Enamide synthesis by copper-catalyzed cross-coupling of amides and potassium alkenyltrifluoroborate salts

Article abstract of DOI:10.1002/anie.200704711

(Chemical Equation Presented) A new partner: Potassium alkenyltrifluoroborate salts undergo coupling with amides to give enamides in the presence of a Cu(OAc)₂ catalyst and under mild oxidative conditions (see scheme). The air- and water-stable alkenyltrifluoroborate salts offer a convenient alternative to alkenyl halides as cross-coupling partners. A range of amides undergo coupling including cyclic amides, imides, and carbamates as well as benzamides.

Full text of DOI:10.1002/anie.200704711

Angewandte
Chemie
DOI: 10.1002/anie.200704711
Copper Catalysis
Enamide Synthesis by Copper-Catalyzed Cross-Coupling of Amides
and Potassium Alkenyltrifluoroborate Salts**
Yuri Bolshan and Robert A. Batey*
Dedicated to Professor William B. Motherwell on the occasion of his 60th birthday
Enamides are key structural motifs in various classes of
natural products[1,2] and are also valuable synthetic inter-
can be used in copper-catalyzed cross-coupling reactions with
amides under mild base-free conditions.
mediates.[3,4] In addition to
a
number of traditionally
Phthalimide was chosen as a test substrate in the initial
experiments to optimize the reaction conditions, because it
had been used by Lam et al.[17] in the coupling of hexenylbor-
onic acid to give the corresponding enamide product 2 in good
yield (79%) in the presence of stoichiometric amounts of CuII
salts, but had provided poor yield (13%) under catalytic
conditions (Cu(OAc)2, 10 mol%). Coupling under the same
catalytic conditions employed by Lam, except at 408C, using
hexenyltrifluoroborate salt 1a similarly gave 2 in low yield
(Table 1, entry 1). The efficiency of the reaction improved on
employed approaches,[5–9] several transition-metal-catalyzed
methods for the synthesis of enamides have recently
emerged.[10–12] Perhaps the most widely applicable metal-
catalyzed method developed to date is the copper-catalyzed
coupling[13] of alkenyl halides with amides,[14] a modern
variant of the Goldberg reaction.[15] Porco, Buchwald, Ma,
and others have shown that the coupling of amides and
alkenyl bromides can be achieved using catalytic quantities of
copper salts.[16] Despite these advances general methods are
still needed for enamide formation, particularly since existing
methods often have limited substrate scope and typically
require elevated temperatures, rigorous exclusion of air and
water, and the use of two or more equivalents of strong base.
Lam et al. have reported the use of (E)-1-hexenylboronic acid
as an alternative coupling partner.[17,18] Unfortunately, this
method lacks generality, and only three examples of amide-
like substrates (1-ethyl-1,3-dihydrobenzoimidazol-2-one, 2-
hydroxypyridine, and phthalimide) were reported, which gave
variable yields under five different sets of reaction conditions.
One of the potential problems with this route, compared to
similar reactions of arylboronic acids,[18,19] is the lower
stability of alkenylboronic acids, particularly under oxidative
conditions. We have previously demonstrated that the use of
potassium organotrifluoroborate salts in copper-catalyzed
cross-coupling reactions with alcohols[20] and amines[21] offer
several advantages over the corresponding reactions of
boronic acids. The tetracoordinate salts possess increased
stability toward air and water, and are readily prepared.[22]
Many are now commercially available,[23] and they are widely
used for other classes of metal-catalyzed transformations.[23–25]
Herein we report that potassium alkenyltrifluoroborate salts
Table 1: Ligand optimization for cross-coupling of phthalimide with
potassium hexenyltrifluoroborate 1a.
Entry Ligand
Amount [mol%] Base (2 equiv) Yield
[%][a]
1
2
3
4
5
6
7
–
–
Et3N
Et3N
13
12
39
51
65
85
quant
1,10-phenanthroline 10
1,10-phenanthroline 10
pyridine
DMAP
imidazole
N-methylimidazole 20
–
–
–
–
–
20
20
20
[a] Yield of product isolated after silica gel chromatography. DMAP=4-
dimethylaminopyridine, M.S.=molecular sieves.
removal of the excess base (Et3N) and was strongly depen-
dant upon the choice of ligand (Table 1, entries 2–7). The
highest yields were obtained in the presence of electron-rich
monodentate amine ligands. Interestingly, the use of N-
methylimidazole as ligand, which has not been used before in
copper-catalyzed coupling reactions, gave the best results,
affording 2 in quantitative yield (Table 1, entry 7). Attempted
reaction of (E)-1-hexenylboronic acid under the same con-
ditions was unsuccessful.
Unfortunately, attempts to expand the substrate scope,
under the optimized conditions (Method A), gave mixed
results with several classes of amides 3 (Table 2). While 2-
hydroxypyridine and isatin exhibited good reactivity (Table 2,
entries 1 and 2), 2-oxazolidinone and 2-pyrrolidinone
[*] Y. Bolshan, Prof. R. A. Batey
Department of Chemistry, University of Toronto
80 St. George Street, Toronto, ON, M5S 3H6 (Canada)
Fax: (+1)416-978-5059
E-mail: rbatey@chem.utoronto.ca
Homepage: http://www.chem.utoronto.ca/staff/RAB/index.html
[**] The Natural Science and Engineering Research Council (NSERC) of
Canada funded this research. Y.B. thanks the NSERC for a
postgraduate scholarship (PGS D3) and the Walter C. Sumner
Memorial Fellowship for funding. We also thank Dr. Alex Young for
mass spectrometry analysis and Dr. Tim Burrowfor assistance with
NMR spectroscopy.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 2: Examination of the scope of the cross-coupling reaction with
other classes of amides (Method A).
Table 3: Optimization of the solvent and ligand for cross-couplings of 2-
pyrrolidone and benzamide with 1a.
Entry
1
Substrate
Product
Yield [%][a]
78
Entry[a]
Substrate
DMSO/ Ligand
Product Yield
[%][a]
CH2Cl2
[mol%]
1
2
3
4
5
6
7
2-pyrrolidinone
2-pyrrolidinone
2-pyrrolidinone
2-pyrrolidinone
benzamide
1:9
1:2
1:1
1:0
1:1
1:1
1:1
20
20
20
20
20
5
3d
3d
3d
3d
3e
3e
3e
68
78
84
24
62
70
81
2
82
3
4
40
22
benzamide
benzamide
0
[a] Yield of product isolated after silica gel chromatography.
5
0
[a] Yield of product isolated after silica gel chromatography.
These results are in contrast to the findings of Altman and
Buchwald, who observed that more electron-deficient
hydroxypyridines gave lower yields than electron-rich exam-
ples in the copper-catalyzed coupling reaction with aryl
halides.[26] In all cases the reactions were highly stereoselec-
tive, and only the trans enamides 3 were observed (ꢀ 97:3 by
1H NMR spectroscopy). Reaction of (E)-1-hexenylboronic
acid with benzamide gave no detectable product with this
protocol, and the reaction of oxazolidin-2-one gave 3c in just
3% yield.
afforded the corresponding enamides in only 40% and 22%
yield, respectively (Table 2, entries 3 and 4). None of the
desired enamide product was obtained in an attempted
coupling using benzamide as a coupling partner (Table 2,
entry 5).
The poor reactivity of 2-pyrrolidinone and benzamide
may arise from a number of factors, including their coordi-
Other potassium alkenyltrifluoroborate salts could also be
employed using the “ligandless” protocol (Method B)
(Figure 1). Coupling of benzamide to give 4, 5, and 6 occurred
in good yields from the corresponding trans alkenyltrifluoro-
borate salts. Reaction of potassium vinyltrifluoroborate with
benzamide to give 7 occurred in lower yield. Coupling of
trans-cinnamamide with potassium trans-styryltrifluoroborate
gave a 56% yield of 9, a precursor to the natural product
lansamide I. Increasing the amount of alkenyltrifluoroborate
salts used led to increased reaction yields. For example, the
formation of 9 occurred in 70% and almost quantitative
yields, respectively when three and five equivalents of the
trans alkenyltrifluoroborate salts were used. Reaction of the
cis-styryl trifluoroborate with benzamide afforded the cis
enamide 8 in only 25% yield following chromatography on
neutral alumina. The cis enamide 8 appeared to be unstable
which is consistent with the observations of Fürstner and co-
workers.[8b]
In conclusion, an efficient synthesis of enamides using a
copper-catalyzed cross-coupling between potassium alkenyl-
trifluoroborate salts and amides has been described that
occurs under an atmosphere of molecular oxygen in the
absence of base at 408C. The mechanism for the reaction is
presumably analogous to those proposed for the coupling of
arylboronic acids with phenols and other nucleophiles.[18]
Further studies on the applications of this and related
methods will be reported in due course.
À
nation ability and their lower N H acidity. In addition, these
substrates are poorly soluble in CH2Cl2. Addition of a polar
cosolvent, such as dimethyl sulfoxide (DMSO), was found to
dramatically improve reaction yields (Table 3). Using Cu-
(OAc)2 (10 mol%) and N-methylimidazole (20 mol%) gave
the best result for the coupling of 2-pyrrolidinone with 1a in
CH2Cl2/DMSO (1:1, Table 3, entry 3). The use of either a
higher or lower proportion of DMSO led to decreased yields
of 3d (Table 3, entries 1, 2, and 4). Similar results were
obtained for the coupling of benzamide to give 3e in 62%
yield (Table 3, entry 5). Further optimization of these con-
ditions revealed that changing the Cu/ligand ratio also
resulted in improved product yields (Table 3, entries 5–7).
Indeed, in sharp contrast to the results obtained for the
coupling of phthalimide in CH2Cl2, where the presence of N-
methylimidazole was essential, removal of the amine ligand
led to the highest yields of product 3e (Table 3, entry 7).
The “ligandless” protocol using the CH2Cl2/DMSO (1:1)
solvent system (Method B) was evaluated with a range of
amide substrates (Table 4). In general, good yields were
obtained for both acyclic (Table 4, entries 1–8) and cyclic
(Table 4, entries 9–12) amides. Notably, electron-deficient
amides (Table 4, entries 2, 3, and 8) afforded the correspond-
ing enamides 3 in higher yields than those obtained from the
reactions of electron-rich amides (Table 4, entries 4, 5, and 7).
2110
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Table 4: Expanding the substrate scope of the cross-coupling reactions
of amides with 1a under “ligandless” conditions (Method B).
Entry
1
Substrate
Product
Yield [%][a]
81
2
3
4
86
72
55
Figure 1. Examples of cross-couplings of various amides and potas-
sium alkenyltrifluoroborate salts using a “ligandless” protocol (Meth-
od B).
was purified by neutral alumina chromatography using EtOAc/
hexanes (1:15).
5
6
65
75
Received: October 12, 2007
Published online: January 31, 2008
Keywords: copper · cross-coupling · enamides ·
.
homogeneous catalysis
7
8
9
67
86
86
[1] For reviews, see a) L. Yet, Chem. Rev. 2003, 103, 4283 – 4306;
b) M. M. JoulliØ, D. J. Richard, Chem. Commun. 2004, 2011 –
2015; c) N.-H. Tan, J. Zhu, Chem. Rev. 2006, 106, 840 – 895.
[2] For selected references of total syntheses of enamide natural
products, see a) A. Fürstner, O. R. Thiel, G. Blanda, Org. Lett.
2000, 2, 3731 – 3734; b) X. Wang, J. A. Porco, Jr., J. Am. Chem.
Soc. 2003, 125, 6040 – 6041; c) R. Shen, C. T. Lin, E. J. Bowman,
B. J. Bowman, J. A. Porco, Jr., J. Am. Chem. Soc. 2003, 125,
7889 – 7901; d) K. L. Yang, B. Blackman, W. Diederich, P. T.
Flaherty, C. J. Mossman, S. Roy, Y. M. Ahn, G. I. Georg, J. Org.
Chem. 2003, 68, 10030 – 10039; e) K. C. Nicolaou, D. W. Kim, R.
Baati, A. OꢀBrate, P. Giannakakou, Chem. Eur. J. 2003, 9, 6177 –
6191; f) Q. Su, J. S. Panek, J. Am. Chem. Soc. 2004, 126, 2425–
8132; g) C. Herb, A. Bayer, M. E. Maier, Chem. Eur. J. 2004, 10,
5649 – 5660; h) R. Shen, T. Inoue, M. Forgac, J. A. Porco, Jr., J.
Org. Chem. 2005, 70, 3686 – 3692; L. C. Dias, L. G. de Oliveira,
J. D. Vilcachagua, F. Nigsch, J. Org. Chem. 2005, 70, 2225– 2234;
i) P. Cristau, T. Temal-Laïb, M. Bois-Choussy, M.-T. Martin, J.-P.
Vors, J. Zhu; C. Sun, J. E. Camp, S. M. Weinreb, Org. Lett. 2006,
8, 1779 – 1781; j) M. Toumi, F. Couty, G. Evano, Angew. Chem.
2007, 119, 578 – 581; Angew. Chem. Int. Ed. 2007, 46, 572 – 575;
k) G. He, J. Wang, D. Ma, Org. Lett. 2007, 9, 1367 – 1369.
[3] R. L. Larock in Comprehensive Organic Transformations: A
Guide to Functional Group Preparations, 2nd ed., Wiley-VCH,
New York, 1999, p. 1507.
10
11
12
80
97
71
[a] Yield of product isolated after silica gel chromatography.
Experimental Section
Method A: CH2Cl2 (2.0 mL) and N-methylimidazole (0.1 mmol) were
added to Cu(OAc)2 (0.05mmol), amide (0.5mmol), potassium
alkenyltrifluoroborate salt (1.0 mmol), and 4-Š molecular sieves
(0.375g). The suspension was stirred for 20 h at 40 8C under an
atmosphere of oxygen. Method B: CH2Cl2 (1.0 mL) and DMSO
(1.0 mL) were added to Cu(OAc)2 (0.05mmol), amide (0.5mmol),
potassium alkenyltrifluoroborate salt (1.0 mmol), and 4-Š molecular
sieves (0.375g). The suspension was stirred for 20 h at 40 8C under an
atmosphere of oxygen. For both methods the reaction mixture was
then filtered through a plug of celite, which was then washed with
EtOAc. The crude products were purified by silica gel chromatog-
raphy using EtOAc/n-hexanes and 1%v/v Et3N. The cis enamide 8
[4] J. R. Dehli, J. Legros, C. Bolm, Chem. Commun. 2005, 973 – 986.
[5] Acid-catalyzed condensation of amides and aldehydes: a) C. A.
Zezza, M. B. Smith, Synth. Commun. 1987, 17, 729 – 740; b) M. J.
Kiefel, J. Maddock, G. Pattenden, Tetrahedron Lett. 1992, 33,
3227 – 3230.
[6] Curtius rearrangement of a,b-unsaturated acyl azides: B. B.
Snider, F. B. Song, Org. Lett. 2000, 2, 407 – 408.
[7] Acylation of imines: R. K. Boeckmann, Jr., W. S. Goldstein,
M. A. Walters, J. Am. Chem. Soc. 1988, 110, 8250 – 8252.
Angew. Chem. Int. Ed. 2008, 47, 2109 –2112
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
2111

Communications
[8] Elimination of b-hydroxy-a-silyl amides: a) D. J. Ager, Org.
[15] a) I. Goldberg, Ber. Dtsch. Chem. Ges. 1906, 39, 1691 – 1692; b) I.
Goldberg, Ber. Dtsch. Chem. Ges. 1907, 40, 4541 – 4546.
[16] a) R. C. Shen, J. A. Porco, Jr., Org. Lett. 2000, 2, 1333 – 1336;
b) R. Shen, C. T. Lin, J. A. Porco, Jr., J. Am. Chem. Soc. 2002,
124, 5650 – 5651; c) L. Jiang, G. E. Job, A. Klapars, S. L.
Buchwald, Org. Lett. 2003, 5, 3667 – 3669; d) X. Pan, Q. Cai, D.
Ma, Org. Lett. 2004, 6, 1809 – 1812; e) C. Han, R. Shen, S. Su,
J. A. Porco, Jr., Org. Lett. 2004, 6, 27 – 30; f) R. S. Coleman, P.-H.
Liu, Org. Lett. 2004, 6, 577 – 580; g) L. Shen, R. P. Hsung, Y.
Zhang, J. E. Antoline, X. Zhang, Org. Lett. 2005, 7, 3081 – 3084;
h) T. Hu, C. Li, Org. Lett. 2005, 7, 2035– 2038; i) C. Sun, J. E.
Camp, S. M. Weinreb, Org. Lett. 2006, 8, 1779 – 1781.
React. 1990, 38, 1 – 223; b) A. Fürstner, C. Brehm, Y. Cancho-
Grande, Org. Lett. 2001, 3, 3955 – 3957.
[9] Condensation of aldehydes or ketones with nitriles: Z. Rappo-
port in The Chemistry of Enamines, Wiley, Chichester, 1994,
pp. 1441 – 1533.
[10] Ru-catalyzed amidation of alkynes: a) T. Kondo, A. Tanaka, S.
Kotachi, Y. Watanabe, J. Chem. Soc. Chem. Commun. 1995,
413 – 414; b) L. J. Gooßen, J. E. Rauhaus, G. Deng, Angew.
Chem. 2005, 117, 4110 – 4113; Angew. Chem. Int. Ed. 2005, 44,
4042 – 4045; Ru-catalyzed co-oligomerization of N-vinylamides:
c) H. Tsujita, Y. Ura, S. Matsuki, K. Wada, T. Mitsudo, T. Kondo,
Angew. Chem. 2007, 119, 5252 – 5255; Angew. Chem. Int. Ed.
2007, 46, 5160 – 5163.
[11] Fe- and Rh-catalyzed isomerization of N-allylamides: a) J. K.
Stille, Y. Becker, J. Org. Chem. 1980, 45, 2139 – 2145; b) S.
Sergeyev, M. Hesse, Synlett 2002, 1313 – 1317; c) S. A. Sergeyev,
M. Hesse, Helv. Chim. Acta 2003, 86, 750 – 755.
[12] Pd-catalyzed intramolecular coupling between amides and
alkenyl halides: a) Y. Kozawa, M. Mori, Tetrahedron 2002, 58,
111 – 114; Pd-catalyzed oxidative amidation of conjugated
olefins: b) J. M. Lee, D.-S. Ahn, D. Y. Jung, J. Lee, Y. Do, S. K.
Kim, S. Chang, J. Am. Chem. Soc. 2006, 128, 12954 – 12962; Pd-
catalyzed Heck reaction: c) P. Harrison, G. Meek, Tetrahedron
Lett. 2004, 45, 9277 – 9280; Pd-catalyzed coupling between
amides and enol ethers: d) A. Klapars, K. R. Campos, C.-y.
Chen, R. P. Volante, Org. Lett. 2005, 7, 1185– 1188; e) J. L. Brice,
J. E. Meerdink, S. S. Stahl, Org. Lett. 2004, 6, 1845– 1848; f) D. J.
Wallace, D. J. Klauber, C.-y. Chen, R. P. Volante, Org. Lett. 2003,
5, 4749 – 4752.
[13] In recent years, there has been an increased interest in copper-
catalyzed transformations; for recent reviews, see a) J. Hassan,
M. Sevignon, C. Gozzi, E. Schulz, M. Lemaire, Chem. Rev. 2002,
102, 1359 – 1469; b) J. P. Finet, A. Y. Fedorov, S. Combes, G.
Boyer, Curr. Org. Chem. 2002, 6, 597 – 626; c) K. Kunz, U.
Scholz, D. Ganzer, Synlett 2003, 2428 – 2439; d) S. V. Ley, A. W.
Thomas, Angew. Chem. 2003, 115, 5558 – 5607; Angew. Chem.
Int. Ed. 2003, 42, 5400 – 5449; e) I. P. Beletskaya, A. V. Chepra-
kov, Coord. Chem. Rev. 2004, 248, 2337 – 2364; f) S. R. Chemler,
P. H. Fuller, Chem. Soc. Rev. 2007, 36, 1153 – 1160.
[17] P. Y. S. Lam, G. Vincent, D. Bonne, C. G. Clark, Tetrahedron
Lett. 2003, 44, 4927 – 4931.
[18] D. M. T. Chan, P. Y. S. Lam in Boronic Acids (Ed.: D. G. Hall),
Wiley-VCH, Weinheim, 2005, pp. 205– 240.
[19] For selected references, see a) D. M. T. Chan, K. L. Monaco, R.-
P. Wang, M. P. Winters, Tetrahedron Lett. 1998, 39, 2933 – 2936;
b) P. Y. S. Lam, C. G. Clark, S. Saubern, J. Adams, M. P. Winters,
D. M. T. Chan, A. Combs, Tetrahedron Lett. 1998, 39, 2941 –
2944; c) P. Y. S. Lam, G. Vincent, C. G. Clark, S. Deudon, P. K.
Jadhav, Tetrahedron Lett. 2001, 42, 3415– 3418.
[20] T. D. Quach, R. A. Batey, Org. Lett. 2003, 5, 1381 – 1384.
[21] T. D. Quach, R. A. Batey, Org. Lett. 2003, 5, 4397 – 4400.
[22] E. Vedejs, S. C. Fields, M. R. Schrimpf, J. Am. Chem. Soc. 1993,
115, 11612 – 11613.
[23] H. A. Stefani, R. Cella, A. S. Vieira, Tetrahedron 2007, 63, 3623 –
3658.
[24] For examples of Suzuki–Miyaura cross-coupling, see a) J.-P.
GenÞt, S. Darses, J.-L. Brayer, J.-P. Demoute, Tetrahedron Lett.
1997, 38, 4393 – 4396; b) G. A. Molander, M. R. Rivero, Org.
Lett. 2002, 4, 107 – 109; c) R. A. Batey, T. D. Quach, Tetrahedron
Lett. 2002, 43, 9099 – 9103; d) G. A. Molander, N. Ellis, Acc.
Chem. Res. 2007, 40, 275– 286.
[25] For examples of leading references for Rh- or Pd-catalyzed
additions to aldehydes, ketones, and enones, see a) R. A. Batey,
A. N. Thadani, D. V. Smil, Org. Lett. 1999, 1, 1683 – 1686; b) M.
Pucheault, S. Darses, J.-P. GenÞt, Eur. J. Org. Chem. 2002, 35 5 2 –
3557; c) A. Duursma, J.-G. Boiteau, L. Lefort, J. A. F. Boogers,
A. H. M. de Vries, J. G. de Vries, A. J. Minnaard, B. L. Feringa,
J. Org. Chem. 2004, 69, 8045– 8052; d) M. Pucheault, S. Darses,
J.-P. GenÞt, J. Am. Chem. Soc. 2004, 126, 15356 – 15357.
[26] R. A. Altman, S. L. Buchwald, Org. Lett. 2007, 9, 643 – 646.
[14] T. Ogawa, T. Kiji, K. Hayami, H. Suzuki, Chem. Lett. 1991,
1443 – 1446.
2112
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