A valuable synthesis of pyrrolo[1,2-a]quinoxalines, indolo[1,2-a] quinoxalines and their aza-analogues by palladium-catalyzed intramolecular carbon-nitrogen bond formation

Article abstract of DOI:10.1055/s-2005-916033

A novel and efficient method for the construction of pyrrolo[1,2-a] quinoxalines, indolo[1,2-a]quinoxalines and their aza-analogues is described. The reaction involves a Pd-catalyzed intramolecular cyclization as the key step and provides the desired prod

Full text of DOI:10.1055/s-2005-916033

PAPER
2881
A Valuable Synthesis of Pyrrolo[1,2-a]quinoxalines, Indolo[1,2-a]quinoxalines
and their Aza-Analogues by Palladium-Catalyzed Intramolecular Carbon–
Nitrogen Bond Formation
S
ynthesisof Pyrro
i
lo[1,2-
a
o
]quinoxalin
r
s
and
I
n
g
dolo[1,2-
a
]q
i
uinoxa
o
lines Abbiati,a Egle M. Beccalli,*a Gianluigi Broggini,b Giuseppe Paladino,a Elisabetta Rossia
a
Istituto di Chimica Organica ‘A. Marchesini’, Facoltà di Farmacia, Università di Milano, via Venezian 21, 20133 Milano, Italy
Dipartimento di Scienze Chimiche e Ambientali, Università dell’Insubria, via Valleggio 11, 22100 Como, Italy
Fax +39(02)50314476; E-mail: egle.beccalli@unimi.it
b
Received 15 April 2005; revised 30 May 2005
were reported to show antihypertensive and vascular
smooth muscle relaxant activities.5
Abstract: A novel and efficient method for the construction of pyr-
rolo[1,2-a]quinoxalines, indolo[1,2-a]quinoxalines and their aza-
analogues is described. The reaction involves a Pd-catalyzed in-
tramolecular cyclization as the key step and provides the desired
products in only two steps and good overall yields.
Few methods are available for the synthesis of pyrroloqui-
noxalines and their aza-analogues. Most of them are based
on the N-arylation of pyrrole with 2-nitroaryl derivatives,
followed by reduction of the nitro group and cyclization to
form the oxo-piperazine ring.3,4,6 However, these path-
ways require the use of activated substrates, hazardous re-
agents such as phosgene or harsh reaction conditions.
Also, the procedures for azole arylation are limited. Phe-
nylation with electrophilic aromatic compounds was re-
ported,7 while the reaction mediated by KF adsorbed onto
alumina was efficient only with electron-poor aryl ha-
lides.8 The copper-mediated azole arylation requires high
temperatures and often toxic solvents,9 the aza-Wittig re-
action of iminophophorane pyrrole derivatives was also
reported.10 The indoloquinoxalines were prepared starting
from 1-(2-nitrophenyl)indol-2-carboxylate11 in a similar
manner as reported for pyrrole derivatives or via photocy-
clization of 2-aroylquinoxalines.12
Key words: palladium catalyst, aminations, cyclizations, fused-
ring systems, indoles, lactams
In recent years, pharmacological evaluation and struc-
ture–activity relationships of a series of simple or fused
quinoxalinones have been described. Pyrroloquinoxalines
and heteroaromatic-related derivatives like pyridopyrrol-
opirazine have become interesting in the fields of anti-
HIV agents (A, Figure 1),1 as hypoglycemic2 compounds
and especially as 5-HT3 receptor agonists (B, Figure 1).3
A technique which involves the transition metal-catalyzed
displacement of a suitable leaving group would be partic-
ularly useful, since many transition metal coupling reac-
tions occur under mild conditions and are highly tolerant
of a variety of functional groups.13 In particular the catal-
ysis by palladium has become an efficient and useful pro-
cess for the synthesis of heterocyclic systems.14 In this
context, the Pd-catalyzed amination of aryl halides is an
important methodology for C–N bond formation and has
many applications for the synthesis of functionalized
anilines.15 In contrast, the Pd-catalyzed coupling to form
aryl nitrogen bonds in N-aryl azoles has been reported
only recently,16 but intermolecular reactions were exclu-
sively observed.
Figure 1
The potential therapeutic role of 5-HT3 receptor agonists
was based on their modulation of acetylcholine release in
vivo, which makes these compounds of interest for the
treatment of neurodegenerative and neuropsychiatric dis-
orders. These compounds were also evaluated to have an-
algesic-like properties.3c A series of these derivatives have
been patented and described as antiallergics,4 antiasthmat-
ics,4 and anxiolytics.3b,4 Tetrahydropyrrolo[1,2-a]quinoxa-
lines and tetrahydropyrido[3,2-e]pyrrolo[1,2-a] pyrazines
As a part of our ongoing program to develop synthetic ap-
plications of Pd-catalyzed amination reactions on hetero-
cyclic substrates,17 we report here the synthesis of
pyrroloquinoxalines and indoloquinoxalines by way of
pyrrole-2-carboxamides or indole-2-carboxamides bear-
ing a suitable o-halosubstituted aryl- or heteroaryl group
at the amide nitrogen. The synthetic strategy, involving
few steps, was based on the palladium-catalyzed intramo-
lecular N-arylation forming a C–N bond on the oxo-piper-
azine ring. Starting from pyrrole- or indole-2-carboxylic
acids 1 and 2-haloanilines or halopyridines 2, the amides
SYNTHESIS 2005, No. 17, pp 2881–2886
Advanced online publication: 29.09.2005
DOI: 10.1055/s-2005-916033; Art ID: Z07705SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
5

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G. Abbiati et al.
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Scheme 1
3 were prepared via unisolable acyl chlorides in the pres- paucity of representatives as well as synthetic entries re-
ence of triethylamine. The preliminary methylation of the ported in the literature.3b,c,4a,b
commercially available 2-haloanilines or halopyridines
In summary, a concise and efficient synthetic sequence to
was effected to avoid later a concomitant palladium com-
various heteropolycyclic products is reported. Different
plexation. The amides 3 were then treated following the
isomeric and homologous derivatives are under study.
Buchwald–Hartwig reaction conditions to give the cy-
clized products 4 as depicted in Scheme 1.
Melting points were measured with a Büchi B-540 heating unit and
are not corrected. NMR spectra were recorded with an AVANCE
Table 1 Compounds 3,4 Prepared
400 Bruker at 400 MHz for 1H NMR and 100 MHz for 13C NMR in
CDCl3. Chemical shifts, relative to TMS as internal standard, are
given as d values in ppm. IR spectra were taken with a Perkin-Elmer
1725X FT-IR spectrophotometer. Compounds 2a18 and 2c19 were
prepared according to literature procedures.
Substrates
Products (Yield in %)
3aa (78)
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
2a
2b
2c
2d
2e
2a
2b
2c
2d
2e
4aa (91)
4ab (79)
4ac (90)
4ad (95)
4ae (74)
4ba (98)
4bb (77)
4bc (66)
4bd (69)
4be (74)
3ab (82)
Synthesis of (4-Chloro-2-iodophenyl)methylamine (2b)
A solution of 4-chloro-2-iodo-aniline (2.53 g, 10 mmol) in anhyd
THF (50 mL) was cooled to –78 °C under N2 atmosphere, then n-
BuLi 1.6 M (7.5 mL, 12 mmol) was added dropwise and the result-
ing solution was stirred at –78 °C for 30 min. After this time
(CH3)2SO4 (1.42 mL, 15 mmol) was added and the mixture was al-
lowed to warm to r.t. After 16 h the solvent was evaporated and the
residue diluted with 1 M HCl (10 mL) and extracted with Et2O (30
mL). The organic layer was stirred 30 min with concd NH4OH (30
mL) and the aqueous layer was removed. The organic phase was
washed with H2O (30 mL) and brine (30 mL), dried (Na2SO4) and
evaporated under reduced pressure. The residue was chromato-
graphed on a silica gel column (light petroleum → CH2Cl2–light pe-
troleum, 5:1).
3ac (58)
3ad (59)
3ae (64)
3ba (66)
3bb (63)
3bc (68)
3bd (55)
3be (60)
Yield: 76%, mp 53–54 °C (white crystals from hexane).
IR (Nujol): 3405 cm–1.
1H NMR: d = 2.81 (s, 3 H), 4.20 (br s, 1 H, absent after deuteration),
6.46 (dd, J = 1.8, 7.4 Hz, 1 H), 7.26 (d, J = 1.8 Hz, 1 H), 7.62 (d,
J = 7.4 Hz, 1 H).
The best conditions were Pd(OAc)2 (5 mol%) in presence
of BINAP (10 mol%) and Cs2CO3 as base in toluene as
solvent, heating the mixture at 110 °C for 24 h. The pos-
sible concomitant Heck pathway involving cyclization on
the 3-position of the pyrrole nucleus was never observed.
As shown in Table 1, our approach is general for the prep-
aration giving good yields of pyrrolo[1,2-a]quinoxalin-4-
ones and indolo[1,2-a]quinoxalin-6-ones from halo-
anilines as well as of pyridopyrrolopirazines and pyrido-
13C NMR: d = 36.0 (q), 89.2 (s), 121.0 (d), 124.0 (s), 124.7 (d),
140.5 (d), 149.3 (s).
Anal. Calcd for C7H7ClIN (267.49): C, 36.23; H, 3.04; N, 6.04.
Found: C, 36.43; H, 2.97; N, 6.15.
indolopirazines from haloaminopyridines. The latter goal Synthesis of N-(3-Bromo-5-methylpyridin-2-yl)-N-methyl-
amine (2d)
– the obtainment of pyrido-fused compounds 4ad, 4ae,
4bd and 4be – is particularly noteworthy in view of the
To a solution of 2-amino-3-bromo-5-methylpyridine (2 g, 10.7
mmol) in anhyd THF (50 mL) cooled to 0 °C, 60% NaH (556 mg,
13.9 mmol) was added in small portions under N2 atmosphere. The
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Synthesis of Pyrrolo[1,2-a]quinoxalines and Indolo[1,2-a]quinoxalines
2883
resulting mixture was stirred and allowed to warm to r.t., then MeI
(1.34 mL, 21.4 mmol) was added dropwise in anhyd THF (5 mL).
After 4 h the solvent was evaporated and the residue diluted with 1
M HCl (10 mL) and extracted with Et2O (2 × 20 mL). The organic
phase was dried (Na2SO4) and evaporated under reduced pressure.
The residue was chromatographed on a silica gel column (CH2Cl2).
N-(4-Chloro-2-iodophenyl)-N-methyl-1H-pyrrole-2-carbox-
amide (3ab)
Yield: 82%, mp 195 °C (cream crystals from CH2Cl2–hexane).
IR (Nujol): 1623, 3296 cm–1.
1H NMR: d = 3.31 (s, 3 H), 4.72 (d, J = 1.4 Hz, 1 H), 5.97 (d, J = 2.2
Hz, 1 H), 6.84 (d, J = 1.4 Hz, 1 H), 7.26 (d, J = 6.6 Hz, 1 H), 7.41
(d, J = 6.6 Hz, 1 H), 7.95 (dd, J = 1.4, 2.2 Hz, 1 H), 9.49 (br s, 1 H,
absent after deuteration).
Yield: 87%, yellow oil.
IR (film): 3440 cm–1.
1H NMR: d = 2.32 (s, 3 H), 2.47 (s, 3 H), 4.41 (br s, 1 H, absent after
deuteration), 7.81 (d, J = 1.7 Hz, 1 H), 8.27 (d, J = 1.7 Hz, 1 H).
13C NMR: d = 26.4 (q), 34.1 (q), 105.6 (s), 124.7 (s), 139.6 (d),
148.0 (d), 158.2 (s).
13C NMR: d = 37.4 (q), 102.0 (s), 109.7 (d), 113.4 (d), 122.2 (d),
125.3 (s), 130.7 (d), 131.4 (d), 134.4 (s), 139.5 (d), 146.3 (s), 161.1
(s).
Anal. Calcd for C12H10ClIN2O (360.58): C, 39.97; H, 2.80; N, 7.77.
Found: C, 39.80; H, 2.99; N, 7.90.
Anal. Calcd for C7H9BrN2 (201.07): C, 41.82; H, 4.51; N, 13.93.
Found: C, 41.65; H, 4.59; N, 13.81.
N-(2-Bromo-4-methylphenyl)-N-methyl-1H-pyrrole-2-carbox-
amide (3ac)
Yield: 58%, mp 207–210 °C (cream powder from CH2Cl2–hexane).
IR (Nujol): 1633, 3296 cm–1.
1H NMR: d = 2.44 (s, 3 H), 3.36 (s, 3 H), 4.94 (s, 1 H), 5.95 (s, 1 H),
6.85 (s, 1 H), 7.20–7.28 (2 H, overlapping), 7.55 (s, 1 H), 9.74 (br
s, 1 H, absent after deuteration).
13C NMR: d = 21.3 (q), 37.3 (q), 110.3 (d), 113.2 (d), 121.3 (d),
123.9 (s), 125.4 (s), 130.1 (d), 130.4 (d), 134.7 (d), 140.7 (s), 140.9
(s), 161.7 (s).
Synthesis of N-(2-Bromopyridin-3-yl)-N-methylamine (2e)
2 M LDA (6.95 mL, 13.9 mmol) was added dropwise to an anhyd
THF solution (50 mL) of 3-amino-2-bromopyridine (2 g, 11.6
mmol) at –78 °C, under N2 atmosphere. The mixture was warmed
to 0 °C and allowed to react for 1 h, then cooled to –78 °C before
MeI (1.44 mL, 23.2 mmol) was added dropwise. The reaction was
kept at –78 °C for 1 h, then allowed to warm to r.t. overnight. Aq
NH4Cl (30 mL) and EtOAc (30 mL) were added. The organic ex-
tracts were washed with brine (30 mL) and dried (Na2SO4). The
mixture was filtered and concentrated under vacuum. The crude
product was purified by chromatography on silica gel (light petro-
leum → light petroleum–Et2O, 5:1).
Anal. Calcd for C13H13BrN2O (293.17): C, 53.26; H, 4.47; N, 9.56.
Found: C, 53.39; H, 4.56; N, 9.64.
Yield: 85%, yellow oil.
IR (film): 3420 cm–1.
1H NMR: d = 2.88 (s, 3 H), 4.42 (br s, 1 H, absent after deuteration),
6.81 (d, J = 8.1 Hz, 1 H), 7.09 (dd, J = 7.9, 8.1 Hz, 1 H), 7.68 (d,
J = 7.9 Hz, 1 H).
N-(3-Bromo-5-methylpyridin-2-yl)-N-methyl-1H-pyrrole-2-
carboxamide (3ad)
Yield: 59%, mp 161–162 °C (cream crystals from Et2O).
IR (Nujol): 1603, 3295 cm–1.
1H NMR: d = 2.43 (s, 3 H), 3.40 (s, 3 H), 5.05 (d, J = 1.6 Hz, 1 H),
5.95 (d, J = 2.7 Hz, 1 H), 6.84 (d, J = 1.6, 2.7 Hz, 1 H), 7.83 (d,
J = 2.1 Hz, 1 H), 8.38 (d, J = 2.1 Hz, 1 H), 9.71 (br s, 1 H, absent
after deuteration).
13C NMR: d = 18.1 (q), 35.6 (q), 110.2 (d), 112.5 (d), 120.3 (s),
121.6 (d), 125.5 (s), 135.8 (s), 143.4 (d), 149.2 (d), 152.6 (s), 161.9
(s).
13C NMR: d = 36.2 (q), 124.6 (d), 125.2 (d), 134.6 (s), 142.3 (d),
149.1 (s).
Anal. Calcd for C6H7BrN2 (187.04): C, 38.53; H, 3.77; N, 14.98.
Found: C, 38.70; H, 3.65; N, 14.87.
Preparation of the Heteroamides 3; General Procedure
A solution of 1 (10 mmol) and SOCl2 (3.2 mL, 44.5 mmol) in tolu-
ene (10 mL) was stirred at 70 °C for 2.5 h. After evaporation of the
solvent, the residue was taken up with CH2Cl2 (20 mL). A solution
of 2 (13.3 mmol) and TEA (1.9 mL, 13.6 mmol) in CH2Cl2 (5 mL)
was added dropwise at 0 °C. After stirring for 5 h at r.t. the solution
was washed with 5% HCl (2 × 20 mL) and then with 5% aq NaOH
(2 × 20 mL). The organic layer was dried (Na2SO4) and the solvent
evaporated under reduced pressure. The residue was chromato-
graphed on a silica gel column (CH2Cl2) to give compounds 3.
Compounds 3aa, 3ab, 3ae, 3bc were directly crystallized.
Anal. Calcd for C12H12BrN3O (294.15): C, 49.00; H, 4.11; N, 14.29.
Found: C, 49.19; H, 3.95; N, 14.38.
N-(2-Bromopyridin-3-yl)-N-methyl-1H-pyrrole-2-carbox-
amide (3ae)
Yield: 64%, mp 185–187 °C (ivory crystals from Et2O).
IR (Nujol): 1601, 3296 cm–1.
1H NMR: d = 3.40 (s, 3 H), 4.95 (br s, 1 H), 5.98 (s, 1 H), 6.88 (s, 1
H), 7.42 (dd, J = 7.6, 7.7 Hz, 1 H), 7.70 (dd, J = 1.7, 7.7 Hz, 1 H),
8.49 (dd, J = 1.7, 7.6 Hz, 1 H), 9.82 (br s, 1 H, absent after deutera-
tion).
13C NMR: d = 37.3 (q), 110.5 (d), 113.6 (d), 122.0 (d), 123.8 (d),
124.9 (s), 139.1 (d), 141.1 (s), 144.2 (s), 149.9 (d), 161.1 (s).
N-(2-Iodophenyl)-N-methyl-1H-pyrrole-2-carboxamide (3aa)20
Yield: 78%, mp 182–183 °C (white crystals from CH2Cl2–hexane).
IR (Nujol): 1619, 3259 cm–1.
1H NMR: d = 3.37 (s, 3 H), 4.83 (br s, 1 H), 5.95 (br s, 1 H), 6.85 (s,
1 H), 7.17 (ddd, J = 1.6, 7.4, 8.6 Hz, 1 H), 7.38 (dd, J = 1.8, 8.6 Hz,
1 H), 7.45 (ddd, J = 1.8, 7.4, 8.2 Hz, 1 H), 7.97 (dd, J = 1.6, 8.2 Hz,
1 H), 9.49 (br s, 1 H, absent after deuteration).
13C NMR: d = 37.8 (q), 100.2 (s), 109.9 (d), 113.8 (d), 121.6 (d),
126.6 (d), 130.1 (d), 130.3 (d), 134.1 (s), 138.4 (d), 146.7 (s), 162.0
(s).
Anal. Calcd for C11H10BrN3O (280.13): C, 47.17; H, 3.60; N, 15.00.
Found: C, 47.23; H, 3.71; N, 14.87.
N-(2-Iodophenyl)-N-methyl-1H-indole-2-carboxamide (3ba)
Yield: 66%, mp 201–202 °C (white crystals from Et2O).
IR (Nujol): 1608, 3279 cm–1.
1H NMR: d = 3.42 (s, 3 H), 5.14 (s, 1 H), 7.04 (dd, J = 7.2, 7.4 Hz,
1 H), 7.18–7.24 (overlapping, 2 H), 7.33–7.50 (overlapping, 4 H),
Anal. Calcd for C12H11IN2O (325.99): C, 44.19; H, 3.40; N, 8.59.
Found: C, 44.02; H, 3.58; N, 8.46.
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G. Abbiati et al.
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7.99 (dd, J = 1.0, 7.6 Hz, 1 H), 9.38 (br s, 1 H, absent after deutera-
tion).
13C NMR: d = 37.8 (q), 100.0 (s), 106.6 (d), 111.9 (d), 120.4 (d),
122.4 (d), 124.6 (s), 124.8 (d), 130.1 (d), 130.3 (d), 130.6 (d), 135.7
(s), 140.4 (s), 140.6 (d), 146.4 (s), 162.0 (s).
13C NMR: d = 37.6 (q), 106.9 (d), 112.1 (d), 120.9 (d), 122.6 (d),
124.1 (d), 125.4 (d), 128.0 (s), 129.2 (s), 135.9 (s), 138.8 (s), 139.0
(d), 139.4 (s), 149.8 (d), 150.2 (s).
Anal. Calcd for C15H12BrN3O (330.19): C, 54.57; H, 3.66; N, 12.73.
Found: C, 54.66; H, 3.78; N, 12.90.
Anal. Calcd for C16H13IN2O (376.20): C, 51.08; H, 3.48; N, 7.45.
Found: C, 51.17; H, 3.57; N, 7.60.
Cyclization of Heteroamides 3 to Give Compounds 4; General
Procedure
A mixture of compound 3 (1 mmol), Pd(OAc)2 (11 mg, 0.05 mmol),
BINAP (62 mg, 0.1 mmol) and Cs2CO3 (325 mg, 1 mmol) in tolu-
ene (10 mL) was stirred at 110 °C for 24 h. The residue was diluted
with brine (15 mL) and extracted with Et2O (2 × 20 mL). The organ-
ic layer was dried with Na2SO4 and evaporated under reduced pres-
sure. The residue was chromatographed on a silica gel column, elu-
ent CH2Cl2–Et2O (10:1) to give compounds 4. Compound 4aa was
directly crystallized.
N-(4-Chloro-2-iodophenyl)-N-methyl-1H-indole-2-carbox-
amide (3bb)
Yield: 63%, mp 188–190 °C (cream crystals from EtOAc–hexane).
IR (Nujol): 1605, 3281 cm–1.
1H NMR: d = 3.42 (s, 3 H), 5.31 (s, 1 H), 7.06 (dd, J = 7.5, 7.7 Hz,
1 H), 7.25 (d, J = 7.5 Hz, 1 H), 7.35 (d, J = 8.5 Hz, 1 H), 7.40–7.48
(overlapping, 2 H), 7.50 (dd, J = 2.3, 8.3 Hz, 1 H), 8.01 (d, J = 2.3
Hz, 1 H), 9.67 (br s, 1 H, absent after deuteration).
13C NMR: d = 38.0 (q), 100.5 (s), 106.9 (d), 112.1 (d), 120.8 (d),
122.7 (d), 125.2 (d), 128.2 (s), 129,6 (s), 130.5 (d), 130.7 (d), 135.5
(s), 135.9 (s), 140.2 (d), 145.4 (s), 162.1 (s).
5-Methylpyrrolo[1,2-a]quinoxalin-4(5H)-one (4aa)6c
Yield: 91%, mp 134–135 °C (cream crystals from CH2Cl2–hexane).
IR (Nujol): 1624 cm–1.
1H NMR: d = 3.70 (s, 3 H), 6.68 (dd, J = 3.1, 3.1 Hz, 1 H), 7.25–
7.28 (overlapping, 2 H), 7.33–7.39 (overlapping, 2 H), 7.68 (d,
J = 8.3 Hz, 1 H), 7.72 (d, J = 8.1 Hz, 1 H).
Anal. Calcd for C16H12ClIN2O (410.64): C, 46.80; H, 2.95; N, 6.82.
Found: C, 46.97; H, 2.99; N, 6.96.
13C NMR: d = 28.8 (q), 113.0 (d), 113.6 (d), 114.9 (d), 116.0 (d),
N-(2-Bromo-4-methylphenyl)-N-methyl-1H-indole-2-carbox-
amide (3bc)
Yield: 68%, mp 235–236 °C (cream crystals from CH2Cl2).
IR (Nujol): 1601, 3280 cm–1.
1H NMR: d = 2.33 (s, 3 H), 3.28 (s, 3 H), 5.17 (s, 1 H), 6.86 (dd,
J = 7.4, 7.4 Hz, 1 H), 7.06 (dd, J = 7.4, 7.7 Hz, 1 H), 7.12 (d, J = 7.7
Hz, 1 H), 7.16 (d, J = 8.3 Hz, 1 H), 7.24 (d, J = 7.4 Hz, 1 H), 7.30
(d, J = 8.3 Hz, 1 H), 7.43 (s, 1 H), 10.10 (br s, 1 H, absent after deu-
teration).
116.3 (d), 123.2 (d), 123.7 (s), 124.4 (s), 125.9 (d), 130.7 (s), 155.9
(s).
Anal. Calcd for C12H10N2O (198.23): C, 72.71; H, 5.08; N, 14.13.
Found: C, 72.65; H, 5.17; N, 13.99.
8-Chloro-5-methylpyrrolo[1,2-a]quinoxalin-4(5H)-one (4ab)
Yield: 79%, mp 189–190 °C (ochre crystals from CH2Cl2).
IR (Nujol): 1637 cm–1.
13C NMR: d = 21.1 (q), 37.5 (q), 105.9 (d), 112.2 (d), 120.0 (d),
122.1 (d), 123.3 (s), 124.2 (d), 127.7 (s), 130.1 (d), 130.2 (d), 134.5
(d), 135.9 (s), 140.4 (s), 140.9 (s), 141.0 (s), 162.2 (s).
1H NMR: d = 3.64 (s, 3 H), 6.68 (dd, J = 1.2, 3.4 Hz, 1 H), 7.21–
7.24 (overlapping, 2 H), 7.28 (dd, J = 2.0, 8.8 Hz, 1 H), 7.58 (d,
J = 1.2 Hz, 1 H), 7.64 (d, J = 2.0 Hz, 1 H).
13C NMR: d = 28.9 (q), 113.6 (d), 114.1 (d), 115.0 (d), 116.6 (d),
Anal. Calcd for C17H15BrN2O (343.23): C, 59.49; H, 4.41; N, 8.16.
Found: C, 59.60; H, 4.47; N, 7.99.
117.1 (d), 123.6 (s), 125.0 (s), 125.7 (d), 128.7 (s), 129.3 (s), 155.5
(s).
N-(3-Bromo-5-methylpyridin-2-yl)-N-methyl-1H-indole-2-car-
boxamide (3bd)
Yield: 55%, mp 205–206 °C (light yellow crystals from CH2Cl2–
hexane).
IR (Nujol): 1621, 3299 cm–1.
1H NMR: d = 2.46 (s, 3 H), 3.47 (s, 3 H), 5.34 (br s, 1 H), 7.05 (dd,
J = 7.3, 7.7 Hz, 1 H), 7.25 (dd, J = 7.7, 8.0 Hz, 1 H), 7.40 (d, J = 7.3
Hz, 1 H), 7.42 (d, J = 8.0 Hz, 1 H), 7.84 (d, J = 1.8 Hz, 1 H), 8.42
(d, J = 1.8 Hz, 1 H), 9.30 (br s, 1 H, absent after deuteration).
13C NMR: d = 18.2 (q), 36.0 (q), 105.9 (d), 112.0 (d), 120.7 (d),
121.3 (s), 122.5 (d), 123.1 (s), 125.0 (s), 126.1 (d), 135.9 (s), 136.0
(s), 143.5 (d), 149.3 (d), 152.5 (s), 162.8 (s).
Anal. Calcd for C12H9ClN2O (232.66): C, 61.95; H, 3.90; N, 12.04.
Found: C, 61.81; H, 3.97; N, 11.86.
5,8-Dimethylpyrrolo[1,2-a]quinoxalin-4(5H)-one (4ac)
Yield: 90%, mp 125–126 °C (light yellow crystals from CH2Cl2–
hexane).
IR (Nujol): 1639 cm–1.
1H NMR: d = 2.45 (s, 3 H), 3.65 (s, 3 H), 6.79 (dd, J = 1.2, 3.4 Hz,
1 H), 7.20–7.27 (overlapping, 2 H), 7.31 (dd, J = 1.0, 8.8 Hz, 1 H),
7.61 (d, J = 1.2 Hz, 1 H), 7.73 (d, J = 1.0 Hz, 1 H).
13C NMR: d = 19.4 (q), 28.2 (q), 112.6 (d), 114.2 (d), 115.4 (d),
116.6 (d), 117.5 (d), 123.8 (d), 125.4 (s), 125.5 (d), 128.7 (s), 129.3
(s), 165.5 (s).
Anal. Calcd for C16H14BrN3O (344.21): C, 55.83; H, 4.10; N, 12.21.
Found: C, 55.72; H, 3.97; N, 12.33.
Anal. Calcd for C13H12N2O (212.09): C, 73.56; H, 5.70; N, 13.20.
Found: C, 73.70; H, 5.55; N, 13.39.
N-(2-Bromopyridin-2-yl)-N-methyl-1H-indole-2-carboxamide
(3be)
Yield: 60%, mp 195–196 °C (ochre crystals from CH2Cl2–hexane).
IR (Nujol): 1632, 3183 cm–1.
2,5-Dimethylpyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one
(4ad)
Yield: 95% mp 241–244 °C (ivory crystals from Et2O).
1H NMR: d = 3.49 (s, 3 H), 5.31 (br s, 1 H), 7.06 (dd, J = 7.4, 7.6
Hz, 1 H), 7.26 (dd, J = 7.4, 7.9 Hz, 1 H), 7.40–7.47 (overlapping, 3
H), 7.77 (dd, J = 1.8, 7.7 Hz, 1 H), 8.56 (dd, J = 1.8, 4.7 Hz, 1 H),
9.77 (br s, 1 H, absent after deuteration).
IR (Nujol): 1650 cm–1.
1H NMR: d = 2.45 (s, 3 H), 3.77 (s, 3 H), 6.69 (dd, J = 1.2, 3.6 Hz,
1 H), 7.23 (d, J = 1.2 Hz, 1 H), 7.61 (d, J = 3.6 Hz, 1 H), 7.73 (s, 1
H), 8.19 (s, 1 H).
Synthesis 2005, No. 17, 2881–2886 © Thieme Stuttgart · New York

PAPER
Synthesis of Pyrrolo[1,2-a]quinoxalines and Indolo[1,2-a]quinoxalines
2885
13C NMR: d = 18.2 (q), 28.4 (q), 113.2 (d), 113.6 (d), 116.4 (d),
120.2 (s), 122.3 (d), 123.9 (s), 128.2 (s), 140.8 (s), 144.8 (d), 156.5
(s).
1H NMR: d = 2.53 (s, 3 H), 3.82 (s, 3 H), 7.41 (dd, J = 7.4, 7.6 Hz,
1 H), 7.55 (dd, J = 7.6, 8.2 Hz, 1 H), 7.62 (s, 1 H), 7.92 (d, J = 8.2
Hz, 1 H), 8.17 (s, 1 H), 8.20 (d, J = 7.4 Hz, 1 H), 8.37 (s, 1 H).
Anal. Calcd for C12H11N3O (213.14): C, 67.59; H, 5.20; N, 19.71.
Found: C, 67.70; H, 5.07; N, 19.90.
13C NMR: d = 20.6 (q), 29.7 (q), 107.5 (d), 111.6 (s), 114.1 (d),
122.9 (d), 123.2 (d), 123.9 (d), 126.0 (d), 128.3 (s), 128.4 (s), 129.7
(s), 134.7 (s), 142.7 (d), 157.6 (s).
5-Methylpyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (4ae)
Yield: 74%, mp 196–197 °C (ivory crystals from Et2O).
IR (Nujol): 1644 cm–1.
Anal. Calcd for C16H13N3O (263.30): C, 72.99; H, 4.98; N, 15.96.
Found: C, 72.80; H, 4.91; N, 15.88.
5-Methylpyrido[3¢,2¢:5,6]pyrazino[1,2-a]indol-6(5H)-one (4be)
1H NMR: d = 3.62 (s, 3 H), 6.67 (s, 1 H), 7.25–7.29 (overlapping, 2
H), 7.54 (d, J = 8.1 Hz, 1 H), 8.08 (s, 1 H), 8.20 (d, J = 7.4 Hz, 1 H).
13C NMR: d = 28.4 (q), 113.8 (d), 114.5 (d), 117.9 (d), 121.3 (d),
122.8 (d), 123.6 (s), 126.5 (s), 136.4 (s), 141.7 (d), 155.4 (s).
Yield: 74%, mp 197–199 °C (white crystals from CH2Cl2–hexane).
IR (Nujol): 1633 cm–1.
1H NMR: d = 3.69 (s, 3 H), 7.26 (dd, J = 7.3, 8.0 Hz, 1 H), 7.41 (dd,
J = 7.4, 7.5 Hz, 1 H), 7.54–7.60 (overlapping, 3 H), 7.86 (d, J = 8.0
Hz, 1 H), 8.35 (d, J = 7.3 Hz, 1 H), 9.21 (d, J = 8.5 Hz, 1 H).
13C NMR: d = 28.8 (q), 108.5 (d), 117.9 (d), 119.5 (d), 122.1 (d),
122.6 (d), 123.7 (d), 125.9 (s), 126.2 (d), 127.7 (s), 129.0 (s), 134.9
(s), 139.6 (s), 141.8 (d), 156.4 (s).
Anal. Calcd for C11H9N3O (199.21): C, 66.32; H, 4.55; N, 21.09.
Found: C, 66.44; H, 4.63; N, 20.90.
5-Methylindolo[1,2-a]quinoxalin-6(5H)-one (4ba)
Yield: 98%, mp 158–160 °C (cream crystals from CH2Cl2–hexane).
IR (Nujol): 1631 cm–1.
Anal. Calcd for C15H11N3O (249.27): C, 72.28; H, 4.45; N, 15.86.
Found: C, 72.41; H, 4.57; N, 15.93.
1H NMR: d = 3.71 (s, 3 H), 7.31–7.39 (overlapping, 4 H), 7.51 (ddd,
J = 0.8, 8.1, 8.6 Hz, 1 H), 7.58 (s, 1 H), 7.89 (d, J = 7.9 Hz, 1 H),
8.25 (d, J = 8.6 Hz, 1 H), 8.34 (d, J = 9.0 Hz, 1 H).
13C NMR: d = 29.3 (q), 107.2 (d), 114.6 (d), 115.7 (d), 115.9 (d),
122.8 (d), 123.6 (d), 123.8 (d), 124.5 (d), 125.7 (d), 127.0 (s), 128.5
(s), 129.6 (s), 130.2 (s), 134.6 (s), 156.9 (s).
Acknowledgment
The authors gratefully acknowledge the MIUR for financial sup-
port.
Anal. Calcd for C16H12N2O (248.29): C, 77.40; H, 4.87; N, 11.28.
Found: C, 77.52; H, 4.97; N, 11.37.
References
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Ramunno, A.; Armaroli, S.; Nacci, V.; Garofano, A.; Graco,
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2-Chloro-5-methylindolo[1,2-a]quinoxalin-6(5H)-one (4bb)
Yield: 77%, mp 204–206 °C (ivory crystals from CH2Cl2–hexane).
IR (Nujol): 1627 cm–1.
1H NMR: d = 3.63 (s, 3 H), 7.10 (d, J = 7.3 Hz, 1 H), 7.17 (d,
J = 7.0 Hz, 1 H), 7.23 (s, 1 H), 7.33 (dd, J = 7.3, 7.6 Hz, 1 H), 7.50
(dd, J = 7.0, 7.6 Hz, 1 H), 7.82 (d, J = 8.0 Hz, 1 H), 8.14 (d, J = 8.0
Hz, 1 H), 8.24 (s, 1 H).
13C NMR: d = 29.9 (q), 107.8 (d), 114.3 (d), 115.7 (d), 116.9 (d),
123.2 (d), 123.6 (d), 124.2 (d), 126.1 (d), 127.9 (s), 128.2 (s), 128.8
(s), 128.9 (s), 129.4 (s), 134.7 (s), 156.5 (s).
Anal. Calcd for C16H11ClN2O (282.73): C, 67.97; H, 3.92; N, 9.91.
Found: C, 67.80; H, 3.97; N, 9.84.
2,5-Dimethylindolo[1,2-a]quinoxalin-6(5H)-one (4bc)
Yield: 66%, mp 216–217 °C (ivory crystals from Et2O).
IR (Nujol): 1627 cm–1.
1H NMR: d = 2.54 (s, 3 H), 3.71 (s, 3 H), 7.14 (d, J = 8.4 Hz, 1 H),
7.27 (d, J = 8.4 Hz, 1 H), 7.38 (dd, J = 7.0, 7.4 Hz, 1 H), 7.53 (ddd,
J = 1.0, 7.0, 8.6 Hz, 1 H), 7.59 (s, 1 H), 7.90 (d, J = 7.4 Hz, 1 H),
8.18 (s, 1 H), 8.30 (d, J = 8.6 Hz, 1 H).
13C NMR: d = 21.6 (q), 29.3 (q), 107.1 (d), 114.7 (d), 115.8 (d),
116.3 (d), 122.7 (d), 123.6 (d), 125.2 (d), 125.5 (d), 127.0 (s), 128.0
(s), 128.7 (s), 129.6 (s), 133.5 (s), 134.6 (s), 156.9 (s).
Anal. Calcd for C17H14N2O (262.31): C, 77.84; H, 5.38; N, 10.68.
Found: C, 77.71; H, 5.43; N, 10.79.
2,5-Dimethylpyrido[2¢,3¢:5,6]pyrazino[1,2-a]indol-6(5H)-one
(4bd)
Yield: 69%, mp 145 °C (cream crystals from Et2O–hexane).
IR (Nujol): 1630 cm–1.
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