A general copper-catalyzed coupling of azoles with vinyl bromides

Article abstract of DOI:10.1021/jo901105r

(Chemical Equation Presented) A copper-catalyzed methodology for the coupling of vinyl bromides with azoles has been developed. This protocol uses a combination of 10 mol % of copper iodide and 20 mol % of ethylenediamine as catalyst. The reaction proceed

Full text of DOI:10.1021/jo901105r

pubs.acs.org/joc
Peterson7 olefination reaction. Although these protocols
A General Copper-Catalyzed Coupling of Azoles with
Vinyl Bromides
provided access to N-vinylazoles, they suffered limitation
in scope, selectivity, and generality. Furthermore, some
procedures required harsh reaction conditions. A straight-
forward transition-metal-catalyzed N-vinylation of azoles
by vinyl halides is an attractive alternative for the known
methods. Palladium-catalyzed efficient vinylation of azoles
with vinyl bromides has been reported.8 Nevertheless, the use
of expensive palladium limited the attractiveness of these
methods for industrial applications. As far as copper-
mediated methods were concerned, which had been widely
used in many C-N bond formation,9 N-vinylation with
vinyl boronic acids displayed the major advantage of pro-
ceeding at room temperature but suffered from requirements
for stoichiometric amount of cupric acetate.10 More recently,
copper-catalyzed methods involving N,N-bis(pyridin-2-
ylmethylene)cyclohexane-1,2-diamine or L-proline as li-
gands enabled the coupling of vinyl bromides with azoles.11
These protocols only worked for (E)-β-bromostyrene.
The development of general, cheap, stereospecific syn-
thetic methodologies to create N-alkenylazoles is still cha-
llenging. Herein we would like to report copper-catalyzed
N-vinylation of azoles with various vinyl bromides involving
commercially available ethane-1,2-diamine as ligand.
Qian Liao, Yuxing Wang, Liyun Zhang, 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 May 29, 2009
A copper-catalyzed methodology for the coupling of
vinyl bromides with azoles has been developed. This
protocol uses a combination of 10 mol % of copper
iodide and 20 mol % of ethylenediamine as catalyst.
The reaction proceeds with various azoles and vinyl
bromides, and the double bond geometry of vinyl bro-
mides is retained under the reaction conditions.
Initial attempts to prepare 1a by CuI-catalyzed cross-
coupling between indole 2a and R-bromostyrene 3a failed.
For example, the use of toluene as solvent, in combination
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N-Vinylazoles are important classes of building blocks in
organic synthesis and are also key structural motifs in many
medicaments. For instance, N-vinylazoles have been shown
to serve as monomers for the synthesis of poly(N-
vinylazoles),1 which could be used as semiconductors and
photosensitive materials. N-Vinylazoles have also been
found to display antifungal activity.2 Conventionally, pro-
tocols for their preparation included direct addition of azoles
to alkynes,3 alkylation of azoles with 1,2-dibromoethane,
followed by dehydrohalogenation of the corresponding
2-haloethylazole.4 Another way to prepare N-vinylazoles
involved creation of the carbon-carbon double bond by
Wittig-Horner,5 Horner-Wadsworth-Emmons,6 and
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DOI: 10.1021/jo901105r
r
Published on Web 07/15/2009
J. Org. Chem. 2009, 74, 6371–6373 6371
2009 American Chemical Society

Liao et al.
JOCNote
TABLE 2. Expanding the Substrate Scope of the Coupling of Azoles
with Vinyl Bromides
FIGURE 1. Comparison of ligands in CuI-catalyzed coupling of
indole with R-bromostyrene.
TABLE 1. Base, Solvent, Copper Salts, and Temperature Optimization
for Coupling of 2a and 3a
entry
base
solvent
CuX
T (°C)
1a yield (%)
1
2
3
4
5
6
7
8
9
Cs2CO3
K2CO3
K3PO4
KOH
toluene
toluene
toluene
toluene
toluene
THF
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuBr
CuCl
110
110
110
110
110
80
110
110
80
90
66
91
33
<1
8
tBuOK
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
DMF
6
dioxane
dioxane
dioxane
dioxane
dioxane
99
71
NR
56
49
10
11
12
25
110
110
a 1H NMR yields were obtained in proportion to the
integral area of the CH2Cl2 signal; CH2Cl2 was used as inter-
nal standard.
with CuI and Cs2CO3, did not lead to the expected product at
all. Stimulated by Buchwald’s observation that 1,2-diamines
were suitable ligands in copper-promoted C-N couplings,12
the effect of such chelates on the indole/vinyl cross-coupling
reaction was next evaluated. To our delight, the presence
of such ligands affected the transformation significantly.
Thus addition of N,N0-dimethylethane-1,2-diamine 4 or
a 1H NMR yield, using CH2Cl2 or mesitylene as internal
standard; yields referring to isolated products are given in
parentheses. b2-(1-Phenylvinyl)indazole was also observed
(10%). c(Z)-2-Styrylindazole was also observed (8%). dCuI
(20 mol %), L (40 mol %).
(12) For representative examples, see: (a) Martı
´
Buchwald, S. L. Angew. Chem., Int. Ed. 2006, 45, 7079–7082. (b) Martı
´
n, R.; Rivero, M. R.;
n, R.;
Cuenca, A.; Buchwald, S. L. Org. Lett. 2007, 9, 5521–5524. (c) Strieter, E. R.;
Bhayana, B.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 78–88. (d)
Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 7421–
7428. (e) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem.
Soc. 2001, 123, 7727–7729.
6372 J. Org. Chem. Vol. 74, No. 16, 2009

Liao et al.
JOCNote
trans-N,N0-dimethylcyclohexane-1,2-diamine 5 resulted in
the formation of 1a in 80 and 72% yields, respectively.
Gratifyingly, the use of the simplest ethylenediamine gave
the expected product in 90% yield. The use of tertiary
diamine (TMEDA) 7 and diethylethane-1,2-diyldicarba-
mate 8 gave the expected product in 23 and 35% yields,
respectively (Figure 1).
Next, the applicability of other bases and solvents was
also evaluated (Table1). Clearly, Cs2CO3 and K3PO4 proved
to be superior to K2CO3 and KOH (entries 1-4). The
stronger base KOBut yielded only a trace of the product
(entry 5).12c,12d The reaction also showed a strong solvent
dependence. Besides toluene, dioxane was the most applic-
able (entry 8), whereas the use of THF and DMF proved to
be inappropriate (entries 6 and 7).
The effect of other coppersaltswas also examined inthe test
reaction. Using K3PO4 as base, dioxane as solvent, ethylene-
diamine as ligand, CuBr and CuCl as precatalyst gave product
in 56 and 49% yield, respectively (entries 11 and 12).
The reaction also showed a strong dependence for tem-
perature. When the reaction was treated at room tempera-
ture, the reaction did not proceed (entry 10). When the
reaction mixture was warmed to 80 °C, the desired product
was formed in 71% yield (entry 9).
On the basis of these results, the optimal conditions
involved the following parameters: CuI as precatalyst,
K3PO4 as base, ethylenediamine as ligand, and dioxane as
solvent. Under these optimized conditions, a study on the
substrate scope was carried out, and the results are summar-
ized in Table 2.
First, various azoles were coupled with R-bromostyrene
3a. Indole 2a, carbazole 2c, and 1H-indazole 2d proved
suitable substrates, and the corresponding products were
formed in excellent yields (entries 1, 9, and 12). 3-Methyl-1H-
indole 2b afforded moderate yield (entry 8). 1H-Imidazole 2f
also afforded moderate yield with high loading of CuI and
ligand (entry 16). 4-Methyl-1H-imidazole 2e and H-pyrrole
2g gave low yields (entries 14 and 17). Although the R-
bromostyrene 3a was applicable, other vinyl bromides were
also useful. 2-Bromoprop-1-ene 3b and (E)-β-bromostyrene
3c performed well under the reaction conditions and aff-
orded the desired products in good yields (entries 2, 3, 11,
and 15). The vinylation of indole 2a, carbazole 2c, and 1H-
indazole 2d with (Z)-β-bromostyrene 3c gave (Z)-1-styryl-
1H-indole 1d, (Z)-9-styryl-9H-carbazole 1j, and (Z)-1-styryl-
1H-indazole 1m in excellent yields, respectively (entries 4, 10,
and 13), which are in contrast to the report on the vinylation
of azoles catalyzed by CuI-N,N-bis(pyridin-2-ylmethylene)-
cyclohexane-1,2-diamine catalyst system.11d 2-Bromobut-2-
ene 3e, a commercial vinyl source available as a mixture of both
E- and Z-isomers in a E to Z ratio of 3.9:3, was accepted as
substrate, and its coupling proceeded with complete retention of
configuration
(as
confirmed
by
NMR
spectro-
scopy); the vinylation products were formed in high yield with
stereospecificity (entry 5). Furthermore, tetrasubstituted vinyl
bromide 3f performed well under the reaction conditions and
afforded the corresponding product 1f in high yield. Vinyl
bromides bearing a NMePh moiety 3g were also compatible,
and the corresponding product 1g was formed in excellent yield
under the reaction conditions. When triazoles and tetrazoles,
such as 1H-1,2,3-triazole, 1H-1,2,4-triazole, 1H-benzo[d]-
[1,2,3]triazole, and 5-phenyl-1H-tetrazole were treated with
vinyl bromides under the similar reaction conditions, the desired
products were not observed.
In summary, a general copper-catalyzed methodology for
the coupling of vinyl bromides with azoles has been
described. This protocol has low reagent (CuI as precatalyst,
ethylenediamine as ligand) cost and broader substrates with
double bond geometry of vinyl bromides retained under the
reaction conditions
Experimental Section
General procedure for N-vinylation: CuI (10 mg, 0.1 mmol),
azole (1.2 mmol), and K3PO4 (425 mg, 2.0 mmol) were added to
a screwcapped test tube with a Teflon-lined septum. The tube
was then evacuated and backfilled with N2 (3 cycles). Vinyl
bromide (1 mmol), ethylenediamine (0.2 mmol), and 1,4-diox-
ane (1.0 mL) were added by syringe at room temperature. The
tube was then sealed, and the reaction mixture was stirred at
110 °C for indicated time. The reaction was cooled to room
temperature. Ethyl acetate (3 mL) was added and stirred for
10 min. The deposition was separated and washed with ethyl
acetate (3 mLꢀ3). The organic phase was combined. The solvent
was removed under vacuum, and the residue was analyzed by 1H
NMR. For example, preparation of N-(2-(indolyl-1)-allyl)-N-
methylaniline (1g), the crude product was purified by column
chromatography on silica gel with petroleum ether/EtOAc =
15/1 to give the desired product as pale yellow oil: Rf = 0.6
(petroleum ether); 1H NMR (300 MHz, CDCl3) δ 7.65-7.62 (d,
J=7.5 Hz, 1H), 7.56-7.53 (d, J=8.2 Hz, 1H), 7.27-7.14 (m,
5H), 6.77-6.74 (m, 3H), 6.59-6.58 (d, J=3.1 Hz, 1H), 5.37 (s,
1H), 5.31 (s, 1H), 4.27 (s, 2H), 2.99 (s, 3H); 13C NMR (75.45
MHz, CDCl3) δ 149.0, 140.7, 136.1, 129.3, 129.1, 126.4, 122.4,
121.1, 120.4, 117.2, 112.5, 111.2, 108.8, 103.3, 56.5, 38.4; GC-
MS (EI, m/z) 262 (Mþ), 144, 120; HRMS calcd for C15H12N2
220.1000, found 220.1003.
Acknowledgment. This work was supported by the Nat-
ional Natural Science Foundation of China (20572058 and
20872076).
Supporting Information Available: Experimental proce-
dures and full characterization including 1H NMR and 13C
NMR data for compounds 1e-1h and 1l-1n. NMR spectra for
1a-1q. This material is available free of charge via the Internet
at http://pubs.acs.org.
J. Org. Chem. Vol. 74, No. 16, 2009 6373