3
- C ( 3 4 - 0 ( 3 6 - 0 ( 3 6 - 0 ( 3 6 - 0 ( 3 8 ] - 0 ( 3 8 ] - C ( 3 9 ] - C ( 3 9 ] - 0 ( 3 9 ] - 0 ( 4 3 ^ - C ( 4 3 ' - 0 ( 4 4 - C ( 4 4 - C ( 4 4 - C ( 4 5 - C ( 4 6 - 0 ( 4 8 - 0 ( 4 3 - 0 ( 4 8 ] - 0 ( 5 0 ' - C ( 5 0 ] - C ( 5 2 , - C ( 5 2 ] - 0 ( 5 2 ]
) - 0 ( 1 4
) - C ( l ) ) - 0 ( 1 5 - C ( 1 5 ) ) - 0 ( 1 4
- 0 ( 1 5 - C ( 1 9 - 0 ( 1 7 ] - 0 ( 2 2 , - 0 ( 1 8 ]
) - 0 ( 1 4 - C ( 1 5 - C ( 1 8 - 0 ( 1 8
) - C ( 4 4 ) - C ( 3 1 ) - C ( 3 3 ) - 0 ( 3 9 ) - C ( 3 5 > - C ( 3 7 - 0 ( 3 5 j - 0 ( 3 9 ] - 0 ( 4 2 ) - 0 ( 3 6 ) - 0 ( 3 3 ) - 0 ( 3 6 ) - 0 ( 3 6 ) - 0 ( 4 2 ) - 0 ( 4 4 ) - 0 ( 3 1 ] - 0 ( 4 5 ] - 0 ( 4 5 ] - 0 ( 4 4 ] - 0 ( 4 7 ] - 0 ( 4 9 ] - 0 ( 4 7 ] - 0 ( 5 2 ] - 0 ( 4 8 ] - 0 ( 4 4 ] - 0 ( 4 8 ] - 0 ( 4 5 ] - 0 ( 4 5 ]
) 1 1 7 . 0 1 0 8 . 8
) 1 1 0 . 5 1 1 4 . 5
) 1 0 6 . 9 > 1 0 2 . 2 (
1 1 4 . 1 ( 1 1 5 . 0 ( 1 1 9 . 0 ( 1 2 7 . 7 (
) 1 0 7 . 5 115 . 8 1 1 3 . 6
9 4 . 4 ) 1 2 3 . 6 ) 1 2 1 . 1 ) 1 3 1 . 5 ) 1 0 0 . 6
1 0 2 . 7 1 1 7 . 7 1 1 6 . 0 1 1 9 . 7 1 2 6 . 4 1 2 0 . 6 1 1 3 . 8 1 1 3 . 7
9 3 . 6 1 1 7 . 0 1 1 6 . 5 1 0 8 . 5 1 1 0 . 6 1 1 2 . 8 1 0 7 . 2 1 0 2 . 8 1 1 4 . 5 1 1 4 . 4 1 1 9 . 0 1 2 7 . 5 1 0 7 . 2 1 1 3 . 1 1 1 5 . 9
9 3 . 9
C3) ' 3 )
3 ) 3 )
3 )
3 )
3 )
3 )
4 ) 3 )
( 3 )
( 3 )
( 4 )
[ 3 ) ( 3 )
( 4 )
( 4 )
( 3 )
( 3 )
( 4 )
( 3 )
( 4 )
: 3 )
3 )
4 )
3 )
3 )
. 4 )
[ 3 )
L 3 )
[ 3 )
( 3 )
[ 3 )
[ 3 )
[ 3 )
[ 4 )
( 4 )
( 3 )
( 3 )
( 4 )
( 4 )
( 3 )
Symmetry t r a n s f o r m a t i o n s used t o genera te e q u i v a l e n t atomsi
135
Table A4 Anisotropic displacement parameters [A x 10 ] for 55.
U l l U22 U33 U23 U13 U12
0 ( 1 ) 0 ( 1 ) 0 ( 2 ) 0 ( 3 ) 0 ( 4 ) 0 ( 5 ) 0 ( 6 ) 0 ( 7 ) 0 ( 8 )
0 ( 9 ) 0 ( 1 0 ) 0 ( 1 1 ) 0 ( 1 2 ) 0 ( 1 3 ) 0 ( 1 3 ) 0 ( 1 4 ) 0 ( 1 5 ) 0 ( 1 6 ) 0 ( 1 7 ) 0 ( 1 8 ) 0 ( 1 9 ) 0 ( 2 0 ) 0 ( 2 1 ) 0 ( 2 2 ) 0 ( 2 3 ) 0 ( 2 4 ) 0 ( 3 1 ) 0 ( 3 1 ) 0 ( 3 2 ) 0 ( 3 3 )
0 ( 3 4 ) 0 ( 3 5 ) 0 ( 3 6 ) 0 ( 3 7 ) 0 ( 3 8 )
0 ( 3 9 ) 0 ( 4 0 ) 0 ( 4 1 ) 0 ( 4 2 ) 0 ( 4 3 ) 0 ( 4 3 . )
C ( 4 4 )
5 8 ( 2 ) 4 1 ( 2 ) 5 3 ( 2 ) 7 0 ( 3 ) 7 2 ( 3 ) 6 9 ( 3 ) 5 3 ( 2 ) 9 3 ( 4 ) 5 0 ( 2 ) 5 7 ( 3 ) 6 6 ( 3 ) 8 3 ( 4 )
6 6 ( 2 ) 4 5 ( 2 ) 7 3 ( 2 ) 3 7 ( 2 ) 3 4 ( 2 ) 4 1 ( 2 ) 4 9 ( 2 ) 4 1 ( 2 ) 6 7 ( 3 ) 4 1 ( 2 ) 3 5 ( 2 ) 4 7 ( 2 )
6 5 ( 3 ) 8 0 ( 3 )
7 8 ( 2 )
4 5 ( 2 )
5 7 ( 3 )
6 4 ( 3 ) 6 4 ( 3 ) 5 5 ( 3 ) 5 1 ( 2 ) 8 3 ( 3 )
4 9 ( 2 ) 5 2 ( 3 ) 5 1 ( 3 ) 7 5 ( 3 ) 6 9 ( 2 ) 4 8 ( 2 )
6 8 ( 2 )
4 1 ( 2 )
4 7 ( 2 ) 4 0 ( 2 ) 3 4 ( 2 ) 4 2 ( 2 ) 7 4 ( 3 ) 7 0 ( 3 ) 4 5 ( 2 ) 7 3 ( 4 ) 3 8 ( 2 ) 5 6 ( 3 ) 9 1 ( 4 ) 7 7 ( 3 ) 3 7 ( 2 ) 4 5 ( 3 ) 4 1 ( 2 ) 3 7 ( 2 ) 6 2 ( 3 ) 7 0 ( 3 ) 6 5 ( 3 ) 5 4 ( 3 ) 8 6 ( 4 ) 3 8 ( 2 )
' 6 0 ( 2 ) 5 3 ( 3 ) 8 7 ( 4 ) 5 2 ( 3 ) 3 9 ( 2 ) 3 3 ( 2 ) 3 4 ( 2 ) 3 5 ( 2 ) 4 9 ( 3 ) 5 7 ( 3 ) 4 2 ( 2 ) 5 8 ( 3 ) 3 3 ( 2 ) 5 3 ( 3 )
1 0 0 ( 4 ) 6 8 ( 3 ) 3 2 ( 2 ) 4 1 ( 2 ) 5 3 ( 2 )
3 6 ( 2 )
4 5 ( 2 ) 4 0 ( 2 ) 3 8 ( 2 ) 3 8 ( 2 ) 4 8 ( 3 ) 5 0 ( 3 ) 4 1 ( 2 ) 5 3 ( 3 ) 3 8 ( 2 ) 4 0 ( 2 ) 6 8 ( 3 ) 4 7 ( 3 ) 4 6 ( 2 ) 4 1 ( 2 ) 6 2 ( 2 ) 3 8 ( 2 ) 4 0 ( 2 ) 5 4 ( 3 ) 4 8 ( 2 ) 3 7 ( 2 ) 4 2 ( 2 ) 3 6 ( 2 ) 5 3 ( 2 ) 4 0 ( 2 ) 6 1 ( 3 ) 6 2 ( 3 ) 5 7 ( 2 ) 4 4 ( 2 ) 3 9 ( 2 ) 4 1 ( 2 ) 4 8 ( 2 ) 3 9 ( 2 ) 3 4 ( 2 ) 4 9 ( 3 )
• 3 2 ( 2 ) 4 2 ( 2 ) 7 0 ( 3 ) 4 4 ( 2 ) 3 4 ( 1 ) 3 6 ( 2 ) 5 3 ( 2 ) 3 5 ( 2 )
- 5 ( 1 ) 3 ( 2 )
- 4 ( 2 ) - 5 ( 2 ) - 4 ( 2 ) 1 0 ( 2 )
5 ( 2 ) 1 0 ( 3 ) - 1 ( 2 ) - 4 ( 2 ) - 3 ( 3 ) - 4 ( 3 ) - 4 ( 1 ) - 4 ( 2 )
- 1 1 ( 2 ) - 3 ( 2 )
- 1 3 ( 2 ) - 8 ( 2 )
- 2 0 ( 2 ) - 7 ( 2 )
1 ( 2 ) - 1 2 ( 2 ) - 1 1 ( 2 )
- 6 ( 2 ) - 1 1 ( 3 )
4 ( 2 ) - 2 ( 2 )
0 ( 2 ) 4 ( 2 ) 4 ( 2 )
1 2 ( 2 ) 6 ( 2 )
- 2 ( 2 ) - 1 1 ( 2 )
5 ( 2 ) 1 ( 2 )
3 ( 3 ) 5 ( 2 )
- 1 ( 1 ) 2 ( 2 ) 3 ( 2 )
- 1 ( 2 )
3 ( 1 ) 5 ( 2 ) 5 ( 2 ) 7 ( 2 )
1 6 ( 2 ) 1 8 ( 2 )
5 ( 2 ) 4 ( 3 ) 7 ( 2 ) 5 ( 2 )
• 7 ( 3 ) - 4 ( 3 )
2 ( 1 ) 7 (2 ) 3 ( 2 ) 4 ( 2 )
- 1 ( 2 ) 1 0 ( 2 )
9 (2 ) 4 ( 2 ) 7 ( 2 ) 2 ( 2 ) 4 ( 1 )
1 1 ( 2 ) 2 2 ( 2 ) 1 2 ( 3 ) 1 2 ( 2 ) 1 4 ( 2 ) 1 1 ( 2 )
8 ( 2 ) 7 ( 2 )
1 3 ( 2 )
7 ( 2 ) 6 ( 2 ) 9 ( 2 ) 8 ( 2 )
1 0 ( 2 ) - 3 ( 2 ) 1 0 ( 1 )
7 ( 2 ) 7 ( 2 )
1 2 ( 2 )
1 0 ( 2 ] - 6 ( 2 ;
1 ( 2 ] 3 ( 2 ]
1 1 ( 3 ] - 6 ( 3 ;
0 ( 2 ] 1 8 ( 3 ; - 3 ( 2 )
- 8 ( 2 ;
- 2 3 ( 3 ;
- 4 ( 3 ;
4 ( 1 ) 1 ( 2 ]
- 1 3 ( 2 ) - 5 ( 2 ) - 7 ( 2 ;
8 ( 2 ;
0 ( 2 ; - 5 ( 2 ; - 2 ( 3 ; - 2 ( 2 ;
- 3 ( 1 ) - 1 4 ( 2 ; - 2 5 ( 3 ; - 1 7 ( 3 ;
- 7 ( 2 ]
1 ( 2 ; 2 ( 2 ;
1 2 ( 2 ] - 4 ( 2 ;
6 ( 2 ] 4 ( 2 ]
- 4 ( 3 ; 1 ( 2 ] 8 ( 2 ] 9 ( 3 ;
1 8 ( 3 ; 6 ( 1 ) 1 ( 2 ;
2 0 ( 2 ;
2 ( 2 ;
136
Table A4 Continued.
Ull U22 U33 U23 U13 U12
C(45) 34(2) 55(3) 38(2) -2(2). 2(2) -4(2) 0(46) 50(2) 55(3) 0(47) 61(3) 55(3) 0(49) 80(3) 97(4) 0(48) 49(2) 60(3) 0(50) 41(2) 34(2)
0(51) 42(2) 67(2) 0(52) 46(2) 61(3) 0(53) 61(3) 99(4) 0(54) 79(3) 67(3)
4 3 ( 2 ) 4 3 ( 2 ) 3 6 ( 2 ) 2 3 ( 2 ) 4 3 ( 2 )
5 7 ( 2 ) 3 9 ( 2 ) 6 5 ( 3 ) 5 8 ( 3 )
- 5 ( 2 ) 8 ( 2 )
- 1 0 ( 3 ) - 7 ( 2 ) - 2 ( 2 )
- 2 ( 2 ) - 7 ( 2 ) - 7 ( 3 )
- 1 3 ( 3 )
1 0 ( 2 ) 1 0 ( 2 ) - 1 ( 2 )
1 ( 2 ) 0 ( 2 )
- 3 ( 1 ) 1 3 ( 2 ) 2 7 ( 3 ) 1 8 ( 3 )
- 2 0 ( 2 ) - 9 ( 2 }
- 1 5 ( 3 ) - 1 2 ( 2 )
- 4 ( 2 )
- 9 ( 2 ) - 6 ( 2 )
- 1 ( 3 ) 1 1 ( 3 )
137
Table A5 Hydrogen coordmates [ x 10*] and isotropic displacement parameters [A x 10 ] for 55.
U(eq)
H H H H H H H H H H H H H H H H
H( H( H( H( H(
H( H( H( H( H( H H
H( H( H( H( H( H< H( H(
H(
H( H( H(
(3A)
(4A) (4B) [5A) (5B) (7A) (7B) ( 7 0 ) ( lOA) ( lOB) ( IOC) ( l l A ) ; 1 1 B ) 1 1 0 ) 15A) 16A) 16B) 17A) 17B) 19A) 19B) 19C) 23A) 23B) 2 3 0 ) 24A) 24B) 2 4 0 ) 33A) 34A) 34B) 35A) 35B) 37A) 3 7 B ) 37C)
40A) 40B) 40O) 41A)
9762
8681
7964
8496
9170
11157
11690
10534
11789
12534
12160
10355
11291
11665
10999
11376
10534
9097
9974
8805
7941
7696
11294
11647
10740
8988
9358
10265
4346
6936
6210
6925
6232
4551
3983
5293
3216
2652
2654
4749
(4
(4
(4
(4
(4
(5
(5
(5
(4
(4
(4
(5
(5
(5
(3
(3
(3
(4
(4
(4
(4
(4
(4
(4
(4
(4
(4
(4
(4
(4
(4
(4
(4
(5
(5
(5
(4
(4
(4
(4
7741
6962
6630
5136
5411
4609
4618
4042
6571
6280
7357
6611
7332
6304
6434
5311
4722
4785
5237
6716
7250
6179
6466
7419
7453
7861
8286
8252
5939
5377
5698
3851
4177
2920
2610
2341
4238
4007
5068
5152
(3
(4
(4
(4
(4
(4
(4
(4
(4
(4
(4
(4
(4
(4 (3
(4
(4
(3 (3
(4
(4
(4
(4
(4
(4
(3
(3
(3
(3
(3
(3
(3
(3
(3
(3
(3
(4
(4
(4
(4
10466(3
11747(4
10595(4
10869(4
12041(4
11984(4
10892(4
10958(4
9853(4
10977(4
10753(4
12654(4
12453(4
12677(4
7551(3
6169(3
6320(3
5383(3
4700(3
3846(3
4505(3
4131(3
5157(4
5309(4
4724(4
6753(4
5681(4
6766(4
-579(3
-713(3
-1847(3
-1297(3
-2442(3
-2686(4
-1664(4
-1730(4
-376(4
-1587(4
-1146(4
-2929(3
60
77
77
74
74
110
110
110
113
113
113
108
108
108
55
65
65
65
65
98
98
98
104
104
104
97
97
97
56
65
65
59
59
96
96
96
110
110
110
95
138
Table A5 Conthiued.
U ( e q )
H ( 4 1 B ) 3 5 8 0 ( 4 ) 5 6 2 1 ( 4 ) - 2 6 8 8 ( 3 ) 95 H ( 4 1 C ) 3 5 7 8 ( 4 ) 4 5 6 0 ( 4 ) - 3 1 2 9 ( 3 ) . 95
H ( 4 5 A ) 3 9 6 1 ( 3 ) 3 8 8 5 ( 3 ) 1 8 3 6 ( 3 ) 5 1 H ( 4 6 A ) 4 8 7 3 ( 4 ) 2 2 2 2 ( 3 ) 2 1 8 5 ( 3 ) 59 H ( 4 6 B ) 3 8 2 3 ( 4 ) 2 4 2 9 ( 3 ) 2 8 3 4 ( 3 ) 59 H ( 4 7 A ) 6 1 5 3 ( 4 ) 2 2 4 1 ( 3 ) 3 7 4 8 ( 3 ) 63 H ( 4 7 B ) 5 0 9 3 ( 4 ) 2 3 2 9 ( 3 ) 4 4 0 3 ( 3 ) 63 H ( 4 9 A ) 5 6 9 1 ( 4 ) 3 6 9 6 ( 4 ) 5 7 1 0 ( 3 ) 108 H ( 4 9 B ) 6 3 9 9 ( 4 ) 4 5 7 2 ( 4 ) 5 3 4 6 ( 3 ) 108
H ( 4 9 0 ) 6 9 7 0 ( 4 ) 3 5 4 3 ( 4 ) 5 4 6 4 ( 3 ) 108 H ( 5 3 A ) 3 4 4 9 ( 4 ) 3 2 7 3 ( 5 ) 4 0 7 9 ( 4 ) 110 H ( 5 3 B ) 2 8 6 8 ( 4 ) 4 2 4 9 ( 5 ) 3 6 4 4 ( 4 ) 110 H ( 5 3 0 1 3 6 5 8 ( 4 ) 4 2 0 8 ( 5 ) 4 7 9 7 ( 4 ) 110 H ( 5 4 A ) 5 4 1 8 ( 4 ) 5 4 8 1 ( 4 ) 3 2 0 0 ( 4 ) 1 0 1 H ( 5 4 B ) 4 8 4 4 ( 4 ) 5 5 3 3 ( 4 ) 4 2 6 7 ( 4 ) 1 0 1 H ( 5 4 C ) 4 0 5 4 ( 4 ) 5 5 7 9 ( 4 ) 3 1 1 4 ( 4 ) 1 0 1
139
Table A6 Optimized Cartesian coordinated (B3LYP/6-31G**) of 60 and 61.
7 B3LYP/6-31G(d ,p) f o r m y l k e t e n e (60) C - 1 . 0 7 3 2 3 5 4 3 0 5 -0 .097662971 0 .8521660337 0 - 1 . 6 9 3 5 0 8 0 2 4 1 -0 .6102152876 -0 .0612306652 H - 1 . 5 3 2 6 9 1 1 9 4 7 0.0655345381 1.848466356 C 0 . 3 1 7 5 8 0 3 2 4 3 0.3651752612 0 .7845443464 C 1 .0075222676 0.2385041797 -0 .3476518737 H 0 .8117193145 0.8142343812 1.6379958299 0 1 .594729138 0.1207318202 -1 .3413709879
18 B3LYP/6-31G(d ,p) d e s - m e t h y l camphorke tene ( 6 1 ) C - 1 . 3 5 6 6 6 6 0 1 5 4 1.0896578628 -1 .1739002754 C - 1 . 1 8 9 4 6 1 3 2 1.0381356648 0.3777321477 C 0 .9395843634 0.8525587729 -0 .4010472697 C 0 .1115619016 1.0072679416 -1 ,7061327704 H - 1 . 9 8 8 8 2 4 3 8 2 6 0.2778732778 -1 .5432326443 H - 1 . 8 3 3 2 4 8 9 4 5 2 2.0314774517 -1 .4617039627 H 0 .2685221055 0.1717443124 -2 .3923155387 H 0 .3963195613 1.9263531224 -2 .2294205187 C 0 .1536194726 1.771394686 0.5674244532 H 0 .5309228352 1.7404441465 1.5933166951 H 0 .1231037795 2.8104783823 0.2228735144 C - 0 . 8 0 2 7 9 7 3 7 8 8 -0 .4109783639 0.7211975696 C 0 .5973522135 -0 .5123433126 0.206403822 H - 2 . 0 5 3 9 2 8 0 8 9 2 1.3804200664 0.9469023448 H 2 .0073833822 1.0505750763 -0 .5045391106 C 1 .3311576432 -1 .6074348702 0.2410399574 0 1 .9691074388 -2 .5840634765 0 .2969953815 0 - 1 . 4 8 8 6 5 9 3 7 9 9 -1 .260801039 1.2494813078
140
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141
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