Facile Access to 1,4-Disubstituted Pyrrolo[1,2- a ]pyrazines from α-Aminoacetonitriles

Article abstract of DOI:10.1055/s-0039-1690699

An efficient and practical synthetic protocol for the synthesis of 1,4-disubstituted pyrrolo[1,2- a ]pyrazine derivatives is described that originates from α-substituted pyrroloacetonitriles which, in turn, are readily available from aryl and alkyl aldehydes. The α-pyrroloacetonitriles were subjected to a Friedel-Crafts acylation with methyl chlorooxoacetate followed by reduction of the nitrile group under Pd-catalyzed hydrogenation conditions and finally aromatization with DDQ leading to the desired pyrrolo[1,2- a ]pyrazine derivatives. This method was generalized and successfully applied to various aryl, heteroaryl, and alkyl substrates. The developed protocol provides direct and convenient access to 1,4-disubstituted ring systems in moderate to good overall yields (51-68percent) without the need for purification of the intermediates. Further functionalization via the stepwise halogenation (bromination, iodination) and nitration was also demonstrated. In addition, the potential of the ester functionality for elaboration was demonstrated by manipulating into heterocyclic ring systems, exemplified by conversion into benzoxazole derivatives.

Full text of DOI:10.1055/s-0039-1690699

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–I
paper
A
en
A. Karmakar et al.
Paper
Synthesis
Facile Access to 1,4-Disubstituted Pyrrolo[1,2-a]pyrazines from
-Aminoacetonitriles
Ananta Karmakara
Sridharan Ramalingama
Mushkin Bashaa
0
0
0
0-0
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0
3-
3
7
9
5-5
8
0
7
3
N 2
O
O
4
1
(1) Clauson–Kaas reaction
(2) Acylation
R
CN
N
R
Gopi Kumar Indasia
Makonen Belemab
Nicholas A. Meanwellb
T. G. Murali Dharb
Richard Rampullab
Arvind Mathurb
(3) in situ reduction/cyclization/
aromatization
NH2
R = aryl, heteroaryl
and alkyl
16 examples
yields 51–68%
0
0
0
0-0
0
0
2-
8
8
5
7-1
5
1
5
Anuradha Guptaa
Arun Kumar Gupta*a
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0
0
2-4
6
5
1-8
5
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9
a Department of Discovery Synthesis, Biocon Bristol Myers Squibb Research Centre,
Plot 2 & 3, Bommasandra Industrial Estate - Phase-IV, Bommasandra-Jigani Link
Road, Bengaluru, Karnataka 560099, India
Arunkumar.Gupta@syngeneintl.com
b Department of Discovery Synthesis, Bristol-Myers Squibb Research and Develop-
ment, P. O. Box 4000, Princeton, NJ 08543-4000, USA
Received: 12.07.2019
Accepted after revision: 16.09.2019
Published online: 01.10.2019
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DOI: 10.1055/s-0039-1690699; Art ID: ss-2019-z0387-op
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Cl
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Abstract An efficient and practical synthetic protocol for the synthesis
of 1,4-disubstituted pyrrolo[1,2-a]pyrazine derivatives is described that
originates from -substituted pyrroloacetonitriles which, in turn, are
readily available from aryl and alkyl aldehydes. The -pyrroloacetoni-
triles were subjected to a Friedel–Crafts acylation with methyl chloroo-
xoacetate followed by reduction of the nitrile group under Pd-catalyzed
hydrogenation conditions and finally aromatization with DDQ leading
to the desired pyrrolo[1,2-a]pyrazine derivatives. This method was gen-
eralized and successfully applied to various aryl, heteroaryl, and alkyl
substrates. The developed protocol provides direct and convenient ac-
cess to 1,4-disubstituted ring systems in moderate to good overall
yields (51–68%) without the need for purification of the intermediates.
Further functionalization via the stepwise halogenation (bromination,
iodination) and nitration was also demonstrated. In addition, the poten-
tial of the ester functionality for elaboration was demonstrated by ma-
nipulating into heterocyclic ring systems, exemplified by conversion
into benzoxazole derivatives.
N
vasopressin 1b receptor antagonist
F
dual AChE/5-HT4
receptor antagonist
F
NH
Cl
NH
COOH
N
N
N
N
O
N
N
CN
N
O
mGluR5 antagonist
COOH
CK2 inhibitor
cannnabinoid receptor
modulator
NH2
O
HO2C
O
N
S
O
N
N
N
Key words pyrrolo[1,2-a]pyrazine, -aminoacetonitriles, Clauson–
Kass reaction, aromatization, cyclization
N
N
N
S
O
CF3
CRTH2 antagonist
Pyrrolo[1,2-a]pyrazines possess a bicyclic heteroaro-
matic structure that is prominent in drug design1 associated
with, for example, vasopressin 1b receptor antagonism,1a
dual AChE/5-HT4 receptor antagonism,1b mGluR5 antago-
nism,1c CK2 inhibition,1d cannabinoid receptor modula-
tion,1e CRTH2 antagonism,1f and inhibition of sPLA-2 and
hypoxia inducible factor-11h (Figure 1).
hypoxia inducible
factor-1 inhibitor
sPLA-2 inhibitor
Figure 1 Select pharmacologically active pyrrolo[1,2-a]pyrazine deriv-
atives
Consequently, a variety of synthetic procedures have
been developed for the preparation of pyrrolo[1,2-a]pyra-
zines that incorporate varied patterns of substitution.2–8
Among these, one of the oldest approaches was reported by
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–I
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
A. Karmakar et al.
Paper
Synthesis
Herz and Tocker and involves the condensation of 1H-pyr-
role-2-carboxaldehyde with aminoacetaldehyde diethyl ac-
etal followed by treatment with a mixture of POCl3 and
polyphosphoric acid, a process with modest overall yields
(18–24%) (Scheme 1a).2 In 1996, Minguez et al. reported an
improved approach that utilizes pyrrole as the starting ma-
terial (Scheme 1b).3
(Scheme 1e).6 Palladium-catalyzed, directed C6 arylation of
pyrrolo[1,2-a]pyrazines with a range of aryl bromides has
also been reported.7
A need arose to access the pyrrolo[1,2-a]pyrazine ring
system as part of a program directed toward the prepara-
tion of inhibitors of the hepatitis C virus NS5A replication
complex, prompting the development of a new synthetic
route that was specifically focused on the preparation of
1,4-disubstituted derivatives.9 Herein, we report an ap-
proach that provides direct and convenient access to this
ring system starting from commercially available and inex-
pensive -aminoacetonitriles.
(a) Herz, W.; Tocker, S.2b
N
CHO
(EtO)2CHCH2NH2
POCl3
H+
EtO
N
N
HN
HN
OEt
Scheme 2 depicts a retrosynthetic analysis for the
preparation of 1,4-disubstituted pyrrolo[1,2-a]pyrazine de-
rivatives on which the synthetic strategy was based. An ap-
propriate disconnection between C-1 and N-2 of 4 envi-
sioned construction by a reductive cyclization/aromatiza-
tion process conducted on a methyl 2-oxo-2-(1H-pyrrol-2-
yl)acetate derivative 3. In turn, 3 could be readily accessed
through a Friedel–Crafts type acylation of an -substituted
2-(1H-pyrrol-1-yl)acetonitrile derivative 2 with methyl
chlorooxoacetate, syntheses of which have been reported in
the literature as the products of a Clauson–Kaas reaction
that originates with -aminoacetonitrile derivatives 1.
(unsubstituted)
(b) Minguez et al.3
N
N
(1) ClCH2CH2NH2
(2) HCOOH
Pd/C
xylene, reflux
N
HN
N
(unsubstituted)
(c) Chen et al.4
R2
R1
N
N
Cs2CO3, DMF
R2
CHO
+
conditions
R1
N3
HN
(3,4-disubstituted)
(d) Alfonsi et al.5
R
R
NH3/MeOH; TiCl4
reduction and
in situ cyclization/
aromatization
μW; 130 °C
N
N
O
O
O
N
2
N
O
CN
3
O
O
1
R
N
R
N
4
(1,3-disubstituted)
4
3
(e) Batra et al.6
acylation
OAc
R
COOMe
(a) saponification
COOMe
CHO
R
CHO
N
N
R
(b) Curtius reaction
CN
modified
Clauson–Kaas reaction
CN
HN
K2CO3, DMF, rt
N
R
N
NH2
R
1
2
R = aryl, heteroaryl, alkyl
O
(f) This work
OCH3
O
O
Scheme 2 Retrosynthetic analysis of 1,4-disubstituted pyrrolo-
[1,2-a]pyrazines 4
CN
Cl
(a) Pd/C, H2
CN
CO2CH3
N
N
O
AcOH, MeOH
O
R
N
R
N
benzene
R
(b) DDQ, THF
70 °C
There are a number of procedures described for the syn-
thesis of -aminoacetonitriles.10–13 In the 1960’s, -amino-
acetonitriles 1 were prepared from N-trimethylsilylimines
(N-TMS imines) by reaction with cyanides.10
(1,4-disubstituted)
R = aryl, heteroaryl, alkyl
Scheme 1 Previously described synthetic approaches to pyrrolo-
[1,2-a]pyrazines
Hart’s group11 and, subsequently, Chu et al.12 reported
their elegant work on the application of N-TMS imines, de-
rived from the reaction of LiHMDS with aldehydes 5, which
were treated with acetone cyanohydrin as the source of ni-
trile anion to generate -aminoacetonitriles 1 (Scheme 3).
The experimentally straightforward conversion of 1 to 2
was achieved under modified Clauson–Kaas reaction condi-
tions that involved heating the -aminoacetonitrile 1 with
2,5-dimethoxytetrahydrofuran and H2O (1.2 mL/mmol of 1)
Other routes include the cyclization between 1H-pyr-
role-2-carboxaldehyde and a vinyl azide (Scheme 1c),4
a
cascade route comprised of TiCl4-catalyzed heteroatom cy-
clization of N-alkynylpyrroles under microwave irradiation
conditions (Scheme 1d),5 and a sequence involving the re-
action of 1H-pyrrole-2-carboxaldehyde with substituted
acrylates in a Morita–Baylis–Hillman process followed by
saponification and
a Curtius rearrangement reaction
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–I

C
A. Karmakar et al.
Paper
Synthesis
at 100 °C for 2 hours.14 This process furnished -substituted
pyrroloacetonitriles 2 in good to excellent overall yields
(80–90%) (Scheme 3).15
sequently, the crude reaction material from the reduction
was directly treated with 2,3-dichloro-5,6-dicyano-1,4-
benzo-quinone (DDQ) leading to the isolation of 4a in 68%
overall yield from 2a.
A broad range of -substituted pyrroloacetonitrile de-
rivatives 2a–p, captured in Table 1, were synthesized and
elaborated via the described protocol to access 4a–p as a
means of evaluating the scope and limitations of the pro-
cess. Derivatives 4a–p were obtained from 2a–p in moder-
ate to good overall yields that ranged from 51–68% for the
three-step process.
(a) LiHMDS (1.2 equiv), THF
CN
–78 °C to 0 °C, 2 h
R
CHO
R
NH2
(b) acetone cyanohydrin
5
1
R = aryl, heteroaryl,
alkyl
modified
Clauson–Kaas
reaction
CN
R
N
Table 1 The Preparation of 1,4-Disubstituted Pyrrolo[1,2-a]pyrazines
4a–pa–c
2
Scheme 3 Synthesis -substituted pyrroloacetonitriles 2
CN
N
N
CO2CH3
A typical synthetic sequence for our approach, which to
the best of our knowledge has not been disclosed in the lit-
erature, is illustrated by the preparation of methyl 4-phen-
ylpyrrolo[1,2-a]pyrazine-1-carboxylate (4a) from 2-phe-
nyl-2-(1H-pyrrol-1-yl)acetonitrile (2a), as summarized in
Scheme 4. The pyrroloacetonitrile 2a was subjected to a
Friedel–Crafts acylation with methyl chlorooxoacetate fol-
lowed by reduction of the nitrile group under Pd-catalyzed
hydrogenation conditions. This provided the desired pyrro-
lo[1,2-a]pyrazine 4a along with a considerable amount of
6a (35%). Attempts to purify intermediate 6a by a range of
chromatographic methods were not successful due to its
susceptibility to oxidation, which resulted in contamination
with a significant amount of 4a. Although close mechanistic
investigation to delineate the intermediates involved was
not conducted, we hypothesize that partial reduction of the
nitrile moiety to an imine followed by dehydrative cycliza-
tion affords 4a, whereas complete reduction of the nitrile to
the amine results in the formation of 6a. Although one
could not rule out the possibility that 6a could oxidize to 4a
under the reaction conditions (Pd/C), we opted to utilize an
external oxidant to ensure completion of the process. Con-
N
R
R
2a–p
4a–p
N
N
CO2CH3
N
N
CO2CH3
F
N
N
CO2CH3
CO2CH3
CO2CH3
F
F
4a (68%)
4b (55%)
4c (62%)
N
N
N
N
CO2CH3
N
N
CO2CH3
Cl
Br
Cl
Cl
4d (66%)
4e (57%)
4f (49%)
N
CO2CH3
MeO
N
CO2CH3
MeO
N
N
N
N
R
HO
4g: (R = Br) not observed
4a: (R = H) isolated (59%)
4h (60%)
4i (52%)
CO2CH3
N
N
N
N
CO2CH3
N
N
CO2CH3
O
O
CO2CH3
O
CN
CN
Cl
N
Pd/C, H2
N
H3CO2C
Boc
AcOH, MeOH
O
Ph
N
N
Ph
4j (57%)
4k (56%)
4l (54%)
benzene
25 °C, 2 h
95 °C, 4 h
2a
3a
N
N
CO2CH3
N
N
CO2CH3
N
N
CO2CH3
N
N
CO2CH3
85%
H
CO2CH3
N
CO2CH3
N
N
DDQ, THF
70 °C, 2 h
4m (54%)
4n (51%)
4o (61%)
4p (61%)
Ph
N
Ph
80%
a Starting materials 2 were prepared from the corresponding aldehyde by
following the literature protocol as described in Scheme 3.
6a
4a
b Yields presented are overall isolated yields starting from 2.
c Formation of only the des-bromo product 4a rather than 4g from 2g was
observed as the result of hydrogenolysis during the reduction.
Scheme 4 Synthesis of methyl 4-phenylpyrrolo[1,2-a]pyrazine-1-car-
boxylate (4a)
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–I

D
A. Karmakar et al.
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Synthesis
The halogenated products 4b–f were isolated in 49–66%
yields with the exception of the 4-bromophenyl substrate
2g, which suffered from dehalogenation during the reduc-
tion step to afford 4a in 58% overall yield rather than pro-
viding the targeted product 4g. This result provides one
boundary to substituent tolerance and underscores the po-
tential for dehalogenation under the reduction conditions
involving hydrogenation over Pd/C. The other halogenated
substrates, including bromide 2f, produced the targeted de-
rivatives with negligible amounts (5–7%) of over-reduced,
dehalogenated product. The differing outcomes for the re-
gioisomeric bromides 4f and 4g is noteworthy since it was
not anticipated. Other functional groups, including me-
thoxyaryl (2h), hydroxymethoxyaryl (2i), and a carboxylic
ester (2j), were well tolerated under the reaction condi-
tions, providing 4h, 4i, and 4j, respectively. Substrate scope
was further expanded to include heteroaromatic and ali-
phatic moieties, with the 3-pyridyl- and 5-indole contain-
ing substrates 2k and 2l providing 4k and 4l in 56% and 54%
isolated yield, respectively. Products incorporating a cyclo-
hexyl (4m), isopropyl (4n), and tert-butyl (4o) substituent
were isolated in similar overall yields, while the unsubsti-
tuted ester 4p was obtained in 61% yield. The structure of
4b was confirmed by single crystal X-ray structural analy-
sis, as shown in Figure 2 which revealed that the ester moi-
ety is in-plane with the pyrrolo[1,2-a]pyrazine ring (ring-
ester torsion angle, 1.5°) while the fluorophenyl group is
twisted out of plane (ring-ring torsion angle, 52.6°).
tive cyclization in neat POCl3 to afford 6g. Aromatization of
6g was accomplished by heating the crude product with
DDQ to provide 4g in 59% overall yield.
O
NH2
CN
O
Cl
NaBH4, CoCl2, THF
0–25 °C, 5 h
O
N
N
Et3N, CH2Cl2
0–25 °C, 4 h, 85%
90%
Br
Br
Br
2g
7g
H
N
CO2Me
CO2CH3
N
N
POCl3
25 °C, 12 h
O
N
Br
8g
6g
CO2CH3
N
N
DDQ, THF
70 °C, 2 h
77%
after 2 steps
Br
4g
Scheme 5 Synthesis of methyl 4-(4-bromophenyl)pyrrolo[1,2-a]pyra-
zine-1-carboxylate (4g)
To demonstrate the potential for additional structural
diversification, halogenation and nitration of 4a were ex-
plored, with the results summarized in Schemes 6 and 7,
respectively.
Bromination of 4a using N-bromosuccinimide (NBS) in
CH2Cl2 at room temperature for 3 hours led to the isolation
of the 6-bromo derivative 9 in 73% yield accompanied by a
minor amount (<5%) of the 6,8-dibromide 10 (Scheme 6).
Conducting the reaction with two equivalents of NBS for 3
hours resulted in the isolation of the 6,8-dibromide 10 in
68% yield or, alternatively, exposing 9 to 1 equivalent of NBS
in CH2Cl2 at room temperature for 3 hours gave 10 in 70%
yield. The sequential nature of the halogenation allowed for
alternate functionalization, with the bromide 9 affording
the 6-bromo,8-iodo derivative 11 in 67% isolated yield
when treated with 1 equivalent of N-iodosuccinimide (NIS)
in DMF. The sites of halogenation were confirmed by deter-
mination of single crystal X-ray structures of 9 and 11 (Fig-
ure 3). In the solid state, the phenyl ring in both 9 and 11
adopts a more orthogonal disposition with respect to the
pyrrolo[1,2-a]pyrazine ring (ring-ring torsion angles, 77.7°
and 74.9°, respectively), compared to 4b. This may be at-
tributed to the presence of the bromine atom at the adja-
cent position on the ring. While the ester group in 9 is
found to approach a coplanar arrangement with the pyrro-
lo[1,2-a]pyrazine ring (ring-ester torsion angle = 11.8°), in
11 the ester moiety adopts an out-of-plane conformation
(ring-ester torsion angle = 53.5°), presumably due to unfa-
vorable steric effects associated with the adjacent iodine
substituent.
N
O
O
F
N
4b
Figure 2 Single crystal X-ray structure of pyrrolo[1,2-a]pyrazine 4b16
The hydrogenation step using Pd/C as the catalyst was
considered to be a limiting factor beyond dehalogenation
since other functional groups of potential interest to a me-
dicinal chemistry campaign, including alkene, alkyne, ni-
trile, and nitro substituents, that could serve as handles for
further functionalization, would potentially be compro-
mised. To overcome this limitation, the alternate route de-
picted in Scheme 5, in which the reaction sequence is rear-
ranged, was developed. 2-(4-Bromophenyl)-2-(1H-pyrrol-
1-yl)acetonitrile (2g) was selected as an illustrative exam-
ple since it failed to provide the targeted product 4g using
the first protocol. Reduction of nitrile 2g to the amine 3g
was accomplished in 90% isolated yield. Acylation of the
amine of 7g with methyl chlorooxoacetate under basic con-
ditions afforded amide 8g, which was subjected to dehydra-
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–I

E
A. Karmakar et al.
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Synthesis
In contrast to halogenation, nitration of the pyrrolo[1,2-
a]pyrazine ring was not a selective process. Exposing 4a to
HNO3 (1.2 equiv) and H2SO4 (5 equiv) at 0–5 °C for 2 hours
gave a mixture of mono- (<5%), di- (30%) and trinitro (<10%)
derivatives along with 39% of unreacted starting material
(Scheme 7). However, by using an excess of HNO3 (3.5
equiv) and H2SO4 (12 equiv) and stirring for 5 hours at room
temperature, the trinitro derivative 12 was produced di-
rectly in 57% yield.17
The heavy content of NO2 groups in 12 gave cause for
concern with respect to thermal stability, which was as-
sessed by conducting a differential scanning calorimetry
(DSC) study. The results indicate that 12 is a highly energet-
ic substance (energy 2245 J/g) with the onset of exotherm
occurring at 63 °C. Compound 12 is predicted to be shock
sensitive and it is strongly recommended that isolating
quantities of this compound in pure form should be avoid-
ed.18
N
N
CO2CH3
Br
Ph
NBS (2 equiv), DMF
25 °C, 3 h
Br
10
68%
NBS (1 equiv)
CH2Cl2, rt, 3 h
70%
2
N
N
N
CO2CH3
CO2CH3
NBS (1 equiv)
1
3
CH2Cl2, 25 °C, 3 h
Ph
Ph
N
4
73%
8
5
6
7
Br
9
4a
NIS (1 equiv)
DMF, 25 °C, 3 h
67%
N
N
CO2CH3
I
Ph
Further synthetic elaboration of 4j toward the prepara-
tion of HCV NS5A replication complex inhibitors is summa-
rized in Scheme 8 and required manipulation of the ester
moiety.9 Conversion of 4j to the bisphenacyl chloride 13
was accomplished by exposing to chloroiodomethane, with
subsequent conversion to diester 15 by alkylation of
(2S,5S)-N-Boc-5-methylpyrrolidine-2-carboxylic acid 14.
Heating diester 15 with ammonium acetate in xylene at
130 °C in a sealed tube provided the bis-imidazole 16
(Scheme 8).
Elaboration of an ester functionality present in 4a to an
alternate heterocycle is illustrated in Scheme 9. Saponifica-
tion of 4a afforded the carboxylic acid 17, which was ex-
posed to 2-aminophenol in the presence of propylphos-
phonic anhydride (PPACA, T3P®) and N,N-diisopropylethyl-
amine (DIPEA) in EtOAc under microwave heating (150 °C)19
for 1 hour to afford 18.
Br
11
Scheme 6 Bromination and iodination of methyl 4-phenylpyrrolo[1,2-
a]pyrazine-1-carboxylate (4a)
HNO3 (3.5 equiv)
H2SO4 (12 equiv)
25 °C, 5 h
N
N
CO2CH3
NO2
CO2CH3
O2N
N
N
57%
O2N
4a
12
HNO3 (1.2 equiv)
H2SO4 (5 equiv)
0–5 °C, 2 h
mono-nitro: <5%
di-nitro: ~30%
tri-nitro: <10%
4a: 39%
Scheme 7 Nitration of 4a
LDA, CH2ICl, THF
–78 °C, 1 h
O
N
O
N
MeO2C
CO2Me
N
N
Cl
Cl
4j
13
O
N
O
HOOC
14
N
Boc
Boc
O
N
O
O
N
KI, DIPEA, CH3CN
0 °C to rt, 2 h
N
Boc
O
15
93% after 2 steps
NH4OAc, xylene
130 °C, sealed tube
18 h, 12%
N
N
N
HN
N
Boc
Boc
NH
N
N
16
Scheme 8 Synthesis of bis-imidazole 16
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–I

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A. Karmakar et al.
Paper
Synthesis
at 25 °C. Chemical shifts are reported relative to the solvent residual
value:  = 7.26 (CDCl3), 2.50 (DMSO-d6) for 1H NMR and  = 77.16 (CD-
Cl3), 39.52 (DMSO-d6) for 13C NMR. Resonance patterns are reported
with the standard notations. In addition, the notation br is used to in-
dicate a broad signal. Coupling constants (J) are reported in hertz
(Hz). LCMS data were recorded on an Agilent 1200 series connected
to an Agilent 6140 quadruple MS instrument. SOR was measured on a
RUDOLPH Autopol® V automatic polarimeter. Compound purities
were determined by analytical reversed-phase HPLC on an Agilent
1200 series instrument. Melting points were recorded using a Büchi
M-560 instrument. FTIR were recorded on a Thermo Scientific iS50
FT-IR instrument. Differential scanning calorimetry (DSC) was per-
formed on a Universal V4.5A TA Instrument. Accurate mass measure-
ments (HRMS) were performed on an Accela UHPLC system, hyphen-
ated with an LTQ-Orbitrap XL mass spectrometer (Thermo scientific)
equipped with a positive electrospray (ESI) mode.
O
O
N
N
Br
9
O
O
N
N
I
Br
11
Detailed synthetic procedures, analytical, and spectral data for all
compounds 2a–p and 4a–p are provided in the Supporting Informa-
tion.
Figure 3 Single crystal X-ray structures of 916 and 1116
Methyl 4-Phenylpyrrolo[1,2-a]pyrazine-1-carboxylate (4a)
(i) 2-Phenyl-2-(1H-pyrrol-1-yl)acetonitrile (2a)
H2N
O
N
N
N
O
HO
OR
N
In a 100 mL round-bottomed flask, 2,5-dimethoxytetrahydrofuran
(0.490 mL, 3.78 mmol) was dissolved in deionized H2O (0.6 mL, 33.3
mmol) and the reaction mixture was heated at 100 °C for 2 h. The
mixture was cooled to rt, CH2Cl2 (2 mL), 2-amino-2-phenylacetoni-
trile 1a (500 mg, 3.78 mmol), and NaOAc (745 mg, 9.08 mmol) were
added and stirring was continued for 18 h at rt. The mixture was
quenched by adding sat. aq Na2CO3 and extracted with EtOAc (2 × 15
mL). The combined organic layers were washed with brine (25 mL),
dried (Na2SO4), and concentrated. The crude product was purified by
Combi-Flash chromatography (12 g Redi-Sep silica column; 10% EtO-
Ac/PE) to afford 2a as a colorless gummy liquid; yield: 550 mg (80%).
N
T3P, DIPEA
EtOAc, 150 °C
microwave
43%
18
4a (R = Me)
17 (R = H)
a
a: NaOH, THF/H2O (4:1), 25 °C, 4 h, 90%
Scheme 9 Synthesis of 2-(4-phenylpyrrolo[1,2-a]pyrazin-1-yl)ben-
zo[d]oxazole (18)
In summary, we have demonstrated a new and practical
synthetic protocol for the synthesis of 1,4-disubstituted
pyrrolo[1,2-a]pyrazine derivatives that originates with -
substituted pyrroloacetonitriles which, in turn, are readily
available from aryl and alkyl aldehydes. The developed pro-
tocol provides direct and convenient access to 1,4-disubsti-
tuted ring systems in moderate to good overall yields (51–
68%) without the need for purification of the intermediates.
Further functionalization via the stepwise halogenation
(bromination, iodination) and nitration was also demon-
strated. In addition, we have demonstrated the potential of
the ester functionality to be manipulated into heterocyclic
ring systems by converting it to imidazole and benzoxazole
derivatives. We believe these observations add further to
the potential applications of pyrrolo[1,2-a]pyrazine deriva-
tives in synthesis and drug design.
1H NMR (300 MHz, CDCl3):  = 7.52–7.32 (m, 5 H), 6.83–6.75 (m, 2 H),
6.32–6.24 (m, 2 H), 6.15 (s, 1 H).
LCMS (ESI+): m/z [M + H]+ calcd for C12H10N2: 183.1; found: 183.2
(ii) Methyl {1-[Cyano(phenyl)methyl]-1H-pyrrol-2-yl}(oxo)acetate
(3a)
2-Phenyl-2-(1H-pyrrol-1-yl)acetonitrile (2a; 200 mg, 1.098 mmol)
and methyl chlorooxoacetate (0.145 mL, 1.64 mmol) were dissolved
in benzene (6 mL) and the reaction mixture was heated at 95 °C for
4 h in a 50 mL round-bottomed flask. The mixture was quenched by
adding cold NaHCO3 solution and extracted with EtOAc (2 × 15 mL).
The combined organic layers were washed with brine (15 mL), dried
(Na2SO4), and concentrated. The crude product was purified by Com-
bi-Flash chromatography (using a 12 g Redi-Sep silica column; eluted
with 10–12% EtOAc/PE) to afford 3a as a gummy liquid; yield: 250 mg
(0.930 mmol, 85%).
1H NMR (300 MHz, CDCl3):  = 7.74 (s, 1 H), 7.53–7.48 (m, 1 H), 7.47–
7.38 (m, 5 H), 7.30 (dd, J = 2.71, 1.58 Hz, 1 H), 6.42–6.38 (m, 1 H), 3.96
(s, 3 H).
Commercially available reagents were used without additional purifi-
cation, unless otherwise stated. TLC was carried out using plates coat-
ed with Kieselgel 60F254. For column chromatography, Combi-Flash
chromatogram and Res-Sep Silica columns were used. NMR spectra
were recorded on 300 MHz or 400 MHz spectrometer for 1H and on
75 MHz or 100 MHz spectrometer for 13C at T = 300 K. NMR character-
ization of the isolated products was carried out in CDCl3 or DMSO-d6
LCMS (ESI–): m/z [M – H] calcd for C15H12N2O3: 267.2; found: 267.0
(iii) Methyl 4-Phenylpyrrolo[1,2-a]pyrazine-1-carboxylate (4a)
Pd/C (31.7 mg, 0.030 mmol) and AcOH (0.043 mL, 0.746 mmol) were
added to a solution of 3a (200 mg, 0.746 mmol) in MeOH (10 mL). The
reaction mixture was stirred at r.t. for 4 h under 1 atm of H2 pressure.
After completion, the mixture was filtered through a bed of Celite,
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–I

G
A. Karmakar et al.
Paper
Synthesis
and washed with MeOH (2 × 15 mL). The solvent was evaporated to
leave crude methyl 4-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazine-1-
carboxylate (6a; 200 mg), which was taken as such in the next step.
This material was dissolved in THF (10 mL) and DDQ (338 mg, 1.491
mmol) added. The reaction mixture was heated at 70 °C for 2 h,
cooled to r.t. and quenched by adding 10% aq NaHCO3. The mixture
was extracted with EtOAc (2 × 15 mL), the combined organic layers
were washed sequentially with H2O (20 mL) and brine (20 mL), dried
(Na2SO4), and concentrated. The crude product was purified by Com-
bi-Flash chromatography (using a 12 g Redi-Sep silica column; eluted
with 25% EtOAc/PE) to afford 4a as yellowish gummy liquid; yield:
150 mg (0.596 mmol, 80%, after 2 steps).
fied by Combi-Flash chromatography (using a Redi-Sep silica column
and eluted with 12–15% EtOAc/PE) to give 8g as a gummy colorless
liquid; yield: 0.38 g (85%).
1H NMR (400 MHz, DMSO-d6):  = 7.57–7.51 (m, 2 H), 7.22–7.17 (m, 2
H), 6.91–6.89 (m, 2 H), 6.05–6.01 (m, 2 H), 5.49–5.41 (m, 1 H), 3.99–
3.80 (m, 2 H), 3.78–3.73 (m, 3 H).
LCMS (ESI+): m/z [M + H]+ calcd for C15H15BrN2O3: 351.0 and 352.0;
found: 351.0 and 353.0.
(iii) Methyl 4-(4-Bromophenyl)pyrrolo[1,2-a]pyrazine-1-carboxyl-
ate (4g)
A
slurry of methyl {[2-(4-bromophenyl)-2-(1H-pyrrol-1-yl)eth-
FTIR: 2949.1, 1590.1, 1482.5, 1443.3, 1358.7, 1161.6, 1078.1, 1052.8,
yl]amino}(oxo)acetate (8g; 0.3 g, 0.854 mmol) in POCl3 (1.592 mL,
17.08 mmol) was stirred at rt for 12 h. The reaction mixture was con-
centrated under vacuum to remove the POCl3 and the residue was di-
luted with EtOAc (20 mL) and washed with 10% aq NaHCO3 (20 mL)
followed by brine (2 × 20 mL). The organic layer was dried (Na2SO4)
and concentrated under reduced pressure to leave crude methyl 4-(4-
bromophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-1-carboxylate (6g)
as a brown solid (260 mg). This intermediate was characterized by
LCMS. [LCMS (ESI+): m/z [M + H]+ calcd for C15H13BrN2O2: 333.1 and
335.1; found: 333.1 and 335.1]. DDQ (338 mg, 1.491 mmol) was add-
ed to a solution of the crude material in THF (10 mL) and the mixture
heated at 70 °C for 2 h. The mixture was quenched by adding 10% aq
NaHCO3 and extracted with EtOAc (2 × 25 mL). The combined organic
layers were washed sequentially with H2O (25 mL) and brine (25 mL),
dried (Na2SO4), and concentrated. The crude material was purified by
Combi-Flash chromatography (using a 12 g Red-Sep silica column and
the product eluted with 22–25% EtOAc/PE) to afford 4g as a colorless
gummy liquid; yield: 0.21 g (0.657 mmol, 77% after 2 steps).
1H NMR (400 MHz, DMSO-d6):  = 7.88–7.71 (m, 5 H), 7.70–7.63 (m, 1
H), 7.45–7.36 (m, 1 H), 7.17–7.09 (m, 1 H), 3.97 (s, 3 H).
13C NMR (100 MHz, DMSO-d6):  = 164.7, 140.8, 132.8, 131.7, 131.1,
130.7, 127.3, 126.2, 124.2, 117.6, 114.8, 106.3, 53.0.
LCMS (ESI+): m/z [M + H]+ calcd for C15H11BrN2O2: 331.0 and 333.0;
found: 331.0 and 333.0.
HRMS (ESI): m/z [M + H]+ calcd for C15H12BrN2O2: 331.0082 and
333.0062; found: 331.0088 and 333.0065.
695.3 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.70–7.62 (m, 4 H), 7.61–7.55 (m, 4 H),
7.04 (dd, J = 4.20, 2.64 Hz, 1 H), 4.09 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 159.9, 135.7, 128.2, 127.0, 126.0,
125.6, 124.8 (2 C), 124.6, 123.7, 122.8, 121.0, 112.2, 109.2, 101.8, 48.1.
LCMS (ESI+): m/z [M + H]+ calcd for C15H12N2O2: 253.0; found: 253.0.
HRMS (ESI): m/z [M + H]+ calcd for C15H13N2O2: 253.0977; found:
253.0958.
Methyl 4-(4-Bromophenyl)pyrrolo[1,2-a]pyrazine-1-carboxylate
(4g)
(i) 2-(4-Bromophenyl)-2-(1H-pyrrol-1-yl)ethan-1-amine (7g)
CoCl2·6H2O (228 mg, 0.957 mmol) was added to a stirred solution of
2-(4-bromophenyl)-2-(1H-pyrrol-1-yl)acetonitrile (2g; 500 mg, 1.915
mmol) in MeOH (10 mL) at 0 °C maintained under an inert atmo-
sphere. After 10 min, NaBH4 (362 mg, 9.57 mmol) was added in 3
equal portions to the reaction mixture over a period of 15 min, and
the mixture was allowed to warm to rt and stirred for 5 h. The reac-
tion mixture was quenched by slowly adding cold H2O (20 mL), fil-
tered through a bed of Celite, washed with MeOH (20 mL), and the
clear filtrate concentrated under reduced pressure. The aqueous resi-
due was extracted with EtOAc (4 × 20 mL), the combined organic lay-
ers were washed with brine (2 × 25 mL), dried (Na2SO4), and concen-
trated in vacuo to leave 7g as a colorless gummy liquid; yield: 0.45 g
(0.832 mmol, 90%).
1H NMR (400 MHz, DMSO-d6):  = 7.66–7.46 (m, 2 H), 7.29–7.08 (m, 2
H), 6.89 (br s, 2 H), 6.14–5.94 (m, 2 H), 5.23–4.94 (m, 1 H), 3.24–3.08
(m, 2 H).
LCMS (ESI+): m/z [M + H]+ calcd for C12H13BrN2: 265.0 and 267.0;
found: 265.0 and 267.0
Methyl 6-Bromo-4-phenylpyrrolo[1,2-a]pyrazine-1-carboxylate
(9)
NBS (31.7 mg, 0.178 mmol) was added to a solution of methyl 4-
phenylpyrrolo[1,2-a]pyrazine-1-carboxylate (4a; 90 mg, 0.357 mmol)
in CH2Cl2 (5 mL) maintained at 0 °C. The reaction mixture was stirred
at 0 °C for 3 h, quenched by the addition of H2O, and the mixture ex-
tracted with EtOAc (2 × 25 mL). The combined organic layers were
washed with brine, dried (Na2SO4), and concentrated in vacuo. The
crude material was purified by preparative HPLC to afford 9 as a yel-
low solid; yield: 86 mg (0.260 mmol, 73%); mp 164 °C.
1H NMR (400 MHz, CD3OD):  = 7.69 (d, J = 4.6 Hz, 1 H), 7.60–7.41 (m,
6 H), 7.06–7.00 (m, 1 H), 4.16–3.98 (m, 3 H).
13C NMR (75 MHz, CD3OD):  = 163.9, 133.3, 131.1, 130.4, 129.6,
129.3, 127.9, 127.4, 122.2, 108.4, 52.0.
(ii) Methyl {[2-(4-Bromophenyl)-2-(1H-pyrrol-1-yl)ethyl]ami-
no}(oxo)acetate (8g)
Et3N (0.276 mL, 1.98 mmol) was added to a stirred solution of 2-(4-
bromophenyl)-2-(1H-pyrrol-1-yl)ethan-1-amine (7g; 350 mg, 1.32
mmol) in CH2Cl2 (5 mL) at 0 °C followed by the dropwise addition of
methyloxalyl chloride (0.073 mL, 0.792 mmol). The mixture was
warmed to rt, stirred for 4 h, diluted with CH2Cl2 (25 mL), and the or-
ganic layer was washed sequentially with 10% aq NaHCO3 (20 mL) and
brine (20 mL). The organic layer was dried (Na2SO4) and concentrated
under reduced pressure to leave the crude product, which was puri-
LCMS (ESI+): m/z [M + H]+ calcd for C15H11BrN2O2: 331.1 and 333.1;
found: 331.2 and 333.2.
HRMS (ESI): m/z [M + H]+ calcd for C15H12BrN2O2: 331.0082 and
333.0062; found: 331.0084 and 333.0065.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–I

H
A. Karmakar et al.
Paper
Synthesis
Methyl 6,8-Dibromo-4-phenylpyrrolo[1,2-a]pyrazine-1-carboxyl-
HRMS (ESI): m/z [M + H]+ calcd for C15H10N5O8: 388.0529; found:
ate (10)
388.0524.
NBS (70.6 mg, 0.396 mmol) was added to a solution of methyl 4-
phenylpyrrolo[1,2-a]pyrazine-1-carboxylate (4a; 100 mg, 0.396
mmol) in DMF (2 mL). The reaction mixture was stirred at rt for 3 h,
diluted with H2O, and extracted with EtOAc (2 × 20 mL). The com-
bined organic layers were washed with H2O (25 mL) and brine (25
mL), dried (Na2SO4) and concentrated under vacuum. The crude prod-
uct was purified by preparative HPLC to afford 10 as an off-white sol-
id; yield: 110.5 mg (0.269 mmol, 68%); mp 169.5 °C.
1H NMR (400 MHz, DMSO-d6):  = 7.60–7.50 (m, 5 H), 7.48–7.46 (m, 1
H), 7.41–7.40 (m, 1 H), 4.00 (s, 3 H).
13C NMR (75 MHz, DMSO-d6):  = 164.5, 144.5, 131.4, 130.6, 130.4,
129.8, 127.6, 123.6, 123.1, 98.1, 91.4, 52.9.
2-(4-Phenylpyrrolo[1,2-a]pyrazin-1-yl)benzo[d]oxazole (18)
Compound 18 was prepared from the intermediate acid 17 (85 mg,
0.356 mmol) by following a literature protocol19 using T3P and DIPEA
in EtOAc at 150 °C under microwave condition for 1 h; light brown
gummy liquid; yield: 48 mg (0.154 mmol, 43%).
1H NMR (400 MHz, CDCl3):  = 8.04–8.00 (m, 1 H), 7.96–7.91 (m, 1 H),
7.78–7.68 (m, 5 H), 7.64–7.54 (m, 3 H), 7.50–7.40 (m, 2 H), 7.11–7.05
(m, 1 H).
13C NMR (75 MHz, CDCl3):  = 159.9, 150.7, 142.0, 132.0, 131.9, 130.2
(3 C), 129.3 (3 C), 126.6, 126.5, 126.3, 124.9, 121.0, 116.7, 114.2,
111.2, 106.9.
LCMS (ESI+): m/z [M + H]+ calcd for C15H10Br2N2O2: 410.0; found:
411.0.
HRMS (ESI): m/z [M + H]+ calcd for C15H11Br2N2O2: 410.9167; found:
410.9164.
LCMS (ESI+): m/z [M + H]+ calcd for C20H13N3O: 312.2; found: 312.2.
HRMS (ESI): m/z [M + H]+ calcd for C20H14N3O: 312.1137; found:
312.1140.
Methyl 6-Bromo-8-iodo-4-phenylpyrrolo[1,2-a]pyrazine-1-car-
boxylate (11)
Acknowledgment
The authors express their appreciation to the Department of Discov-
ery Analytical Sciences (DAS) for analytical support and Analytical
Research and Development (ARD), Biocon Bristol-Myers Squibb Re-
search Centre, Bangalore, India for X-ray diffraction (XRD) analysis of
the samples.
NIS (82 mg, 0.362 mmol) was added to a solution of methyl 6-bromo-
4-phenylpyrrolo[1,2-a]pyrazine-1-carboxylate (9; 120 mg, 0.362
mmol) in DMF (5 mL) and the mixture stirred at rt for 3 h. The mix-
ture was quenched by adding H2O and extracted with EtOAc (2 × 15
mL). The combined organic layers were washed with brine, dried
(Na2SO4), and concentrated under vacuum. The crude material was
purified by preparative HPLC to furnish 11 as a white solid; yield: 111
mg (0.242 mmol, 67%); mp 178 °C.
Supporting Information
1H NMR (400 MHz, DMSO-d6):  = 7.59–7.50 (m, 5 H), 7.46–7.44 (m, 1
H), 7.41 (s, 1 H), 4.08–3.98 (m, 3 H).
13C NMR (75 MHz, DMSO-d6):  = 165.0, 146.0, 132.2, 131.9, 131.1,
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690699.
S
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n
130.3, 129.2, 129.1, 128.3, 128.1, 126.6, 99.7, 59.5, 53.3.
LCMS (ESI+): m/z [M + H]+ calcd for C15H10BrIN2O2: 456.9 and 457.9;
References
found: 456.9 and 457.8.
HRMS (ESI): m/z [M + H]+ calcd for C15H11BrIN2O2: 456.9049 and
458.9028; found: 456.9043 and 458.9020.
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Methyl 6,8-Dinitro-4-(4-nitrophenyl)pyrrolo[1,2-a]pyrazine-1-
carboxylate (12)
Methyl 4-phenylpyrrolo[1,2-a]pyrazine-1-carboxylate (4a; 100 mg,
0.396 mmol) was added to concentrated H2SO4 (211 L, 3.96 mmol)
and the mixture cooled to 0 °C. Concentrated HNO3 (53.1 L, 1.189
mmol) was added and the mixture warmed to rt and stirred for 5 h.
The crude reaction mixture was quenched by adding ice cold H2O, ex-
tracted with CH2Cl2 (2 × 25 mL) and the combined organic layers were
dried (Na2SO4). The solvent was removed under vacuum and the
crude material purified by preparative HPLC to afford 12 as a light yel-
low colored solid; yield: 87 mg (0.224 mmol, 57%); mp 71 °C (dec.,
turned gummy black).
1H NMR (400 MHz, DMSO-d6):  = 8.98–8.92 (m, 1 H), 8.84–8.78 (m, 1
H), 8.32–8.24 (m, 1 H), 7.83–7.76 (m, 1 H), 7.73 (s, 1 H), 7.69–7.65 (m,
1 H), 7.44–7.40 (m, 1 H), 7.31–7.31 (m, 1 H), 7.15–7.12 (m, 1 H), 4.01–
3.95 (m, 3 H).
13C NMR (75 MHz, DMSO-d6):  = 163.7, 148.27, 147.98, 144.19,
138.04, 135.9, 133.4, 131.9, 131.0, 127.3, 127.1, 124.3, 122.1, 120.8,
117.3, 53.3.
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LCMS (ESI+): m/z calcd [M + H]+ for C15H9N5O8: 387.2; found: 388.0.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–I

I
A. Karmakar et al.
Paper
Synthesis
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