Short communication
Tetrabutylammonium Bromide in Water as a Green Media for the Synthesis of Pyrano[2,3-d]pyrimidinone and Tetrahydrobenzo[#]pyran Derivatives
Akbar Mobinikhaledi1'* and Mohammad Ali Bodaghi Fard1'2
1 Department of Chemistry, Faculty of Sciences, Arak University, Arak 38156-879, Iran.
2 Payam Noor University, Farmahin, Markazi Province, Iran.
* Corresponding author: E-mail: a-mobinikhaledi@araku.ac.ir Fax: +98-861-4173406
Received: 01-03-2010
Abstract
Tetrabutylammonium bromide (TBAB) was used as a green catalyst for the synthesis of tetrahydrobenzo[b]pyran and pyrano[2,3-d]pyrimidinone derivatives in water as a solvent. Use of nontoxic reaction components, short reaction times, easy work-up and high yields are some important advantages of this method.
Keywords: Tetrabutylammonium bromide, multicomponent reaction, catalyst, Knoevenagl reaction.
1. Introduction
Recently, the development of environmentally benign and clean synthetic procedures has become the goal of organic synthesis. Water plays an essential role in life processes and also as a medium for organic reactions.1,2 The use of water as a reaction medium exhibits a remarkable benefit because of its highly polarity and therefore immiscibility with the most organic compounds. Reactions in aqueous media are environmentally safe, have less carcinogenic effects with a simple work up and are especially important in industry. Thus, there is a need for developing multicomponent reactions (MCR's) in water, without the use of any harmful organic solvents and catalysts.
Tetrahydrobenzo[b]pyrans are an important class of heterocyclic scaffolds in the field of drugs and pharmaceuticals. These compounds are widely used as anti-coagulant, diuretic, spasmolytic, anticancer and anti-anaphy-lactic agents.3-5 Numerous methods have been reported for the synthesis of 4H-benzo[b]pyrans.3,614 However, some of these methods have drawbacks such as long reaction times, use of expensive reagents, low yields, harsh reaction conditions, effluent pollution and tedious work-up procedures. On the other hand, due to the diverse bio-
logical properties of pyranopyrimidinone derivatives, there is a widespread interest in their synthesis. Compounds with an uracil moiety, have shown antitumor, antibacterial, anti hypertensive, hepatoprotective, vasodilator, antiallergic, antifungal, antimalarial and herbicidal activi-ties.15-20 There are several methods for the synthesis of pyranopyrimidinones under traditional thermal condition or microwave irradiation.21-25 Each of these methods has its own advantages with some limitations such as extreme experimental conditions, long reaction times, low yields, and effluent pollution.
In addition to its use as an ionic liquid, tetrabutylammonium bromide (TBAB) has been used as an efficient catalyst in various organic transformations.26-31 TBAB is an inexpensive, readily available and has inherent properties like environmental compatibility, greater selectivity, operational simplicity, non-corrosive nature and ease of reusability.
As a part of our work on one-pot multicomponent reactions (MCRs) for the synthesis of various heterocyclic compounds,32,33 we report here a highly efficient procedure for the preparation of 4H-benzo[b]pyrans and pyra-no[2,3-d]pyrimidinones via a domino Knoevenagel-cyclocondensation reaction using TBAB as a catalyst in water.
2. Results and Discussion
In a typical experimental procedure, a mixture of aromatic aldehyde 1, malononitrile 2, dimedone 3 or barbituric acid 5 in water under reflux condition, was stirred in the presence of a catalytic amount of TBAB (10 mol%) to afford the 4H-benzo[b] pyrans (4a-n) and pyrano[2,3-d] pyrimidinones (6a-h) in high yields (Scheme 1).
In Scheme 2 we have proposed a possible mechanism for this reaction. In the first step of the reaction, the olefin 8 is produced by a Knoevenagel condensation between aryl aldehyde 1 and malononitrile 3, promoted by TBAB. Barbituric acid in the presence of TBAB could be converted to its corresponding tetrabutylam-monium barbiturate 9 that could easily react with olefin 8 to give intermediate 10 which converts to product 6
Scheme 1: TBAB in water efficiently catalyzed the synthesis of pyrano[2,3-d]pyrimidinones and 4H-benzo[b]pyrans.
In the absence of TBAB, the reaction was not preceded and only a poor yield of products was obtained after 10 h.
The structure of products was confirmed by physical and spectroscopic (IR, 1H NMR) data, and by elemental analysis. The work-up of the reaction is accomplished by simple filtration of the product after cooling of the reaction mixture, followed by recrystalization. Tables 1 and 2 show the results obtained in the reaction of a series of aldehydes with malononitrile and dimedone or barbituric acid. Reactions are very clean and yield 4H-ben-zo[b] pyrans (4a-n) or pyrano[2,3-d] pyrimidinones (6a-h) as a sole products within short reaction times in good to high yields.
after proton transfer and tautomerization. The formation of intermediate 8 was confirmed by the separate condensation of benzaldehyde and malonitrile in the presence of TBAB.
3. Experimental
3. 1. General
Melting points were determined using an electro thermal digital apparatus and are uncorrected. IR spectra were recorded on a Galaxy series FT-IR 5000 spectrometer and NMR spectra were recorded on a
Table 1: TBAB catalyzed synthesis of 4H-benzo[b]pyrans in water.
Product Ar		Time	Yield	m.p.	(°C)
		(min)	(%)a	Found	Reported [Llt.
4a	C6H5	40	90	227-229	228-230 [6
4b	4-Br-C6H4	30	95	205-207	203-205 [7
4c	3-CI-C6H4	45	89	229-231	224-225 [9
4d	4-CI-C6H4	35	94	212-214	209-211 [6
4e	2,3-Cl2-C6H3	40	90	249-252	252-254 [13b
4f	2,4-0,-^	30	92	182-183	180-182 [13b
4g	4-OH-C6H4	35	90	205-207	206-208 [13a
4h	3-OH-C6H4	35	91	229-231	236-238 [13a
4i	3-NO2-C6H4	40	90	210-212	212-214 [9
4j	4-NO2-C6H4	45	93	178-180	177-178 [9
4k	2-NO2-C6H4	45	91	227-230	224-226 [9
41	4-CH3-C6H4	30	94	212-215	223-225 [13a
4m	4-N(Me)2-C6H4	35	92	223-225	230 [12
4n	4-OCH3-C6H4	40	95	201-203	203 [12
a Yields refer to isolated products.
Table 2: TBAB catalyzed synthesis of pyrano[2,3-d]pyrimidinones in water.
Product Ar
6a 6b 6c 6d 6e 6f 6g 6h
4-Br-C6H4
3-Cl-C6H4
2.3-Cl2-C6H3
2.4-Cl2-C6H3
3-OH-C6H4 3-NO2-C6H4
4-CN-C6H4
Time	Yield	m.p. (°C)	
(min)	(%)a	Found	Reported [Lit]
25	85	229-230	230-231 [24]
30	80	242-244	240-241 [24]
35	88	243-245	240-242 [24]
30	90	239-241	241-242 [24]
30	87	160-162	158-160 [24]
35	81	271-272	268-270 [24]
35	80	239-241	239-240 [24]
30	88	252-253	254-256 [24]
Yields refer to isolated products.
Scheme 2: The proposed mechanism for one-pot synthesis of pyrano[2,3-d]pyrimidinones catalyzed by TBAB in water as a solvent medium.
Bruker 300 MHz spectrometer in DMSO-d6 using TMS as an internal standard. Microanalyses were performed by the Elemental Analyzer (Elemental, Vario EL III). The progress of the reaction was followed by TLC using n-hexane/ethyl acetate (3:1 v/v) as an elu-ent.
3. 2. General Procedure for Synthesis of Tetrahydrobenzo[£]pyrans and Pyrano[2,3-d]pyrimidinones:
A mixture of an aromatic aldehyde (1, lmmol), ma-lononitrile (2,1 mmol), dimedone (3, 1mmol) or barbituric
4-NO2-C6H4
acid (5,1 mmol) and TBAB (10% mol) in H2O (10 ml) was stirred under reflux condition for a suitable time (see Table 1). After completion of the reaction as indicated by TLC, water was added and the mixture cooled in a refrigerator. The solid product was filtered and washed with cold water (2 x 10 ml). The pure product was obtained by re-crystallization from ethanol:water (4:1).
3. 3. Selected Data for Products (4a-n), (6a-h) and Intermediate 8
Intermediate 8: IR (KBr) v: 3032, 2224, 1591, 1568, 1450, 1217, 678 cm1.1H NMR (300 MHz, CDCl3) 5: 7.13 (2H, t, H-Ar), 7.22 (1H, t, H-Ar), 7.37 (1H, s, H-Vinyl), 7.50 (2H, d, H-Ar) ppm. Anal. Calcd for C10H6N2: C, 77.91; H, 3.92; N, 18.17. Found C, 78.05; H, 3.98; N, 18.04.
4a: IR (KBr) v: 3393, 3317, 3185, 2958, 2196, 1687, 1652, 1367 cm-1. 1H NMR (300 MHz, DMSO-d6) 5: 0.94 (3H, s, CH3), 1.04 (3H, s, CH3), 2.08 (1H, d, J = 16.0 Hz, H-6), 2.23 (1H, d, J = 16.0 Hz, H-6'), 2.50 (2H, m, CH2), 4.11 (1H, s, H-4), 7.06 (2H, br s, NH2), 7.19 (3H, m, H-Ar), 7.33 (2H, m, H-Ar) ppm. Anal. Calcd for C18H18N2O2: C, 73.45; H, 6.16; N, 9.52. Found C, 73.97; H, 6.79; N, 9.42.
4b: IR (KBr) v: 3398, 3319, 3211, 2966, 2191, 1683, 1656, 1369 cm-1. 1H NMR (300 MHz, DMSO-d6) 5: 0.97 (3H, s, CH3), 1.06 (3H, s, CH3), 2.12 (1H, d, J = 16.0 Hz, H-6), 2.28 (1H, d, J = 16.0 Hz, H-6'), 2.54 (2H, m, CH2), 4.21 (1H, s, H-4), 7.13 (2H, br s, NH2), 7.15 (2H, d, J = 8.5 Hz, H-Ar), 7.50 (2H, d, J = 8.5 Hz, H-Ar) ppm. Anal. Calcd for C18H17BrN2O2: C, 57.92; H, 4.59; N, 7.51. Found C, 58.17; H, 4.71; N, 7.43. 4f: IR (KBr) v: 3533, 3364, 3153, 2966, 2193, 1685, 1658, 1367 cm-1. 1H NMR (300 MHz, DMSO-d6) 5: 1.00 (3H, s, CH3), 1.06 (3H, s, CH3), 2.11 (1H, d, J = 16.0 Hz, H-6), 2.27 (1H, d, J = 16.0 Hz, H-6'), 2.47-2.61 (2H, m, CH2), 4.70 (1H, s, H-4), 7.15 (2H, br s, NH2), 7.25 (1H, d, J = 8.4 Hz, H-Ar), 7.39 (1H, d, J = 8.4 Hz, H-Ar), 7.56 (1H, s, H-Ar) ppm. Anal. Calcd for C18H16Cl2N2O2: C, 59.52; H, 4.44; N, 7.71. Found C, 59.91; H, 4.63; N, 7.63. 4j: IR (KBr) v: 3394, 3323, 3213, 2970, 2193, 1683,
1655,	1523, 1365 cm-1. 1H NMR (300 MHz, DMSO-d6) 5: 0.99 (3H, s, CH3), 1.06 (3H, s, CH3), 2.14 (1H, d, J = 16.0 Hz, H-6), 2.30 (1H, d, J = 16.0 Hz, H-6'), 2.53-2.57 (2H, m, CH2), 4.39 (1H, s, H-4), 7.24 (2H, br s, NH2), 7.48 (2H, d, J = 8.4 Hz, H-Ar), 8.21 (2H, d, J = 8.4 Hz, H-Ar) ppm. Anal. Calcd for C18H17N3O4: C, 63.71; H, 5.05; N, 12.38. Found C, 63.99; H, 5.17; N, 12.25.
4m: IR (KBr) v: 3381, 3321, 3209, 2962, 2191, 1682,
1656,	1367 cm-1. 1H NMR (300 MHz, DMSO-d6) 5: 0.97 (3H, s, CH3), 1.06 (3H, s, CH3), 2.10 (1H, d, J = 16.0 Hz, H-6), 2.27 (1H, d, J = 16.0 Hz, H-6'), 2.47-2.55 (2H, m, CH2), 2.87 (6H, s, -N(Me)2), 4.06 (1H, s, H-4), 6.66 (2H, d, J = 8.7 Hz, H-Ar), 6.95 (2H, br s, NH2), 6.97 (2H, d, J = 8.7 Hz, H-Ar) ppm. Anal. Calcd for C20H23N3O2: C,
71.19; H, 6.87; N, 12.45. Found: C, 71.49; H, 6.71; N, 12.33.
6a: IR (KBr) v: 3391, 3302, 3188, 3072, 2197, 1718, 1674, 1408, 1280 cm-1. 1H NMR (300 MHz, DMSO-d6) 5: 4.26 (1H, s, H-5), 7.20 (2H, br s, NH2), 7.22 (2H, d, J = 8.2 Hz, H-Ar), 6.51 (2H, d, J = 8.2 Hz, H-Ar) 11.12 (1H, br s, NH), 12.14 (1H, br s, NH) ppm. Anal. Calcd for C14H9BrN4O3: C, 46.56; H, 2.51; N, 15.51. Found C, 47.11; H, 24.63; N, 15.39.
6d: IR (KBr) v: 3389, 3305, 3184, 3078, 2193, 1718, 1676, 1410, 1282 cm-1. 1H NMR (300 MHz, DMSO-d6) 5: 4.75 (1H, s, H-5), 7.25 (2H, br s, NH2), 7.38 (2H, s, H-Ar), 7.57 (1H, s, H-Ar), 11.13 (1H, br s, NH), 12.17 (1H, br s, NH) ppm. Anal. Calcd for C14H8Cl2N4O3: C, 47.89; H, 2.30; N, 15.96. Found C, 47.772; H 2.41; N, 15.85.
4. Conclusions
We have developed an efficient and ecologically safe method for the synthesis of 4H-benzo[fc]pyrans and pyrano[2,3-d]pyrimidinone derivatives using a green procedure. This methodology has some advantages such as operational simplicity, neutral conditions, high yields, use of TBAB as a green, nontoxic and efficient catalyst, and easy work-up.
5. Acknowledgment
We gratefully acknowledge the Research Council of Arak University for the financial support.
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Povzetek
V prispevku je opisana uporaba tetrabutilamonijevega bromida (TBAB) kot okolju prijaznega katalizatorja za sintezo derivatov tetrahidrobenzo[ft]pirana in pirano[2,3-d]pirimidinona v vodi kot topilu. Pomembne prednosti te reakcije so kratki reakcijski časi, enostavna izolacija produkta, visoki izkoristki in uporaba nestrupenih reaktantov.