A mild process of carbon–carbon bond formation in aqueous medium: synthesis of bis(pyrrolo[2,3-d]pyrimidinyl)methanes, a novel class of compounds

Abstract

Bis(pyrrolo[2,3-d]pyrimidinyl)methanes, a novel class of compounds, were synthesized from the reaction of pyrrolo[2,3-d]pyrimidines and aldehydes/ketones via a mild process of carbon–carbon bond formation using iodine as catalyst in aqueous medium. The pure products were obtained in excellent yield via simple Buchner filtration.

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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 The 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, lots of efforts have been made towards the synthesis and molecular manipulation of this molecule.¹⁵ However, bis(pyrrolo[2,3-d]pyrimidine compounds are not known so far.

An important aspect of green chemistry relates to the elimination of volatile, flammable and toxic organic solvents and their replacement by inexpensive “green solvents”. Water fulfils all these harsh requirements as it is a naturally occurring inexpensive, non-toxic and abundant solvent. Consequently, in the last two decades, there has been increased recognition of the use of water as solvent in organic synthesis. In many cases, it offers advantages over those occurring in organic solvents in terms of selectivity and yields.¹⁶

Carbon–carbon bond formation is the core of organic synthesis which provides the foundation for the synthesis of complicated organic molecules from simpler ones.¹⁷ In the recent years C–C bond formation reaction in aqueous medium has got tremendous attention of the scientific community, and a number of reviews have appeared in literature.¹⁸

As a part of our continued interest in the synthesis of diverse heterocyclic compounds,¹⁹ particularly annelated pyrimidines of biological importance,²⁰ we report here the first synthesis of bis(pyrrolo[2,3-d]pyrimidinyl)methanes 3, a novel class of compounds, from the reaction of pyrrolo[2,3-d]pyrimidines 1(ref. 15e and 21) and aldehydes/ketones 2 via a mild process of carbon–carbon bond formation catalyzed by molecular iodine in aqueous medium (Scheme 1).

Scheme 1

We initiated the study with the reaction of 1,3-dimethylpyrrolo[2,3-d]pyrimidine-2,4-dione 1a and benzaldehyde 2a in presence of iodine as catalyst in different solvents (Table 1). The reaction did not occur in toluene, DMF and dioxane. However, some conversions were observed in protic solvents viz. methanol and ethanol in refluxing conditions (entry 4 & 5, Table 1). Interestingly, the reaction occurred smoothly in acetonitrile, even at room temperature giving 50–55% yield of the product 3a (entry 6, Table 1). Surprisingly, when water was used as solvent, it not only enhanced the rate of the reaction but also gave almost quantitative yield of the product at room temperature. Initially, it was observed that 1,3-dimethylpyrrolo[2,3-d]pyrimidine-2,4-dione 1a was not soluble in water and no reaction occurred even after stirring the reaction mixture for a long time. Then, we raised the reaction temperature to 80 °C, and noticed that the compound partially dissolved in water and participated in the reaction to give the desired product 3a in very low yield. Therefore, presuming the insolubility of the reactant was the problem, we considered the use of SDS (sodium dodecylsulfate) as a surfactant, since it forms micelles in water and can solubilize organic compounds, which are otherwise insoluble in water. Accordingly, we studied the reaction by utilizing 1,3-dimethylpyrrolo[2,3-d]pyrimidine-2,4-dione 1a (2 mmol) and benzaldehyde 2a (1 mmol) in presence of catalytic amount of iodine (5 mol%) at room temperature using water (5 mL) as solvent in the presence of a SDS (0.08 mmol). The compound 1a dissolved in a very short time and it was exciting to observe that the reaction occurred immediately on stirring the reaction mixture at room temperature and was complete in 2 h giving bis(pyrrolo[2,3-d]pyrimidinyl)methanes 3a in 96% yield. The solid product formed was isolated by simple Buchner filtration. Very interestingly, the filtrate was again used for another batch of the reaction of 1a and 2a without adding additional catalyst and SDS which afforded 55% yield of the product 3a. The structure of the compound was established from the spectroscopic data and elemental analysis. ¹H NMR spectra of compound 3a was first recorded using DMSO-d₆ as solvent, and then in (CDCl₃ + TFA) system. The ¹H NMR spectra (DMSO-d₆) clearly showed the presence of the isolated proton of 3a at δ 5.40 as singlet, the two isolated protons of the two symmetric indole rings at δ 5.76 as singlet, six protons of two symmetric >NMe groups at δ 3.19 as singlet. Unfortunately, the peak for the other two symmetric >NMe protons at δ 3.39 were overlapped with the solvent peak at δ 3.36. However, when the spectra was recorded in (CDCl₃ + TFA) system, clear peaks of the N–Me protons were observed, while the peaks for the >NH protons were disturbed by TFA of that solvent system. Again, as expected,^15e,21,22 the typical doublets at δ 6.77 in the ¹H NMR spectra of the pyrrolo[2,3-d]-pyrimidine 1a was not seen in the product 3a which further evidenced that the 2-position of the compound 1a was involved in the reaction process. The reaction did not occur in absence of iodine. The generality of the reaction was established by synthesizing a series of compound 3b–t and characterizing them. Our observations are recorded in Table 2.

Table 1 Screening of solvents in the synthesis of 3a

Entry^a	Solvent	Temperature (°C)	Time (h)	Yield^b (%)
a Reaction conditions: N,N-dimethylpyrrolo[2,3-d]pyrimidinone 1a (2 mmol), benzaldehyde (1 mmol) and I2 (5 mol%), solvent (5 mL).b Isolated yield by filtration.c With SDS (0.08 mmol).
1	Toluene	20–80	2	NR
2	DMF	20–80	2	NR
3	Dioxane	20–80	2	NR
4	CH3OH	20–25	2	NR
		Reflux	2	20
5	C2H5OH	20–25	2	NR
		Reflux	2	25
6	CH3CN	20–25	2	55
7	Water^c	20–25	2	96

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Table 2 Synthesis of bis(pyrrolo[2,3-d]pyrimidinyl)-methanes 3^a

Ent.	R^1	R^2	R^3	R.T. (h)	Pd.	Yd.
a Ent. = entry; R.T. = room temperature; Pd. = product; Yd. = yield.
1	CH3	C6H5	H	2	3a	96
2	CH3	p-Me-C6H4	H	2	3b	92
3	CH3	p-OMe-C6H4	H	2	3c	90
4	CH3	p-Cl-C6H4	H	2	3d	93
5	CH3	p-Br-C6H4	H	2	3e	92
6	CH3	p-NO2-C6H5	H	2	3f	93
7	CH3	Thiophenyl	H	2	3g	90
8	CH3	(CH3)2CH	H	2	3h	91
9	CH3	CH3	CH3	2	3i	91
10	CH3	Cyclohexyl	—	2	3j	92
11	H	C6H5	H	3	3k	94
12	H	p-Me-C6H4	H	3	3l	94
13	H	p-OMe-C6H4	H	3	3m	95
14	H	p-Cl-C6H4	H	3	3n	96
15	H	p-Br-C6H4	H	3	3o	91
16	H	p-NO2-C6H5	H	3	3p	92
17	H	Thiophenyl	H	3	3q	90
18	H	(CH3)2CH	H	3	3r	90
19	H	CH3	CH3	3	3s	91
20	H	Cyclohexyl	—	3	3t	91

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We also studied the electronic effect of substituent in the reaction process. It was observed that the nature of substituent at aryl aldehyde does not affect the overall yield of the product and in all the cases reaction occurred with complete conversion of the starting materials. Aliphatic aldehyde (entries 8 and 18, Table 2), heterocyclic aldehyde viz. thiophene aldehyde (entries 7 and 17 Table 2) and ketones [both acyclic (entries 9 & 19) and cyclic (entries 10 & 20) Table 2] are equally active and produce excellent yield of the products. However, 1,3-dimethylpyrrolo[2,3-d]pyrimidine-2,4-dione 1a was found to be more reactive than 3-methylpyrrolo[2,3-d]pyrimidine-2-4-dione 1b and takes less time for the completion of the reactions.

The probable mechanism of the reaction is outlined in the Scheme 2. The 2-position of pyrrolo[2,3-d]pyrimidinenes is suitable for electrophiles attack which is well documented.^15e,21,22 In the present case, the reaction occurred via initial nucleophilic attack of 1,3-dimethylpyrrolo[2,3-d]pyrimidine-2,4-dione 1a on the benzaldehyde 2a in presence of iodine to give the intermediate [A] by the elimination of water molecule. The intermediate [A] then suffered a nucleophilic attack by the second 1,3-dimethylpyrrolo[2,3-d]pyrimidine-2,4-dione 1a molecule to give an intermediate [B] which rearranges to afford the final product 3a.

Scheme 2 Plausible mechanism for the formation of 3a.

In conclusion, we have reported the first synthesis of bis(pyrrolo[2,3-d]pyrimidinyl)methanes 3, a novel class of compounds via an environment friendly C–C bond formation reaction catalysed by molecular iodine. Water was used as solvent in the reaction, and only water was eliminated in the process of the formation of the product. The products were isolated in the pure form simply by Buchner filtration and washing with water. The reactants were consumed completely in the reaction process and thus products were obtained almost in quantitative yields. The filtrate, which contained the solvent, the catalyst and the surfactant, was successfully used for the second batch of the reaction. This synthesis, which produced a novel and very interesting class of compounds, is a valuable addition to the chemistry of pyrrolopyrimidines in particular and heterocyclic compound as a whole. Moreover, the reaction can further be explored for the synthesis of many other new and complex molecules leading to bioactive compounds. Further study of the reaction is in progress.

Experimental

General procedure for the preparation of 3a–3t

A mixture of 1,3-dimethylpyrrolo[2,3-d]pyrimidine-2,4-dione 1a (2 mmol, 362 mg), benzaldehyde 2a (1 mmol, 105 mg), I₂ (5 mol%, 6 mg) in water (5 mL) was taken in a round bottomed flask. To the reaction mixture SDS (sodium dodecylsulfate) (0.08 mmol, 23 mg) was added and allowed to stir at room temperature for two hour. Initially, the solid compound in the reaction mixture disappeared giving a clear brown solution which slowly changed to greenish brown in color. After completion of the reaction (monitored by TLC), the pink solid product 3a appeared was separated by Buchner filtration, washed with water, and dried. Yield: 428 mg (96%). The compound was recrystallized from methanol. Mp. 288–290 °C; ¹H NMR (DMSO-d₆, 300 MHz) δ 3.19 (s, 6H), 3.39 (s, 6H), 5.40 (s, 1H), 5.76 (s, 2H), 7.22–7.39 (m, 5H), 11.74 (s, 2H, NH); ¹³C NMR (DMSO-d₆, 75 MHz) δ 28.05 (2C), 31.10 (2C), 43.25, 98.46 (2C), 103.15 (2C), 127.50, 128.76 (2C), 128.88 (2C), 132.15 (2C), 139.64 (2C), 141.07, 151.18 (2C), 158.73 (2C); IR (KBr) ν_max: 3373.5, 3278.5, 1687.2, 1557.6 cm⁻¹; MS (ESI): 447.5 ([M + H]⁺); anal. cald. For C₂₃H₂₃N₆O₄: C, 61.87; H, 4.92; N, 18.82%; found: C, 61.88; H, 4.93; N, 18.83%.

Similarly, compounds 3b–t were synthesized and characterized.

Acknowledgements

We thank the CSIR, New Delhi for financial assistance (CAAF-NE project). MS thanks the DST, New Delhi for the INSPIRE Fellowship.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Compound characterizations data, ¹H NMR and ¹³C NMR spectra. See DOI: 10.1039/c4ra00897a

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