Regioselective Cu(I)-catalyzed tandem A3-coupling/ decarboxylative coupling to 3-amino-1,4-enynes

Article abstract of DOI:10.1021/ol3006612

An efficient and novel copper-mediated protocol for the synthesis of 3-amino-1,4-enynes from glyoxylic acid, an amine, and an alkyne was developed. This new reaction involving two sequential C-C bond formations is air and moisture tolerant and proceeds via a tandem A³-coupling and a selective decarboxylative coupling.

Full text of DOI:10.1021/ol3006612

ORGANIC
LETTERS
2012
Vol. 14, No. 7
1942–1945
Regioselective Cu(I)-Catalyzed Tandem
A3-Coupling/Decarboxylative Coupling to
3-Amino-1,4-Enynes
Huangdi Feng,†,‡ Denis S. Ermolat’ev,*,† Gonghua Song,‡ and
Erik V. Van der Eycken*,†
Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC), Department of
Chemstry, Katholieke Universiteit Leuven, Celestijnenlaan 200F, B-3001 Leuven,
Belgium, and Shanghai Key Laboratory of Chemical Biology, East China University of
Science and Technology, 130 Meilong Road, Shanghai 200237, China
denis.ermolatev@chem.kuleuven.be; erik.vandereycken@chem.kuleuven.be
Received March 15, 2012
ABSTRACT
An efficient and novel copper-mediated protocol for the synthesis of 3-amino-1,4-enynes from glyoxylic acid, an amine, and an alkyne was
developed. This new reaction involving two sequential CꢀC bond formations is air and moisture tolerant and proceeds via a tandem A3-coupling
and a selective decarboxylative coupling.
Transition-metal-catalyzed CꢀC bond formation is an
important tool in modern organic chemistry.1 Over the
past decades, the most popular approaches for CꢀC bond
formation employed transition metals such as Pd,2 Cu,3
Fe,4 Ni,5 Ag,6 Ru,7 Rh,8 and Au.9 Currently the transition-
metal-catalyzed decarboxylative couplings have gained
particular interest due to the inherent advantage that
simple carboxylic acids represent a powerful alternative
for CꢀC bond formation under relatively neutral condi-
tions compaired to preformed organometallic reagents.10
In particular, Cu-catalyzed decarboxylative couplings
have widely been used as a valuable synthetic strategy for
the formation of CꢀC bonds.11 In this regard, our group
recently discovered that a Cu-catalyzed decarboxylative
† Katholieke Universiteit Leuven.
‡ East China University of Science and Technology.
(1) (a) de Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling
Reactions; Wiley-VCH: Weinheim, 2004. (b) Beller, M.; Bolm, C. Transi-
tion Metals for Organic Synthesis: Building Blocks and Fine Chemicals;
Wiley-VCH: Weinheim, 2004. (c) For a recent review, see: Torborg, C.;
Beller, M. Adv. Synth. Catal. 2009, 351, 3027. (d) Liu, C.; Zhang, H.; Shi,
W.; Lei, A. W. Chem. Rev. 2011, 111, 1780.
(2) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457. (b)
Beccalli, E. M.; Broggini, G.; Martinelli, M.; Sottocornola, S. Chem.
Rev. 2007, 107, 5318.
(8) For a recent review, see: Colby, D. A.; Bergman, R. G.; Ellman,
J. A. Chem. Rev. 2010, 110, 624.
(9) For a recent review, see: Boorman, T. C.; Larrosa, I. Chem. Soc.
(3) For a recent review, see: (a) Reymond, S.; Cossy, J. Chem. Rev.
2008, 108, 5359. (b) Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev.
2008, 108, 3054.
(4) For a recent review, see: (a) Sherry, D.; Furstner, A. Acc. Chem.
Res. 2008, 41, 1500. (b) Sun, C. L.; Li, B. J.; Shi, Z. J. Chem. Rev. 2011,
111, 1293.
Rev. 2011, 40, 1910.
(10) (a) Trost, B. M.; Bream, R. N.; Xu, J. Angew. Chem., Int. Ed.
2006, 45, 3109. (b) Streuff, J.; White, D.; Virgil, S.; Stoltz, B. Nat. Chem.
2010, 2, 192. (c) Patil, N. T.; Huo, Z.; Yamamoto, Y. J. Org. Chem. 2006,
71, 6991. (d) Enquist, J. A.; Stoltz, B. M. Nature 2008, 453, 1228. (e)
Rodrıguez, N.; Goossen, L. J. Chem. Soc. Rev. 2011, 40, 5030. (f)
´
(5) For a recent review, see: (a) Phapale, V. B.; Cardenas, D. J. Chem.
Soc. Rev. 2009, 38, 1598. (b) Rosen, B. M.; Quasdorf, K. W.; Wilson,
D. A.; Zhang, N.; Resmerita, A. M.; Garg, N. K.; Percec, V. Chem. Rev.
2011, 111, 1346.
(6) For a recent review, see: (a) Weibel, J. M.; Blanc, A.; Pale, P.
Chem. Rev. 2008, 108, 3149.
Weaver, J. D.; Recio, A., III; Grenning, A. J.; Tung, J. A. Chem. Rev.
2011, 111, 1846.
(11) (a) Goossen, L. J.; Deng, G.; Levy, L. M. Science 2006, 313, 662.
(b) Rudolphi, F.; Song, B.; Goossen, L. J. Adv. Synth. Catal. 2011, 353,
337. (c) Park, A.; Park, K.; Kim, Y.; Lee, S. Org. Lett. 2011, 13, 944. (d)
Goossen, L. J.; Zimmermann, B. Angew. Chem., Int. Ed. 2008, 47, 7103.
(e) Bi, H. P.; Zhao, L.; Liang, Y. M.; Li, C. J. Angew. Chem., Int. Ed.
2009, 48, 792.
(7) For a recent review, see: Trost, B. M.; Toste, F. D.; Pinkerton,
A. B. Chem. Rev. 2001, 101, 2067.
r
10.1021/ol3006612
Published on Web 03/28/2012
2012 American Chemical Society

coupling could be applied to efficiently obtain propargy-
lamines and oxazolidinones.12
Table 1. Optimization of the Conditionsa
During recent years, the three-component coupling of
an aldehyde, an alkyne, and an amine (A3-coupling) has
received much attention,13 especially employing a tandem
A3-coupling reaction.14 Recently, Ji and co-workers re-
ported a gold-catalyzed direct alkyne-amine-glyoxylic acid
coupling, intramolecular cyclization for the formation of
polysubstituted butenolides in a tandem manner (Scheme 1,
eq 1).15 Based on this report and our previous work on
decarboxylative three-component couplings (eq 2), we
envisaged the possibility of a decarboxylative coupling of
glyoxylic acid, an amine, and an alkyne to synthesize
3-amino-1,4-enynes (eq 3), which are valuable intermedi-
ates for the preparation of useful and unusual carbocyclic
products via cycloisomerization.16
CuX (mol %)/
ligand (mol %)
2a/3a
time
yieldb
(%)
entry
(mmol)
(min)
1
2
3
4
5
6
7
CuBr(30)/none
CuBr(30)/none
1:3
1:5
1:6
1:6
1:6
1:6
1:6
30
30
30
30
30
30
30
50
65
68
84
71
55
39
CuBr(30)/none
CuBr(30)/PPh3(30)
CuBr(30)/TOTP(30)
CuBr(30)/TFP(30)
CuBr(30)/
DPEPhos(30)
8
CuBr(30)/DPPF(30)
CuBr(30)/DPPB(30)
CuBr (30)/DPPP(30)
CuBr (30)/
1:6
1:6
1:6
1:6
30
30
30
30
72
60
65
53
9
Scheme 1
10
11
10-Phenanthroline (30)
CuBr(15)/PPh3(30)
CuBr (30)/PPh3(60)
CuBr(40)/PPh3(40)
CuBr(30)/PPh3(30)
CuBr(30)/PPh3(30)
CuBr(30)/PPh3(30)
CuBr(30)/PPh3(30)
CuBr(30)/PPh3(30)
12
1:6
1:6
1:6
1:6
1:6
1:6
1:6
1:6
30
30
30
30
30
20
45
24 h
72
77
73
79
74
80
73
67
13
14
15c
16d
17
18
19e
a Reactions were performed using 1 (0.55 mmol), 2a (0.5 mmol), 3a,
and toluene (1 mL) under microwave irradiation at 110 °C and 80 W
maximum power. b Isolated yields based on 2a. c Reaction carried out at
130 °C. d Reaction carried out at 95 °C. e Conventional heating. TOTP =
Tri-ortho-tolylphosphine. TFP = Tri-(2-furyl)-phosphine. DPPF =
Bis(diphenylphosphino)ferrocene. DPPB = 1,4-Bis(diphenylphosphino)-
butane. DPEPhos = Bis(2-diphenyl-phosphinophenyl)ether. DPPP = 1,3-
Bis(diphenylphosphino) propane.
In our initial investigations, employing glyoxylic acid 1,
N-methylbenzylamine 2a, and phenylacetylene 3a as mod-
el substrates, we evaluated the efficiency of various sol-
vents and copper catalysts under microwave irradiation
without ligands. From the results, we found that toluene is
the solvent of choice, and CuBr seemed to be the most
effective for the formation of the 3-amino-1,4-enynes 4a.17
Furtherinspection of the reactionparameters revealedthat
the ratio of substrates 2a/3a significantly affects the yield.
A 1:6 ratio provided the best result (Table 1, entries 1ꢀ3).
Encouraged by these findings, we subsequently evaluated
the influence of the application of ligands. To our delight,
when a combination of CuBr and PPh3 was used, 3-amino-
1,4-enyne 4a was obtained in 84% yield (Table 1, entry 4).
Thus, a variety of ligands were examined, but all of them
failed to further improve the yields (Table 1, entries 5ꢀ11).
Regarding the ratio of CuBr to the PPh3 ligand, we found
that when using 30% of both additives the highest yield
was obtained (Table 1, entries 4 and 12ꢀ14). Further
screening of the reaction temperature and reaction time
showed that increasing either the temperature or the
reaction time resulted in a decreased yield (Table 1, entries
15 and 18), while the reaction at a lower temperature or in a
shorter reaction period afforded 4a in 74% and 80% yield
(12) (a) Feng, H. D.; Ermolat’ev, D. S.; Song, G. H.; Van der Eycken,
E. V. J. Org. Chem. 2011, 76, 7608. (b) Feng, H. D.; Ermolat’ev, D. S.;
Song, G. H.; Van der Eycken, E. V. Adv. Synth. Catal. 2012, 354, 505.
(13) (a) Wei, C. M.; Li, Z. G.; Li, C. J. Synlett 2004, 1472. (b) Li, C. J.;
Wei, C. M. Chem. Commun. 2002, 268. (c) Yoo, W. J.; Zhao, L.; Li, C. J.
Aldrichimica Acta 2011, 44, 43. (d) Gommermann, N.; Koradin, K.;
Polborn, K.; Knochel, P. Angew. Chem., Int. Ed. 2003, 42, 5763. (e)
Sakaguchi, S.; Mizuta, T.; Furuwan, M.; Kubo, T.; Ishii, Y. Chem.
Commun. 2004, 1638. (f) Sakaguchi, S.; Kubo, T.; Ishii, Y. Angew.
Chem., Int. Ed. 2001, 40, 2534. (g) Gommermann, N.; Knochel, P.
Chem.;Eur. J. 2006, 12, 4380. (h) Peshkov, V. A.; Pereshivko, O. P.;
Van der Eycken, E. V. Chem. Soc. Rev. 2012, DOI: 10.1039/
C2CS15356D.
(14) (a) Bariwal, J. B.; Ermolat’ev, D. S.; Van der Eycken, E. V.
Chem.;Eur. J. 2010, 16, 3281. (b) Chernyak, N.; Gevorgyan, V. Angew.
Chem., Int. Ed. 2010, 49, 2743. (c) Suzuki, Y.; Ohta, Y.; Oishi, S.; Fujii,
N.; Ohno, H. J. Org. Chem. 2009, 74, 4246. (d) Yan, B.; Liu, Y. H. Org.
Lett. 2007, 9, 4323.
(15) Zhang, Q.; Cheng, M.; Hu, X. Y.; Li, B. G.; Ji, J. X. J. Am. Chem.
Soc. 2010, 132, 7256.
(16) (a) Shi, X.; Gorin, D. J.; Toste, F. D. J. Am. Chem. Soc. 2005,
127, 5802. (b) Prasad, B. A. B.; Yoshimoto, F. K.; Sarpong, R. J. Am.
Chem. Soc. 2005, 127, 12468. (c) Marion, N.; Dıez-Gonzalez, S.; De
Fremont, P.; Noble, A. R.; Nolan, S. P. Angew. Chem., Int. Ed. 2006, 45,
3647. (d) Buzas, A.; Gagosz, F. J. Am. Chem. Soc. 2006, 128, 12614. (e)
Vasu, D.; Das, A.; Liu, R. S. Chem. Commun. 2010, 46, 4115. (f) Sato, T.;
Onuma, T.; Nakamura, I.; Terada, M. Org. Lett. 2011, 13, 4992.
(17) See the Supporting Information for details.
Org. Lett., Vol. 14, No. 7, 2012
1943

67% to 85%. The reaction was not significantly affected
when an amine 2iꢀm bearing two aliphatic substituents
was used, although slightly lower yields were obtained. To
expand the scope of the protocol, the application of a series
of alkynes was also investigated. Both electron-poor and
-rich aryl-substituted alkynes 3bꢀd, 3eꢀh were effective,
yielding the desired compounds 4abꢀah in 50ꢀ74% yield
(Table 2, entries 14ꢀ20). However, similar to A3-coupling,
the aliphatic alkynes usually provided the desired com-
pounds only in low yield. In this protocol, no product 4ai
was observed when the cyclohexylalkyne (3i) was used
(Table 2, entry 21). Finally, we evaluated the reaction of
different amines and alkynes. The desired 3-amino-1,4-
enynes 4hcꢀch were obtained in moderate to good yields
(Table 2, entries 22ꢀ25).
Table 2. Scope and Limitations of the Protocol
Scheme 2. Proposed Mechanism
Based on these findings, a plausible mechanism for this
tandem A3-coupling/decarboxylative coupling is presented
in Scheme 2. Iminium salt A, in situ formed from glyoxylic
acid 1 and amine 2, undergoes a Cu(I)-catalyzed A3-
coupling of copper acetylide B resulting in the formation
of intermediate C. Then a Cu(I)-catalyzed decarboxy-
lation of C affords the copper-propargylamine species
D.11b,18 Further conversion results in the formation of
the allene E in conjunction with the regeneration of the
Cu(I) catalyst. It is worth mentioning that if the proto-
nation occurs at the carbon atom attached to copper, the
propargylamine would be obtained.19 Finally, electro-
philic addition of this allene E to copper acetylide B would
form 3-amino-1,4-enynes 4 via a plausible transition state
E0.20 The coupling constants (J13 = 15.8ꢀ16.1 Hz) in the
1H NMR spectrum support the E-configuration of the
vinyl motif.
respectively (Table 1, entries 16 and 17). In comparison,
when the reaction was conducted under conventional
heating using the same conditions, the desired product 4a
was obtained in a yield of 67% after an extended reaction
time of 24 h (Table 1, entry 19).
Having optimized the reaction conditions (Table 1, entry 4),
we next evaluated the scope and limitations of the process.
A variety of secondary amines were reacted with glyoxylic
acid and phenylacetylenes to afford the corresponding
3-amino-1,4-enynes 4aaꢀma in good and high yields
(Table 2, entries 1ꢀ13). Amines 2aꢀh bearing both an
aliphatic R1-substituent and a benzylic R2-substituent
provided good yields of the desired products ranging from
(18) Xiao, Q.; Xia, Y.; Li, H.; Zhang, Y.; Wang, J. B. Angew. Chem.,
Int. Ed. 2011, 50, 1114.
(19) By application of our previously optimized conditions, the
propargylamine 5 was formed in 60% yield when amine 2c and acetylene
3g were used.
(20) Ma, S. M. Acc. Chem. Res. 2009, 42, 1679.
Org. Lett., Vol. 14, No. 7, 2012
1944

In summary, we have successfully developed a novel
microwave-assisted three-component cascade approach
for the selective preparation of diversely functionalized
3-amino-1,4-enynes starting from glyoxylic acid, an al-
kyne, and an amine. This tandem reaction involves a
Cu(I)-catalyzed A3-coupling followed by a decarboxyla-
tive coupling. Interestingly, the Cu(I)-catalyzed decarbox-
ylative coupling of glyoxylic acid can serve as a C1 source,
and this approach may open up potentially relevant
copper-catalyzed chemical processes.
the Research Fund of the Katholieke Universiteit Leuven
and the Industrial Research Fund of the Katholieke Uni-
versiteit Leuven for financial support to the laboratory.
D.S.E. is grateful to the FWO for obtaining a postdoc
fellowship. H.D.F. thanks the China Scholarship Council
for financial support.
Supporting Information Available. Experimental pro-
cedures and copies of 1H NMR and 13C NMR spectra for
all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
Acknowledgment. The authors wish to thank the FWO
(Fund for Scientific ResearchꢀFlanders (Belgium)) and
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 7, 2012
1945