Synthesis of pyrrole and indole quinoxalinone and oxazinone derivatives by intramolecular copper-catalyzed reactions

Article abstract of DOI:10.1039/c1ob05269a

Intramolecular N-arylation of pyrrole and indole carboxamides and carboxylates linked with a pendant haloarene by Cu-catalyzed reactions to synthesize pyrrole and indole quinoxalinone and oxazinone derivatives is reported. The ring closure reactions were carried out by conventional heating and MW irradiation. The use of conventional heating affords moderate to good yields of the quinoxalinone and oxazinone derivatives (34-72%), while by using MW heating the best results are obtained (41-99%). The Royal Society of Chemistry 2011.

Full text of DOI:10.1039/c1ob05269a

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PAPER
Synthesis of pyrrole and indole quinoxalinone and oxazinone derivatives by
intramolecular copper-catalyzed reactions†
Victoria A. Vaillard, Roberto A. Rossi* and Sandra E. Mart´ın*
Received 18th February 2011, Accepted 31st March 2011
DOI: 10.1039/c1ob05269a
Intramolecular N-arylation of pyrrole and indole carboxamides and carboxylates linked with a pendant
haloarene by Cu-catalyzed reactions to synthesize pyrrole and indole quinoxalinone and oxazinone
derivatives is reported. The ring closure reactions were carried out by conventional heating and MW
irradiation. The use of conventional heating affords moderate to good yields of the quinoxalinone and
oxazinone derivatives (34–72%), while by using MW heating the best results are obtained (41–99%).
Quinoxalinones have been also used as building blocks to
obtain indolo and pyrrolo[1,2-a]quinoxalines with oral antiallergic
Introduction
activity,9 HIV-1 reverse transcriptase inhibitory activity10 and an-
timalarial activity.11 Oxazinones also constitute an important class
of heterocycles, which has attracted much synthetic interest due
to its wide range of biological activities.12 Many benzoxazinones
exhibit diverse pharmacological properties, such as antitumor,13
antiviral,14 antithrombotic,15 antiinflammatory16 antidiabetic and
hypolipidaemic17 effects. Additional, they have been reported as
inhibitors of human leukocyte elastase18 and serotonin reup-
take.19
However, despite the growing, general, and widespread interest
of medicinal chemistry in these structures, there are relatively
few synthetic routes leading to quinoxalinones.7 Particularly, the
construction of pyrrolo[1,2-a]quinoxalines was commonly estab-
lished from 2-nitroanilines and proceeds in three steps including
the cyclization with triphosgene.11,20 These approaches suffer
from a limited number of suitable substrates and inconvenient
processes. Recently, the Pd-catalyzed intramolecular C–N bond
formation strategy from 2-haloanilines and pyrrole-2-carboxylic
acids was described.21 However, the preliminary methylation of
the commercially available 2-haloanilines limits the scope of this
method. Thus, there is a special need for developing a new
methodology that would allow access to this type of quinoxaline
derivative.
Ma and Yuan22 have synthesized a family of pyrrolo[1,2-
a]quinoxalines, by means of CuI/L-proline system starting from
2-halotrifluoroacetanilides with pyrrole-2-carboxylate esters. The
same procedure has been used to provide tetracyclic products from
indole-2-carboxylate esters. In similar approaches, aza-fused poly-
cyclic quinolines23 and pyrrolo[1,2-a]quinoxaline24 were obtained
by Cu-catalyzed cascade reactions. Additionally, pyrazolo[1,5-
a]benzimidazoles were achieved by intramolecular Cu-catalyzed
reaction.25 In this case, when different Pd/ligand systems were used
to afford the C–N bond, only low yields were obtained. Therefore,
Cu-catalyzed reactions appear to be an efficient strategy to carry
out intramolecular arylation of heterocycles.
The century-old Cu-mediated arylation of amines, the classical
Ullmann reaction, has been known as a powerful reaction for
C–N bond formation,1 although the scope of this reaction was
limited by the use of a stoichiometric amount of Cu and harsh
reaction conditions. However, in the past few years this reaction
has been considerably revitalized by the introduction of Cu-
catalyzed Ullmann-type reactions and by the development of
new procedures.2 The renewed interest in Ullmann-type reactions
was principally developed due to the discovery of versatile and
efficient Cu salts with several ligand systems that allowed the
use of catalytic amounts of the metal under mild conditions.3
Cu-catalyzed reactions have been the preferred method for the
N-arylation of pyrroles, indoles, pyrazoles, indazoles, imidazoles,
and triazoles.3a,4 In addition to intermolecular N-arylation, Cu-
catalysis has been further extended for the synthesis of nitrogen
heterocycles involving intramolecular N-arylation.5
Nitrogen-containing heterocycles constitute the main structure
within a large number of natural products, pharmacologically ac-
tive compounds and organic materials.6 Particularly, quinoxaline
derivatives have received much attention in recent years owing
to their well-known biological properties and pharmaceutical
applications. The quinoxalinone moiety is frequently found in
compounds displaying a variety of medicinal properties, such as
anticancer, anxiolytic, antimicrobial, analgesic and antiallergic
activity.7 Many of these biologically active quinoxalinone com-
pounds have been tested in clinical trials.8
INFIQC, Departamento de Qu´ımica Orga´nica, Facultad de Ciencias
Qu´ımicas, Universidad Nacional de Co´rdoba, 5000 Co´rdoba, Argentina.
E-mail: martins@fcq.unc.edu, rossi@fcq.unc.edu.ar; Fax: +54 351 4333030
Int. 151; Tel: +54 351 4334170/73
† Electronic supplementary information (ESI) available: Supplementary
data associated with experimental details, spectroscopic data for all
compounds and 1H NMR and 13C NMR spectra, as well as COSY 1H–1H
and HSQC 1H–13C NMR experiments for products 3a–f and 5a–d. See
DOI: 10.1039/c1ob05269a
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In general, these catalyzed reactions require long reaction times.
Direct and rapid heating by microwave (MW) irradiation in many
cases enables reactions to be carried out in a fraction of the time
generally required using conventional heating.26 MW irradiation
has been used in several Cu-catalyzed reactions and excellent yields
have been obtained in short times.27
The pyrrole and indole ester derivatives 1f–g and 2d were
synthesized by formation of the 1,1¢-carbonyldiimidazole (CDI)
intermediates followed by reaction with 2-halophenol (Scheme 3).
Herein, we report a practical and efficient route to pyrrole
and indole quinoxalinone and oxazinone derivatives from pyrrole
and indole carboxamides and carboxylates via Cu-catalyzed
intramolecular arylation of the NH group in the heterocyclic
moiety (Scheme 1). We also compare the use of the conventional
heating vs. MW irradiation in these reactions.
Scheme 3 Synthesis of pyrrole and indole ester derivatives.
Cu-catalyzed intramolecular N-arylation. Optimization of
reaction conditions
Scheme 1 Cu-catalyzed intramolecular N-arylation.
The Cu-catalyzed intramolecular reaction of the N-(2-
bromophenyl)-1H-pyrrole-2-carboxamide (1a) was investigated as
a model reaction under different reaction conditions, the results of
which are shown in Table 1. For this reaction, time, temperature
and solvents (entries 1–3, Table 1) as well as bases (entries 4–6,
Table 1) and ligands (entries 7–9, Table 1) were evaluated.
The best yield of 3a was obtained when the reaction was carried
out with 10 mol% of CuI in the presence of 20 mol% of L-proline
and 2.5 equiv of NaH in dioxane at 110 ◦C for one hour (entry 3,
Table 1). Similar results were found when the reaction was carried
out under the same conditions in DMF at reflux (entry 2, Table
1). Screening of different bases established that the strongest base
NaH was clearly superior to weaker bases such as K2CO3, K3PO4
and Cs2CO3 (entries 4–6, Table 1). Among the different bidentate
ligands evaluated for the cyclization (entries 8 and 9, Table 1), L-
proline led to the highest yield of 3a. The effect of varying ligand
loading on cyclization was found to be relatively negligible (entry
7, Table 1). Moreover, when the reaction was performed without
ligand, 64% of 3a was obtained (entry 10, Table 1). This behaviour
can be explained on the basis of the ortho-substituent effect
previously described.28 In some cases, substrate 1a was recovered
(entries 1, 6, 7, 9 and 10, Table 1) and debrominated product 4a
was observed (entries 1–5, Table 1). Control experiments showed
that in the reaction carried out in the absence of catalyst; only 48%
of 1a was recovered, while no product was detected.
Results and discussion
Synthesis of pyrrole and indole carboxamides and ester derivatives
1a–g and 2a–d
The pyrrole and indole carboxamides 1a–e and 2a–c required
to carry out the cyclizations were obtained by the reaction of
commercially available 2-carboxylic acid of pyrrole and indole
with an excess of oxalyl chloride to form the acid chloride
derivatives. Without isolation, the acid chloride reacts with 2-
haloanilines to give the corresponding amides in moderate to good
isolated yields (Scheme 2). We were unable to achieve the pyrrole
carboxamide substituted with a NO2 group.
We then evaluated the intramolecular N-arylation reaction of
pyrrole carboxamide 1a by using MW irradiation. Since similar
results were obtained with dioxane and DMF as solvent in the
cyclization reaction, we decided to use DMF, due to the solvent
being more sensitive to MW irradiation.29 We started with the
optimized reaction conditions in DMF (entry 2, Table 1) and
explored different methods and systems for MW irradiation, such
as dynamic heating at fixed temperature in an open vessel or fixed
power in a sealed pressurized system. The results are summarized
in the Table 2.
It is remarkable that for all reactions under MW irradiation
the debrominated product 4a was not observed. When the open
Scheme 2 Synthesis of pyrrole and indole carboxamides.
4928 | Org. Biomol. Chem., 2011, 9, 4927–4935
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Table 1 Optimization of reaction conditions for the Cu-catalyzed synthesis of pyrrolo[1,2-a]quinoxalin-4(5H)-one (3a)a
Entry
Ligand
Base
Solvent/Temperature
DMF/90 ◦
Yield 3ab
Yield 4ab
Conversion
1c
2
3
4
5
L-proline
L-proline
L-proline
L-proline
L-proline
L-proline
L-proline
DMEDAe
1,10-phenf
—
NaH
NaH
NaH
K2CO3
K3PO4
Cs2CO3
NaH
NaH
NaH
C
30%
66%
73%
62%
50%
20%
68%
68%
36%
64%
—
20%
20%
18%
9%
10%
—
—
—
—
—
50%
100%
100%
100%
100%
53%
69%
100%
45%
DMF/reflux
dioxane/110 ◦
DMF/reflux
DMF/reflux
DMF/reflux
DMF/reflux
DMF/reflux
DMF/reflux
DMF/reflux
DMF/reflux
C
6
7d
8
9
10
NaH
NaH
83%
52%
11g
—
—
a The reactions were performed using 0.25 mmol of substrate, 10 mol% of CuI, 20 mol% of ligand and 0.62 mmol of base in 2.5 mL of anhydrous
DMF or dioxane under N2 atmosphere for 1 h. b Yields were determined by GC (internal standard method). c 24 h. d 10 mol% of L-proline. e N,N-
dimethylethylenediamine. f 1,10-phenanthroline. g Without CuI.
Table 2 Different reaction conditions for the Cu-catalyzed synthesis of 3a from 1a under MW irradiation
Entry
MW conditions
System
Yield 3aa
Conversion
1
2
3
4
5
6
Dynamic method: 2 min 130 ◦C–3 min 140 ◦
Dynamic method: 3 min 140 ◦C–7 min 150 ◦
Dynamic method; 2 min 140 ◦C–3 min 150 ◦
C
C
C
Open-vessel
Open-vessel
Sealed-vessel
Sealed-vessel
Sealed-vessel
Sealed-vessel
33%
57%
82%
64%
82%
99%
66%
60%
88%
86%
100%
100%
Dynamic method; 12 min 150 ◦
C
Fixed Power 50 w; 10 min 140–160 ◦
Fixed Power 50 w; 5 min 140–160 ◦
C
C
a Yields were determined by GC (internal standard method).
vessel system was used, substrate 1a was recovered in high amount
(entries 1 and 2, Table 2). As expected, MAOS in sealed-vessel
techniques provided more satisfactory results. The best system
for the cyclization reaction was that using a sealed-vessel in a
pressurized system and when a fixed power of 50 watts was applied,
reducing the reaction times (entry 6, Table 2).
The presence of substituents such as methyl and chloride groups
on the aryl moiety in the para position decreased the yields of the
ring closed products (entries 2–3, Table 3). Moreover, for chlorine
derivative 1c, a high amount of reduction product was observed
(entry 3, Table 3). With the pyrrole carboxamide 1d a complex
mixture of products and hydrolyzed substrate was achieved under
conventional and MW heating. Using K2CO3 as base and only
under MW irradiation the product 3d was obtained in 32% yield
(entry 4, Table 3). Our general reaction conditions were effective
to acquire benzo[h]pyrrolo[1,2-a]quinoxalin-4(5H)-one 3e (entry
5, Table 3).
Synthesis of pyrrole and indole quinoxalinone and oxazinone deri-
vatives
Once the reaction conditions with pyrrole carboxamide 1a had
been thoroughly optimized, we examined the scope and generality
of the method by exploring the effects of aryl substituents in pyr-
role and indole carboxamides 1b–e and 2a–c on the intramolecular
cyclization to obtain quinoxalines. In addition, we evaluated the
possibility of extending the methodology to achieve oxazinone
derivatives by employing pyrrole and indole esters 1f–g and 2d.
The results are summarized in the Table 3.
For all substrates, the best results were accomplished when the
reaction was carried out under MW irradiation, where higher
yields in lower reaction times were achieved. Furthermore, in
MW heated reactions only traces of dehalogenated products were
observed and the reaction mixtures were cleaner than those when
conventional heating was applied.
To further develop the described methodology, we carried out
the intramolecular N-arylation with esters. The ester 1f did not
provide any cyclization product under the optimized conditions,
and only 2-bromophenol was found as product (entry 6, Table 3).
No improvement was found by using a weaker base such as K2CO3
under conventional heating or MW irradiation, and only 1f was
recovered (entry 7, Table 3). When the halogen of the pyrrolo ester
was iodide, 41% of product 3f was achieved under MW irradiation
(entry 8, Table 3). However, the reaction was successfully carried
with 1g when K2CO3 was used as base. The yields of 3f were
increased by both conventional heating (72%, entry 9, Table 3)
and MW irradiation (92%, entry 9, Table 3).
The amide derivatives from indole required longer reaction
times under conventional heating. For instance, substrate 2a did
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Table 3 Synthesis of benzo-quinoxaline and oxazinone derivatives from pyrrole and indole systemsa
Conventional heatinga,b
Time (min)
Yield (%)d
MW heatinga,c
Entry
1
Substrate
Product
Time (min)
5
Yield (%)d
99 (91)
1a
3a
60
66
2
1b
1c
1d
1e
3b
3c
3d
3e
60
120
60
40
34
—
40
5
25
5
58 (48)
44 (40)
32 (19)
61 (54)
3
4e
f
5
60
5
g
h
g
6
1f
3f
3f
5a
60
60
—
—
5
5
—
—
h
7e
i
8
1g
2a
60
60
—
72
5
5
41
9e
92 (81)
10
11
60
120
56j
67
5
87 (80)
73 (65)
12
2b
5b
120
60
5
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Table 3 (Contd.)
Conventional heatinga,b
MW heatinga,c
Entry
13
Substrate
Product
Time (min)
120
Yield (%)d
Time (min)
5
Yield (%)d
77 (68)
2c
5c
58
14
2d
5d
120
—
5
41 (32)
a The reactions were performed using 0.25 mmol of substrate, 10 mol% of CuI, 20 mol% L-proline and 0.62 mmol of NaH (2.5 equiv) in 2.5 mL of
anhydrous DMF under N2 atmosphere. b Conventional heating, 140 ◦C. c MW irradiation, sealed-vessel at fixed power (50 watts), 140–160 ◦C. d Yields
were determined by GC (internal standard method). Isolated yields in brackets. e K2CO3 was used as base. f Complex mixture of products and hydrolyzed
substrate was observed. g 2-Bromophenol as hydrolyzed substrate was observed. h Substrate without reaction was recovered. i 2-Iodophenol as hydrolyzed
substrate was observed. j 26% of substrate was recovered.
not react completely after 1 h (entry 10, Table 3), and 2 h were
needed to complete the reaction (entry 11, Table 3). Therefore, this
reaction time was used for all indole derivatives. Excellent yields
of indolo quinoxalinone 5a were observed with MW irradiation
(entry 10, Table 3). The intramolecular N-arylation of substituted
indole derivatives gave very good yields of the corresponding
quinoxalinones when MW irradiation was applied (entries 12 and
13). However, in the same reaction conditions the indolo ester 2d
afforded product 5d in moderate yield (entry 14, Table 3).
carbonyldiimidazole, 2-bromo-4-methylaniline, sodium hydride,
potassium carbonate, potassium phosphate, caesium carbonate,
L-proline, 1,10-phenanthroline, N,N-dimethylethylendiamine and
CuI were commercially available and used as received from the
supplier. 2-Bromo-4-chloroaniline 4-amino-3-bromobenzonitrile,
2-bromo-4-nitroaniline and 1-bromo-2-naphthylamine were ob-
tained by reported methods.30 THF and DMF were dried and store
˚
under nitrogen, over molecular sieves (4 A). The purification of
compounds was carried out by chromatography column on silica
gel or by radial thin layer chromatography. In all purifications
analytical grade solvents were distilled before used.
Conclusions
1H NMR (400.16 MHz) and 13C NMR (100.62 MHz) were
conducted on a High Resolution Spectrometer Bruker Advance
400 in Cl3CD or DMSO-d6 as a solvent otherwise indicated, and
referenced with residual solvent signal. Gas Chromatographic
(GC) analyses were performed on an instrument with a flame
ionization detector equipped with a VF-5ms column (30 m ¥
0.25 mm ¥ 0.25 mm). Gas Chromatographic-Mass Spectrometer
analyses were carried out on a GC-MS QP 5050 equipped with
a quadrupole detector and a VF-5ms column (30 m ¥ 0.25 mm
¥ 0.25 mm). High Resolution Mass Spectra were performed in a
MS/MS instrument on pure products. These data were obtained
by ESI or APPI mode ionization and TOF detection. Melting
points were performed with an electrical instrument and are
uncorrected. MW-induced reactions were performed in a CEM
Focused MicrowaveTM Synthesis System, Model Discover single
mode instrument equipped with non-contact infrared sensor
to measure the temperature, direct pressure control system by
measurement of pressure of the reaction vessel contents and
We have developed a practical and efficient synthetic approach
to obtain new quinoxalinones and oxazinones derived from
pyrrole and indole by intramolecular Cu-catalyzed Ullmann-type
reactions. We also established that MW-assisted organic synthesis
is a useful tool to carry out these reactions, rapidly and in high
yields.
In addition, the interest in this simple methodology is further
enhanced by the potential usefulness of pyrrole and indole
quinoxalinones and oxazinone derivatives as building blocks to
achieve compounds with biological applications.
Experimental section
General
1H-pyrrole-2-carboxylic acid, 1H-indole-2-carboxylic acid, oxalyl
chloride, 2-bromoaniline, 2-bromophenol, 2-iodophenol, 1,1¢-
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cooling system by compressed air. Quantification by GC was
performed by the Internal Standard Method.
289 (5), 210 (15), 94 (100), 66 (26). HRMS (ESI) [M+ H+] calcd.
for C12H8BrN3O 289.9924, found 289.9931.
N-(1-Bromonaphthalen-2-yl)-1H-pyrrole-2-carboxamide (1e)
This compound was obtained following procedure for 1a. The
Procedure for the preparation of N-(2-bromophenyl)-1H-pyrrole-
2-carboxamide (1a)
◦
1
product was isolated as white solid, mp: 258–260 C. H NMR
(400 MHz, CDCl3) d: 6.36 (m, 1H), 6.89 (m, 1H), 7.05 (m, 1H),
7.46 (m, 1H), 7.59 (m, 1H), 7.83 (t, 2H, J = 8.9 Hz), 8.18 (d, 1H,
J = 8.5), 8.50 (bs, 1H), 8.62 (d, 1H, J = 8.9 Hz), 9.49 (bs, 1H).
13C NMR (100 MHz, CDCl3) d: 110.3, 110.6, 111.3, 120.5, 122.9,
125.4, 126.0, 126.5, 127.8, 128.2, 128.4, 131.4, 132.1, 134,4, 158.9.
GC-MS (m/z): 316 (13), 314 (M+,13), 296 (20), 295 (13), 285 (20),
284 (10), 268 (13), 257 (11), 247 (10), 236 (27), 235 (98), 234 (11),
226 (12), 224 (31), 223 (100), 222 (20), 221 (88), 207 (53), 170 (10),
166 (18), 163 (12), 162 (17), 160 (11), 151 (11), 144 (15), 142 (12),
141 (31), 140 (29), 126 (20), 119 (20), 118 (15), 114 (22), 113 (19),
105 (20), 101 (15), 95 (29), 94 (36), 69 (11), 66 (43). HRMS (ESI)
[M+ Na+] calcd. for C15H11BrN2O 336.9947, found 336.9971.
1-H-Pyrrole-2-carboxylic acid (2.00 mmol, 222 mg) was heated
at 50 ◦C under nitrogen in oxalyl chloride (1 mL) for 1 h. The
oxalyl chloride was then evaporated, and the resulting solid was
dissolved in anhydrous dichloromethane (3 mL). The reaction was
cooled in an ice bath and 2-bromoaniline (5.0 mmol, 860 mg)
was added. After addition, the mixture was warmed to r.t.
and stirred overnight. Water (100 mL) was then added and the
reaction mixture was extracted with dichloromethane (3 ¥ 30 ml).
The organic layer was dried with sodium sulphate, filtered and
concentrated under vacuum. The pure product was obtained by
chromatography (silica gel, petroleum ether/dichloromethane).
The product was isolated as a white solid, mp: 172–174 ◦C (lit:31
174–177 ◦C). 1H NMR (400 MHz, CDCl3) d: 6.31 (m, 1H), 6.80
(m, 1H), 7.00 (m, 2H), 7.34 (m, 1H), 7.56 (dd, 1H, J = 8.0 Hz,
1.5 Hz), 8.24 (bs, 1H), 8.48 (dd, 1H, J = 8.3 Hz, 1.5 Hz), 10.18 (bs,
1H). 13C NMR (100 MHz, CDCl3) d: 110.2, 110.3, 113.4, 121.4,
123.2, 124.8, 125.8, 128.5, 132.3, 135.8, 159.0. GC-MS (m/z): 265
(13), 264 (M+, 11), 263 (21), 261 (21), 91 (100), 65 (13). The
spectroscopic data agree with those of the literature.31
N-(2-Bromophenyl)-1H-indole-2-carboxamide (2a)
This compound was obtained following the procedure applied for
1a. The product was isolated as a white solid, mp: 216–218 ◦C.
1H NMR (400 MHz, CDCl3) d: 7.03 (td, 1H, J = 7.6 Hz, 1.5 Hz),
7.09 (d, 1H, J = 1.7 Hz), 7.18 (m, 1H), 7.36 (m, 2H), 7.48 (dd, 1H,
J = 8.4 Hz, 0.7 Hz), 7.60 (dd, 1H, J = 8.1 Hz, 1.4 Hz), 7.72 (d,
1H, J = 8.1 Hz), 8.54 (m, 2H), 9.51 (bs, 1H). 13C NMR (100 MHz,
CDCl3) d: 103.2, 112.1, 113.5, 121.1, 121.6, 122.3, 125.2, 125.3,
127.6, 128.6, 130.5, 132.4, 135.5, 136.8, 159.4. GC-MS (m/z): 316
(16), 314 (M+, 14), 236 (16), 235 (90), 145 (12), 144 (100), 143
(29), 118 (23), 116 (23), 89 (60). HRMS (ESI) [M+ H+] calcd. for
C15H11BrN2O 315.0128, found 315.0137.
N-(2-Bromo-4-methylphenyl)-1H-pyrrole-2-carboxamide (1b)
This compound was obtained following the procedure used for
1a. The product was isolated as a white solid, mp: 182–183 ◦C. 1H
NMR (400 MHz, CDCl3) d: 2.32 (s, 3H), 6.31 (m, 1H), 6.78 (m,
1H), 7.01 (m, 1H), 7.15 (dd, 1H, J = 8.5 Hz, 1.0 Hz), 7.40 (d, 1H,
J = 1.1 Hz), 8.12 (bs, 1H), 8.30 (d, 1H, J = 8.3 Hz), 9.69 (bs, 1H).
13C NMR (100 MHz, CDCl3) d: 20.5, 109.9, 110.3, 113.2, 121.3,
122.7, 126.0, 129.1, 132.5, 133.2, 134.0, 158.8. GC-MS (m/z): 280
(16), 279 (8), 278 (M+, 18), 199 (52), 198 (10), 78 (20). HRMS
(ESI) calcd. for C12H12BrN2O [M+ H+] 279.0128, found 279.0129.
N-(2-Bromo-4-methylphenyl)-1H-indole-2-carboxamide (2b)
This compound was obtained following the procedure used for
1a. The product was isolated as a white solid, mp: 259–260 ◦C
1
(decompose). H NMR (400 MHz, CDCl3) d: 2.34 (s, 3H), 7.08
(m, 1H), 7.19 (m, 2H), 7.33 (m, 1H), 7.43 (d, 1H, J = 1.3 Hz),
7.47 (dd, 1H, J = 8.3 Hz, 0.8 Hz), 7.72 (dd, 1H, J = 8.0 Hz,
0.7 Hz), 8.38 (d, 1H, J = 8.3 Hz), 8.43 (bs, 1H), 9.42 (bs, 1H).
13C NMR (100 MHz, CDCl3) d: 20.6, 103.0, 112.0, 113.4, 121.0,
121.4, 122.2, 125.1, 127.7, 129.2, 130.6, 132.6, 132.9, 135.4, 136.7,
159.3. GC-MS (m/z): 330 (18), 328 (M+, 13), 250 (28), 249 (100),
187 (29), 185 (25), 144 (83), 143 (20), 124 (13), 116 (34), 115 (13),
106 (14), 89 (79), 77 (16), 63 (10). HRMS (ESI) [M+ H+] calcd.
for C16H13BrN2O 329.0284, found 329.0294.
N-(2-Bromo-4-chlorophenyl)-1H-pyrrole-2-carboxamide (1c)
This compound was obtained following the procedure appl◦ied for
1a. The product was isolated as a white solid, mp: 210–212 C. 1H
NMR (400 MHz, CDCl3) d: 6.33 (m, 1H), 6.79 (m, 1H), 7.32 (dd,
1H, J = 8.9 Hz, 2.5 Hz), 7.57 (d, 1H, J = 2.5 Hz), 8.14 (bs, 1H), 8.43
(d, 1H, J = 8.9 Hz), 9.46 (bs, 1H). 13C NMR (100 MHz, CDCl3) d:
110.2, 110.6, 113.3, 121.9, 123.0, 125.7, 128.6, 129.0, 131.7, 134.6,
158.6. GC-MS (m/z): 300 (7), 299 (M+, 2), 298 (10), 219 (23), 209
(11), 207 (59), 205 (46), 94 (100), 66 (49), 63 (11). HRMS (APPI)
[M+ H+] calcd. for C11H8BrClN2O 300.9560, found 300.9585.
N-(2-Bromo-4-chlorophenyl)-1H-indole-2-carboxamide (2c)
This compound was obtained following the procedure adopted
for 1a. The product was isolated as a white solid, mp: 195–197 ◦C.
1H NMR (400 MHz, CDCl3) d: 7.08 (d, 1H, J = 1.5 Hz), 7.20
(m, 1H), 7.37 (m, 1H), 7.47 (dd, 1H, J = 8.3 Hz, 0.8 Hz), 7.61
(d, 1H, J = 2.3 Hz), 7.72 (dd, 1H, J = 8.0 Hz, 0.8 Hz), 8.44 (bs,
1H), 8.50 (d, 1H, J = 8.9 Hz), 9.20 (bs, 1H). 13C NMR (100 MHz,
CDCl3) d: 107.0, 111.3, 111.7, 120.1, 121.1, 122.1, 124.2, 125.2,
125.6, 128.1, 130.8, 137.6, 140.5, 150.8, 158.4. GC-MS (m/z):353
(3), 350 (M+, 3), 348 (3), 269 (18), 145 (11), 144 (100), 143 (20),
N-(2-Bromo-4-cyanophenyl)-1H-pyrrole-2-carboxamide (1d)
This compound was obtained following the procedure applied for
1a. The product was isolated as a white, mp: 214.6–215.1 ◦C. 1H
NMR (400 MHz, CDCl3) d: 6.36 (m, 1H), 6.84 (m, 1H), 7.07 (m,
1H), 7.63 (dd, 1H, J = 8.6 Hz, 1.9 Hz), 7.86 (d, 1H, J = 1.9 Hz),
8.38 (bs, 1H), 8.68 (d, 1H, J = 8.6 Hz), 9.40 (bs, 1H). 13C NMR
(100 MHz, CDCl3) d: 110.9, 111.0, 111.6, 117.5, 119.7, 120.5,
123.8, 129.1, 132.6, 135.7, 140.1, 158.6. GC-MS (m/z): 291 (6),
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116 (24), 115 (11), 89 (80), 63 (25). HRMS (ESI) [M+ Na+] calcd.
for C15H10BrClN2O 370.9557, found 370.9576.
General procedure for the preparation of pyrrolo[1,2-a]quinoxalin-
4(5H)-one 3a–e, indolo[1,2-a]quinoxalin-6(5H)-one 5a–c and
oxazinones 3f and 5d under MW-assisted heating
Procedure for the preparation of 2-bromophenyl-1H-pyrrole-
2-carboxylate (1f)
A tube was charged with 10 mol% of CuI (0.025 mmol, 5.0 mg),
20 mol% of L-proline (0.05 mmol, 6.0 mg), amide or ester derivative
(0.25 mmol, 1 equiv) and NaH (0.62 mmol, 15 mg, 2.5 equiv)
in 2.5 mL of anhydrous DMF and under nitrogen. Then the
tube was sealed with a rubber cap and heated to 140–160 ◦C
for 5 min under MW irradiation (Fixed Power, 50 W) using air
cooling. After that, the reaction was cooled to r.t. and the crude
was then filtered through a short column of silica gel and eluted
with dichloromethane. DMF was evaporated under vacuum.
The pure product was obtained by chromatography (silica gel,
petroleum/ethyl ether).
A mixture of 1H-pyrrole-2-carboxylic acid (2.00 mmol, 222 mg)
and CDI (2.20 mmol, 357 mg) in dry THF, under nitrogen,
was heated at reflux for 3 h. Then, the reaction was cooled
to r.t. and 2-bromophenol (2.00 mmol, 346 mg) was added
and stirred for 24 h. The solvent was evaporated under vac-
uum. The pure product was obtained by chromatography (silica
1
gel, petroleum/dichloromethane), as transparent oil. H NMR
(400 MHz, CDCl3) d: 6.33 (m, 1H), 7.03 (m, 1H), 7.11 (m, 1H),
7.23 (dd, 1H, J = 8.1 Hz, 1.69 Hz), 7.33 (m, 1H), 7.60 (dd, 1H, J =
8.1 Hz, 1.54 Hz), 9.23 (bs, 1H). 13C NMR (100 MHz, CDCl3) d:
111.1, 116.5, 117.5, 121.4, 124.0, 124.3, 127.3, 128.5, 133.4, 148.0,
158.3. GC-MS (m/z): 267 (2), 265 (M+, 2), 94 (100), 66 (21).
HRMS (ESI) calcd. for C11H8INO2 [M+ H+] 265.9816, found
265.9811.
N-Phenyl-1H-pyrrole-2-carboxamide (4a)
This compound was obtained following the procedure described
for 1a. The product was isolated as a white solid, mp: 181–182 ◦C.
1H NMR (400 MHz, CDCl3) d: 6.27 (m, 1H), 6.77 (m, 1H), 6.97
(m, 1H), 7.11 (m, 1H), 7.34 (m, 2H), 7.62 (m, 1H), 7.89 (bs, 1H),
8.02 (bs, 1H), 9.99 8bs, 1H). 13C NMR (100 MHz, CDCl3) d: 104.2,
109.9, 110.1, 120.1, 122.5, 124.1, 126.1, 129.0, 137.9, 159.3, 162.7.
GC-MS (m/z): 186 M+, 25), 94 (47), 93 (100), 66 (31). HRMS
(ESI) calcd. for C11H10N2O [M+ H+] 187.0866, found 187.0866.
2-Iodophenyl-1H-pyrrole-2-carboxylate (1g)
This compound was obtained following the procedure carried out
for 1f. The product was isolated as a yellowish solid, mp: 80–81 ◦C.
1H NMR (400 MHz, CDCl3) d: 6.38 (m, 1H), 7.00 (td, 1H, J =
7.6 Hz, 1.4 Hz), 7.08 (m, 1H), 7.21–7.26 (m, 2H), 7.40 (m, 1H), 7.86
(dd, 1H, J = 8.1 Hz, 1.44 Hz), 9.33 (bs, 1H). 13C NMR (100 MHz,
CDCl3) d: 90.5, 111.1, 117.6, 121.7, 123.3, 124.3, 127.5, 129.4,
139.4, 150.8, 158.3. HRMS (ESI) calcd. for C11H8INO2 [M+ Na+]
335.9492, found 335.9488.
Pyrrolo[1,2-a]quinoxalin-4(5H)-one (3a)
This compound was obtained following the procedure described
for the MW-assisted reactions. The product was isolated as a white
◦
1
solid, mp: 188.5–190.5 C. H NMR (400 MHz, CDCl3) d: 6.38
(m, 1H), 7.05 (m, 1H), 7.10 (m, 1H), 7.32 (m, 2H), 7.54 (m, 1H),
7.66 (m, 1H), 10.51 (bs, 1H). 13C NMR (100 MHz, CDCl3) d:
110.4, 110.8, 113.2, 118.8, 119.8, 123.0, 124.4, 124.6, 141.8, 150.2,
158.2. 185 (13), 184 (M+, 100), 92 (11), 64 (13), 63 (13). The
spectroscopic data agree with those of the literature.22
2-Iodophenyl-1H-indole-2-carboxylate (2d)
This compound was obtained following the procedure used for
1f. The product was isolated as a white solid, mp: 174–176 ◦C
1
(decompose). H NMR (400 MHz, CDCl3) d: 7.04 (td, 1H, J =
7.6 Hz, 1.5 Hz), 7.20 (m, 1H), 7.30 (dd, 1H, J = 8.2 Hz, 1.3 Hz),
7.36–7.47 (m, 3H), 7.55 (m, 1H), 7.76 (dd., 1H, J = 8.1 Hz,
0.6 Hz), 7.89 (dd, 1H, J = 7.9 Hz, 1.5 Hz), 9.04 (bs, 1H). 13C
NMR (100 MHz, CDCl3) d: 90.3, 111.1, 112.1, 121.2, 123.0, 123.2,
126.0, 126.2, 127.5, 127.8, 129.5, 137.4, 139.6, 150.8, 159.3. GC-
MS (m/z): 363 (M+, 8), 355 (5), 270 (26), 236 (46), 207 (37), 115
(12), 114 (149, 94 (100), 73 (22), 66 (17). HRMS (ESI) calcd. for
C15H11INO2 [M+ H+] 363.9829, found 363.9819.
8-Methylpyrrolo[1,2-a]quinoxalin-4(5H)-one (3b)
This compound was obtained following the procedure described
for the MW-assisted◦reactions. The product was isolated as a white
1
solid, mp: 168–170 C. H NMR (400 MHz, DMSO-d6) d: 2.44
(s, 3H), 6.27 (m, 1H), 6.93 (m, 1H), 7.09 (m, 1H), 7.16 (d, 1H, J =
8.1 Hz), 7.49 (s, 1H), 7.53 (d, 1H, J = 8.1 Hz), 12.19 (bs, 1H). 13
C
NMR (100 MHz, DMSO-d6) d: 21.2, 110.0, 110.4, 112.4, 118.1,
118.9, 123.7, 125.5, 134.2, 139.5, 149.7, 157.2. GC-MS (m/z): 199
(52), 198 (M+, 100), 78 (20). The spectroscopic data agree with
those of the literature.22
General procedure for the preparation of pyrrolo[1,2-a]quinoxalin-
4(5H)-one 3a–e and indolo[1,2-a]quinoxalin-6(5H)-one 5a–c and
oxazinone 3f under conventional heating
8-Chloropyrrolo[1,2-a]quinoxalin-4(5H)-one (3c)
A mixture of 10 mol% of CuI (0.025 mmol, 5.0 mg), 20 mol% of L-
proline (0.05 mmol, 6 mg), amide or ester derivative (0.25 mmol,
1.0 equiv) and NaH (0.62 mmol, 15 mg, 2.5 equiv) in 2.5 mL
of anhydrous DMF and under nitrogen, was heated at 140 ◦C
for 1 h. After that, the reaction was cooled to r.t. and the crude
was then filtered through a short column of silica gel and eluted
with dichloromethane. DMF was evaporated under vacuum.
The pure product was obtained by chromatography (silica gel,
petroleum/ethyl ether).
This compound was obtained following the procedure described
for the MW-assisted◦reactions. The product was isolated as a white
1
solid, mp: 220–223 C. H NMR (400 MHz, CDCl3) d: 6.38 (m,
1H), 7.05 (m, 1H), 7.09 (m, 1H), 7.30 (dd, 1H, J = 8.4 Hz, 1.9 Hz),
7.54 (m, 2H), 10.10 (bs, 1H). 13C NMR (100 MHz, CDCl3) d:
110.0, 111.1, 113.6, 119.2, 119.4, 123.3, 125.2, 129.8, 140.6, 150.3,
158.7. GC-MS (m/z): 220 (29), 219 (14), 218 (M+, 100), 191 (12),
155 (22), 63 (31). The spectroscopic data agree with the literature.11
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8-Cyanopyrrolo[1,2-a]quinoxalin-4(5H)-one (3d)
2-Chloroindolo[1,2-a]quinoxalin-6(5H)-one (5c)
This compound was obtained following the procedure described
for the MW-assisted◦reactions. The product was isolated as a white
This compound was obtained following the procedure described
for the MW-assisted reactions. The product was isolated as a white
solid, mp: 185–186 ◦C (decompose). 1H NMR (400 MHz, CDCl3)
d: 7.19 (m, 1H), 7.33 (m, 2H), 7.40 (m, 2H), 7.61 (m, 2H), 7.73
(dd, 1H, J = 8.0 Hz, 0.7 Hz), 9.53 (bs, 1H). 13C NMR (100 MHz,
CDCl3) d: 107.0, 111.3, 111.7, 120.0, 121.1, 122.1, 124.2, 125.2,
125.6, 128.1, 130.8, 137.6, 140.5, 150.8, 158.4. GC-MS (m/z): 270
(33), 269 (18), 268 (M+, 100), 205 (15), 134 (15), 115 (12), 89 (11),
63 (21). HRMS (ESI) calcd. for C15H9ClN2O [M+ H+] 269.0476,
found 269.0451.
1
solid, mp: 250–252 C. H NMR (400 MHz, DMSO-d6) d: 6.34
(m, 1H), 7.08 (m, 1H), 7.21 (m, 1H), 7.80 (m, 2H), 8.23 (bs, 1H),
12.45 (bs, 1H). 13C NMR (100 MHz, DMSO-d6) d: 105.8, 110.8,
114.6, 114.7, 117.8, 119.0, 119.5, 125.6, 129.3, 146.0, 148.9, 160.4.
GC-MS (m/z): 210 (14), 209 (M+, 100). HRMS (ESI) calcd. for
C12H7N3O [M-H+] 208,0488, found 208.0505.
Benzo[h]pyrrolo[1,2-a]quinoxalin-4(5H)-one (3e)
4H-Benzo[b]indolo[1,2-d][1,4]oxazin-4-one (5d)
This compound was obtained following the procedure described
for the MW-assisted reactions. The product was isolated as white
This compound was obtained following the procedure described
for the MW-assisted◦reactions. The product was isolated as a white
◦
1
solid, mp: 234–236 C. H NMR (400 MHz, CDCl3) d: 6.41 (m,
1H), 7.06 (m, 1H), 7.16 (m, 1H), 7.52 (m, 1H), 7.64 (m, 1H), 7.78
(d, 2H, J = 1.3 Hz), 7.97 (d, 1H, J = 8.3 Hz), 8.27 (d, 1H, J = 8.3 Hz),
9.84 (bs, 1H). 13C NMR (100 MHz, CDCl3) d: 110.9, 112.4, 118.0,
120.0, 120.2, 120.3, 122.4, 125.3, 125.4, 126.9, 128.7, 131.4, 138.2,
145.6, 157.5. GC-MS (m/z): 235 (16), 234 (M+, 100), 117 (11), 114
(43), 113 (21), 88 (14). HRMS (ESI) calcd. for C15H10N2O [M+
H+] 235.0866, found 235.0885.
1
solid, mp: 204–205 C. H NMR (400 MHz, CDCl3) d: 7.27 (m,
1H), 7.40 (m, 3H), 7.58 (m, 1H), 7.73 (d, 1H, J = 0.79 Hz), 7.88
(m, 1H), 8.19 (m, 2H). 13C NMR (100 MHz, CDCl3) d: 111.8,
113.8, 115.2, 118.5, 122.2, 122.9, 123.8, 124.9, 125.1, 125.2, 127.3,
128.8, 134.8, 142.3, 155.3. GC-MS (m/z): 236 (36), 235 (M+, 100),
191 (18), 190 (31), 178 (22), 164 (15), 152 (26), 117 (10), 90 (12),
89 (48), 76 (19), 75 (15), 74 (12), 63 (14). HRMS (ESI) calcd. for
C15H9NO2 [M+ H+] 236.0706, found 236.0725.
4H-Benzo[b]pyrrolo[1,2-d][1,4]oxazin-4-one (3f)
Acknowledgements
This compound was obtained following the procedure described
for the MW-assisted◦reactions. The product was isolated as a white
We thank ACC, CONICET, FONCYT, and SECYT for their
continuous support to our work. V.A.V. gratefully acknowledges
receipt of a fellowship from CONICET.
◦
1
solid, mp: 132–134 C (lit:32 132–133 C). H NMR (400 MHz,
CDCl3) d: 6.68 (dd, 1H, J = 4.0 Hz, 2.8 Hz), 7.30 (m, 2H), 7.37
(m, 2H), 7.60 (m, 1H), 7.64 (dd, 1H, J = 2.7 Hz, 1.4 Hz). 13C
NMR (100 MHz, CDCl3) d: 114.1, 114.2, 117.5, 117.6, 118.4,
118.5, 122.6, 124.8, 126.4, 143.1, 153.9. GC-MS (m/z): 186 (11),
185 (M+, 100), 157 (16), 141 (10), 140 (13), 130 (12), 129 (12), 114
(15), 102 (19), 79 (11), 76 (10).
Notes and references
1 (a) F. Ullmann, Ber. Dtsch. Chem. Ges., 1903, 36, 2382–2384; (b) F.
Ullmann, Ber. Dtsch. Chem. Ges., 1904, 37, 853–854; (c) J. Lindley,
Tetrahedron, 1984, 40, 1433–1456.
2 For reviews about Ullmann-type reactions see: (a) I. P. Beletskaya and
A. V. Cheprakov, Coord. Chem. Rev., 2004, 248, 2337–2364; (b) F.
Monnier and M. Taillefer, Angew. Chem., Int. Ed., 2009, 48, 6954–
6971.
3 (a) J. C. Antilla, A. Kaplars and S. L. Buchwald, J. Am. Chem. Soc.,
2002, 124, 11684–11688; (b) B. Tang, S. Guo, M. Zhang and J. Li,
Synthesis, 2008, 1707–1716; (c) M. Periasamy, P. Vairaprakash and M.
Dalai, Organometallics, 2008, 27, 1963–1966; (d) G. Chouhan, D. Wang
and H. Alper, Chem. Commun., 2007, 4809–4811; (e) H. C. Ma and X.
Z. Jiang, J. Org. Chem., 2007, 72, 8943–8946.
4 For some examples see: (a) J. C. Antilla, J. M. Baskin, T. E. Barder and S.
L. Buchwald, J. Org. Chem., 2004, 69, 5578–5587; (b) H. Zhang, Q. Cai
and D. Ma, J. Org. Chem., 2005, 70, 5164–5173; (c) R. Hosseizadeh, M.
Tajbakhsh, M. Alikarami and M. Mohadjerani, J. Heterocyclic Chem.,
2008, 45, 1815–1818 and reference therein; (d) R. Koteshwar Rao, A.
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855–861.
Indolo[1,2-a]quinoxalin-6(5H)-one (5a)
This compound was obtained following the procedure described
for the MW-assisted ◦reactions. The product was isolated as a white
1
1
solid, mp: 245–247 C (97% of purity by H NMR). H NMR
(400 MHz, CDCl3) d: 7.18 (m, 1H), 7.31 (m, 1H), 7.37 (m, 2H),
7.41 (m, 2H), 7.61 (m, 1H), 7.73 (m, 2H), 9.76 (bs, 1H). 13C NMR
(100 MHz, CDCl3) d: 106.5, 110.6, 111.7, 119.6, 120.9, 122.0,
124.8, 124.9, 124.9, 125.2, 128.1, 137.5, 141.64, 150.6, 157.9. GC-
MS (m/z): 235 (17), 234 (M+, 100), 205 (13), 117 (13). HRMS
(ESI) calcd. for C15H10N2O [M+ H+] 235.0866, found 235.0883.
2-Methylindolo[1,2-a]quinoxalin-6(5H)-one (5b)
5 For selected examples see: (a) D. Ma and C. Xia, Org. Lett., 2001, 3,
2583–2586; (b) G. Evindar and R. A. Batey, Org. Lett., 2003, 5, 133–
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6 J. A. Joule, K. Mills, Heterocyclic Chemistry, 4th ed.; Blackwell Science:
Oxford, UK, 2000.
This compound was obtained following the procedure described
for the MW-assisted reactions. The product was isolated as a white
solid, mp: 226–228 ◦C (decompose). 1H NMR (400 MHz, CDCl3)
d: 2.52 (s, 3H), 7.18 (m, 2H), 7.29 (m, 1H), 7.36 (d, 1H, J = 1.1 Hz),
7.40 (m, 2H), 7.59 (d, 1H, J = 8.2 Hz), 7.73 (d, 1H, J = 8.2 Hz), 9.69
(bs, 1H). 13C NMR (100 MHz, CDCl3) d: 22.0, 106.2, 110.9, 111.8,
119.1, 121.0, 122.1, 124.9, 125.1, 126.2, 128.3, 135.9, 137.6, 139.6,
151.0, 157.5. GC-MS (m/z): 249 (25), 248 (M+, 100), 247 (27), 124
(22). The spectroscopic data agree with those of the literature.22
7 (a) X. Li, K. Yang, W. Li and W. Xu, Drugs Future, 2006, 31, 979–
989; (b) A. Carta, S. Piras, G. Loriga and G. Paglietti, Mini-Rev. Med.
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