INTRODUCTION:

To run a chemical reaction under an environment friendly condition is a challenge now-a-days. The development of environmentally benign chemical processes have received much attention in recent years and water as solvent fulfils a major requirement because it is readily available, cheap and environmentally benign^1-3. Keeping in touch with our recent reports on green synthesis of isoxazolidine derivatives^4-7, we report herein for the first time synthesis of novel C,N-diphenyl-α-amino nitrone (1) and novel isoxazolidine derivatives (2-4) in water at room temperature with extremely high yield in a short reaction time (Scheme-1, Table-1). Nitrone (1) has been synthesized from benzamide following the general methodology suggested by Gilchrist and his group⁸.

EXPERIMENTAL:

Melting points were determined in open capillary tubes and are uncorrected. ¹H NMR spectra were recorded with a Bruker Avance DPX 400 spectrometer (400 MHz, FT NMR) using TMS as internal standard. ¹³C NMR spectra were recorded on the same instrument at 100 MHz. IR spectra were obtained with a Perkin-Elmer RX 1-881 machine as film or as KBr pellets for all the products. MS spectra were recorded with a Jeol SX-102 (FAB) instrument. The HRMS spectra were recorded on a Q – Tof micro instrument (YA–105). Elemental analyses (CHN) were performed with a Perkin-Elmer 2400 series CHN Analyzer. TLC’s were run on Fluka silica gel precoated TLC plates. All other reagents and solvents were purified after receiving from commercial suppliers. N-phenylhydroxylamine was prepared following standard methods available in the literature and has been used already for the synthesis of aldehydes^9-12, ketones¹³ and cycloaddition reactions with α-chloro^14,15 and amino nitrones¹⁶.

General procedure for the preparation of C,N-diphenyl-α-amino nitrone (1) in aqueous phase

To a well stirred solution of N-phenylhydroxylamine (250 mg, 2.29 mmol) in 15 mL water was added pure benzamide (277 mg, 1 equivalent). The reaction mixture was kept at RT with constant stirring with a magnetic stirrer under N₂ atmosphere for 7 hour. The formation of nitrone 1 was monitored by TLC (R_f = 0.55, silica gel; ethyl acetate : benzene = 1: 10). Nitrone 1 was isolated by extraction with ether (2 x 25 mL), the organic layer was washed with brine water (2 x 15 mL), dried over sodium sulphate and concentrated on a rotary evaporator and finally obtained as white niddle shaped crystals (87%; m.p 47⁰c, uncorrected). The nitrone decomposes rapidly at room temperature and hence in-situ cycloaddition reactions were performed instead of isolating the nitrone.

1. IR (KBr): 3234 (m), 1610 (s), 1345 (m), 1180 (m), 785 (s) cm^-1; ¹H NMR (CDCl₃): δ 7.20 (br, s, 2H, NH₂), 6.90 – 6.72 (m, 10H, C₆H₅ protons); ¹³C NMR (CDCl₃): δ 144.50 (C=N⁺), 138.80, 137.55, 135.82, 134.00, 133.00, 131.76,

130.90, 128.50 (aromatic carbons); HRMS – EI: Calcd. for C₁₃H₁₂N₂O, (M), 212.1220, Found, M⁺, 212.1205.

General Procedure for aqueous phase 1,3-dipolar cycloaddition reaction with nitrone 1

As nitrone 1 decomposes rapidly at room temperature, therefore in-situ reactions were performed for the synthesis of isoxazolidine derivatives. Dipolarophiles (1 equivalent) were added at the time of formation of nitrone 1 and the reaction mixture was stirred at RT with a magnetic stirrer under N₂ atmosphere for further 3 - 4 hour. The progress of the reaction was monitored by TLC. The crude products were isolated by extraction with ether (2 x 25 mL), the organic layer was washed with brine water (2 x 15 mL), dried over sodium sulphate and concentrated on a rotary evaporator and finally the crude cycloadducts were purified and separated by silica gel column chromatography using ethyl acetate – hexane combinations. This procedure was followed for the substrates listed in Table 1.

Table-1: Physical characteristics of the spiro cycloadducts

Entry	Nitrone	Dipolarophile^a	Cycloadduct^band m.p ( C)	Time (hr)	Yield^c (% )
1	R = Me	N-methyl maleimide	2: White crystals, 86	3 (25)	95 (71)
2	R = Me	N-phenyl maleimide	3: Brown solid, 74	3(28)	92(65)
3	R = Me	N-cyclohexyl maleimide	4: White solid, 96	4(29)	90(62)

^a Reaction condition : α-amino nitrone (2 mmol), dipolarophile (1 equivalent), water, N₂ atmosphere, RT

^b All the compounds were characterized by IR, ¹H NMR, ¹³C NMR, MS, HRMS spectral data.

^cIsolated yields after purification

Figures in parentheses indicate reactions performed in CH₂Cl₂

2. Spectral data of 3-amino-dihydro-5-methyl-2,3-diphenyl-2H-pyrrolo[3,4-d]isoxazole-4,6(5H,6aH)-dione

IR (KBr): 3296 – 3260 (br), 2824 (m), 1762 (s), 1660 (s), 1445 (m), 1360 (m), 780 (s) cm^-1; ¹H NMR (CDCl₃): δ 7.34 - 7.13 (m, 10H, C₆H₅protons), 7.03 (br, s, 2H, NH₂), 5.12 (d, 1H, J = 6.54 Hz, C₅H), 3.84 (d, 1H, J = 8.20 Hz, C₄H), 2.17 (s, 3H, CH₃); ¹³C NMR (CDCl₃): δ 188.20, 184.50 (carbonyl carbons), 136.30, 135.00,134.12, 133.40, 132.00, 131.28, 129.00, 128.10 (aromatic carbons), 89.27 (C₅), 77.43 (C₃)_, 59.00 (C₄), 32.76 (N-Me); MS (m/z): 323 (M⁺), 308, 246, 230, 216, 169, 77; HRMS - EI: Calcd. for C₁₈H₁₇O₃N₃ (M), 323.1720, Found; M⁺, 323.1704. Anal. Found: C, 66.72; H, 5.19; N, 12.84. C₁₈H₁₇O₃N₃ requires C, 66.84; H, 5.30; N, 13.00%.

3. Spectral data of 3-amino-dihydro-2,3,5-triphenyl-2H-pyrrolo[3,4-d]isoxazole-4,6(5H,6aH)-dione

IR (KBr): 3350 - 3290 (br), 2800 (m), 1760 (s), 1660 (s), 1470 (m), 1320 (m), 775 (s) cm^-1; ¹H NMR (CDCl₃): δ 7.55 - 7.24 (m, 15H, C₆H₅protons), 7.10 (br, s, 2H, NH₂), 4.82 (d, 1H, J = 6.06 Hz, C₅H), 3.90 (d, 1H, J = 9.08 Hz, C₄H); ¹³C NMR (CDCl₃): δ 178.90, 169.50 (carbonyl carbons), 138.90, 136.00, 135.00, 134.70, 132.65, 130.45, 129.12, 128.00, 127.22, 126.00, 124.80, 123.24 (aromatic carbons), 87.50 (C₅), 76.00 (C₃)_, 59.40 (C₄); MS (m/z): 385 (M⁺), 308, 292, 231, 154, 77; HRMS - EI: Calcd. for C₂₃H₁₉O₃N₃ (M), 385.1930, Found; M⁺, 385.1919. Anal. Found: C, 71.52; H, 4.83; N, 10.80. C₂₃H₁₉O₃N₃ requires C, 71.65; H, 4.97; N, 10.90%.

4. Spectral data of 3-amino-5-cyclohexyl-dihydro-2,3-diphenyl-2H-pyrrolo[3,4-d]isoxazole-4,6(5H,6aH)-dione

IR (KBr): 3320 - 3197 (br), 2846 (m), 1660 (s), 1365 (s), 1255 (s), 1140 (m), 780 (s) cm^-1; ¹H NMR (CDCl₃): δ 7.24 (br, s, 2H, NH₂), 7.05 – 6.86 (m, 10H, C₆H₅protons), 4.90 (d, 1H, J = 6.80 Hz, C₅H), 3.67 (d, 1H, J = 7.52 Hz, C₄H), 2.14 – 1.66 (m, 11H); ¹³C NMR (CDCl₃): δ 186.60,184.00 (carbonyl carbons), 135.80, 134.00, 133.20, 131.00, 130.32, 129.00, 128.00, 127.15 (aromatic carbons), 86.20 (C₅), 75.35 (C₃)_, 55.00 (C₄), 26.15, 25.00, 23.65, 22.50, 21.00, 19.75 (cyclohexyl carbons); MS (m/z): 391(M⁺), 314, 298, 237, 231, 83, 77; HRMS – EI: Calcd. for C₂₃H₂₅O₃N₃ (M), 391.2410, Found; M⁺, 391.2391. Anal. Found: C, 70.43; H, 4.85; N, 10.66. C₂₃H₂₅O₃N₃ requires C, 70.55; H, 4.97; N, 10.74%.

RESULTS AND DISCUSSION:

1,3 dipolar cycloaddition reaction of nitrone 1 with maleimides are very fast (3-4 hrs) in water compared with organic solvents (Table-1). Studies of organic reactions in aqueous media shows that reactions are much more faster rather than conventional organic solvents¹⁷. It is possible that water promotes the reaction through hydrogen bond formation with the carbonyl oxygen atom of the α,β- unsaturated carbonyl compounds, thereby increasing the eletrophilic character at the β- carbon which is attacked by nucleophilic oxygen atom of the nitrone. Like most of the nitrones, nitrone 1 also exists exclusively in Z configuration and syn cycloadducts are formed from Z nitrone through an exo transition state geometry. Another important feature of these cycloaddition reaction is the introduction of chirality by a single step reaction. Three new chiral centers are developed in the newly formed cycloadducts at C₃, C₄, C₅ positions. The relative configurations of C₄, C₅ protons of the cycloadducts (2-4) are syn as evidenced by their coupling constant (J = 6.06 - 9.08 Hz, for C₄-C₅ protons) values^18,19. In these cycloaddition the C-C and C-O bond formation in the transition state may not happen in a synchronous manner. The C-C bond of isoxazolidine ring is more developed in the transition state than C-O bond. This process would afford products having syn configuration at C₅ and C₄ respectively¹⁹. Expected fragmentation peaks are obtained in mass spectra which gives strong evidence in favour of the structure of the novel isoxazolidines. ¹³C NMR spectra also agreed well with the assigned structures of nitrone 1 and cycloadducts (2-4). Studies of HRMS spectra shows almost exact masses in the reported novel isoxazolidines.

CONCLUSION:

In summary, the present procedure provides an example of green chemistry methodology for the synthesis of α-amino nitrone and novel isoxazolidines in aqueous phase with high yield in a short reaction time. The notable factors of this methodology are: (a) high yields (b) faster reaction (c) mild reaction conditions and (d) green synthesis avoiding use of organic solvents. Therefore, it is believed that procedure described here will find important applications in the synthesis of isoxazolidine derivatives and thereby offering greater scope for aqueous phase cycloaddition reactions.

ACKNOWLEDGEMENTS:

The authors are pleased to acknowledge the financial support from UGC, New Delhi (grant no.34-304/2008-SR). The authors are grateful to SAIF, CDRI, Lucknow and Prof. A.K Nanda, University of North Bengal, Darjeeling for providing spectral data. Finally, the authors would like to thank Prof. B.C. Ranu, IACS, Kolkata for his constructive ideas related to aqueous phase synthesis.

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Received on 14.06.2010 Modified on 28.06.2010

Asian J. Research Chem. 4(2): February 2011; Page 191-194