Palladium catalyzed one-pot sequential Suzuki cross-coupling-direct C-H functionalization of imidazo[1,2- a ]pyrazines

Article abstract of DOI:10.1021/ol3029059

An efficient one-pot selective functionalization at C3/C6 of imidazo[1,2-a]pyrazines has been developed via a palladium-catalyzed sequential Suzuki-Miyaura cross-coupling/direct C-H arylation, vinylation, and benzylation. The procedure remains effective in the presence of a methyl thioether group at C8, which may in turn be successfully engaged in a cross-coupling method to afford 3,6,8-trisubstituted imidazo[1,2-a]pyrazines. This work paves the way for the design of biologically relevant compounds in an imidazo[1,2-a]pyrazine series.

Full text of DOI:10.1021/ol3029059

ORGANIC
LETTERS
2012
Vol. 14, No. 23
6012–6015
Palladium Catalyzed One-Pot Sequential
Suzuki Cross-CouplingÀDirect CÀH
Functionalization of Imidazo[1,2‑a]pyrazines
Vincent Gembus,*,†,‡ Jean-Franc-ois Bonfanti,§ Olivier Querolle,§ Philippe Jubault,†,‡
Vincent Levacher,† and Christophe Hoarau*,†,
ꢀ
CNRS UMR 6014 “COBRA” & FR 3038 “INC3M”, Universite de Rouen,
1 rue Tesniere, 76821 Mont St Aignan Cedex, France, INSA de Rouen,
ꢁ
ꢀ
Avenue de l’Universite, 76800 St Etienne du Rouvray, France, and JANSSEN Research
and Development, Medicinal Chemistry Department, Campus de Maigremont,
BP 615 27106 Val de Reuil Cedex, France
vincent.gembus@insa-rouen.fr; christophe.hoarau@insa-rouen.fr
Received October 22, 2012
ABSTRACT
An efficient “one-pot” selective functionalization at C3/C6 of imidazo[1,2-a]pyrazines has been developed via a palladium-catalyzed sequential
SuzukiÀMiyaura cross-coupling/direct CÀH arylation, vinylation, and benzylation. The procedure remains effective in the presence of a methyl
thioether group at C8, which may in turn be successfully engaged in a cross-coupling method to afford 3,6,8-trisubstituted imidazo[1,2-a]-
pyrazines. This work paves the way for the design of biologically relevant compounds in an imidazo[1,2-a]pyrazine series.
One of the most important challenges in organic synth-
esis is to synthesize efficiently complex molecular struc-
tures from trivial compounds. Thus, the development
of multistep sequences in a single flask, such as tandem,
cascade, or sequential reactions, has been the focus of
much attention in the organic chemistry community.1 A
number of advantages of these processes are extremely
attractive for synthetic chemists and pharmaceutical com-
panies, such as the reduction of cost, time, and waste. One
of the most appealing aspects of this strategy is to produce
a large molecular diversity and to introduce a wide degree
of complexity in a single transformation. In this context,
transition-metal-catalyzed CÀH bond activation has re-
cently emerged as a powerful tool that may be advanta-
geously associated with more commonplace cross-coupling
methods to develop one-pot sequential functionalization
of various relevant fused heterocycles.
The imidazo[1,2-a]pyrazine is an important pharmaco-
phore prevalent in a number of biologically active mole-
cules,2 such as acid pump antagonists,2c kinase aurora
(2) For selected examples, see: (a) Sablayrolles, C.; Cros, G.; Milhavet,
J.-C.; Rechenq, E.; Chapat, J.-P.; Boucard, M.; Serrano, J. J.; McNeill,
J. H. J. Med. Chem. 1984, 27, 206–212. (b) Shimokawa, H.; Yamagishi, T.
(Pfizer Inc.). PCT Int. Appl. WO/2008/059373A1, 2008; AN 2008:607625.
(c) Zimmermann, P. J.; Brehm, C.; Buhr, W.; Palmer, A. M.; Volz, J.; Simon,
W.-A. Bioorg. Med. Chem. 2008, 16, 536–541. (d) Ken-Ichi, K.; Hiroshi, Y.;
Kohei, N.; Hiroshi, H.; Genta, T.; Jun, S.; Yuusuke, T.; Yasunori, M.
(Oncotherapy Science, Inc.). US/2012/0059162A1, 2012; AN 2012:346056.
(e) Belanger, D. B.; Curran, P. J.; Hruza, A.; Voigt, J.; Meng, Z.; Mandal, A. K.;
Siddiqui, M. A.; Basso, A. D.; Gray, K. Bioorg. Med. Chem. Lett. 2010, 20,
† CNRS UMR 6014 COBRA.
‡ Insa de Rouen.
§ Janssen Research and Development.
ꢀ
Universite de Rouen.
(1) For general references, see: (a) Tietze, L. F.; Brasche, G.; Gericke,
K. Domino Reactions in Organic Synthesis; Wiley-VCH: Weinheim, 2006.
(b) Nicolaou, K. C.; Montagnon, T.; Snyder, S. A. Chem. Commun. 2003,
551–564. (c) Padwa, A. Pure Appl. Chem. 2004, 76, 1933–1952. (d) Wu,
G.; Yin, W.; Shen, H. C.; Huang, Y. Green Chem. 2012, 14, 580–585.
ꢀ
5170–5174. (f) Bartolome-Nebreda, J. M.; Conde-Ceide, S.; Macdonald,
G. J.; Pastor-Fernandez, J.; Van Gool, M. L.; Martin-Martin, M. L.;
Vanhoof, G. C. (Janssen Pharmaceutica NV). WO/2011/110545A1, 2011;
AN 2011:1164004.
r
10.1021/ol3029059
Published on Web 11/14/2012
2012 American Chemical Society

inhibitors,2e and phosphodiesterase inhibitors.2f Several
procedures for transition-metal-catalyzed direct CÀH fun-
ctionalization of imidazoazines have been developed, notably
in the imidazo[1,2-a]pyridine3 and imidazo[1,2-a]pyrimidine4
series. Remarkably, Guillaumet et al. have described the
first sequential functionalization of imidazo[1,2-a]pyridines
by implementing SuzukiÀMiyaura and direct CÀH cross-
coupling reactions.3b However, the imidazo[1,2-a]pyrazine
series remains almost unexplored since only one paper
reporting on the palladium-catalyzed direct CÀH aryla-
tion at C3 of the naked imidazo[1,2-a]pyrazine skeleton
with iodobenzene was recently disclosed by Chatani.5 Among
the available imidazo[1,2-a]pyrazine scaffolds, the readily
prepared 6-bromoimidazo[1,2-a]pyrazine flanked with a
methyl ether (1a) or a methyl thioether (1b) group at C8
position6 represent attractive candidates for sequential
coupling reactions.3b,7 Herein, we report an efficient proce-
dure for the sequential functionalization of 6-bromoimidazo-
[1,2-a]pyrazine 1a and 1b at C3/C6 positions through a
palladium-catalyzed one-pot SuzukiÀMiyauraÀdirect CH
cross-coupling sequence. To the best of our knowledge, this
work constitutes one of the rare successful palladium-
catalyzed direct CÀH functionalization conducted in the
presence of a sulfide group8 which could act as a poison of
palladium catalyst.9
within 3 h, and the expected 6-phenylimidazopyrazine 2a
was further isolated in quantitative yield (entry 1). The first
sequential selective C6-Br/C3-H double arylation was then
carried out by simply adding bromobenzene in the wake of
the initial SuzukiÀMiyaura cross-coupling reaction. The
resulting reaction mixture was then stirred for a further
18h whileraising the temperatureto120 °C. Pleasingly, the
expected diarylated imidazopyrazine 3aa was obtained in
fairly good 67% isolated yield (entry 2), along with a 20%
yield of the monoarylated intermediate 2a. This prelimin-
ary result is all the more interesting as no further addition
of palladium catalyst is required for the subsequent C3-H
functionalization step.
Table 1. Optimization of Reaction Conditionsa
entry
ligand
PPh3
base
yieldc (%) of 1a/2a/3aa
1b
2
3
4
5
6
7
8
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
0/99/0
Our study was initiated with the SuzukiÀMiyaura cou-
pling reaction between 1a and phenylboronic acid under a
palladium-based catalysis in the presence of Pd(OAc)2/
PPh3 and Cs2CO3 base in dioxane at 90 °C (Table 1). These
conditions previously proved to be effective in the direct
C3-H arylation of imidazoazines.4a The complete conver-
sion of the reaction (monitoring by GCÀMS) was attained
PPh3
0/20/67
Po-Tol3
0/50/47
PtBu3 HBF4
0/20/66
3
PCy3 HBF4
0/70/20
3
CyJohnPhos
CyJohnPhose
CyJohnPhose
0/0/99 (95)d
0/0/87 (85)d
0/23/68 (63)d
a Reaction conditions: A mixture of 10 mol % of Pd source, 20 mol %
of phosphine ligand, 0.2 mmol of 1a, 1 equiv of PhB(OH)2, and 5 equiv
of base in 1 mL of dioxane was heated to 90 °C for 3 h, and then 1.5 equiv
of bromobenzene was added and the resulting mixture was heated to
120 °C for a further 18 h. b 10 mol % of Pd source, 20 mol % of phos-
phine ligand, 0.2 mmol of 1a, 1 equiv of PhB(OH)2, 5 equiv of base, 1 mL
of solvent, 90 °C. c Yields determinated by NMR and GC analysis with
internal standard. d Isolated yields of 3aa. e 5 mol % of Pd source and
10 mol % of ligand were used.
ꢀ
(3) (a) Toure, R. B.; Lane, B. S.; Sames, D. Org. Lett. 2006, 8, 1979–
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Mouaddib, A.; Guillaumet, G. Synthesis 2009, 271–276. (e) Singhaus,
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H. Y.; Chen, L.; Doucet, H. J. Org. Chem. 2012, 77, 4473–4478.
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1365.
A survey of different phosphines (entries 3À6) revealed
that 2-(dicyclohexylphosphino)biphenyl (CyJohnPhos)
displayed the best performance, providing the expected
diarylated imidazopyrazine 3aa in 95% isolated yield
(entry 6). Interestingly, no significant drop of the yield
(85%) was observed when using a catalyst loading as low
as 5 mol % (entry 7). When the reaction was performed
in the presence of K2CO3, diarylated imidazopyrazine 3aa
was obtained with a somewhat lower yield (63%) together
with the monoarylated imidazopyrazine 2a (23%), point-
ing out the superiority of Cs2CO3 in the CÀH bond activa-
tion step (entry 8).
The scope and limitation of this SuzukiÀMiyaura cross-
coupling/C3ÀH bond activation sequence was then inves-
tigated using the optimized procedure; namely Pd(OAc)2
(5 mol %), CyJohnPhos (10 mol %), Cs2CO3 (5.0 equiv) in
dioxane byusing variousarylboronicacids and arylhalides
(Table 2).
(6) Compounds 1a and 1b were prepared according to the literature
ꢂ ꢂ
ꢂ
procedures; see: Bradac, J.; Furek, Z.; Janezic, D.; Molan, S.; Smerkolj,
ꢂ
ꢂ
I.; Stanovnik, B.; Tisler, M.; Vercek, B. J. Org. Chem. 1977, 42, 4197–
4201and ref 2e.
(7) For selected examples of one-pot palladium-catalyzed coupling
reactions, see: (a) Handy, S. T.; Sabatini, J. J. Org. Lett. 2006, 8, 1537–
1539. (b) Handy, S. T.; Wilson, T.; Muth, A. J. Org. Chem. 2007, 72,
8496. (c) Zhang, X.; Liu, A.; Chen, W. Org. Lett. 2008, 10, 3849–3852.
Wong, N. W. Y.; Forgione, P. Org. Lett. 2012, 14, 2738–2741.
(8) For selected examples, see: (a) Shabashov, D.; Daugulis, O.
J. Am. Chem. Soc. 2010, 132, 3965–3972. (b) Yu, M.; Xie, Y.; Xie, C.;
Zhang, Y. Org. Lett. 2012, 14, 2164–2167.
(9) (a) Hegedus, L. L.; McCabe, R. W. In Catalyst Poisoning; Marcel
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Chemistry; Wilkinson, G., Gillard, R. D., McCleverty, J. A., Eds.; Pergamon:
Oxford, U.K., 1984; Vol. 5.
Org. Lett., Vol. 14, No. 23, 2012
6013

Table 2. Synthesis of Compounds 3aa
Table 3. Synthesis of Compounds 3ba
yieldb
yieldb
entry
R1
R2X
product (%)
entry
1 Ph
R1
R2X
product (%)
1
2c
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
2b
98
30
62
66
61
73
65
72
65
0d
30
0d
0d
PhBr
PhBr
PhCl
PhI
3aa
3ab
3ab
3ab
3ac
3ad
3ae
93
89
81
90
73
81
56
63
90
81
71
30
65
66c
65c
60c
PhBr
PhBr
3ba
3ba
3bb
3bc
3bd
3be
3bf
3bg
2 4-MeOC6H4
3 4-MeOC6H4
4 4-MeOC6H4
5 4-FC6H4
3-NCC6H4Br
3-MeOC6H4Br
3,4-MeC6H3Br
4-MeC6H4Br
PhBr
3-CF3C6H4
3-ClC6H4
6 3-CF3C6H4
4-Me2NC6H4Br
7 4-Me2NC6H4 4-ClC6H4Br
4-EtO2CC6H4 PhBr
8 Ph
2-bromo-6-methoxypyridine 3af
3-O2NC6H4
PhBr
9 Ph
4-NCC6H4Br
3ag
3ah
3ai
10 4-MeOC6H4
11 4-MeOC6H4
PhBr
10 Ph
4-MeSC6H4Br
PhI
3bh
11 Ph
3-MeO2CC6H4Br
3-bromothiophene
BnCl
12 Ph
13 Ph
1-bromo-2-methylpropene
BnCl
12 Ph
3aj
13 Ph
3ak
3al
a Reaction conditions: A mixture of boronic acid (1 equiv), 1b (0.5 mmol,
1 equiv), Pd(OAc)2 (0.1 equiv), CyJohnPhos (0.2 equiv), Cs2CO3 (5equiv) in
2.5 mL of dioxane was heated to 90 °C under N2 for appropriate time after
which R2X (1.5 equiv) was added, and the resulting mixture was heated to
120 °C for a further 18 h. b Isolated yields. c Reaction performed with 5 mol %
of Pd(OAc)2. d Only the Suzuki coupling product was isolated.
14 Ph
1-bromo-2-methylpropene
1-chloro-2-methylpropene
2-bromopropene
15 Ph
3al
16 3-NO2C6H4
17 4-Pyd
18 2-thienyld
19 2-benzofuranyld
3am
a Reaction conditions: A mixture of boronic acid (1 equiv), 1a
(0.5 mmol, 1 equiv), Pd(OAc)2 (0.05 equiv), CyJohnPhos (0.1 equiv),
and Cs2CO3 (5 equiv) in 2.5 mL of dioxane was heated to 90 °C under N2
for an appropriate time after which R2X (1.5 equiv) was added, and the
resulting mixture was heated to 120 °C for a further 18 h. b Isolated
yields. c 3 equiv of R2X were used. d The Suzuki coupling does not occur.
pleased to observe the formation of the desired diarylated
imidazopyrazine 3ba, albeit in a modest 30% yield, when the
imidazopyrazine 1b was subjected to the whole reaction
sequence (entry 2). This preliminary result could be signifi-
cantly improved when 10 mol % of catalyst was used,
producing 3ba in a fair 62% yield (entry 3). With the
optimized conditions in hand, we then exemplified this one-
pot diarylation process with a variety of arylboronic acids
and aryl halides, providing a novel library of 3,6-diarylated
8-methylthioimidazopyrazines 3b (entries 4À11). In only one
case, we found that subsequent to the SuzukiÀMiyaura
cross-coupling reaction between 1b and the electron-rich
4-methoxyphenylboronic acid, the resulting monoarylated
product 2b failed to undergo C3ÀH arylation with bromo-
benzene (entry 10). However, the desired diarylated imida-
zopyrazine 3bh could be formed in a modest 30% yield by
using the more reactive iodobenzene (entry 11). In contrast to
6-bromo-8-methoxyimidazopyrazine 1a, attempts to achieve
arylation/CÀH vinylation or benzylation sequences from the
8-methylthio analogue 1b proved unfruitful (entries 12 and 13).
We finally took advantage of the presence of the methoxy
and methylthio groups at C8 in both imidazopyrazines 3ad
and 3bb, respectively, to implement an additional cross-
coupling reaction which aimed at providing straightforward
access to trisubstituted imidazopyrazines (Scheme 1). Thus,
by applying a previously reported nickel-catalyzed cross-
coupling method,10 the triarylated imidazopyrazine 4 was
As first observations, good to high yields of imidazopyr-
azine 3a were obtained with a large range of arylboronic
acids and aryl halides bearing either electron-donating or -
withdrawing groups (entries 2À11). However, SuzukiÀ
Miyaura cross-coupling reactions of 1a with commercially
available heteroarylboronic acids failed to give the desired
cross-coupling product under these conditions (entries
17À19). Gratifyingly, the challenging palladium-catalyzed
direct C3-H functionalization appeared to be efficient with
both 4-iodoanisole and 4-choroanisole (entries 3 and 4) as
well as heteroaryl bromides (entries 8 and 12).
More importantly, subsequent to the SuzukiÀMiyaura
coupling reaction, direct CÀH vinylation and benzyla-
tion could be successfully achieved using various vinyl
bromides and benzyl chloride as electrophiles, affording
3akÀam in fair yields (entries 13À16). In addition, the
survival of the palladium during C3ÀH arylation of 2a
flanked with a sulfide function (entry 10) encouraged us to
explore the scope of this sequential C6-Br/C3-H cross-
coupling method further with a structural analogue of 1a,
namely the 6-bromo-8-methylthioimidazo[1,2-a]pyazine
1b (Table 3). After checking that the initial SuzukiÀ
Miyaura cross-coupling step afforded 6-phenylimidazo-
pyrazine 2b in a quantitative yield (entry 1), we were
(10) For examples of CÀO activation by Nickel catalyst: (a) Dankwardt,
J. W. Angew. Chem., Int. Ed. 2004, 43, 2428–2432. (b) Xie, L.-G.; Wang,
Z.-X. Chem.;Eur. J. 2011, 17, 4972–4975.
6014
Org. Lett., Vol. 14, No. 23, 2012

and 4-methoxyphenylboronic acid, affording the 3,6,8-triary-
lated imidazopyrazine 5 in 64% yield.
Scheme 1. Access to 3,6,8-Triarylated Imidazo[1,2-a]pyrazines
In summary, an original two-step single flask palladium-
catalyzed SuzukiÀMiyaura cross-coupling/direct CÀH fun-
ctionalization sequence has been developed from the readily
available 8-methoxy- or 8-methylthio-6-bromoimidazo-
[1,2-a]pyrazines 1a and 1b, allowing the straightforward
functionalization at both the C3 and C6 positions of these
readily available imidazopyrazine scaffolds. In addition,
facile access to 3,6,8-trifunctionalized imidazo[1,2-a]pyrazines
was also demonstrated by implementing a third cross-
coupling reaction. This sequential cross-coupling approach
supplies a large range of mono-, di-, or trifunctionalized
imidazo[1,2-a]pyrazines being potentially pharmaceutically
relevant heterocyclic products. Furthermore, this work
reports one of the few examples of palladium-catalyzed
direct CÀH arylation with heteroaryl halides bearing a
sulfide group.
ꢀ
Acknowledgment. We thank the Region Haute-
Normandie, FEDER 32819 (European fund for regional
development), the University of Rouen, the INSA of Rouen,
and Janssen for their support of our research projects.
isolated in 77% yield from its corresponding 3,6-diarylated
methyl ether imidazopyrazine precursor 3ad. Pleasingly, the
palladium- and copper-catalyzed cross-coupling of hetero-
aromatic thioethers and boronic acids previously reported by
Liebeskind11 has been successfully applied to compound 3bb
Supporting Information Available. Experimental pro-
tocols for the synthesis of compounds 2a, 2b, 3aaÀam,
3baÀbh, 4, and 5 and their characterization. Copies of 1H
and 13C NMR spectra of the new compounds 2a, 2b,
3aaÀam, 3baÀbh, 4, and 5. This material is available free
of charge via the Internet at http://pubs.acs.org.
(11) (a) Liebeskind, L. S.; Srogl, J. Org. Lett. 2002, 4, 979–981. (b)
Alphonse, F.-A.; Suzenet, F.; Keromnes, A.; Lebret, B.; Guillaumet, G.
Synlett 2002, 447–450.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 23, 2012
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