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

Abstract

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.

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Introduction

Pyrrolo[2,3-d]pyrimidines represent an important class of compounds with diverse biological activities such as anti-microbial,¹ analgesic,² anti-inflammatory,³ anti-viral,⁴ anti-cancer,⁵ antioxidant and neuroprotective activity.⁶ Compounds with this ring system are protein kinase inhibitors,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 antineoplastic activity. Some of their representatives have significant 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 pp60^c-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]pyrimidine 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 chloroacetaldehyde¹⁶ which was first reported by Secrist et al., and later on modified by Kretschmer.¹⁷ Literature survey also revealed some other methods of the synthesis of pyrrolo[2,3-d]pyrimidines.¹⁸ Very recently, Kaim et al. reported the 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.

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 pharmaceutical 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

As a part of our continued interest in the synthesis of diverse heterocyclic compounds²⁵ of biological importance, particularly diverse heterocycle fused uracil derivatives,²⁶ we report herein a simple and efficient method for the synthesis of 5-arylamino-pyrrolo[2,3-d]pyrimidines 4 from the reaction of N,N-dimethyl-6-aminouracil 1, aryl glyoxal monohydrates 2 and aryl amines 3 under microwave irradiation using acetic acid as solvent as well as catalyst (Scheme 1).

Scheme 1 Synthesis of 5-arylamino-pyrrolo[2,3-d]pyrimidines.

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 optimization 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 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 1 Optimization of reaction conditions

Entry	Solvent	Catalyst	Temp (°C)	Time (min)	Yield (%)
1	EtOH	—	75	5	25
2	EtOH	PTSA	75	5	40
3	EtOH	InCl3	75	5	35
4	EtOH	Sc(OTf)3	75	5	30
5	CH3CN	PTSA	80	5	Trace
6	Toulene	PTSA	100	5	Trace
7	DMF	PTSA	100	5	Trace
8	AcOH	—	100	5	84
9	AcOH	—	110	5	88

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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 irradiation at 110 °C for 5 min, which afforded the 5-phenylamino-pyrrolo[2,3-d]pyrimidine 4a in 88% yield (Table 2). The structure of the compound was ascertained from the spectroscopic data and elemental analysis. The generality of the reaction was established by employing N,N-dimethyl-6-aminouracil 1 with various aryl glyoxal monohydrates 2 and aryl amines 3 in the reaction process which proceeded effectively to produce the 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 filtration, and purified by recrystallization from EtOH. The structures of the compounds were determined from their ¹H NMR, ¹³C NMR, IR, MS spectroscopic data and elemental analysis.

Table 2 Synthesis of pyrrolo[2,3-d]pyrimidines 4 under MW

Entry	Ar^1	Ar^2	Product	Yield (%)
1	Ph	Ph	4a	88
2	Ph	4-CH3Ph	4b	84
3	Ph	4-ClPh	4c	85
4	Ph	4-BrPh	4d	84
5	4-CH3Ph	Ph	4e	86
6	4-CH3Ph	4-CH3Ph	4f	84
7	4-CH3Ph	4-ClPh	4g	85
8	4-CH3Ph	4-BrPh	4h	84
9	4-OCH3Ph	Ph	4i	83
10	4-OCH3Ph	4-CH3Ph	4j	82
11	4-OCH3Ph	4-ClPh	4k	85
12	4-OCH3Ph	4-BrPh	4l	83
13	4-ClPh	Ph	4m	91
14	4-ClPh	4-CH3Ph	4n	87
15	4-ClPh	4-ClPh	4o	89
16	4-ClPh	4-BrPh	4p	88
17	4-BrPh	Ph	4q	90
18	4-BrPh	4-CH3Ph	4r	89
19	4-BrPh	4-ClPh	4s	88
20	4-BrPh	4-BrPh	4t	86

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On the basis of experimental results, a reasonable mechanism 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 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.

Scheme 2 Mechanism for the formation of compound 4.

Conclusion

In conclusion, we have developed a new and highly efficient microwave-assisted one-pot synthesis of pyrrolo[2,3-d]pyrimidines from the reaction of readily available N,N-dimethyl-6-aminouracil, aryl glyoxal monohydrates and aromatic amines. Moreover, the product viz 5-arylamino-pyrrolo-[2,3-d]pyrimidines represent a novel class of 5-substituted derivatives of the parent molecule. Acetic acid was used both as solvent and catalyst in the reaction process. The solid product formed were isolated simply by filtration and purified by recrystallization from ethanol. This is an elegant methodology for the synthesis of 5-arylamino-pyrrolo[2,3-d]pyrimidines as it involves three-component in one-pot reaction, non-conventional energy source, mild reaction condition, shorter reaction time and simple operational procedure. Further study of the reaction is in progress.

Experimental

General procedure for preparation of 4

In typical experimental procedure, equimolar amounts of N,N-dimethyl-6-aminouracil 1 (1 mmol, 0.155 g), phenyl glyoxal monohydrate 2a (1 mmol, 0.152 g), and aniline 3a (1 mmol, 0.093 g) in acetic acid (5 mL) were taken in the vessel of a Synthos 3000 microwave reactor, and irradiated under microwave 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 filtered and then purified 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)

White solid; yield: 304 mg (88%); mp > 300 °C; ¹H NMR (300 MHz, DMSO-d₆) δ 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) δ 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, cm⁻¹): 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 C₂₀H₁₈N₄O₂: 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.

Acknowledgements

The authors thank CSIR, New Delhi for financial support in the form of the Project CAAF-NE. PSN thanks UGC, New Delhi for Senior Research Fellowship.

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Footnote

† Electronic supplementary information (ESI) available: Compound characterizations data, ¹H NMR and ¹³C NMR Spectra. See DOI: 10.1039/c3ra47143h

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