A novel one-pot three-component reaction for the synthesis of 5-arylamino-pyrrolo[2,3-d]pyrimidines under microwave irradiation

Article abstract of DOI:10.1039/c3ra47143h

Some novel 5-arylamino-pyrrolo[2,3-d]pyrimidine derivatives were synthesized via microwave-assisted three-component reaction of N,N-dimethyl-6-aminouracil, aryl glyoxal monohydrates and aryl amines. The products were obtained in good to excellent yields (82-91%) using a simple work-up procedure.

Full text of DOI:10.1039/c3ra47143h

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A novel one-pot three-component reaction for the
synthesis of 5-arylamino-pyrrolo[2,3-d]pyrimidines
under microwave irradiation†
Cite this: RSC Adv., 2014, 4, 9942
Received 29th November 2013
Accepted 24th January 2014
*
P. Seetham Naidu and Pulak J. Bhuyan
DOI: 10.1039/c3ra47143h
www.rsc.org/advances
Some novel 5-arylamino-pyrrolo[2,3-d]pyrimidine derivatives were chloroacetaldehyde16 which was rst reported by Secrist et al.,
synthesized via microwave-assisted three-component reaction of and later on modied by Kretschmer.17 Literature survey
N,N-dimethyl-6-aminouracil, aryl glyoxal monohydrates and aryl also revealed some other methods of the synthesis of pyrrolo-
amines. The products were obtained in good to excellent yields (82– [2,3-d]pyrimidines.18 Very recently, Kaim et al. reported the
91%) using a simple work-up procedure.
synthesis of pyrrolo[2,3-d]-pyrimidines through activation of
N-benzyl groups by distal amides.19 However, there is still the
need to develop efficient method for the synthesis of this
class of important molecules.
Introduction
Multi-component reactions (MCRs), by virtue of their
convergence, productivity, elegance, ease of execution and
selectivity, have become one of the most powerful
platforms to access diverse complex molecules.20 Accordingly,
these reactions have attracted considerable attention of
medicinal chemistry, combinatorial synthesis,21 phar-
Pyrrolo[2,3-d]pyrimidines represent an important class of
compounds with diverse biological activities such as anti-
microbial,1 analgesic,2 anti-inammatory,3 anti-viral,4 anti-
cancer,5
antioxidant
and
neuroprotective
activity.6
Compounds with this ring system are protein kinase inhibi-
tors,7 E1 enzyme inhibitors,8 insulin-like growth factor 1
receptor inhibitors,9 STAT6 inhibitors10 and 2 microtubule
targeting agents.11 Pyrrolo[2,3-d]-pyrimidine molecular unit is
commonly found in various biologically active nucleosides12
such as toyocamycine, tubercidin and sangivamycin which
possess antiviral, antimicrobial, antiparasitic and antineo-
plastic activity. Some of their representatives have signicant
activity against a variety of RNA, DNA viruses, HSV-1, HSV-2
and HCMV.13 5-Substituted pyrrolo[2,3-d]pyrimidines possess
antifolate, antitumor and pp60c-Src tyrosine kinase inhibitor
activities.14 Because of their proven biological activity and
medicinal utility lot of efforts have been made towards the
molecular manipulation of this molecule.15 However, it is very
interesting to note that, there are only very few methods
available for the synthesis of the basic pyrrolo[2,3-d]pyrimi-
dine molecular unit, and no report of direct synthesis of
5-arylamino-pyrrolo[2,3-d]pyrimidines. The most common
and widely used method for the synthesis of pyrrolo[2,3-d]-
pyrimidines is from the reaction of 6-aminouracils and
maceutical industry22 and modern drug discovery
development.23
&
In recent years, microwave-assisted reaction has gained
popularity in synthetic organic chemistry as it minimizes the
energy consumption required for heating, improves isolated
yields of products and remarkably decreases the time necessary
to carry out reactions.24
Medicinal Chemitry Division, CSIR-North East Institute of Science & Technology,
Jorhat 785006, Assam, India. E-mail: pulak_jyoti@yahoo.com; Fax: +91-376-
2370011; Tel: +91-376-2370121
† Electronic supplementary information (ESI) available: Compound
characterizations data, 1H NMR and 13C NMR Spectra. See DOI:
10.1039/c3ra47143h
Scheme 1 Synthesis of 5-arylamino-pyrrolo[2,3-d]pyrimidines.
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As a part of our continued interest in the synthesis of diverse irradiation at 110 ꢀC for 5 min, which afforded the 5-phenyl-
heterocyclic compounds25 of biological importance, particularly amino-pyrrolo[2,3-d]pyrimidine 4a in 88% yield (Table 2). The
diverse heterocycle fused uracil derivatives,26 we report herein a structure of the compound was ascertained from the spectro-
simple and efficient method for the synthesis of 5-arylamino- scopic data and elemental analysis. The generality of the reac-
pyrrolo[2,3-d]pyrimidines 4 from the reaction of N,N-dimethyl- tion was established by employing N,N-dimethyl-6-aminouracil
6-aminouracil 1, aryl glyoxal monohydrates 2 and aryl amines 3 1 with various aryl glyoxal monohydrates 2 and aryl amines 3 in
under microwave irradiation using acetic acid as solvent as well the reaction process which proceeded effectively to produce the
as catalyst (Scheme 1).
desired products 4a–t, in very good to excellent yields (Table 2).
It was observed that aryl glyoxal monohydrates with electron-
withdrawing substituent such as chloro and bromo groups
exhibited good reactivity (Table 2, 4m–t), whereas electron
donating groups such as methyl, methoxyl groups slightly
reduced the reactivity (Table 2, 4e–l). Aromatic amines with
electron donating and electron-withdrawing substituents
exhibited almost same reactivity with aryl glyoxal monhydrates
2 and N,N-dimethyl-6-aminouracil 1. In general, the reaction
proceeds at high speed and completes in short reaction times
(5 min). Notably, water is the sole by-product in the reaction
process, which makes the reaction work-up very convenient. In
all cases, solid product was formed on pouring the reaction
mixture in cold water which was isolated simply by ltration,
and puried by recrystallization from EtOH. The structures of
the compounds were determined from their 1H NMR, 13C NMR,
IR, MS spectroscopic data and elemental analysis.
Result and discussion
Our investigation was initiated by three component reaction of
N,N-dimethyl-6-aminouracil 1, phenyl glyoxal monohydrate
2a,27 and aniline 3a under microwave irradiation. For optimi-
zation of conditions, the reaction was screened in various
solvents and acid catalysts. The representative data were
summarized in Table 1. Initially, the reaction was performed in
ethanol, in absence of catalyst under microwave irradiation at
75 ꢀC for 5 min which afforded the desired compound 4a in very
poor yield (Table 1, entry 1). Then we studied the reaction in
presence of different acid catalysts such as PTSA, InCl3 and
Sc(OTf)3 in ethanol under identical reaction conditions, and
some increase in the yield of the desired product 4a was
observed (Table 1, entry 2–4). When the reaction was performed
in solvents like CH3CN, toluene and DMF in presence of PTSA,
only trace amount of product 4a was formed (Table 1, entry 5–7).
An excellent yield of 84% was achieved when acetic acid was
used as a solvent without any added catalyst under microwave
On the basis of experimental results, a reasonable mecha-
nism for the formation of compound 4 is postulated in
Scheme 2. Acetic acid acts as Bronsted acid promoter as well as
solvent in the reaction process. First, the condensed compound
ꢀ
irradiation at 100 C for 5 min (Table 1, entry 8). Gratifyingly,
the reaction proceeded efficiently in AcOH at 110 ꢀC to give the
corresponding product 4a in 88% yield (Table 1, entry 9).
Further increase in the temperature of the reaction could not
improve the yield of the desired product 4a.
Table 2 Synthesis of pyrrolo[2,3-d]pyrimidines 4 under MW
With these optimized conditions in hand, equimolar
amounts of N,N-dimethyl-6-aminouracil 1, phenyl glyoxal 2a,
and aniline 3a in acetic acid were reacted under microwave
Entry
Ar1
Ar2
Product
Yield (%)
Table 1 Optimization of reaction conditions
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
88
84
85
84
86
84
85
84
83
82
85
83
91
87
89
88
90
89
88
86
4-CH3Ph
4-ClPh
4-BrPh
Ph
4-CH3Ph
4-ClPh
4-BrPh
Ph
4-CH3Ph
4-ClPh
4-BrPh
Ph
4-CH3Ph
4-ClPh
4-BrPh
Ph
4-CH3Ph
4-CH3Ph
4-CH3Ph
4-CH3Ph
4-OCH3Ph
4-OCH3Ph
4-OCH3Ph
4-OCH3Ph
4-ClPh
4-ClPh
4-ClPh
4-ClPh
4-BrPh
4-BrPh
4-BrPh
4-BrPh
9
Entry
Solvent
Catalyst
Temp (ꢀC)
Time (min)
Yield (%)
10
11
12
13
14
15
16
17
18
19
20
1
2
3
4
5
6
7
8
9
EtOH
EtOH
EtOH
EtOH
CH3CN
Toulene
DMF
—
75
75
75
75
80
100
100
100
110
5
5
5
5
5
5
5
5
5
25
40
35
30
Trace
Trace
Trace
84
PTSA
InCl3
Sc(OTf)3
PTSA
PTSA
PTSA
—
4-CH3Ph
4-ClPh
4-BrPh
AcOH
AcOH
4s
4t
—
88
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0.093 g) in acetic acid (5 mL) were taken in the vessel of a
Synthos 3000 microwave reactor, and irradiated under micro-
ꢀ
wave at 110 C for 5 min. The reaction mixture was cooled to
room temperature and then added cold water (10 mL) into the
mixture. The solid product appeared was ltered and then
puried by recrystallization from EtOH to afford the desired
product 4a as a white solid.
1,3-Dimethyl-6-phenyl-5-(phenylamino)-1,7-dihydro-2H-
pyrrolo[2,3-d]pyrimidine-2,4(3H)-dione (4a)
1
ꢀ
White solid; yield: 304 mg (88%); mp > 300 C; H NMR (300
MHz, DMSO-d6) d 11.54 (s, 1H), 7.73 (d, 2H), 7.47–7.23 (m, 3H),
7.07 (t, 2H), 6.64 (d, 2H), 6.20 (s, 1H), 3.60 (s, 3H), 3.22 (s, 3H);
13C NMR (75 MHz, DMSO-d6) d 159.12, 151.61, 140.01, 136.25,
131.74, 129.98, 128.83, 128.16, 125.59, 117.40, 115.13, 113.57,
107.42, 96.83, 30.82, 27.55; IR (KBr, cmÀ1): 3454.4, 3352.3,
3189.6, 1698.1, 1635.0, 1592.1, 1561.0, 1509.0, 1437.4, 1330.1,
1035.4, 972.9, 743.9; MS (m/z): 347.3 [M + 1]; anal. calcd for
C
20H18N4O2: C, 69.35; H, 5.24; N, 16.17. Found: C, 69.39; H,
5.27; N, 16.14.
Similarly compound 4b–t were synthesized and characterized.
Scheme 2 Mechanism for the formation of compound 4.
Acknowledgements
The authors thank CSIR, New Delhi for nancial support in the
form of the Project CAAF-NE. PSN thanks UGC, New Delhi for
Senior Research Fellowship.
A forms from the reaction of compounds 2 and 3 which
undergoes nucleophilic addition to compound 1 in presence of
acid to give intermediate B. The intermediate B then undergoes
through an intramolecular cyclization process in presence of
acid catalyst to produce the intermediate C, which subsequently
eliminates water molecule to afford the desired product 4.
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In conclusion, we have developed a new and highly efficient
microwave-assisted one-pot synthesis of pyrrolo[2,3-d]pyrimi-
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General procedure for preparation of 4
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