7-Deazapurines: Synthesis of new pyrrolo[2,3-d]pyrimidin-4-ones catalyzed by a Br?nsted-acidic ionic liquid as a green and reusable catalyst

Article abstract of DOI:10.1016/j.cclet.2009.09.002

Some new 2-aryl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-ones have been prepared through cyclocondensation of 2-amino-1H-pyrrole-3-carboxamides with aromatic aldehydes followed by air oxidation in the presence of 3-methyl-1-(4-sulfonic acid)butylimidazolium hydrogen sulfate [(CH₂)₄SO₃HMIM][HSO₄], a Br?nsted-acidic ionic liquid, as a green and reusable catalyst in solvent-free conditions.

Full text of DOI:10.1016/j.cclet.2009.09.002

Available online at www.sciencedirect.com
Chinese Chemical Letters 21 (2010) 1–4
www.elsevier.com/locate/cclet
7-Deazapurines: Synthesis of new pyrrolo[2,3-d]pyrimidin-4-ones
catalyzed by a Brønsted-acidic ionic liquid as a green and
reusable catalyst
*
A. Davoodnia , M. Bakavoli, R. Moloudi, M. Khashi, N. Tavakoli-Hoseini
Department of Chemistry, Faculty of Sciences, Islamic Azad University, Mashhad Branch, Mashhad 91735-413, Iran
Received 2 July 2009
Abstract
Some new 2-aryl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-ones have been prepared through cyclocondensation of 2-amino-
1H-pyrrole-3-carboxamides with aromatic aldehydes followed by air oxidation in the presence of 3-methyl-1-(4-sulfonic
acid)butylimidazolium hydrogen sulfate [(CH2)4SO3HMIM][HSO4], a Brønsted-acidic ionic liquid, as a green and reusable
catalyst in solvent-free conditions.
# 2009 A. Davoodnia. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Pyrrolo[2,3-d]pyrimidin-4-ones; 7-Deazapurines; Aromatic aldehydes; Brønsted-acidic ionic liquids
Pyrrolo[2,3-d]pyrimidine (I) may be regarded as an analogue of purine (II) in which its N-7 has been replaced by a
CH group and therefore can be named as 7-deazapurine. Literature reports had already established pyrrolo[2,3-
d]pyrimidins as antitumor [1], antimicrobial [2], antiangiogenic [3] agents with potential application as enzyme
inhibitors [4]. 7-Deazapurine moiety is also found in some important antibiotics [5–7]. Moreover, these compounds
have been shown to induce neurogenesis in murine embryonic stem cells [8]. On the other hand, 7-deazapurines have
been synthesized as analogues of potent A1- and A2-adenosine receptor antagonists [9]. Some of 2-phenyl-4-
substituted aminopyrrolo[2,3-d]pyrimidin derivatives have been identified as selective A1-adenosine receptor
antagonists [10]. The later compounds are generally prepared from pyrrolo[2,3-d]pyrimidin-4-ones as precursors [10].
* Corresponding author.
E-mail addresses: adavoodnia@yahoo.com, adavoodnia@mshdiau.ac.ir (A. Davoodnia).
1001-8417/$ – see front matter # 2009 A. Davoodnia. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2009.09.002

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A. Davoodnia et al. / Chinese Chemical Letters 21 (2010) 1–4
Fig. 1. Brønsted-acidic IL structure.
Scheme 1.
Prompted by these findings and due to our interest in the synthesis of new heterocyclic compounds with potential
biological activities [11–16], in this paper we wish to report an efficient approach to the synthesis of new 2-aryl-3,7-
dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-ones 3a–i (7-deazapurines) using 3-methyl-1-(4-sulfonic acid)butylimidazo-
lium hydrogen sulfate [(CH2)4SO3HMIM][HSO4] (Fig. 1), a Brønsted-acidic ionic liquid (IL), as a green and reusable
catalyst through cyclocondensation of 2-amino-1H-pyrrole-3-carboxamides 1a–b with aromatic aldehydes followed
by air oxidation (Scheme 1).
Ionic liquids (ILs), being recognized as environmentally benign media, have been widely applied in many reactions
as catalysts or dual catalyst–solvent due to their low vapor pressure, reusability and high thermal and chemical stability
[17,18]. The introduction of Brønsted-acidic functional groups into cations or anions of the ILs, especially the SO3H-
functional groups, obviously enhanced their acidities and water solubilities [19–21]. Therefore, Brønsted-acidic ILs
can be used as highly efficient acidic catalysts. 3-Methyl-1-(4-sulfonic acid)butylimidazolium hydrogen sulfate
[(CH2)4SO3HMIM][HSO4] is one of Brønsted-acidic ILs that can be easily prepared from the inexpensive available
reagents [22]. There are many reports in the literature for the application of this catalyst in organic synthesis [22–24].
Treatment of 2-amino-1H-pyrrole-3-carboxamides 1a–b [25] with aromatic aldehydes in the presence of
[(CH2)4SO3HMIM][HSO4] as catalyst (Method A) in solvent-free conditions gave products identified as 2-aryl-3,7-
dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-ones 3a–i. In the absence of the catalyst, the products were obtained in low
yields, while good results were obtained in the presence of [(CH2)4SO3HMIM][HSO4]. The optimal amount of
[(CH2)4SO3HMIM][HSO4] was 20 mol%, the higher amount of the catalyst did not increase the yields noticeably. The
yields increased as the reaction temperature was raised and at 85 8C the products 3a–i were obtained in good yields.
Under these conditions, attempts to isolate the intermediates 2-aryl-1,2,3,7-tetrahydro-4H-pyrrolo[2,3-d]pyrimidin-4-
ones 2a–i failed when we carefully monitored the reactions. The formation of the products 3a–i was assumed to
proceed via a cyclocondensation reaction followed by air oxidation of the intermediates 2a–i (Scheme 1). The
structural assignments of new compounds 3a–i were based upon the spectral data (Section 1).
The preparation of the compounds 3a–i in boiling glacial acetic acid and in the absence of the catalyst (Method B)
was also investigated. Therefore, compounds 1a–b were refluxed with various aromatic aldehydes in glacial acetic
acid for the indicated time (Table 1). From the data in Table 1, it is obvious that in the presence of
[(CH2)4SO3HMIM][HSO4], the reaction times are shorter and the yields are higher which is a good indication of the
catalytic effect of the Brønsted-acidic IL.

A. Davoodnia et al. / Chinese Chemical Letters 21 (2010) 1–4
3
Table 1
Effect of the catalyst on the synthesis of compounds 3a–ia.
Entry
R
Ar
Method A
Method B
m.p. (8C)
Time (min)
Yield (%)b
Time (min)
Yield (%)b
3a
3b
3c
3d
3e
3f
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
C6H11
C6H11
C6H11
C6H11
3-ClC6H4
90
60
70
60
60
50
60
50
50
81
82
84
86
79
85
88
90
88
420
270
360
300
300
210
300
240
240
71
73
73
75
70
76
78
80
76
285–287
296–298
248–250
287–289
268–270
367–369
338–340
318–320
352–354
4-ClC6H4
3-MeC6H4
4-MeC6H4
4-MeOC6H4
4-ClC6H4
3g
3h
3i
3-MeC6H4
4-MeC6H4
4-MeOC6H4
a
Method A: carboxamides 1a–b (1 mmol), aromatic aldehyde (1.3 mmol) in the presence of [(CH2)4SO3HMIM][HSO4] (20 mol%) at 85 8C in
solvent-free conditions. Method B: carboxamides 1a–b (1 mmol), aromatic aldehyde (1.3 mmol) in boiling glacial acetic acid (15 mL).
b
Isolated yields.
In conclusion, we have reported the synthesis of some new 2-aryl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-ones
3a–i (7-deazapurines) through cyclocondensation of 2-amino-1H-pyrrole-3-carboxamides 1a–b with aromatic
aldehydes followed by air oxidation in the presence and absence of [(CH2)4SO3HMIM][HSO4], a Brønsted-acidic IL.
In the presence of [(CH2)4SO3HMIM][HSO4], the reaction times are shorter and the yields are higher. It is also
noteworthy to mention that the catalyst can be recovered and reused without loss of its structure and activity.
1. Experimental
All chemicals were commercially available and used without further purification. The Brønsted-acidic ionic liquid
[(CH2)4SO3HMIM][HSO4] was synthesized according to the literature. Melting points were recorded on an
electrothermal type 9100 melting point apparatus. The IR spectra were obtained on a 4300 Shimadzu
spectrophotometer as KBr disks. The 1H NMR (100 MHz) spectra were recorded on a Bruker AC 100 spectrometer.
The mass spectra were determined on a Shimadzu GCMS 17A instrument.
1.1. Preparation of 2-aryl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-ones 3a–i: general procedure
1.1.1. Method A
A mixture of 2-amino-1H-pyrrole-3-carboxamides 1a–b (1 mmol), the appropriate aromatic aldehyde (1.3 mmol)
and [(CH2)4SO3HMIM][HSO4] (0.2 mmol, 20 mol%) was heated on the oil bath at 85 8C for 50–90 min. The reaction
was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature and
then water was added. The precipitate was filtered off and recrystallized from EtOH/CHCl3 to give compounds 3a–i in
good yields. The catalyst is soluble in water and therefore could be recycled of the filtrate by evaporation of the water
in vacuo. The recovered catalyst was washed with diethyl ether, dried at 50 8C under vacuum for 1 h and reused in
another reaction without appreciable reduction in the catalytic activity. Such procedure applied for 3d in a second run
resulted in 84% yield.
1.1.2. Method B
To a solution of 2-amino-1H-pyrrole-3-carboxamides 1a–b (1 mmol) in boiling glacial acetic acid (15 mL), the
appropriate aromatic aldehyde (1.3 mmol) was added. The reaction mixture was heated under reflux for 3.5–7 h. After
the completion of the reaction (monitored by TLC, n-hexane:ethylacetate, 80:20), the mixture was cooled to room
temperature and allowed to stand at room temperature overnight. The precipitate was then collected and recrystallized
from EtOH/CHCl3 to give compounds 3a–i in good yields.
7-Benzyl-2-(3-chlorophenyl)-5,6-diphenyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 3a. 1H NMR (CDCl3): d
5.45 (s, 2H, CH2), 6.90–8.10 (m, 19H, arom-H), 11.32 (br s, 1H, NH); IR (KBr disc): y 1665 (C O), 3448 cmÀ1 (NH);
MS, m/z: 489 (M++2), 487 (M+).

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A. Davoodnia et al. / Chinese Chemical Letters 21 (2010) 1–4
7-Benzyl-2-(4-chlorophenyl)-5,6-diphenyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 3b. 1H NMR (CDCl3): d
5.47 (s, 2H, CH2), 6.90–8.30 (m, 19H, arom-H), 11.90 (br, 1H, NH); IR (KBr disc): y 1667 (C O), 3409 cmÀ1 (NH);
MS, m/z: 489 (M++2), 487 (M+).
1
7-Benzyl-2-(3-methylphenyl)-5,6-diphenyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 3c. H NMR (CDCl3):
d 2.30 (s, 3H, CH3), 5.41 (s, 2H, CH2), 6.85–8.10 (m, 19H, arom-H), 11.30 (br s, 1H, NH); IR (KBr disc): y 1666
(C O), 3393 cmÀ1 (NH); MS, m/z: 467 (M+).
1
7-Benzyl-2-(4-methylphenyl)-5,6-diphenyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 3d. H NMR (CDCl3):
d 2.36 (s, 3H, CH3), 5.41 (s, 2H, CH2), 6.80–8.10 (m, 19H, arom-H), 12.05 (br s, 1H, NH); IR (KBr disc): y 1667
(C O), 3378 cmÀ1 (NH); MS, m/z: 467 (M+).
7-Benzyl-2-(4-methoxyphenyl)-5,6-diphenyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 3e. 1H NMR
(CDCl3): d 3.71 (s, 3H, CH3O), 5.37 (s, 2H, CH2), 6.50–8.40 (m, 19H, arom-H), 12.50 (br s, 1H, NH); IR (KBr
disc): y 1656 (C O), 3395 cmÀ1 (NH); MS, m/z: 483 (M+).
2-(4-Chlorophenyl)-7-cyclohexyl-5,6-diphenyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 3f. 1H NMR
(CDCl3): d 1.10–2.20 (m, 8H, cyclohexyl), 2.50–3.05 (m, 2H, cyclohexyl), 3.80–4.30 (m, 1H, CH-N), 6.90–8.25
(m,14H, arom-H), 12.52(brs, 1H, NH);IR(KBrdisc):y1673(C O), 3386 cmÀ1 (NH);MS, m/z:481(M++2), 479(M+).
7-Cyclohexyl-2-(3-methylphenyl)-5,6-diphenyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 3g. 1H NMR
(CDCl3): d 1.05–2.20 (m, 8H, cyclohexyl), 2.32 (s, 3H, CH3), 2.55–3.10 (m, 2H, cyclohexyl), 3.80–4.30 (m, 1H,
CH-N), 7.00–8.20 (m, 14H, arom-H), 11.65 (br s, 1H, NH); IR (KBr disc): y 1649 (C O), 3380 cmÀ1 (NH); MS, m/z:
459 (M+).
7-Cyclohexyl-2-(4-methylphenyl)-5,6-diphenyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 3h. 1H NMR
(CDCl3): d 0.90–2.10 (m, 8H, cyclohexyl), 2.28 (s, 3H, CH3), 2.45–3.00 (m, 2H, cyclohexyl), 3.70–4.15 (m, 1H,
CH-N), 6.75–8.20 (m, 14H, arom-H), 12.09 (br s, 1H, NH); IR (KBr disc): y 1672 (C O), 3348 cmÀ1 (NH); MS, m/z:
459 (M+).
7-Cyclohexyl-2-(4-methoxyphenyl)-5,6-diphenyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 3i. 1H NMR
(CDCl3): d 0.90–2.20 (m, 8H, cyclohexyl), 2.40–3.00 (m, 2H, cyclohexyl), 3.55–4.15 (m, 4H, CH3O and CH-N),
6.40–8.30 (m, 14H, arom-H), 12.26 (br s, 1H, NH); IR (KBr disc): y 1648 (C O), 3395 cmÀ1 (NH); MS, m/z: 475
(M+).
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