Synthesis of 6,7-disubstituted-5H-pyrrolo[2,3-b]pyrazines via palladium-catalyzed heteroannulation

Article abstract of DOI:10.1016/j.tetlet.2005.01.105

A concise and efficient method for the preparation of 6,7-disubstituted-5H- pyrrolo[2,3-b]pyrazines via a palladium-catalyzed heteroannulation is reported. Both conventional and microwave heating were used to perform the reactions, with the latter showing dramatically improved results.

Full text of DOI:10.1016/j.tetlet.2005.01.105

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1845–1848
Synthesis of 6,7-disubstituted-5H-pyrrolo[2,3-b]pyrazines
via palladium-catalyzed heteroannulation
Corey R. Hopkins* and Nicola Collar
Department of Medicinal Chemistry, Drug Innovation and Approval, Aventis Pharmaceuticals, Route 202-206,
Bridgewater, NJ 08807, USA
Received 11 January 2005; revised 19 January 2005; accepted 20 January 2005
Abstract—A concise and efficient method for the preparation of 6,7-disubstituted-5H-pyrrolo[2,3-b]pyrazines via a palladium-
catalyzed heteroannulation is reported. Both conventional and microwave heating were used to perform the reactions, with the
latter showing dramatically improved results.
Ó 2005 Elsevier Ltd. All rights reserved.
The indole ring systemis ubiquitous in nature and also
in pharmaceutical products, and has attracted the atten-
tion of medicinal chemists due to its wide ranging bio-
logical activities and interesting structural variations.1
Due to the wide range of activities, much attention has
also been spent on finding surrogates for this structural
class. The pyrrolo[2,3-b]pyridine (azaindole) core
structure has surfaced over the past few years due to
its potential as a pharmaceutical agent.2
R
R
LDA, THF,
N
N
R1
N
N
–20 oC → rt, 16 h
N
N
H
R1
Figure 1. Synthesis of 6,7-disubstituted-5H-pyrrolo[2,3-b]pyrazines by
base mediated cyclization.3c
The pyrrolo[2,3-b]pyrazine ring structure has recently
received much attention from the pharmaceutical indus-
try, both as a surrogate structure for the indole or aza-
indole, and as a novel kinase inhibitor.3 However, even
though the popularity of these compounds has in-
creased, references to their synthesis are still scarce,4
especially for the 6,7-disubstituted variants.3c The most
general methodology for these compounds involves the
reaction of an appropriately chosen 2-alkyl substituted
pyrazine with an aryl nitrile (Fig. 1). However, this reac-
tion sequence is still relatively undesirable due to the few
commercially available 2-alkyl substituted pyrazines, the
low reaction yields, and the need for an arylnitrile
partner.
The dearth of publications on the synthesis of 6,7-disub-
stituted-5H-pyrrolo[2,3-b]pyrazines led us to investigate
the extension of our recently reported methodology to
include these compounds.5 Our methodology takes
advantage of previously published work for the synthe-
sis of 2,3-disubstituted indoles and 2,3-disubstituted-
pyrrolopyridines.6 We were able to overcome the need
for an arylnitrile coupling partner and include alkyl sub-
stituents in the 6-position. Herein we report the synthe-
sis of 6,7-disubstituted-5H-pyrrolo[2,3-b]pyrazines via a
palladium-catalyzed heteroannulation, utilizing both
conventional and microwave heating.
In this work we again started with N-(3-chloropyrazin-
2-yl)-methanesulfonamide 1.7 Thus, our first attempts
used the optimized reaction conditions that were previ-
ously reported (Cl2Pd(dppf), LiCl, Na2CO3) while heat-
ing at 100 °C in DMF8 (Table 1). The reaction
Keywords:
6,7-Disubstituted-5H-pyrrolo[2,3-b]pyrazine;
Hetero-
annulation; Palladium; Cyclization.
*
Corresponding author. Tel.: +1 908 231 3351; fax: +1 908 231
3351; e-mail: corey.hopkins@aventis.com
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.105

1846
C. R. Hopkins, N. Collar / Tetrahedron Letters 46 (2005) 1845–1848
Table 1. Synthesis of 6,7-disubstituted-5H-pyrrolo[2,3-b]pyrazines via
conventional heating
Table 2. Optimization of reaction conditions
R
Conditions, DMF, MW
(100W, 150 oC, 45 min)
N
N
N
Cl
R
Cl2Pd(dppf), LiCl,
N
Cl
Na2CO3, DMF, 100 oC
N
N
R1
R1
N
Ph
N
NHMs
H
N
H
R
R1
N
1
NHMs
1
2b
3b: R1 = Ph, R = propyl
3b': R1 = propyl, R = Ph
2a-b
3a-b
Entry
R
R1
Product Time (h)
Yield (%)
Entry
Conditions
3b:3b0
Yield (%)
1
2
Me
–(CH2)2CH3
Ph
Ph
3a
3b
18
84
10a
26b
1
Cl2Pd(dppf), Na2CO3, LiCl
Cl2Pd(PPh3)2, Na2CO3, LiCl
Pd(OAc)2, PCy3, K2CO3
Pd(OAc)2, Pt-Bu3, K2CO3
Pd(OAc)2, 6, K2CO3
3:1
—
36
Dec.
6
2
a 3:1 mixture of regioisomers (1H NMR).
b 3.8:1 mixture of regioisomers (1H NMR).
3
3.6:1
3.7:1
2.4:1
3.3:1
3.6:1
4.5:1
4.6:1
3.8:1
—
4
15
27
18
5
5
6
Pd(OAc)2, 7, K2CO3
Pd(OAc)2, 8, K2CO3
proceeded but the time required was considerably longer
than previous examples. Also, the reaction yield was
quite low with a large amount of starting material recov-
ered. The following trial was allowed to proceed for a
longer time (84 h) resulting in a higher yield, but the
time was prohibitive. Also, the differentially substituted
alkynes gave mixtures of regioisomers, which were not
observed in the analagous reactions with indoles and
azaindoles.6
7
8
Pd(OAc)2, 9, K2CO3
Pd(OAc)2, 4, K2CO3
12
8
9
10
11
Pd(OAc)2, 5, K2CO3
Pd(OAc)2, 10, K2CO3
8.5
Dec.
P(t-Bu)2
P(Cy)2
P(t-Bu)2
Me2N
Taking note of a recent publication by Senanayake and
co-workers9 detailing work using o-chloroanilines to
synthesize 2,3-disubstituted indoles, we next decided to
investigate alternative conditions for the reaction.
Senanayake and co-workers utilized electron-rich phos-
phine ligands in order to affect the transformation.
Thus, we tried a variety of electron-rich ligands (Table
2). Due to the long reaction times encountered using
conventional heating, we explored the reaction using
microwave irradiation in an attempt to shorten the reac-
tion times to a more reasonable level. Our initial entry,
fromour previously optimized reaction, proved to be
optimal in this reaction sequence also. Even the opti-
mized reaction conditions for the indole equivalent9
(Table 2, entry 8) proved inferior using our substrate,
confirming our previously reported conditions for the
synthesis of 6-substituted-5H-pyrrolo[2,3-b]pyrazines.5
We were unable to attain the same levels of regio-
chemistry as that reported for the indole substrates. This
lack of specificity observed may be due, in part, to the
methanesulfonyl protecting group on the nitrogen. How-
ever, we did not see any of the amination/dimer coupling
product as seen in the reaction of the o-chloroaniline
substrate.9
4
5
6
P(Cy)2
PR2
PR2
8, R = Ph
Me2N
Fe
9, R = t-Bu
10, R = i-Pr
7
Table 3. Synthesis of 6,7-disubstituted-5H-pyrrolo[2,3-b]pyrazines via
microwave conditions
Cl2Pd(dppf), LiCl,
Na2CO3, DMF, MW (100 W,
R
N
Cl
N
N
time, temp)
R1
N
H
R
R1
N
NHMs
1
2a-i
3a-i
Entrya
R
R1
Product Yield (%)
After having settled on the optimized conditions for the
reaction, the first entries were performed on the same
substrates as the conventional heating for a direct com-
parison. As can be seen in Table 3, the use of microwave
irradiation dramatically shortened the reaction times and
improved the yields to a more synthetically useful level
(entries 1 and 2). The use of microwave reaction condi-
tions allowed the cyclization to proceed in a matter of
minutes versus hours (and even days) under conventional
heating, and also improved the reaction yields. As can be
seen in Table 3, the reaction proceeds with a variety of
substrates utilizing alkyl, aryl, and heteroaryl substitu-
ents and even a free alcohol (entry 7). When the phenyl
1
2
3
4
5
6
7
8
9
Me
–(CH2)2CH3
Ph
Ph
Ph
3a
3b
3c
3d
3e
37b
36c
41
45b
Dec.
42
Ph
Ph
–(CH2)3CH3
Me
–(CH2)2CH3
TMS
–(CH2)2CH3 3f
–CH(OH)CH(CH3)2 Ph
–(CH2)3CH3
–(CH2)3CH3
3g
3h
39
37
2-Thiazole
2-Thiophene 3i
40
a Reactions were run for 45 min and 150 °C, except entry 2, which was
run at 175 °C.
b 5:1 mixture of regioisomers (1H NMR).
c 3:1 mixture of regioisomers (1H NMR).

C. R. Hopkins, N. Collar / Tetrahedron Letters 46 (2005) 1845–1848
1847
substituted alkyl alkynes were used (entries 1, 2, and 4),
Acknowledgements
the products were isolated as regioisomeric mixtures.10
However, using the heteroaryl substituted alkyl alkynes
(entries 8 and 9) only one regioisomer was isolated. This
could be due to the electron-rich nature of the hetero-
cyclcs biasing one position of the alkyne to insertion.9
The authors thanks Mr. Neil Moorcroft for his help in
setting up the microwave reactions and Mr. Vincent
Morrison and Dr. Dirk Freidrich for obtaining the
NOESY data.
Noting the use of silyl-protected internal alkynes in pre-
vious palladium-catalyzed cyclizations led us to investi-
gate this useful group as a potential surrogate for further
manipulation. We have previously tried using silyl
alkynes5a and observed that the products undergo desily-
lation after cyclization. However, using the internal
silylated alkyne, there was no product observed either
with or without the silyl group. It was suspected that
the TMS group was just too labile for these conditions;
however, use of either TIPS or TBDMS groups gave the
same result. Even though a variety of groups are toler-
ated under these reaction conditions (alkyl, hydroxy,
aryl, heteroaryl), silyl groups to this point do not partici-
pate and only lead to undesired byproducts.
References and notes
1. (a) Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V.
Compr. Heterocycl. Chem. II 1996, 2, 207–257; (b)
Gribble, G. W. Contemp. Org. Synth. 1994, 145–172; (c)
Pindur, U.; Adam, R. J. Heterocycl. Chem. 1988, 25, 1–8;
(d) Moody, C. J. Synlett 1994, 681–688; (e) Sundberg, R.
J. Indoles; Academic: San Diego, CA, 1996; (f) Gilchrist,
T. L. J. Chem. Soc., Perkin Trans. 1 1999, 2849–
2866.
2. (a) Willette, R. E. Adv. Heterocycl. Chem. 1968, 9, 27–105;
(b) Yakhontov, L. N. Russ. Chem. Rev. 1968, 37, 1258–
1287; (c) Yakhontov, L. N.; Prokopov, A. A. Russ. Chem.
Rev. 1980, 49, 814–847.
3. (a) Kunick, C.; Lauenroth, K.; Leost, M.; Meijer, L.;
Lemcke, T. Bioorg. Med. Chem. Lett. 2004, 14, 413–416;
(b) Doble, B. W.; Woodgett, J. R. Cell Sci. 2003, 116,
1175–1186; (c) Mettey, Y.; Gompel, M.; Thomas, V.;
Garnier, M.; Leost, M.; Ceballos-Picot, I.; Noble, M.;
Endicott, J.; Vierfond, J.-m.; Meijer, L. J. Med. Chem.
2003, 46, 222–236.
4. (a) Vierfond, J. M.; Mettey, Y.; Mascrier-Demagny, L.;
Miocque, M. Tetrahedron Lett. 1981, 22, 1219–1222; (b)
Klutchko, S.; Hansen, H. V.; Meltzer, R. I. J. Org. Chem.
1965, 30, 3454–3457; (c) Clark, B. A. J.; Parrick, J.;
Dorgan, R. J. J. J. Chem. Soc., Perkin Trans. 1 1976, 13,
1361–1363.
5. (a) Hopkins, C. R.; Collar, N. Tetrahedron Lett. 2004, 45,
8087–8090; (b) Hopkins, C. R.; Collar, N. Tetrahedron
Lett. 2004, 45, 8631–8633.
6. (a) Larock, R. C.; Yum, E. K. J. Am. Chem. Soc. 1991,
113, 6689–6690; (b) Ujjainwalla, F.; Warner, D. Tetrahe-
dron Lett. 1998, 39, 5355–5358; (c) Eriksson, A.; Jeschke,
T.; Annby, U.; Gronowitz, S.; Cohen, L. A. Tetrahedron
Lett. 1993, 34, 2823–2826; (d) Park, S. S.; Choi, J.-K.;
Yum, E. K.; Ha, D.-C. Tetrahedron Lett. 1998, 39, 627–
630.
Representative example:11 N-(3-Chloropyrazin-2-yl)-
methanesulfonamide 1 (179.6 mg; 0.8650 mmol), 1-
phenyl-1-propyne (130 lL; 1.03 mmol), Cl2Pd(dppf)
(37.9 mg; 0.0464 mmol), LiCl (44.8 mg; 1.06 mmol),
and Na2CO3 (188.1 mg; 1.775 mmol) were dissolved
in DMF (4.0 mL) and the resulting mixture was de-
gassed by passing an N2 streamthrough the sample.
After 10 min, the reaction vessel was reacted under
microwave conditions (100 W, 150 °C, 45 min). The
reaction mixture was cooled to rt, diluted with H2O,
and extracted with EtOAc. The organic extracts were
washed with brine, dried (Na2SO4), and concentrated.
The residue was purified by column chromatography
(10 g pre-packed SiO2 column from ISCO; 50%
EtOAc/heptane eluent) to yield 66.5 mg (0.319 mmol;
37%) of 7-methyl-6-phenyl-5H-pyrrolo[2,3-b]pyrazine
and 6-methyl-7-phenyl-5H-pyrrolo[2,3-b]pyrazine (mix-
ture of regioisomers, 4:1, respectively), 3a as a tan
solid.
HPLC
(SYNGERI
2U
HYDRO-RP
20X4.0MM COL, water (0.1% trifluoroacetic acid)/ace-
tonitrile (0.1% trifluoroacetic acid) = 10/90!90/10):
Rf = 3.06 min. C13H11N3 (209.25) MS (ESI) 210
(M+H). 1H NMR (300 MHz, DMSO-d6) Major d
12.1 (s, 1H), 8.35 (d, 1H, J = 2.6 Hz), 8.20 (d, 1H,
J = 2.6 Hz), 7.78–7.71 (m, 2H), 7.54 (t, 2H,
J = 7.8 Hz), 7.46–7.41 (m, 1H), 2.45 (s, 3H). Minor d
8.33 (d, 0.2H, J = 2.6 Hz), 8.16 (d, 0.2H, J = 2.6 Hz),
7.28–7.24 (m, 0.2H), 2.61 (s, 0.6H).
7. As with the previous examples, the 2-amino-3-chloro-
pyrazine did not participate in this reaction (Ref.
5).
8. Increasing the temperature (even up to 175 °C) did not
improve the reaction yields or times.
9. Shen, M.; Li, G.; Lu, B. Z.; Hossain, A.; Roschangar, F.;
Farina, V.; Senanayake, C. H. Org. Lett. 2004, 6, 4129–
4132.
1
10. Both H and NOESY NMR spectra were acquired for 3a
to determine the correct regiochemistry with respect to the
major and minor species present. The 1H and NOESY
NMR data are consistent with the structures below for the
major and minor species. The key NOESY correlations
that distinguish the major isomerÕs regiochemistry are
those between the pyrrolo[2,3-b]pyrazine methyl protons
at 2.47 ppmand the phenyl ortho protons at 7.79 ppmand
between the pyrrolo[2,3-b]pyrazine amine proton at
In conclusion, the palladium-catalyzed heteroannulation
that was previously reported for the synthesis of mono-
substituted pyrrolopyrazines has been extended to in-
clude disubstituted variants. The reaction proceeds
under microwave irradiation conditions to yield the
desired products in modest overall yields. This method-
ology offers an extension of the previously known reac-
tion sequence and allows for a variety of substrates to be
synthesized that were not available via the previous
methods. Efforts are underway to extend this methodol-
ogy to include more elaborate compounds and results
will be reported in due course.
12.13 ppmand the saem phenyl
ortho protons at
7.79 ppm. The key NOESY correlations that distinguish
the minor isomerÕs regiochemistry are those between the
pyrrolo[2,3-b]pyrazine methyl protons at 2.62 ppm and the
phenyl ortho protons at 7.76 ppmand the pyrrolo[2,3-
b]pyrazine amine proton at 12.10 ppm and the same

1848
C. R. Hopkins, N. Collar / Tetrahedron Letters 46 (2005) 1845–1848
methyl protons at 2.62 ppm. All of these NMR spectra
were obtained in DMSO-d6 at 25 °C using a Varian Unity
Inova 500 MHz spectrometer.
11. All new compounds were characterized by high resolution
LC–MS and 1H NMR and found to be in agreement with
their structures.
nOe
2.47
7.79
H
7.76
2.62
N
N
H
N
N
+
nOe
N
H
H
N
H
12.13
7.79
12.10
Minor Isomer
nOe
nOe
Major Isomer
.