Vijay B.
Yadav
,
Pragati
Rai
,
Hozeyfa
Sagir
,
Akhilesh
Kumar
and
I. R.
Siddiqui
*
Laboratory of Green Synthesis, Department of Chemistry, University of Allahabad, Allahabad, 211002, India. E-mail: dr.irsiddiqui@gmail.com; Tel: +91-9335153359
First published on 22nd November 2017
Herein, we present the synthesis of pyrrolo[2,3-d]pyrimidine derivatives, which are important heterocyclic scaffolds in the field of synthetic and pharmaceutical research, via biomimetic catalysis. This strategy involves the use of β-cyclodextrin as a reusable promoter and water as an eco-friendly reaction medium. The merits of this protocol are high atom economy, mild reaction conditions, good yields of desired products in short reaction times, and reusable reaction medium.
Pyrrolo[2,3-d]pyrimidine is a basic structural feature widely distributed in several natural products as well as in synthetic drugs.4 Pyrrolo[2,3-d]-pyrimidine is structurally similar to purines and pyrimidines, which shows varied biological activities such as antitumor,5 antiviral,6 antifolate,7 antagonist to receptors,8 analgesic,9 antimicrobial,10 antifungal,11 anticancer,12 antibiotic,13 and antiproliferative.14 In addition, its derivatives are powerful inhibitors of protein kinases, such as the enzyme Janus kinase 3 (JAK 3), and therefore, beneficial for the treatment of several immunological syndromes.15 Various clinically permitted medicines have pyrrolo[2,3-d]-pyrimidine nuclei, for example, pemetrexed, used in chemotherapy for the treatment of pleural mesothelioma and lung cancer,16 and to facitinib, utilized in the treatment of rheumatoid arthritis (RA), psoriasis, and inflammatory bowel disease.17 Pyrrolo[2,3-d]pyrimidine and its derivatives also display strong UV-blue fluorescence and are used as fluorescent functional resources.18 Thus, considering their wide applications, various methods have been reported for the synthesis of this targeted moiety. However, most of these protocols suffer from several limitations such as the use of expensive, toxic, and non-recyclable catalysts, long reaction times, tedious work-ups, and formation of undesirable side products.19 Therefore, we decided to develop a more convenient and efficient synthetic procedure for the synthesis of the abovementioned moiety.
Scheme 1 Synthesis of pyrrolo[2,3-d]-pyrimidine in the presence of β-cyclodextrin in an aqueous medium. |
Preliminary investigations on the title reaction were performed using arylglyoxal monohydrate (1a), malononitrile (2), and 6-amino-1,3-dimethyluracil (3) as model substrates to optimize the reaction conditions (Scheme 2).
Scheme 2 The model reaction to optimize the reaction conditions for the synthesis of pyrrolo[2,3-d]-pyrimidine. |
For optimization, the chemical reaction was carried out under several conditions. Initially, we optimized the catalyst for this transformation. When the reaction was carried out in the absence of β-cyclodextrin, a very low yield of the product was obtained in a longer reaction time. Further, in the presence of an ionic liquid, no significant increase in the yield was observed, and the time taken for the completion of the reaction was 5 hours (Table 1, entry 2). Cerric ammonium nitrate and bismuth triflate (Table 1, entries 3 and 4) provided a better yield of products than the ionic liquid. Malic acid provided higher yields as compared to the abovementioned catalysts (Table 1, entry 5). To our delight, a noticeable improvement in the yield of the product was observed when the reaction occurred in the presence of β-cyclodextrin (Table 1, entry 8).
Entry | Catalyst (10 mol%) | Time (h) | Yieldb (%) |
---|---|---|---|
a Reaction conditions: arylglyoxal monohydrate (1.0 mmol), malononitrile (1.0 mmol) and 6-amino-1,3-dimethyluracil (1.0 mmol), in water. b Isolated yield of product. | |||
1 | No catalyst | 5.0 | 21 |
2 | [Bmim]Br | 5.0 | 35 |
3 | Cerric ammonium nitrate | 5.0 | 41 |
4 | Bismuth(III) triflate | 5.0 | 47 |
5 | Malic acid | 5.0 | 49 |
6 | α-Cyclodextrin | 4.0 | 51 |
7 | γ-Cyclodextrin | 5.0 | — |
8 | β-Cyclodextrin | 1.5 | 89 |
After optimization of the catalyst, we optimized the loading amount of the catalyst. The best result was obtained for 10 mol% of catalyst that provided excellent yields of the corresponding products within 1.5 hours under aqueous conditions. However, an increase in the amount of catalyst did not result in any improvement in the yield of the product (Table 2, entry 3). The time taken for completion of the reaction was also the same. All the results are presented in Table 2.
Next, we optimized the temperature and found that temperature played an important role. When the reaction was carried out at room temperature, only a trace of product was obtained after a long reaction time (Table 3, entry 1). Subsequently, the temperature was increased from 40 °C to 75 °C. It was found that the yield of the product increased upon increasing the temperature, and 65 °C (Table 3, entry 3) was found to be optimum for this conversion.
After optimizing the reaction conditions, a variety of pyrrolo[2,3-d]pyridinedione derivatives were constructed, and the results are listed in Table 4. It was observed that various types of arylglyoxals having substitution on the phenyl ring undergo a smooth transformation via this proposed protocol. After the successful demonstration of this strategy, the scope of this methodology was extended with several thiols, and pyrrolo[2,3-d]pyrimidinedione derivatives were formed in good yields (Table 4, entry 4). Water was used as the reaction medium for all the entries at 65 °C. In all the cases, the yield of the product was good. The structures of all the corresponding products were confirmed via1H NMR and 13C NMR spectroscopies and mass spectrometry.
Entry | 1a–c | 4a–c | Yieldb (%) |
---|---|---|---|
a Reaction conditions: arylglyoxal monohydrate (1.0 mmol), malononitrile (1.0 mmol), and 6-amino-1,3 dimethyl uracil (1.0 mmol), in water with beta cyclodextrin (10 mol%) at 65 °C. b Isolated yield of product. c Reaction conditions: arylglyoxal monohydrate (1.0 mmol), thiols (1.0 mmol), and 6-amino-1,3 dimethyl uracil (1.0 mmol), in water with β-cyclodextrin (10 mol%) at 65 °C. d Isolated yield of product. | |||
1 | 85 | ||
2 | 89 | ||
3 | 88 |
Based on the abovementioned results and in accordance with the literature survey, a plausible reaction mechanism is proposed that illustrates the role of β-CD in the synthesis of pyrrolo[2,3-d]-pyrimidine. According to the literature and our experimental results, the mechanism proceeds via the activation of arylglyoxal by the OH group of β-cyclodextrin due to hydrogen bonding. In the first step, malononitrile reacts with arylglyoxal to provide the Knoevenagel product (a) that undergoes a Michael addition reaction with 6-aminouracil to form the adduct (b); the adduct (b) then undergoes ring opening to form the compound (6). The same pathway is followed to form adduct (c). Various thiols undergo nucleophilic addition to form compound (d), which further undergoes a cyclisation reaction to the form the desired products (5) (Scheme 3).
Footnote |
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c7nj03577b |
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