1,1-dibromo-1-alkenes as valuable partners in the copper-catalyzed direct alkynylation of azoles

Article abstract of DOI:10.1021/ol1016433

The copper-catalyzed direct alkynylation of azoles with 1,1-dibromo-1-alkenes as electrophiles is described. These easily accessible substrates are a useful addition to the field of direct alkynylations in an efficient and functional group tolerant reaction to provide a straightforward entry to diverse alkynyl heterocycles.

Full text of DOI:10.1021/ol1016433

ORGANIC
LETTERS
2010
Vol. 12, No. 18
4038-4041
1,1-Dibromo-1-alkenes as Valuable
Partners in the Copper-Catalyzed Direct
Alkynylation of Azoles
Beatriz Pacheco Berciano,†,‡ Sabrina Lebrequier,‡ Franc¸ois Besselie`vre,†,‡ and
Sandrine Piguel*,†,‡
UniV Paris-Sud, Orsay F-91405, France, and Institut Curie/CNRS, UMR 176,
Baˆt. 110-112, Centre UniVersitaire, 91405 Orsay, France
sandrine.piguel@curie.u-psud.fr
Received July 15, 2010
ABSTRACT
The copper-catalyzed direct alkynylation of azoles with 1,1-dibromo-1-alkenes as electrophiles is described. These easily accessible substrates
are a useful addition to the field of direct alkynylations in an efficient and functional group tolerant reaction to provide a straightforward entry
to diverse alkynyl heterocycles.
Acetylenes are key building blocks in organic chemistry,
chemical biology, and materials science.1 The Sonogashira
Scheme 1. General Approaches for Alkynylation
cross-coupling reaction between a (hetero)aryl or alkenyl
halide and a terminal alkyne has become an indispensable
and powerful tool for the organic chemist to introduce such
a motif.2 An attractive and complementary strategy relies
on the transition-metal-catalyzed direct C-H bond func-
tionalization between an sp2-hybridized (hetero)aryl carbon
and an sp-hybridized carbon of an alkynyl halide. This direct
alkynylation of “unreactive” C-H bonds has been rarely
studied until recently, when notable advances were reported
(Scheme 1).3 Despite this remarkable interest, the use of 1,1-
dibromo-1-alkenes in the direct functionalization of C-H
bonds has not yet been studied (Scheme 1).
reagents including organotin, magnesium, borane, and zinc
compounds to give the corresponding trisubstituted alkenes
with high stereoselectivity.5 In addition, the gem-dihalovinyl
moiety has become a key unit for the synthesis of various
heterocycles and carbocycles through tandem catalysis.6
More recently, 1,1-dibromo-1-alkenes proved to be reactive
partners in copper-mediated couplings as shown by the
synthesis of ynamides or ketene N,N-acetals.7
The versatility of 1,1-dihalo-1-alkenes has been exploited,
notably, as alkyne equivalents in the synthesis of 1,3-diynes
or internal alkynes.4 1,1-Dihalo-1-alkenes have also served
in cross-coupling reactions with various organometallic
† University Paris-Sud.
‡ Institut Curie/CNRS.
(1) (a) Siemsen, P.; Livingston, R. C.; Diederich, F. Angew. Chem., Int.
Ed. 2000, 39, 2632. (b) Acetylene Chemistry; Diederich, F., Tykwiski, R. R.,
Stang, P., Eds; Wiley-VCH: Weinheim, Germany, 2005.
(2) Chinchilla, R.; Na´jera, C. Chem. ReV. 2007, 107, 874.
Herein, we disclose that 1,1-dibromo-1-alkenes can be
employed as alkynyl equivalents in the copper-catalyzed
10.1021/ol1016433  2010 American Chemical Society
Published on Web 08/24/2010

direct alkynylation of azoles, providing an efficient new route
to diverse (hetero)aryl alkynes (Scheme 1).
Table 1. Optimization toward Direct Alkynylation of
As part of our program directed toward the development
of metal-catalyzed C-H bond functionalization, we found
that the copper/diphosphine duet enabled the direct alkyny-
lation of various azoles with 1-bromoalkynes.3j Furthermore,
we hypothesized that their direct precursors, the 1,1-bromo-
1-alkenes, could serve as a reaction partner in such a process.
Indeed, treatment of 5-phenyloxazole 1 with 1,1-dibromosty-
rene 2 in the presence of CuBr·SMe2 (15 mol %), DPEPhos
(15 mol %) as ligand, LiOt-Bu (4 equiv) as base in dioxane
at 120 °C (Table 1, entry 1) delivered the desired product
3a in 40% yield after 2 h but without complete conversion.
Following this encouraging preliminary result, a brief
optimization of the reaction conditions was performed. While
no improvement in yield was obtained even after prolonged
heating (Table 1, entry 2), an increase in the amount of LiOt-
Bu (from 4 equiv) gave a positive effect, giving 3a in 58%
yield (5 equiv) and 70% yield (6 equiv) with complete
conversion (Table 1, entries 3 and 4). Mixing organic and
inorganic bases was detrimental to the direct alkynylation
process returning starting material (Table 1, entries 5-7).
The catalyst loading could be decreased down to 5 mol %
without affecting the yield. However, at these low loadings,
a 2:1 ratio ligand to catalyst proved to be crucial to maintain
the highest yield (Table 1, entries 8-10). A brief examination
of ligand structure showed no striking effect when XantPhos
and BINAP were used (Table 1, entries 11 and 12). Thus,
the optimum conditions were shown to be CuBr·SMe2 (5
mol %), DPEPhos (10 mol %), and LiOt-Bu (6 equiv) in
dioxane at 120 °C.
5-Phenyloxazolea
CuBr·SMe2
(mol %)
DPEPhos
(mol %)
LiOtBu
(equiv)
entry
yield (%)b
1
2
3
4
5
6
7
8
15
15
15
15
15
15
15
10
5
15
15
15
15
15
15
15
10
5
4
4
5
6
40
48c
58
70
0
2 + 2 DBU
2 + 3 Cs2CO3
2 + 3 Li2CO3
tracesd
tracesd
71
6
6
6
6
6
9
58
10
11
12
5
5
5
10
10
10
69
69e
50f
a All reactions were performed at 0.35 M of 5-phenyloxazole 1a (1
equiv), 2,2-dibromovinylbenzene 2a (2 equiv), CuBr·SMe2 (15 mol %),
DPEPhos (15 mol %), LiOt-Bu in dioxane heated at 120 °C for 2 h.
b Isolated yields. c The reaction was run overnight. d 2,2-Dibromovinylbenzene
(1.5 equiv) was used, and the reaction was run for 24 h. e XantPhos was
used as ligand. f BINAP was used as ligand.
readily accessible 1,1-dibromo-1-alkenes (Scheme 2). These
building blocks are commonly prepared from the corre-
sponding commercially available aldehydes via the Ramirez
procedure.8 Both electron-rich (Scheme 2: 3a, 3b, 3c, 3d,
3e, 3f) and electron-deficient (Scheme 2: 3g, 3h, 3i) gem-
dibromoolefins reacted regioselectively at the C-2 position
of 5-phenyloxazole 1a in good yields, with substitution being
tolerated at each of the ortho, meta, and para positions.
Importantly, these conditions proved to be compatible with
the presence of important functional groups on the aromatic
moiety such as halides (63-65%), nitro (44%), and cyano
(48%). It is noteworthy that the acetal group survives these
reaction conditions, providing the expected compound 3m
in a satisfactory 55% yield. In addition to the aryl group,
the reaction also proceeds equally well with different gem-
dibromoolefins including heteroaryl- and alkenyl-substituted
alkenes (Scheme 2: 3j, 3k, 3l). Unfortunately, these condi-
tions were not found to be applicable to related 1,1-
dibromoalkenes bearing a simple alkyl substituent. The
apparent lack of reactivity for this substrate is still unclear
at this stage, and investigations to overcome this issue are
ongoing.
This optimized protocol was subsequently applied to the
direct alkynylation of 5-phenyloxazole 1a with various
(3) (a) Kalinin, V. K.; Pashchenko, D. N.; She, F. MendeleeV Commun.
1992, 2, 60. (b) Kobayashi, K.; Arisawa, M.; Yamaguchi, M. J. Am. Chem.
Soc. 2002, 124, 8528. (c) Trofimov, B. A.; Stepanova, Z. V.; Sobenina,
L. N.; Mikhaleva, A. I.; Ushakov, I. A. Tetrahedron Lett. 2004, 45, 6513.
(d) Amemiya, R.; Fujii, A.; Yamaguchi, M. Tetrahedron Lett. 2004, 45,
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2007, 124, 8528. (f) Gu, Y.; Wang, X. Tetrahedron Lett. 2009, 50, 763.
(g) Tobisu, M.; Ano, Y.; Chatani, N. Org. Lett. 2009, 11, 3250. (h) For a
single example of palladium-catalyzed direct alkynylation of sidnones (34%
yield), see: Rodriguez, A.; Fennessy, R.; Moran, W. Tetrahedron Lett. 2009,
50, 3942. (i) Matsuyama, N.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett.
2009, 11, 4156. (j) Besselie`vre, F.; Piguel, S. Angew. Chem., Int. Ed. 2009,
48, 9953. (k) Brand, J. P.; Charpentier, J.; Waser, J. Angew. Chem., Int.
Ed. 2009, 48, 9346. (l) Dudnik, A. S.; Gevorgyan, V. Angew. Chem., Int.
Ed. 2010, 49, 2096. (m) Kawano, T.; Matsuyama, N.; Hirano, K.; Satoh,
T.; Miura, M. J. Org. Chem. 2010, 75, 1764. (n) Kim, S. H.; Chang, S.
Org. Lett. 2010, 12, 1868.
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2857, and references cited therein. (b) Lera, M.; Hayes, C. J. Org. Lett.
2000, 2, 3873. (c) Chelucci, G.; Capitta, F.; Baldino, S. Tetrahedron 2008,
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12, 2048.
(5) Wang, J.-R.; Manabe, K. Synthesis 2009, 9, 1405, and references
cited therein.
Next, the reaction scope was also investigated with respect
to the heterocycles. The C-2 position of oxazoles bearing
electronically different aryl/styryl groups at C-5 was alky-
nylated to furnish 4, 5 and 6 in 61%, 75% and 53% yields
respectively (Scheme 3). Moreover, the electron-donating
dimethylamino group was tolerant of the reaction conditions
(6) (a) Bryan, C. S.; Lautens, M. Org. Lett. 2010, 12, 2754, and
references cited therein. (b) Arthuis, M.; Pontikis, R.; Florent, J.-C. Org.
Lett. 2009, 11, 4608. (c) Vieira, T. O.; Meaney, L. A.; Shi, Y.-L.; Alper,
H. Org. Lett. 2008, 10, 4899. (d) Thielges, S.; Meddah, E.; Bisseret, P.;
Eustache, J. Tetrahedron Lett. 2004, 45, 907. (e) Wang, L.; Shen, W.
Tetrahedron Lett. 1998, 39, 7625.
(7) (a) Newman, S. G.; Aureggi, V.; Bryan, C. S.; Lautens, M. Chem.
Commun. 2009, 5236. (b) Coste, A.; Karthikeyan, G.; Couty, F.; Evano,
G. Angew. Chem., Int. Ed. 2009, 48, 4381. (c) Coste, A.; Couty, F.; Evano,
G. Org. Lett. 2009, 11, 4454. (d) Yuen, J.; Fang, Y.-Q.; Lautens, M. Org.
Lett. 2006, 8, 653.
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84, 1745.
Org. Lett., Vol. 12, No. 18, 2010
4039

Scheme 2
.
Scope of Direct Alkynylation of 5-Phenyloxazole
with Vinyl Dibromidesa
Scheme 3.
Scope with Respect to the Heterocyclesa
a Reaction run with 2 equiv of 2,2-dibromovinylbenzene 2a and 1 equiv
of heterocycle, CuBr·SMe2 (5 mol %), DPEPhos (10 mol %), LiOtBu (6
equiv) in dioxane at 120 °C for 2 h. Yields are calculated on isolated
products (average of two runs).
of the alkynyl bromide onto B presumably gives a four-
coordinated copper(III) complex C. A subsequent reductive
elimination would lead to the expected compound 3 and
regenerate the catalytic copper(I) species A in the process.
In path 2, the first steps would involve the direct alkenylation
of azoles on the more reactive trans C-Br bond of the gem-
dibromoolefin to furnish the trisubstituted alkene 13. Dehy-
drobromination would then take place at the late stage to
generate the expected compound 3. However, the synthesis
a Reaction conditions: 5-phenyloxazole 1a (1 equiv), gem-dibromovi-
nylbenzene 2a (2 equiv), LiOt-Bu (6 equiv), dioxane (0.35 M), 120 °C for
2 h. Yields are calculated on isolated products (average of two runs).
b gem-Dibromovinylbenzene (3 equiv), CuBr·SMe2 (10 mol %), and
DPEPhos (10 mol %) were used. c CuBr·SMe2 (10 mol %) and DPEPhos
(10 mol %) were used.
Scheme 4
. Mechanistic Proposal for Copper-Catalyzed Direct
Alkynylation of Heterocycles with gem-Dibromoolefin
(Scheme 3: 6). This substitution pattern along with the acetal
group in compound 3m have never been reported before in
such a process. Oxazole itself was regioselectively alkyny-
lated at the C-2 position, however only a low yield was
obtained. Other heterocycles, such as benzoxazole, ben-
zothiazole, 1,2,4-triazole and N-benzyl-6-chloropurine were
also found to be suitable substrates with varying reactivities
(Scheme 3: 8, 9, 10 and 11).
An overview of the proposed mechanism is shown in
Scheme 4. The sequence begins with the deprotonation of
the oxazole by LiOt-Bu followed by lithium-copper trans-
metalation to generate a copper(I)(oxazolate) intermediate
B as illustrated by Daugulis for the copper-catalyzed direct
arylation of heterocycles.9 Then, two hypotheses both
involving the formation of a copper(III) complex C or D
could be considered.10 Path 1 involves the preliminary
formation of alkynyl bromide 12 by dehydrobromination of
the 1,1-dibromo-1-alkene 2. Subsequent oxidative addition
4040
Org. Lett., Vol. 12, No. 18, 2010

of 1-bromoalkynes in the presence of base is a well-known
and easy transformation. Taking into account that these
compounds have been identified in the crude reaction mixture
and 13 was never isolated, it is reasonable to suppose that
this direct alkynylation with 1,1-dibromo-1-alkenes proceeds
through path 1.
In summary, we have shown that 1,1-dibromo-1-alkenes
are useful new coupling partners in the direct alkynylation
of various azoles under copper catalysis. The reaction is
rapid, functional group tolerant, and proceeds in moderate
to good yields. In this way, 1,1-dibromo-1-alkenes act as
synthetic equivalents of 1-bromoalkynes, thus representing
a new landmark in the field of direct alkynylation reactions.
(9) Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2007, 129, 12404.
(10) For discussion of mechanisms involving copper(III) species, see:
(a) Casitas, A.; King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.; Ribas, X.
Chem. Sci. 2010, 326. (b) Strieter, E. R.; Bhayana, B.; Buchwald, S. L.
J. Am. Chem. Soc. 2009, 131, 78. (c) Phipps, R. J.; Gaunt, M. J. Science
2009, 323, 1593. (d) Monnier, F.; Turtaut, F.; Duroure, L.; Taillefer, M.
Org. Lett. 2008, 10, 3203. (e) Huffman, L. M.; Stahl, S. S. J. Am. Chem.
Soc. 2008, 130, 9196, and references cited therein. (f) Ouali, A.; Spindler,
J.-F.; Jutand, A.; Taillefer, M. AdV. Synth. Catal. 2007, 349, 1906. (g)
Altman, R. A.; Koval, E. D.; Buchwald, S. L. J. Org. Chem. 2007, 72,
6190. (h) Zhang, S.-L.; Liu, L.; Fu, Y.; Guo, Q.-X. Organometallics 2007,
26, 4546. (i) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42,
5400.
Acknowledgment. The Institut Curie and the Agence
Nationale de la Recherche are thanked for financial support.
Supporting Information Available: Experimental pro-
cedures, and copies of 1H and 13C for all compounds 1b, 2c,
2m, 3a-m, 4, 5, 6, 7, 8, 9, 10, and 11. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL1016433
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