Synthesis of 5-alkyl(or aryl)pyrrolo[1,2-a]quinoxalin-4(5H)-ones by denitrocyclisation of N-alkyl(or aryl)-1-(2-nitrophenyl)-1H-pyrrole-2- carboxamides. Evidence of a Smiles rearrangement

Article abstract of DOI:10.1016/j.tet.2004.09.048

An efficient method for the synthesis of hitherto unknown alkyl(or aryl)pyrrolo[1,2-a]quinoxalin-4(5H)-ones 8a-g, 16 and 17 has been established. The method is based on the synthesis of the corresponding N-alkyl(or aryl)-1-(2-nitrophenyl)-1H-pyrrole-2-carboxamides 3a-c and 7a-c,e which undergo denitrocyclisation with NaH in DMF in 4.5 or 2 h. When 3a was treated with NaH in DMF for 30 min the product of a Smiles rearrangement, 9, was isolated. Under similar conditions but for 4.5 h 9 was converted into 8a. This confirms the involvement of a Smiles rearrangement during the denitrocyclisation process. Conversion of 3b into isomeric pyrroloquinoxalinones 12 and 13 confirms a process involving two pathways, direct denitrocylisation of 3b and Smiles rearrangement of 3b followed by denitrocylisation, respectively. Furthermore, denitrocylisation of 7d into pyrroloquinoxalinones 16 and 17 suggests that similar cyclisation pathways are followed by N-arylcarboxamides.

Full text of DOI:10.1016/j.tet.2004.09.048

Tetrahedron 60 (2004) 10825–10832
Synthesis of 5-alkyl(or aryl)pyrrolo[1,2-a]quinoxalin-4(5H)-ones
by denitrocyclisation of N-alkyl(or aryl)-1-(2-nitrophenyl)-1H-
pyrrole-2-carboxamides. Evidence of a Smiles rearrangement
*
Georgios Rotas, Athanasios Kimbaris and George Varvounis
Department of Chemistry, University of Ioannina, GR-451 10 Ioannina, Greece
Received 16 July 2004; revised 25 August 2004; accepted 16 September 2004
Available online 2 October 2004
Abstract—An efficient method for the synthesis of hitherto unknown alkyl(or aryl)pyrrolo[1,2-a]quinoxalin-4(5H)-ones 8a–g, 16 and 17 has
been established. The method is based on the synthesis of the corresponding N-alkyl(or aryl)-1-(2-nitrophenyl)-1H-pyrrole-2-carboxamides
3a–c and 7a–c,e which undergo denitrocyclisation with NaH in DMF in 4.5 or 2 h. When 3a was treated with NaH in DMF for 30 min the
product of a Smiles rearrangement, 9, was isolated. Under similar conditions but for 4.5 h 9 was converted into 8a. This confirms the
involvement of a Smiles rearrangement during the denitrocyclisation process. Conversion of 3b into isomeric pyrroloquinoxalinones 12 and
13 confirms a process involving two pathways, direct denitrocylisation of 3b and Smiles rearrangement of 3b followed by denitrocylisation,
respectively. Furthermore, denitrocylisation of 7d into pyrroloquinoxalinones 16 and 17 suggests that similar cyclisation pathways are
followed by N-arylcarboxamides.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
of N-alkyl(or aryl)-1-(2-nitrophenyl)-1H-pyrrole-2-
carboxamides.
Pyrrolo[1,2-a]quinoxalines are best known as high-affinity
and selective agonists of the 5-HT3 receptors.1–3 More
recently, several bispyrrolo[1,2-a]quinoxaline derivatives
were found to have significant antimalarial activity4
whereas certain pyrrolo[1,2-a]quinoxalin-4(5H)-ones have
shown promising antiviral5 and antiallergic6 properties.
Carboxamides 3a–c were prepared by reacting appropriate
2-trichloroacetylpyrroles 2a–b, derived by treating
1-arylpyrroles 1a–b with trichloroacetyl chloride, with
diethylamine or cyclohexylamine in 1,4-dioxane for 1.5 h
(Scheme 1).
5-Alkylpyrrolo[1,2-a]quinoxalin-4(5H)-ones may be
formed by first synthesising the lactam derivatives1–3,7
followed by alkylation.5 Other routes include the use of
benzimidazolium N-ylides in 1,3-dipolar cycloadditions
with alkenes6,8 and alkynes9 or reaction with 2,2-dihydro-
poly(per)fluoroalkanoates,10 and by reductive ring-opening/
ring-closure of pyridazinoquinoxalinones.11
In contrast, the preparation of aromatic carboxamides 7a–e
required first hydrolysis of trichloroacetyl derivative 2a to
the carboxylic acid 4, conversion of the latter with thionyl
chloride into acid chloride 5 and then, without isolation,
treatment of 5 with aromatic amines 6a–e for 2 days in a 1:1
pyridine–toluene mixture (Scheme 2). Attempts to react
4-chloro-2-nitroaniline or 2-trifluoromethylaniline with acid
chloride failed. This is probably due to a combination of
steric and electronic reasons which is reflected in the low
yield (45%) of 7b. Railey and Johnson have previously
prepared a large number of N-alkyl(or aryl)-4,5-dihalo-1H-
pyrrole-2-carboxamides, as potential antibacterial agents, in
a similar manner.13
2. Results and discussion
Following our previous interest in the synthesis of
pyrrolo[1,2-a]quinoxalines12 we now wish to report our
findings that lead to the synthesis of 5-alkyl(or aryl)-
pyrrolo[1,2-a]quinoxalin-4(5H)-ones by denitrocyclisation
Upon treating carboxamides 3a,c or 7a–c,e with NaH in
DMF for 4.5 or 2 h, pyrroloquinoxalinones 8a–f were
obtained in excellent yields (77–95%). The work-up
involved adding to water and neutralising with 2 N HCl.
This led to hydrolysis of the initially formed ester 8e to the
carboxylic acid 8d. The ester 8e was isolated when the
Keywords: Pyrroles; Pyrroloquinoxalinones; Denitrocyclisation; Defluoro-
cyclisation; Smiles rearrangement.
* Corresponding author. Tel.: C30 26510 98382; fax: C30 26510 98799;
e-mail: gvarvoun@cc.uoi.gr
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.09.048

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G. Rotas et al. / Tetrahedron 60 (2004) 10825–10832
Scheme 3. Reagents (a) NaH (60% in oil), DMF.
of 9 with NaH in DMF for 4.5 h gave 8a as sole product.
TLC examination of this reaction after 0.5 h revealed three
spots that corresponded to 3a, 8a and starting material 9.
From the above observations we can confidently propose
that carboxamide 3a undergoes a Smiles rearrangement to
give carboxamide 9. However, although there is ample
indication that the transformation of 3a to 9 is reversible,
there is no direct evidence as to whether 3a or 9 or both lead
to 8a.
Scheme 1. Reagents (a) Cl3CCOCl, 1,4-dioxane; (b) 70% EtNH2 in H2O,
CH2Cl2 or cyclohexylamine, Et3N, 1,4-dioxane, 75 8C.
Further insight into the mechanism of 4-alkylpyrroloquin-
oxalinone formation was obtained by reacting carboxamide
3b with NaH in DMF for 1.5 h. This gave a mixture
containing pyrroloquinoxalinones 12 and 13 (Scheme 5).
Since the separation of these two compounds by column
chromatography was not possible, 12 was synthesised
unambiguously by N-ethylating 7-methylpyrrolo[1,2-a]-
quinoxalin-4(5H)-one3 with ethyl iodide in DMF containing
NaH. The 1H NMR spectra of compound 12 and that of the
mixture 12/13 were then compared and the peaks corre-
sponding to 12 and 13 assigned. It turned out that 12 and 13
are in a ratio of about 44:36. Compounds 12 and 13 could
only have been obtained from the corresponding anions of
carboxamides 10 and 11 by denitrocyclisation through paths
b and d. Compound 11 can only be obtained from 10 by a
Smiles rearrangement that follows path a. Furthermore,
based on previous observations (vide infra), it is quite
reasonable to assume that the transformation of 10 to 11 is
reversible through path c.
Scheme 2. Reagents (a) 10% aq. NaOH, reflux; (b) SOCl2, reflux; (c) 6a
PhNH2, 6b 2-MeO2C6H4NH2, 6c 4-ClC6H4NH2, 6d 2,4-F2C6H3NH2 or 6e
4-MeOC6H4NH2, pyridine.
reaction mixture was poured into ice-water containing
sodium bicarbonate. To the best of our knowledge, this
intramolecular displacement of an aromatic nitro group by
N-substituted carboxamides, under mild conditions, to form
5-substituted pyrroloquinoxalinones, is unprecedented in
the literature. The closest analogy was published by Nacci
et al.7c who cyclised 1-(2-nitrophenyl)-1H-pyrrole-2-
carboxamide to the parent pyrrolo[1,2-a]quinoxalin-4(5H)-
one, by heating in DMF containing potassium carbonate
(Scheme 3).
In order to verify whether a Smiles rearrangement occurred
during the denitrocyclisation of aromatic carboxamides
7a–c,e to pyrroloquinoxalinones 8c,e–g, N-(2,4-difluorophe-
nyl)carboxamide 7d was employed as a potentially useful
precursor. When 7d was treated with NaH in DMF for 1.5 h,
two products 16 and 17 were obtained in 75 and 15% yield,
respectively. A proposed mechanism for this reaction is
shown in Scheme 6. The initially formed carboxamide anion
14 could follow two paths a or b. Path a would lead to
pyrroloquinoxalinone 16 by direct denitrocylisation whereas
path b would lead to intermediate carboxamide 15 via a
Smiles rearrangement. Taking into account previous obser-
vations (vide infra) it is reasonable to assume that 15 can
reverse to 14 through path e and denitrocyclise to 16 through
path c. On the other hand, pyrroloquinoxalinone 17 can only
be formed through path d, that is, intramolecular nucleophilic
displacement of fluoride anion by pyrrolyl anion of
It was interesting to note that TLC examination of reactions
3a or c with NaH in DMF after 0.5 h, revealed a new spot
together with spots corresponding to starting material and
product. We therefore investigated further the reaction of 3a
with NaH in DMF by allowing it to proceed for 0.5 h. After
work-up and column chromatography three compounds
were isolated, starting material 3a, pyrroloquinoxalinone 8a
and carboxamide 9 in 13, 27 and 21% yield, respectively
(Scheme 4). This result provides conclusive evidence that a
Smiles rearrangement is taking place. Furthermore, reaction

G. Rotas et al. / Tetrahedron 60 (2004) 10825–10832
10827
Scheme 4. Reagents (a) NaH (60% in oil), DMF, 30 min; (b) NaH (60% in oil), DMF, 4.5 h.
Scheme 5. Reagents (a) NaH (60% in oil), DMF, 1.5 h.
Scheme 6. Reagents (a) NaH (60% in oil), DMF, 4.5 h.

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G. Rotas et al. / Tetrahedron 60 (2004) 10825–10832
intermediate 15. The formation of 17 strongly suggests that
intermediate 15 is its precursor. However, there is no
substantial evidence to support that 16 is obtained directly
from 14 or from intermediate 15 or from both.
4.1.1.1. 2,2,2-Trichloro-1-[1-(2-nitrophenyl)-1H-
pyrrol-2-yl)]ethanone 2a. 4.20 g, 89%, as pale yellow
needles (ethanol), mp 115–117 8C. [Found: C, 43.19; H,
2.15; N, 8.41. C12H7Cl3N2O3 requires, 43.21; H, 2.12; N,
8.40%]; nmax (Nujol) 1660, 1520, 1340 cmK1; dH
(400 MHz; CDCl3) 6.41 (t, JZ3.8 Hz, 1H, H-4), 6.96
(s, 1H, H-3),07.34 (d, JZ7.8 Hz, 1H, H-60), 07.54–7.60 (2H,
m, H-5, H-4 ), 70.65 (t, JZ7.7 Hz, 1H, H-5 ), 8.08 (d, JZ
8.1 Hz, 1H, H-3 ); dC (100 MHz; CDCl3) 111.60, 122.60,
124.76, 125.19, 130.13, 130.34, 133.65, 134.75, 135.03,
145.41, 171.73; m/z (EI) 332 (MCC1, 32), 215 (92), 187
(82), 171 (100%).
3. Conclusion
In conclusion, we have shown that denitrocyclisation of
N-alkyl(or aryl)-1-(2-nitrophenyl)-1H-pyrrole-2-carbox-
amides is a mild method that gives 5-alkyl(or aryl)pyrrolo
[1,2-a]quinoxalin-4(5H)-ones in high yields. For N-alkyl-1-
(2-nitrophenyl)-1H-pyrrole-2-carboxamides there is direct
evidence that reaction occurs through two pathways:
(a) intramolecular nitro group displacement by the anion
of N-alkyl-1-(2-nitrophenyl)-1H-pyrrole-2-carboxamides
and (b) Smiles rearrangement of N-alkyl-1-(2-nitrophenyl)-
1H-pyrrole-2-carboxamide anions into N-(2-nitrophenyl)-N-
alkyl(or aryl)-1H-pyrrole-2-carboxamide anions, followed by
intramolecular pyrrolyl anion displacement of the nitro group.
It is highly probable that N-aryl-1-(2-nitrophenyl)-1H-
pyrrole-2-carboxamides give 5-arylpyrrolo[1,2-a]quinoxa-
lin-4(5H)-ones by following similar pathways.
4.1.1.2. 2,2,2-Trichloro-1-[1-(4-methyl-2-nitrophe-
nyl)-1H-pyrrol-2-yl)]ethanone 2b. 37.9 g, 88%, as pale
yellow needles (ethanol), mp 122–124 8C. [Found: C, 45.03;
H, 2.67; N, 8.01. C13H9Cl3N2O3 requires C, 44.92; H, 2.61;
N, 8.06%]; nmax (Nujol) 3124, 1670, 1528, 1347 cmK1; dH
(400 MHz; CDCl3) 2.52 (s, 3H, Me), 6.47 (dd, JZ4.3,
2.7 Hz, 1H, H-4), 7.02 (dd, JZ2.6, 1.6 Hz, 1H, H-5), 7.29
(d, JZ7.9 Hz, 1H, H-60), 7.51 (dd, JZ7.9, 1.3 Hz, 1H,
H-50), 7.66 (dd, JZ4.4, 1.5 Hz, 1H, H-3), 7.96 (d, JZ
1.3 Hz, 1H, H-30); dC (100 MHz; CDCl3) 20.88, 95.44,
111.00, 123.64, 124.31, 125.61, 129.34, 131.71, 132.77,
134.44, 140.59, 145.09, 172.28; m/z (EI) 348 (MCC2, 6),
346 (MC, 7), 302 (5) 300 (5), 283 (7), 265 (5), 229 (50), 201
(40), 183 (100), 154 (21), 84 (30%).
4. Experimental
4.1. General methods
4.1.2. Preparation of 1H-pyrrole-2-carboxamides 3a,b:
general procedure B. To a solution of 2,2,2-trichloro-1-
(1H-pyrrol-2-yl)ethanone 2a or 2b (9.04 mmol) in dichloro-
methane (40 mL) was added a solution of ethylamine 70%
in water (3.5 mL, 54.225 mmol). The reaction mixture was
stirred at room temperature for 18 h. Water was added
(90 mL), the organic phase separated and the aqueous phase
extracted with dichloromethane (3!30 mL). The combined
organic phases were dried (Na2SO4) and the solvent
removed under reduced pressure to afford a residue which
was triturated with toluene and filtered. The residue was
purified by dissolving in ethyl acetate and precipitating by
addition of hexane to afford N-ethyl-1-(2-nitrophenyl)-1H-
pyrrole-2-carboxamide 3a or N-ethyl-1-(4-methyl-2-nitro-
phenyl)-1H-pyrrole-2-carboxamide 3b.
Melting points were taken on a Bu¨chi 510 apparatus and are
uncorrected. Infrared spectra were recorded on a Perkin–
Elmer 257 spectrometer, as Nujol mulls and liquids between
sodium chloride discs. Elemental analyses were performed
on a Perkin–Elmer 2400 or a Carlo Erba 1106 elemental
analysers. Nuclear magnetic resonance spectra were
measured at 360 MHz on a Bru¨ker AM 360 spectrometer
or at 400 MHz on a Bru¨ker AMX 400 spectrometer using
tetramethylsilane as internal standard. Mass spectra were
obtained using a JEOL JMS-AX 505W or a Bruker Apex III
high-resolution instruments. Analytical TLC was carried
out on Fluka silica gel 60 F254. Preparative flash
chromatography was carried out for all separations using
Merck 9385 silica gel. Solvents and reagents were used as
received from the manufacturers, except for dichloro-
methane, ethanol, ethyl acetate, hexane and methanol that
were purified and dried according to recommended
procedures.14
4.1.2.1. N-Ethyl-1-(2-nitrophenyl)-1H-pyrrole-2-car-
boxamide 3a. 2.16 g, 92%, as a pale-yellow solid (ethyl
acetate/hexane); mp 93–95 8C; nmax (CCl4) 3450, 2980,
1665, 1350 cmK1; dH (400 MHz; CDCl3) 1.05 (t, JZ
7.4 Hz, 3H, Me), 3.20 (q, JZ6.9 Hz, 2H, CH2), 5.79 (br, s,
1H, NH), 6.26 (t, JZ3.3 Hz, 1H, H-4), 6.60 (d, JZ3.9 Hz,
1H, H-3), 6.82 (s, 1H, H-5), 7.37 (d, JZ7.9 Hz, 1H, H-60),
7.47 (dd, JZ8.0, 7.7 Hz, 1H, H-40), 7.59 (dd, JZ7.9,
7.7 Hz, 1H, H-50), 7.98 (d, JZ8.0 Hz, 1H, H-30); dC
(100 MHz; CDCl3) 14.80, 34.03, 109.54, 112.24, 124.67,
127.01, 127.49, 128.67, 129.58, 133.31, 134.95, 145.02,
160.48; m/z (EI) 259 (MC, 20), 213 (100), 188 (24), 171
(71) 169 (80), 155 (22), 143 (30), 118 (22%). HRMS (EI):
(MC), found 259.0961. C13H13N3O3 requires 259.0957.
4.1.1. Preparation of 2-trichloroacetylpyrroles 2a,b:
general procedure A. To a recently distilled solution of
trichloroacetyl chloride (41.8 mL, 372 mmol) in dry 1,4-
dioxane (140 mL), a solution of pyrrole 1a or 1b in
(0.124 mol) in dry 1,4-dioxane (140 mL) was added
dropwise. The reaction mixture was left to stir at room
temperature for 6 days and then a saturated solution of
potassium carbonate was slowly added until the pH was 7.
Water (120 mL) was added and extracted with dichlor-
omethane (3!80 mL). The combined organic extracts were
dried (Na2SO4) and the solvent removed under reduced
pressure to afford a residue, which on crystallisation from
ethanol gave 2,2,2-trichloro-1-(1-(2-nitrophenyl)-1H-
pyrrol-2-yl)ethanone 2a or 2,2,2-trichloro-1-(1-(4-methyl-
2-nitrophenyl)-1H-pyrrol-2-yl)-ethanone 2b.
4.1.2.2. N-Ethyl-1-(4-methyl-2-nitrophenyl)-1H-
pyrrole-2-carboxamide 3b. 2.22 g, 90%, as a pale-yellow
solid (ethyl acetate/hexane); mp 115–117 8C. [Found: C,
61.48; H, 5.47; N, 15.34; C14H15N3O3 requires C, 61.53; H,

G. Rotas et al. / Tetrahedron 60 (2004) 10825–10832
10829
5.53; N, 15.38%]; nmax (Nujol) 3290, 1631, 1530,
1353 cmK1; dH (400 MHz; CDCl3) 1.10 (t, JZ7.2 Hz, 3H,
Me), 2.47 (s, 3H, Me), 3.25 (q, JZ7.2 Hz, 2H, CH2), 5.92
(br, s, 1H, NH), 6.30 (dd, JZ3.9, 2.8 Hz, 1H, H-4), 6.65
(dd, JZ3.9, 1.6 Hz, 1H, H-3), 6.80 (dd, JZ2.8, 1.6 Hz, 1H,
H-5), 7.29 (d, JZ8.1 Hz, 1H, H-60), 7.45 (dd, JZ8.1,
1.3 Hz, 1H, H-50), 7.86 (d, JZ1.3 Hz, 1H, H-30); dC
(100 MHz; CDCl3) 14.79, 20.80, 34.00, 109.26, 111.91,
125.03, 127.04, 127.49, 128.31, 132.31, 133.83, 139.38,
145.60, 160.49; m/z (EI) 273 (MC, 10), 227 (100), 199 (16),
185 (46), 183 (27), 158 (19%).
4.1.5. Preparation of 1H-pyrrole-2-carboxamides 7a–e:
general procedure C. A suspension of 1-(2-nitrophenyl)-
1H-pyrrole-2-carboxylic acid 4 (1.5 mmol) in freshly
distilled thionyl chloride (8 mL) was heated to reflux
under argon for 1 h. Removal of excess thionyl chloride,
addition of dry benzene (7 mL) and then evaporation under
vacuo gave a brownish oily residue. The residue was
dissolved in dry benzene (7 mL) and then added dropwise
under argon to a solution of the appropriate amine
(1.5 mmol) in dry pyridine (7 mL). The reaction mixture
was stirred at room temperature for 2 days. The solvents
were evaporated in vacuo, a saturated solution of sodium
bicarbonate (50 mL) was added and extracted with dichloro-
methane (3!20 mL). The combined organic extracts were
dried (Na2SO4) and the solvent removed under reduced
pressure to afford a residue that was purified by flash
chromatography (25% ethyl acetate/hexane) to give 1-(2-
nitrophenyl)-N-phenyl-1H-pyrrole-2-carboxamide7a,methyl
2-(1-(2-nitrophenyl)-1H-pyrrole-5-carboxamido)benzoate
7b, N-(4-chlorophenyl)-1-(2-nitrophenyl)-1H-pyrrole-2-
carboxamide 7c, N-(2,4-difluorophenyl)-1-(2-nitrophenyl)-
1H-pyrrole-2-carboxamide 7d, or N-(4-methoxyphenyl)-1-
(2-nitrophenyl)-1H-pyrrole-2-carboxamide 7e.
4.1.3. N-Cyclohexyl-1-(2-nitrophenyl)-1H-pyrrole-2-
carboxamide 3c. To a solution of 2,2,2-trichloro-1-(1-(2-
nitrophenyl)-1H-pyrrol-2-yl)ethanone 2a (3 g, 9.04 mmol)
in dry 1,4-dioxane (150 mL) under argon was added
dropwise freshly distilled cyclohexylamine (5.17 mL,
45.18 mmol) and triethylamine (1.56 mL, 11.296 mmol) in
dry 1,4-dioxane. The reaction mixture was stirred at 75 8C
for 2 h and then the solvent removed under reduced
pressure. Water was added (60 mL), the solution acidified
with 2 N hydrochloric acid until the pH was 5 and then
extracted with dichloromethane (3!20 mL). The combined
organic extracts were dried (Na2SO4) and the solvent
removed under reduced pressure to afford a residue which
was photosensitive. The residue was suspended in toluene,
filtered, and then purified from ethyl acetate/hexane to give
the title compound 3c as a pale-yellow solid (2.75 g, 97%);
mp 98–100 8C; nmax (Nujol) 3294, 1627, 1609, 1531,
1357 cmK1; dH (400 MHz; CDCl3) 1.09–1.90 [m, 10H,
(CH2)5], 3.67–3.74 (m, 1H, CH), 5.73 (s, 1H, NH), 6.32 (dd,
JZ3.8, 2.8 Hz, 1H, H-4), 6.66 (dd, JZ3.8, 1.7 Hz, 1H, H-
3), 6.82 0(dd, JZ2.8, 1.7 Hz, 1H, H-5), 7.44 (d, JZ7.8 Hz,
1H, H-6 ), 7.53 (dd, JZ8.0, 7.6 Hz, 1H, H-40), 7.66 (dd, JZ
7.8, 7.6 Hz, 1H, H-50), 8.04 (d, JZ8.0 Hz, 1H, H-30); dC
(100 MHz; CDCl3) 24.84, 25.44, 33.07, 47.91, 109.48,
111.93, 124.67, 126.98, 127.80, 128.64, 129.55, 133.26,
134.92, 146.01, 159.69; m/z (EI) 313 (MC, 20), 267 (88),
215 (26), 185 (80), 171 (88) 169 (100), 155 (52), 143 (32),
118 (22%). HRMS (EI): (MC), found 313.1422,
C17H19N3O3 requires 313.1426.
4.1.5.1. 1-(2-Nitrophenyl)-N-phenyl-1H-pyrrole-2-
carboxamide 7a. 387 mg, 84%, as a pale-yellow solid
(ethyl acetate/hexane); mp 144–145 8C; nmax (Nujol) 3320,
1637, 1540, 1355 cmK1; dH (400 MHz; CDCl3) 6.17–6.20
(m, 1H, H-4), 6.66–6.68 (m, 2H, H-3, H-5), 6.84 (d, JZ
7.1 Hz, 1H, H-400), 7.02–7.11 (m, 02H, H-300, H-500), 7.20–
7.53 (m, 6H, H-200,0H-600, H-60, H-5 , H-40, NH), 7.87 (d, JZ
7.6 Hz, 1H, H-3 ); dC (100 MHz; DMSO-d6) 109.60,
114.88, 120.36, 123.46, 124.75, 125.98, 128.70, 129.01,
129.19, 129.99, 134.15, 134.72, 139.11, 145.99, 158.79; m/z
(EI) 307 (MC, 33), 261 (22), 215 (32), 169 (100), 140 (17),
114 (12%); HRMS (EI): (MC), found 307.0965,
C17H13N3O3 requires 307.0957.
4.1.5.2. Methyl 2-(1-(2-nitrophenyl)-1H-pyrrole-5-
carboxamido)benzoate 7b. 247 mg, 45%, as a pale-yellow
solid (ethyl acetate/hexane); mp 166–168 8C. [Found: C,
62.31; H, 4.35; N, 11.45; C19H15N3O5 requires C, 62.46; H,
4.14; N, 11.50%]; nmax (Nujol) 3257, 3136, 1690, 1669,
1607, 1528, 1350 cmK1; dH (400 MHz; DMSO-d6) 6.45–
6.48 (m, 1H, H-4), 7.08–7.16 (m, 2H, H-3, H-400), 7.26–7.27
(m, 1H, H-5), 7.51–7.61 (m, 2H, H-60, H-500), 7.71 (t, JZ
7.7 Hz, 1H, H-40), 7.84 (t, JZ7.6 Hz, 1H, H-50), 7.97 (d, JZ
7.9 Hz, 1H, H-600), 8.16 0(d, JZ8.0 Hz, 1H, H-300), 8.26
(d, JZ8.4 Hz, 1H, H-3 ), 11.41 (br, s, 1H, NH); dC
(100 MHz; DMSO-d6) 52.77, 110.15, 114.24, 116.00,
120.21, 122.85, 124.82, 126.73, 129.55, 129.89, 130.16,
130.86, 134.17, 134.26, 134.52, 140.56, 145.84, 158.21,
168.31; m/z (EI) 365 (MC, 29), 319 (22), 287 (21), 215 (28),
188 (26), 169 (100), 145 (34%).
4.1.4. 1-(2-Nitrophenyl)-1H-pyrrole-2-carboxylic acid 4.
A suspension of 2,2,2-trichloro-1-[1-(2-nitrophenyl)-1H-
pyrrol-2-yl)]ethanone 2a (11.5 g, 35 mmol) in 10% aqueous
sodium hydroxide (70 mL) was heated under reflux for
1.5 h. The resulting solution was allowed to cool and then
acidified with 2 N hydrochloric acid to pH 4. The precipitate
was filtered, washed with water, dried and recrystallised
from propan-2-ol to give the title compound 4 as deep
yellow microcrystals (6.81 g, 84%); mp 195.5–197 8C.
[Found: C, 57.22; H, 3.52; N, 12.08; C11H8N2O4 requires
C, 56.90; H, 3.47; N, 12.06%]; nmax (Nujol) 3257, 3136,
1690, 1669, 1607, 1528, 1350 cmK1; dH (400 MHz; CDCl3)
6.39 (t, JZ3.3 Hz, 1H, H-4), 6.94 (s, 1H, H-3), 7.20 (d, JZ
3.9 Hz, 1H, H-5), 7.41 (d, JZ7.8 Hz, 1H, H-60), 7.59 (t, JZ
7.7 Hz, 1H, H-40)0, 7.68 (t, JZ7.7 Hz, 1H, H-50), 8.09 (d, JZ
8.0 Hz, 1H, H-3 ), 12.32 (s, 1H, COOH); dC (100 MHz;
CDCl3) 110.05, 118.67, 124.19, 124.18, 129.55, 129.93,
130.22, 134.07, 134.28, 145.93, 161.21; m/z (EI) 232
(MC, 47), 187 (100), 171 (65), 159 (28) 143 (38), 131 (35),
102 (23), 83 (23), 77 (24%).
4.1.5.3. N-(4-Chlorophenyl)-1-(2-nitrophenyl)-1H-
pyrrole-2-carboxamide 7c. 379 mg, 74%, as a pale-yellow
solid (ethyl acetate/hexane); mp 136–137 8C; nmax (Nujol)
3320, 1635, 1520, 1350 cmK1; dH (400 MHz; CDCl3) 6.39
(dd, JZ3.8, 2.8 Hz, 1H, H-4), 6.86–6.90 (m, 2H, H-3, H-50)0,
7.18–7.26 (m, 2H, H-300, H-500), 7.35–7.38 (d, m, 2H, H-2 ,
H-600), 7.46 (dd, JZ7.7, 1.5 Hz, 1H, H-60), 7.57 (t, JZ
7.6 Hz 1H, H-40), 7.65–7.70 (m, 2H, H-50, NH), 8.07 (d, JZ

10830
G. Rotas et al. / Tetrahedron 60 (2004) 10825–10832
7.9 Hz, 1H, H-30); dC (100 MHz; DMSO-d6) 107.51, 109.6,
115.09, 121.73, 124.74, 126.64, 126.98, 128.56, 129.24,
130.01, 134.16, 134.56, 138.07, 145.93, 158.73; m/z (EI)
343 (MCC2, 8), 341 (MC, 24), 297 (4), 295 (10), 215 (43),
171 (23), 169 (100), 140 (14), 114 (10%); HRMS (EI):
(MC), found 341.0557, C17H12ClN3O3 requires 341.0567.
(dd, JZ3.6, 2.8 Hz, 1H, H-2), 7.12–7.19 (m, 2H, H-3, H-8),
7.24–7.27 (m, 2H, H-6, H-7), 7.57 (dd, JZ2.8, 1.6 Hz, 1H,
H-1), 7.61 (d, JZ7.6 Hz, 1H, H-9); dC (100 MHz; CDCl3)
13.19, 36.58, 112.85, 113.61, 115.19, 115.96, 116.21,
123.07, 123.75, 124.63, 125.98, 129.56, 155.59; m/z (EI)
212 (MC, 79), 197 (39), 184 (100) 167 (25), 155 (17%).
4.1.5.4. N-(2,4-Difluorophenyl)-1-(2-nitrophenyl)-1H-
pyrrole-2-carboxamide 7d. 443 mg, 86%, as a pale-yellow
solid (ethyl acetate/hexane); mp 81–83 8C. [Found: C,
59.33; H, 3.29; N, 12.16;. C17H11F2N3O3 requires C, 59.48;
H, 3.23; N, 12.24%]; nmax (Nujol) 3237, 1639, 1524,
1359 cmK1; dH (400 MHz; CDCl3) 6.42 (t, JZ3.3 Hz, 1H,
H-4), 6.77 (dddd, JZ9.2, 8.3, 2.8, 010 .7 Hz, 1H, H-500), 6.84
(ddd, JZ11.3, 8.3, 2.8 Hz, 1H, H-3 ), 6.91–6.92 (m, 2H, H-
3, H-5), 7.47 (dd, JZ7.8, 1.3 Hz, 1H, H-60), 7.58 (td, JZ
8.1, 1.3 Hz, 1H, H-40), 7.67–7.71 (m, 2H, H-50, NH), 8.03
(td, JZ9.2, 6.0 Hz, 1H, H-600), 8.10 (dd, JZ8.1, 1.4 Hz, 1H,
H-30); dC (100 MHz; CDCl3) 103.47 (dd, JZ26.6, 23.7 Hz),
110.13, 111.09 (dd, JZ21.5, 3.7 Hz), 113.75, 122.40 (dd,
JZ10.4, 3.8 Hz), 122.95 (dd, JZ9.0, 2.1 Hz), 124.99,
126.84, 128.63, 129.21, 129.81, 133.52, 134.47, 146.00,
153.77 (dd, JZ246.2, 11.8 Hz), 158.29, 158.94 (dd, JZ
246.0, 11.4 Hz); dF (376 MHz; CDCl3) K115.37 (tdd, JZ
8.3, 6.0, 4.6 Hz, 1F, F-400), K126.27 (ddddd, JZ11.0, 9.2,
4.6, 2.9, 1.7 Hz, 1F, F-200); m/z (EI) 343 (MC, 23), 215 (36),
169 (100), 119 (51), 105 (85%).
4.1.6.2. 5-Cyclohexylpyrrolo[1,2-a]quinoxalin-4(5H)-
one 8b. 149 mg, 86%, as a pale-yellow solid (ethyl acetate/
hexane); mp 109–111 8C. [Found: C, 76.38; H, 6.88; N,
10.46;. C17H18N2O requires C, 76.66; H, 6.81; N, 10.52%];
nmax (Nujol) 3115, 1640, 1609 cmK1; dH (400 MHz; CDCl3)
1.25–2.63 [m, 10H, (CH2)5], 4.75 (br, s, 1H, CH), 6.63–6.64
(m, 1H, H-2), 7.22–7.16 (m, 2H, H-3, H-8), 7.28 (t, JZ
7.3 Hz, 1H, H-7), 7.60–7.56 (m, 2H, H-1, H-6), 7.66 (d, JZ
7.8 Hz, 1H, H-9); dC (100 MHz; CDCl3) 25.32, 26.51,
29.15, 55.98, 112.08, 113.03, 114.84, 115.30, 116.43,
122.43, 123.79, 124.31, 124.82, 129.76, 155.97; m/z (EI)
266 (MC, 18), 184 (100), 155 (12), 129 (8%).
4.1.7. Preparation of pyrrolo[1,2-a]quinoxalin-4(5H)-
ones 8c,d,f,g: general procedure E. To a stirred solution
of the corresponding carboxamide 7a–c,e (0.65 mmol) in
dry DMF (10 mL) under argon, was added NaH (60% in oil,
1.10 mmol) and left to stir at room temperature for 4.5 h.
The reaction mixture was poured into water (50 mL),
neutralised with 2 N HCl and the precipitate filtered, washed
with water and dried to afford 5-phenylpyrrolo[1,2-a]quin-
oxalin-4(5H)-one 8c, 2-(4-oxo-pyrrolo[1,2-a]quinoxalin-
5(4H)-yl)benzoic acid 8d.
4.1.5.5. N-(4-Methoxyphenyl)-1-(2-nitrophenyl)-1H-
pyrrole-2-carboxamide 7e. 390 mg, 77%, as a pale-yellow
solid (ethyl acetate/hexane); mp 107–109 8C;. nmax (Nujol)
3315, 1630, 1510, 1345 cmK1; dH (400 MHz; CDCl3) 3.75
(s, 3H, OMe), 060 .37–6.39 (m, 1H, H-4), 6.79 (d, JZ7.3 Hz,
2H, H-300, H-5 ),060 .83–6.87 (m, 2H, H-3, H-5), 7.30 (d, JZ
7.3 Hz, 2H, H-2 , H-600), 7.46 (d, JZ7.8 Hz, 1H, H-600),
7.52–7.56 (m, 2H, H-40, NH), 7.66 (t, JZ7.8 Hz, 1H, H-5 ),
8.05 (d, JZ8.1 Hz, 1H, H-30); dC (100 MHz; CDCl3) 55.35,
109.53, 113.85, 114.42, 122.00, 124.71, 127.07, 128.71,
129.13, 129.95, 132.07, 134.13, 134.77, 145.99, 155.51,
158.51; m/z (EI) 337 (MC, 85), 291 (14), 215 (40), 169
(100), 149 (30), 134 (15); HRMS (EI): (MC), found
337.1060, C18H15N3O4 requires 337.1063.
4.1.7.1. 5-Phenylpyrrolo[1,2-a]quinoxalin-4(5H)-one
8c. 178 mg, 89%, as a pale-yellow solid (ethyl acetate/
hexane); mp 168–170 8C. [Found: C, 78.10; H, 4.68; N,
10.74;. C17H12N2O requires C, 78.44; H, 4.65; N, 10.76%];
nmax (Nujol) 3110, 1652 cmK1; dH (400 MHz; CDCl3) 6.50
(dd, JZ8.4, 1.1 Hz, 1H, H-6), 6.75 (dd, JZ3.9, 2.6 Hz, 1H,
H-2), 7.11 (dd, JZ3.9, 1.4 Hz, 1H, H-3), 7.18 (td, JZ7.8,
1.1 Hz, 1H, H-8), 7.26 (td,0JZ7.7, 1.2 Hz, 1H, H-7), 7.40 (0d,
JZ7.2 Hz, 2H, H-20, H-6 ), 7.56 (t, JZ7.3 Hz, 1H, H-4 ),
7.63 (t, JZ7.4 Hz, 2H, H-30, H-50), 8.16 (dd, JZ8.1, 1.2 Hz,
1H, H-9), 8.29 (dd, JZ2.6, 1.4 Hz, 1H, H-1); dC (100 MHz;
CDCl3) 112.40, 113.16, 115.26, 116.73, 118.22, 122.68,
122.99, 123.03, 125.46, 128.76, 129.57, 129.93, 130.98,
136.70, 154.32; m/z (EI) 260 (MC, 100), 259 (100), 231 (6)
205 (7), 178 (6), 166 (7), 115 (8), 102 (8%).
4.1.6. Preparation of pyrrolo[1,2-a]quinoxalin-4(5H)-
ones 8a,b: general procedure D. To a stirred solution of
carboxamide 3a or c (0.65 mmol) in dry DMF (10 mL)
under argon, was added NaH (60% in oil, 1.10 mmol) and
left to stir at room temperature for 1.5 h. The reaction
mixture was poured into water (50 mL), neutralised with
2 N HCl and extracted with ethyl acetate (3!10 mL). The
combined organic phases were dried (Na2SO4) and
evaporated in vacuo. The oily residue was triturated with
hexane, the solid collected and purified by flash chroma-
tography (25% ethyl acetate/hexane) to afford 5-ethylpyr-
rolo[1,2-a]quinoxalin-4(5H)-one 8a or 5-cyclo-hexyl-
pyrrolo[1,2-a]quinoxalin-4(5H)-one 8b.
4.1.7.2. 2-(4-Oxopyrrolo[1,2-a]quinoxalin-5(4H)-
yl)benzoic acid 8d. 162 mg, 82%, as a pale-yellow solid
(2 N NaOH/2 N HCl); mp 260–262 8C. [Found: C, 70.73; H,
4.03; N, 9.17; C18H12N2O3 requires C, 71.05; H, 3.97; N,
9.21%]; nmax (Nujol) 2900, 3135, 1709, 1651 cmK1; dH
(250 MHz; DMSO-d6) 6.43 (d, JZ8.1 Hz, 1H, H-6), 6.73–
6.76 (m, 1H, H-2), 7.11 (m, 1H, H-3), 7.17 (t, JZ7.5 Hz,
1H, H-8), 7.25 (t, JZ7.5 Hz, 1H, H-7), 7.49 (d, JZ7.7 Hz,
1H, H-600), 7.69 (t, JZ7.6 Hz, 1H, H-40), 7.86 (t, JZ7.6 Hz,
1H, H-5 ), 8.17 (d, JZ7.7 Hz, 2H, H-9, H-30), 8.29 (m, 1H,
H-1), 12.80 (bs, 1H, CO2H); dC (63 MHz; DMSO-d6)
112.63, 113.32, 115.45, 116.63, 118.42, 123.07 (2C),
123.34, 125.76, 129.57, 130.56, 131.37, 131.68, 132.13,
134.13, 136.74, 154.70, 165.79; m/z (EI) 304 (MC, 60), 259
(100%).
4.1.6.1. 5-Ethylpyrrolo[1,2-a]quinoxalin-4(5H)-one
8a. 119 mg, 85%, as a pale-yellow solid (ethyl acetate/
hexane); mp 78–80 8C. [Found: C, 73.45; H, 5.63; N, 13.14;.
C13H12N2O requires C, 73.56; H, 5.70; N, 13.20%]; nmax
(Nujol) 3118, 1638 cmK1; dH (400 MHz; CDCl3) 1.29 (t,
JZ7.0 Hz, 3H, CH3), 4.25, (q, JZ7.2 Hz, 2H, CH2), 6.58

G. Rotas et al. / Tetrahedron 60 (2004) 10825–10832
10831
4.1.7.3. Methyl 2-(4-oxopyrrolo[1,2-a]quinoxalin-
5(4H)-yl)benzoate 8e. 159 mg, 77%, as a pale-yellow
solid (ethyl acetate /hexane); mp 159–161 8C. [Found: C,
71.40; H, 4.48; N, 8.77; C19H14N2O3 requires C, 71.69; H,
4.43; N, 8.80%]; nmax (Nujol) 3148, 1724, 1660 cmK1; dH
(250 MHz; DMSO-d6) 3.55 (s, 1H, Me), 6.41 (d, JZ8.1 Hz,
1H, H-6), 6.74–6.77 (m, 1H, H-2), 7.09–7.11 (m, 1H, H-3),
7.16 (t, JZ7.8 Hz, 1H, H-8), 7.26 (t, JZ7.7 Hz, 1H, H-7),
7.54 (d, JZ7.7 Hz, 1H, H-600), 7.72 (t, JZ7.6 Hz, 1H, H-40),
7.88 (t, JZ7.6 Hz, 1H, H-5 ), 8.18 (d, JZ7.7 Hz, 2H, H-9,
H-30), 8.30–8.31 (m, 1H, H-1); dC (63 MHz; DMSO-d6)
52.26, 112.68, 113.12, 113.27, 115.45, 116.45, 118.52,
122.92, 123.13, 123.31, 125.73, 128.94, 129.68, 131.16,
131.84, 134.59, 136.92, 154.61, 164.37; m/z (EI) 318
(MC, 56), 259 (100%).
4.1.8.1. N-Ethyl-N-(2-nitrophenyl)-1H-pyrrole-2-car-
boxamide 3a. 29 mg, 17%, as a pale-yellow solid (ethyl
acetate/hexane), mp 93–95 8C, identical in all respects to an
authentic sample (vide infra).
4.1.8.2. 5-Ethylpyrrolo[1,2-a]quinoxalin-4(5H)-one
8a. 51 mg, 37%, as a pale-yellow solid (ethyl acetate/
hexane), mp 78–80 8C, identical in all respects to an
authentic sample (vide infra).
4.1.8.3. N-Ethyl-N-(2-nitrophenyl)-1H-pyrrole-2-car-
boxamide 9. 36 mg, 21%, as a pale-yellow solid (ethyl
acetate/hexane); mp 165.5–167.5 8C. [Found: C, 60.30; H,
5.26; N, 16.25; C13H13N3O3 requires C, 60.22; H, 5.05; N,
16.21%]; nmax (Nujol) 3268, 1615 cmK1; dH (400 MHz;
CDCl3) 1.29 (t, JZ7.2 Hz, 3H, Me), 3.60 (br, s, 1H, CH2),
4.27–4.32 (m, 1H, CH2) 4.94 (br, s, 1H, H-4), 5.96 (s, 1H,
H-3), 6.87 (s, 1H, H-5), 7.50 (dd,0JZ7.8, 1.4 Hz, 1H, H-60),
7.66 (td,0JZ7.6, 1.3 Hz, 1H, H-4 ), 7.77 (td, JZ7.7, 1.5 Hz,
1H, H-5 ), 8.12 (dd, JZ8.1, 1.5 Hz, 1H, H-30), 9.69 (br, s,
1H, NH); dC (100 MHz; CDCl3) 13.47, 46.00, 110.35,
112.99, 121.87, 125.05, 126.35, 129.83, 132.93, 134.55,
136.78, 147.67, 161.18; m/z (EI) 259 (MC, 27), 213 (65),
184 (6) 166 (54), 151 (25), 131 (7), 106 (42), 94 (100), 66
(26%).
4.1.7.4. 5-(4-Chlorophenyl)pyrrolo[1,2-a]quinoxalin-
4-(5H)-one 8f. 182 mg, 82%, as a pale-yellow solid (ethyl
acetate/hexane); mp 236–238 8C. [Found: C, 68.93; H, 3.82;
N, 9.47; C17H11ClN2O requires C, 69.28; H, 3.76; N,
9.50%]; nmax (Nujol) 3088, 1660 cmK1; dH (400 MHz;
DMSO-d6) 6.55 (dd, JZ8.3, 1.1 Hz, 1H, H-6), 6.77 (dd, JZ
3.8, 2.8 Hz, 1H, H-2), 7.13 (dd, JZ3.8, 1.4 Hz, 1H, H-3),
7.21 (td, JZ7.8, 1.1 Hz, 1H, H-8), 7.29 (td, JZ7.7, 1.2 Hz,
1H, H-7), 7.48 (d, JZ8.6 Hz, 2H, H-20, H-60), 7.70 (d, JZ
8.6 Hz, 2H, H-30, H-50), 8.19 (dd, JZ8.1, 1.2 Hz, 1H, H-9),
8.32 (dd, JZ2.8, 1.4 Hz, 1H, H-1); dC (100 MHz; DMSO-
d6) 113.46, 114.11, 116.21, 117.62, 119.27, 123.45, 124.03,
126.47, 130.92, 131.66, 132.54, 134.32, 136.51, 155.20; m/z
(EI) 294 (MC, 100), 258 (18), 230 (11) 204 (6), 167 (7), 130
(12), 115 (9).
4.1.9. Preparation of 5-ethyl-7-methylpyrrolo[1,2-a]-
quinoxalin-4(5H)-one 12. To a stirred solution of
7-methylpyrrolo[1,2-a]quinoxalin-4(5H)-one1 (300 mg,
1.51 mmol) in dry DMF (10 mL) under argon, was added
NaH (60% in oil, 65 mg, 1.61 mmol) and left to stir at room
temperature for 1 h. Ethyl iodide (242 mg, 1.55 mmol) was
added and the reaction mixture stirred for 15 min. Water
(50 mL) was added and extracted with ethyl acetate
(3!20 mL). The combined organic extracts were dried
(Na2SO4) and evaporated in vacuo. The oily residue was
purified by flash chromatography (25% ethyl acetate/
hexane) to afford 5-ethyl-7-methylpyrrolo[1,2-a]quinoxa-
lin-4(5H)-one 12 (270 mg, 79%) as a colourless solid
(propan-2-ol/hexane); mp 104–105 8C. [Found: C, 73.98;
H, 6.29; N, 12.36; C14H14N2O requires C, 74.31; H, 6.24; N,
12.38%]; nmax (Nujol) 3130, 1651 cmK1; dH (400 MHz;
CDCl3) 1.34 (t, JZ7.2 Hz, 3H, CH2CH3), 2.42 (s, 3H, Me),
4.27 (q, JZ7.2 Hz, 2H, CH2CH3), 6.60 (dd, JZ3.9, 2.8 Hz,
1H, H-2), 6.97 (dd, JZ8.2, 0.8 Hz, 1H, H-8), 7.06 (s, 1H,
H-6), 7.17 (dd, JZ3.9, 1.6 Hz, 1H, H-3), 7.50 (d, JZ8.2 Hz,
1H, H-9), 7.55 (dd, JZ2.8, 1.6 Hz, 1H, H-1); dC (100 MHz;
CDCl3) 12.65, 35.94, 68.54, 111.94, 112.75, 114.39, 115.50,
115.66, 121.85, 122.94, 123.27, 128.76, 135.38, 155.15; m/z
(EI) 226 (MC, 100), 211 (43), 198 (96), 181 (25), 169 (14%).
4.1.7.5. 5-(4-Methoxyphenyl)pyrrolo[1,2-a]quinoxa-
lin-4-(5H)-one 8g. 208 mg, 95%, as a pale-yellow solid
(ethyl acetate/hexane); mp 207–209 8C. [Found: C, 74.16;
H, 4.90; N, 9.58; C18H14N2O2 requires C, 74.47; H, 4.86; N,
9.65%]; nmax (Nujol) 3148, 1724, 1660 cmK1; dH
(400 MHz; DMSO-d6) 3.85 (s, 3H, Me), 6.55 (d, JZ
8.1 Hz, 1H, H-6), 6.74 (dd, JZ3.8 Hz, 2.7 Hz, 1H, H-2),
7.09 (dd, JZ3.8, 1.5 Hz, 1H, H-3), 7.20–7.14 (m, 3H, H-8,
H-20, H-60), 7.25 (td, JZ7.5, 1.1 Hz, 1H, H-7), 7.29 (d, JZ
8.8 Hz, 2H, H-30, H-50), 8.12 (d, JZ8.1 Hz, 1H, H-9), 8.27
(dd, JZ2.7, 1.5 Hz, 1H, H-1); dC (100 MHz; DMSO-d6)
55.60, 112.55, 113.35, 115.33, 115.42, 117.09, 118.36,
123.01, 123.15, 123.27, 125.67, 128.25, 130.80, 131.52,
154.78, 159.39; m/z (EI) 290 (MC, 100), 275 (11), 167 (18),
145 (8%).
4.1.8. Reaction of N-ethyl-1-(2-nitrophenyl)-1H-pyrrole-
2-carboxamide 3a with NaH in DMF. To a stirred solution
of carboxamide 3a (170 mg, 0.65 mmol) in dry DMF
(10 mL) under argon, was added NaH (60% in oil, 44 mg,
1.10 mmol) and left to stir at room temperature for 30 min.
The reaction mixture was added to a cold saturated aqueous
sodium bicarbonate solution (50 mL), neutralised with 2 N
HCl and extracted with ethyl acetate (3!10 mL). The
combined organic phases were dried (Na2SO4) and
evaporated in vacuo. The oily residue was triturated with
hexane, the solid collected and purified by flash chroma-
tography (25, 50% ethyl acetate/hexane) to afford N-ethyl-
1-(2-nitrophenyl)-1H-pyrrole-2-carboxamide 3a, 5-ethyl-
pyrrolo[1,2-a]quinoxalin-4(5H)-one 8a and N-ethyl-N-(2-
nitrophenyl)-1H-pyrrole-2-carboxamide 9.
4.1.10. Reaction of N-ethyl-1-(4-methyl-2-nitrophenyl)-
1H-pyrrole-2-carboxamide 3b with NaH in DMF.
Following general procedure
D carboxamide 3b
(0.65 mmol) in dry DMF (10 mL) and NaH (60% in oil,
1.10 mmol) at room temperature for 1.5 h gave a mixture
(118 mg, 80%) of 5-ethyl-7-methylpyrrolo[1,2-a]quinoxa-
lin-4(5H)-one 12 (44% in mixture from 1H NMR) and
5-ethyl-8-methylpyrrolo[1,2-a]quinoxalin-4(5H)-one 13
1
(44% in mixture from H NMR); dH (400 MHz; CDCl3)
1.29–1.34 (m, 4H, 2!CH2CH3 of 12 and 13), 2.41 (s, 3H, Me
of 12), 2.42 (s, 3H, Me of 13), 4.24–4.30 (m, 4H, 2!CH2CH3
of 12 and 13), 6.59–6.62 (m, 2H, 2!H-2 of 12 and 13), 6.97

10832
G. Rotas et al. / Tetrahedron 60 (2004) 10825–10832
(d, JZ8.2 Hz, 1H, H-8 of 12), 7.06 (s, 1H, H-6 of 12), 7.07
(d, JZ7.8 Hz, H-7 of 13), 7.14–7.18 (m, 3H, H-3 of 12 and
13, H-6 of 13), 7.45 (s, 1H, H-9 of 13), 7.50 (d, JZ8.2 Hz,
1H, H-9 of 12), 7.55 (dd, JZ2.8, 1.6 Hz, 1H, H-1 of 12).
Vocational Training of the Hellenic Ministry of Education
under the 3rd Community Support Framework and the
European Social Fund (to G. R.) and partly by a PENED
grant (91ED102) (to A. K.) from the General Secretariat of
Research and Technology, Athens. We thank Professor
Dr. B. Stanovnik of the University of Ljubljana and
Professor N. Hadjiliadis of the University of Ioannina for
elemental analyses. We are particularly grateful to
A. Cakebread and R. Tye for mass spectra, and, J. Cobb
for NMR spectra of fluorine containing compounds,
obtained on machines funded by the University of London
Intercollegiate Research Services Scheme.
4.1.11. Reaction of N-(2,4-difluorophenyl)-1-(2-nitrophe-
nyl)-1H-pyrrole-2-carboxamide 7d with NaH in DMF.
Following general procedure
E
carboxamide 7d
(0.65 mmol) in dry DMF (10 mL) and NaH (60% in oil,
1.10 mmol) at room temperature for 4.5 h gave, after
purification by flash chromatography (33% ethyl acetate/
hexane), 5-(2,4-difluorophenyl)pyrrolo[1,2-a]quinoxalin-
4(5H)-one 16 and 8-fluoro-5-(2-nitrophenyl)pyrrolo[1,2-a]
quinoxalin-4(5H)-one 17.
4.1.11.1. 5-(2,4-Difluorophenyl)pyrrolo[1,2-a]quinox-
alin-4(5H)-one 16. 144 mg, 75%, as a pale-yellow solid
(ethyl acetate/hexane); mp 200–202 8C. [Found: C, 69.07;
H, 3.65; N, 9.35; C17H10F2N2O requires C, 68.92; H, 3.40;
N, 9.46%]; nmax (Nujol) 3122, 1659 cmK1; dH (400 MHz;
DMSO-d6) 6.63 (d, JZ8.2 Hz, 1H, H-6), 6.77 (dd, JZ3.9,
2.8 Hz, 1H, H-2), 7.17 (dd, JZ3.9, 1.5 Hz, 1H, H-3), 7.23
(td, JZ7.8, 1.3 Hz, 1H, H-7), 7.31 (td, JZ7.8, 1.3 Hz, 1H,
H-8), 7.36 (ddd, JZ8.8, 8.7, 2.8, Hz, 1H, H-50), 7.61 (ddd,
JZ10.1, 9.2, 2.8 Hz, 1H, H-30), 7.67 (td, JZ8.8, 6.2 Hz,
1H, H-60) 8.19 (dd, JZ8.1, 1.3 Hz, 1H, H-9), 8.32 (dd, JZ
2.8, 1.5 Hz, 1H, H-1); dC (100 MHz; DMSO-d6) 105.94 (dd,
JZ27.1, 24.2 Hz), 113.37 (dd, JZ22.5, 3.5 Hz), 113.56,
113.78, 115.93, 116.52, 119.27, 120.62 (dd, JZ13.5,
3.9 Hz), 122.49, 123.55, 124.01, 126.32, 130.34, 133.51
(d, JZ10.4 Hz), 154.38, 158.90 (dd, JZ251.1, 13.3 Hz),
162.80 (dd, JZ248.6, 11.8 Hz); dF (376 MHz; DMSO-d6)
K107.70 (dddd, JZ9.2, 8.7, 8.6, 6.2 Hz, 0 1F, F-40),
K117.05 (ddd, JZ10.1, 8.8, 8.6 Hz, 1F, F-2 ); m/z (EI)
296 (MC, 100), 277 (57), 247 (6%).
References and notes
1. Campiani, G.; Morelli, E.; Gemma, S.; Nacci, V.; Butini, S.;
Hamon, M.; Novellino, E.; Greco, G.; Cagnotto, A.; Goegan,
M.; Cervo, L.; Dalla Valle, F.; Fracasso, C.; Caccia, S.;
Mennini, T. J. Med. Chem. 1999, 42, 4362.
2. Campiani, G.; Cappelli, A.; Nacci, V.; Anzini, M.; Vomero, S.;
Hamon, M.; Cagnotto, A.; Cagnotto, A.; Fracasso, C.; Uboldi,
C.; Caccia, S.; Consolo, S.; Mennini, T. J. Med. Chem. 1997,
40, 3670.
3. Prunier, H.; Rault, S.; Lancelot, J.-C.; Robba, M.; Renard, P.;
Delagrange, P.; Pfeiffer, B.; Caignard, D.-H.; Misslin, R.;
Guardiola-Lemaitre, B.; Hamon, M. J. Med. Chem. 1997, 40,
1808.
´
4. Guillon, J.; Grellier, P.; Labaied, M.; Sonnet, P.; Leger, J.-M.;
´ ˆ
Deprez-Poulain, R.; Forfar-Bares, I.; Dallemagne, P.; Lemaıtre,
´
N.; Pehourcq, F.; Rochette, J.; Sergheraert, C.; Jarry, C. J. Med.
Chem. 2004, 47, 1997.
5. Campiani, G.;Aiello, F.;Fabbrini, M.;Morelli, E.;Ramunno, A.;
Armaroli, S.; Nacci, V.; Garofalo, A.; Greco, G.; Novellino, E.;
Maga, G.; Spadari, S.; Bergamini, A.; Ventura, L.; Bongiovanni,
B.; Capozzi, M.; Bolacchi, F.; Marini, S.; Coletta, M.; Guiso, G.;
Caccia, S. J. Med. Chem. 2001, 44, 305.
4.1.11.2. 8-Fluoro-5-(2-nitrophenyl)pyrrolo[1,2-
a]quinoxalin-4(5H)-one 17. 32 mg, 15%, as a pale-yellow
solid (ethyl acetate/hexane); mp 264–265 8C. [Found: C,
63.32; H, 3.33; N, 12.86; C17H10FN3O3 requires C, 63.16;
6. Ager, I. R.; Barnes, A. C.; Danswan, G. W.; Hairsine, P. W.;
Kay, D. P.; Kennewell, P. D.; Matharu, S. S.; Miller, P.;
Robson, P.; Rowlands, D. A.; Tully, W. R.; Westwood, R.
J. Med. Chem. 1998, 31, 1098.
H, 3.12; N, 13.00%]; nmax (Nujol) 1661, 1514, 1346 cmK1
;
dH (400 MHz; DMSO-d6) 6.64 (dd, JZ9.0, 5.1 Hz, 1H,
H-6), 6.81 (t, JZ3.6 Hz, 1H, H-2), 7.10 (td, JZ9.0, 2.7 Hz,
1H, H-7), 7.16 (dd, JZ3.8, 1.2 Hz, 1H, H-3), 7.77 (d, JZ
7.8 Hz, 1H, H-30), 7.87 (td, 0JZ7.8, 1.3 Hz, 1H, H-50), 8.01
(td, JZ7.7, 1.3 Hz, 1H, H-4 ), 8.26 (dd, JZ9.8, 2.7 Hz, 1H,
H-9), 8.32–8.36 (m, 2H, H-1, H-60); dC (100 MHz; DMSO-
d6) 103.31 (d, JZ28.4 Hz), 112.84 (d, JZ22.8 Hz), 113.91,
114.02, 118.35 (d, JZ9.6 Hz), 119.88, 122.25, 124.25
(d, JZ11.4 Hz), 126.16, 126.95, 129.86, 131.13, 132.65,
135.80, 147.26, 153.85, 158.36 (d, JZ240.3 Hz); dF
(376 MHz; DMSO-d6) K118.25 (ddd, JZ9.8, 9.0, 5.1 Hz,
1F, F-8); m/z (EI) 323 (MC, 39), 277 (100), 247 (15),
222 (8%).
7. (a) Kumashiro, I. Nippon Kagaku Zasshi 1961, 82, 1072.
Chem. Abstr. 1963, 59, 607. (b) Nagarajan, K.; Ranga Rao, V.;
Venkateswarlu, A. Indian J. Chem. 1972, 10, 344.
(c) Campiani, G.; Nacci, V.; Corelli, F.; Anzini, M. Synth.
Commun. 1991, 21, 1567.
8. Matsuda, Y.; Yamashita, M.; Takahashi, K.; Ide, S.; Torisu,
K.; Furuno, K. Heterocycles 1992, 33, 295.
9. (a) Meth-Cohn, O. Tetrahedron Lett. 1975, 6, 413. (b) Zhang,
X.-C.; Huang, W.-Y. Tetrahedron 1998, 54, 12465.
10. Zhang, X.-C.; Huang, W.-Y. Tetrahedron Lett. 1997, 38, 4827.
11. Abbott, P. J.; Acheson, R. M.; Foxton, M. W.; Raulins, N. R.;
Robinson, G. E. J. Chem. Soc., Perkin Trans. 1 1972, 2182.
12. Korakas, D.; Kimbaris, A.; Varvounis, G. Tetrahedron 1996,
52, 10751.
Acknowledgements
13. Railey, D. M.; Johnson, R. E. J. Med. Chem. 1973, 16, 1300.
14. Armarego, W. L. F.; Perrin, D. D. Purification of Laboratory
Chemicals; Butterworth-Heinemann: Oxford, 1996.
This research was funded by the programme “Heraklitos” of
the Operational Programme for Education and Initial