Synthesis of pyrrolo[1,2-a]pyrazines and pyrazino[1,2-a]indoles by Curtius reaction in Morita-Baylis-Hillman derivatives

Article abstract of DOI:10.1016/j.tet.2011.07.074

Synthesis of substituted pyrrolo[1,2-a]pyrazines and pyrazino[1,2-a]indoles from the Morita-Baylis-Hillman derivatives of acrylates via saponification followed by Curtius reaction is described.

Full text of DOI:10.1016/j.tet.2011.07.074

Tetrahedron 67 (2011) 7563e7569
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Synthesis of pyrrolo[1,2-a]pyrazines and pyrazino[1,2-a]indoles by Curtius
reaction in MoritaeBayliseHillman derivativesq
*
Maloy Nayak, Garima Pandey, Sanjay Batra
Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, PO Box 173, Lucknow 226001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 May 2011
Received in revised form 23 July 2011
Accepted 23 July 2011
Synthesis of substituted pyrrolo[1,2-a]pyrazines and pyrazino[1,2-a]indoles from the MoritaeBaylise
Hillman derivatives of acrylates via saponification followed by Curtius reaction is described.
Ó 2011 Elsevier Ltd. All rights reserved.
Available online 29 July 2011
1. Introduction
of the ester I. Working on the envisaged strategy we discovered that
the synthesis of the title compounds can be readily achieved in high
Pyrrolo[1,2-a]pyrazines and pyrazino[1,2-a]indoles are impor-
tant templates from medicinal perspective. Compounds repre-
senting the pyrrolo[1,2-a]pyrazine core are known to act as
Vasopressin1b antagonist,1 5HT2C agonist,2 selective non-
competitive mGluR5 antagonists,3 HIV-1 integrase inhibitors4 and
neuroleptics.5 Likewise pyrazino indole also forms sub-structural
unit of several compounds, which display diverse pharmacologi-
cal activities including serotoninergic,6 anti-inflammatory,7 anti-
bacterial8 and anti-obesity.9 Although several synthetic
methodologies for their preparation are available in the literature,10
their significance in medicinal chemistry demands development of
newer approaches for accessing them.
yields without any elaborate synthetic requirements. We report
herein the results of our efforts to develop the envisaged protocol
for achieving the synthesis of these scaffolds.
For many years, we have been interested in development of
general protocols for the synthesis of heterocycles of biological
significance using MoritaeBayliseHillman derivatives as the key
intermediates.11 The substituted allylamines afforded from the aza-
MBH reaction or MBH acetates are precursors to a variety of aza-
heterocycles.11c,12,13 As part of our ongoing interest, we envisaged
the synthesis of pyrrolo[1,2-a]pyrazines and pyrazino[1,2-a]indoles
from substituted allylamines afforded from the SN20-reaction be-
tween the MBH acetate of acrylate and pyrrole-2-carboxaldehyde
or 3-methyl-indole-2-carbox-aldehyde, respectively. It is worth-
while to mention that these allylamines have been prepared by
Raghunathan et al.14a,b and Kim et al.14c previously for different
objectives. The retrosynthetic analysis illustrated in Scheme 1 ex-
plains our strategy. Cleavage of the pyrazine ring of the product IV
gives III, which in turn can be synthesized from the acid II via
Curtius reaction. The acid II can be easily obtained by saponification
Scheme 1. Retrosynthetic analysis for the synthesis of pyrrolo[1,2-a]pyrazine and
pyrazino[1,2-a]indole using MBH derivatives.
2. Results and discussion
The study commenced with preparation of 2a from MBH acetate
1a by reacting it with pyrrole-2-carboxaldehyde in DMF at rt for 3 h
(Scheme 2). Saponification of 2a with LiOH in aq THF at rt afforded
the acrylic acid 3a. The next objective was transforming of the acid
group of 3a to amine via Curtius reaction. Gratifyingly, after per-
forming a series of reactions we were able to optimize the condi-
tions as follows. Reacting 3a with ethyl chloroformate followed by
sodium azide in THF at ꢀ10 ꢁC to rt for 30 min resulted in acrolyl
azide. The formation of the azide derivative was confirmed by
characteristic peak at 2135 cmꢀ1 for the azido group in the IR
q
CDRI Communication No. 8102.
* Corresponding author. Tel.: þ91 522 2612411 18x4234, 4368; fax: þ91 522
2623405, 2623938; e-mail addresses: batra_san@yahoo.co.uk, s_batra@cdri.res.in
(S. Batra).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.07.074

7564
M. Nayak et al. / Tetrahedron 67 (2011) 7563e7569
spectrum. Without any purification, the azide was transformed to
isocyanate by heating it in toluene at 65 ꢁC. The formation of iso-
cyanate was established by the IR spectrum, which displayed the
peak for isocyanate functionality at 2223 cmꢀ1. Treating the iso-
cyanate with 90% formic acid and catalytic amount of DMAP in
methylene chloride at rt for 4 h afforded a single product, which
was isolated via column chromatography in 76% yields. Spectro-
scopic analysis of the product led us to assign its structure as 4a.
The formation of pyrrolo[1,2-a]pyrazine 4a implied that expectedly
the generated amino group participate in intramolecular cycliza-
tion with the formyl moiety of the pyrrole ring. The success of the
protocol inspired us to investigate its general applicability. Hence
several MBH acetates 2bei were treated with pyrrole-2-
carboxaldehyde to afford corresponding products 3bei. It was
a delight to observe that a similar set of reactions with 3bei under
the optimized protocol resulted in the formation of respective
substituted pyrrolo[1,2-a]pyrazines 4bei in 68e76% yields. Im-
portantly purification was performed only at the final step wherein
passing the crude material through a small band of silica gel fur-
nished the products as solids or oils.
gave corresponding acid 10c,f, which upon similar series of re-
actions afforded products, which were identified as ketones 11c,f
(Scheme 4). The formation of the ketone can be rationalized on the
basis that the generated enamine is unstable under the reaction
conditions and is readily oxidized to furnish the ketone. The for-
mation of ketone was chemically ascertained by reacting 11c with
hydroxylamine to produce the oxime 12 as diastereomeric mixture.
Scheme 4. Reagents and conditions: (i) Indole, TBAB, 50% aq NaOH, PhMe, rt, 3e4 h;
(ii) LiOH, THF/H2O (1:1, v/v), rt, 6 h; (iii) (a) ClCO2Et, NMM, THF, 0 ꢁC, 10 min; (b) NaN3,
30 min; (c) PhMe, 65 ꢁC, 30 min; (iv) Formic acid, DMAP, CH2Cl2, rt, 2 h; (iv)
NH2OH.HCl, NaOAc, MeOH, reflux, 2 h.
3. Conclusions
In summary we have developed a new protocol for the synthesis
of pyrrolo[1,2-a]pyrazines and pyrazino[1,2-a]indoles via saponifi-
cation followed by Curtius reaction in the MBH derivatives. This
work further showcase the significance of the MBH derivatives in
the realm of heterocyclic chemistry. Additionally, this route can also
be employed for installing substitution containing
the azoles.
b-keto group in
Scheme 2. Reagents and conditions. (i) Pyrrole-2-carboxaldehyde, K2CO3, DMF, rt,
3e4 h; (ii) LiOH, THF/H2O (1:1, v/v), rt, 6e8 h; (iii) (a) ClCO2Et, NMM, THF, 0 ꢁC, 10 min;
(b) NaN3, 30 min; (c) PhMe, 65 ꢁC, 30 min; (iv) Formic acid, DMAP, CH2Cl2, rt, 4e5 h.
4. Experimental
4.1. General
Given the success of the strategy we considered to expand the
scope by employing the indole-2-carboxaldehyde in place of pyr-
role-2-carboxaldehyde. The required substrate 6cee were prepared
following the literature procedure.14b Treating 6cee with aq LiOH
produced the corresponding acid 7cee (Scheme 3). Similar set of
reactions as described earlier with 7cee afforded the required
pyrazino[1,2-a]indoles (8cee) in 79e85% yields.
Melting points are uncorrected and were determined in capil-
lary tubes on an apparatus containing silicon oil. IR spectra were
recorded using a PerkineElmer’s RX I FTIR spectrophotometer. 1H
NMR and 13C NMR spectra were recorded either on a Bruker DPX-
200 FT or Bruker Avance DRX-300 spectrometer, using TMS as an
internal standard (chemical shifts in d). The ESMS were recorded on
MICROMASS Quadro-II LCMS system. The HRMS were recorded as
ESI or DART on a suitable mass spectrometer. Elemental analyses
were performed on a Carlo Erba’s 108 or an Elementar’s Vario EL III
microanalyzer. All yields described herein are the isolated yields
after column chromatography. Intermediate azides and isocyanates
were used without purification and therefore no corresponding
spectroscopic data exist. Spectroscopic data for previously reported
derivatives in Ref. 14 are not included.
4.2. General procedure for the preparation of compound 2aei
as exemplified for 2a
Scheme 3. Reagents and conditions. (i) Ref. 14b. (ii) LiOH, THF/H2O (1:1, v/v), rt, 6e8 h;
(iii) (a) ClCO2Et, NMM, THF, 0 ꢁC, 10 min; (b) NaN3, 30 min; (c) PhMe, 65 ꢁC, 30 min; (d)
Formic acid, DMAP, CH2Cl2, rt, 2 h.
To a stirred solution of compound 1b (1.0 g, 3.2 mmol) in DMF
(10 mL), pyrrole-2-carboxaldehyde (0.34 g, 3.5 mmol) and K2CO3
(0.67 g, 4.8 mmol) were added and reaction was continued at rt for
3.0 h. After completion, EtOAc (20 mL) and water (50 mL) were
added and the mixture was partitioned in separating funnel. The
organic layers were collected and the aq layer was extracted with
Mechanistic considerations generated interest to study the fate
of the Curtius reaction in the absence of the formyl group in
the system. For this objective compounds 9c,f were prepared
by reacting the allyl bromide 5c,f with indole. Hydrolysis of 5c,f

M. Nayak et al. / Tetrahedron 67 (2011) 7563e7569
7565
EtOAc (3ꢂ20 mL). The organic layers were combined and washed
with brine solution, dried over Na2SO4 and concentrated under
reduced pressure to afford the crude product. Purification by col-
umn chromatography on silica gel (hexanes/EtOAc, 19:1) led to
furnish 1.07 g of pure 2b as a white solid (86%).
130.0, 131.8, 131.9, 132.5, 138.7, 142.3, 166.8, 179.7; mass (ESþ)
m/z¼294.9 (Mþþ1); Anal. Calcd for: C17H14N2O3 (Exact mass:
294.1004); C, 69.38; H, 4.79; N, 9.52. Found C, 69.46; H, 4.66; N,
9.67.
4.2.6. Methyl (E)-3-(2-fluorophenyl)-2-[(2-formyl-1H-pyrrol-1-yl)
methyl]prop-2-enoate (2h). Yield 75% as oil (0.43 g from 0.5 g);
Rf¼0.47 (hexanes/EtOAc, 80:20, v/v); nmax (Neat) 1659 (CHO), 1720
4.2.1. Methyl (E)-3-(2-bromophenyl)-2-[(2-formyl-1H-pyrrol-1-yl)
methyl]prop-2-enoate (2b). Mp 184e185 ꢁC; Rf¼0.48 (hexanes/
EtOAc, 80:20, v/v); nmax (KBr) 1661 (CHO), 1701 (CO2Me) cmꢀ1; 1H
(CO2Me) cmꢀ1
;
1H NMR (300 MHz, CDCl3)
d¼3.77 (s, 3H, OCH3),
NMR (300 MHz, CDCl3)
d
¼3.79 (s, 3H, OCH3), 5.37 (s, 2H, CH2), 6.17
5.41 (s, 2H, CH2), 6.18 (dd, 1H, J1¼2.7 Hz, J2¼3.8 Hz, ArH),
6.91e6.93 (m, 2H, ArH), 7.11e7.14 (m, 3H, ArH), 7.32e7.39 (m, 1H,
ArH), 8.02 (s, 1H, ]CH), 9.52 (s, 1H, CHO); 13C NMR (75 MHz,
(dd, 1H, J1¼2.6 Hz, J2¼3.9 Hz, ArH), 6.87e6.91 (m, 2H, ArH),
7.08e7.10 (m, 1H, ArH), 7. 18e7.29 (m, 2H, ArH), 7.61 (dd, 1H,
J1¼0.9 Hz, J2¼7.6 Hz, ArH), 8.00 (s, 1H, ]CH), 9.49 (d, 1H, J¼0.7 Hz,
CDCl3)
d
¼45.3, 52.6, 110.1, 115.9, 116.2, 124.46, 124.51, 124.9, 129.6,
CHO); 13C NMR (50 MHz, CDCl3)
d¼44.5, 52.6, 110.1, 123.9, 124.7,
129.8, 129.9, 130.0, 131.5, 131.6, 131.9, 137.46, 137.51, 158.8, 166.9,
179.6; mass (ESþ) m/z¼288.2 (Mþþ1). Anal. Calcd for: C16H14FNO3
(Exact mass: 287.0958); C, 66.89; H, 4.91; N, 4.88. Found C, 67.02;
H, 4.94; N, 4.71.
127.6, 129.3, 129.7, 129.8, 130.6, 131.8, 133.0, 134.9, 143.7, 166.8,
179.6; mass (ESþ) m/z¼347.9 (Mþþ1); Anal. Calcd for: C16H14BrNO3
(Exact mass: 347.0157); C, 55.19; H, 4.05; N, 4.02. Found C, 55.01; H,
3.88; N, 4.22.
4.2.7. Methyl (E)-3-(4-fluorophenyl)-2-((2-formyl-1H-pyrrol-1-yl)
methyl) prop-2-enoate (2i). Yield 73% as a yellow oil (0.66 g from
0.8 g); Rf¼0.49 (hexanes/EtOAc, 80:20, v/v); nmax (Neat) 1656
4.2.2. Methyl (E)-3-(2-chlorophenyl)-2-[(2-formyl-1H-pyrrol-1-yl)
methyl]prop-2-enoate (2c). Yield 79% as a yellow solid (0.45 g from
0.5 g); mp 78e80 ꢁC Rf¼0.46 (hexanes/EtOAc, 80:20, v/v); nmax
(CHO), 1712 (CO2Me) cmꢀ1
;
1H NMR (300 MHz, CDCl3)
d
¼3.79
(KBr) 1662 (CHO), 1713 (CO2Me) cmꢀ1
;
1H NMR (300 MHz, CDCl3)
(s, 3H, OCH3), 5.45 (s, 2H, CH2), 6.20e6.23 (m, 1H, ArH),
6.93e6.98 (m, 2H, ArH), 7.02e7.08 (m, 2H, ArH), 7.22e7.26 (m,
2H, ArH), 8.02 (s, 1H, ]CH), 9.58 (s, 1H, CHO); 13C NMR (50 MHz,
d
¼3.79 (s, 3H, OCH3), 5.38 (s, 2H, CH2), 6.17 (t, 1H, J¼3.1 Hz, ArH),
6.88e6.91 (m, 2H, ArH), 7.10 (d, 1H, J¼7.2 Hz, ArH), 7. 20e7.32 (m,
2H, ArH), 7.43 (d, 1H, J¼7.7 Hz, ArH), 8.07 (s, 1H, ]CH), 9.49 (s, 1H,
CDCl3)
d
¼45.2, 52.6, 110.1, 111.4, 116.1, 116.3, 125.1, 126.5, 129.2,
CHO); 13C NMR (75 MHz, CDCl3)
d¼44.8, 52.6, 110.2, 124.8, 127.0,
130.2, 130.3, 131.4, 131.5, 131.9, 144.1, 161.9, 165.2, 167.5, 179.8;
mass (ESþ) m/z¼288.1 (Mþþ1); Anal. Calcd for: C16H14FNO3
(Exact mass: 287.0958); C, 66.89; H, 4.91; N, 4.88. Found C, 67.10;
H, 5.11; N, 4.67.
129.1, 129.6, 129.8, 129.9, 130.6, 131.9, 133.0, 134.1, 141.7, 166.9,
179.6; mass (ESþ) m/z¼304.1 (Mþþ1); Anal. Calcd for: C16H14ClNO3
(Exact mass: 303.0662); C, 63.27; H, 4.65; N, 4.61. Found C, 63.41; H,
4.49; N, 4.75.
4.3. General procedure for the preparation of compounds
4.2.3. Methyl (E)-3-(2,4-dichlorophenyl)-2-[(2-formyl-1H-pyrrol-1-
yl)methyl]prop-2-enoate (2e). Yield 76% as a yellow solid (0.42 g
from 0.5 g); mp 82e84 ꢁC; Rf¼0.47 (hexanes/EtOAc, 80:20, v/v);
3aei, 7cee and 10c,f as exemplified by 3a
To a stirred solution of compound 2a (0.5 g, 1.7 mmol) in THF/
H2O(1:1, v/v) (20 mL), LiOH (0.2 g, 8.3 mmol) was added and stirred
at rt for 8 h. After completion of the reaction, reaction mixture was
acidified with 50% HCl and EtOAc (20 mL) was added and layers
were separated. The aq layer was again extracted with EtOAc
(3ꢂ20 mL). The combined organic layer was washed with brine
solution, dried over Na2SO4 and concentrated under reduced
pressure to afford the crude product. The crude product on re-
crystallization with hexanes/EtOAc yielded 0.43 g of pure 3a as
a white solid (90%).
nmax (KBr) 1659 (CHO), 1715 (CO2Me) cmꢀ1 1H NMR (300 MHz,
;
CDCl3)
d
¼3.81 (s, 3H, OCH3), 5.24 (s, 2H, CH2), 6.04 (t, 1H, J¼6.1 Hz,
ArH), 6.78 (d, 1H, J¼2.4 Hz, ArH), 6.86 (s, 1H, ArH), 7.20 (t, 1H,
J¼7.9 Hz, ArH), 7. 30e7.33 (m, 2H, ArH), 7.65 (s, 1H, ]CH), 9.41 (s,
1H, CHO); 13C NMR (75 MHz, CDCl3)
d¼45.3, 52.6, 109. 9, 124.4,
128.1, 130.2, 130.9, 131.6, 132.4, 133.2, 134.3, 137.1, 166.3, 179.3; mass
(ESþ) m/z¼338.1 (Mþþ1); Anal. Calcd for: C16H13Cl2NO3 (Exact
mass: 337.0272); C, 56.82; H, 3.87; N, 4.14. Found C, 56.80; H, 4.11;
N, 3.89.
4.2.4. Methyl (E)-2-[(2-formyl-1H-pyrrol-1-yl)methyl]-3-(4-
4.3.1. (E)-2-[(2-Formyl-1H-pyrrol-1-yl)methyl]-3-phenylprop-2-
methylphenyl)prop-2-enoate (2f). Yield 82% as
a
white solid
enoic acid (3a). Mp 136e137 ꢁC; Rf¼0.23 (hexanes/EtOAc, 70:30, v/
(0.47 g from 0.5 g); mp 79e80 ꢁC; Rf¼0.45 (hexanes/EtOAc, 80:20,
v); nmax (KBr) 1663 (CHO and CO2H), 3413 (OH) cmꢀ1 1H NMR
;
v/v); nmax (KBr) 1655 (CHO), 1710 (CO2Me) cmꢀ1
;
1H NMR
(300 MHz, DMSO-d6)
d
¼5.28 (s, 2H, CH2), 6.23 (dd, 1H, J1¼2.6 Hz,
(300 MHz, CDCl3)
d
¼2.35 (s, 3H, CH3), 3.77 (s, 3H, OCH3), 5.47 (s,
J2¼3.9 Hz, ArH), 7.06e7.09 (m, 2H, ArH), 7.31e7.42 (m, 5H, ArH),
8.00 (s, 1H, ]CH), 9.54 (d, 1H, J¼0.8 Hz, CHO), 12.97 (br s, 1H,
2H, CH2), 6.20 (dd, 1H, J1¼2.6 Hz, J2¼3.8 Hz, ArH), 6.95e6.97 (m,
2H, ArH), 7.16 (s, 4H, ArH), 8.05 (s, 1H, ]CH), 9.59 (d, 1H, J¼0.7 Hz,
COOH); 13C NMR (50 MHz, DMSO-d6)
d
¼44.8, 109.9, 124.2, 127.2,
CHO); 13C NMR (50 MHz, CDCl3)
d
¼21.5, 45.4, 52.5, 110.0, 124.9,
128.9, 129.1, 129.3, 129.6, 131.6, 134.1, 143.8, 167.9, 179.7; mass (ESþ)
m/z¼256.1 (Mþþ1); Anal. Calcd for: C15H13NO3 (Exact mass:
255.0895); C, 70.58; H, 5.13; N, 5.49. Found C, 70.74; H, 5.20;
N, 5.66.
125.5, 129.1, 129.5, 129.7, 131.2, 132.0, 140.0, 145.5, 167.7, 179.7;
mass (ESþ) m/z¼283.9 (Mþþ1); Anal. Calcd for: C17H17NO3 (Exact
mass: 283.1208); C, 72.07; H, 6.05; N, 4.94. Found C, 72.25; H, 6.16;
N, 4.78.
4.3.2. (E)-3-(2-Bromophenyl)-2-[(2-formyl-1H-pyrrol-1-yl)methyl]
prop-2-enoic acid (3b). Yield 90% as a white solid (0.52 g from
0.6 g); mp 73e74 ꢁC; Rf¼0.19 (hexanes/EtOAc, 70:30, v/v);
4.2.5. Methyl (E)-3-(4-cyanophenyl)-2-[(2-formyl-1H-pyrrol-1-yl)
methyl]prop-2-enoate (2g). Yield 70% as a yellow solid (0.4 g from
0.5 g); mp 65e66 ꢁC Rf¼0.49 (hexanes/EtOAc, 80:20, v/v); nmax
nmax (KBr) 1654 (CHO), 1689 (CO2H), 3412 (OH) cmꢀ1
;
(KBr) 1665 (CHO), 1720 (CO2Me), 2226 (CN) cmꢀ1
;
1H NMR
1H NMR (300 MHz, CDCl3)
d
¼5.38 (s, 2H, CH2), 6.17e6.19
(300 MHz, CDCl3)
d
¼3.80 (s, 3H, OCH3), 5.42 (s, 2H, CH2), 6.20 (s,1H,
(m, 1H, ArH), 6.89e6.90 (m, 1H, ArH), 6.94 (s, 1H, ArH), 7.09e7.11
(m, 1H, ArH), 7.20e7.30 (m, 2H, ArH), 7.61e7.65 (m, 1H, ArH), 8.13
ArH), 6.90e6.93 (m, 2H, ArH), 7.33 (d, 2H, J¼7.0 Hz, ArH), 7.65 (d,
2H, J¼6.4 Hz, ArH), 7.98 (s, 1H, ]CH), 9.52 (s, 1H, CHO); 13C NMR
(s, 1H, ]CH), 9.48 (s, 1H, CHO); 13C NMR (50 MHz, CDCl3)
d
¼44.5,
(50 MHz, CDCl3)
d¼44.9, 52.8, 110.3, 113.0, 118.3, 125.2, 129.6, 129.7,
110.4, 124.0, 125.2, 127.7, 128.6, 129.8, 130.1, 130.9, 131.8, 133.1,

7566
M. Nayak et al. / Tetrahedron 67 (2011) 7563e7569
134.7, 145.7, 171.1, 179.9; mass (ESþ) m/z¼334.1 (Mþþ1);
DART-HRMS calcd for C15H13BrNO3 [MH]þ: 334.0079. Found:
334.0076.
124.3, 129.8, 130.4, 130.5, 131.5, 132.5, 139.1, 141.0, 167.5, 179.6; mass
(ESþ) m/z¼281.1 (Mþþ1); Anal. Calcd for: C16H12N2O3 (Exact mass:
280.0848); C, 68.56; H, 4.32; N, 9.99. Found C, 68.39; H, 4.45;
N, 10.20.
4.3.3. (E)-3-(2-Chlorophenyl)-2-[(2-formyl-1H-pyrrol-1-yl)methyl]
prop-2-enoic acid (3c). Yield 92% as a yellow solid (0.44 g from
0.5 g); mp 84e85 ꢁC; Rf¼0.18 (hexanes/EtOAc, 70:30, v/v); nmax
4.3.8. (E)-3-(2-Fluorophenyl)-2-[(2-formyl-1H-pyrrol-1-yl)methyl]
prop-2-enoic acid (3h). Yield 91% as a white solid (0.43 g from
0.5 g); mp 129e130 ꢁC; Rf¼0.19 (hexanes/EtOAc, 70:30, v/v); nmax
(KBr) 1659 (CHO), 1676 (CO2H), 3414 (OH) cmꢀ1
;
1H NMR
(300 MHz, CDCl3)
d
¼5.38 (s, 2H, CH2), 6.19 (dd, 1H, J1¼2.6 Hz,
(KBr) 1659 (CHO and CO2H), 3432 (OH) cmꢀ1 1H NMR (300 MHz,
;
J2¼4.0 Hz, ArH), 6.91 (dd, 1H, J1¼1.7 Hz, J2¼4.0 Hz, ArH), 6.95 (s,
1H, ArH), 7.10 (d, 1H, J¼7.5 Hz, ArH), 7.22 (dt, 1H, J1¼1.1 Hz,
J2¼7.5 Hz, ArH), 7.31 (dt, 1H, J1¼1.4 Hz, J2¼7.6 Hz, ArH), 7.43 (dd,
1H, J1¼1.1 Hz, J2¼8.0 Hz, ArH), 8.21 (s, 1H, ]CH), 9.49 (d, 1H,
CDCl3)
d
¼5.41 (s, 2H, CH2), 6.20 (dd, 1H, J1¼3.0 Hz, J2¼3.7 Hz, ArH),
6.93e6.97 (m, 2H, ArH), 7.09e7.14 (m, 3H, ArH), 7. 34e7.40 (m, 1H,
ArH), 8.15 (s, 1H, ]CH), 9.51 (s, 1H, CHO); 13C NMR (100 MHz,
CDCl3)
d
¼45.2, 110.2, 116.0, 116.3, 122.0, 122.2, 124.6, 125.3, 128.7,
J¼0.9 Hz, CHO); 13C NMR (50 MHz, CDCl3)
d¼44.7, 110.3, 125.2,
130.0, 130.1, 131.9, 132.0, 139.6, 159.3, 161.8, 171.4, 179.9; mass
(ESþ) m/z¼274.1 (Mþþ1); Anal. Calcd for: C15H12FNO3 (Exact mass:
273.0801); C, 65.93; H, 4.43; N, 5.13. Found C, 66.11; H, 4.60;
N, 5.19.
127.1, 129.8, 130.0, 130.1, 130.8, 131.1, 131.8, 132.9, 134.2, 143.5,
163.9, 179.9; mass (ESþ) m/z¼290.1 (Mþþ1); Anal. Calcd for:
C15H12ClNO3 (Exact mass: 289.0506); C, 62.19; H, 4.17; N, 4.83.
Found C, 62.20; H, 4.32; N, 4.65.
4.3.9. (E)-3-(4-Fluorophenyl)-2-((2-formyl-1H-pyrrol-1-yl)methyl)
acrylic acid (3i). Yield 90% as a white solid (0.43 g from 0.5 g);
Rf¼0.18 (hexanes/EtOAc, 70:30, v/v); nmax (KBr) 1660 (CHO and
4.3.4. (E)-3-(4-Chlorophenyl)-2-[(2-formyl-1H-pyrrol-1-yl)methyl]
prop-2-enoic acid (3d). Yield 89% as a white solid (0.42 g from
0.5 g); mp 184e185 ꢁC; Rf¼0.19 (hexanes/EtOAc, 70:30, v/v); nmax
CO2H), 3434 (OH) cmꢀ1
;
1H NMR (300 MHz, CDCl3)
d¼5.48 (s, 2H,
(KBr) 1661 (CHO), 1685 (CO2H), 3412 (OH) cmꢀ1
;
1H NMR
CH2), 6.23 (t, 1H, J¼3.2 Hz, ArH), 6.99 (d, 2H, J¼3.3 Hz, ArH),
(300 MHz, CDCl3)
d
¼5.45 (s, 2H, CH2), 6.24 (dd, 1H, J1¼2.6 Hz,
7.26e7.30 (m, 2H, ArH), 7.34e7.39 (m, 3H, ArH), 8.19 (s, 1H, ]CH),
J2¼3.8 Hz, ArH), 6.97e7.00 (m, 2H, ArH), 7.21 (d, 2H, J¼8.4 Hz,
9.58 (s, 1H, CHO); 13C NMR (50 MHz, CDCl3)
d
¼44.3, 109.5, 115.3,
ArH), 7.36 (d, 2H, J¼8.4 Hz, ArH), 8.12 (s, 1H, ]CH), 9.58 (s, 1H,
115.8, 124.7, 128.6, 129.1, 129.2, 130.8, 131.0, 160.5, 165.5, 171.3,
179.2; mass (ESþ) m/z¼274.1 (Mþþ1); Anal. Calcd for: C15H12FNO3
(Exact mass: 273.0801); C, 65.93; H, 4.43; N, 5.13. Found C, 66.19; H,
4.66; N, 5.31.
CHO); 13C NMR (75 MHz, CDCl3)
d
¼45.2, 109.9, 125.0, 127.4, 128.7,
129.0, 129.3, 130.5, 131.0, 131.6, 132.6, 135.6, 143.7, 168.8, 179.6;
mass (ESþ) m/z¼290.1 (Mþþ1); Anal. Calcd for: C15H12ClNO3
(Exact mass: 289.0506); C, 62.19; H, 4.17; N, 4.83. Found C, 62.26;
H, 3.96; N, 4.97.
4.3.10. (E)-3-(2-Chlorophenyl)-2-[(2-formyl-3-methyl-1H-indol-1-
yl)methyl]prop-2-enoic acid (7c). Yield 92% as a yellow solid
(0.35 g from 0.4 g); mp 184e185 ꢁC; Rf¼0.20 (hexanes/EtOAc,
4.3.5. (E)-3-(2,4-Dichlorophenyl)-2-((2-formyl-1H-pyrrol-1-yl)
methyl)acrylic acid (3e). Yield 92% as a white solid (0.44 g from
0.5 g); mp 185e186 ꢁC; Rf¼0.18 (hexanes/EtOAc, 70:30, v/v); nmax
70:30, v/v); nmax (KBr) 1661 (CHO), 1696 (CO2H), 3426 (OH) cmꢀ1
;
1H NMR (300 MHz, CDCl3)
d
¼2.49 (s, 3H, CH3), 5.69 (s, 2H, CH2),
(KBr) 1665 (CHO and CO2H), 3422 (OH) cmꢀ1
;
1H NMR (300 MHz,
6.99e7.09 (m, 4H, ArH), 7.12e7.17 (m, 1H, ArH), 7.28e7.30 (m, 2H,
ArH), 7.52 (d, 1H, J¼8.0 Hz, ArH), 7.93 (s, 1H, ]CH), 10.00 (s, 1H,
DMSO-d6)
d
¼5.21 (s, 2H, CH2), 6.13 (dd, 1H, J1¼2.5 Hz, J2¼3.9 Hz,
ArH), 6.92e6.93 (m, 1H, ArH), 7.03 (s, 1H, ArH), 7.22 (d, 1H,
J¼8.1 Hz, ArH), 7.40e7.43 (m, 1H, ArH), 7.68 (d, 1H, J¼1.8 Hz, ArH),
7.75 (s, 1H, ]CH), 9.40 (s, 1H, CHO), 12.97 (br s, 1H, COOH); 13C
CHO); 13C NMR (50 MHz, CDCl3)
d
¼8.3, 41.5, 111.1, 120.0, 120.8,
125.9, 126.2, 126.8, 126.9, 128.9, 129.2, 129.9, 131.0, 131.6, 132.9,
133.1, 138.1, 138.9, 168.1, 181.5; mass (ESþ) m/z¼354.1 (Mþþ1);
DART-HRMS calcd for C20H17ClNO3 [MH]þ: 354.0897. Found:
354.0908.
NMR (50 MHz, CDCl3þDMSO-d6) ¼44.0, 109.3, 123.8, 126.5, 128.7,
d
129.2, 129.8, 130.0, 130.8, 131.0, 133.8, 134.6, 138.8, 167.0, 178.5;
mass (ESþ) m/z¼323.8 (Mþþ1); Anal. Calcd for: C15H11Cl2NO3
(Exact mass: 323.0116); C, 55.58; H, 3.42; N, 4.32. Found C, 55.67;
H, 3.50; N, 4.51.
4.3.11. (E)-3-(4-Chlorophenyl)-2-[(2-formyl-3-methyl-1H-indol-1-
yl)methyl]prop-2-enoic acid (7d). Yield 90% as a yellow solid (0.43 g
from 0.5 g); mp 181e182 ꢁC; Rf¼0.21(hexanes/EtOAc, 70:30, v/v);
4.3.6. (E)-2-[(2-Formyl-1H-pyrrol-1-yl)methyl]-3-(4-methylphenyl)
nmax (KBr) 1664 (CHO), 1691 (CO2H), 3423 (OH) cmꢀ1 1H NMR
;
prop-2-enoic acid (3f). Yield 89% as
a
white solid (0.42
g
(400 MHz, CDCl3)
d
¼2.52 (s, 3H, CH3), 5.76 (s, 2H, CH2), 6.89 (d, 1H,
from 0.5 g); mp 159e160 ꢁC; Rf¼0.19 (hexanes/EtOAc, 70:30,
J¼8.4 Hz, ArH), 7.07e7.10 (m, 3H, ArH), 7.23e7.28 (m, 3H, ArH), 7.58
v/v); nmax (KBr) 1661 (CHO and CO2H), 3435 (OH) cmꢀ1 1H NMR
;
(d,1H, J¼8.0 Hz, ArH), 7.87 (s,1H, ]CH),10.01 (s,1H, CHO); 13C NMR
(300 MHz, CDCl3)
d
¼2.36 (s, 3H, CH3), 5.47 (s, 2H, CH2), 6.23
(100 MHz, CDCl3)
d¼8.6, 41.3, 111.0, 120.5, 121.5, 127.5, 128.6, 129.4,
(t, 1H, J¼3.2 Hz, ArH), 7.00 (d, 2H, J¼3.2 Hz, ArH), 7.18 (s, 4H,
130.0, 131.3, 132.7, 135.0, 139.3, 142.2, 170.7, 181.8; mass (ESþ)
m/z¼354.1 (Mþþ1); DART-HRMS calcd for C20H17ClNO3 [MH]þ:
354.0897. Found: 354.0905.
ArH), 8.17 (s, 1H, ]CH), 9.60 (s, 1H, CHO); 13C NMR (75 MHz,
CDCl3)
d
¼21.6, 45.3, 110.2, 124.6, 125.3, 129.3, 129.8, 129.9, 131.0,
131.9, 140.9, 147.7, 172.3, 179.9; mass (ESþ) m/z¼270.1 (Mþþ1);
DART-HRMS calcd for C16H16NO3 [MH]þ: 270.1130. Found:
270.1143.
4.3.12. (E)-3-(2,4-Dichlorophenyl)-2-[(2-formyl-3-methyl-1H-indol-
1-yl)methyl]prop-2-enoic acid (7e). Yield 87% as a yellow solid
(0.42 g from 0.5 g); mp 152e153 ꢁC; Rf¼0.18 (hexanes/EtOAc,
4.3.7. (E)-3-(4-Cyanophenyl)-2-[(2-formyl-1H-pyrrol-1-yl)methyl]
prop-2-enoic acid (3g). Yield 88% as a yellow solid (0.42 g from
0.5 g); mp 175e176 ꢁC; Rf¼0.20 (hexanes/EtOAc, 70:30, v/v); nmax
70:30, v/v); nmax (KBr) 1659 (CHO), 1693 (CO2H), 3447 (OH) cmꢀ1
;
1H NMR (300 MHz, CDCl3þDMSO-d6)
¼2.47 (s, 3H, CH3), 5.60 (s,
d
2H, CH2), 6.80e6.87 (m, 2H, ArH), 7.04e7.16 (m, 3H, ArH),
7.26e7.31 (m, 1H, ArH), 7.50 (d, 1H, J¼7.8 Hz, ArH), 7.64 (s, 1H,
] CH), 9.97 (s, 1H, CHO); 13C NMR (75 MHz, CDCl3þDMSO-d6)
(KBr) 1660 (CHO and CO2H), 2230 (CN), 3432 (OH) cmꢀ1 1H NMR
;
(300 MHz, DMSO-d6)
d
¼5.27 (s, 2H, CH2), 6.19 (d, 1H, J¼2.7 Hz,
ArH), 7.00 (d, 1H, J¼2.5 Hz, ArH), 7.09 (s, 1H, ArH), 7.50 (d, 2H,
d
¼7.6, 41.1, 110.2, 119.5, 120.1, 125.3, 125.5, 126.0, 126.3, 127.5, 129.6
J¼8.0 Hz, ArH), 7.84 (d, 2H, J¼8.0 Hz, ArH), 7.92 (s,1H, ]CH), 9.45 (s,
130.0, 130.8, 132.0, 132.5, 133.3, 135.4, 138.1, 167.0, 180.5; mass
1H, CHO); 13C NMR (50 MHz, DMSO-d6)
d
¼44.6, 109.9, 111.5, 118.7,
(ESþ) m/z¼388.0 (Mþþ1); Anal. Calcd for: C20H15Cl2NO3 (Exact

M. Nayak et al. / Tetrahedron 67 (2011) 7563e7569
7567
mass: 387.0429); C, 61.87; H, 3.89; N, 3.61. Found C, 62.03; H, 4.11;
N, 3.43.
103.4, 115.0, 116.3, 125.1, 127.6, 127.8, 128.5, 131.6, 133.1, 137.1, 138.5,
144.5; mass (ESþ) m/z¼287.5 (Mþþ1); DART-HRMS calcd for
C14H12BrN2 [MH]þ: 287.0184. Found: 287.0198.
4.3.13. (E)-3-(2-Chlorophenyl)-2-(1H-indol-1-ylmethyl)prop-2-enoic
acid (10c). Yield 92% as a white solid (0.44 g from 0.5 g); mp
119e120 ꢁC; Rf¼0.17 (hexanes/EtOAc, 80:20, v/v); nmax (KBr) 1691
4.4.3. 3-(2-Chlorobenzyl)pyrrolo[1,2-a]pyrazine (4c). Yield 72% as
brown oil (0.12 g from 0.2 g); Rf¼0.50 (hexanes/EtOAc, 80:20, v/v);
(CO2H), 3426 (OH) cmꢀ1; 1H NMR (200 MHz, CDCl3)
d¼5.04 (s, 2H,
1H NMR (300 MHz, CDCl3)
d
¼4.16 (s, 2H, CH2), 6.74 (s,1H, ArH), 6.82
CH2), 6.46 (d, 1H, J¼4.8 Hz, CH2), 6.98e7.17 (m, 4H, ArH), 7.20e7.28
(s, 1H, ArH), 7.22e7.41 (m, 5H, ArH), 7.53 (s, 1H, ArH), 8.77 (s, 1H,
(m, 2H, ArH), 7.31e7.40 (m, 1H, ArH), 7.49e7.60 (m, 2H, ArH), 8.20
ArH); 13C NMR (50 MHz, CDCl3)
d
¼38.7, 103.3, 114.86, 114.95, 116.2,
(s, 1H, ]CH); 13C NMR (75 MHz, CDCl3)
d
¼42.2, 101.9, 109.7, 119.7,
127.1, 127.6, 128.2, 129.8, 131.5, 134.5, 136.8, 137.1, 144.9; mass (ESþ)
m/z¼243.2 (Mþþ1); ESI-HRMS calcd for C14H12ClN2 [MH]þ:
243.0689. Found: 243.0700.
121.0, 121.7, 127.2, 127.5, 128.8, 129.1, 130.19, 130.22, 131.0, 132.9,
134.4, 136.2, 143.2, 172.2; mass (ESþ) m/z¼312.1 (Mþþ1); Anal.
Calcd for: C18H14ClNO2 (Exact mass: 311.0713); C, 69.35; H, 4.53; N,
4.49. Found: C, 69.42; H, 4.67; N, 4.71.
4.4.4. 3-(4-Chlorobenzyl)pyrrolo[1,2-a]pyrazine (4d). Yield 71% as
dark brown oil (0.15 g from 0.25 g); Rf¼0.48 (hexanes/EtOAc, 80:20,
4.3.14. (E)-2-(1H-Indol-1-ylmethyl)-3-(4-methylphenyl)prop-2-
enoic acid (10f). Yield 91% as a white solid (0.43 g from 0.5 g); mp
160e161 ꢁC; Rf¼0.16 (hexanes/EtOAc, 80:20, v/v); nmax (KBr) 1669
v/v); 1H NMR (300 MHz, CDCl3)
d
¼3.99 (s, 2H, CH2), 6.75 (d, 1H,
J¼3.6 Hz, ArH), 6.83 (s, 1H, ArH), 7.19e7.33 (m, 5H, ArH), 7.55 (s, 1H,
ArH), 8.75 (s, 1H, ArH); 13C NMR (75 MHz, CDCl3)
d
¼40.5, 103.6,
(CO2H), 3430 (OH) cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
¼2.38 (s, 3H,
115.0, 115.1, 115.9, 128.9, 129.1, 130.6, 131.2, 132.5, 137.8, 138.3, 144.9;
mass (ESþ) m/z¼243.1 (Mþþ1); ESI-HRMS calcd for C14H12Cl1N2
[MH]þ: 243.0689. Found: 243.0685.
CH3), 5.15 (s, 2H, CH2), 6.47 (d, 1H, J¼3.1 Hz, CH2), 7.08e7.15 (m, 4H,
ArH), 7.20 (d, 2H, J¼8.0 Hz, ArH), 7.27 (d, 2H, J¼8.4 Hz, ArH), 7.62 (m,
2H, J¼7.6 Hz, ArH), 8.16 (s, 1H, ]CH); 13C NMR (100 MHz, CDCl3)
d
¼21.6, 42.3, 101.6, 109.8, 119.7, 121.1, 121.7, 125.6, 127.1, 129.0,
4.4.5. 3-(2,4-Dichlorobenzyl)pyrrolo[1,2-a]pyrazine (4e). Yield 78%
as brown oil (0.13 g from 0.2 g); Rf¼0.47 (hexanes/EtOAc, 80:20, v/
129.88, 129.92, 131.4, 136.3, 140.7, 146.8, 172.3; mass (ESþ)
m/z¼292.0 (Mþþ1); DART-HRMS calcd for C19H18NO2 [MH]þ:
292.1338. Found: 292.1345.
v); 1H NMR (300 MHz, CDCl3)
d
¼4.10 (s, 2H, CH2), 6.76 (d, 1H,
J¼4.0 Hz, ArH), 6.84 (dd,1H, J1¼2.5 Hz, J2¼4.0 Hz, ArH), 7.22 (dd,1H,
J1¼2.0 Hz, J2¼8.3 Hz, ArH), 7.26e7.30 (m, 1H, ArH), 7.34 (s, 1H, ArH),
7.41 (d, 1H, J¼2.0 Hz, ArH), 7.56 (s, 1H, ArH), 8.76 (s, 1H, ArH); 13C
4.4. General procedure for the preparation of compound
4aei, 8cee and 11c,f
NMR (50 MHz, CDCl3)
d
¼36.5, 103.4, 114.9, 115.1, 128.6, 128.8, 134.7,
136.0, 136.6, 144.7; mass (ESþ) m/z¼277.0 (Mþþ1); DART-HRMS
A stirred solution of compound 3a (0.25 g, 0.83 mmol) in THF
(10 mL) was cool to ꢀ10 ꢁC and then ethyl chloroformate (0.09 mL,
0.92 mmol) and NMM (0.10 mL, 0.92 mmol) were added. After 5 min
NaN3 (80 mg,1.25 mmol) dissolved in 0.1 mL of water was added to it
and stirred for 30 min. After completion of the reaction water
(20 mL) and EtOAc (10 mL) were added, layers were separated and
aq layer was further extracted with EtOAc (2ꢂ10 mL). The organic
layer were pooled and washed with brine solution (20 mL), dried
over Na2SO4 and concentrated under reduced pressure to afford the
crude product. The crude product was dissolved in toluene (10 mL)
and heated at 65 ꢁC for 30 min. Thereafter toluene was removed
under reduced pressure and the crude reaction mixture was dis-
solved in CH2Cl2 (10 mL) and 98% formic acid (0.08 mL, 1.70 mmol)
and DMAP (0.003 g, 0.25 mmol) were added and the mixture stirred
for 4 h. The reaction mixture was quenched with water (20 mL) and
layers were separated. The aq layer was further extracted with
CH2Cl2 (2ꢂ15 mL). The organic layers were combined, washed with
brine solution (20 mL), dried over Na2SO4 and concentrated under
reduced pressure to provide the crude product. Purification by col-
umn chromatography on silica gel (hexanes/EtOAc, 9:1) led to 0.12 g
of pure 4a as dark brown oil (75%).
calcd for C14H11Cl2N2 [MH]þ: 277.0299. Found: 277.0292.
4.4.6. 3-(4-Methylbenzyl)pyrrolo[1,2-a]pyrazine (4f). Yield 73% as
brown oil (0.12 g from 0.2 g); Rf¼0.49 (hexanes/EtOAc, 80:20, v/v);
1H NMR (300 MHz, CDCl3)
d¼2.33 (s, 3H, CH3), 3.99 (s, 2H, CH2),
6.72 (d, 1H, J¼4.1 Hz, ArH), 6.80 (dd, 1H, J1¼2.5 Hz, J2¼4.0 Hz, ArH),
7.13 (d, 2H, J¼7.9 Hz, ArH), 7.20 (d, 2H, J¼8.0 Hz, ArH), 7.29 (s, 1H,
ArH), 7.51 (s, 1H, ArH), 8.75 (s, 1H, ArH); 13C NMR (75 MHz, CDCl3)
d
¼20.2, 39.6, 102.6, 114.0, 114.9, 126.5, 128.2, 128.4, 128.6, 128.7,
134.9, 135.2,137.9, 143.6; mass (ESþ) m/z¼223.2 (Mþþ1); ESI-HRMS
calcd for C15H15N2 [MH]þ: 223.1235. Found: 223.1253.
4.4.7. 4-(Pyrrolo[1,2-a]pyrazin-3-ylmethyl)benzonitrile (4g). Yield
69% as brown oil (0.12 g from 0.2 mg); Rf¼0.48 (hexanes/EtOAc,
80:20, v/v); nmax (Neat) 2229 (CN) cmꢀ1; 1H NMR (300 MHz, CDCl3)
d
¼4.05 (s, 2H, CH2), 6.77 (d, 1H, J¼3.8 Hz, ArH), 6.84e6.86 (m, 1H,
ArH), 7.36 (m, 1H, ArH), 7.41 (d, 2H, J¼8.0 Hz, ArH), 7.60 (d, 2H,
J¼8.1 Hz, ArH), 7.64 (s,1H, ArH), 8.75 (s,1H, ArH); 13C NMR (50 MHz,
CDCl3)
d¼40.1, 103.7, 110.4, 110.5, 115.1, 115.2, 116.1, 119.0, 124.9,
127.4, 129.9, 130.7, 132.4, 137.0, 145.0; mass (ESþ) m/z¼234.2
(Mþþ1); ESI-HRMS calcd for C15H12N3 [MH]þ: 234.1031. Found:
234.1037.
4.4.1. 3-Benzylpyrrolo[1,2-a]pyrazine (4a). Rf¼0.47 (hexanes/EtOAc,
80:20, v/v); 1H NMR (300 MHz, CDCl3)
d
¼4.03 (s, 2H, CH2), 6.73 (d,
4.4.8. 3-(2-Fluorobenzyl)pyrrolo[1,2-a]pyrazine (4h). Yield 72% as
a brown solid (0.12 g from 0.2 g); mp 59e60 ꢁC; Rf¼0.53 (hexanes/
1H, J¼4.0 Hz, ArH), 6.81 (t, 1H, J¼3.2 Hz, ArH), 7.26e7.33 (m, 6H,
ArH), 7.52 (s, 1H, ArH), 8.76 (s, 1H, ArH); 13C NMR (50 MHz, CDCl3)
EtOAc, 80:20, v/v); 1H NMR (300 MHz, CDCl3)
d¼4.05 (s, 2H, CH2),
d
¼41.1, 103.5, 115.0, 116.0, 126.7, 128.8, 129.3, 138.8, 139.1, 144.8;
6.73 (d, 1H, J¼2.4 Hz, ArH), 6.80e6.82 (m, 1H, ArH), 7.02e7.12 (m,
mass (ESþ) m/z¼209.1 (Mþþ1); ESI-HRMS calcd for C14H13N2
2H, ArH), 7.20e7.24 (m, 1H, ArH), 7.32e7.35 (m, 2H, ArH), 7.58 (s,
[MH]þ: 209.1079. Found: 209.1066.
1H, ArH), 8.75 (s, 1H, ArH); 13C NMR (50 MHz, CDCl3)
d
¼34.17 (d,
J¼3.2 Hz), 103.3, 114.8, 114.9, 115.2, 115.7, 115.8, 124.2, 124.3, 126.1,
126.4, 127.5, 128.4, 128.5, 131.4, 131.5, 137.3, 144.7, 158.8, 163.6; mass
(ESþ) m/z¼227.1 (Mþþ1); DART-HRMS calcd for C14H12F1N2 [MH]þ:
227.0985. Found: 227.0952.
4.4.2. 3-(2-Bromobenzyl)pyrrolo[1,2-a]pyrazine (4b). Yield 76% as
a brown solid (0.13 g from 0.2 g); mp 71e72 ꢁC; Rf¼0.49 (hexanes/
EtOAc, 80:20, v/v); 1H NMR (300 MHz, CDCl3)
d
¼4.17 (s, 2H, CH2),
6.74 (d, 1H, J¼3.8 Hz, ArH), 6.81e6.82 (m, 1H, ArH), 7.13 (t, 1H,
J¼6.9 Hz, ArH), 7.28e7.36 (m, 3H, ArH), 7.52 (s, 1H, ArH), 7.59 (d, 1H,
4.4.9. 3-(4-Fluorobenzyl)pyrrolo[1,2-a]pyrazine (4i). Yield 68% as
dark brown oil (0.11 g from 0.2 g); Rf¼0.51 (hexanes/EtOAc, 80:20,
J¼7.9 Hz, ArH), 8.77 (s, 1H, ArH); 13C NMR (50 MHz, CDCl3)
¼41.3,
d

7568
M. Nayak et al. / Tetrahedron 67 (2011) 7563e7569
v/v); 1H NMR (300 MHz, CDCl3)
d
¼3.99 (s, 2H, CH2), 6.74 (d, 1H,
2 h. Thereafter, EtOH was evaporated and residue was extracted
with EtOAc (3ꢂ15 mL) and water (30 mL). The organic layers were
combined, washed with brine solution (20 mL) and dried over
Na2SO4 and concentrated under reduced pressure to afford 0.086 g
of pure 12 as white solid (82%).
J¼4.0 Hz, ArH), 6.82 (dd, 1H, J1¼2.5 Hz, J2¼4.0 Hz, ArH), 7.01 (t, 2H,
J¼8.7 Hz, ArH), 7.24e7.28 (m, 2H, ArH), 7.32 (s, 1H, ArH), 7.54 (s, 1H,
ArH), 8.75 (s, 1H, ArH); 13C NMR (50 MHz, CDCl3)
d
¼40.2, 103.8,
115.1, 115.2, 115.4, 115.7, 115.9, 127.5, 130.6, 130.7, 134.8, 138.5, 144.8,
160.2, 163.4; mass (ESþ) m/z¼227.1 (Mþþ1); ESI-HRMS calcd for
C14H12F1N2 [MH]þ: 227.0985. Found: 227.0991.
4.5.1. 1-(2-Chlorophenyl)-3-(1H-indol-1-yl)acetone oxime (dia-
stereomeric mixture 2:1) (12). Mp 105e106 ꢁC; Rf¼0.41 (hexanes/
EtOAc, 80:20, v/v); nmax (KBr) 3292 (OH) cmꢀ1; 1H NMR (300 MHz,
4.4.10. 3-(2-Chloro-benzyl)-10-methyl-pyrazino[1,2-a]indole
(8c). Yield 79% as a yellow solid (0.15 g from 0.22 g); mp
110e112 ꢁC; Rf¼0.43 (hexanes/EtOAc, 80:20, v/v); 1H NMR
CDCl3)
d
¼3.30 (s, 2H, CH2), 3.78 (s, 2H, CH2), 4.73 (s, 2H, CH2), 5.12
(s, 2H, CH2), 6.47 (d, 1H, J¼3.0 Hz, ArH), 6.53 (d, 1H, J¼3.2 Hz, ArH),
6.87 (d, 1H, J¼3.2 Hz, ArH), 6.98e7.07 (m, 2H, ArH), 7.07e7.23 (m,
8H, ArH), 7.28e7.32 (m, 1H, ArH), 7.37 (d, 1H, J¼7.9 Hz, ArH), 7.59 (d,
1H, J¼7.2 Hz, ArH), 7.64 (d, 1H, J¼7.7 Hz, ArH); 13C NMR (75 MHz,
(300 MHz, CDCl3)
d
¼2.63 (s, 3H, CH3), 4.20 (s, 2H, CH2), 7.21e7.26
(m, 2H, ArH), 7.36e7.42 (m, 4H, ArH), 7.78e7.85 (m, 3H, ArH), 8.98
(d, 1H, J¼1.3 Hz, ArH); 13C NMR (75 MHz, CDCl3)
¼8.1, 38.6, 104.2,
d
110.8, 114.6, 120.4, 122.2, 122.9, 126.6, 127.1, 128.2, 128.5, 128.6,
129.7, 131.4, 133.1, 134.4, 137.1, 145.7; mass (ESþ) m/z¼307.2
(Mþþ1). ESI-HRMS calcd for C19H16ClN2 [MH]þ: 307.1002. Found:
307.1004.
CDCl3)
d
¼30.0, 34.9, 42.5, 48.6, 102.3, 102.5, 109.5, 109.8, 119.8,
120.0, 121.1, 121.2, 122.0, 122.3, 126.9, 127.2, 128.2, 128.5, 128.7,
128.8, 128.9, 129.71, 129.74, 131.1, 131.2, 133.3, 133.8, 134.3, 134.5,
136.5, 136.6, 154.9, 156.0; mass (ESþ) m/z¼299.1 (Mþþ1); Anal.
Calcd. For: C17H15ClN2O (Exact mass: 298.087); C, 68.34; H, 5.06; N,
9.38. Found: C, 68.52; H, 5.17; N, 9.16.
4.4.11. 3-(4-Chloro-benzyl)-10-methyl-pyrazino[1,2-a]indole
(8d). Yield 81% as a yellow solid (0.21 g from 0.3 g); mp
122e124 ꢁC; Rf¼0.45 (hexanes/EtOAc, 80:20, v/v); 1H NMR
Acknowledgements
(300 MHz, CDCl3)
d
¼2.64 (s, 3H, CH3), 4.04 (s, 2H, CH2), 7.26e7.32
(m, 4H, ArH), 7.36e7.44 (m, 2H, ArH), 7.80e7.87 (m, 3H, ArH), 8.97
Two of the authors (M.N. and G.P.) acknowledge the financial
support in the form of fellowship from CSIR, New Delhi and UGC,
New Delhi, respectively. This work was supported by a grant from
DST, New Delhi. Authors acknowledge the SAIF Division for pro-
viding the spectroscopic and analytical data.
(d, 1H, J¼1.3 Hz, ArH); 13C NMR (75 MHz, CDCl3)
¼8.2, 40.5, 104.4,
d
110.8, 114.2, 120.5, 122.4, 123.0, 126.6, 128.6, 128.7, 128.9, 130.5,
132.5, 134.5, 138.1, 145.9; mass (ESþ) m/z¼307.2 (Mþþ1). ESI-HRMS
calcd for C19H16ClN2 [MH]þ: 307.1002. Found: 307.1006.
4.4.12. 3-(2,4-Dichloro-benzyl)-10-methyl-pyrazino[1,2-a]indole
(8e). Yield 85% as a yellow solid (0.19 g from 0.25 mg); mp
162e163 ꢁC; Rf¼0.44 (hexanes/EtOAc, 80:20, v/v); 1H NMR
Supplementary data
Copies of 1H and 13C NMR spectra of all new compounds are
provided. Supplementary data associated with this article can be
found in the online version, at doi:10.1016/j.tet.2011.07.074. These
data include MOL files and InChIKeys of the most important com-
pounds described in this article.
(300 MHz, CDCl3)
d
¼2.64 (s, 3H, CH3), 4.16 (s, 2H, CH2), 7.22 (dd, 1H,
J1¼2.0 Hz, J2¼8.3 Hz, ArH), 7.31 (d, 1H, J¼8.2 Hz, ArH), 7.36e7.44 (m,
3H, ArH), 7.81e7.87 (m, 3H, ArH), 8.98 (d, 1H, J¼1.1 Hz, ArH); 13C
NMR (75 MHz, CDCl3)
d
¼8.2, 38.1, 104.5, 110.9, 114.8, 120.5, 122.4,
122.1, 126.6, 127.4, 128.6, 128.7, 129.5, 132.1, 132.7, 133.2, 135.1, 135.8,
145.9; mass (ESþ) m/z¼341.2 (Mþþ1); ESI-HRMS calcd for
C19H15Cl2N2 [MH]þ: 341.0612. Found: 341.0608.
References and notes
1. Arban, R.; Bianchi, F.; Buson, A.; Cremonesi, S.; Di Fabio, R.; Gentile, G.; Micheli,
F.; Pasquarello, A.; Pozzan, A.; Tarsi, L.; Terreni, S.; Tonelli, F. Bioorg. Med. Chem.
Lett. 2010, 20, 5044e5049.
2. Fong, C. J.; Addo, J.; Dukat, M.; Smith, C.; Mitchell, N. A.; Herrick-Davis, K.;
Teitler, M.; Glennon, R. A. Bioorg. Med. Chem. Lett. 2002, 12, 155e158.
3. Micheli, F.; Bertani, B.; Bozzoli, A.; Crippa, L.; Cavanni, P.; Di Fabio, R.; Donati, D.;
Marzorati, P.; Merlo, G.; Paio, A.; Perugini, L.; Zarantonello, P. Bioorg. Med. Chem.
Lett. 2008, 18, 1804e1809.
4. Fisher, T. E.; Kim, B.; Staas, D. D.; Lyle, T. A.; Young, S. D.; Vacca, J. P.; Zrada, M.
M.; Hazuda, D. J.; Felock, P. J.; Schleif, W. A.; Gabryelski, L. J.; Anari, M. R.;
Kochanskyd, C. J.; Wai, J. S. Bioorg. Med. Chem. Lett. 2007, 17, 6511e6515.
5. (a) Rault, S.; Lancelot, J. C.; Prunier, H.; Robba, M.; Renard, P.; Delagrange, P.;
Pfeiffer, B.; Caignard, D. H.; Guardiola-Lemaitre, B.; Hamon, M. J. Med. Chem.
1996, 39, 2068e2080; (b) Campiani, G.; Morelli, E.; Gemma, S.; Nacci, V.;
Butini, S.; Hamon, M.; Novellino, E.; Greco, G.; Cagnotto, A.; Goegan, M.;
Cervo, L.; Valle, F. D.; Fracasso, C.; Caccia, S.; Mennini, T. J. Med. Chem. 1999,
42, 4362e4379.
6. Ruppelt, M.; Bartel, S.; Guarnieri, W.; Raddatz, S.; Rosentreter, U.; Wild, H.;
Endermann, R.; Kroll, H. P. Ger. Offen. DE 19802235, 1999; Chem. Abstr. 1999,
131, 129985.
7. Goldberg, D. R.; Choi, Y.; Cogan, D.; Corson, M.; DeLeon, R.; Gao, A.; Gruenbaum,
L.; Hao, M. H.; Joseph, D.; Kashem, M. A.; Miller, C.; Moss, N.; Netherton, M. R.;
Pargellis, C. P.; Pelletier, J.; Sellati, R.; Skow, D.; Torcellini, C.; Tseng, Y.-C.; Wang,
J.; Wasti, R.; Werneburg, B.; Wua, J. P.; Xiong, Z. Bioorg. Med. Chem. Lett. 2008, 18,
938e941.
4.4.13. 1-(2-Chlorophenyl)-3-(1H-indol-1-yl)acetone
(11c). Yield
75% as a white solid (0.14 g from 0.2 g); mp 126e127 ꢁC; Rf¼0.48
(hexanes/EtOAc, 80:20, v/v); nmax (KBr) 1725 (CO) cmꢀ1 1H NMR
;
(300 MHz, CDCl3)
d
¼3.71 (s, 2H, CH2), 4.93 (s, 2H, CH2), 6.60 (d, 1H,
J¼3.1 Hz, ArH), 7.05e7.14 (m, 2H, ArH), 7.16e7.25 (m, 5H, ArH),
7.36e7.39 (m, 1H, ArH), 7.65 (d, 1H, J¼7.7 Hz, ArH); 13C NMR
(50 MHz, CDCl3)
d
¼44.5, 55.4, 103.0, 109.0, 120.2, 121.4, 122.4, 127.2,
128.5, 128.9, 129.1, 129.7, 131.9, 134.4, 136.6, 202.6; mass (ESþ)
m/z¼284.1 (Mþþ1); ESI-HRMS calcd for C17H15ClNO [MH]þ:
284.0842. Found: 284.0774.
4.4.14. 1-(1H-Indol-1-yl)-3-(4-methylphenyl)acetone
(11f). Yield
76% as a white solid (0.14 g from 0.2 g); mp 89e90 ꢁC; Rf¼0.46
(hexanes/EtOAc, 80:20, v/v); nmax (KBr) 1725 (CO) cmꢀ1 1H NMR
;
(300 MHz, CDCl3)
d
¼2.34 (s, 3H, CH3), 3.56 (s, 2H, CH2), 4.84 (s, 2H,
CH2), 6.58 (d, 1H, J¼3.0 Hz, ArH), 6.97e7.05 (m, 4H, ArH), 7.11e7.21
(m, 4H, ArH), 7.65 (d, 1H, J¼7.3 Hz, ArH); 13C NMR (50 MHz, CDCl3)
d
¼21.2, 46.4, 54.7,102.9,109.0,120.1,121.4,122.3,128.6,128.8,129.4,
129.7,129.9,136.5,137.2, 203.9; mass (ESþ) m/z¼264.1 (Mþþ1); ESI-
8. Tiwari, R. K.; Singh, D.; Singh, J.; Yadav, V.; Pathak, A. K.; Dabur, R.; Chhillar, A.
K.; Singh, R.; Sharma, G. L.; Chandra, R.; Verma, A. K. Bioorg. Med. Chem. Lett.
2006, 16, 413e416.
HRMS calcd for C18H18NO [MH]þ: 264.1388. Found: 264.1345.
ꢀ
9. Rover, S.; Adams, D. R.; Benardeau, A.; Bentley, J. M.; Bickerdike, M. J.; Bourson,
4.5. Typical procedure for the synthesis of compound 12
A.; Cliffe, I. A.; Coassolo, P.; Davidson, J. E. P.; Dourish, C. T.; Hebeisen, P.;
Kennett, G. A.; Knight, A. R.; Malcolm, C. S.; Mattei, P.; Misra, A.; Mizrahi, J.;
Muller, M.; Porter, R. H. P.; Richter, H.; Taylor, S.; Vickers, S. P. Bioorg. Med. Chem.
Lett. 2005, 15, 3604e3608.
To a stirred solution of compound 11c (0.1 g, 0.35 mmol), in
EtOH (15 mL) was added NH2OH$HCl (0.03 g, 0.42 mmol) and
NaOAc (0.035 g, 0.42 mmol) and stirred at reflux temperature for
10. Only a few citations. (a) For pyrrolo[1,2-a]pyrazine see Chen, W.; Hu, M.;
Wu, J.; Zou, H.; Yu, Y. Org. Lett. 2010, 12, 3863e3865; (b) Alfonsi, M.;

M. Nayak et al. / Tetrahedron 67 (2011) 7563e7569
7569
Dell’Acqua, M.; Facoetti, D.; Arcadi, A.; Abbiati, G.; Rossi, E. Eur. J. Org. Chem.
2009, 17, 2852e2862; (c) Mınguez, J. M.; Castellote, M. I.; Vaquero, J. J.;
García-Navio, J. L.; Alvarez-Builla, J.; Castano, O.; Andres, J. L. J. Org. Chem.
1996, 61, 4655e4664; (d) For indolo[1,2-a]pyrazine see Laliberte, S.; Dornan,
P. K.; Chen, A. Tetrahedron Lett. 2010, 51, 363e366; (e) Abbiati, G.; Arcadi, A.;
Bellinazzi, A.; Beccalli, E.; Rossi, E.; Zanzola, S. J. Org. Chem. 2005, 70,
4088e4095.
12. (a) Declerck, V.; Martinez, J.; Lamaty, F. Chem. Rev. 2009,109,1e48 and references
cited therein; (b) Zhong, W.; Liu, Y.; Wang, G.; Hong, L.; Chen, Y.; Chen, X.; Zheng,
Y.; Zhang, W.; Ma, W.; Shen, Y.; Yao, Y. Org. Prep. Proced. Int. 2011, 43, 1e66.
13. (a) Mishra, A.; Batra, S. Eur. J. Org. Chem. 2010, 4832e4840; (b) Nag, S.;
Bhowmik, S.; Gauniyal, H. M.; Batra, S. Eur. J. Org. Chem. 2010, 4705e4712; (c)
Mishra, A.; Batra, S. Synthesis 2009, 3077e3088; (d) Singh, V.; Hutait, S.; Batra,
S. Eur. J. Org. Chem. 2009, 3454e3466; (e) Nag, S; Batra, S. Tetrahedron 2011, doi:
10.1016/j.tet.2011.07.087 released on web on 3 August.
11. (a) Basavaiah, D.; Reddy, B. S.; Singh, B. S. Chem. Rev. 2010, 110, 5447e5674 and
references cited therein; (b) Gowrisankar, S.; Lee, H. S.; Kim, S. H.; Lee, K. Y.;
Kim, J. N. Tetrahedron 2009, 65, 8769e8780; (c) Singh, V.; Batra, S. Tetrahedron
2008, 64, 4511e4574 and references cited therein.
14. (a) Kathiravan, S.; Ramesh, E.; Raghunathan, R. Tetrahedron Lett. 2009, 50,
2389e2391; (b) Kathiravan, S.; Raghunathan, R. Synlett 2009, 952e954; (c) Lee,
H. S.; Kim, S. H.; Kim, T. H.; Kim, J. N. Tetrahedron Lett. 2008, 49, 1773e1776.