Copper-catalyzed amination of alkenyl halides: Efficient method for the synthesis of enamines

Article abstract of DOI:10.1021/ol1009416

A copper-catalyzed method for the coupling of alkenyl halides with secondary amines has been developed. This protocol used a combination of 10 mol % copper iodide and 20 mol % N,N′-dimethylethane-1,2-diamine as catalyst. The reaction proceeded with various aromatic amines and alkenyl bromides or alkenyl iodides, and the enamines were formed in high yields with excellent regioselectivity and stereoselectivity under the reaction conditions.

Full text of DOI:10.1021/ol1009416

ORGANIC
LETTERS
2010
Vol. 12, No. 13
2951-2953
Copper-Catalyzed Amination of Alkenyl
Halides: Efficient Method for the
Synthesis of Enamines
Yuxing Wang, Qian Liao, and Chanjuan Xi*
Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of
Education), Department of Chemistry, Tsinghua UniVersity, Beijing 100084, China
cjxi@tsinghua.edu.cn
Received April 23, 2010
ABSTRACT
A copper-catalyzed method for the coupling of alkenyl halides with secondary amines has been developed. This protocol used a combination
of 10 mol % copper iodide and 20 mol % N,N′-dimethylethane-1,2-diamine as catalyst. The reaction proceeded with various aromatic amines
and alkenyl bromides or alkenyl iodides, and the enamines were formed in high yields with excellent regioselectivity and stereoselectivity
under the reaction conditions.
Enamines are valuable intermediates in organic synthesis.1 They
are extensively employed as nucleophiles in Michael-type
additions, intermediates in the synthesis of heterocycles, and
precursors of chiral amines upon asymmetric transformations
and intermediates in natural product synthesis.2 The classical
approach for the synthesis of enamines is the condensation of
a secondary amine with a carbonyl compound, which usually
happens under acid catalysis.3 However, this method presents
several limitations, such as harsh reaction conditions, lack of
regio- and chemoselectivity, and low functional group tolerance.
Alternative methods for the synthesis of enamines are hy-
droaminations of alkynes4 and methylenation of amides.5
On the other hand, in recent years, great interest has been
devoted to the development of metal catalyzed cross-coupling
reactions of aryl halides with N-centered nucleophiles. In
particular, the high stability and low cost of the copper
catalysts enable these transformations6,7 to be a useful
complement to the more extensively studied palladium-
catalyzed processes.8 The application of the same cross-
coupling reaction to alkenyl halides would furnish enamines
or imines. This protocol has concentrated on the formation of
enamines or imines with only a few examples of palladium-
catalyzed vinylation of amines.9 However, copper-catalyzed
amination of alkenyl halides for formation of enamines has been
scarcely studied, to the best of our knowledge, although copper-
catalyzed the reactions of an alkenyl halide with amides10,11
(4) (a) Barluenga, J.; Aznar, F.; Liz, R.; Rodes, R. J. Chem. Soc., Perkin
Trans. 1 1980, 2732. (b) Beller, M.; Breindl, C.; Eichberger, M.; Hartung,
C. G.; Seayad, J.; Thiel, O. R.; Tillack, A.; Trauthwein, H. Synlett 2002,
10, 1579. (c) Bytschkov, I.; Doye, S. Eur. J. Org. Chem. 2003, 935. (d)
Shimada, T.; Yamamoto, Y. J. Am. Chem. Soc. 2002, 124, 12670. (e)
Tillack, A.; Garc´ıa Castro, I.; Hartung, C. G.; Beller, M. Angew. Chem.,
Int. Ed. 2002, 41, 2541.
(5) Petasis, N. A.; Lu, S. P. Tetrahedron Lett. 1995, 36, 2393.
(6) For reviews, see: (a) Beletskaya, I. P.; Cheprakov, A. V. Coord.
Chem. ReV. 2004, 248, 2337. (b) Chemler, S. R.; Fuller, P. H. Chem. Soc.
ReV. 2007, 36, 1153. (c) Evano, G.; Blanchard, N.; Toumi, M. Chem. ReV.
2008, 108, 3054.
(1) Whitesell, J. K. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991.
(7) (a) Zou, B.; Yuan, Q.; Ma, D. Angew. Chem., Int. Ed. 2007, 46,
2598. (b) Rao, H.; Fu, H.; Jiang, Y.; Zhao, Y. J. Org. Chem. 2005, 70,
8107. (c) Jiang, Q.; Jiang, D.; Jiang, Y.; Fu, H.; Zhao, Y. Synlett 2007, 72,
1836. (d) Kunz, K.; Scholz, U.; Ganzer, D. Synlett 2003, 2428. (e) Ley,
S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400. (f) Deng,
W.; Liu, L.; Guo, Q.-X. Chin. J. Org. Chem. 2004, 24, 150. (g) Xia, N.;
Taillefer, M. Angew. Chem., Int. Ed. 2009, 48, 337.
(2) (a) The Chemistry of Enamines; Rappaport, Z., Ed.; Wiley: New
York, 1994. (b) Cook, A. G., Ed. Enamines; New York: Marcel Decker,
1988.
(3) (a) Hickmott, P. W. Tetrahedron 1982, 38, 1975. (b) White, W. A.;
Weingarten, H. J. Org. Chem. 1967, 32, 213.
10.1021/ol1009416  2010 American Chemical Society
Published on Web 06/03/2010

and azoles12 have been previously reported. Herein we report
the copper-catalyzed alkenylation of amines with various
vinyl halides to afford enamines.
Table 1. Base, Solvent, Temperature, and Time Optimization
for Coupling of 1a and 2a
On the basis of our previous work on the copper-catalyzed
reaction of an alkenyl halide with azoles,12a we felt that the
use of an appropriate ligand and base would allow us to achieve
a mild and general procedure for the synthesis of enamines.
Using 1,2-diphenyl-1-iodobut-1-ene (1a) and diphenylamine
(2a) as the prototypical substrate combination, an initial ligand
yielda (%)
of 3a
t
screen was carried out with CuI as a precatalyst and BuONa
entry
base
solvent
temp (°C) time (h)
as a base. To our delight, among the five ligands examined,
N,N′-dimethylethane-1,2-diamine (DMEDA) (L4) gave an
excellent result (Figure 1). 2,2′-Bipyridine (L1), ethane-1,2-
1
2
3
4
5
6
7
8
tBuONa toluene
tBuONa toluene
tBuONa toluene
140
140
140
140
140
140
140
140
140
140
140
80
110
125
140
140
140
24
16
8
95
93
73
65
60
40
NR
21
10
NR
NR
NR
33
NaOH
Cs2CO3
K3PO4
Na2CO3
toluene
toluene
toluene
toluene
16
16
16
16
16
16
16
16
16
16
16
16
16
16
tBuONa NMP
9
tBuONa DMF
10
11
12
13
14
15
16
17
tBuONa DMSO
tBuONa dioxane
tBuONa toluene
tBuONa toluene
tBuONa toluene
tBuONa toluene
tBuONa toluene
tBuONa toluene
68
86b
80c
NRd
a GC yield. b 5 mol % of CuI was added. c 1 mol % of CuI was added.
d without the addition of CuI.
Cs2CO3, and K3PO4 (entries 2 and 4-6). Na2CO3 proved to be
inefficient (entry 7). The reaction also showed a strong solvent
dependence. Except toluene, other solvents such as NMP, DMF,
DMSO, and 1,4-dioxane proved to be inappropriate (entries
8-11). The reaction also showed a significant dependence on
temperature. When the reaction was treated at 80 °C, the
reaction did not proceed (entry 12). When the reaction mixture
was warmed to 110 and 125 °C, the desired product was formed
in 33% and 68% yields, respectively (entries 13 and 14).
Reducing the amount of CuI to 5 mol % and 1 mol % within
16 h also afforded good yields (entries 15 and 16). It is
noteworthy that when CuI was not used, the reaction did not
proceed (entry 17).
Figure 1. Comparison of ligands in CuI-catalyzed coupling of
diphenylamine and 2,2-diphenyl-1-iodobut-1-ene.
diamine (L3), and tetramethylethane-1,2-diamine (L5) also gave
satisfying results. In the absence of ligand, the reaction can also
proceed in 60% yield under the reaction conditions. Next, the
applicability of other bases and solvents was also evaluated
On the basis of these results, the optimal conditions involved
the following parameters: CuI as precatalyst, tBuONa as base,
N,N′-dimethylethane-1,2-diamine as ligand, and toluene as
solvent, with reaction temperature at 140 °C. Under these
t
(Table 1). Clearly, BuONa proved to be superior to KOH,
(10) (a) Jiang, B.; Tian, H.; Huang, Z.-G.; Xu, M. Org. Lett. 2008, 10,
2737. (b) Lu, H.; Yuan, X.; Zhu, S.; Sun, C.; Li, C. J. Org. Chem. 2008,
73, 8665. (c) Martin, R.; Cuenca, A.; Buchwald, S. L. Org. Lett. 2007, 9,
5521. (d) Cesati, R. R., III; Dwyer, G.; Jones, R. C.; Hayes, M. P.;
Yalamanchili, P.; Casebier, D. S. Org. Lett. 2007, 9, 5617. (e) Martin, R.;
Larsen, C. H.; Cuenca, A.; Buchwald, S. L. Org. Lett. 2007, 9, 3379. (f)
He, G.; Wang, J.; Ma, D. Org. Lett. 2007, 9, 1367. (g) Yang, L.; Deng, G.;
Wang, D.-X.; Huang, Z.-T.; Zhu, J.-P.; Wang, M.-X. Org. Lett. 2007, 9,
1387.
(8) For reviews, see: (a) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem.
2002, 219, 131. (b) Hartwig, J. F. In Handbook of Organopalladium
Chemistry for Organic Synthesis; Negichi, E.-I., Ed.; Wiley: New York,
2002; Vol. 1, p 1051. (c) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed.
2002, 41, 4176. (d) Prim, D.; Campagne, J. M.; Joseph, D.; Rioletti, B.
Tetrahedron 2002, 58, 2041. (e) Yang, B. Y.; Buchwald, S. L. J. Organomet.
Chem. 1999, 576, 125. (f) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.;
Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805. (g) Hartwig, J. F. Angew.
Chem., Int. Ed. 1998, 37, 2046. (h) Hartwig, J. F. Acc. Chem. Res. 1998,
31, 852. (i) Dehli, J. R.; Bolm, C. J. Org. Chem. 2004, 69, 8518. (j) Surry,
D. S.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 6338.
(9) (a) Barluenga, J.; Ferna´ndez, M. A.; Aznar, F.; Valde´s, C. Chem.
Commun. 2002, 2362. (b) Barluenga, J.; Ferna´ndez, M. A.; Aznar, F.;
Valde´s, C. Chem.sEur. J. 2004, 10, 494. (c) Willis, M. C.; Brace, G. N.
Tetrahedron Lett. 2002, 43, 9085.
(11) (a) Rivero, M. R.; Buchwald, S. L. Org. Lett. 2007, 9, 973. (b)
Toumi, M.; Couty, F.; Evano, G. Angew. Chem., Int. Ed. 2007, 46, 572.
(c) Yuan, X.; Xu, X.; Zhou, X.; Yuan, J.; Mai, L.; Li, Y. J. Org. Chem.
2007, 72, 1510. (d) Lu, H.; Li, C. Org. Lett. 2006, 8, 5365. (e) Dehli, J. R.;
Bolm, C. AdV. Synth. Catal. 2005, 347, 239. (f) Dehli, J. R.; Legros, J.;
Bolm, C. Chem. Commun. 2005, 973. (g) Martn, R.; Rivero, M. R.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2006, 45, 7079.
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Org. Lett., Vol. 12, No. 13, 2010

optimized conditions, a study on the substrate scope was carried
out, and the results are summarized in Table 2.
alkenyl bromides with amines also afforded enamines in
excellent yields (entries 5-8). To the best of our knowledge,
this is the first example of the copper-catalyzed amination
of an unactivated alkenyl bromide. It is worth noting that
this protocol could proceed with di- and trisubstituted vinyl
halides under the reaction conditions and afford the desired
enamines in excellent yields. In contrast, when alkenyl
halides bearing ꢀ-hydrogen, such as R-bromostyrene and
ꢀ-bromostyrene, were treated with diphenylamine under the
same reaction conditions, the desired products were not
observed. A small amount of enyne was examined by
GC-MS, which occurred to undergo an E2-type elimination
and coupling reaction.12e,13 Furthermore, the reaction of
alkenyl chloride with 2a did not proceed.
Table 2. Expanding the Substrate Scope of the Coupling of
Vinyl Halides with Amines
Besides the diphenylamine 2a, other substituted anilines were
all viable substrates. Excellent results were obtained for the
aromatic substituted N-ethylaniline (2c) and N-methylaniline
(2d) (entries 9 and 10). In these reactions, the products were
formed as a mixture of two isomers. Coupling reaction of
N-naphthalenylaniline (2e) with 1a afforded an exclusive
enamine in high yield (entry 11) due to increased steric
hindrance. The coupling reaction also proceeded in excellent
yields with bis(4-methoxyphenyl)amine (entry 8), di(p-tolyl)-
amine (entries 12 and 13), or bis(4-chlorophenyl)amine (entry
14). To our delight, the crystal of 3j was suitable for single-
crystal analysis, and its structure was fully characterized by the
X-ray diffraction analysis. Coupling reaction of alkenyl halides
with primary amines gave rise to imines as a mixture of two
isomers (as confirmed by NMR spectroscopy) after tautomer-
ization of the initially formed enamine (entries 15 and 16).
However, aliphatic amines were not suitable substrates for such
reaction to form enamines under the reaction conditions. In this
case, amines are remained.
In summary, we have developed the copper-catalyzed
cross-coupling reaction of amines with alkenyl iodides and
alkenyl bromides. The enamines were formed in high yields
with excellent regioselectivity and stereoselectivity under the
reaction conditions.
Acknowledgment. This work was supported by the Na-
tional Natural Science Foundation of China (20872076) and
(20972085). Miss Yun-Gu Hao is gratefully acknowledged for
her kind English corrections.
Supporting Information Available: Experimental pro-
1
cedures and full characterization including H NMR and 13C
NMR data for compounds 3a-n. NMR spectra for 3a-n. X-ray
crystallography data for complex 3j (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
a GC yield; isolated yields are given in parentheses. b Combined yield
of two isomers.
OL1009416
(12) (a) Liao, Q.; Wang, Y.; Zhang, L.; Xi, C. J. Org. Chem. 2009, 74,
6371. (b) Bao, W.; Liu, Y.; Lv, X. Synthesis 2008, 1911. (c) Ouali, A.;
Laurent, R.; Caminade, A.-M.; Majoral, J.-P.; Taillefer, M. J. Am. Chem.
Soc. 2006, 128, 15990. (d) Taillefer, M.; Ouali, A.; Renard, B.; Spindler,
J.-F. Chem.sEur. J. 2006, 12, 5301. (e) Wang, Z.; Bao, W.; Jiang, Y. Chem.
Commun. 2005, 2849. (f) Mao, J.; Hua, Q.; Guo, J.; Shi, D.; Ji, S. Synlett
First, various alkenyl iodides were coupled with diphe-
nylamine (2a). (E)-(1-Iodobut-1-ene-1,2-diyl)dibenzene (1a),
3-ethyl-4-iodohex-3-ene (1b), (E)-4-ethyl-5-iodooct-4-ene
(1c), and (Z)-ethyl 3-iodo-2,3-diphenylacrylate (1d) proved
to be suitable substrates, and the corresponding products were
formed in excellent yields (entries 1-4). The reaction of
2008, 2011
(13) Bates, C. G.; Saejueng, P.; Venkataraman, D. Org. Lett. 2004, 6,
1441
.
.
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