Alkenyl bromides: useful coupling partners for the palladium-catalysed coupling with heteroaromatics via a C-H bond activation

Article abstract of DOI:10.1016/j.tetlet.2008.03.020

Alkenyl bromides were found to be useful reactants for the palladium-catalysed direct C-H activation/functionalisation reaction of heteroaromatics such as benzoxazole or benzothiazole. Moderate to good yields of coupling products were obtained using both α- and β-substituted alkenyl bromides or even the trisubstituted alkenyl bromide 2-bromo-3-methylbut-2-ene. This reaction is environmentally attractive as it provides only HX associated to the base as a by-product.

Full text of DOI:10.1016/j.tetlet.2008.03.020

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2926–2930
Alkenyl bromides: useful coupling partners for the
palladium-catalysed coupling with heteroaromatics
via a C–H bond activation
Aditya L. Gottumukkala a, Fazia Derridj b, Safia Djebbar b, Henri Doucet a,*
a Institut Sciences Chimiques de Rennes, UMR 6226 CNRS-Universite´ de Rennes ‘Catalyse et Organometalliques’,
Campus de Beaulieu, 35042 Rennes, France
b Laboratoire d’hydrome´tallurgie et chimie inorganique mole´culaire, Faculte´ de Chimie, U.S.T.H.B. Bab-Ezzouar, Algeria
Received 18 January 2008; revised 29 February 2008; accepted 5 March 2008
Available online 8 March 2008
Abstract
Alkenyl bromides were found to be useful reactants for the palladium-catalysed direct C–H activation/functionalisation reaction of
heteroaromatics such as benzoxazole or benzothiazole. Moderate to good yields of coupling products were obtained using both a- and
b-substituted alkenyl bromides or even the trisubstituted alkenyl bromide 2-bromo-3-methylbut-2-ene. This reaction is environmentally
attractive as it provides only HX associated to the base as a by-product.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: C–H bond activation; Vinyl halides; Palladium; Catalysis; Benzoxazole
The palladium-catalysed alkenylation reaction of
heteroaromatics is one of the most powerful methods for
the preparation of alkenyl-substituted heteroarenes.1 The
efficiency of several methods such as palladium or nickel
catalysed Stille,2 Negishi,3 Kumada4 or Suzuki5 cross-
couplings for the reaction of alkenyl halides with
thiophenes, furans, thiazoles or oxazoles has been
described. However, these reactions require the prior
preparation of an organometallic derivative of a hetero-
aromatic, and provide an organometallic salt (MX) as a
by-product (Scheme 1).
R'
+
R'
+
X
X
B
B
[Pd]
[Pd] or [Ni]
RMX
B
B
B
B
R'
A
HX
MR
H
A
A
X = I, Br, Cl
A = O, S or NR''
B = C or N
M = Zn, Mg, Sn or B
Scheme 1.
Since a few years, a new palladium-catalysed procedure
for the functionalisation of heteroaromatics has emerged.
It consists in directly functionalising the heteroaromatics
via a C–H bond activation of the heteroarene. This proce-
dure proceeds nicely for the coupling of several heteroaro-
matics with aryl or heteroaryl iodides, bromides and
chlorides, or even triflates.6–13 For such couplings, no prep-
aration of an organometallic derivative is required. More-
over, this reaction provides only HX associated to a base,
instead of a metallic salt as a by-product and therefore is
very interesting in terms of both atom-economy and non-
toxic wastes (Scheme 1). However, so far, most of the
results for this reaction were obtained with aryl halides
or triflates. To our knowledge, only a few results employing
other functionalisation reactants have been described. For
example, the synthesis of a range of pyrroloquinolines via
*
Corresponding author. Tel.: +33 2 23 23 63 84; fax: +33 2 23 23 69 39.
E-mail address: henri.doucet@univ-rennes1.fr (H. Doucet).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.020

A. L. Gottumukkala et al. / Tetrahedron Letters 49 (2008) 2926–2930
2927
R2
R2
R3
N
Br
PdCl(C3H5)(dppb)
R3
N
O
+
R1
DMF, Cs2CO3, 80-140 °C
O
R1
1-6
Scheme 2.
C–H bond activation/functionalisation using norborn-
adiene was described by Hulcoop and Lautens employing
Pd(OAc)2/PPh3 as the catalytic system.14 Recently, Ma
and co-workers described the direct 3-allylation of indole
derivatives with electron-deficient allyl acetates in the pres-
ence of Pd(dba)2/2,20-bipyridine as the catalyst.15 The palla-
dium-catalysed direct alkynylation of N-fused heterocycles
using terminal alkynes has also been reported recently.16
The extension of heteroaromatic C–H bond activation/
functionalisation procedure to a wider diversity of sub-
strates both at the laboratory scale and in the industry
would be a considerable advantage for sustainable develop-
ment because of the lower cost, lower mass and the wider
diversity of reactants, as well as for the treatment of the
relatively nontoxic waste.
herein report on the coupling of a- or b-substituted alkenyl
bromides with benzoxazole, benzothiazole or 2-n-propyl-
thiazole. A simple access to 2-alkenyloxazole or thiazole
derivatives would be useful due to their anticancer, anti-
HIV or antimicrobial properties.17
For this study, based on the previous results,11,12
DMF or DMAc was chosen as the solvent and K2CO3,
Cs2CO3 or KOAc as the base. The reactions were con-
ducted at 80–140 °C under argon in the presence of
PdCl(C3H5)(dppb)18 as the catalyst. For low boiling point
alkenyl bromides, the reactions were performed in auto-
claves. The reactions were performed using 2 equiv of
heterocyclic coupling partner, due to partial decomposi-
tion of these substrates at elevated temperatures. How-
ever, in most cases, a large amount of these substrates
was recovered unreacted allowing to perform these
reactions with a smaller excess of the reactant.
In order to further extend the scope of the functionali-
sation of heteroaromatics via C–H bond activation, we
Table 1
Direct arylations of alkenyl bromides with benzoxazole catalysed by PdCl(C3H5)(dppb) complex (Scheme 2)20,21
Entry
Alkenyl bromide
Reaction temp (°C)
Product
Yielda (%)
100 (61)
N
O
1
100
b
Br
1
N
O
N
O
2
3
4
140
140
140
77 (54)c
64 (47)c
68 (58)c
Br
Br
2
3
N
O
Br
Br
4
N
O
5
140
73 (51)c
5
N
O
N
O
6
7
140
80
87 (55 of 6b)c
Br
d
Z: 6a and E: 6b
50c
Conditions: catalyst PdCl(C3H5)(dppb) (0.05 equiv), see Ref. 18, alkenyl bromide (1 equiv), benzoxazole (2 equiv), Cs2CO3 (2 equiv), DMF, 20 h, under
argon, GC and NMR yields.
a
Yields in parentheses correspond to isolated yields.
Ratio of stereoisomers Z/E: 9/91.
Reaction performed in autoclave, 4% of 6a was also observed in GC/MS and NMR of the crude mixture.
Ratio of stereoisomers Z/E: 50/50.
b
c
d

2928
A. L. Gottumukkala et al. / Tetrahedron Letters 49 (2008) 2926–2930
R2
R2
R3
N
Br
PdCl(C3H5)(dppb)
R3
N
S
+
R1
DMF, Cs2CO3, 100-140 °C
S
R1
7-11
Scheme 3.
In order to determine the most suitable reaction condi-
tions for this reaction, we studied the reactivity of benzox-
azole with b-bromostyrene in the presence of 5 mol %
PdCl(C3H5)(dppb) using various bases and solvents
(Scheme 2 and Table 1). Employing K2CO3 as the base
and DMF as the solvent at 100 °C, the expected product
1 was not observed. Using KOAc under similar conditions,
1 was obtained in a very low yield. The most suitable base
appears to be Cs2CO3. With this base, using DMF at
100 °C as reaction conditions, 1 was obtained selectively
in 61% isolated yield. At a slightly higher temperature
(120 °C), the dimerisation of b-bromostyrene was observed
in relatively large amounts, especially when traces of oxygen
were present in the reaction mixture. On the other hand, at
80 °C relatively low yields of product 1 were obtained due to
moderate conversion of b-bromostyrene. DMAc as the
solvent gave a mixture of 1 and b-bromostyrene dimers.
Several other catalytic systems such as Pd(OAc)2, or
[PdCl(C3H5)]2 associated to PPh3, dppe or in the absence
of ligand have been employed for this reaction, using
Cs2CO3 as the base in DMF at 100 °C. However, they led
to very low to moderate yields of 1. A yield of 39% was
obtained using Pd(OAc)2 in the presence of dppb.
Then, using the most suitable reaction conditions
(DMF, Cs2CO3 and PdCl(C3H5)(dppb)), we examined
the scope and limitation of the reaction using various
mono-, bi- or trisubstituted alkenyl bromides (Scheme 2
and Table 1).
b-Disubstituted alkenyl bromide: 1-bromo-2-methyl-
prop-1-ene gave the coupling product 2. However, a higher
reaction temperature (140 °C) was required in order to
obtain a high conversion (77%) of 1-bromo-2-methyl-
prop-1-ene and a moderate isolated yield of 2 (54%) (Table
1, entry 2). The a-substituted alkenyl bromides: 2-bromo-
but-1-ene and 2-bromoprop-1-ene gave 3 and 4 in 47 and
58% yields, respectively, revealing a low influence of the
substituent position on alkenyl bromides on the yields
(Table 1, entries 3 and 4). These results were confirmed
using the a- and b-substituted alkenyl bromide: 2-bromo-
3-methylbut-2-ene, which gave 5 in a similar yield of 51%
(Table 1, entry 5). We also studied the reactivity of a mix-
ture of (Z)- and (E)-2-bromobut-1-ene (50/50) (Table 1,
entries 6 and 7). Coupling product 6b was selectively
obtained in 55% yield. The formation of 4% of the other
stereoisomer 6a was also observed. A small amount of
the starting material 2-bromobut-2-ene in a ratio 69/31 of
Table 2
Direct arylations of alkenyl bromides with benzothiazole catalysed by PdCl(C3H5)(dppb) complex (Scheme 3)20,21
Entry
Alkenyl bromide
Reaction temp (°C)
Product
Yielda (%)
100 (69)
N
1
100
b
Br
S
N
7
2
3
140
140
53 (47)c
46 (32)c
Br
Br
S
N
8
S
9
N
S
4
5
120
120
67 (58)
Br
10
N
S
N
S
35 (27) (ratio Z: 11a/E: 11b 9/91)19
+
Br
d
Z: 11a and E: 11b
Conditions: catalyst PdCl(C3H5)(dppb) (0.05 equiv), see Ref. 18, alkenyl bromide (1 equiv), benzothiazole (2 equiv), Cs2CO3 (2 equiv), DMF, 20 h, under
argon, GC and NMR yields.
a
Yields in parentheses correspond to isolated yields.
Ratio of stereoisomers Z/E: 9/91.
Reaction performed in autoclave.
Ratio of stereoisomers Z/E: 50/50.
b
c
d

A. L. Gottumukkala et al. / Tetrahedron Letters 49 (2008) 2926–2930
2929
Z/E stereoisomers was also recovered unreacted. These
Acknowledgements
results indicate that there is apparently some isomerisation
of the alkenyl double bond in the course of the reaction,
and that both (Z)- and (E)-2-bromobut-1-ene can be con-
verted to 6b. (E) stereoisomer appears to be slightly more
reactive than the (Z)-2-bromobut-1-ene.
A.G. is grateful to EGIDE for a Grant. We thank the
Centre National de la Recherche Scientifique and ‘Rennes
Metropole’ for providing financial support.
Next, we examined the reactivity of benzothiazole
(Scheme 3 and Table 2). The coupling with b-bromo-
styrene, 2-bromobut-1-ene, 2-bromoprop-1-ene or 2-
bromo-3-methylbut-2-ene led selectively to the target
products 7–10 in moderate to good yields (Table 2, entries
1–4). (Z)- and (E)-2-Bromobut-1-ene (ratio 50/50) led to a
9/91 mixture of 11a and 11b (Table 2, entry 5). It should be
noted that for most of these reactions, no side products
were formed. The moderate yields of some reactions arise
mostly from incomplete conversions of the alkenyl
bromides. Therefore, on a large scale, the recycling of
unreacted alkenyl bromides should be possible.
Finally, we performed the selective 5-alkenylation of
2-n-propylthiazole using 2-bromo-3-methylbut-2-ene. This
heteroarene was found to be slightly less reactive than
benzoxazole or benzothiazole. The reaction gave product
12 in 36% isolated yield (Scheme 4). For this reaction,
48% of 2-bromo-3-methylbut-2-ene was recovered
unreacted.
References and notes
1. Li, J. J.; Gribble, G. W. Palladium in Heterocyclic Chemistry;
Pergamon: Amsterdam, 2000.
2. For examples of arylation of alkenyl halides with heteroaromatics via
Stille coupling: (a) Rossi, R.; Carpita, A.; Ciofalo, M.; Lippolis, V.
Tetrahedron 1991, 47, 8443; (b) Nicolaou, K. C.; He, Y.; Roschangar,
F.; King, N. P.; Vourloumis, D.; Li, T. Angew. Chem., Int. Ed. 1998,
37, 84; (c) Beccalli, E. M.; Clerici, F.; Gelmi, M. L. Tetrahedron 1999,
55, 781; (d) Edvardsen, K. R.; Benneche, T. J. Org. Chem. 2000, 65,
3085; (e) Roethle, P. A.; Trauner, D. Org. Lett. 2006, 8, 345; (f) Tang,
B.; Bray, C. D.; Pattenden, G. Tetrahedron Lett. 2006, 47, 6401; (g)
Deska, J.; Kazmaier, U. Angew. Chem., Int. Ed. 2007, 46, 4570.
3. For examples of arylation of alkenyl halides with heteroaromatics via
Negishi coupling: (a) Tius, M. A.; Trehan, S. J. Org. Chem. 1986, 51,
765; (b) Ennis, D. S.; Gilchrist, T. L. Tetrahedron Lett. 1989, 30, 3735;
(c) Paterson, I.; Gardner, M. Tetrahedron 1989, 45, 5283; (d) Bellina,
F.; Carpita, A.; De Santi, M.; Rossi, R. Tetrahedron Lett. 1994, 35,
6913; (e) Crowe, E.; Hossner, F.; Hughes, M. J. Tetrahedron 1995, 51,
8889; (f) Prasad, A. S. B.; Stevenson, T. M.; Citineni, J. R.; Nyzam,
V.; Knochel, P. Tetrahedron 1997, 53, 7237; (g) Vicart, N.; Castet-
´
Caillabet, D.; Ramondenc, Y.; Ple, G.; Duhamel, L. Synlett 1998,
In summary, the functionalisation of heteroaromatics
via C–H bond activation is not limited to the use of aryl
halides or triflates. We have demonstrated, for the first time
to our knowledge, that alkenyl halides are also useful cou-
pling partners in C–H bond activation. In the presence of
PdCl(C3H5)(dppb), the reaction of the electron-rich hetero-
aromatic derivatives benzoxazole, benzothiazole or 2-n-
propylthiazole with alkenyl bromides led to the coupling
products in low to relatively high yields. Both a- and b-
substituted alkenyl bromides have been employed success-
fully. Even a trisubstituted alkenyl bromide gave the
expected coupling product. For this reason, this method
is applicable to the coupling of a wide variety of alkenyl
bromides. It should be noted that, despite their interest,
most of the products prepared by this method are new,
indicating a relatively limited access to such compounds
using more traditional cross-coupling procedures. More-
over, due to environmental reasons, the advantage of such
atom-economy and nontoxic wastes procedure, (formation
of CsBr and CO2 as side products) should become increas-
ingly important for industrial processes. The extension of
this procedure to other heterocycles such as furans or thio-
phenes and mechanistic studies are currently under investi-
gation, and will be reported in due course.
411; (h) Herz, H.-G.; Queiroz, M. J. R. P.; Maas, G. Synthesis 1999,
1013; (i) Villiers, P.; Vicart, N.; Ramondenc, Y.; Ple´, G. Eur. J. Org.
Chem. 2001, 561; (j) Shi, J.-c.; Negishi, E.-i. J. Organomet. Chem.
2003, 687, 518.
4. For examples of arylation of alkenyl halides with heteroaromatics via
Kumada coupling: (a) Tamao, K.; Kodama, S.; Nakajima, I.;
Kumada, M. Tetrahedron 1982, 38, 3347; (b) Minato, A.; Suzuki,
K.; Tamao, K.; Kumada, M. Tetrahedron Lett. 1984, 25, 83; (c)
Babudri, F.; Fiandanese, V.; Mazzone, L.; Naso, F. Tetrahedron Lett.
1994, 35, 8847.
5. For examples of arylation of alkenyl halides with heteroaromatics via
Suzuki coupling: (a) Silva, N. O.; Abreu, A. S.; Ferreira, P. M. T.;
Monteiro, L. S.; Queiroz, M.-J R. P. Eur. J. Org. Chem. 2002, 2524;
(b) Berthiol, F.; Doucet, H.; Santelli, M. Eur. J. Org. Chem. 2003,
1091; (c) Huang, Q.; Fazio, A.; Dai, G.; Campo, M. A.; Larock, R. C.
J. Am. Chem. Soc. 2004, 126, 7460.
6. Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. Rev. 2002, 102, 1731.
7. Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174.
8. Satoh, T.; Miura, M. Chem. Lett. 2007, 36, 200.
9. Doucet, H.; Hierso, J. C. Curr. Opin. Drug Discovery Dev. 2007, 10,
672.
10. Campeau, L.-C.; Stuart, D. R.; Fagnou, K. Aldrichim. Acta 2007, 40,
35.
11. (a) Battace, A.; Lemhadri, M.; Zair, T.; Doucet, H.; Santelli, M.
Organometallics 2007, 26, 472; (b) Battace, A.; Lemhadri, M.; Zair,
T.; Doucet, H.; Santelli, M. Adv. Synth. Catal. 2007, 349, 2507.
12. (a) Gottumukkala, A. L.; Doucet, H. Eur. J. Inorg. Chem. 2007, 3626;
(b) Derridj, F.; Djebbar, S.; Benali-Baitich, O.; Doucet, H. J.
Organomet. Chem. 2008, 693, 135.
13. Roger, J.; Doucet, H. Org. Biomol. Chem. 2008, 6, 169.
14. Hulcoop, D. G.; Lautens, M. Org. Lett. 2007, 9, 1761.
15. Ma, S.; Yu, S.; Peng, Z.; Guo, H. J. Org. Chem. 2006, 71, 9865.
16. Seregin, I. V.; Ryabova, V.; Gevorgyan, V. J. Am. Chem. Soc. 2007,
129, 7742.
17. (a) Okamura, N.; Suemoto, T.; Shimadzu, H.; Suzuki, M.; Shiomitsu,
T.; Akatsu, H.; Yamamoto, T.; Staufenbiel, M.; Yanai, K.; Arai, H.;
Sasaki, H.; Kudo, Y.; Sawada, T. J. Neurosci. 2004, 24, 2535; (b)
Rida, S. M.; Ashour, F. A.; El-Hawash, S. A. M.; Elsemary, M. M.;
N
Br
PdCl(C3H5)(dppb)
N
+
S
DMF, Cs2CO3, 120 °C
nPr
S
nPr
36%
12
Scheme 4.

2930
A. L. Gottumukkala et al. / Tetrahedron Letters 49 (2008) 2926–2930
Badr, M. H.; Shalaby, M. A. Eur. J. Med. Chem. 2005, 40, 949; (c)
21. All new compounds gave satisfactory 1H, 13C and elementary
analysis. 1H NMR (200 MHz, CDCl3) of new compounds: 2 d 7.72
(m, 1H), 7.51 (m, 1H), 7.31 (m, 2H), 6.28 (s, 1H), 2.38 (s, 3H), 2.07 (s,
3H); 3 d 7.74 (m, 1H), 7.53 (m, 1H), 7.33 (m, 2H), 6.30 (s, 1H), 5.62 (s,
1H), 2.71 (q, J = 7.4 Hz, 2H), 1.30 (t, J = 7.4 Hz, 3H); 4 d 7.75 (m,
1H), 7.54 (m, 1H), 7.33 (m, 2H), 6.27 (s, 1H), 5.63 (s, 1H), 2.31 (s,
3H); 5 d 7.73 (m, 1H), 7.53 (m, 1H), 7.33 (m, 2H), 2.28 (s, 3H), 2.21 (s,
3H), 2.00 (s, 3H); 6b d 7.73 (m, 1H), 7.50 (m, 1H), 7.31 (m, 2H), 6.96
(qq, J = 7.0 and 1.2 Hz, 1H), 2.21 (s, 3H), 1.95 (d, J = 7.0 Hz, 3H); 8
Vinsova, J.; Cermakova, K.; Tomeckova, A.; Ceckova, M.; Jampilek,
J.; Cermak, P.; Kunes, J.; Dolezal, M.; Staud, F. Bioorg. Med. Chem.
2006, 14, 5850.
´
18. Cantat, T.; Genin, E.; Giroud, C.; Meyer, G.; Jutand, A. J.
Organomet. Chem. 2003, 687, 365.
19. Florio, S.; Ingrosso, G.; Ronzini, L.; Epifani, E. Tetrahedron 1991, 47,
3365.
20. As a typical experiment (Table 1, entry 1), the reaction of b-
bromostyrene (0.183 g, 1 mmol), benzoxazole (0.238 g, 2 mmol) and
Cs2CO3 (0.652 g, 2 mmol) at 100 °C over 20 h in dry DMF (10 mL) in
the presence of PdCl(C3H5)(dppb) complex (0.05 mmol) under argon
afforded the corresponding product 1 after evaporation and filtration
on silica gel in 61% (0.135 g) isolated yield. 1H NMR (200 MHz,
CDCl3) d 7.81 (d, J = 16.5 Hz, 1H), 7.73 (m, 1H), 7.68–7.47 (m, 3H),
7.46–7.30 (m, 5H), 7.10 (d, J = 16.5 Hz, 1H); 13C NMR (50 MHz,
CDCl3) d 162.6, 150.2, 142.0, 139.3, 135.0, 129.6, 128.8, 127.4, 125.1,
124.4, 119.7, 113.8, 110.2.
d
8.04 (d, J = 8.3 Hz, 1H), 7.87 (d, J = 8.3 Hz, 1H), 7.48 (t,
J = 7.5 Hz, 1H), 7.38 (t, J = 7.5 Hz, 1H), 5.99 (s, 1H), 5.52 (s, 1H),
2.79 (q, J = 7.4 Hz, 2H), 1.27 (t, J = 7.4 Hz, 3H); 9 d 8.04 (d,
J = 8.3 Hz, 1H), 7.86 (d, J = 8.3 Hz, 1H), 7.48 (t, J = 7.5 Hz, 1H),
7.38 (t, J = 7.5 Hz, 1H), 5.98 (s, 1H), 5.55 (s, 1H), 2.36 (s, 3H); 10 d
8.03 (d, J = 8.3 Hz, 1H), 7.88 (d, J = 8.3 Hz, 1H), 7.48 (t, J = 7.5 Hz,
1H), 7.38 (t, J = 7.5 Hz, 1H), 2.20 (s, 3H), 2.06 (s, 3H), 1.96 (s, 3H);
12 d 7.34 (s, 1H), 2.94 (t, J = 7.4 Hz, 2H), 2.00 (s, 3H), 1.87 (sext.,
J = 7.4 Hz, 2H), 1.84 (s, 3H), 1.82 (s, 3H), 1.05 (t, J = 7.4 Hz, 3H).