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Tetrahedron Letters 56 (2015) 283–295
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Tetrahedron Letters
journal homepage: www.elsevier .com/ locate/ tet le t
Digest Paper
Recent advances in copper-catalyzed propargylic substitution
http://dx.doi.org/10.1016/j.tetlet.2014.11.1120040-4039/� 2014 Published by Elsevier Ltd.This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).
⇑ Corresponding author. Tel.: +86 411 84379276; fax: +86 411 84684746.E-mail addresses: [email protected], [email protected] (X.-P. Hu).
De-Yang Zhang, Xiang-Ping Hu ⇑Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, China
a r t i c l e i n f o
Article history:Received 13 September 2014Revised 18 November 2014Accepted 18 November 2014Available online 1 December 2014
Keywords:CopperPropargylic substitutionAsymmetric catalysisN-NucleophilesC-Nucleophiles
a b s t r a c t
The copper-catalyzed propargylic substitution reaction has become a powerful synthetic method to pre-pare the compounds containing the propargylic subunit. Compared with the other transition-metalsapplied in the propargylic substitution, copper has many obvious advantages, such as much more inex-pensive, easier to handle, milder reaction condition, and higher selectivity. This digest summarizes therecent development in the copper-catalyzed propargylic substitutions with various nitrogen, carbon, oxy-gen, and sulfur nucleophiles. In addition, the cycloadditions involving the copper-catalyzed propargylicsubstitution as the key step are included.� 2014 Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/3.0/).
Contents
Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283Propargylic substitution using nitrogen nucleophiles. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284
Propargylic amination of propargylic esters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284Ring-opening reaction of ethynyl epoxides with amines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287Decarboxylative propargylic amination of propargyl carbamates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287Propargylic amination/cyclization tandem reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287
Propargylic substitution using carbon nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287
Ketone enolates or their equivalents as nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287Propargylic alkylation of enoxysilanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287Propargylic alkylation of enamines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288Decarboxylative propargylic alkylation of propargyl b-ketoesters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289
Propargylic alkylation of aldehydes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290Propargylic alkylation of b-dicarbonyl compounds. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290Propargylic substitution of indoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291Propargylic substitution of terminal alkynes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291Propargylic trifluoromethylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291Propargylic alkylation/cycloaddition tandem reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293
Propargylic substitution of oxygen and sulfur nucleophiles. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294Conclusions and future outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294Acknowledgment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294References and notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294
Introduction
Propargylic compounds are common motifs in many naturalproducts, fine chemicals, and synthetic pharmaceuticals, as wellas useful synthetic intermediates in organic synthesis. The presence
R1
HN
R2+R
OLG CuCl (1-5 mol%)
50 oC or refluxTHF, 2 h
R
N
21 3
R1 R2
C5H11
N
91% yield
Et Et
Ph
N
75% yield
N
85% yield
HN
85% yield
PhN
60% yield
Bn
C5H11
N
84% yield 80% yield
N
95% yield
OH
2 equiv
OHN
OH
C5H11
LG = Ac or PO(OEt)2
Bn
Scheme 1. Cu-catalyzed propargylic amination.
284 D.-Y. Zhang, X.-P. Hu / Tetrahedron Letters 56 (2015) 283–295
of the nucleophilic triple bond, accompanied by a fairly acidic ter-minal acetylenic hydrogen in many cases, make these propargyliccompounds highly potential for a wide variety of transformations.1
The Nicholas reaction,2 a well-known substitution reaction ofpropargylic alcohol derivatives with various nucleophiles, repre-sents one of the most effective methods for the synthesis of a widerange of propargylic compounds. However, this reaction requires astoichiometric amount of toxic Co2(CO)8, which significantly lim-ited its application. Therefore, the development of a catalytic prop-argylic substitution becomes a pre-requisite task for organicchemists. In comparison with the transition-metal-catalyzedallylic substitution reaction which is one of the most reliable meth-ods in organic synthesis,3 the catalytic propargylic substitutionreaction has been lagging far behind. To date, the catalytic propar-gylic substitution reaction was mostly limited to work using Pd,Cu, Ti, and Ru catalysts,4 and the first catalytic asymmetric version5
occurred until 2003. Among various catalysts used in the propargy-
NO
N N
OPh
Ph
Ph
Ph
diPh-pybox L1
OAc
Ar+
a Condition A: CuI (10 mol%)/diPh-pybox L1 (12 mol%), iPr2NEt (4.0 equiv),MeOH, -20 oC. Condition B: CuOTf 1/2C6H5 (5 mol%)/(R)-Cl-MeO-BIPHEP L2 (10 mol%), iPr2NEt (4.0 equiv), MeOH, 0 oC. b Thereaction was performed at 40 oC. c The reaction was performed at rt.
N
Ar
R2
1 2 3
R1
Cl
MeOMeO
Cl
PPh2PPh2
(R)-Cl-MeO-BIPHEP L2
NH
R2R1
abcdb
efcghijkl
Ph1-naphthyl2-pyridyl
iPrPhPhPh
4-BrC6H44-MeC6H4
PhPhPh
Ar Yield
858574408760858581898053
Ee of 3
979180279490969198966490
R1
HHHHH
MeMeMeMeMe
R2
2-MeOC6H42-MeOC6H42-MeOC6H42-MeOC6H4
PhPhPhPhPh
4-ClC6H4-(CH2)5-
Conditionsa
AAAAAABBBBBB PhH
Conditions
2.0 equiv
Scheme 2. Cu-catalyzed asymmetric propargylic amination.
lic substitution reaction, copper salts display some distinct advan-tages: (1) low cost, (2) low toxicity, (3) mild reaction condition, (4)operational simplicity, (5) broad substrate scope, (6) excellentselectivity. In particular, recent progress in the Cu-catalyzed asym-metric propargylic substitution further demonstrated its superior-ity. Although some recent reviews about propargylic substitutionhave been reported,4 there are no specific reviews focused on thecopper-catalyzed propargylic substitution reaction. Herein, wedescribe recent developments in the emerging field of copper-cat-alyzed propargylic substitution reactions, classified by thenucleophiles.
Propargylic substitution using nitrogen nucleophiles
Propargylic amines are versatile building blocks and intermedi-ates for organic synthesis.6 Transition-metal catalyzed propargylicsubstitution using nitrogen nucleophile is one of the most attrac-tive strategies to synthesize these compounds. In recent years,the copper-catalyzed propargylic substitutions using nitrogennucleophiles have made great progress. Different kinds of cop-per-catalyzed propargylic aminations, as well as the cycloadditionswith propargylic amination as the key step, have been developed.
Propargylic amination of propargylic esters
In 1960, Hanzel and co-workers developed a propargylic amina-tion of tertiary propargylic chlorides with various amines.7 It wasfound that the copper catalyst (CuCl–Cu) was necessary to achievegood yields when the aromatic amines were used as the nucleo-philes. The formation of a more reactive copper acetylide specieswas proposed to be responsible for the improved reactivity. In1994, Murahashi and co-workers developed a highly effectiveCuCl-catalyzed propargylic amination of propargylic acetates andphosphates 1 with various amines 2 under mild conditions(Scheme 1).8 The reaction was highly regioselective and no allenyl-amine byproducts were observed. Additionally, a terminal acety-lenic proton was essential for this copper-catalyzed amination,and an internal alkyne did not undergo the amination even undersevere conditions. This result suggested a copper–acetylide com-plex should be formed as the key intermediate. Although still inthe racemic series at this stage, this work sets the stage for anenantioselective version.
However, it is until 2008, van Maarseveen and Nishibayashiindependently reported the first copper-catalyzed asymmetricpropargylic amination.9,10 These methods provided an efficient
Ar
OAcCuL*
Ar
OAc
CuL*
Ar
OAc
iPr2NEt
NHR1R2Ar
NHR1R2
CuL*
iPr2NEt AcOH
Ar
NR1R2
CuL* Cu-acetylide complex
Cu-allenylidene complex
iPr2NHEtiPr2NHEt
Ar
NR1R2
ArCuL*
γα
β
••Ar
CuL*
D
A
•
iPr2NEt
Ar
O
CuL*
OH
Me
iPr2NEt
E
B
C
F
G
2
1
3
Scheme 3. Proposed reaction pathway for Cu-catalyzed propargylic amination.
Cu PP
H
H+
pseudoaxial
pseudoequatorial
edge to faceinteraction
Ph
NPh
(S)
re face attack
HOMe
γ
α
β
PhHN
Scheme 4. Model of the transition state of the copper–allenylidene complexbearing (R)-BIPHEP.
OCOC6F5
Alkyl+ ArNHR1
3.0 equiv
CuOTf 1/2C6H5 (5 mol%)(R)-BINAP L3 (10 mol%)
iPr2NEt (1.2 equiv)
MeOH, 0 oC, 96 h
N
Alkyl
R1 Ar
N
50% yield82% ee
N
50% yield89% ee
N
57% yield82% ee
21 3
N
50% yield83% ee
Cl
PPh2PPh2
(R)-BINAP L3
Scheme 5. Cu-catalyzed asymmetric propargylic amination of propargylic penta-fluorobenzoates with secondary amines.
OLG+ ArNH2
2.0 equiv
CuI (10 mol%)Me-pybox L4 (12 mol%)
iPr2NEt (4.0 equiv)
MeOH, rt, 24-48 h
HN
Alkyl
Ar
NO
N N
O
Me-pybox L4
HN
96% yield85% ee
HN
77% yield82% ee
1 2 3
MeO MeO
Alkyl
HN
59% yield90% ee
MeO
HN
84% yield67% ee
MeO
MeO
LG = Ac or Piv
Scheme 6. Cu-catalyzed asymmetric propargylic amination of propargylic esterswith o-anisidines.
ab
bcdeb
fghijc
klmn
PhPh
4-CF3C6H44-MeC6H4
2-furylPh
4-FC6H44-MeC6H4
PhPhBnCynPrCy
R Yield (%)
9093969089959792959178819193
ee (%)
8589858492869084877745527669
R1
HHHHH
MeMeMeEt
Fe
PPh2
(Sc,Rp)-L5
R2
Ph2-MeOC6H42-MeOC6H42-MeOC6H42-MeOC6H4
PhPhPhEt
-(CH2)5-
PPh2
N
(Rc)-L6
OAc
R + NH
R2R1 N*
R
R2R1
1 2 3
N
Conditions
Conditionsa
a Condition A: CuCl (5 mol%)/(Sc,RP)-L5 (10 mol%), iPr2NEt (1.2 equiv),MeOH, 0 oC, 12-24 h. Condition B: Cu(OAc)2 H2O (10 mol%)/(Rc)-L6 (12 mol%), iPr2NEt (4.0 equiv), MeOH, 0 oC, 60 h. b The reaction
was performed at -20 oC for 48 h. c CuOTf 1/2C6H6 was used instead ofCuCl.
AAAAAAAAAABBBB
HH
MeMe
2-MeOC6H42-MeOC6H4
PhPh
NN
Scheme 7. Cu-catalyzed asymmetric propargylic amination with chiral P,N,N-ligands.
NH+Ar
OAcCuOTf 1/2C6H6 (5 mol %)
(R)-BICMAP L7 (10 mol %)
iPr2NEt (1.2 equiv)MeOH, -10 oC, 18 h
Ar
N
21 3
R1 R2
1.5 equiv
O
O
PPh2PPh2
(R)-BICMAP L7
R2R1
abcdefgh
Ph4-ClC6H4
4-MeOC6H42-MeC6H4
PhPhPhPh
PhPhPhPh
4-ClC6H4PhPh
Ar R1 Yield
8787378190824470
Ee (%)
6868856870548377
·
R2
MeMeMeMeMeEtH
Indoline
Scheme 8. Cu-catalyzed asymmetric propargylic amination with (R)-BICMAP.
D.-Y. Zhang, X.-P. Hu / Tetrahedron Letters 56 (2015) 283–295 285
route to prepare optically active propargylic amines 3 in highyields and with good enantioselectivities. The major differencebetween van Maarseveen’ and Nishibayashi’s methods is thestructure of the chiral ligand. In van Maarseveen’s method, a chiral2,6-bis(oxazolinyl)pyridine-type ligand (diPh-pybox L1) incombination with CuI was used as the catalyst, and primaryamines proved to be more suitable nucleophiles (up to 88% ee,Scheme 2). In comparison, Nishibayashi employed the complexof CuOTf�1/2C6H5 with an atropisomeric diphosphine ligand(Cl-MeO-BIPHEP L2) as the catalyst and only secondary aminesworked as suitable nucleophiles (up to 98% ee, Scheme 2).
Nishibayashi and co-workers made an exhaustive research onthe reaction mechanism and proposed a reaction pathway similarto van Maarseveen’s (Scheme 3).11 The experimental resultsrevealed that the copper–allenylidene complex should be the keyintermediate. This conclusion is also supported by density func-tional theory calculations for the model reaction. Here the attackof the amines to the Cc atom of the copper allenylidene complexD is the key step in determining both the regio- and stereoselectiv-ities. This mechanism explains why the reaction requires the use ofpropargyl substrates with terminal acetylene.
A transition state of the copper–allenylidene complex with thechiral ligand (R)-BIPHEP L2 is proposed to account for high enanti-oselectivity of the reaction (Scheme 4).11 The re-face of the c-car-bon of the copper–allenylidene complex is open to attack by theN-methylaniline. The edge-to-face interaction between the car-bonAhydrogen bond of the substrate and the phenyl group at thepseudo-equatorial position of (R)-BIPHEP L2 is considered as anessential factor in achieving high enantioselectivity.
In 2011, Nishibayashi and co-workers realized the copper-cata-lyzed enantioselective propargylic amination of aliphatic propar-gylic esters 1, a challenging substrate class, with secondary
OAcNHAr
CuOTf 1/2C6H6 (5 mol%)(R)-L4 or L8 (10 mol%)
iPr2NEt (1.2 equiv)MeOH, 0 oC, 8-30 h
·N Ar
4 5
N
L4: 87% yield, 93% eeL8: 91% yield, 90% ee
N
L4: 89% yield, 93% eeL8: 89% yield, 96% ee
N
L4: 81% yield, 98% eeL8: 83% yield, 93% ee
BrF
NO
N N
O
R RL4: R = MeL8: R = Ph
R1 R1
Scheme 9. Cu-catalyzed asymmetric intramolecular propargylic amination ofpropargylic acetates bearing a secondary amine moiety.
OAc
OAc
CuOTf 1/2C6H6 (5 mol%)Ph-pybox L8 (10 mol%)
iPr2NEt (2.4 equiv)MeOH, rt, 4 h
·NPh*
70% yield (meso/dl = 5/1), 75% ee6 7
*+ PhNH2
1.2 equiv
6 PhHNNHPh+
CuOTf 1/2C6H6 (5 mol%)Ph-pybox L8 (10 mol%)
iPr2NEt (2.4 equiv)MeOH, rt, 20 h
·
68% yield (meso/dl = 8/1), 66% ee
8
*NPh
NPh*
1.2 equiv
Scheme 10. Cu-catalyzed sequential inter- and intramolecular double propargylicamination.
R+
1.2 equiv
Cu(OTf)2 (2 mol%)(R)-DTBM-MeO-BIPHEP L9 (5 mol%)
iPr2NEt (10 mol%)acteone, -20 oC
O
R
NR1R2HO
MeOMeO
PAr2PAr2
Ar = 3,5-tBu2-4-MeOC6H2(R)-DTBM-MeO-BIPHEP
9 2 10
L9
Ph
HNHO
95% yield79% ee
Ph
HNHO
96% yield75% ee
Me
Ph
HNHO
93% yield94% ee
CF3
Ph
NHO
91% yield52% ee
R1
HN
R2
tBu
HNHO
80% yield69% ee
CF3
Ph
HO
87% yield55% ee
HN tBu
Scheme 11. Cu-catalyzed asymmetric ring-opening reaction of ethynyl epoxideswith amines.
*
HN*
N
*
S
**N N N
O O O
Cl Me
*
N
*N
*N
96% yield94% ee
90% yield89% ee
93% yield96% ee
93% yield94% ee
94% yield91% ee
93% yield82% ee
94% yield95% ee
92% yield97% ee
O
PPh2
N
(S)-L10
N
Ph
R2N
R1O
O
ArCu(OAc)2 H2O (5 mol%)
(S)-L10 (5.5 mol%)
Et3N (1.2 equiv)MeOH, 0 oC, 12 h
Ar*
NR2R1
O O
N
CO2
R2R1
Cu/N-N-P*
3
Et3N
·
•
•
Ar
CuL*
11
Scheme 12. Cu-catalyzed asymmetric decarboxylative propargylic amination ofpropargyl carbamates.
286 D.-Y. Zhang, X.-P. Hu / Tetrahedron Letters 56 (2015) 283–295
amines 2, in which moderate yields with high enantioselectivitieswere achieved in the presence of 5 mol % CuOTf�1/2C6H5/(R)-BINAPL3 complex (up to 90% ee, Scheme 5).12 The introduction of penta-fluorobenzoate in place of the acetate group as a leaving group wasfound to be necessary to promote the amination of aliphatic prop-argylic esters with secondary amines. However, primary amineswere less efficient in this catalytic system.
The copper-catalyzed enantioselective amination of non-aro-matic propargylic esters 1 with primary amines 2 could be realizedwith van Maarseveen’s method, in which good yields and highenantioselectivities were achieved by use of 10 mol % CuI withMe-pybox L4 (up to 90% ee, Scheme 6).13 Some secondary amineswere also tested, however, only moderate enantioselectivities wereachieved.
In 2012, Hu and co-workers demonstrated that chiral tridentateP,N,N-ligands, (Sc,Rp)-L5 and (R)-L6, were highly efficient for theCu-catalyzed asymmetric propargylic amination of propargylicacetates 1.14 In the presence of CuCl/(Sc,Rp)-L5 complex, both pri-mary aromatic amines and secondary amines 2 were found to besuitable nucleophiles, providing the corresponding propargylicamines 3 in high yields and with excellent enantioselectivities(up to 97% ee for secondary amines, and up to 96% ee for primaryamines, Scheme 7). Moreover, in the catalysis of Cu(OAc)2�H2O/(R)-L6 complex, aliphatic propargylic acetates also served well, provid-ing the products with good enantioselectivities (Scheme 7). It wasnoteworthy that this Cu/P,N,N-ligand catalytic system representsthe first successful example in which both primary and secondary
amines could be used as efficient nucleophiles for the highly enan-tioselective catalytic propargylic amination of both aliphatic andaromatic propargylic acetates.
In 2013, Sakamoto and co-workers reported the copper-cata-lyzed asymmetric propargylic amination of aromatic propargylicesters 1 with amines 2 using (R)-BICMAP L7 as a chiral ligand, giv-ing the desired products 3 in good yields (up to 85% yield) and withmoderate to high enantioselectivities (up to 90% ee, Scheme 8).15
D.-Y. Zhang, X.-P. Hu / Tetrahedron Letters 56 (2015) 283–295 287
Very recently, Nishibayashi and co-workers disclosed a copper-catalyzed asymmetric intramolecular propargylic amination ofpropargylic acetates 4 bearing a secondary amine moiety at a suit-able position.16 In the catalysis of CuOTf�1/2C6H6/Pybox (L4 or L8)complex, a variety of optically active 1-ethynylisoindolines 5 wereobtained in good yields and with high enantioselectivities (up to98% ee, Scheme 9). They also made a preliminary investigationon the sequential inter- and intramolecular double propargylicamination, however, the result was still far from satisfactory(Scheme 10).
Ring-opening reaction of ethynyl epoxides with amines
In 2009, Nishibayashi and co-workers reported the copper-cat-alyzed asymmetric ring-opening reaction of ethynyl epoxides 9with amines 2 catalyzed by Cu(OTf)2/DTBM-MeO-BIPHEP L9 com-plex. Optically active b-amino alcohols 10 bearing a tertiary carbonat the a-position of the amine were obtained in high yields withhigh enantioselectivities (up to 94% ee, Scheme 11).17 The catalyticreaction was considered to proceed via copper–allenylidene com-plexes as the key intermediates. Furthermore, good yields andexcellent enantioselectivities were also observed even in the pres-ence of only 0.1 mol % of copper catalyst (84% yield, 94% ee,TON = 840).
Decarboxylative propargylic amination of propargylcarbamates
Although great advances have been made in propargylic substi-tution using nitrogen nucleophiles, the development of new strat-egy for the catalytic synthesis of propargylic amines remains ahighly desirable and challenging task. In 2014, Hu and co-workersreported a Cu-catalyzed asymmetric decarboxylative propargylicamination of propargyl carbamates 11 with a tridentate ketimineP,N,N-ligand L10 (Scheme 12).18 The reaction could be performedunder very mild condition for a broad range of substrates, provid-ing the corresponding propargylic amines 3 in good yields andwith high enantioselectivities (up to 97% ee). In this method, boththe nucleophile and the electrophile were formed in situ by theloss of CO2 in catalytic concentration (Scheme 12). This reactionrepresents a new and complementary strategy for access to opti-cally active propargylic amines.
Propargylic amination/cyclization tandem reactions
The catalytic sequential reaction using transition metal com-plexes have attracted much attention due to the advantage of sim-plicity and facility in the preparation of complex and usefulcompounds. Recently, some cycloaddition reactions based on thecopper-catalyzed propargylic amination have also been developed.
+
CuOTf 1/2C6H6 (5 mol%)(R)-L2 (10 mol%)iPr2NEt (1.2 equiv)
MeOH0 oC, 24 h; then rt, 8h
12 cis-131.2 equiv
·
Ar
OAc
1
PhHN
N
Ar
Ph
N
Ph
Ph
82% yieldcis/trans = 20/1
88% ee (cis)
NPh
84% yieldcis/trans >30/1
90% ee (cis)
NPh
87% yieldcis/trans = 19/1
85% ee (cis)
S O
NPh
88% yieldcis/trans = 17/1
80% ee (cis)
SBr
Scheme 13. Cu-catalyzed asymmetric propargylic amination/cycloaddition tandemreaction of propargylic acetates with N-(E)-penta-2,4-dienylaniline.
In 2010, Nishibayashi and co-workers reported the copper-catalyzed asymmetric propargylic amination/[4+2]-cycloadditiontandem reaction of propargylic acetates 1 with N-(E)-penta-2,4-dienylaniline 12 to give chiral 1,2-disubstituted tetrahydroisoindolederivatives 13 in high yields and with high diastereo-/enantiose-lectivities (up to >30/1 dr, up to 90% ee, Scheme 13).19 Thiswork is the first example of the copper-catalyzed diastereo- andenantioselective sequential reaction, in which only a single coppercomplex worked as a catalyst to promote both the propargylicamination and the intramolecular [4+2] cycloaddition reaction.
A proposed reaction pathway is shown in Scheme 14. At first, N-(E)-2,4-pentadienylaniline 12 might attack the copper acetylidecomplex A bearing a cationic c-carbon atom from the re face to giveC with high enantioselectivity. Then, the intramolecular [4+2] cyclo-addition reaction occurs via the copper acetylide complex D, whichis formed from C and the chiral copper complex. The direct transfor-mation from B to D without the formation of C as a reactive interme-diate may also be conceivable in the sequential reactions.
In 2011, Zhan and co-workers described a Cu(OTf)2-catalyzedtandem reaction of propargylic alcohols 14 with amidine 15 to pro-vide 2,4-disubstituted or 2,4,6-trisubstituted pyrimidines 16 inmoderate to good yields (up to 91% yield, Scheme 15), which areimportant heterocyclic units in pharmaceuticals, agrochemicals,biologically active molecules, and novel materials.20 The reactionis proposed to undergo a propargylation/cyclization/oxidation tan-dem mechanism (Scheme 16). In the initial step, Cu(OTf)2-inducedpropargylic amination of propargyl alcohol 14 with benzimida-mide leads to C. The intramolecular nucleophilic attack of amidinenitrogen at the Cu-activated triple bond of alkyne produces cyclicdihydropyrimidine intermediate D (6-endo-dig). Then, the dihy-dropyrimidine D is aromatized to the pyrimidine ring via the oxi-dation with air. In this reaction, the Cu(OTf)2 acts as abifunctional catalyst, not only does it assist in the leaving of thehydroxyl group from the propargylic alcohol, furnishing the prop-argylic cation B, but also activate the triple bond, rendering thecyclization process more facile.
Propargylic substitution using carbon nucleophiles
The development of new, efficient, and valuable syntheticmethodologies for the direct construction of the carbonAcarbonbond is a highly important task in organic chemistry. The propar-gylic substitution using carbon nucleophile offers a straightfor-ward and efficient route to form the new carbonAcarbon singlebond, whereas synthesizes the compound bearing the carbonAcar-bon triple bond. In recent years, the copper-catalyzed propargylicsubstitutions using carbon nucleophiles have attracted muchattention, and some related cycloadditions have also beendeveloped.
Ketone enolates or their equivalents as nucleophiles
Propargylic alkylation of enoxysilanesIn 2007, Zhan and co-workers reported a very efficient method
for the synthesis of b-alkynyl ketones 18 by the substitution reac-tion of propargylic acetates 1 with enoxysilanes 17 in the catalysisof 1 mol % Cu(OTf)2 (Scheme 17).21 The reaction was completedrapidly within 5 min under the mild condition. It was noticed thatthe steric bulkiness of side chains (R2) in propargylic acetates 1 hada significant effect on the regioselectivity of the reaction (18 vs 19).Propargylic acetates 1 bearing the terminal or internal alkynegroup were also tolerated. Furthermore, the substitution reactioncould be followed by a TsOH-catalyzed cyclization without purifi-cation of the b-alkynyl ketone intermediates, offering a straightfor-ward synthetic route to polysubstituted furans 20.
Ph
OAc
PhCuL*
Ph
HN
PhNH
Ph
PhN
Ph
N
Ph
Ph
+
+A
BD
iPr2NEt
iPr2NEt·AcOH
CuL*
PhN
PhCuL*
*LCu
N
Ph
Ph
H+
[Cu]+
[Cu]+
113
H+
E
H+
12
C
C
Scheme 14. Proposed catalytic cycle for copper-catalyzed sequential reactions.
+R1
OH Cu(OTf)2 (20 mol%)
PhCl, reflux, air1.5-24 h
1514 16
H2N NH
R2
PhN N
Ph
R1 R2
R2 = TMS 87% yieldR2 = H 68% yield
N N
Ph
79% yield
N N
Ph
Ph Ph75% yield
N N
Ph
R2 = TMS 85% yield
N N
Ph
73% yield
N N
Ph
Ph
Ph
OMe
S
R2 = TMS 89% yieldR2 = H 69% yield
N N
Ph
Scheme 15. Cu-catalyzed tandem reactions of propargylic alcohols with amidines.
+R1
OHCu(OTf)2 (20 mol%)
PhCl, reflux, air1.5-24 h
1514 16
H2N NH
R2
PhN N
Ph
R1 R2
R1
HO
R2
Cu2+
R1
R2
15
H+
+R1
HN
R2
NH
Ph
Cu2+
6-endo-digHN N
Ph
R1 R2
aromatization air
A B C D
Scheme 16. Proposed reaction pathway for copper-catalyzed tandem synthesis ofpyrimidines.
OAc
R3
R1
R2
Cu(OTf)2 (1 mol %)
MeCN, RT5 min
17 18
65-85% Yield
3.0 equiv
abcdefgh
PhPhPhPhPhPhPhPh
HHPhHHHHPh
R1 R2 Yield (%, I8:I9)
84:088:038:5282:087:089:093:00:87
R3
HPhPhH
PhH
TMSPh
+OTMS
R4
R5
R3
R1
R2
R4
O
R5
R4 R5
PhPhPhMeMe
HHHHH
-(CH2)4-
-(CH2)4-
-(CH2)4-
+R1
R2
R3
R4
O19
TsOH, toluenereflux, 0.5-2 h
O
R2 = H
R3
R1 R5
R4
20
·
1R5
Scheme 17. Cu-catalyzed propargylic alkylation of enoxysilanes.
288 D.-Y. Zhang, X.-P. Hu / Tetrahedron Letters 56 (2015) 283–295
Propargylic alkylation of enaminesIn 2009, Hou and co-workers developed the first copper-cata-
lyzed asymmetric propargylic substitution of propargylic acetates1 with enamines 21 catalyzed by 5 mol % of Cu(CH3CN)4ClO4/(R)-Cl-MeO-BIPHEP complex (Scheme 18).22 A series of b-ethynylketones 22 were prepared in good yields and with good enantiose-lectivities (up to 91% ee). The aliphatic enamine derived fromcyclohexanone was also examined, providing the product in 33%yield with 10:1 dr and 72% ee when a propargylic benzoate insteadof the acetate was used.
Very recently, Hu and co-workers reported a highly diastereo-/enantioselective copper-catalyzed propargylic alkylation of mor-pholine-derived acyclic ketone enamines 23 with propargylic
OAc
R1 +
[Cu(CH3CN)4]ClO4 (5 mol %)(R)-Cl-MeO-BIPHEP L2 (5 mol %)
iPr2NEt (4.0 equiv)MeOH, -15 oC
77% yield85% ee
NEt2
R2
R1
O
R2H3O
Ph
O
Ph
95% yield82% ee
O
Ph
80% yield67% ee
O
95% yield73% ee
O
Ph
61% yield91% ee
Ph
O
63% yield82% ee
Ph
O
Cl
40% yield84% ee
85% yield78% ee
Ph
O
1 21 222.0 equiv
O
NO2
Cl
Ph
O
N
Scheme 18. Cu-catalyzed asymmetric propargylic alkylation of enamines withpropargylic acetates.
OAc
R1+
Cu(OTf)2 (5 mol%)(S)-L10 (5.5 mol%)
iPr2NEt (1.2 equiv)MeOH, -10 oC, 12 h
94% yieldsyn/ ant i >95/5>99% ee (syn)
N
R2
R1
O
R2H3O
O
Ph
O
Ph
Cl
OO
Ph
Ph
O
Ph
O
Me Ph
O
Ph
O
1 23 24-syn1.2 equiv
S
O
R3
R3
93% yieldsyn/anti >95/599% ee (syn)
90% yieldsyn/ ant i = 94/699% ee (syn)
96% yieldsyn/ ant i >95/597% ee (syn)
92% yieldsyn/ ant i >95/5>99% ee (syn)
93% yieldsyn/anti = 93/7>99% ee (syn)
92% yieldsyn/ant i >95/5>99% ee (syn)
60% yieldsyn/anti = 81/19
99% ee (syn)
F
Scheme 19. Cu-catalyzed diastereo-/enantioselective propargylic alkylation ofacyclic ketone enamines with propargylic acetates.
O O
OR1 R2
O
R1 R2
N
PPh2N
Ph
Cu(CH3CN)4BF4 (5 mol%)(S)-L10 (5.5 mol%)
(S)-L10
2225
abcdefgha
ijkl
Ph2-ClC6H4
4-BrC6H4
4-MeC6H4
4-NO2C6H4
2-naphthyl2-thienyl
MePhPhPhPh
PhPhPhPhPhPhPhPh
4-MeC6H4
4-CF3C6H4
2-naphthyl2-thienyl
R1 R2
Et3N (1.2 equiv)toluene, 0 oC, 12 h
Yield (%)
959395959496958589959788
ee (%)
966595939695918891969492
a The reaction was performed in MeOH at a catalyst loading of 10 mol%.
Scheme 20. Cu-catalyzed asymmetric decarboxylative propargylic alkylation ofpropargyl b-ketoesters.
Ph
O
O O
PhCuL*+
Ph
O
O O
Ph
CuL*
Ph
O O
O-
Ph
O O-
O
Ph
CuL*
O
OHPh
O
Ph
O
PhCuL*
Ph
O
O O
Ph
Ph
O
Ph
Et3N
Et3NH+
A
B
C
D
E
F
25
22
Et3NH+
Et3N CO2
H
••
PhCuL*
••
PhCuL*
Scheme 21. Proposed reaction pathway for decarboxylative propargylic alkylation.
R1
O
OH
O
+ R
OAc Cu(CH3CN)4BF4 (5 mol%)(S)-L10 (5.5 mol%)
Et3N (1.2 equiv)MeOH, 0 oC, 12 h
R1 R
O
26 1 22
N
PPh2N
Ph
(S)-L10
abcdef
Ph4-MeC6H4
4-BrC6H4
MePhPh
PhPhPhPh
4-FC6H4
2-thienyl
R1 R Yield (%)
989698749693
ee (%)
918592659089
1.1 equiv
Scheme 22. Cu-catalyzed asymmetric intermolecular decarboxylative propargylicalkylation of b-keto acids with propargylic esters.
D.-Y. Zhang, X.-P. Hu / Tetrahedron Letters 56 (2015) 283–295 289
esters 1 in the presence of a bulky and structurally rigid tridentateketamine P,N,N-ligand (S)-L10 to forge two vicinal tertiary stereo-centers, in which excellent diastereoselectivities (up to >95:5 dr)and perfect enantioselectivities (up to >99% ee) were obtained fora wide range of substrates (Scheme 19).23
Decarboxylative propargylic alkylation of propargyl b-ketoesters
Although some ketone enolate equivalents proved to be suit-able reagents for catalytic asymmetric propargylic substitutions,the use of simple ketone enolates as nucleophiles is still very lim-ited. In 2014, a breakthrough was made by Hu and co-workers.They developed an intramolecular asymmetric decarboxylativepropargylic alkylation of propargyl b-ketoesters 25 by use ofCu(CH3CN)4BF4/(S)-L10 (5 mol %) as the catalyst, in which a varietyof b-ethynyl ketones 22 were obtained in good yields and withhigh enantioselectivities (up to 98% ee) (Scheme 20).24
In this reaction, both the nucleophile and the electrophile wereformed in situ in catalytic concentration by the loss of CO2, instead
OCOC6F5
Ar+
2.0 equiv
CuOTf 1/2C6H5 (10 mol%)Chiral amine L11 (20 mol%)rac-BINAP L3 (20 mol%)
ClCH2CH2Cl, rt, 1.5-2 h
53% yieldsyn/ant i = 3.2/198% ee (syn)96% ee (ant i)
R1
O
Ar
R1
O
+Ar
R1
O
28-syn 28-anti
NaBH4EtOH
0 oC, 1 h
Ar
R1
OH
+Ar
R1
OH29-syn 29-anti
Ar = 1-naphthyl
NH OTMS
Ar1
Ar1
Ar1 = 3,5-(CF3)2C6H3chiral amine
Ar
OHPh
Ar
OH
52% yieldsyn/ant i = 3.2/197% ee (syn)98% ee (anti)
Ar
OH
58% yieldsyn/anti = 3.5/183% ee (syn)94% ee (anti)
64% yieldsyn/anti = 3.5/184% ee (syn)94% ee (ant i)
Ar
OH
Cl
1 27
(S)-L11
•
Scheme 23. Cooperative catalytic asymmetric propargylic alkylation of aldehydes.
290 D.-Y. Zhang, X.-P. Hu / Tetrahedron Letters 56 (2015) 283–295
of the need to prepare preformed enolate equivalents. The nucleo-philic attack of the enolate to the c-carbon atom of the copperallenylidene complex should be the key step in determiningstereoselectivity (Scheme 21). This work also represents the firstsuccessful example of the catalytic asymmetric decarboxylativepropargylic alkylation. In addition, the reaction showed to be lesssensitive to the nature of the solvent, and the best reaction solventwas toluene in terms of enantioselectivity. This result is differentwith those observed in the copper-catalyzed enantioselectivepropargylic substitution, in which only a polar protic solvent suchas MeOH proved to be suitable.
A copper-catalyzed intermolecular enantioselective decarboxy-lative propargylic alkylation of propargylic esters 1 with b-ketoacids 26 was subsequently developed by the same group.25 A vari-ety of b-keto acids 26 with propargylic esters 1 underwent thedecarboxylative propargylic alkylation to give the corresponding
OCOC6F5
Ar+
cat. L11cat. CuOTf + LR1
O
Ar
R1
O
+ C6F5CO2H
Ar
OCOC6F5
HAr
L*Cu
ArH
L*Cu
CuL*R1
Nenamine
ArH
L*Cu·
R1
N
Ar
L*Cu
R1
N
Ar
CuL*
alkyne complex
allenylidene complex acetylide complex
alkyne complex
CuL* -H2OL11 -CuL*
281 27
-C6F5CO2H
·· ·
H2O -L11
R1
O
γ
αβ
δ δ
αβ
γ
Scheme 24. Proposed reaction pathway for cooperative catalytic propargylicalkylation.
b-ethynyl ketones 22 in good yields with excellent enantioselectiv-ities (up to 98% ee, Scheme 22). In comparison to the correspond-ing intramolecular decarboxylative propargylic alkylation ofpropargyl b-ketoesters 25, this method displays some significantadvantages: (1) more readily available substrates; (2) generallybetter enantioselectivities; (3) broader substrate scope, especiallyfor aliphatic propargylic esters.
Propargylic alkylation of aldehydes
Recently, the combination of distinct catalysts for dual activa-tion of distinct reacting partners has emerged as a new strategyfor developing novel and valuable reactions that are difficult orimpossible by the use of single catalyst.26 In 2011, Nishibayashiand co-workers reported the asymmetric propargylic alkylationof propargylic pentafluorobenzoate 1 with aldehydes 27 using aCuOTf�1/2C6H6/racemic BINAP L3 complex and a chiral secondaryamine L11 as the co-catalyst. The reaction gave propargylic alkyl-ation products 29 as a mixture of two diastereoisomers in goodyields and with high enantioselectivities (Scheme 23).27 Interest-ingly, the stereochemistry of BINAP did not affect the enantioselec-tivity of the alkylation product 29.
In this reaction, copper complex (transition metal catalyst) andsecondary amine L11 (organocatalyst) activated propargylic esters1 and aldehydes 27, respectively, and both catalysts worked coop-eratively and simultaneously to promote the propargylic alkylationenantioselectively (Scheme 24). This work is an extension of thestudy of asymmetric propargylic substitution of propargylic alco-hols with aldehydes using a thiolate-bridged diruthenium complexand a chiral secondary amine as cocatalysts.28 However, higherdiastereoselectivity but lower catalytic activity was observed inthe copper-catalyzed propargylic alkylation.
Propargylic alkylation of b-dicarbonyl compounds
In 2011, van Maarseveen and co-workers attempted the firstcopper-catalyzed asymmetric propargylic substitution of 1-phe-nyl-2-propynyl acetate with 2,2,5-trimethyl-1,3-dioxane-4,6-dione, a cyclic derivative of malonate. However, only low enanti-oselectivity (6% ee) was obtained.13 The development of a catalytic
OAc
R+
1
O OR1 R
O OR1
3130
O O
95% yield98% ee
OO
O O
O O
85% yield>99% ee
O O
65% yielda
97% ee
F3C
O O
90% yield86% ee
88% yield91% ee
O OOO
83% yield>99% ee
94% yieldanti /syn = 3.5/199% ee (anti)
O
65% yield97% ee
MeO2C
Cu(CH3CN)4BF4 (5 mol%)(R)-L10 (7.5 mol%)
iPr2NEt (2.4 equiv)MeOH, 0 oC, 12 h1.2 equiv
a The reaction was performed at RT under a catalyst loading of 10 mol %.
Scheme 25. Cu-catalyzed asymmetric propargylic alkylation of b-dicarbonylcompounds.
OAc
R1 +
1 3332
94% yield98/2 dr98% ee
CuBr or Cu(acac)2 (5 mol%)sec-butyl-pybox L12 (6 mol%)
iPr2NEt (2.0 equiv)MeOH, 20 oC, 0.5-12 h2.0 equiv
R3
R4 O
O
CO2R2R3
R4 O
O
CO2R2
R1
O
O
CO2Et
91% yield91/9 dr94% ee
O
O
CO2Et90% yield91/9 dr92% ee
O
O
CO2Et93% yield89/11 dr78% ee
O
O
CO2Et
91% yield91/9 dr94% ee
O
O
CO2Me
Ph
91% yield90/10 dr93% ee
O
O
CO2Et
Ph
90% yield91/9 dr92% ee
O
O
CO2Et
Ph
MeCl
Br
MeO
79% yield91/9 dr88% ee
O
O
CO2Et
PhMe
NO
N N
O
sec-butyl-pybox L12
Scheme 26. Cu-catalyzed diastereo- and enantioselective propargylic alkylation of2-substituted benzofuran-3(2H)-ones.
OAc
Ph+
2.0 equiv
CuI (10 mol%)pybox ligand L1 (12 mol%)
iPr2NEt (4.0 equiv)MeOH, -20 oC, 24 h Ph
NO
N N
O
Ph PhdiPh-pybox L1 71% yield
94% ee91% yield98% ee
PhPh
NR
NR
Ph
NH
Ph
N
1 34 35
Scheme 27. Cu-catalyzed asymmetric propargylic alkylation of indoles.
D.-Y. Zhang, X.-P. Hu / Tetrahedron Letters 56 (2015) 283–295 291
system that could catalyze the asymmetric propargylic substitu-tion in broad substrate spectrum with regard to b-dicarbonyl com-pounds is therefore highly desirable.
Recently, Hu and co-workers reported the first highly enantio-selective copper-catalyzed propargylic alkylation of propargylicacetates 1 with b-diketones 30 by employing the chiral tridentate
OH
R1 +2.0 equiv
Cu(OTf) (10 mol%)
DCE, 4A MSreflux, 5 min R1
14 36 37
up to 87% yield
R2
R3
R3
R2
Ph
87% yield
Ph
PhPh
72% yield
Ph
76% yield
nBu80% yield
TMS
R1 = Aryl, Alkyl; R2 = Aryl, Alkyl, TMS, H;R3 = Aryl, Alkenyl; R4 = Aryl, Alkyl
Br OMe Br
°
Scheme 28. Cu-catalyzed propargylic alkylation of terminal alkynes.
ketimine P,N,N-ligand (R)-L10. A series of propargylic alkylationproducts 29 were obtained in high yields and with excellentenantioselectivities (up to >99% ee, Scheme 25).29 The catalyticsystem was also efficient for cyclic b-ketoesters and cyclic malon-ate derivatives as nucleophiles. In this reaction, the use of thebulky and structurally rigid chiral ketimine-type P,N,N-ligand(R)-L10 was critical to achieve good performance.
Very recently, Wu and co-workers developed a diastereo- andenantioselective propargylic alkylation of 2-substituted benzofu-ran-3(2H)-ones 32 with propargylic esters in the catalysis of a cop-per–pybox complex (Scheme 26).30 A series of 2,2-disubstitutedbenzofuran-3(2H)-ones 33 bearing two vicinal chiral centers andone terminal alkyne functional group were obtained in good toexcellent diastereoselectivities (up to 98:2 dr) and enantioselectiv-ities (up to 98% ee).
Propargylic substitution of indoles
In 2011, van Maarseveen and co-workers reported a copper-cat-alyzed asymmetric propargylation of propargylic acetates 1 withindoles 34 in the presence of diPh-pybox ligand L1 (Scheme 27).13
Indole and N-methylindole were suitable nucleophiles, giving the3-propargylindoles 35 in high yields (up to 91% yield) and withexcellent enantioselectivities (up to 98% ee). This is different withthe Ru-catalyzed asymmetric propargylation of indoles, in whichthe presence of a bulky group such as triisopropylsilyl at the nitro-gen atom of indoles was essential for achieving high enantioselec-tivity.31 However, the limited scope of the reaction was examined.
Propargylic substitution of terminal alkynes
1,4-Diynes are traditionally obtained by the nucleophilic substi-tution of propargyl halides or sulfonates with metal acetylides, inwhich large amounts of salt waste are generated simultaneously.32
In 2011, Zhan and co-workers reported a copper-catalyzed propar-gylic substitution of propargyl alcohols 14 with terminal alkynes36 using 10 mol % Cu(OTf)2 as the catalyst.33 The reaction couldbe finished in 5 min with water as the only byproduct. A range ofpropargyl alcohols 14 and terminal alkynes 36 were well tolerated,and a variety of 1,4-diynes products 37 were obtained in goodyields (up to 87% yield, Scheme 28).
Propargylic trifluoromethylation
The introduction of a trifluoromethyl (CF3) group into organicmolecules has attracted considerable attention since the resulting
+
CuTC (5 mol%)KF (1.5 equiv)
THF60 oC, 20 h39
1.5 equiv
Cl
38a
RCF3SiMe3 CF3
R
·
R = 4-CF3C6H4, 75% yieldR = 4-MeC6H4, 83% yieldR = 1-naphthyl , 86% yieldR = Bn, 80% yield
40
R
CF3
+
CuTC (5 mol%)KF (1.5 equiv)
THF60 oC, 20 h
39
1.5 equivCl
38b
R
CF3SiMe3
41a
R = 4-MeC6H4, 79% yieldR = 4-ClC6H4, 81% yieldR = PhCH2CH2, 71% yield
Scheme 29. Cu-catalyzed trifluoromethylation of propargylic chlorides withtrifluoromethyltrimethylsilane.
CuI (10 mol%)DMEDA (10 mol%)
NaO2CCF2Br (25 mol%)
KF, DMF, 50 oC, 14 hactivation
O
42
R
CF3
R
R
CF3
·CF2Br
O
+
40
41bR = 4-MeOC6H4, 72% yield, 40/41b = 4.0/1R = 2-Naphthyl, 57% yield, 40/41b = 3.8/1R = PhCH2CH2, 70% yield, 40/41b = 1.2/1
Scheme 30. Cu-catalyzed decarboxylative trifluoromethylation of propargylbromodifluoroacetates.
O
R
CF3
R
R
CF3
·CF2Br
O
+40
41b
O CF2Br
O
LnCuLnCuINaO CF2Br
O
LnCu CF3
KFKBr+CO2
KF
42
Scheme 31. Proposed catalytic cycle via an activation procedure.
Scheme 33. Mechanism for propargylic alkylation/cycloisomerization tandemreaction.
292 D.-Y. Zhang, X.-P. Hu / Tetrahedron Letters 56 (2015) 283–295
trifluoromethylated compounds are highly promising skeletons inthe field of pharmaceuticals, agrochemicals, and materials.34
Recently, Nishibayashi and co-workers reported the reaction of pri-mary and secondary propargylic halides 38a–b with trifluorometh-yltrimethylsilane (CF3SiMe3) 39 in the presence of 5 mol %copper(I) thiophene-2-carboxylate (CuTC) to give the correspond-ing trifluoromethylated products 40 and 41a in good to high yields.This represents the first example on the catalytic trifluoromethyla-tion of propargylic halides by directly using CF3SiMe3 as a trifluo-romethylating reagent (Scheme 29).35
The study indicated that the regioselectivity of the reaction wasdictated by the substrate, with primary propargyl chlorides provid-
R1
X+
Cu(OTf)2 (5 mol %)O
R4R3
O
toluene, reflux0.5-3 h O
O
R4R1
R2
O
O
EtO
X = OH 65% yieldX = OAc 76% yield
OX = OH 53% yieldX = OAc 64% yield
O
O
X = OH 60% yieldX = OAc 78% yield
O
O
O
EtO
X = OH 50% yieldX = OAc 60% yield
Ph
R2R3
Br
X = OH (14) or OAc (1)R1 = ArylR2 = TMS, H, Ph, nBuR3 = R4 = -(CH2)3-, CH3; or R3 = CH3, R4 = OEt
14 or 1 30 43
Scheme 32. Cu-catalyzed tandem reactions of propargylic alcohols or acetates with1,3-dicarbonyl compounds.
ing propargyl trifluoromethanes and secondary propargyl chlo-rides affording trifluoromethylallenes. The authors proposed thatthe catalytic reaction should proceed via a pathway involving cat-ionic propargyl/allenyl-copper complexes as reactive intermedi-ates, not via an anti-SN20 pathway.
Very recently, Altman and co-workers developed a two-stepcopper-catalyzed decarboxylative trifluoromethylation of propar-gyl bromodifluoroacetates 42 into a mixture of propargyl trifluo-romethanes 40 and trifluoromethylallenes 41b (Scheme 30).36 Inthe reaction, an activation procedure and the use of N,N0-dimethyl-ethylenediamine (DMEDA) as a ligand significantly improved theyield of product. The activation procedure presumably served toconvert the pre-catalytic combination of CuI/DMEDA/sodiumbromo(difluoro)acetate (NaO2CCF2Br)/KF into the active catalyst,(DMEDA)Cu–CF3 (Scheme 31). Moreover, the activation proceduremight circumvent an induction period, during which the substratecould be destroyed via nonproductive pathways. Since NaO2CCF2Brparticipated only in the activation procedure, it was required justat a substoichiometric amount (25 mol %) in this reaction.
130
R1
O
OMe
O
R
OAc
+
Cu(OTf)2 (5 mol%)(S)-L10 (5.5 mol%)
Et3N (1.2 equiv)MeOH, rt, 15 h
OR1
MeO2C R
N
PPh2N
Ph
(S)-L10
abcdefghij a
ka
Ph4-MeOC6H4
4-ClC6H4
2-ClC6H4
2-naphthyl2-thienyl
MePhPhPhPh
PhPhPhPhPhPhPh
4-FC6H4
2-naphthylMe
cyclohexyl
R1 R Yield (%)
9596959197978796928391
ee (%)
9081868984889090887165
44
a Corresponding propargylic pentafluorobenzoates were used.
1.1 equiv
Scheme 34. Cu-catalyzed asymmetric cycloaddition of b-ketoesters with propar-gylic acetates.
Scheme 36. Proposed mechanism for [3+3] cycloaddition of propargyl ester withcyclic enamine.
+
38 or 1
XO
CuCl2 2H2O (0.1-0.3 mol %)DBU
CH3CN0 oC, 5-24 h
R
HO
R
47
abc
H4-OMe4-CN
RX = ClYield
836386
696778
X = OCO2CH3Yield
X = OCOCF3Yield
707086
·
48
D.-Y. Zhang, X.-P. Hu / Tetrahedron Letters 56 (2015) 283–295 293
Propargylic alkylation/cycloaddition tandem reaction
In 2009, Zhan and co-workers reported a convenient one-potpropargylic alkylation/cycloisomerization tandem process to con-struct substituted furans derivatives 43 from 1,3-dicarbonyl com-pounds 30 and propargylic alcohols 14 or acetates 1 catalyzed bycopper(II) triflate as a bifunctional catalyst in good yields (up to93% yield, Scheme 32).37 Increased yields were obtained in all caseswhen propargylic acetates were used as substrates instead of prop-argylic alcohols.
The authors proposed the mechanism as outlined in Scheme 33.Initially, the ionization of propargylic alcohols 14 would lead topropargylic cation B and the subsequent propargylic substitutionof the enol A gives c-alkynyl ketone D. Coordination of cationiccopper(II) to the alkyne forms the p–alkyne copper complex Eand enhances the electrophilicity of alkyne. Subsequent 5-exo-dig nucleophilic attack of the hydroxy group on b-carbon ofCu(II)–alkyne complex E would generate the alkenyl-copper deriv-ative F. Protonolysis of F affords dihydrofuran G, which then under-goes isomerization to furan 43.
Since dihydrofurans are widely found in many natural productsand pharmaceutical molecules, and also serve as attractive precur-sors for an array of organic transformations.38 If the last isomeriza-tion step of alkylene-2,3-dihydrofurans G in Scheme 33 can beefficiently interrupted, it would provide a concise access to synthe-size 2-alkylene-2,3-dihydrofurans. Based on this consideration,very recently, Hu and co-workers reported the first copper-cata-lyzed asymmetric formal [3+2] cycloaddition of b-ketoesters 30with propargylic esters 1 to generate optically active 2,3-hydrofu-rans 44 bearing the exocyclic C@C bond in high yields and enanti-oselectivities (up to 97% ee, Scheme 34).39 Bulky and structurallyrigid chiral ketimine-type P,N,N-ligand was critical to achieve goodperformance. A range of substitution patterns at the b-ketoesters30 and propargylic acetates 1 were well tolerated. It was noted thatthe reaction worked well for the aliphatic propargylic substrateswhen an aliphatic pentafluorobenzoates were used instead of the
X
OR
X
OR
R
OLG
X
NEt2
+
Cu(OAc)2.H2O (5 mol%)
(Rc,Sp)-L5 (5.5 mol%)
iPr2NEt (1.2 equiv)MeOH, 0-40 oC, 12-60 h
1 45 endo-46 exo-46
+
O
O O O
OO
78% yield, 93% eeendo/exo >98/2
O
86% yield, 95% eeendo/exo >98/2
O
88% yield, 98% eeendo/exo >98/2
O
86% yield, 95% eeendo/exo >98/2
84% yield, 89% eeendo/exo >98/2trans/cis = 95/5
76% yield, 89% eeendo/exo >98/2
Cl
OO
58% yield, 97% eeendo/exo >98/2
Fe
N
PPh2
N
(Rc,Sp)-L5
1.2 equiv
48% yield, 98% eeendo/exo >98/2
OPh
LG = Ac or COOEt
Scheme 35. Cu-catalyzed asymmetric [3+3] cycloaddition of propargyl esters withcyclic enamines.
de
4-NO24-COCH3
8880
8178
7886
Scheme 37. Cu-catalyzed propargylic etherification of propargylic chlorides oresters with phenols.
+
38
ClO
R2R1R2
R1
CuI (2 mol%)K2CO3 (2 equiv)
KI (1.7 equiv)
DMF, 65 oC65 oC, 0.5-2 h
R3
HO
R3
47
abcdefgh
MeMeMeMeMeMeEt
R1
4096722195
1009185
MeMeMeMeMeEtEt
Yield (%)
4-H4-CN
4-C2F54-Et2-CN4-CN4-CN4-CN
48
R2 R3
2 equiv
-(CH2)5-O R2
R1R3
PhNEt2DMF
140-150 oC51-90%
49
Scheme 38. Cu-catalyzed propargylic etherification of propargylic chlorides withphenols.
corresponding acetates. In addition, the exocyclic double bondcan be hydrogenated in a highly diastereoselective fashion to giveunusual cis-2,3-dihydrofuran derivatives, which further enhancesthe scope of this transformation.
In 2012, Hu and co-workers developed a new Cu-catalyzedasymmetric [3+3] cycloaddition of propargyl esters 1 with cyclic
CuCl2 (1 mol%)DBU (3.0 equiv)
CH3CN0 oC, 12 h
+
13.0 equiv
47 48
MOMO OMOM
OHOCO2Me O
MOMO OMOM
O O
O
O
OH
OH
tovophyllin B50
Scheme 39. Synthesis of the intermediate for tovophyllin B.
OH
R3
Nu
R3
CuBr2 (5 mol%)
MeNO2rt, 2-15 h
+
513.0 equiv
14 52
NuH
abcdefghijkl
MeMeMePhPhH
MeMeMePhPhPh
R1 R2 Yield (%)
849857543874578296788638
NuH
EtOHBnOH
H2C=CHCH2OHCl(CH2)2OH
EtOHEtOHEtOH
Cl(CH2)2OHEtSHCySHEtSHCySH
R3
PhPhPhPhHHPhPhPhPhPhPh
-(CH2)5--(CH2)5-
MeMe
MeMe
-(CH2)5--(CH2)5-
R1
R2R1
R2
Scheme 40. Cu-catalyzed propargylic etherification of propargylic alcohols withalcohols and thiols.
294 D.-Y. Zhang, X.-P. Hu / Tetrahedron Letters 56 (2015) 283–295
enamines 45 with a combination of Cu(OAc)2�H2O and the chiraltridentate ferrocenyl P,N,N-ligand (Rc,Sp)-L5 as the catalyst.40
Under mild conditions, perfect endo selectivities (endo/exo >98:2)and excellent enantioselectivities (up to 98% ee) for endo cycload-ducts 46 were achieved for a wide range of substrates (Scheme 35).The mild conditions, broad substrate scope, good yields, and highdiastereo- and enantioselectivities make this process highly usefulin the synthesis of optically active bicyclo[n.3.1] frameworks.
The plausible mechanism is proposed as shown in Scheme 36.The cyclic enamine Cb attacks at the Cc atom of the copper alleny-lidene complex, which should be the key step for the stereoselec-tion. Then, H atom shifts to Cb of the Cu–acetylide complex togive Cu–vinylidene complex E and subsequent intramolecularnucleophilic attack of the cyclic enamine Cb at the Ca atom of Eaffords alkenyl complex F.
Propargylic substitution of oxygen and sulfur nucleophiles
In comparison with N- and C-nucleophiles, less progress hasbeen made with O- and S-nucleophiles. In 1994, Godfrey and co-workers reported the copper-catalyzed propargylic etherificationof propargylic chlorides 38 or esters 1 with phenols 47 to give aryl1.1-dimethylpropargyl ether 48 in good yields under mild condi-tions (up to 88% yield, Scheme 37).41 Importantly, the reaction pro-ceeded regioselectively and no allenic byproducts were observed.
Later, Mann and co-workers also developed the propargylicetherification of dialkylpropargyl chlorides 38 with phenols 47 in
the present of 2 mol% CuI to give 1.1-dialkylpropargyl ethers 48in 21–100% yields (Scheme 38).42 The study indicated that phenolsbearing the electron-withdrawing group tended to give higheryields. Moreover, the resulting propargylic ethers could be readilyconverted into 2H-1-benzopyrans 49.
Nicolaou and coworkers applied the copper-catalyzed propar-gylic etherification in the total synthesis of biologically active com-pounds 50, tovophyllin B, which possesses a significant inhibitoryactivity against Mycobacterium tuberculosis (Scheme 39).43 TheO-propargylation of the readily available phenol 47 with methyl2-methyl-3-yn-2-yl carbonate in the presence of DBU and the cat-alytic amount of CuCl2 proceeded smoothly to afford 1,1-dimethyl-propargyl ether 48, a key intermediate in the total synthesis oftovophyllin B 50.
In 2008, Huang and co-workers developed a novel copper-cata-lyzed propargylic etherification reaction of propargylic alcohols 14with alcohols in the presence of copper(II) bromide with excellentregioselectivity and high yields under very mild conditions (up to98% yield, Scheme 40).44 Importantly, thiols were also toleratedin the reaction.
Conclusions and future outlook
In summary, significant advances have been achieved in thecopper-catalyzed propargylic substitutions over the last two dec-ades. Diverse nucleophiles such as nitrogen, carbon, oxygen, sulfurnucleophiles have been successfully applied in the reaction. Manykinds of propargylic compounds have been prepared in satisfactoryyields, regioselectivities, and enantioselectivities under very mildconditions. Especially, some carbo- or heterocyclic scaffolds, thatare hard to prepare with conventional methods, could be readilysynthesized by copper-catalyzed propargylic substitution/cycliza-tion tandem reactions. Although great progress has been achieved,the Cu-catalyzed propargylic substitution, in particular its asym-metric version, is still in underdeveloped and full of challenges.For instances, only a limited number of chiral ligands are foundto be efficient. The scope of the propargylic substrates is narrow,and no successful asymmetric example has been reported foreither propargylic esters with an internal alkyne moiety or tertiarypropargylic esters. The range of suitable nucleophiles is quite lim-ited, and O- or S-nucleophiles has never been employed in anasymmetric reaction. Moreover, the diastereo- and enantioselec-tive construction of multi-stereogenic centers via the copper-cata-lyzed asymmetric propargylic substitution remains rarelyexplored. It is expected, however, that with a deeper understand-ing of these reactions, new chiral ligands as well as new strategieswill be developed, and the scope of both the nucleophiles and thesubstrates will be expanded in the future.
Acknowledgment
Financial support from the Dalian Institute of Chemical Physics(CAS) is gratefully acknowledged.
References and notes
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