An improved method for the synthesis of 6-substituted-5H-pyrrolo[2,3-b] pyrazines via palladium-catalyzed heteroannulation using microwave heating

Article abstract of DOI:10.1016/j.tetlet.2004.09.152

We herein report an improved synthesis of 6-substituted-5H-pyrrolo[2,3-b] pyrazines utilizing microwave heating. The reaction is a palladium-catalyzed heteroannulation process followed by deprotection to yield the desired substrates in good yield.

Full text of DOI:10.1016/j.tetlet.2004.09.152

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8631–8633
An improved method for the synthesis of
6-substituted-5H-pyrrolo[2,3-b]pyrazines via palladium-catalyzed
heteroannulation using microwave heating
Corey R. Hopkins* and Nicola Collar
Department of Medicinal Chemistry, Drug Innovation and Approval, Aventis Pharmaceuticals, Route 202–206, Bridgewater,
NJ 08807, USA
Received 22 September 2004; accepted 23 September 2004
Available online 8 October 2004
Abstract—We herein report an improved synthesis of 6-substituted-5H-pyrrolo[2,3-b]pyrazines utilizing microwave heating. The
reaction is a palladium-catalyzed heteroannulation process followed by deprotection to yield the desired substrates in good yield.
Ó 2004 Elsevier Ltd. All rights reserved.
Microwave-assisted organic synthesis has received a vast
amount of attention over the last several years.1 The
breadth of reactions that have been performed under
these conditions is an ever increasing entity. One such
reaction that has been used successfully under micro-
wave conditions is transition metal-catalyzed couplings
using a variety of substrates and conditions. The Sono-
gashira coupling,2 Stille reaction,3 Suzuki reaction,4 aryl
amination,5 allylic alkylations,6 and Heck reactions7
have all been investigated and have been shown to per-
form well in the microwave. One distinct advantage of
using microwave conditions is that it can increase the
rate of reaction, sometimes very drastically.
was shown to work well with a variety of substrates;
however, when alkyl alkynes were used the reaction
times were dramatically increased over the aromatic
alkynes. The reaction yields ranged from 36% to 63%
for a one-pot, three-step reaction.9 In this communica-
tion, we report improved reaction conditions to synthe-
size these compounds utilizing microwave conditions
to increase the reaction rates (especially with alkyl
alkynes).
In the previously described study, we were unable to
affect the coupling and subsequent cyclization with an
unsubstituted aniline derivative. Using the microwave
reaction conditions, we felt that the increased reactivity
might allow this transformation to occur. However, as
shown in Scheme 1,10 the Sonogashira coupling did take
place (under the appropriate conditions), but the aniline
did not participate in the cyclization. As in the previous
examples, the cyclization could be accomplished with a
second, base-induced step. However, in the absence of
CuI, neither the Sonogashira coupling,11 nor the
cyclization, took place, even under extended reaction
times (Cl2Pd(dppf), LiCl, Na2CO3, DMF, MW, 100W,
150°C, 4h).
We have previously reported8 a novel synthesis of 6-sub-
stituted-5H-pyrrolo[2,3-b]pyrazines via a palladium-cat-
alyzed heteroannulation process (Fig. 1). This process
Cl2Pd(dppf), LiCl,
N
N
Cl
Na2CO3, DMF, 100 oC
N
N
R1
N
H
NHMs
R1
36-63%
3-20 h
Figure 1. Synthesis of 6-substituted-5H-pyrrolo[2,3-b]pyrazines via
conventional heating.
Next, we turned our attention to the sulfonamide 5,
which was successful in the previous examples. The reac-
tion proceeds with this starting material to yield the de-
sired 6-substituted-5H-pyrrolo[2,3-b]pyrazines, 4a–j, in
good overall yield (Table 1).12 There were a number of
reaction conditions that were evaluated and most of
them investigated gave acceptable results. The lone
Keywords: 6-Substituted-5H-pyrrolo[2,3-b]pyrazine; Heteroannula-
tion; Palladium; Cyclization; Microwave.
*
Corresponding author. Tel./fax: +1 908 231 3351; e-mail: corey.
hopkins@aventis.com
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.09.152

8632
C. R. Hopkins, N. Collar / Tetrahedron Letters 45 (2004) 8631–8633
Cl2Pd(PPh3)2, CuI,
Ph
TMG, DMF, MW (100W,
150 oC, 20 min)
N
N
N
N
Cl
H
Ph
+
70%
2a
NH2
NH2
1
3
KOtBu, NMP,
70 oC
N
Ph
60%
N
H
N
4a
Scheme 1. Synthesis of 6-substituted-5H-pyrrolo[2,3-b]pyrazine via two-step protocol of Sonogashira coupling under microwave conditions followed
by base-induced cyclization.
Table 1. Cyclization with 2-chloro-3-(N-methansulfonamide) pyrazine utilizing a microwave reaction protocol
Conditions, MW (100 W,
N
N
N
Cl
150 oC, DMF)
R
N
H
N
NHMs
R
5
4a-j
2a-j
Entry
R
Methoda
Time (min)
Product
Yield (%)
1
Phenyl
3-Pyridyl
A
A
A
B
15
15
15
20
20
20
20
20
20
20
20
20
20
20
4a
4b
4c
4a
4d
4e
4f
39
48
49
46
24
65
64
19
57
54
45
43
55
60
2
3
4-Fluorophenyl
Phenyl
2-Methylphenyl
4
5
B
6
2-Trifluoromethylphenyl
4-Methoxyphenyl
Phenyl
B
7
B
8
C
D
D
D
D
D
D
4a
4a
4c
4g
4h
4i
9
Phenyl
10
11
12
13
14
4-Fluorophenyl
4-Cyanophenyl
4-Acetonitrilephenyl
Butyl
–(CH2)4OTBDPS
4j
a Method A: Cl2Pd(PPh3)2, CuI, 1,1,3,3-tetramethylguanidine; method B: Cl2Pd(dppf), CuI, 1,1,3,3-tetramethylquanidine; method C: Pd(OAc)2,
LiCl, K2CO3, PPh3; method D: Cl2Pd(dppf), LiCl, Na2CO3.
Table 2. Comparison of reactions performed under conventional
heating with those performed under microwave conditions
exception was method C, which gave only 19% of the
desired compound. This set of conditions also per-
formed poorly under the conventional heating. From
the table it can be determined that the reaction proceeds
smoothly13 giving the desired compounds in good yields
for the overall three-step protocol. The cyclization
sequence performs equally well with (methods A and B)
and without (method D) the addition of CuI. The micro-
wave conditions also tolerate much functional diversity
(both electron-donating and electron-withdrawing func-
tionalities). Halogens as well as cyano groups are well
tolerated, along with silyl protected alcohols.
Compd
Conventional heating
(time, yield)
Microwave heating
(time, yield)
4a
4d
4e
4i
3h, 63%
1.5h, 57%
1h, 57%
15h, 52%
20h, 63%
20min, 57%
20min, 24%
20min, 65%
20min, 55%
20min, 60%
4j
and desulfonylated cyclized materials was isolated. In
contrast, when the microwave conditions were used only
the desulfonylated material was isolated.
The direct comparison of the conventional and micro-
wave heating conditions can be seen in Table 2. As
can be seen from the table, all the substrates investigated
perform well with much decreased reaction times in the
microwave as compared to the conventional heating.
The most drastic decrease in reaction times were
observed for the alkyl alkynes (4i and 4j). Also of note,
when compound 4i was synthesized under the conven-
tional heating method a mixture of the sulfonylated
In conclusion, we are reporting an improved synthesis
of 6-substituted-5H-pyrrolo[2,3-b]pyrazines utilizing
microwave reaction conditions. This methodology
improves upon our earlier results using conventional
heating to affect the same transformation. The reaction
conditions are operationally simple and dramatic
increases in the reaction rates can be observed. Further

C. R. Hopkins, N. Collar / Tetrahedron Letters 45 (2004) 8631–8633
8633
9. For an alternative approach to the synthesis of 6-substi-
tuted-5H-pyrrolo[2,3-b]pyrazines, see: Mettey, Y.; Gom-
pel, M.; Thomas, V.; Garnier, M.; Leost, M.; Cebellos-
Picot, I.; Noble, M.; Endicott, J.; Vierfond, J.-M.; Meijer,
L. J. Med. Chem. 2003, 46, 222–236.
extension of this methodology to include more elaborate
substrates are currently on-going in our laboratory and
will be reported in due course.
10. Compound 1 was obtained in good yield by reacting the
commercially available 2,3-dichloropyrazine with ammo-
nium hydroxide.
11. For selected copper-free Sonogashira couplings, see: (a)
Gelman, D.; Buchwald, S. L. Angew. Chem., Int. Ed. 2003,
42, 5993–5996; (b) Pal, M.; Parasuraman, K.; Gupta, S.;
Yeleswarapu, K. R. Synlett 2002, 12, 1976–1982; (c)
Fukuyama, T.; Shinmen, M.; Nishitani, S.; Sato, M.; Ryu,
Acknowledgements
The authors would like to thank Mr. Neil Moorcroft for
his help using the microwave apparatus.
References and notes
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252 (M+H). H NMR (300MHz, CDCl3) d ppm: 12.4 (s,
1H), 8.34 (d, 1H, J = 2.6Hz), 8.18 (d, 1H, J = 2.6Hz), 7.94
(d, 2H, J = 8.5Hz), 7.52 (d, 2H, J = 8.5Hz), 7.08 (d, 1H,
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13. The reaction was monitored at times: 5, 10, 15 and 20min
and the reaction was deemed complete at 20min due to
full consumption of the SM.
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