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. In touch with the recent developments we have also successfully reported aqueous phase and solvent free cycloaddition reactions of novel N-cyclohexyl-α-amino nitrone^4,5,6, N-phenyl-α-chloro nitrone⁷ in one pot. Surprisingly aqueous phase condition gave high yield, greater selectivity in a much lesser time⁸. Nitrones are versatile synthetic intermediates and excellent spin trapping reagents⁹ and can be used also as a stable potential oxidizing reagents in the synthesis of aldehydes^10-13 and ketones¹⁴. Keeping in touch with green synthesis of isoxazolidine derivatives¹⁵, we report herein for the first time high yield synthesis of some novel isoxazolidine derivatives in water at room temperature using novel N-phenyl-α-amino nitrone in a short reaction time (Scheme 1, Table 1).

EXPERIMENTAL:

¹H NMR spectra were recorded with a Bruker Avance DPX 300 spectrometer (300 MHz, FT NMR) using TMS as internal standard. ¹³C NMR spectra were recorded on the same instrument at 75 MHz. The coupling constants (J) are given in Hz. IR spectra were obtained with a Perkin-Elmer RX 1-881 machine as film or KBr pellets for all the products.

MS spectra were recorded with a Jeol SX-102 (FAB) instrument. The HRMS spectra were recorded on a DART-HRMS, JMS–T100LC, Accu-TOF instrument. TLC was carried out on Fluka silica gel TLC cards while column chromatography was performed with silica gel (E.Merck India) 60–200 mesh. All other reagents and solvents were purified after receiving from commercial suppliers. N-phenylhydroxylamine was prepared following standard methods available in literature and has been used in synthesis^16,17,18.

General procedure for the synthesis of nitrone 1 (R = Ph)

N-phenylhydroxylamine (250mg, 2.30 mmole) was added to dry, distilled formamide (0.9 mL, 1 equivalent) in water (15 mL) under N₂ atmosphere and the reaction mixture was kept at RT with constant stirring with a magnetic stirrer for 8 hr. The formation of nitrone was monitored by TLC (R_f = 0.33). After completion of reaction, the nitrone was extracted with ether (2 X 25 mL), the organic layer was washed with saturated brine (2 X 15 mL), dried over anhydrous Na₂SO₄ and concentrated. The nitrone was isolated under reduced pressure vaccum pump as white needle shape crystals (92%; m.p:42°C, uncorrected, UV_λmax: 238 nm) which decomposes at RT and hence trapped insitu for the cycloaddition reactions.

General procedure of cycloaddition in aqueous phase

To a stirred solution of N-phenylhydroxylamine and formamide (1 equivalent each) in 15 mL water dipolarophiles (1 equivalent) were added insitu at the time of formation of nitrone (monitored by TLC) and stirred at RT with a magnetic stirrer under N₂ atmosphere for 3-4 hr. The progress of the reaction was monitored by TLC.

After completion of the reaction, the products were extracted with ether (2 X 25 mL), the organic layer was washed with saturated brine (2 X 15 mL), dried over anhydrous Na₂SO₄ and concentrated. The mixture of diastereomers were purified and separated by column chromatography using ethyl acetate - hexane to afford cycloadducts 2-4 (Scheme 1). This procedure was followed for the substrates 1–3 listed in Table 1.

(3S)–3-(amino)-5-methyl-2-phenyldihydro-2H pyrrolo[3,4-d]isoxazole-4,6 (5H,6 a-H)-dione, 2a

White crystals.Yield 68%; R_f= 0.44; IR (KBr): 3385 (br), 3020 (m), 2900 (m), 1760 (s), 1665 (s), 1485 (m), 1305 (m), 1175 (s) cm^-1;¹H NMR (CDCl₃): δ 6.86 – 6.75 (m, 5H, C₆H₅), 5.80 (br,s, 2H, NH₂, exchanged in D₂O), 5.24 (d, 1H, J = 6.06 Hz, C₅H), 4.93 (dd, 1H, J = 6.60, 6.52 Hz, C₄H), 3.23 (d, 1H, J = 6.20 Hz, C₃H), 2.14 (s, 3H, CH₃);¹³C NMR (CDCl₃): δ 172.43, 171.00 (carbonyl carbons), 133.40, 131.00, 129.13, 127.90 (aromatic carbons), 84.76 (C₅), 77.42 (C₃), 55.82 (C₄), 37.60 (CH₃); MS: m/z 247 (M⁺), 232, 170, 155, 154 (B.P), 136, 77; HRMS – EI: Calcd for C₁₂H₁₃O₃N₃ (M) m/z 247.0930. Found: M⁺ 247.0914. Anal. Found: C, 58.19; H, 5.22; N, 16.89. C₁₂H₁₃O₃N₃requires C, 58.27; H, 5.30; N, 17.00%.

(3R)–3-(amino)-5-methyl-2-phenyl dihydro-2H pyrrolo[3,4-d]isoxazole- 4,6(5H,6 a-H)-dione, 2b

White crystals. Yield 28%; R_f= 0.52; IR (KBr): 3392 (br), 3028 (m), 2910 (m), 1764 (s), 1660 (s), 1482 (m), 1300 (m), 1170 (s) cm^-1;¹H NMR (CDCl₃): δ 6.73 – 6.64 (m, 5H, C₆H₅), 5.94 (br,s, 2H, NH₂, exchanged in D₂O), 5.15 (d, 1H, J = 2.54 Hz, C₅H), 4.70 (dd, 1H, J = 3.40, 3.10 Hz, C₄H), 2.12 (s, 3H, CH₃), 1.96 (d, 1H, J = 1.86 Hz, C₃H);¹³C NMR (CDCl₃): δ 175.20, 174.32 (carbonyl carbons), 135.18, 134.00, 132.95, 130.50 (aromatic carbons), 85.10 (C₅), 79.37 (C₃), 53.63 (C₄), 34.75 (CH₃); MS: m/z 247 (M⁺), 232, 231, 170, 154 (B.P), 136, 77; HRMS – EI: Calcd for C₁₂H₁₃O₃N₃ (M) m/z 247.0930. Found: M⁺ 247.0906. Anal. Found: C, 58.21; H, 5.24; N, 16.86. C₁₂H₁₃O₃N₃ requires C, 58.27; H, 5.30; N, 17.00%.

(3S)-3- (amino)- 2,5 diphenyl dihydro-2H pyrrolo[3,4-d]isoxazole-4,6(5H,6 a-H)- dione, 3a

Brown solid. Yield 70%; R_f= 0.54; IR (KBr): 3376 (br), 3032 (s), 2924 (s), 1760 (s), 1658 (s), 1476 (m), 1285 (m), 1180 (s) cm^-1; ¹H NMR (CDCl₃): δ 7.74 - 7.50 (m, 2 X 5H, C₆H₅protons), 6.18 (br,s, 2H, NH₂, exchanged in D₂O), 5.16 (d, 1H, J = 7.26 Hz, C₅H), 4.15 (dd, 1H, J = 7.24, 7.50 Hz, C₄H), 3.55 (d, 1H, J = 6.80 Hz, C₃H); ¹³C NMR (CDCl₃): δ 170.25, 168.43 (carbonyl carbons), 136.24, 135.17, 134.06, 133.28, 131.26, 129.53, 128.32, 127.95 (aromatic carbons), 85.27 (C₅), 74.57 (C₃), 57.42 (C₄); MS: m/z 309 (M⁺), 293, 292, 232, 216 (B.P), 136, 77; HRMS – EI: Calcd. for C₁₇H₁₅O₃N₃, (M) m/z 309.1110. Found: M⁺ 309.1096. Anal. Found: C, 65.85; H, 4.80; N, 13.49. C₁₇H₁₅O₃N₃ requires C, 65.99; H, 4.89; N, 13.59%.

Table 1 - Physical characteristics of the cycloadducts

Entry

Nitrone

Dipolarophile^a

Cycloadduct^band m.p (°C)

2a - 4a : cis ; 2b – 4b: trans

Cis/trans ratio

Time (hr)

Yield^c (%)

R = Me

N-methyl maleimide

2a: White crystals, 86

2b: White crystals, 67

2a:68

2b:28

3 (37)

96 (73)

R = Me

N-phenyl maleimide

3a:Brown solid, 74

3b:Yellow solid, 54

3a:70

3b:24

3 (38)

94 (70)

R = Me

N-cyclohexyl maleimide

4a: White solid, 96

4b: White crystals, 82

4a:63

4b:31

4 (40)

94 (66)

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

^bAll 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

(3R)-3- (amino)- 2,5 diphenyl dihydro-2H pyrrolo[3,4-d]isoxazole-4,6(5H,6a-H)-dione, 3b

Yellow solid. Yield 24%; R_f= 0.60; IR (KBr): 3382 (br), 3030 (s), 2920 (s), 1760 (s), 1660(s), 1485 (m), 1280 (m), 1186 (s) cm^-1; ¹H NMR (CDCl₃): δ 7.42 - 7.23 (m, 2 X 5H, C₆H₅protons), 6.05 (br,s, 2H, NH₂, exchanged in D₂O), 4.94 (d, 1H, J = 2.80 Hz, C₅H), 4.26 (dd, 1H, J = 2.08, 1.94 Hz, C₄H), 2.06 (d, 1H, J = 1.76 Hz, C₃H); ¹³C NMR (CDCl₃): δ 168.72, 167.00 (carbonyl carbons), 135.54, 133.62, 130.00, 129.10, 127.21, 126.05, 125.20, 124.33 (aromatic carbons), 87.44 (C₅), 76.64 (C₃), 55.07 (C₄); MS: m/z 309 (M⁺), 293, 232, 216 (B.P), 155, 136, 77; HRMS – EI: Calcd. for C₁₇H₁₅O₃N₃, (M) m/z 309.1110. Found: M⁺ 309.1087. Anal. Found: C, 65.86; H, 4.70; N, 13.43. C₁₇H₁₅O₃N₃ requires C, 65.99; H, 4.89; N, 13.59%.

(3S)-3- (amino)-5-cyclohexyl – 2- phenyl dihydro-2H pyrrolo[3,4-d]isoxazole-4,6(5H, 6a-H)-dione, 4a

White solid. Yield 63%, R_f = 0.48; IR (KBr): 3390 (br), 3033 (s), 2916 (s), 1766 (s), 1664(s), 1480 (m), 1270 (m), 1190 (s) cm^-1; ¹H NMR (CDCl₃): δ 6.98 - 6.93 (m, 5H, C₆H₅protons), 5.84 (d, 1H, J = 6.80 Hz, C₅H), 4.96 (br,s, 2H, NH₂, exchanged in D₂O), 3.51 (dd, 1H, J = 6.08, 6.14 Hz, C₄H), 3.27 (d, 1H, J = 6.12 Hz,C₃H), 1.62 – 1.15 (m,11H); ¹³C NMR (CDCl₃): δ 171.95, 169.37 (carbonyl carbons), 134.57, 132.28, 130.62, 128.85 (aromatic carbons), 84.30 (C₅), 73.70 (C₃), 57.52 (C₄), 24.53, 22.88, 20.43, 19,12, 17.80, 16.14 (cyclohexyl carbons); MS: m/z 315 (M⁺), 299, 238, 232, 222 (B.P), 136, 83, 77; HRMS – EI: Calcd. for C₁₇H₂₁O₃N₃, (M) m/z 315.1460. Found: M⁺ 315.1443. Anal. Found: C, 64.66; H, 6.64; N, 13.26. C₁₇H₂₁O₃N₃ requires C, 64.75; H, 6.71; N, 13.33%.

(3R)-3- (amino)-5-cyclohexyl – 2- phenyl dihydro-2H pyrrolo[3,4-d]isoxazole-4,6(5H, 6a-H)-dione, 4b

White crystals. Yield 31%, R_f = 0.55; IR (KBr): 3395 (br), 3030 (s), 2923 (s), 1762 (s), 1660(s), 1476 (m), 1276 (m), 1206 (s) cm^-1; ¹H NMR (CDCl₃): δ 6.90 - 6.82 (m, 5H, C₆H₅protons), 5.80 (d, 1H, J = 3.24 Hz, C₅H), 4.90 (br,s, 2H, NH₂, exchanged in D₂O), 3.56 (dd, 1H, J = 1.70, 1.86 Hz, C₄H), 1.92 (d, 1H, J = 2.46 Hz,C₃H), 1.78 – 1.22 (m,11H); ¹³C NMR (CDCl₃): δ 173.06, 171.00 (carbonyl carbons), 133.85, 132.04, 131.00, 129.16 (aromatic carbons), 85.00 (C₅), 72.96 (C₃), 59.04 (C₄), 26.42, 24.18, 23.22, 20.66, 18.67, 17.05 (cyclohexyl carbons); MS: m/z 315 (M⁺), 299, 298, 238, 232, 222 (B.P), 83, 77; HRMS – EI: Calcd. for C₁₇H₂₁O₃N₃, (M) m/z 315.1460. Found: M⁺ 315.1437. Anal. Found: C, 64.63; H, 6.60; N, 13.24. C₁₇H₂₁O₃N₃ requires C, 64.75; H, 6.71; N, 13.33%.

RESULTS AND DISCUSSION:

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. Novel N-phenyl-α-amino nitrone 1 has been synthesized from formamide following the general methodology suggested by Eschenmoser and his group¹⁹.

Excellent diastereofacial selectivity is observed in nitrone additions in water. The addition of nitrone 1 to maleimides result in a mixture of diastereomer 2a–4a and 2b–4b (almost 65:35 ratio in all cases) and generation of as many as three asymmetric centers in a single step. Studies of organic reactions in aqueous media shows that there is a higher probability of the formation of mixture of diastereomers when water is used as solvent rather than conventional organic solvents⁸. These results can be rationalized by an exo approach of nitrone 1 which has Z configuration for the formation of major cycloadducts 2a–4a (transition state I). The minor cycloadducts 2b–4b are formed by the endo approach of Z nitrone (transition state II). The mixture of diastereomers are identified by considering the multiplicity of the proton signals at 3-H and 4-H along with their coupling constant values^20,21. The most significant differences in the ¹H NMR data for the diastereomers are the position and multiplicity of the 3-H signal. In the minor adducts 2b–4b, 3-H resonates upfield around δ_H 2.00 while for the same proton in major adducts 2a–4a around δ_H 3.30 and J_3,4 ~ 6.20 Hz for major adducts whilst for minor adducts J_3,4is ~ 2.00 Hz. These differences can be explained by considering the available isoxazolidine ring conformations. Due to the 4,5-fused pyrrolidindione, the isoxazolidine ring adopts an envelope conformation and allowing for inversion, its nitrogen atom will either extend out from the envelope, i.e., minor conformation, or point inside the envelope, i.e., major conformation. The minor conformer has the N-lone pair antiperiplanar and therefore, capable of shielding 3-H proton, so this conformation is assigned to the minor conformer (Figure 1).

The diastereomeric isoxazolidines 2a–4a and 2b–4b were separated by column chromatography and obtained in analytically pure form. The endo/exo stereochemistry mentioned above is based on extensive NMR investigations. Most relevant are the coupling constants (J_{H3, H4}) of the diastereomers. For 2a-4a, this coupling constant is almost 6.50–7.00 Hz, implying a cis relationship between H-3 and H-4, whereas for 2b–4b, the coupling constant is almost 1.70–2.50 Hz which implies a trans relationship between H-3 and H-4^20,21. In all the diastereomers, the configurations of H-5 and H-4 are cis as evidenced from their coupling constant values.

The structures of 2–4 have been confirmed by ¹H and ¹³CNMR spectroscopy in CDCl₃ solution along with MS and IR spectra. ¹H NMR spectra and TLC studies of 2–4 indicate that these isoxazolidine derivatives are formed as a mixture of diastereomers in almost 65:35 ratio with cis and trans configurations relative to the spatial orientation of the NH₂ group at C₃ with respect to the H atom at C₄ position. These diastereomers have been separated by column chromatography and recrystallized from heptane-ethyl acetate²². 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 respectively²¹. In the ¹³C NMR spectrum, four signals were obtained in case of phenyl ring carbon atoms due to the equivalent nature of C-2 and C-6 and, C-3 and C-5 carbons. Studies of HRMS spectra shows almost exact mass in the majority of the compounds. In general, the reactions are very clean and high yielding compared to usual cycloaddition reactions of nitrones. No catalyst or co-organic solvent are required.

CONCLUSION:

In summary, the present procedure provides an example of green chemistry methodology for the synthesis of diastereoselective novel isoxazolidines in aqueous phase with high yield in a very 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:

Authors are thankful to Dr.M.P Kharel, Principal, Sikkim Government College for providing facilities and constant encouragement. We are pleased to acknowledge the financial support from UGC, New Delhi (Grant no:34-304/2008-SR) and also to SAIF-CDRI, Lucknow for providing spectral data.

REFERENCES:

1. Li C J., Chang T H. Organic reactions in aqueous media (Wiley, New York), 2007, 1997.

2. Hayashi Y. Angew Chem Int Ed (Engl), 2006, 45, 8103-8105.

3. Brogan A P., Dickerson T J., Janda K D. Angew Chem Int Ed (Engl), 2006, 45, 8100-8102.

4. Chakraborty B., Chettri M S. Indian J Chem, 2010, 49B, 103-106 and 394.

5. Chakraborty B., Chettri M S. Indian J Heterocyclic Chem, 2008, 18, 201-203.

6. Chakraborty B., Chettri M S., Samanta A. Indian J Chem, 2010, 49B, 1155-1160.

7. Chakraborty B., Kafley S., Chettri M S., Samanta A. Indian J Chem, 2010, 49B, 209-215.

8. Grieco P A. Organic synthesis in water (Blackie Academic and Professional, London), 1998.

9. Breuer E. The Chemistry of amino nitroso and nitro compounds, edited by S Patai (John Willy), 1982, 459.

10. Chakraborty B., Sharma P., Chhetri M S., Kafley S., Ghosh A R. Rasayan J Chem, 2009, 2 (4), 946-952.

11. Chakraborty B., Chhetri M S. Indian J Chem, 2008, 47B, 485-488.

12. Chakraborty B., Sharma P., Kafley S., Rai N.,Chhetri M S. J Chem Res (RSC), 2010, 3, 147-150.

13. Chakraborty B., Kafley S., Chhetri M S., Sharma P., Ghosh A R. J Ind Chem Soc, 2010 (in press).

14. Chakraborty B., Kafley S., Chhetri M S., Sharma P., Ghosh A R. J Ind Chem Soc, 2010 (in press).

15. Chakraborty B., Sharma P., Rai N. Synth Commun, 2010 (in press).

16. Chakraborty B., Kafley S., Chhetri M S. Indian J Heterocycl Chem, 2008, 17, 213-216.

17. Chakraborty B., Kafley S., Chhetri M S. Indian J Chem, 2009, 48B, 447-451.

18. Chakraborty B., Kafley S., Chhetri M S. Indian J Heterocycl Chem, 2009, 18, 283-286.

19. Heinzer F., Saukup M,. Eschenmoser A. Helv Chim Acta, 1978, 61, 2851-2857.

20. Deshong P., Li W., Kennington J W., Ammon H L. J Org Chem, 1991, 56, 1364-1371.

21. Gandolfi R., Grunanger P. The Chemistry of Heterocyclic Compounds (Wiley Interscience), 1999, 49 (2), 774-791.

22. Najera C J M., Angew Chem Int Ed (Engl), 2005, 44, 6272-6275.

Received on 13.10.2010 Modified on 26.10.2010

Asian J. Research Chem. 4(2): February 2011; Page 289-292