Copper-catalyzed coupling of imidazoles and pyrazoles with 1,1-dibromo-1-alkenes: A distinct approach for direct N-alkynylation of heteroarenes

Article abstract of DOI:10.1016/j.tetlet.2011.09.117

The direct N-alkynylation of heteroarenes, imidazoles, and pyrazoles with 1,1-dibromo-1-alkene has been carried out for the first time using [Cu(Phen)PPh₃Br] (as a catalyst) and Cs₂CO₃ in DMSO at 80 °C. The products are formed in good to high yields (66-85%) within 3 h. No side products could be detected.

Full text of DOI:10.1016/j.tetlet.2011.09.117

Tetrahedron Letters 52 (2011) 6497–6500
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Copper-catalyzed coupling of imidazoles and pyrazoles with
1,1-dibromo-1-alkenes: a distinct approach for direct N-alkynylation
of heteroarenes q
⇑
Biswanath Das , N. Salvanna, Gandolla Chinna Reddy, Penagaluri Balasubramanyam
Organic Chemistry Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 July 2011
Revised 22 September 2011
Accepted 24 September 2011
Available online 29 September 2011
The direct N-alkynylation of heteroarenes, imidazoles, and pyrazoles with 1,1-dibromo-1-alkene has
been carried out for the first time using [Cu(Phen)PPh3Br] (as a catalyst) and Cs2CO3 in DMSO at 80 °C.
The products are formed in good to high yields (66–85%) within 3 h. No side products could be detected.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Imidazole
Pyrazole
N-Alkynylation
1,1-Dibromo-1-alkene
[Cu(Phen)PPh3Br]
N-Alkynyl heteroarenes exhibit interesting biological1 and pho-
toconductive properties.2 They are also useful intermediates in or-
ganic synthesis3 and in medicinal chemistry.1b However, the
general and mild methods for the synthesis of these compounds
are limited and as a consequence these compounds have not been
properly explored. The methods reported previously for the syn-
thesis of N-alkynyl heteroarenes are multistep procedures involv-
ing the coupling of alkynyliodonium salts,4a elimination of
haloenamines,4b and isomerisation of propargyl groups.4c Ligand-
assisted or ligand-free Cu-catalyzed syntheses of these compounds
are also known.5 However, long reaction times and formation of
the side products are the problems. Here, we describe a distinct ap-
proach for direct N-alkynylation of heteroarenes applying a Cu (I)-
based complex.
N
N
N
N
Cu (PPh3)Br
Cu
NO3
Cu
B
Ph3P
Br
Ph3P
PPh3
[Cu(Phen)PPh3Br]
[Cu (Phen)(PPh3)2]NO3
A
C
N
N
[Cu(bipy)(PPh3)Br]
H3C
Ph3P
CH3
Cu
Br
D
[Cu(neocup)PPh3Br]
In connection with our work6 on the development of useful
synthetic methodologies we have observed that heteroarenes,
when treated with 1,1-dibromo-1-alkenes using [Cu(Phen)PPh3Br]
(Fig. 1) (as a catalyst) and Cs2CO3 in DMSO at 80 °C, produced the
corresponding N-alkylnyl derivatives in 3 h (Scheme 1).
E
Figure 1. Cu-complexes used for N-alkynylation of heteroarenes.
Initially the reaction of benzimidazole (1a) with 1,1-dibromo-2-
tolyl alkene (2a) was thoroughly studied using different copper
sources, bases, and solvents (Table 1). Besides the copper source
[Cu(Phen)PPh3Br] the following other Cu-complexes (Fig. 1) were
used to catalyze the reaction. The screening studies showed that
among all the Cu-sources [Cu(Phen)PPh3Br] (A) was most effective
in DMSO using Cs2CO3 as a base (Table 1, entry 8). The conversion
was complete in 3 h and the yield of the N-alkynyl derivative 3a
was 82%. The reaction was conducted at 80 °C. At room tempera-
ture the yield was low even after 12 h. The other Cu-complex E
was also highly effective—using this catalyst and Cs2CO3 in DMSO
the yield of 3a was 76% at 80 °C (entry 11).
q
Part 228 in the series ‘Studies on novel synthetic methodologies’.
⇑
Corresponding author. Tel./fax: +91 40 27160512.
E-mail address: biswanathdas@yahoo.com (B. Das).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.09.117

6498
B. Das et al. / Tetrahedron Letters 52 (2011) 6497–6500
involve in the reaction and remained unchanged. However, alkene
10 mol%
underwent homocoupling8 to produce 1,3-diyne (1,4-diphenyl
but-1,3-diyne) in good yield (67%).
[Cu(phen)(PPh3)Br]
2.0 eq Cs2CO3
A
N
Br
Br
A
B
B
The above N-alkynylation reaction of imidazoles was also suc-
cessfully applied to pyrazoles (Table 2, entries 3n, 3o). The reaction
was complete in 3 h and the corresponding N-alkynyl derivatives
were formed in high yields (68–69%). In each reaction only a single
derivative was formed. The structures of the products were estab-
lished from their spectral (IR, 1H and 13C NMR, and ESIMS) data.
The catalyst, [Cu(Phen)PPh3Br] (A) can easily be prepared9 by
the addition of 1,10-phenantholine to a solution of tris-(triphenyl
phosphine) copper(I) bromide in CHCl3 at room temperature. The
complex is stable in air and soluble in DMSO. It is also economi-
cally favorable compared to the complexes derived from noble
metals.
DMSO (2.0 mL)
80 oC, 3h
R1
N
H
R1=aromatic,
aliphatic
A=N, B=CH
A=CH, B=N
R1
66-85 %
3
1
2
Scheme 1. Copper-catalyzed C–N cross coupling.
The catalytic activity of other Cu-sources was not so impressive.
CuI and Cu2O could not catalyze the conversion under ligand-free
conditions (entries 13 and 14). Different other bases such as
KOH, LiO-t-Bu, and K3PO4 were also used but the yield of 3a was
decreased. Similarly, the other solvents, toluene and 1,4-dioxane
diminished the yield. Thus, it was evident that N-alkylnylation of
benzimidazole (1a) with 1,1-dibromo-2-tolyl alkene (2a) took
place most efficiently in the presence of [Cu(Phen)PPh3Br] (A) as
a catalyst using Cs2CO3 in DMSO at 80 °C and afforded the product
3a in highest yield in 3 h.
Following the above optimized conditions a series of N-alkyny-
limidazoles (3) were prepared. Several substituted imidazoles
including benzimidazole were applied. The imidazoles contained
alkyl groups as well as aryl groups as substituents at different posi-
tions. Both aromatic and aliphatic gem-dibromo alkenes were used.
These compounds were conveniently prepared from the corre-
sponding aldehydes by treatment with CBr4.7 1,1-Dibromo 2-(1-
naphthyl) ethylene was also applied for N-alkynylation. The yields
of N-alkynyl imidazoles were high (66–85%). No side product was
observed and only the starting heteroarenes were recovered.
When an amide such as benzamide was treated with 1,1-dibro-
mo 2-phenyl ethylene under the present conditions amide did not
Table 2
Cu(I) catalyzed N-alkynylation of heteroarenesa,b
10 mol%
[Cu(phen)(PPh3)Br]
2.0 eq Cs2CO3
A
N
Br
Br
A
B
B
DMSO (2.0 mL)
80 oC, 3h
R1
N
H
R1=aromatic,
A=N, B=CH
A=CH, B=N
aliphatic
R1
3
1
2
S. No
Imidazole/pyrazole (1)
R1 (2)
Product (3)
Yieldc (%)
a
b
C6H5
4Me-C6H4
3a
3b
78
82
N
c
d
e
4Cl-C6H4
4F-C6H4
CH3(CH2)5CH2
3c
3d
3e
85
76
75
N
H
N
f
C6H5
C6H5
3f
66
69
N
H
N
Table 1
Screening of Cu(I)-sources, solvents and bases for N-alkynylation of heteroarenesa
g
3g
N
N
H
Cu-Source
N
Br
Base
h
i
C6H5
4Me-C6H4
3h
3i
78
84
N
N
solvent,
N
H
Br
80 oC, 3h
N
H
N
1b
2b
j
C6H5
3j
71
74
N
H
N
S. No
Cu(I)-source
Cu(PPh3)3Br
Base
Solvent
Yieldb (%)
Ph
k
1-Naphthyl
3k
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Cs2CO3
Cs2CO3
KOH
Cs2CO3
Cs2CO3
LiO-t-Bu
K3PO4
Cs2CO3
LiO-t-Bu
K3PO4
Cs2CO3
KOH
Toluene
1,4-Dioxane
1,4-Dioxane
DMSO
1,4-Dioxane
1,4-Dioxane
DMSO
DMSO
DMSO
DMSO
DMSO
61
67
53
63
64
68
57
82
72
69
76
66
0c
N
H
[Cu(Phen)PPh3Br]
[Cu(Phen)PPh3Br]
[Cu(Phen)(PPh3)2]NO3
[Cu(bipy)PPh3Br]
[Cu(bipy)PPh3Br]
[Cu(bipy)PPh3Br]
[Cu(Phen)PPh3Br]
[Cu(Phen)PPh3Br]
[Cu(Phen)PPh3Br]
[Cu(neocup)PPh3Br]
[Cu(neocup)PPh3Br]
CuI
l
m
4Cl-C6H4
CH3(CH2)4CH2
3l
3m
81
72
Ph
N
N
H
N
n
o
C6H5
C6H5
3n
3o
69
68
N
H
DMSO
DMSO
DMSO
DMSO
Cs2CO3
Cs2CO3
Cs2CO3
N
Cu2O
CuI/DMEDA
0c
64
N
H
a
a
Reaction conditions: Benzimidazole (1.0 mmol), 1,1-dibromo-2-tolyl-alkene
Reaction conditions: Imidazole or pyrazole (1.0 mmol), 1,1-dibromo-2-aryl-
(1.2 mmol), Cu source (10 mol %), 2.0 equiv of base, 2.0 mL of solvent at 80 °C for
alkene (1.2 mmol), [Cu(Phen)PPh3Br] (10 mol %), 2.0 equiv of Cs2CO3, 2.0 mL of
3 h.
DMSO at 80 °C for 3 h.
b
b
Isolated yield after column chromatography.
Homocoupling of 1,1-dibromo-2-tolyl-alkene and 1,3-diyne was formed.
Compounds 3b, 3c, 3d, 3e, 3i, 3k, 3l, 3m are unknown.
Isolated yield after chromatography.
c
c

B. Das et al. / Tetrahedron Letters 52 (2011) 6497–6500
6499
A plausible mechanism10 of the present conversion using this
catalyst is shown in Scheme 2. The mechanism involves the (het-
eroaryl) Cu(I) intermediate I and the Cu(III) complex II to yield
the N-alkynyl derivative 3.
In another probable mechanism alkynyl bromides derived from
1,1-dibromo-1-alkenes interact with I to form the complex IV
Though it is reported11 in some cases that alkynyl bromides (de-
rived from the gem-dibromo alkenes by dehydrobromination) re-
quire strong bases and higher temperature, we feel under the
conditions mentioned here the second mechanism (Scheme 3) is
more favorable for the present conversion leading to the alkynylat-
ed products.5c
In conclusion we have developed for the first time an efficient
method12 for direct N-alkynylation of heteroarenes with 1,1-dibro-
mo 1-alkene using [Cu(Phen)PPh3Br] as a cost-effective catalyst.
which subsequently produces the alkynylated derivative
(Scheme 3).
3
The present conversion took place spontaneously and we were
not able to isolate any intermediate. However, to get an idea about
the mechanism of the conversion we carried out two reactions
which are mentioned below.
Acknowledgments
The authors thank CSIR and UGC, New Delhi for the financial
assistance. They are also thankful to NMR, Mass, and IR Divisions
of IICT for spectral recording.
(i) Only 1,1-dibromo-1-alkene (without using an heterocycle)
was applied8 for the conversion under the present reaction
conditions.
present
Br
References and notes
reaction
conditions
Br
1. (a) Reisch, J.; Seeger, U. Arch. Pharm. 1977, 310, 851; (b) Joshi, R. V.; Xu, Z. Q.;
Ksebati, M. B.; Kessel, D.; Corbett, T. H.; Drach, J. C.; Zemlicka, J. J. Chem. Soc.,
Perkin Trans. I 1994, 1089.
2. Brabec, C.; Scharber, M.; Johansson, H.; Comoretto, D.; Dellepiane, G.; Moggio,
I.; Cravino, A.; Hummelen, J. C.; Sariciftci, N. S. Synth. Met. 1999, 101, 298.
3. Isihara, T.; Mantani, T.; Konno, T.; Yamanaka, H. Tetrahedron 2006, 62, 3783.
4. (a) Kitamura, T.; Tashi, N.; Tsuda, K.; Chen, H.; Fujiwara, T. Heterocycles 2000,
52, 303; (b) Brandsma, L.; Mal’kina, A. G.; Trofimov, B. A. Synth. Commun. 1994,
24, 2721; (c) Wei, L.; Mulder, J. A.; Xiong, H.; Zificsak, C. A.; Douglas, C. J.;
Hsung, R. P. Tetrahedron 2001, 57, 459.
5. (a) Laroche, C.; Li, J.; Freyer, M. W.; Ketwin, S. M. J. Org. Chem. 2008, 73, 6462;
(b) Burley, G. A.; Davies, D. L.; Griffith, G. A.; Lee, M.; Sing, K. J. Org. Chem. 2010,
75, 980; (c) Das, B.; Reddy, G. C.; Balasubramanyam, P.; Salvanna, N. Synthesis
2011, 816.
6. (a) Das, B.; Srinivas, Y.; Harish, H.; Krishnaiah, M.; Narendar, R. Chem. Lett.
2007, 36, 1270; (b) Das, B.; Damodar, K.; Bhunia, N. J. Org. Chem. 2009, 74, 5607;
(c) Das, B.; Balasubramanyam, P.; Veeranjaneyulu, B.; Reddy, G. C. J. Org. Chem.
2009, 74, 9505; (d) Das, B.; Reddy, C. R.; Kumar, D. N.; Krishnaiah, M.; Narendar,
R. Synlett 2010, 391; (e) Das, B.; Sudhakar, C.; Srinivas, Y. Synth. Commun. 2010,
40, 2667.
7. Ramirez, F.; Desai, N. B.; McKelvie, N. J. Am. Chem. Soc. 1962, 84, 1745.
8. Shen, W.; Thomas, S. A. Org. Lett. 2000, 2, 2857.
9. Gujadhur, R. K.; Bates, C. G.; Venkataraman, D. Org. Lett. 2001, 3, 4315.
10. Coste, A.; Karthikeyan, G.; Couty, F.; Evano, G. Angew. Chem., Int. Ed. 2009, 48,
4381.
11. (a) Frederick, M. O.; Mulder, J. A.; Tracey, M. R.; Hsung, R. P.; Huang, J.; Kurtz, K.
C. M.; Shen, L.; Douglas, C. J. J. Am. Chem. Soc. 2003, 125, 2368; (b) Zhang, Y.;
Hsung, R. P.; Tracey, M. R.; Kurtz, K. C. M.; Vera, E. L. Org. Lett. 2004, 6, 1151.
12. General experimental procedure for N-alkynylation of imidazole and pyrazole
derivatives: To a solution of 1,1 dibromo alkene 2 (1.0 mmol) in DMSO (2 mL)
(ii) An imidazole was treated5c with bromoacetylene under the
present reaction conditions.
present
N
N
reaction
conditions
N
+
Ph
Br
N
H
1a
3a
Ph
76%
LL1CuBr
N
N
Cs2CO3
N
N
N
H
1
N
LLICuBr
Br
CuLLI
I
R
Cs2CO3
N
Br
R
Br
R
N
Br
3
LL1
R
N
N
2
imidazole (or) pyrazole
1 (1.5 mmol), Cs2CO3 (2.0 equiv), and [Cu(Phen)
Cu
(PPh3)Br] (10 mol %) were added. The mixture was heated on an oil bath at
80 °C for 3 h. The reaction was monitored by TLC. Upon completion, the
mixture was cooled to room temperature and cold H2O (10 mL) was added to
the residue. The mixture was extracted with EtOAc (2 Â 10 mL). The organic
layers were dried (anhydrous Na2SO4) and concentrated in vacuo. The viscous
mass was purified by column chromatography (silica gel, Merck 60–120 mesh,
1–4% EtOAc–hexane) to afford the pure product (3). The unreacted heteroarene
was also recovered.
Br
II
LLICuBr =Cu(Phen)(PPh3)Br
Scheme 2. Probable mechanism of the copper-catalyzed C–N cross coupling.
The spectral data of the unknown products.
Compound 3b. White solid. Mp 83–84 °C; IR: 2255, 1606, 1489, 1452,
catalyzed C-N cross coupling
1283 cmÀ1 1H NMR (200 MHz, CDCl3): d 8.10 (1H, s), 7.81 (1H, d, J = 8.0 Hz),
;
LL1CuBr
N
7.62 (1H, d, J = 8.0 Hz), 7.43 (2H, d, J = 8.0 Hz), 7.33 (2H, d, J = 8.0 Hz), 7.19 (2H,
d, J = 8.0 Hz), 2.41 (3H, s); 13C NMR (50 MHz, CDCl3): d 143.8, 142.2, 139.5,
134.6, 132.0, 129.3, 124.8, 124.1, 121.0, 118.2, 111.1, 75.9, 73.8, 21.5; ESIMS:
m/z 233 [M+H]+; Anal. Calcd for C16H12N2: C, 82.73; H, 5.21; N, 12.06. Found: C,
82.68; H, 5.27; N, 12.10.
Cs2CO3
N
1
H
N
N
LLICuBr
N
N
Compound 3c. Brown solid. Mp 81–83 °C; IR: 2258, 1605, 1490, 1455,
LLICuBr =Cu(Phen)(PPh3)Br
1239 cmÀ1 1H NMR (200 MHz, CDCl3): d 8.11 (1H, s), 7.82 (1H, d, J = 8.0 Hz),
;
7.62 (1H, d, J = 8.0 Hz), 7.49 (2H, d, J = 8.0 Hz), 7.42–7.31 (4H, m); 13C NMR
(50 MHz, CDCl3): d 143.6, 142.2, 135.1, 134.4, 133.0, 129.0, 125.1, 124.2, 121.0,
119.9, 110.8, 73.0, 70.1; ESIMS: m/z 253, 255 [M+H]+; Anal. Calcd for
C15H9N2Cl: C, 71.29; H, 3.59; N, 11.09. Found: C, 71.34; H, 3.52; N, 11.12.
Compound 3d. Yellow solid. Mp 86–87 °C; IR: 2254, 1599, 1492, 1459,
CuLLI
I
Br
R
3
N
Br
R
2
Cs2CO3
Br
N
1230 cmÀ1 1H NMR (200 MHz, CDCl3): d 8.14 (1H, s), 7.84 (1H, d, J = 8.0 Hz),
;
BrCuLLI
7.63 (1H, d, J = 8.0 Hz), 7.59–7.52 (2H, m), 7.48–7.32 (2H, m), 7.17–7.05 (2H,
m); 13C NMR (50 MHz, CDCl3): d 163.1 (d, J = 280.0 Hz), 143.9, 141.9, 133.8,
133.7, 124.9, 124.0, 120.9, 117.2, 115.8 (d, J = 10.0 Hz), 110.9, 76.1, 72.2;
ESIMS: m/z 237 [M+H]+; Anal. Calcd for C15H9N2F: C, 76.26; H, 3.84; N, 11.86.
Found: C, 76.29; H, 3.78; N, 11.79.
R
IV R
Scheme 3. An alternative probable mechanism of the copper-catalyzed C–N cross
Compound 3e. Yellow oil; IR: 2270, 1613, 1496, 1460, 1225 cmÀ1 1H NMR
;
(200 MHz, CDCl3): d 7.98 (1H, s), 7.75 (1H, d, J = 8.0 Hz), 7.50 (1H, d, J = 8.0 Hz),
coupling.

6500
B. Das et al. / Tetrahedron Letters 52 (2011) 6497–6500
7.35–7.23 (2H, m), 2.43 (2H, t, J = 7.0 Hz), 1.69–1.61 (2H, m), 1.51–1.42 (2H, m),
NMR (200 MHz, CDCl3): d 8.20–8.10 (3H, m), 7.83 (2H, t, J = 8.0 Hz), 7.66 (1H, d,
J = 8.0 Hz), 7.52–7.40 (6H, m), 7.38 (1H, br s), 7.17 (1H, br s); 13C NMR (50 MHz,
CDCl3): d 138.2, 135.9, 133.1, 130.5, 129.9, 129.1, 129.0, 128.7, 128.3, 127.1,
126.3, 126.2, 125.5, 125.1, 123.8, 122.2, 70.9, 69.6; ESIMS: m/z 295 [M+H]+;
Anal. Calcd for C21H14N2: C, 85.69; H, 4.79; N, 9.52. Found: C, 85.73; H, 4.81; N,
9.56.
1.39–1.22 (6H, m), 0.98 (3H, t, J = 7.0 Hz); 13C NMR (50 MHz, CDCl3): d 144.0,
142.2, 135.1, 124.5, 123.9, 121.0, 110.9, 73.3, 68.8, 31.9, 29.0, 28.9, 28.8, 22.9,
18.8, 14.2; ESIMS: m/z 241 [M+H]+; Anal. Calcd for C16H20N2: C, 79.96; H, 8.39;
N, 11.66. Found: C, 79.89; H, 8.47; N, 11.73.
Compound 3i. Brown oil; IR: 2257, 1498, 1428, 1376, 1256 cmÀ1 1H NMR
;
(200 MHz, CDCl3): d 7.34 (2H, d, J = 8.0 Hz), 7.13 (2H, d, J = 8.0 Hz), 7.02 (1H, br
s), 6.88 (1H, br s), 3.29 (1H, m), 2.39 (3H, s), 1.40 (6H, d, J = 7.0 Hz); 13C NMR
(50 MHz, CDCl3): d 143.4, 134.4, 130.5, 129.2, 128.3, 127.1, 121.2, 78.1, 72.6,
27.0, 21.5, 20.8; ESIMS: m/z 225 [M+H]+; Anal. Calcd for C15H16N2: C, 80.32; H,
7.19; N, 12.49. Found: C, 80.27; H, 7.15; N, 12.54.
Compound 3l. Yellow solid. Mp 182–184 °C; IR: 2259, 1593, 1482, 1411,
1145 cmÀ1 1H NMR (200 MHz, CDCl3): d 7.81 (1H, s), 7.72 (2H, d, J = 8.0 Hz),
;
7.48–7.32 (7H, m), 7.23 (1H, t, J = 8.0 Hz); 13C NMR (50 MHz, CDCl3): d 142.3,
140.1, 135.2, 132.8, 132.7, 129.1, 128.9, 127.9, 125.2, 119.8, 116.8, 78.9, 70.0;
ESIMS: m/z 279, 281 [M+H]+; ESIMS: m/z 295 [M+H]+; Anal. Calcd for
Compound 3k. Brown oil; IR: 2254, 1506, 1473, 1434, 1384, 1287 cmÀ1
;
1H
C17H11N2Cl: C, 73.25; H, 3.98; N, 10.05. Found: C, 73.21; H, 3.93; N, 10.09.