Rapid and efficient, microwave-assisted, base-catalyzed synthesis of some novel 2,7-disubstituted pyrrolopyrimidinones

Article abstract of DOI:10.1080/00397911.2011.576324

A rapid synthesis of a series of new 5,6-dimethyl-7-phenyl-2-alkyl-3,7- dihydro-4H-pyrrolo[2,3-d]pyrimidinones and 5,6-dimethyl-7-benzyl-2-alkyl-3,7- dihydro-4H-pyrrolo[2,3-d]pyrimidinones was accomplished in good yields using microwave irradiation under

Full text of DOI:10.1080/00397911.2011.576324

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Rapid and Efficient, Microwave-Assisted,
Base-Catalyzed Synthesis of Some Novel
2,7-Disubstituted Pyrrolopyrimidinones
Murty Deverakonda a , Raghu Prasad Mailavaram a , Pran Kishore Deb
b , Narsaiah Banda c & Girija Sastry Vedula d
a Department of Pharmaceutical Chemistry, Shri Vishnu College of
Pharmacy, Bhimavaram, Andhra Pradesh, India
b Pharmaceutical Chemistry Division, University Institute of
Pharmaceutical Sciences, Panjab University, Chandigarh, India
c Fluoro-organics Division, Indian Institute of Chemical Technology,
Hyderabad, Andhra Pradesh, India
d Department of Pharmaceutical Chemistry, College of
Pharmaceutical Sciences, Andhra University, Vizag, Andhra Pradesh,
India
Accepted author version posted online: 10 Jan 2012.Version of
record first published: 17 Aug 2012.
To cite this article: Murty Deverakonda , Raghu Prasad Mailavaram , Pran Kishore Deb , Narsaiah
Banda & Girija Sastry Vedula (2012): Rapid and Efficient, Microwave-Assisted, Base-Catalyzed
Synthesis of Some Novel 2,7-Disubstituted Pyrrolopyrimidinones, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 42:21, 3103-3111
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Synthetic Communications1, 42: 3103–3111, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.576324
RAPID AND EFFICIENT, MICROWAVE-ASSISTED,
BASE-CATALYZED SYNTHESIS OF SOME NOVEL
2,7-DISUBSTITUTED PYRROLOPYRIMIDINONES
Murty Deverakonda,1 Raghu Prasad Mailavaram,1
Pran Kishore Deb,2 Narsaiah Banda,3 and
Girija Sastry Vedula4
1Department of Pharmaceutical Chemistry, Shri Vishnu College of
Pharmacy, Bhimavaram, Andhra Pradesh, India
2Pharmaceutical Chemistry Division, University Institute of Pharmaceutical
Sciences, Panjab University, Chandigarh, India
3Fluoro-organics Division, Indian Institute of Chemical Technology,
Hyderabad, Andhra Pradesh, India
4Department of Pharmaceutical Chemistry, College of Pharmaceutical
Sciences, Andhra University, Vizag, Andhra Pradesh, India
GRAPHICAL ABSTRACT
Abstract A rapid synthesis of a series of new 5,6-dimethyl-7-phenyl-2-alkyl-3,7-dihydro-4-
H-pyrrolo[2,3-d]pyrimidinones and 5,6-dimethyl-7-benzyl-2-alkyl-3,7-dihydro-4H-pyr-
rolo[2,3-d]pyrimidinones was accomplished in good yields using microwave irradiation
under base catalysis.
Keywords Adenosine antagonist; microwave-assisted synthesis; pyrrolo-pyrimidinones
INTRODUCTION
Hetero-fused pyrazolopyrimidines have been identified as new lead compounds
in drug discovery for adenosine modulation.[1–5] In continuation of our research inter-
ests,[6,7] we are presently working on design, synthesis, and adenosine receptor binding
studies of hetero-fused pyrrolo[2,3-d]pyrimidines (Fig. 1A) as bioisosters of
Received January 31, 2011.
Address correspondence to Raghu Prasad Mailavaram, Department of Pharmaceutical Chemistry,
Shri Vishnu College of Pharmacy, Bhimavaram, West Godavari District, Andhra Pradesh 534202, India.
E-mail: raghumrp@mailcity.com
3103

3104
M. DEVERAKONDA ET AL.
Figure 1. Structure of model compounds. R1 ¼ -C6H5, R2 and R3 ¼ -CH3, and R4 ¼ -H, -CH3, -CH2CH3,
-CH2CH2CH3, -CH(CH3)2, R5 ¼ Alkyl, Aryl.
hetero-fused pyrazolo=thieno pyrimidines to develop selective adenosine receptor
antagonists. They have been found to interact with a variety of P1 purinergic receptors
(adenosine receptors) in the human body, including a number of different subtypes
(i.e., A1, A2a, A2b, A3). As a result of their significant potential as therapeutics, interest
has grown in the development of methods for the efficient and rapid synthesis of its
synthons, pyrrolo[2,3-d]pyrimidinones, especially because the available methods[8,9]
have significant limitations. Not only do pyrrolo[2,3-d]pyrimidinones serve as inter-
mediates for the target compounds, but its 4-aminoalkyl substituted derivatives are
reported for adenosine modulation on A1 receptor subtype (Fig. 1B).[10]
In general, the classical strategy for the synthesis of hetero-fused pyrimidinones
utilizes reaction of ortho amino esters=amides of heterocyclic moiety with a variety
of nitriles under strongly acidic conditions[8] or ortho amino amides of heterocyclic
moiety with a variety of esters under strongly basic conditions.[9] Harsh conditions
and long reaction times are the characteristic limitations of these reactions.
Hence, herewith we are reporting a facile protocol that requires shorter reac-
tion times for the preparation of a series of new pyrrolo[2,3-d]pyrimidinones [2a(i–
v), 2b(i–v)], resulting in good yields.
RESULTS AND DISCUSSION
In recent years, microwave (mW) irradiation has emerged as an efficient tool in
organic synthesis, and its benefits have been well documented. In a number of studies
it has been shown that microwave irradiation can circumvent the need for prolonged
heating, and it generally accelerates the rate of chemical reactions, often increased
yields and cleaner reaction profiles, which allow for more rapid reaction optimiza-
tion and library synthesis. Using the dedicated microwave synthesizer, simplified
online control temperature and pressure profiles are possible, which lead to highly
reproducible reaction conditions.[11–21]
Initially we investigated two different classical procedures for reacting
2-amino-4,5-dimethyl-1-phenyl-1H-pyrrole-3-carboxamide[22] and 2-amino-1-benzyl-
4,5-dimethyl-1H-pyrrole-3-carboxamide[22] with various alkyl nitriles under acidic
conditions and with various alkyl esters under basic conditions as outlined in
Schemes 1–3. The reaction conditions were as follows:
(a) Protocol under acidic conditions: Reaction in the presence of HCl gas in dry
dioxan at roomtemperature for 24 h or under reflux at 100 ꢀC for 12 h.

2,7-DISUBSTITUTED PYRROLOPYRIMIDINONES
3105
(b) Protocol under basic conditions: Reaction in the presence of sodium ethoxide in
absolute ethanol under reflux at 80 ꢀC under a nitrogen atmosphere for 30 h and
80 h respectively.
In the first case, no product was obtained either at room temperature or at
refluxing temperature. Instead, the starting material remained as such after several
hours of reaction.
As a next step we investigated a procedure under basic conditions. The desired
compounds were achieved in moderate yields. It took too long for the reaction com-
pletion (i.e., 30 h and 80 h for 2a and 2b series respectively). However, under micro-
wave irradiation, the products were achieved in 3–4 min (2a) and 15–17 min (2b)
respectively (Table 1). This may be because the presently synthesized compounds
are 2-alkyl derivatives and are less reactive than the reported 2-aryl derivatives.[9]
The lesser reactivity may be attributed to poor stabilization of the intermediate
by the alkyl group due to the absence of resonance stabilization as found in aryl
esters (Fig. 2). Further, the difference in the reaction times between the two series
was because of the presence of a phenyl group at position 1 on the pyrrole moiety in
compound 1a. The electron richness and resonance stabilization by the phenyl ring
activates the system, which results in the formation of the product in less time in
both conventional and microwave methods. Microwave irradiation not only
reduced the reaction time dramatically but also increased the yields considerably
(10–15%).
1
The title compounds were characterized by H NMR, and cyclized product
was confirmed by the corresponding NH signal observed at 10–12 ppm. Further,
a molecular ion peak corresponding to its molecular weight and characteristic
fragmentation pattern in mass spectra revealed the formation of the product.
The elemental analysis showed that all the synthesized compounds are of good purity
as the percentage difference is within ꢁ0.4%.
Scheme 1. Classical synthesis of pyrrolopyrimidinones under strongly acidic conditions.

3106
M. DEVERAKONDA ET AL.
Scheme 2. Classical synthesis of 5,6-dimethyl-7-phenyl-2-alkyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidi-
nones under strongly basic conditions. Series 2a(i–v): R1 ¼ -C6H5, R2 and R3 ¼ -CH3, and R4 ¼ -H,
-CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2.
Scheme 3. Classical synthesis of 5,6-dimethyl-7-benzyl-2-alkyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidi-
nones under strongly basic conditions. Series 2b(i–v): R1 ¼ -CH2C6H5, R2 and R3 ¼ -CH3, and R4 ¼ -H,
-CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2.
All the reactions can be upscaled to multigram amounts with similarly good
yields in the microwave method. The described reaction conditions can be generally
used for all the compounds synthesized.
EXPERIMENTAL
Solvents were purified in the usual way. Thin-layer chromatograpgy (TLC) was
performed using precoated Merck silica gel 60 F254 aluminium sheets. Melting points
Figure 2. Resonance stabilization of the intermediate in aryl derivatives.

2,7-DISUBSTITUTED PYRROLOPYRIMIDINONES
3107
Table 1. Results obtained for conventional and microwave methods
Entry
Substrate
Conditions
A
Time
30 h
Conventional (yield, %)
82
Microwave (yield, %)
92
2a(i)
B
3 min
94
94
A
B
30 h
81
84
2a(ii)
3 min
A
B
30 h
2a(iii)
2a(iv)
2a(v)
3 min
96
95
A
B
30 h
84
85
4 min
A
B
30 h
4 min
86
A
B
80 h
77
2b(i)
15 min
A
B
80 h
79
80
82
89
91
93
2b(ii)
16 min
A
B
80 h
2b(iii)
16 min
A
B
80 h
2b(iv)
2b(v)
17 min
92
A
B
80 h
83
17 min
Note. Method A, ethanol reflux; method B: ethanol reflux= MWI, 100 W, 80 ꢀC, 20 bar.

3108
M. DEVERAKONDA ET AL.
were determined with a high-precision, programmable, microprocessor-based melt-
ing-point apparatus (Veego). NMR spectra were recorded on a Jeol JNM-ECP
400-MHz spectrometer with Me4Si as the internal standard, and chemical shifts
are recorded in d values. Mass spectra were obtained on a Q-TOF Global mass spec-
trometer. Elemental analysis was carried out using a Carlo Erba instrument.
Synthetic Procedure for Compounds 2a(i–v) and 2b(i–v)
2-Amino-4,5-dimethyl-1-phenyl-1H-pyrrole-3-carboxamide
(1a,
114 mg,
0.5 mmol) or 2-amino-1-benzyl-4,5-dimethyl-1H-pyrrole-3-carboxamide (1b,
121 mg, 0.5 mmol), corresponding ester (4.0 mmol), and sodium ethoxide prepared
from 100 mg (4.34 mmol) of sodium metal in 4 ml of absolute ethanol were taken
in the reaction vessel. The reaction mixture was heated to reflux under nitrogen
atmosphere at 100 W, 80 ꢀC, 20 bar in a CEM-Discover microwave oven until the
starting material disappeared as evidenced by thin-layer chromatography (TLC).
After completion of the reaction, the solvent was distilled off and the residue was
added to crush ice, and then neutralized using concentrated hydrochloric acid to
pH 7. The precipitate obtained was separated by filtration, dried, and purified by
recrystallization using petroleum ether.
5,6-Dimethyl-7-phenyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-
4-one [2a(i)]
1
Yellow solid, mp 220 ꢀC; HNMR (400 MHz, CDCl3): d 2.12 (s, 3H, 5-CH3),
2.46 (s, 3H, 6-CH3), 7.31, 7.55 (m, 5H, 7-ArH), 7.80 (s, 1H, 2-ArH), 11.84 (s, 1H,
3-NH); MS (EI) m=z: 239 [Mþ, 30%], 238 [Mþ ꢂ 1, 76%], 162 [Mþ-Ph, 10%] 77
[Mþ-C8H8N3O, 82%]. Anal. calcd. for C14H13N3O: C, 70.28; H, 5.48; N, 17.56; O,
6.69. Found: C, 70.27; H, 5.46; N, 17.56; O, 6.66.
2,5,6-Trimethyl-7-phenyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-
4-one [2a(ii)]
1
Yellow solid, mp 198 ꢀC; HNMR (400 MHz, CDCl3): d 2.12 (s, 3H, 5-CH3),
2.45 (s, 3H, 6-CH3), 2.68 (s, 3H, 2-CH3), 7.31, 7.55 (m, 5H, 7-ArH), 10.75 (s, 1H,
3-NH); MS (EI) m=z: 253 [Mþ, 50%], 252 [Mþ ꢂ 38%], 176 [Mþ-Ph, 10%], 77
[Mþ-C9H10N3O, 50%]. Anal. calcd. for C15H15N3O: C, 71.13; H, 5.97; N, 16.59;
O, 6.32. Found: C, 71.09; H, 5.93; N, 16.56; O, 6.30.
2-Ethyl-5,6-dimethyl-7-phenyl-3,7-dihydro-4H-pyrrolo
[2,3-d]pyrimidin-4-one [2a(iii)]
1
Yellow solid, mp 194 ꢀC; HNMR (400 MHz, CDCl3): d 1.25, 1.29 (t, J ¼ 7.4,
3H, 2-CH2CH3), 2.10 (s, 3H, 5-CH3), 2.43 (s, 3H, 6-CH3), 2.63, 2.69 (q, J ¼ 7.4, 2H,
2-CH2CH3), 7.30, 7.52 (m, 5H, 7-ArH), 10.74 (s, 1H, 3-NH); MS (EI) m=z: 267 [Mþ,
52%], 190 [Mþ-Ph, 10%], 77 [Mþ-C10H12N3O, 100%]. Anal. calcd. for C16H17N3O:
C, 71.89; H, 6.41; N, 15.72; O, 5.98. Found: C, 71.82; H, 6.43; N, 15.69; O, 5.93.

2,7-DISUBSTITUTED PYRROLOPYRIMIDINONES
3109
5,6-Dimethyl-7-phenyl-2-propyl-3,7-dihydro-4H-pyrrolo[2,3-d]
pyrimidin-4-one [2a(iv)]
1
Yellow solid, mp 190 ꢀC; HNMR (400 MHz, CDCl3): d 0.94, 0.98 (t, J ¼ 7.4,
3H, 2-CH2CH2CH3), 1.70, 1.79 (sextet, J ¼ 7.5, 2H, 2-CH2CH2CH3), 2.10 (s, 3H,
5-CH3), 2.43 (s, 3H, 6-CH3), 2.58, 2.61 (t, J ¼ 7.6, 2H, 2-CH2CH2CH3), 7.30, 7.52
(m, 5H, 7-ArH), 10.93 (s, 1H, 3-H). MS (EI) m=z: 281 [Mþ, 85%], 204 [Mþ-Ph,
10%], 77 [Mþ-C11H14N3O, 100%]. Anal. calcd. for C17H19N3O: C, 72.57; H, 6.81;
N, 14.94; O, 5.69. Found: C, 72.52; H, 6.78; N, 14.90; O, 5.67.
5,6-Dimethyl-7-phenyl-2-(propan-2-yl)-3,7-dihydro-4H-pyrrolo
[2,3-d]pyrimidin-4-one [2a(v)]
1
Yellow solid, mp 194 ꢀC; HNMR (400 MHz, CDCl3): d 1.25, 1.29 [d, J ¼ 7.2,
6H, 2-CH(CH3)2], 2.11 (s, 3H, 5-CH3), 2.43 (s, 3H, 6-H), 2.87, 2.94 [m, 1H,
2-CH(CH3)2], 7.31, 7.51 (m, 5H, 7-ArH), 1.17 (s, 1H, 3-NH). MS (EI) m=z: 281
[Mþ, 100%], 204 [Mþ-Ph, 10%], 77 [Mþ-C11H14N3O, 100%]. Anal. calcd. for
C17H19N3O: C, 72.57; H, 6.81; N, 14.94; O, 5.69. Found: C, 72.56; H, 6.78; N,
14.90; O, 5.67.
7-Benzyl-5,6-dimethyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-
4-one [2b(i)]
1
Yellow solid, mp 268 ꢀC; HNMR (400 MHz, CDCl3): d 2.14 (s, 3H, 5-CH3),
2.40 (s, 3H, 6-CH3), 5.36 (s, 2H, 7-CH2-), 7.02, 7.30 (m, 5H, 7-ArH), 7.82 (s, 1H,
2-ArH), 11.25 (s, 1H, 3-NH). MS (EI) m=z: 253 [Mþ, 30%], 162 [Mþ-CH2Ph, 10%],
91 [Mþ-C8H8N3O, 100%], 77 [Mþ-C9H10N3O, 10%]. Anal. calcd. for C15H15N3O:
C, 71.13; H, 5.97; N, 16.59; O, 6.32. Found: C, 71.12; H, 5.94; N, 16.56; O, 6.30.
7-Benzyl-2,5,6-trimethyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-
4-one [2b(ii)]
Yellow solid, mp 264 ꢀC; 1HNMR (400 MHz, CDCl3): d 2.12 (s, 3H, 5-CH3), 2.45
(s, 3H, 6-CH3), 2.58 (s, 3H, 2-CH3), 5.36 (s, 2H, 7-CH2-), 7.31, 7.55 (m, 5H, 7-ArH),
11.25 (s, 1H, 3-NH). MS (EI) m=z: 267 [Mþ, 30%], 176 [Mþ-CH2Ph, 10%], 91 [Mþ-
C9H10N3O, 100%], 77 [Mþ-C10H12N3O, 100%]. Anal. calcd. for C16H17N3O: C,
71.89; H, 6.41; N, 15.72; O, 5.98. Found: C, 71.83; H, 6.38; N, 15.68; O, 5.96.
7-Benzyl-2-ethyl-5,6-dimethyl-3,7-dihydro-4H-pyrrolo[2,3-d]
pyrimidin-4-one [2b(iii)]
1
Yellow solid, mp 232 ꢀC; H NMR (400 MHz, CDCl3): d 1.32, 1.36 (t, J ¼ 7.6,
3H, 2-CH2CH3), 2.09 (s, 3H, 5-CH3), 2.36 (s, 3H, 6-CH3), 2.71, 2.77 (q, J ¼ 7.8, 2H,
2-CH2CH3), 5.33 (s, 2H, 7-CH2-), 7.06, 7.30 (m, 5H, 7-ArH), 11.34 (s, 1H, 3-NH).
Mass (m=z): 281 [Mþ, 45%], 190 [Mþ-CH2Ph, 10%], 77 [Mþ-C11H14N3O, 10%].
Anal. calcd. for C17H19N3O: C, 72.57; H, 6.81; N, 14.94; O, 5.69. Found: C,
72.53; H, 6.81; N, 14.91; O, 5.67.

3110
M. DEVERAKONDA ET AL.
7-Benzyl-5,6-dimethyl-2-propyl-3,7-dihydro-4H-pyrrolo[2,3-d]
pyrimidin-4-one [2b(iv)]
Yellow solid, mp 204 ꢀC; 1H NMR (400 MHz, CDCl3): d 0.97, 1.01 (t, J ¼ 7.4,
3H, 2-CH2CH2CH3), 1.78, 1.87 (sextet, J ¼ 7.44, 2H, 2-CH2CH2CH3), 2.09 (s, 3H,
5-CH3), 2.36 (s, 3H, 6-CH3), 5.32 (s, 2H, 7-CH2-), 7.05, 7.29 (m, 5H, 7- ArH),
11.22 (s, 1H, 3-NH). Mass (m=z): 295 [Mþ, 30%], 204 [Mþ-CH2Ph, 30%], 91 [Mþ-
C11H14N3O, 100%], 77 [Mþ-C12H16N3O, 10%]. Anal. calcd. for C18H21N3O: C,
73.19; H, 7.17; N, 14.23; O, 5.42. Found: C, 73.17; H, 7.15; N, 14.20; O, 5.41.
7-Benzyl-5,6-dimethyl-2-(propan-2-yl)-3,7-dihydro-4H-pyrrolo
[2,3-d]pyrimidin-4-one [2b(v)]
Yellow solid, mp 198 ꢀC; 1H NMR (400 MHz, CDCl3): d 1.33, 1.34 [d, J ¼ 6.4,
6H, 2-CH(CH3)2], 2.10 (s, 3H, 5-CH3), 2.35 (s, 3H, 6-CH3), 2.92, 2.96 [m, 1H,
2-CH(CH3)2], 5.32 (s, 2H, 7-CH2-), 7.08, 7.30 (m, 5H, 7-ArH), 10.53 (s, 1H,
3-NH). Mass (m=z): 295 [Mþ, 30%], 204 [Mþ-CH2Ph, 30%], 91 [Mþ-C11H14N3O,
100%], 77 [Mþ-C12H16N3O, 10%]. Anal. calcd. for C18H21N3O: C, 73.19; H, 7.17;
N, 14.23; O, 5.42. Found: C, 73.16; H, 7.15; N, 14.20; O, 5.42.
ACKNOWLEDGMENTS
R. P. M. thanks the Department of Science and Technology for providing a
grant under Fast Track Fellowship for Young Scientists [SR=FTP=CS-59=2007] to
carry out the research work. Authors thank H. M. Meshram and N. Nageswara
Rao, Indian Institute of Chemical Technology, Hyderabad, for providing a CEM
microwave synthesizer and for the help carrying out the reactions. Authors thank
Shri K. V. Vishnu Raju, chairman, and Shri K. Srinivas Reddy, dean, Shri Vishnu
Educational Society, and D. B. Raju, principal, Shri Vishnu College of Pharmacy,
for providing infrastructural facilities to carry out the research work.
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