Highly selective substitutions in 2,3-dichloropyrazine. A novel general approach to aloisines

Article abstract of DOI:10.1016/j.tet.2006.08.018

A highly efficient synthesis of the potent CDKs (cyclin-dependent kinases) inhibitors, aloisines (substituted 5H-pyrrolo[2,3-b]pyrazines) is presented. The method is based on highly selective monosubstitution of a single chlorine atom in 2,3-dichloropyraz

Full text of DOI:10.1016/j.tet.2006.08.018

Tetrahedron 62 (2006) 9919–9930
Highly selective substitutions in 2,3-dichloropyrazine. A novel
general approach to aloisines
Dmitriy S. Chekmarev,a,b Sergey V. Shorshnev,a Alexander E. Stepanovb
and Alexander N. Kasatkina,
*
aChemBridge Corporation, Malaya Pirogovskaya 1, Build. 5, 119435 Moscow, Russia
bM.V. Lomonosov Moscow State Academy of Fine Chemical Technology, Prospekt Vernadskogo 86, 119571 Moscow, Russia
Received 15 May 2006; revised 19 July 2006; accepted 3 August 2006
Available online 24 August 2006
Abstract—A highly efficient synthesis of the potent CDKs (cyclin-dependent kinases) inhibitors, aloisines (substituted 5H-pyrrolo[2,3-
b]pyrazines) is presented. The method is based on highly selective monosubstitution of a single chlorine atom in 2,3-dichloropyrazine
with lithiated ketones, esters, and nitriles followed by co-cyclization of the resulting intermediates with primary amines or hydrazines.
Ó 2006 Elsevier Ltd. All rights reserved.
R3
1. Introduction
N
N
Cl
N
N
N
N
Cl
Cl
N
O
R2
The family of compounds 1 bearing 5H-pyrrolo[2,3-b]pyra-
zine fragment has recently attracted a great interest since
they have been shown to inhibit cyclin-dependent kinases
(CDKs).1,2 Due to potential applications of CDK inhibitors
as novel agents for a variety of neurodegenerative disorders
such as Alzheimer’s disease, the authors named this family
of compounds as ‘aloisines’, following the first name (Aloiz)
of Dr. Alzheimer.1 Up to now, the two general approaches to
aloisines have been developed, one using the reaction of
methylpyrazines with aromatic nitriles1,3 and the other based
on a cyclization of 2-chloro-3-(methanesulfonamido)pyra-
zine with substituted alkynes under thermal4 or microwave
assisted conditions.5 However, both these methods have lim-
itations concerning yields, variety of R1–R3 substituents, and
utilizing a microwave technology that is rather effective but
still not widely available method. Thus, a more general and
practical approach to the compounds of general formula 1
seemed to be needed.
R2
R1
R1
1
2
Scheme 1.
2. Results and discussion
As it can be seen from our results represented by Table 1, the
reactions of 2,3-dichloropyrazine (2) with 1.1 equiv of vari-
ous ketones, esters, and nitriles and 2.2 equiv of LiHMDS6
led to highly selective formation of the monosubstitution
products 3, 4, and 5, respectively (Scheme 2).
The reactions of 2 with n-alkyl phenyl and n-alkyl hetaryl
ketones provided the corresponding monoketones 3a–g in
moderate to high yields (entries 1–10) although increasing
the temperature from 20 to 60 ꢀC was required in most cases.
Only traces of the disubstitution product were detected by
LC/MS in the reaction with 2.2 equiv of n-PrC(O)Ph and
4.4 equiv of LiHMDS (entry 4). It is noteworthy that the
use of 1.1 equiv of the base decreased conversion of the start-
ing materials, thus, indicating that the Li-enolates of 3 were
the reaction products before hydrolysis. Compared to the
n-alkyl ketones, Li-enolate of i-PrC(O)Ph proved to be much
less reactive presumably owing to steric reasons (entries 11
and 12). Although Pd-complexes are known to be effective
catalysts for arylations of ketone or ester enolates,6–9 the
presence of the catalyst (Pd2dba3+Xantphos)9 did not im-
prove the yield of the desired monoketone 3h (entry 13).
The reaction of 2 with acetone was accompanied by the
formation of aldol type condensation products (entry 14),
In this paper we describe a new general method for the syn-
thesis of aloisines 1 where the substituents R1, R2, and R3
can be varied independently. Our strategy is based on highly
selective substitution of a single chlorine atom in commer-
cially available 2,3-dichloropyrazine (2) with a-lithiated
ketones, esters, and nitriles followed by cyclization with pri-
mary amines or hydrazines (Scheme 1).
Keywords: 2,3-Dichloropyrazine; Aloisines; Substituted 5H-pyrrolo[2,3-
b]pyrazines; a-Arylation; Cross-coupling reactions; Cyclization.
* Corresponding author. Tel.: +7 495 775 0654; fax: +7 495 956 4948;
e-mail: kasatkin@chembridge.ru
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.08.018

9920
D. S. Chekmarev et al. / Tetrahedron 62 (2006) 9919–9930
Table 1. Reactions of 2,3-dichloropyrazine (2) with lithiated ketones, esters, and nitrilesa
Entry
1
Substrate
Product
Temp (ꢀC) Yieldb (%) Entry
Substrate
Product
Temp (ꢀC) Yieldb (%)
N
Cl
O
N
N
Cl
O
O
O
62c
14
20
21g
3a
3i
20
N
N
Ph
Ph
Cl
N
Cl
O
4a
4b
4c
2
3
4
20
60
60
54
96
81d
15
16
17
20
20
20
42
50
92
O
R = Me
O
O
O
3b
R = Et
N
OR
N
Ph
Ph
OR
OR
R = t-Bu
O
N
N
Cl
N
N
Cl
5
6
20
3c 60
34c
51c
18
19
20
20
26
82
O
O
R = Me
R = t-Bu
4d
4e
OR
N
N
O
N
N
N
Cl
Cl
Cl
O
O
O
O
4f
7
8
9
60
53c
50c
61c
20
20
86
3d
OBu-t
N
Ph
OBu-t
OBu-t
N
O
Ph
Cl
N
O
O
O
N
N
O
N
N
O
21
22
4g 20
60
26e
17e
3e
20
OBu-t
N
N
N
N
Cl
Cl
O
5a
3f
N
60
23
N
20
95
S
S
S
O
N
N
N
Cl
Cl
Cl
O
N
N
3g
5b
10
60
85
24
25
20
20
98
98
N
N
N
S
11
12
13
20
60
<5e
8e
<5e,f
O
N
N
Cl
N
N
O
3h
5c
Ph
60
Ph
a
Reaction conditions: 1 equiv of 2, 1.1 equiv of ketone, ester or nitrile, 2.2 equiv of LiHMDS, toluene, 24 h, under Ar.
Isolated yields (average of two runs).
b
c
d
e
f
The products were isolated as ketone and enol mixtures according to 1H NMR data.
The ketone (2.2 equiv) and LiHMDS (4.4 equiv) were used.
More than 70% of the starting material 2 was recovered.
Pd(dba)2 (2.5 mol %) and Xantphos (3 mol %) were added.
The aldol type condensation product of 3i with acetone was isolated in 25% yield.
g
which limits generality of the method; the use of dialkyl
ketones (excluding ones having a trisubstituted a-carbon)
seems to be more problematic.
R2
R3
R1
LiHMDS
R2
N
N
Cl
O
O
The reactions of 2 with a-unbranched tert-butyl esters and
nitriles smoothly afforded the monoesters 4c,e,f (entries
17, 19, and 20) and mononitriles 5a,b (entries 23 and 24)
at room temperature. Although the maximal yield of 26%
was obtained for the a,a-disubstituted ester 4g (entry 21),
the corresponding nitrile (i-PrCN) gave the desired mono-
substitution product 5c in high yield (entry 25). Regarding
variation of the ester group, the yields of the monosubstitu-
tion products decreased in the following order: 4c (R¼
t-Bu)>4b (R¼Et)>4a (R¼Me) (entries 15–17) as well as 4e
(R¼t-Bu)>4d (R¼Me) (entries 18 and 19). Thus, tert-butyl
esters represented most appropriate substrates (probably due
to their low tendency to Claisen type condensations).10
R3
R1 R2
3
O
R3
R1
N
Cl
Cl
N
Cl
O
O
O
R3
N
2
LiHMDS
N
R2
R1
4
R2
N
N
Cl
R1
LiHMDS
C N
C
R2
N
R1
5
It should be pointed out that nucleophilic (SNAr) substitu-
tions of a single chlorine atom in 2 were reported for a variety
Scheme 2.

D. S. Chekmarev et al. / Tetrahedron 62 (2006) 9919–9930
9921
of N-, O-, and S-nucleophiles (including ammonia,5,11
amines12 and aminoalcohols,13 sulfamides,4,5 thiols,14,15
and alcohols15,16). However, the selective monosubstitution
with C-nucleophiles has been studied to a much lesser ex-
tent. To our knowledge, the only known examples included
the use of anions generated from methyl tert-butyl ketone17
and a-stabilized nitriles.18
acid hydrazides exhibited different regiochemistry,19 giving
(in contrast to 6b,c) 2-substituted 1,2-dihydropyridazine
derivatives 9 (Scheme 4). The structures of 6a–c were
confirmed by the presence of characteristic peaks (doublets
of the doublets) of CH-4 protons at 4.42–4.56 ppm in their
1H spectra.
O
O
H
N
Being succeeded in the synthesis of the monosubstitution
products 3–5 (Table 1), we turned our attention to the second
(co-cyclization) step to afford the target aloisines 1. The
chloroketone 3b was chosen as a model representative com-
pound. We found that the reactions of 3b with primary
amines and hydrazines in xylene at 145–170 ꢀC in the pres-
ence of PTSA provided the co-cyclization products 1 and 6
in high yields (Scheme 3; Table 2).
N
N
Cl
N
N
O
R
S
NHNH2
R = Ph, H
R
N
S
9
Scheme 4.
Cyclization of the chloroketones 3 into the furo[2,3-b]pyra-
zines 10 (the oxo-analogs of aloisines) was found to be effec-
tive by treatment of 3 with K2CO3 in DMF at 140 ꢀC
(Scheme 5).20
As it can be seen from Table 2, the treatment of 3b with am-
monia (entry 1), alkylamines (entries 2–4), benzylamine (en-
tries 5–7), ethanolamine (entry 8), and 4-methoxyaniline
(entries 9 and 10) provided the expected trisubstituted 5H-
pyrrolo[2,3-b]pyrazines 1a–f. The use of microwave irradi-
ation in the reaction with 4-MeOC6H4NH2 gave moderate
advantage, shorting the reaction time (entry 10). By the
treatment of 3b with hydrazine hydrate, realization of both
the cyclization pathways of the intermediate 7 (R¼H) took
place, thus, affording the mixture of 5H-pyrrolo[2,3-b]pyra-
zine 1g and 1,4-dihydropyrazino[2,3-c]pyridazine 6a (entry
11). However, when phenyl- and methylhydrazines were
introduced into the reaction, only the corresponding 1,4-di-
hydropyrazino[2,3-c]pyridazines 6b,c were isolated (entries
12–14). The role of PTSA is crucial for the reactions to be
completed: the yields of both 1g and 6a decreased dramati-
cally (entry 11) and the hydrazone 7 (R¼Ph) was obtained as
a main product instead of 6b (entry 13) in the absence of
PTSA. It should be noted that although the imine intermedi-
ates 8 were postulated in the reactions of 3b with primary
amines, we could not isolate or detect them at lower temper-
atures (entries 2, 5, and 6) or in the absence of PTSA. There-
fore for 5H-pyrrolo[2,3-b]pyrazines 1, the alternative
mechanism including Cl-substitution with the amines12,13
followed by cyclization could be suggested.
N
N
Cl
N
N
O
K2CO3
O
R2
DMF, 140 °C, 3 h
R2
R1
R1
10a (R1 = H, R2 = Ph), 97%
3
10b (R1 = H, R2 = 4-Pyridyl), 84%
10c (R1 = H, R2 = 3-Pyridyl), 83%
10d (R1 = Et, R2 = Ph), 98%
Scheme 5.
With the goal to synthesize aloisines 1 having N- and O-sub-
stituents, the possibility of using the chloronitriles 5 and the
chloroesters 4 as appropriate co-cyclizations partners was
briefly investigated.
The reaction of the chloronitrile 5b with isobutylamine
(3 equiv) in xylene at 170 ꢀC (72 h) followed by treatment
of the crude mixture with aq HCl led to the 2-aminosubsti-
tuted 2H-pyrrolo[2,3-b]pyrazine 1h (as HCl-salt) in 49%
isolated yield. The proposed mechanism represented by
Scheme 6 includes the Cl-substitution with the amine at
the first step. This has been confirmed by the fact that the in-
termediate 11 was isolated as a main product from the reac-
tion at 140 ꢀC. Interestingly that our attempts to transform
the hydrochloride into the free base (by addition of aq
It should be pointed out that the similar co-cyclizations of
2-chloro-3-(2-thienoylmethyl)-quinoxaline with carboxylic
R
N
Cl
R
N
N
N
N
RNH2
Ph
N
Ph
∆
65-95%
Et
Et
N
N
Cl
Et
1
O
8
NHR
Ph
N
N
Ph
3b
N
63%
N
N
Cl
NHR
Ph
RNHNH2
∆
Et
N
1
R
N
Et
N
N
7
N
Ph
Et
6
35-65%
Scheme 3.

9922
D. S. Chekmarev et al. / Tetrahedron 62 (2006) 9919–9930
Table 2. Reactions of monosubstitution products 3–5 with amines and hydrazinesa
Entry Amine or hydrazine
Product
Temp Time Yieldb Entry Amine or hydrazine
Product
Temp Time Yieldb
(ꢀC) (h)
(%)
(ꢀC) (h)
(%)
OMe
H
N
NH2
N
N
9
10
145
145
72
24
98
86f
1
NH3
170
72
75c
1f
Ph
1a
N
N
MeO
N
N
Ph
NH2
N
1g
Ph
N
N
N
2
3
145
160
72
48
68
86
63
32g
1b
1c
1d
1e
NH2
Ph
Ph
N
11
H2N–NH2
160
72
H
N
N
N
N
N
N
N
N
N
35
14g
4
145
72
93
6a
NH2
NH2
Ph
Ph
Ph
Ph
Ph
N
5
6
7
80
110
145
100
48
48
12d
51e
95
12
13
150
150
72
72
63
<5g,h
N
N
N
N
Ph
Ph
6b
Ph
H2N
H2N
N
H
Me
N
OH
Ph
N
N
N
N
N
Me
N
NH2
8
145
72
65
14
170
72
65
N
H
6c
HO
a
b
c
d
e
f
All the reactions were carried out in sealed vials in xylene in the presence of 0.1 equiv of PTSA.
Isolated yields (average of two runs).
A solution of NH3 (1.6 M) in MeOH was used.
Benzene was used as a solvent.
Toluene was used as a solvent.
Microwave heating (150 W) was used.
In the absence of PTSA.
The hydrazone intermediate 7 (R¼Ph) was isolated in 65% yield.
g
h
K2CO3) failed due to the fast spontaneous air oxidation of 1h
into the hydroxy derivative 12.21,22
led to the dealkoxycarbonylation product 14 (Scheme 7).
The use of the methyl chloroester 4d instead of 4e (to pre-
vent dealkoxycarbonylation) was accompanied by tarring
and afforded a complex mixture of products. However, the
a-hydroxylactam 15 (as HCl-salt) was detected as a main
product by LC/MS and NMR analyses of the crude mixture
The tert-butyl chloroester 4e when treated with isobutyl-
amine at 130 ꢀC gave mainly the Cl-substitution product
13. Subsequent heating of the reaction mixture at 170 ꢀC
N
Cl
Et
i-BuNH2
N
N
NH
i-BuNH2
N
N
N
NH2
N
N
N
CN
NH
N
N
H
N
Et
Et
Et
5b
11
N
N
N
N
N
N
N
[O]
H
N
-NH3
OH
Et
Et
1h
12
Scheme 6.

D. S. Chekmarev et al. / Tetrahedron 62 (2006) 9919–9930
9923
N
N
Cl
i-BuNH2
130 °C
N
N
NH
CO2Bu-t
N
N
NH
Me
CO2Bu-t
170 °C
Me
4e
Me
14, 56% for two steps
13
Scheme 7.
N
Cl
N
N
N
NH
CO2Me
Me
i-BuNH2
170 °C
N
N
O
[O]
N
O
CO2Me
N
N
N
OH
Me
15
Me
Me
4d
Scheme 8.
after treatment with aq HCl, thus, indicating that the acidic
conditions did not prevent from the oxidation in this case
(Scheme 8).21 The product 1522 was then isolated in pure
form (but only in 30% yield) by column chromatography
of the free base.
Ebra 1106 and 1500 instruments. Infrared (IR) spectra
reported in this paper were measured as thin films (from
dichloromethane solution) on KBr disks or as KBr pellets,
using a Bruker Equinox 55 FT-IR instrument, wave numbers
are given in cmꢁ1. In vacuo refers to evaporation at reduced
pressure using a rotary evaporator and diaphragm pump, fol-
lowed by the removal of trace volatiles using a vacuum (oil)
pump.
3. Conclusion
The results presented here suggest a novel and highly effi-
cient synthesis of the potent CDKs (cyclin-dependent
kinases) inhibitors, aloisines (substituted [5H]pyrrolo[2,3-
b]pyrazines). The suggested approach is based on highly
selective monosubstitution of a single chlorine atom in com-
mercially available 2,3-dichloropyrazine with Li-derivatives
of ketones, esters, and nitriles followed by co-cyclization
of the resulting intermediates with primary amines or hydra-
zines. Compared with other reports, this methodology
delivers the desired products in higher yield and allows to
synthesize a wide range of aloisines where R1–R3 substitu-
ents can be varied independently.
4.2. General procedure for the reactions of 2,3-dichloro-
pyrazine (2) with ketones, esters, and nitriles in the
presence of LiHMDS (Table 1)
LiHMDS (770 mg, 4.60 mmol) and 2 (298 mg, 2.00 mmol)
were suspended in 4 mL of toluene in a screw-capped vial
containing a stirbar. A ketone, an ester, or a nitrile
(2.20 mmol) in 2 mL of toluene was added dropwise to
this suspension. The vial was sealed with a cap containing
a PTFE septum and removed from the drybox. The reaction
mixture was stirred at room temperature or at 60 ꢀC for the
time specified. After cooling, if necessary, the reaction mix-
ture was diluted with Et2O (20 mL) and was quenched with
saturated aq NH4Cl (10 mL). The organic phase was washed
with a saturated NaCl solution (10 mL), dried over Na2SO4,
filtered, and concentrated in vacuo. The residue was purified
by column chromatography on silica gel using 15% ethyl
acetate in hexanes, unless otherwise stated.
4. Experimental
4.1. General
All manipulations were carried out in a nitrogen-filled glove-
box, unless otherwise stated. Toluene and xylene were
distilled under nitrogen from molten sodium. 2,3-Dichloro-
pyrazine (2) was purchased from Aldrich Chemical Co. and
Pyrazine Specialties, Inc. Lithium hexamethyldisilazide
(LiHMDS) was purchased from Aldrich; the bulk of this
material was stored in a nitrogen-filled glovebox. All other
reagents were available from commercial sources and were
used without further purification. Melting points (mp)
were determined on a Kofler hot stage apparatus and are un-
4.2.1. 2-(3-Chloropyrazin-2-yl)-1-phenylethanone, 3a
(Table 1, entry 1). The general procedure was followed.
1-Phenylethanone (265 mg, 2.20 mmol) was used. The reac-
tion was carried out at room temperature for 24 h. The prod-
uct was isolated as ketone and enol mixture. The yield was
1
288 mg (62%), yellow viscous oil. H NMR (DMSO-d6)
for the keto form, d 4.82 (s, 2H), 7.55–7.61 (m, 2H), 7.68–
7.73 (m, 1H), 8.06–8.10 (m, 2H), 8.47 (d, J¼2.6 Hz, 1H),
8.64 (d, J¼2.6 Hz, 1H); for the enol form, d 6.54 (s, 1H),
7.49–7.53 (m, 3H), 7.88–7.92 (m, 2H), 8.25 (d, J¼2.8 Hz,
1H), 8.50 (d, J¼2.8 Hz, 1H), 14.29 (s, 1H). 13C NMR
(DMSO-d6) for the keto form, d 45.53, 128.31, 128.92,
133.84, 135.98, 142.90, 149.01, 151.08, 195.36; for the
enol form, d 89.59, 125.65, 128.80, 130.74, 134.54,
138.55, 138.66, 144.12, 151.26, 165.94. IR, nmax: 3432,
1
corrected. H and 13C NMR spectra were recorded at 400
and 100 MHz, respectively, on a Bruker DRX 400 Avance
spectrometer. Low-resolution mass analyses (MS) were
performed on an Agilent 1100 LC/MS SL series instrument
using atmospheric pressure chemical ionization (APCI) in-
terface. Elemental analyses were carried out with Carlo-

9924
D. S. Chekmarev et al. / Tetrahedron 62 (2006) 9919–9930
2923, 1627, 1576, 1492, 1452, 1432, 1247, 1148, 1072, 899,
774, 743, 688, 466 cmꢁ1. LC/MS: expected, 232.67; ob-
served, m/z: 233.0 [M+H]+. Anal. Calcd for C12H9ClN2O
(232.67): C, 61.95; H, 3.90; Cl, 15.24; N, 12.04. Found: C,
61.87; H, 3.77; Cl, 14.98; N, 12.03.
150.88, 151.18, 163.73. IR, nmax: 3431, 3071, 2924, 2853,
1626, 1490, 1439, 1378, 1256, 1152, 1077, 1019, 845,
793, 751, 696, 473 cmꢁ1. LC/MS: expected, 233.66; ob-
served, m/z: 234.0 [M+H]+. Anal. Calcd for C11H8ClN3O
(233.66): C, 56.55; H, 3.45; Cl, 15.17; N, 17.98. Found: C,
56.51; H, 3.37; Cl, 15.01; N, 17.94.
4.2.2. 2-(3-Chloropyrazin-2-yl)-1-phenylbutan-1-one, 3b
(Table 1, entries 2–4). The general procedure was followed.
1-Phenylbutan-1-one (326 mg, 2.20 mmol) was used. The
reaction was carried out at 60 ꢀC for 24 h. The yield was
4.2.5. 2-(3-Chloropyrazin-2-yl)-1-(2-furyl)ethanone, 3e
(Table 1, entry 8). The general procedure was followed.
1-(2-Furyl)ethanone (242 mg, 2.20 mmol) was used. The re-
action was carried out at room temperature for 24 h. The
product was isolated by column chromatography on silica
gel using 30% ethyl acetate in hexanes as ketone and enol
mixture. The yield was 225 mg (50%), yellow viscous oil.
1H NMR (DMSO-d6) for the keto form, d 4.60 (s, 2H),
6.78 (dd, J¼3.7, 1.7 Hz, 1H), 7.63 (dd, J¼3.7, 0.7 Hz,
1H), 8.06 (dd, J¼1.7, 0.7 Hz, 1H), 8.47 (d, J¼2.5 Hz, 1H),
8.64 (d, J¼2.5 Hz, 1H); for the enol form, d 6.36 (s, 1H),
6.68–6.71 (m, 1H), 7.04–7.06 (m, 1H), 7.90–7.91 (m, 1H),
8.20 (d, J¼2.7 Hz, 1H), 8.44 (d, J¼2.7 Hz, 1H), 13.84 (s,
1H). 13C NMR (DMSO-d6) for the keto form, d 44.89,
112.83, 119.67, 142.94, 143.04, 148.44, 148.84, 150.33,
151.30, 183.27. IR, nmax: 3341, 3132, 2926, 2854, 1677,
1636, 1570, 1466, 1385, 1331, 1276, 1215, 1150, 1085,
1010, 883, 856, 762, 594, 464 cmꢁ1. LC/MS: expected,
222.63; observed, m/z: 223.1 [M+H]+. Anal. Calcd for
C10H7ClN2O2 (222.63): C, 53.95; H, 3.17; Cl, 15.92; N,
12.58. Found: C, 54.15; H, 3.24; Cl, 15.74; N, 12.40.
1
500 mg (96%), yellow viscous oil. H NMR (DMSO-d6)
d 0.94 (t, J¼7.3 Hz, 3H), 1.96–2.16 (m, 2H), 5.21 (dd,
J¼7.7, 5.8 Hz, 1H), 7.48–7.54 (m, 2H), 7.58–7.63 (m,
1H), 7.91–7.95 (m, 2H), 8.41 (d, J¼2.4 Hz, 1H), 8.61 (d,
J¼2.4 Hz, 1H). 13C NMR (DMSO-d6) d 11.90, 23.46,
52.48, 128.07, 128.95, 133.36, 136.11, 142.78, 143.03,
148.35, 153.45, 197.45. IR, nmax: 3057, 2967, 2933, 2875,
1689, 1596, 1447, 1383, 1341, 1281, 1213, 1145, 1101,
1054, 988, 842, 744, 723, 692, 664, 470 cmꢁ1. LC/MS: ex-
pected, 260.73; observed, m/z: 261.1 [M+H]+. Anal. Calcd
for C14H13ClN2O (260.73): C, 64.50; H, 5.03; Cl, 13.60;
N, 10.74. Found: C, 64.69; H, 4.94; Cl, 13.49; N, 10.72.
4.2.3. 2-(3-Chloropyrazin-2-yl)-1-pyridin-4-ylethanone,
3c (Table 1, entries 5 and 6). The general procedure was
followed. 1-Pyridin-4-ylethanone (267 mg, 2.20 mmol)
was used. The reaction was carried out at 60 ꢀC for 24 h.
The product was isolated by column chromatography on sil-
ica gel using 30% hexanes in ethyl acetate as ketone and enol
mixture. The yield was 238 mg (51%), yellow solid, mp
123–125 ꢀC. 1H NMR (DMSO-d6) for the keto form,
d 4.87 (s, 2H), 7.91–7.94 (m, 2H), 8.49 (d, J¼2.6 Hz, 1H),
8.64 (d, J¼2.6 Hz, 1H), 8.85–8.87 (m, 2H); for the enol
form, d 6.71 (s, 1H), 7.81–7.84 (m, 2H), 8.35 (d,
J¼2.7 Hz, 1H), 8.56 (d, J¼2.7 Hz, 1H), 8.70–8.73 (m,
2H), 14.20 (s, 1H). 13C NMR (DMSO-d6) for the keto
form, d 45.69, 121.34, 141.84, 142.97, 143.13, 148.89,
150.40, 151.01, 195.81; for the enol form, d 92.06, 119.47,
138.97, 139.87, 141.66, 144.65, 150.38, 150.58, 162.64.
IR, nmax: 3428, 3028, 2922, 1623, 1593, 1554, 1491, 1435,
1410, 1254, 1149, 1074, 843, 814, 790, 751, 659,
448 cmꢁ1. LC/MS: expected, 233.66; observed, m/z: 234.0
[M+H]+. Anal. Calcd for C11H8ClN3O (233.66): C, 56.55;
H, 3.45; Cl, 15.17; N, 17.98. Found: C, 56.44; H, 3.39; Cl,
14.88; N, 17.93.
4.2.6. 2-(3-Chloropyrazin-2-yl)-1-(3-thienyl)ethanone, 3f
(Table 1, entry 9). The general procedure was followed.
1-(3-Thienyl)ethanone (277 mg, 2.20 mmol) was used.
The reaction was carried out at 60 ꢀC for 24 h. The product
was isolated by column chromatography on silica gel using
30% ethyl acetate in hexanes as ketone and enol mixture.
1
The yield was 290 mg (61%), yellow viscous oil. H NMR
(DMSO-d6) for the keto form, d 4.72 (s, 2H), 7.56–7.58
(m, 1H), 7.67–7.70 (m, 1H), 8.47 (d, J¼2.6 Hz, 1H), 8.64
(d, J¼2.6 Hz, 1H), 8.63–8.65 (m, 1H); for the enol form,
d 6.42 (s, 1H), 7.57–7.59 (m, 1H), 7.65–7.68 (m, 1H),
8.11–8.13 (m, 1H), 8.21 (d, J¼2.8 Hz, 1H), 8.47 (d,
J¼2.8 Hz, 1H), 14.06 (s, 1H); for the keto form, d 46.40,
126.55, 127.85, 134.85, 141.11, 142.92, 148.99, 150.76,
189.46; for the enol form, d 89.75, 125.23, 127.62, 131.61,
137.49, 138.18, 138.72, 148.11, 151.59, 162.34. IR, nmax
:
3336, 3104, 2922, 1675, 1618, 1509, 1491, 1413, 1383,
1317, 1260, 1229, 1175, 1148, 1085, 1061, 1010, 878,
790, 636, 464 cmꢁ1. LC/MS: expected, 238.70; observed,
m/z: 239.2 [M+H]+. Anal. Calcd for C10H7ClN2OS
(238.70): C, 50.32; H, 2.96; Cl, 14.85; N, 11.74; S, 13.43.
Found: C, 50.58; H, 2.91; Cl, 14.45; N, 11.49; S, 13.68.
4.2.4. 2-(3-Chloropyrazin-2-yl)-1-pyridin-3-ylethanone,
3d (Table 1, entry 7). The general procedure was followed.
1-Pyridin-3-ylethanone (267 mg, 2.20 mmol) was used. The
reaction was carried out at 60 ꢀC for 24 h. The product was
isolated by column chromatography on silica gel using 30%
hexanes in ethyl acetate as ketone and enol mixture. The
yield was 245 mg (53%), yellow solid, mp 126–128 ꢀC. 1H
NMR (DMSO-d6) for the keto form, d 4.88 (s, 2H), 7.58–
7.64 (m, 1H), 8.37–8.42 (m, 1H), 8.48 (d, J¼2.7 Hz, 1H),
8.64 (d, J¼2.7 Hz, 1H), 8.83–8.86 (m, 1H), 9.24–9.26 (m,
1H); for the enol form, d 6.59 (s, 1H), 7.49–7.54 (m, 1H),
8.24–8.27 (m, 1H), 8.28 (d, J¼2.7 Hz, 1H), 8.51 (d,
J¼2.7 Hz, 1H), 8.66–8.69 (m, 1H), 9.06–9.08 (m, 1H),
14.31 (s, 1H). 13C NMR (DMSO-d6) for the keto form,
d 45.69, 124.04, 131.35, 135.84, 142.95, 143.04, 148.98,
149.59, 150.62, 153.98, 195.03; for the enol form, d 90.74,
123.79, 130.36, 133.26, 138.62, 139.08, 144.30, 146.80,
4.2.7. 2-(3-Chloropyrazin-2-yl)-1-(2-thienyl)propan-1-
one, 3g (Table 1, entry 10). The general procedure was
followed. 1-(2-Thienyl)propan-1-one (308 mg, 2.20 mmol)
was used. The reaction was carried out at 60 ꢀC for 24 h.
The residue was purified by column chromatography on
silica gel using 30% ethyl acetate in hexanes. The yield
1
was 429 mg (85%), yellow solid, mp 70–71 ꢀC. H NMR
(DMSO-d6) d 1.55 (d, J¼6.9 Hz, 3H), 5.24 (q, J¼6.9 Hz,
1H), 7.22–7.26 (m, 1H), 7.91–7.94 (m, 1H), 7.99–8.03 (m,
1H), 8.45 (d, J¼2.5 Hz, 1H), 8.65 (d, J¼2.5 Hz, 1H). 13C
NMR (DMSO-d6) d 15.84, 47.21, 128.92, 133.42, 135.30,

D. S. Chekmarev et al. / Tetrahedron 62 (2006) 9919–9930
9925
142.47, 142.92, 142.97, 147.89, 154.07, 191.30. IR, nmax
:
47.89; H, 4.52; Cl, 17.67; N, 13.96. Found: C, 48.19; H,
4.66; Cl, 17.44; N, 13.74.
3314, 3083, 3008, 2938, 1666, 1512, 1411, 1384, 1273,
1229, 1140, 1090, 1051, 858, 733, 467 cmꢁ1. LC/MS: ex-
pected, 252.72; observed, m/z: 253.0 [M+H]+. Anal. Calcd
for C11H9ClN2OS (252.72): C, 52.28; H, 3.59; Cl, 14.03;
N, 11.08; S, 12.69. Found: C, 52.22; H, 3.60; Cl, 13.86; N,
11.19; S, 12.59.
4.2.12. tert-Butyl (3-chloropyrazin-2-yl)acetate, 4c (Table
1, entry 17). The general procedure was followed. tert-Butyl
acetate (256 mg, 2.20 mmol) was used. The reaction was
carried out at room temperature for 24 h. The yield was
1
420 mg (92%), pale yellow viscous oil. H NMR (DMSO-
4.2.8. 2-(3-Chloropyrazin-2-yl)-2-methyl-1-phenyl-
propan-1-one, 3h (Table 1, entries 11–13). The general
procedure was followed. 2-Methyl-1-phenylpropan-1-one
(326 mg, 2.20 mmol) was used. The reaction was carried
out at 60 ꢀC for 24 h. The yield was 43 mg (8%), yellow vis-
cous oil. 1H NMR (DMSO-d6) d 1.71 (s, 6H), 7.29–7.35 (m,
2H), 7.43–7.55 (m, 3H), 8.47 (d, J¼2.5 Hz, 1H), 8.81 (d,
J¼2.5 Hz, 1H). 13C NMR (DMSO-d6) d 25.32, 53.13,
128.41, 128.49, 132.69, 135.03, 142.96, 142.99, 147.06,
157.18, 199.72. IR, nmax: 3058, 2982, 2930, 1681, 1465,
d6) d 1.40 (s, 9H), 3.95 (s, 2H), 8.46 (d, J¼2.4 Hz, 1H),
8.61 (d, J¼2.4 Hz, 1H). 13C NMR (DMSO-d6) d 27.62,
42.30, 81.27, 142.82, 143.06, 148.62, 149.84, 167.78. IR,
nmax: 3435, 2986, 2927, 1727, 1407, 1386, 1369, 1339,
1269, 1208, 1155, 1087, 1064, 893, 838, 758, 457 cmꢁ1
.
LC/MS: expected, 228.68; observed, m/z: 172.0
[MꢁC4H9+H]+. Anal. Calcd for C10H13ClN2O2 (228.68):
C, 52.52; H, 5.73; Cl, 15.50; N, 12.25. Found: C, 52.82;
H, 5.95; Cl, 15.39; N, 12.07.
1363, 1245, 1152, 1119, 1061, 973, 864, 718, 481 cmꢁ1
.
4.2.13. Methyl 2-(3-chloropyrazin-2-yl)propanoate, 4d
(Table 1, entry 18). The general procedure was followed.
Methyl propionate (194 mg, 2.2 mmol) was used. The reac-
tion was carried out at room temperature for 24 h. The yield
was 105 mg (26%), pale yellow viscous oil. 1H NMR
(DMSO-d6) d 1.48 (d, J¼7.1 Hz, 3H), 3.62 (s, 3H), 4.35
(q, J¼7.1 Hz, 1H), 8.46 (d, J¼2.5 Hz, 1H), 8.65 (d,
J¼2.5 Hz, 1H). 13C NMR (DMSO-d6) d 15.14, 43.75,
LC/MS: expected, 260.73; observed, m/z: 261.1 [M+H]+.
Anal. Calcd for C14H13ClN2O (260.73): C, 64.50; H, 5.03;
Cl, 13.60; N, 10.74. Found: C, 64.65; H, 4.90; Cl, 13.51;
N, 10.70.
4.2.9. 1-(3-Chloropyrazin-2-yl)acetone, 3i (Table 1, entry
14). The general procedure was followed. Acetone (128 mg,
2.20 mmol) was used. The reaction was carried out at room
temperature for 24 h. The yield was 71 mg (21%), yellow
52.20, 142.97, 143.08, 147.76, 153.45, 171.94. IR, nmax
:
3471, 2991, 2952, 1744, 1522, 1455, 1386, 1322, 1289,
1204, 1150, 1103, 1056, 966, 865, 705, 461 cmꢁ1. LC/MS:
expected, 200.63; observed, m/z: 201.1 [M+H]+. Anal. Calcd
for C8H9ClN2O2 (200.63): C, 47.89; H, 4.52; Cl, 17.67; N,
13.96. Found: C, 48.05; H, 4.54; Cl, 17.47; N, 13.84.
1
viscous oil. H NMR (DMSO-d6) d 2.27 (s, 3H), 4.21 (s,
2H), 8.43 (d, J¼2.5 Hz, 1H), 8.61 (d, J¼2.5 Hz, 1H). 13C
NMR (DMSO-d6) d 30.07, 49.62, 142.86, 142.90, 148.78,
150.54, 203.53. IR, nmax: 3054, 2925, 2853, 1725, 1666,
1449, 1383, 1194, 1145, 1087, 1061, 864, 463 cmꢁ1. LC/
MS: expected, 170.60; observed, m/z: 171.0 [M+H]+. Anal.
Calcd for C7H7ClN2O (170.60): C, 49.28; H, 4.14; Cl,
20.78; N, 16.42. Found: C, 49.22; H, 4.06; Cl, 20.61; N, 16.53.
4.2.14. tert-Butyl 2-(3-chloropyrazin-2-yl)propanoate, 4e
(Table 1, entry 19). The general procedure was followed.
tert-Butyl propionate (286 mg, 2.20 mmol) was used. The
reaction was carried out at room temperature for 24 h. The
yield was 400 mg (82%), pale yellow viscous oil. 1H NMR
(DMSO-d6) d 1.34 (s, 9H), 1.46 (d, J¼7.1 Hz, 3H), 4.19
(q, J¼7.1 Hz, 1H), 8.44 (d, J¼2.4 Hz, 1H), 8.64 (d,
J¼2.4 Hz, 1H). 13C NMR (DMSO-d6) d 14.86, 27.51,
4.2.10. Methyl (3-chloropyrazin-2-yl)acetate, 4a (Table 1,
entry 15). The general procedure was followed. Methyl
acetate (163 mg, 2.20 mmol) was used. The reaction was
carried out at room temperature for 24 h. The yield was
1
157 mg (42%), pale yellow viscous oil. H NMR (DMSO-
d6) d 3.66 (s, 3H), 4.07 (s, 2H), 8.47 (d, J¼2.5 Hz, 1H),
44.77, 80.81, 142.74, 148.04, 153.66, 170.69. IR, nmax:
3451, 2979, 2938, 1734, 1457, 1384, 1369, 1322, 1288,
1252, 1149, 1102, 1052, 850, 752 cmꢁ1. LC/MS: expected,
242.71; observed, m/z: 187.0 [MꢁC4H9+H]+. Anal. Calcd
for C11H15ClN2O2 (242.71): C, 54.44; H, 6.23; Cl, 14.61;
N, 11.54. Found: C, 54.46; H, 6.34; Cl, 14.82; N, 11.41.
8.63 (d, J¼2.5 Hz, 1H). 13C NMR (DMSO-d6) d 40.86,
52.18, 142.94, 143.30, 148.49, 149.43, 169.13. IR, nmax
:
3465, 3001, 2954, 1743, 1521, 1437, 1386, 1339, 1266,
1199, 1175, 1087, 1012, 864, 691, 577, 466 cmꢁ1. LC/MS:
expected, 186.60; observed, m/z: 187.1 [M+H]+. Anal. Calcd
for C7H7ClN2O2 (186.60): C, 45.06; H, 3.78; Cl, 19.00; N,
15.01. Found: C, 45.23; H, 3.69; Cl, 18.93; N, 14.95.
4.2.15. tert-Butyl (3-chloropyrazin-2-yl)(phenyl)acetate,
4f (Table 1, entry 20). The general procedure was followed.
tert-Butyl phenylacetate (422 mg, 2.20 mmol) was used.
The reaction was carried out at room temperature for 24 h.
4.2.11. Ethyl (3-chloropyrazin-2-yl)acetate, 4b (Table 1,
entry 16). The general procedure was followed. Ethyl ace-
tate (194 mg, 2.20 mmol) was used. The reaction was car-
ried out at room temperature for 24 h. The yield was
1
The yield was 523 mg (86%), pale yellow viscous oil. H
NMR (DMSO-d6) d 1.37 (s, 9H), 5.51 (s, 1H), 7.27–7.39
(m, 5H), 8.46 (d, J¼2.5 Hz, 1H), 8.63 (d, J¼2.5 Hz, 1H).
13C NMR (DMSO-d6) d 27.55, 56.03, 81.47, 127.49,
128.25, 129.72, 135.18, 142.67, 143.02, 148.06, 152.61,
168.71. IR, nmax: 3443, 3062, 2978, 2932, 1742, 1497,
1454, 1375, 1300, 1258, 1211, 1142, 1079, 1058, 965,
858, 747, 720, 698, 577, 470 cmꢁ1. LC/MS: expected,
304.78; observed, m/z: 249.0 [MꢁC4H9+H]+. Anal. Calcd
for C16H17ClN2O2 (304.78): C, 63.05; H, 5.62; Cl, 11.63;
N, 9.19. Found: C, 63.10; H, 5.61; Cl, 11.52; N, 9.14.
1
200 mg (50%), pale yellow viscous oil. H NMR (DMSO-
d6) d 1.19 (t, J¼7.1 Hz, 3H), 4.05 (s, 2H), 4.13 (q,
J¼7.1 Hz, 3H), 8.47 (d, J¼2.4 Hz, 1H), 8.63 (d, J¼2.4 Hz,
1H). 13C NMR (DMSO-d6) d 13.99, 41.09, 60.89, 142.90,
143.24, 148.53, 149.52, 168.62. IR, nmax: 2982, 2935,
1739, 1448, 1386, 1333, 1264, 1186, 1086, 1062, 1028,
849, 466 cmꢁ1. LC/MS: expected, 200.63; observed, m/z:
201.1 [M+H]+. Anal. Calcd for C8H9ClN2O2 (200.63): C,

9926
D. S. Chekmarev et al. / Tetrahedron 62 (2006) 9919–9930
4.2.16. tert-Butyl 2-(3-chloropyrazin-2-yl)-2-methylpro-
panoate, 4g (Table 1, entries 21 and 22). Thegeneral proce-
dure was followed. tert-Butyl 2-methylpropanoate (317 mg,
2.20 mmol) was used. The reaction was carried out at room
temperature for 24 h. The yield was 135 mg (26%), pale yel-
low viscous oil. 1H NMR (DMSO-d6) d 1.34 (s, 9H), 1.53 (s,
6H), 8.44 (d, J¼2.4 Hz, 1H), 8.64 (d, J¼2.4 Hz, 1H). 13C
NMR (DMSO-d6) d 24.27, 27.30, 49.08, 80.73, 141.91,
142.41, 149.06, 152.65, 171.22. IR, nmax: 3368, 2978,
2933, 1736, 1469, 1366, 1287, 1256, 1142, 1059, 847,
472 cmꢁ1. LC/MS: expected, 256.73; observed, m/z: 257.1
[M+H]+ (minor); 201.0 [MꢁC4H9+H]+. Anal. Calcd for
C12H17ClN2O2 (256.73): C, 56.14; H, 6.67; Cl, 13.81; N,
10.91. Found: C, 56.24; H, 6.56; Cl, 13.71; N, 10.84.
vessel was added PTSA (23 mg, 0.12 mmol). The pressure
vessel was sealed with a cap containing a PTFE septum
and removed from the drybox. The reaction mixture was
stirred and heated at the temperatures and for the times spec-
ified. After cooling, the reaction mixture was filtered through
a plug of Celite that was then washed with chloroform.
The combined organic phase was concentrated in vacuo.
The residue was purified by column chromatography on
silica gel using 20% ethyl acetate in hexanes, unless other-
wise stated.
4.3.1. 7-Ethyl-6-phenyl-5H-pyrrolo[2,3-b]pyrazine, 1a
(Table 2, entry 1). The general procedure was followed. A
solution of NH3 (1.6 M) in MeOH (2.25 mL, 3.60 mmol)
was used. The reaction was carried out at 170 ꢀC for 72 h.
The residue was purified by column chromatography on sil-
ica gel using 50% ethyl acetate in hexanes. The yield was
201 mg (75%), yellow solid, mp 200–202 ꢀC. 1H NMR
(DMSO-d6) d 1.29 (t, J¼7.5 Hz, 3H), 2.92 (q, J¼7.5 Hz,
2H), 7.43–7.49 (m, 1H), 7.53–7.59 (m, 2H), 7.68–7.73 (m,
2H), 8.22 (d, J¼2.6 Hz, 1H), 8.36 (d, J¼2.6 Hz, 1H),
12.07 (s, 1H). 13C NMR (DMSO-d6) d 14.99, 16.46,
112.83, 128.22, 128.50, 128.86, 131.73, 136.92, 137.59,
138.61, 139.45, 141.96. IR, nmax: 3432, 3152, 3058, 2961,
2928, 2868, 1471, 1398, 1342, 1221, 1177, 1145, 1113,
1043, 926, 842, 769, 696, 588, 446 cmꢁ1. LC/MS: expected,
223.28; observed, m/z: 224.1 [M+H]+. Anal. Calcd for
C14H13N3 (223.28): C, 75.31; H, 5.87; N, 18.82. Found: C,
74.93; H, 5.77; N, 18.56.
4.2.17. (3-Chloropyrazin-2-yl)acetonitrile, 5a (Table 1,
entry 23). The general procedure was followed. Acetonitrile
(90 mg, 2.20 mmol) was used. The reaction was carried out
at room temperature for 24 h. The yield was 292 mg (95%),
yellow viscous oil. 1H NMR (DMSO-d6) d 4.46 (s, 2H), 8.53
(d, J¼2.4 Hz, 1H), 8.69 (d, J¼2.4 Hz, 1H). 13C NMR
(DMSO-d6) d 24.55, 116.28, 142.88, 143.73, 146.54,
147.17. IR, nmax: 3494, 3061, 2915, 2263, 1530, 1447,
1393, 1303, 1192, 1149, 1083, 1062, 946, 854, 728, 483,
448 cmꢁ1. LC/MS: expected, 153.57; observed, m/z: 154.0
[M+H]+. Anal. Calcd for C6H4ClN3 (153.57): C, 46.93; H,
2.63; Cl, 23.09; N, 27.36. Found: C, 47.10; H, 2.70; Cl,
23.02; N, 27.16.
4.2.18. 2-(3-Chloropyrazin-2-yl)butanenitrile, 5b (Table
1, entry 24). The general procedure was followed. Butyro-
nitrile (152 mg, 2.20 mmol) was used. The reaction was
carried out at room temperature for 24 h. The yield was
4.3.2. 7-Ethyl-6-phenyl-5-propyl-5H-pyrrolo[2,3-b]pyra-
zine, 1b (Table 2, entries 2 and 3). The general procedure
was followed. Propylamine (213 mg, 3.60 mmol) was
used. The reaction was carried out at 160 ꢀC for 48 h. The
yield was 273 mg (86%), yellow viscous oil. 1H NMR
(DMSO-d6) d 0.60 (t, J¼7.4 Hz, 3H), 1.17 (t, J¼7.5 Hz,
3H), 1.42–1.54 (m, 2H), 2.66 (q, J¼7.5 Hz, 2H), 4.10 (t,
J¼7.4 Hz, 2H), 7.48–7.53 (m, 2H), 7.54–7.62 (m, 3H),
8.27 (d, J¼2.6 Hz, 1H), 8.41 (d, J¼2.6 Hz, 1H). 13C NMR
(DMSO-d6) d 10.93, 15.17, 16.44, 22.60, 43.36, 113.58,
128.79, 129.03, 129.92, 130.45, 136.54, 137.75, 138.43,
140.98, 141.38. IR, nmax: 3048, 2965, 2932, 2873, 1695,
1555, 1360, 1254, 1196, 1178, 1150, 1056, 949, 841, 764,
703, 567, 466 cmꢁ1. LC/MS: expected, 265.36; observed,
m/z: 266.0 [M+H]+. Anal. Calcd for C17H19N3 (265.36):
C, 76.95; H, 7.22; N, 15.84. Found: C, 76.69; H, 7.18; N,
15.55.
1
356 mg (98%), yellow viscous oil. H NMR (DMSO-d6)
d 1.04 (t, J¼7.3 Hz, 3H), 1.91–2.10 (m, 2H), 4.66 (dd,
J¼8.2, 6.0 Hz, 1H), 8.56 (d, J¼2.5 Hz, 1H), 8.73 (d,
J¼2.5 Hz, 1H). 13C NMR (DMSO-d6) d 11.15, 25.06,
37.42, 118.75, 143.17, 144.20, 146.93, 149.20. IR, nmax
:
3058, 2975, 2938, 2879, 2247, 1522, 1459, 1391, 1314,
1194, 1151, 1076, 1055, 865, 484 cmꢁ1. LC/MS: expected,
181.63; observed, m/z: 182.1 [M+H]+. Anal. Calcd for
C8H8ClN3 (181.63): C, 52.90; H, 4.44; Cl, 19.52; N,
23.14. Found: C, 52.73; H, 4.50; Cl, 19.33; N, 23.15.
4.2.19. 2-(3-Chloropyrazin-2-yl)-2-methylpropane-
nitrile, 5c (Table 1, entry 25). The general procedure was
followed. 2-Methylpropanenitrile (152 mg, 2.20 mmol) was
used. The reaction was carried out at room temperature for
1
24 h. The yield was 358 mg (98%), yellow viscous oil. H
NMR (DMSO-d6) d 1.82 (s, 6H), 8.58 (d, J¼2.4 Hz, 1H),
4.3.3. 7-Ethyl-5-isobutyl-6-phenyl-5H-pyrrolo[2,3-b]pyr-
azine, 1c (Table 2, entry 4). The general procedure was fol-
lowed. Isobutylamine (263 mg, 3.60 mmol) was used. The
reaction was carried out at 145 ꢀC for 72 h. The yield was
312 mg (93%), yellow solid, mp 97–99 ꢀC. 1H NMR
(DMSO-d6) d 0.56 (d, J¼6.7 Hz, 6H), 1.16 (t, J¼7.5 Hz,
3H), 1.71–1.83 (m, 1H), 2.66 (q, J¼7.5 Hz, 2H), 4.02 (d,
J¼7.6 Hz, 2H), 7.48–7.63 (m, 5H), 8.27 (d, J¼2.6 Hz,
1H), 8.41 (d, J¼2.6 Hz, 1H). 13C NMR (DMSO-d6)
d 15.19, 16.43, 19.66, 28.25, 48.90, 113.67, 128.76,
128.98, 129.99, 130.60, 136.56, 137.75, 138.29, 141.25,
141.48. IR, nmax: 3380, 3044, 2960, 2926, 2868, 1693,
1467, 1390, 1353, 1330, 1260, 1197, 1153, 1058, 949,
840, 769, 711, 583, 467, 439 cmꢁ1. LC/MS: expected,
279.39; observed, m/z: 280.2 [M+H]+. Anal. Calcd for
8.72 (d, J¼2.4 Hz, 1H). 13C NMR (DMSO-d6) d 25.44,
37.52, 122.01, 142.45, 144.11, 146.60, 150.83. IR, nmax
:
3053, 2993, 2943, 2239, 1723, 1524, 1466, 1362, 1268,
1210, 1149, 1121, 1058, 864, 774, 481, 449 cmꢁ1. LC/MS:
expected, 181.63; observed, m/z: 182.1 [M+H]+. Anal. Calcd
for C8H8ClN3 (181.63): C, 52.90; H, 4.44; Cl, 19.52;
N, 23.14. Found: C, 52.72; H, 4.55; Cl, 19.62; N, 23.15.
4.3. General procedure for the co-cyclization of the
chloroketone 3b with amines and hydrazines (Table 2)
To a solution of 3b (313 mg, 1.20 mmol) and an amine
(3.60 mmol) in 6 mL of xylene in a screw-cap glass pressure

D. S. Chekmarev et al. / Tetrahedron 62 (2006) 9919–9930
9927
C18H21N3 (279.39): C, 77.38; H, 7.58; N, 15.04. Found: C,
77.14; H, 7.34; N, 14.89.
residue was purified by column chromatography on silica
gel using 50% ethyl acetate in hexanes. The yield was
179 mg (63%), brown solid, mp 92–94 ꢀC. 1H NMR
(DMSO-d6) d 1.23 (t, J¼7.5 Hz, 3H), 2.76 (q, J¼7.5 Hz,
2H), 5.74 (s, 2H), 7.44–4.50 (m, 1H), 7.51–7.57 (m, 2H),
7.58–7.62 (m, 2H), 8.28 (d, J¼2.6 Hz, 1H), 8.40 (d,
J¼2.6 Hz, 1H). 13C NMR (DMSO-d6) d 15.30, 16.55,
110.58, 128.00, 128.34, 129.95, 130.66, 136.64, 136.66,
137.83, 140.64, 141.85. IR, nmax: 3347, 3267, 3053, 2962,
2925, 2863, 1580, 1444, 1350, 1198, 1170, 1126, 1069,
1024, 944, 833, 761, 699, 670, 558, 463 cmꢁ1. LC/MS: ex-
pected, 238.29; observed, m/z: 239.1 [M+H]+. Anal. Calcd
for C14H14N4 (238.29): C, 70.57; H, 5.92; N, 23.51. Found:
C, 70.86; H, 6.12; N, 23.31.
4.3.4. 5-Benzyl-7-ethyl-6-phenyl-5H-pyrrolo[2,3-b]pyra-
zine, 1d (Table 2, entries 5–7). The general procedure
was followed. Benzylamine (386 mg, 3.60 mmol) was
used. The reaction was carried out at 145 ꢀC for 48 h. The
yield was 357 mg (95%), yellow solid, mp 107–109 ꢀC. 1H
NMR (DMSO-d6) d 1.19 (t, J¼7.6 Hz, 3H), 2.69 (q,
J¼7.6 Hz, 2H), 5.38 (s, 2H), 6.75–6.79 (m, 2H), 7.12–7.18
(m, 3H), 7.37–7.42 (m, 2H), 7.48–7.52 (m, 3H), 8.29 (d,
J¼2.5 Hz, 1H), 8.45 (d, J¼2.5 Hz, 1H). 13C NMR
(DMSO-d6) d 15.11, 16.51, 45.02, 114.19, 126.36, 127.11,
128.38, 128.69, 129.09, 130.02, 136.94, 137.76, 138.17,
138.61, 141.10, 141.46. IR, nmax: 3429, 3050, 2964, 2930,
2871, 1457, 1397, 1357, 1195, 1160, 1067, 940, 839, 766,
731, 701, 462 cmꢁ1. LC/MS: expected, 313.41; observed,
m/z: 314.1 [M+H]+. Anal. Calcd for C21H19N3 (313.41):
C, 80.48; H, 6.11; N, 13.41. Found: C, 80.19; H, 5.99; N,
13.29.
4.3.8. 4-Ethyl-3-phenyl-1,4-dihydropyrazino[2,3-c]pyr-
idazine, 6a (Table 2, entry 11). The general procedure
was followed. Hydrazine hydrate (180 mg, 3.60 mmol)
was used. The reaction was carried out at 160 ꢀC for 72 h.
The residue was purified by column chromatography on sil-
ica gel using 50% ethyl acetate in hexanes. The yield was
101 mg (35%), brown solid, mp 193–195 ꢀC. 1H NMR
(DMSO-d6) d 0.73 (t, J¼7.4 Hz, 3H), 1.56–1.69 (m, 2H),
4.42 (dd, J¼7.0, 5.0 Hz, 1H), 7.34–7.46 (m, 3H), 7.85–
7.90 (m, 2H), 8.12 (d, J¼2.5 Hz, 1H), 8.15 (d, J¼2.5 Hz,
1H), 10.85 (s, 1H). 13C NMR (DMSO-d6) d 9.87, 26.06,
40.35, 125.44, 128.62, 128.77, 135.64, 136.22, 138.28,
141.28, 144.32, 146.43. IR, nmax: 3430, 3223, 3133, 3011,
2962, 2923, 1542, 1427, 1364, 1190, 1123, 1075, 955,
835, 760, 688, 600 cmꢁ1. LC/MS: expected, 238.29; ob-
served, m/z: 239.1 [M+H]+. Anal. Calcd for C14H14N4
(238.29): C, 70.57; H, 5.92; N, 23.51. Found: C, 70.28; H,
6.12; N, 23.24.
4.3.5. 2-(7-Ethyl-6-phenyl-5H-pyrrolo[2,3-b]pyrazin-5-
yl)ethanol, 1e (Table 2, entry 8). The general procedure
was followed. 2-Aminoethanol (220 mg, 3.60 mmol) was
used. The reaction was carried out at 145 ꢀC for 72 h. The
residue was purified by column chromatography on silica
gel using 30% hexanes in ethyl acetate. The yield was
208 mg (65%), yellow solid, mp 155–157 ꢀC. 1H NMR
(DMSO-d6) d 1.17 (t, J¼7.5 Hz, 3H), 2.65 (q, J¼7.5 Hz,
2H), 3.52–3.58 (m, 2H), 4.18 (t, J¼6.5 Hz, 2H), 4.78 (t,
J¼5.6 Hz, 1H), 7.51–7.61 (m, 5H), 8.27 (d, J¼2.6 Hz,
1H), 8.42 (d, J¼2.6 Hz, 1H). 13C NMR (DMSO-d6)
d 15.15, 16.51, 44.50, 59.06, 113.47, 128.67, 128.97,
130.24, 130.35, 136.44, 137.74, 138.60, 141.14, 141.81.
IR, nmax: 3278, 3052, 2929, 2879, 1465, 1434, 1399, 1366,
1341, 1193, 1164, 1063, 940, 844, 761, 708, 656, 508,
457 cmꢁ1. LC/MS: expected, 267.33; observed, m/z: 268.1
[M+H]+. Anal. Calcd for C16H17N3O (267.33): C, 71.89;
H, 6.41; N, 15.72. Found: C, 71.98; H, 6.55; N, 15.52.
4.3.9. 4-Ethyl-1,3-diphenyl-1,4-dihydropyrazino[2,3-
c]pyridazine, 6b (Table 2, entries 12 and 13). The general
procedure was followed. Phenylhydrazine (390 mg,
3.60 mmol) was used. The reaction was carried out at
150 ꢀC for 72 h. The residue was purified by column chro-
matography on silica gel using 20% hexanes in ethyl acetate.
The yield was 238 mg (63%), brown solid, mp 141–143 ꢀC.
1H NMR (DMSO-d6) d 0.83 (t, J¼7.5 Hz, 3H), 1.70–1.80
(m, 2H), 4.56 (dd, J¼7.0, 5.3 Hz, 1H), 7.25–7.31 (m, 1H),
7.43–7.50 (m, 5H), 7.62–7.66 (m, 2H), 7.96–8.01 (m, 2H),
8.15 (d, J¼2.7 Hz, 1H), 8.32 (d, J¼2.7 Hz, 1H). 13C NMR
(DMSO-d6) d 10.06, 26.10, 41.18, 124.50, 125.61, 126.04,
128.56, 128.78, 129.49, 134.79, 137.84, 139.56, 140.60,
142.02, 145.36, 146.31. IR, nmax: 3428, 3059, 2958, 2920,
2852, 1592, 1492, 1416, 1374, 1290, 1184, 1154, 1121,
1058, 957, 843, 768, 734, 691, 575, 479 cmꢁ1. LC/MS: ex-
pected, 314.39; observed, m/z: 315.1 [M+H]+. Anal. Calcd
for C20H18N4 (314.39): C, 76.41; H, 5.77; N, 17.82. Found:
C, 76.27; H, 5.65; N, 17.65.
4.3.6. 7-Ethyl-5-(4-methoxyphenyl)-6-phenyl-5H-
pyrrolo[2,3-b]pyrazine, 1f (Table 2, entries 9 and 10).
The general procedure was followed. 4-Methoxyaniline
(443 mg, 3.60 mmol) was used. The reaction was carried
out at 145 ꢀC for 72 h. The yield was 387 mg (98%), dark
1
brown solid, mp 132–134 ꢀC. H NMR (DMSO-d6) d 1.27
(t, J¼7.5 Hz, 3H), 2.80 (q, J¼7.5 Hz, 2H), 3.75 (s, 3H),
6.89–6.94 (m, 2H), 7.14–7.20 (m, 2H), 7.30–7.35 (m, 2H),
7.35–7.42 (m, 3H), 8.23 (d, J¼2.6 Hz, 1H), 8.48 (d,
J¼2.6 Hz, 1H). 13C NMR (DMSO-d6) d 15.03, 16.59,
55.31, 114.01, 114.60, 128.34, 128.38, 128.50, 129.50,
130.25, 130.32, 137.30, 138.59, 138.77, 141.31, 142.19,
158.29. IR, nmax: 3429, 3059, 2964, 2934, 2872, 1608,
1515, 1442, 1348, 1291, 1250, 1208, 1170, 1105, 1023,
831, 766, 699, 577, 452 cmꢁ1. LC/MS: expected, 329.41;
observed, m/z: 330.1 [M+H]+. Anal. Calcd for C21H19N3O
(329.41): C, 76.57; H, 5.81; N, 12.76. Found: C, 76.57;
H, 5.85; N, 12.65.
4.3.10. 4-Ethyl-1-methyl-3-phenyl-1,4-dihydropyra-
zino[2,3-c]pyridazine, 6c (Table 2, entry 14). The general
procedure was followed. Methylhydrazine (166 mg,
3.60 mmol) was used. The reaction was carried out at
170 ꢀC for 72 h. The residue was purified by column chro-
matography on silica gel using 20% hexanes in ethyl ace-
tate. The yield was 197 mg (65%), brown viscous oil.
1H NMR (DMSO-d6) d 0.72 (t, J¼7.5 Hz, 3H), 1.52–
1.71 (m, 2H), 3.56 (s, 3H), 4.43 (dd, J¼7.6, 4.9 Hz, 1H),
4.3.7. 7-Ethyl-6-phenyl-5H-pyrrolo[2,3-b]pyrazin-5-
amine, 1g (Table 2, entry 11). The general procedure was
followed. Hydrazine hydrate (180 mg, 3.60 mmol) was
used. The reaction was carried out at 160 ꢀC for 72 h. The

9928
D. S. Chekmarev et al. / Tetrahedron 62 (2006) 9919–9930
7.38–7.47 (m, 3H), 7.87–7.92 (m, 2H), 8.18 (d, J¼2.7 Hz,
1H), 8.21 (d, J¼2.7 Hz, 1H). 13C NMR (DMSO-d6)
d 9.97, 25.88, 38.12, 40.91, 125.59, 128.65, 129.03,
4.4.2. 6-Pyridin-4-ylfuro[2,3-b]pyrazine, 10b. The general
procedure was followed. Intermediate 3c (234 mg,
1.00 mmol) was used. The residue was purified by column
chromatography on silica gel using pure ethyl acetate. The
135.03, 137.66, 137.72, 140.89, 144.50, 146.21. IR, nmax
:
1
3054, 2965, 2929, 2873, 1700, 1562, 1534, 1435, 1399,
1365, 1308, 1186, 1118, 1079, 1025, 954, 839, 767, 693,
658, 566, 509 cmꢁ1. LC/MS: expected, 252.32; observed,
m/z: 253.1 [M+H]+. Anal. Calcd for C15H16N4 (252.32):
C, 71.40; H, 6.39; N, 22.20. Found: C, 71.11; H, 6.19; N,
22.01.
yield was 165 mg (84%), brown solid, mp 224–225 ꢀC. H
NMR (DMSO-d6) d 7.96–8.00 (m, 2H), 8.12 (s, 1H), 8.43
(d, J¼2.7 Hz, 1H), 8.70 (d, J¼2.7 Hz, 1H), 8.76–8.79 (m,
2H). 13C NMR (DMSO-d6) d 105.72, 119.08, 135.37,
139.05, 141.04, 142.67, 150.68, 155.28, 156.47. IR, nmax
:
3431, 3071, 3032, 2924, 1606, 1554, 1490, 1416, 1367,
1272, 1197, 1028, 849, 821, 784, 670, 441 cmꢁ1. LC/MS:
expected, 197.20; observed, m/z: 198.1 [M+H]+. Anal. Calcd
for C11H7N3O (197.20): C, 67.00; H, 3.58; N, 21.31. Found:
C, 67.13; H, 3.61; N, 21.20.
4.3.11. (1Z)-2-(3-Chloropyrazin-2-yl)-1-phenylbutan-1-
one phenylhydrazone, 7. The general procedure was fol-
lowed. Phenylhydrazine (390 mg, 3.60 mmol) was used.
The reaction was carried out at 150 ꢀC for 72 h in the
absence of PTSA. The residue was purified by column
chromatography on silica gel using 20% hexanes in ethyl
acetate. The product was isolated as a mixture of syn and
anti isomers. The yield was 287 mg (65%), dark brown
viscous oil. 1H NMR (DMSO-d6) d 0.86 (t, J¼7.3 Hz,
3H-syn), 1.07 (t, J¼7.3 Hz, 3H-anti), 1.95–2.20 (m,
2H-syn+2H-anti), 4.42 (dd, J¼9.0, 4.9 Hz, 1H-syn), 4.94–
5.00 (m, 1H-anti), 6.63–6.69 (m, 1H-syn), 6.78–6.85 (m,
2H-syn+1H-anti), 7.03–7.10 (m, 2H-syn), 7.14–7.21
(m, 3H-anti), 7.22–7.29 (m, 3H-syn+1H-anti), 7.37–7.42
(m, 3H-anti), 7.42–7.50 (m, 2H-syn+2H-anti), 8.36 (d,
J¼2.5 Hz, 1H-anti), 8.38 (d, J¼2.4 Hz, 1H-syn), 8.56
(br s, 1H-syn), 8.68 (d, J¼2.4 Hz, 1H-syn), 8.73 (d,
J¼2.5 Hz, 1H-anti), 9.98 (s, 1H-anti). 13C NMR (DMSO-
d6) for syn isomer, d 12.23, 23.54, 52.32, 112.49, 118.72,
127.74, 128.65, 128.76, 129.10, 134.12, 141.95, 142.74,
145.12, 145.75, 149.16, 155.05. IR, nmax: 3334, 3256,
3054, 2967, 2931, 2874, 1691, 1601, 1503, 1445, 1383,
1252, 1151, 1093, 1060, 999, 850, 750, 694, 508,
475 cmꢁ1. LC/MS: expected, 350.85; observed, m/z:
351.1 [M+H]+. Anal. Calcd for C20H19ClN4 (350.85): C,
68.47; H, 5.46; Cl, 10.10; N, 15.97. Found: C, 68.84; H,
5.28; Cl, 9.72; N, 15.70.
4.4.3. 6-Pyridin-3-ylfuro[2,3-b]pyrazine, 10c. The general
procedure was followed. Intermediate 3d (234 mg,
1.00 mmol) was used. The residue was purified by column
chromatography on silica gel using pure ethyl acetate. The
1
yield was 162 mg (83%), brown solid, mp 206–207 ꢀC. H
NMR (DMSO-d6) d 7.58–7.63 (m, 1H), 7.95 (s, 1H), 8.37
(d, J¼2.7 Hz, 1H), 8.38–8.43 (m, 1H), 8.65 (d, J¼2.7 Hz,
1H), 8.68–8.71 (m, 1H), 9.24–9.27 (m, 1H). 13C NMR
(DMSO-d6) d 103.52, 124.14, 124.67, 132.69, 138.14,
141.40, 142.28, 146.58, 150.98, 155.13, 156.84. IR, nmax
:
3431, 3098, 2959, 2925, 1604, 1546, 1483, 1415, 1369,
1268, 1190, 1054, 1010, 923, 897, 850, 810, 785, 700,
646, 435 cmꢁ1. LC/MS: expected, 197.20; observed, m/z:
198.1 [M+H]+. Anal. Calcd for C11H7N3O (197.20): C,
67.00; H, 3.58; N, 21.31. Found: C, 67.06; H, 3.46; N, 21.11.
4.4.4. 7-Ethyl-6-phenylfuro[2,3-b]pyrazine, 10d. The gen-
eral procedure was followed. Intermediate 3b (260 mg,
1.00 mmol) was used. The yield was 220 mg (98%), yellow
solid, mp 49–50 ꢀC. 1H NMR (DMSO-d6) d 1.34 (t,
J¼7.6 Hz, 3H), 2.99 (q, J¼7.6 Hz, 2H), 7.50–7.56 (m,
1H), 7.57–7.63 (m, 2H), 7.83–7.88 (m, 2H), 8.34 (d,
J¼2.7 Hz, 1H), 8.62 (d, J¼2.7 Hz, 1H). 13C NMR
(DMSO-d6) d 13.37, 16.07, 117.68, 127.02, 129.14,
129.21, 129.88, 137.90, 141.39, 141.71, 153.86, 154.25.
IR, nmax: 3430, 3061, 2961, 2928, 2872, 1540, 1464, 1410,
1360, 1195, 1054, 949, 852, 768, 690, 441 cmꢁ1. LC/MS:
expected, 224.26; observed, m/z: 225.0 [M+H]+. Anal. Calcd
for C14H12N2O (224.26): C, 74.98; H, 5.39; N, 12.49. Found:
C, 74.76; H, 5.50; N, 12.31.
4.4. General procedure for the cyclization of the chloro-
ketones 3 into the furo[2,3-b]pyrazines 10
To a solution of 3 (1.00 mmol) in 7 mL of DMF was added
K2CO3 (552 mg, 4.00 mmol), the resulting suspension was
stirred under reflux for 3 h. After cooling, the reaction mix-
ture was filtered through a plug of Celite that was then
washed with chloroform. The combined organic phase was
concentrated in vacuo. The residue was purified by column
chromatography on silica gel using 20% ethyl acetate in
hexanes, unless otherwise stated.
4.4.5. 2-[3-(Isobutylamino)pyrazin-2-yl]butanenitrile,
11. To a solution of 5b (218 mg, 1.20 mmol) in 6 mL of xy-
lene in a screw-cap glass pressure vessel was added isobutyl-
amine (263 mg, 3.60 mmol). The pressure vessel was sealed
with a cap containing a PTFE septum and removed from the
drybox. The reaction mixture was stirred and heated at
140 ꢀC for 72 h. After cooling, the reaction mixture was fil-
tered through a plug of Celite that was then washed with
chloroform. The combined organic phase was concentrated
in vacuo. The residue was purified by column chromato-
graphy on silica gel using 15% ethyl acetate in hexanes.
4.4.1. 6-Phenylfuro[2,3-b]pyrazine, 10a.20 The general
procedure was followed. Intermediate 3a (232 mg,
1.00 mmol) was used. The yield was 190 mg (97%), yellow
solid, mp 112–113 ꢀC. 1H NMR (DMSO-d6) d 7.50–7.61 (m,
3H), 7.80 (s, 1H), 8.02–8.08 (m, 2H), 8.33 (d, J¼2.8 Hz,
1H), 8.61 (d, J¼2.8 Hz, 1H). 13C NMR (DMSO-d6)
d 102.06, 125.49, 128.41, 129.24, 130.58, 137.61, 141.88,
142.00, 155.02, 159.34. IR, nmax: 3426, 3107, 3043, 1545,
1447, 1367, 1264, 1182, 1014, 841, 756, 682, 656,
437 cmꢁ1. LC/MS: expected, 196.21; observed, m/z: 197.1
[M+H]+. Anal. Calcd for C12H8N2O (196.21): C, 73.46; H,
4.11; N, 14.28. Found: C, 73.59; H, 4.14; N, 14.15.
1
The yield was 138 mg (53%), yellow viscous oil. H NMR
(DMSO-d6) d 0.88 (d, J¼6.6 Hz, 3H), 0.89 (d, J¼6.6 Hz,
3H), 1.01 (t, J¼7.3 Hz, 3H), 1.80–2.10 (m, 3H), 3.08–3.22
(m, 2H), 4.44 (dd, J¼8.2, 6.0 Hz, 1H), 6.82 (m, 1H), 7.71
(d, J¼2.7 Hz, 1H), 7.97 (d, J¼2.7 Hz, 1H). 13C NMR
(DMSO-d6) d 11.22, 20.27, 24.42, 27.13, 34.85, 48.09,

D. S. Chekmarev et al. / Tetrahedron 62 (2006) 9919–9930
9929
119.75, 130.08, 136.15, 141.35, 151.78. IR, nmax: 3412,
3050, 2961, 2872, 2246, 1658, 1580, 1511, 1460, 1385,
1256, 1185, 1156, 1105, 1078, 1055, 944, 842, 613,
485 cmꢁ1. LC/MS: expected, 218.30; observed, m/z: 219.2
[M+H]+. Anal. Calcd for C12H18N4 (218.30): C, 66.02; H,
8.31; N, 25.66. Found: C, 66.07; H, 8.35; N, 25.60.
4.4.8. tert-Butyl 2-[3-(isobutylamino)pyrazin-2-yl]propa-
noate, 13. To a solution of 4e (291 mg, 1.20 mmol) in 6 mL
of xylene in a screw-cap glass pressure vessel was added iso-
butylamine (263 mg, 3.60 mmol). The pressure vessel was
sealed with a cap containing a PTFE septum and removed
from the drybox. The reaction mixture was stirred and
heated at 130 ꢀC for 72 h. After cooling, the reaction mixture
was filtered through a plug of Celite that was then washed
with chloroform. The organic phase was concentrated
in vacuo. The residue was purified by column chromato-
graphy on silica gel using 10% ethyl acetate in hexanes to
give the unreacted starting material (48%) and the desired
product. The yield was 75 mg (23%), yellow solid, mp 72–
73 ꢀC. 1H NMR (DMSO-d6) d 0.88 (d, J¼6.8 Hz, 6H),
1.29 (d, J¼6.8 Hz, 3H), 1.33 (s, 9H), 1.86–1.97 (m, 1H),
3.07–3.21 (m, 2H), 4.44 (q, J¼6.8 Hz, 1H), 6.50 (m, 1H),
7.60 (d, J¼2.7 Hz, 1H), 7.84 (d, J¼2.7 Hz, 1H). 13C NMR
(DMSO-d6) d 14.94, 20.29, 27.27, 27.72, 41.63, 48.11,
4.4.6. 7-Ethyl-N,5-diisobutyl-5H-pyrrolo[2,3-b]pyrazin-
6-amine hydrochloride, 1h. To a solution of 5b (218 mg,
1.20 mmol) in 6 mL of xylene in a screw-cap glass pressure
vessel was added isobutylamine (263 mg, 3.60 mmol). The
pressure vessel was sealed with a cap containing a PTFE sep-
tum and removed from the drybox. The reaction mixture was
stirred and heated at 170 ꢀC for 72 h. After cooling, the reac-
tion mixture was transferred to the oxygen-free drybox and
quenched with 0.7 mL of 12 M aq HCl. After removing
fromthedrybox,thesolventwasevaporatedinvacuo;theresi-
due was suspended in 60 mL of hot 40:60 mixture of chloro-
form and ethyl acetate. The suspension was filtered, the
organic phase was concentrated under reduced pressure,
the residue was dissolved in 60 mL of THF under reflux,
the resulting solution was cooled to ꢁ18 ꢀC, and the precipi-
tated i-BuNH2$HCl was filtered out. After concentration of
the organic phase under reduced pressure, the residue was
crystallized from 40 mL of THF to give 183 mg (49% yield)
of the desired product as a hydrochloride salt, yellow solid,
mp 174–178 ꢀC (decomp.). 1H NMR (DMSO-d6) d 0.83 (d,
J¼6.6 Hz, 6H), 0.96 (d, J¼6.6 Hz, 6H), 1.15 (t, J¼7.3 Hz,
3H), 1.88–2.01 (m, 1H), 2.09–2.22 (m, 1H), 2.81 (q,
J¼7.3 Hz, 2H), 3.36 (m, 2H), 4.10 (d, J¼7.8 Hz, 2H), 7.76
(s, 2H), 8.38 (m, 1H), 14.85 (br s, 1H). 13C NMR (DMSO-
d6) d 15.27, 15.86, 19.38, 19.68, 27.40, 29.29, 46.96, 50.13,
79.96, 129.84, 139.79, 142.00, 152.38, 171.67. IR, nmax
:
3423, 2970, 2927, 2870, 1722, 1580, 1512, 1459, 1368,
1322, 1234, 1149, 1085, 848, 758, 481 cmꢁ1. LC/MS:
expected, 279.39; observed, m/z: 280.1 [M+H]+. Anal. Calcd
for C15H25N3O2 (279.39): C, 64.49; H, 9.02; N, 15.04.
Found: C, 64.41; H, 9.01; N, 15.09.
4.4.9. 3-Ethyl-N-isobutylpyrazin-2-amine, 14. The proce-
dure described above for 13 was followed. The reaction mix-
ture was carried out at 170 ꢀC for 72 h. The residue was
purified by column chromatography on silica gel using
30% ethyl acetate in hexanes. The yield was 121 mg
1
(56%), yellow viscous oil. H NMR (DMSO-d6) d 0.87 (d,
J¼6.8 Hz, 6H), 1.18 (t, J¼7.4 Hz, 3H), 1.87–1.99 (m, 1H),
2.62 (q, J¼7.4 Hz, 2H), 3.13 (dd, J¼7.1, 5.9 Hz, 2H),
6.42–6.47 (m, 1H), 7.57 (d, J¼2.7 Hz, 1H), 7.78 (d,
J¼2.7 Hz, 1H). 13C NMR (DMSO-d6) d 10.66, 20.29,
25.38, 27.13, 48.00, 129.62, 138.79, 143.93, 152.57. IR,
nmax: 3364, 3043, 2959, 2871, 1580, 1542, 1509, 1465,
1382, 1352, 1260, 1184, 1069, 1031, 829, 611 cmꢁ1. LC/
MS: expected, 179.27; observed, m/z: 180.1 [M+H]+.
Anal. Calcd for C10H17N3 (179.27): C, 67.00; H, 9.56; N,
23.44. Found: C, 67.21; H, 9.55; N, 23.16.
90.24, 121.44, 126.81, 131.36, 146.40, 154.89. IR, nmax
:
3181, 3148, 3070, 3024, 2960, 2872, 2766, 2566, 1859,
1589, 1523, 1462, 1382, 1292, 1217, 1159, 1102, 1046,
955, 801, 664, 494 cmꢁ1. LC/MS: expected, 274.41; ob-
served, m/z: 275.3 [M+H]+. Anal. Calcd for C16H26N4+HCl
(274.41+36.46): C, 61.82; H, 8.75; Cl, 11.40; N, 18.02.
Found: C, 61.71; H, 8.87; Cl, 11.54; N, 18.00.
4.4.7. (6E)-7-Ethyl-5-isobutyl-6-(isobutylimino)-6,7-di-
hydro-5H-pyrrolo[2,3-b]pyrazin-7-ol, 12. To a solution
of 1h$HCl (90 mg, 0.29 mmol) in 10 mL of chloroform
was added 6 mL (1.45 mmol) of 0.242 M aq K2CO3. The
reaction mixture was stirred at room temperature for 18 h
on air, then filtered through a plug of Celite that was then
washed with chloroform. The organic phase was concen-
trated in vacuo. The residue was purified by column chroma-
tography on silica gel using 30% ethyl acetate in hexanes.
The yield was 75 mg (89%), yellow solid, mp 82–84 ꢀC.
1H NMR (DMSO-d6) d 0.58 (t, J¼7.5 Hz, 3H), 0.86 (d,
J¼6.8 Hz, 3H), 0.89 (d, J¼6.8 Hz, 3H), 0.93 (d, J¼6.7 Hz,
3H), 0.94 (d, J¼6.7 Hz, 3H), 1.71–1.82 (m, 1H), 2.05–
2.24 (m, 3H), 3.41–3.61 and 3.68–3.75 (m, 4H), 6.24 (s,
1H), 7.89 (d, J¼3.2 Hz, 1H), 7.95 (d, J¼3.2 Hz, 1H). 13C
NMR (DMSO-d6) d 7.81, 20.22, 20.23, 20.46, 20.47,
26.31, 29.75, 30.20, 45.98, 54.08, 76.07, 134.39, 141.32,
148.37, 153.62, 157.34. IR, nmax: 3178, 2956, 2869, 1696,
1569, 1482, 1419, 1361, 1311, 1244, 1137, 1106, 1019,
940, 883, 838, 695, 554, 475 cmꢁ1. LC/MS: expected,
290.41; observed, m/z: 291.2 [M+H]+. Anal. Calcd for
C16H26N4O (290.41): C, 66.17; H, 9.02; N, 19.29. Found:
C, 66.21; H, 9.09; N, 19.24.
4.4.10. 7-Hydroxy-5-isobutyl-7-methyl-5,7-dihydro-6H-
pyrrolo[2,3-b]pyrazin-6-one, 15. To a solution of 4d
(241 mg, 1.20 mmol) in 6 mL of xylene in a screw-cap glass
pressure vessel was added isobutylamine (263 mg,
3.60 mmol). The pressure vessel was sealed with a cap con-
taining a PTFE septum and removed from the drybox. The
reaction mixture was stirred and heated at 170 ꢀC for 72 h.
After cooling, the reaction mixture was transferred to the
oxygen-free drybox and quenched with 0.7 mL of 12 M aq
HCl. After removing from the drybox, the solvent was evapo-
rated, the residue was suspended in 50 mL of THF under
reflux, the resulting solution was cooled to ꢁ18 ꢀC, and
the precipitated i-BuNH2$HCl was filtered out. The organic
phase was concentrated in vacuo and the probe was taken for
the NMR. Then the residue was dissolved in 20 mL of chlo-
roform and quenched with 10 mL of saturated aq K2CO3.
The organic layer was separated and the aqueous layer was
extracted twice with additional chloroform. The organics
were combined, dried over Na2SO4, filtered, and concen-
trated in vacuo. The residue was purified by column chroma-
tography on silica gel using 50% ethyl acetate in hexanes.

9930
D. S. Chekmarev et al. / Tetrahedron 62 (2006) 9919–9930
1
Cross, P. E.; Burges, R. A.; Gardiner, D. G. J. Med. Chem.
1989, 32, 562–568.
The yield was 80 mg (30%), yellow viscous oil. H NMR
(DMSO-d6) d 0.87 (d, J¼6.5 Hz, 3H), 0.89 (d, J¼6.5 Hz,
3H), 1.45 (s, 3H), 2.07–2.19 (m, 1H), 3.50 (d, J¼7.3 Hz,
2H), 6.30 (s, 1H), 8.16 (s, 2H). 13C NMR (DMSO-d6)
d 19.94, 21.89, 26.46, 45.50, 71.33, 137.54, 141.69,
148.72, 151.74, 176.58. IR, nmax: 3384, 3065, 2961, 2930,
2873, 1743, 1574, 1460, 1370, 1319, 1250, 1194, 1137,
1045, 922, 846, 756, 627, 569, 508 cmꢁ1. LC/MS: expected,
221.26; observed, m/z: 222.1 [M+H]+. Anal. Calcd for
C11H15N3O2 (221.26): C, 59.71; H, 6.83; N, 18.99. Found:
C, 59.37; H, 6.57; N, 18.95.
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References and notes
1. Mettey, Y.; Gompel, M.; Thomas, V.; Garnier, M.; Leost, M.;
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3. (a) Vierfond, J. M.; Mettey, Y.; Mascrier-Demagny, L.;
Miocque, M. Tetrahedron Lett. 1981, 22, 1219–1222; (b)
Davis, M. L.; Wakefield, B. J.; Wardell, J. A. Tetrahedron
1992, 48, 939–952.
19. El-Deen, I. M.; Mahmoud, F. F. Phosphorus, Sulfur Silicon
Relat. Elem. 2000, 165, 205–212.
4. Hopkins, C. R.; Collar, N. Tetrahedron Lett. 2004, 45, 8087–
8090.
20. For the synthesis of furo[2,3-b]pyrazines by other methods,
see: Armand, J.; Bellec, C.; Boulares, L.; Chaquin, P.;
Masure, D.; Pinson, J. J. Org. Chem. 1991, 56, 4840–4845
and references cited therein.
5. Hopkins, C. R.; Collar, N. Tetrahedron Lett. 2004, 45, 8631–
8633.
6. Previously, lithium hexamethyldisilazide (LiHMDS) was
found to be the most effective base in Pd-catalyzed a-arylations
of esters, giving only traces of diarylated products, see: Moradi,
W. A.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7996–
8002.
7. (a) For ester enolates, also see: Lee, S.; Beare, N. A.; Hartwig,
J. F. J. Am. Chem. Soc. 2001, 123, 8410–8411; (b) Jorgensen,
M.; Lee, S.; Liu, X.; Wolkowski, J. P.; Hartwig, J. F. J. Am.
Chem. Soc. 2002, 124, 12557–12565; (c) Hama, T.; Liu, X.;
Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 125,
11176–11177.
8. (a) For ketone enolates, see: Palucki, M.; Buchwald, S. L.
J. Am. Chem. Soc. 1997, 119, 11108–11109; (b) Hamann,
B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1997, 119, 12382–
12383; (c) Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc.
1999, 121, 1473–1478.
9. For ketone enolates, also see: Fox, J. M.; Huang, X.; Chieffi,
A.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 1360–1370.
10. In the case of R¼Me, Et, the corresponding Claisen type con-
densation products were detected in the crude reaction mix-
tures by TLC and LC/MS ([M+H]+¼229 and 243 for R¼Me
and Et, respectively). For lower tendency of tert-butyl esters
to Claisen type condensations, see also Ref. 6.
21. The facile air oxidation to afford the hydroxy derivatives 12
and 15 is not surprising: the similar oxidation is well known
for 1,3-disubstituted 2-indolinones; see, for instance: (a)
Abou-Gharbia, M.; Ketcha, D. M.; Zacharias, D. E.; Swern,
D. J. Org. Chem. 1985, 50, 2224–2228; (b) Kukla, M. J.;
Breslin, H. J.; Diamond, C. J.; Grous, P. P.; Ho, C. Y.;
Miranda, M.; Rodgers, J. D.; Sherrill, R. G.; De Clercq, E.;
Pauwels, R.; Andries, K.; Moens, L. J.; Janssen, M. A. C.;
Janssen, P. A. J. J. Med. Chem. 1991, 34, 3187–3197; (c)
Labroo, R. B.; Cohen, L. A. J. Org. Chem. 1990, 55, 4901–
4904; (d) Takayama, H.; Matsuda, Y.; Masubuchi, K.; Ishida,
A.; Kitajima, M.; Aimi, N. Tetrahedron 2004, 60, 893–900.
22. The structures of the compounds 12 and 15 were confirmed by
their two dimensional 1H–13C HSQC and 1H–13C HMBC spec-
tra. Namely, cross-peaks were observed between CH2-8 and
C-6, C-7, C-7a; CH2-9 and C-4a, C-6 in both 12 and 15;
between CH2-10 and C-6 in 12; and between OH and C-6,
C-7, C-7a, C-8 in 15, which reveals interactions of the cor-
responding carbons and protons.
9
9
N5
4
N
4N
1N
4a
7a
4a
11. Dennin, F.; Blondeau, D.; Sliwa, H. J. Heterocycl. Chem. 1990,
27, 1639–1643.
12. (a) Slepukhin, P. A.; Kim, D. G.; Rusinov, G. L.; Charushin,
V. N.; Chupakhin, O. N. Khim. Geterotsikl. Soedin. 2002,
9, 1300–1302; (b) Arrowsmith, J. E.; Campbell, S. F.;
N5
3
3
2
6
O
N
7
6
7
2
7a
8
N
10
OH
OH
1
8
12
15