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Synlett 2005(10): 1521-1526  
DOI: 10.1055/s-2005-869850
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of N-Protected β-Aminocyclopropanedicarboxylates and Their Ring Transformation to N-Benzhydryl-3-alkoxycarbonyl-4,4-dialkyl­pyrrolidin-2-ones

Sven Mangelinckx, Norbert De Kimpe*
Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure links 653, 9000 Gent, Belgium
Fax: +32(9)2646243; e-Mail: norbert.dekimpe@UGent.be;
Further Information

Publication History

Received 31 January 2005
Publication Date:
07 June 2005 (online)

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Abstract

An easy and short synthesis of new N-protected β-aminocyclopropanedicarboxylates, a rather unexplored class of highly activated conformationally constrained β-amino acid derivatives, is described. Michael-induced ring closure (MIRC) of diphenylmethylidenamine to 2-bromoalkylidenemalonates leads to 3,3-dialkyl-2-(diphenylmethylidenamino)cyclopropane-1,1-dicarboxylates, the reactivity of which with hydrides was investigated, yielding 3-(alkoxycarbonyl)pyrrolidin-2-ones.

Key words

Michael-induced ring closure - rearrangement - cyclopropanes - β-amino acids - N-heterocycles

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General Experimental Procedure.
t-BuOH was dried by distillation over CaH2. To a mixture of malonate 3 (10 mmol) and anhyd t-BuOH (15 mL) was added diphenylmethylidenamine (10 mmol) and Et3N (10 mmol). The reaction mixture was stirred at reflux temperature (4a: 16 h; 4b, 4d: 85 h; 4c: 24 h). For 4c, 0.7 equiv of t-BuOK were added and the reaction mixture was stirred at reflux temperature overnight. The reaction mixture was then evaporated, diluted with dry Et2O (40 mL), filtered and concentrated. The pure cyclopropanes 4 were obtained by flash column chromatography (neutral Al2O3, hexane-Et2O, 2:1) and recrystallisation (Et2O-hexane) for 4a; repeated flash column chromatography (basic Al2O3, hexane-Et2O, 9:1) for 4b-d.

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All compounds gave satisfactory analytical and spectral data.
Dimethyl 3-[(Diphenylmethylidene)amino]-2,2-dimethylcyclopropane-1,1-dicarboxylate ( 4a).
White crystals. R f (neutral Al2O3, hexane-Et2O 2:1) = 0.32. Mp 87.3-87.7 °C. 1H NMR (270 MHz, CDCl3): δ = 1.14 (s, 3 H), 1.56 (s, 3 H), 3.47 (s, 1 H), 3.68 (s, 3 H), 3.74 (s, 3 H), 7.22-7.59 (m, 10 H). 13C NMR (67.5 MHz, CDCl3): δ = 18.5, 20.5, 34.4, 46.2, 52.2, 52.5, 55.8, 128.0, 128.35, 128.41, 128.44, 128.8, 130.0, 136.2, 139.3, 166.9, 168.5, 169.2. IR (KBr): ν = 1745, 1731, 1618 cm-1. MS (ES, pos. mode): m/z (%) = 366 (100) [M + H+]. Anal. Calcd for C22H23NO4: C, 72.31; N, 3.83. Found: C, 72.04; N, 3.70.
Dimethyl 3-[(Diphenylmethylidene)amino]-2,2-diethylcyclopropane-1,1-dicarboxylate ( 4b).
Viscous oil. R f (silica gel, hexane-Et2O, 9:1) = 0.03. 1H NMR (300 MHz, CDCl3): δ = 0.80 (t, J = 7.4 Hz, 3 H), 1.01 (t, J = 7.4 Hz, 3 H), 1.28-1.57 (m, 2 H), 1.95-2.19 (m, 2 H), 3.51 (s, 1 H), 3.68 (s, 3 H), 3.72 (s, 3 H), 7.25-7.64 (m, 10 H). 13C NMR (75 MHz, CDCl3): δ = 9.8, 10.6, 20.3, 21.7, 44.2, 47.2, 52.1, 52.5, 55.9, 128.0, 128.3, 128.4, 128.5, 128.8, 129.9, 136.2, 139.5, 166.9, 167.0, 168.7. IR (NaCl): ν = 1732, 1622 cm-1. MS (ES, pos. mode): m/z (%) = 394 (100) [M + H+]. Anal. Calcd for C24H27NO4: C, 73.26; N, 3.56. Found: C, 73.02; N, 3.47.
Dimethyl 2-[(Diphenylmethylidene)amino]spi-ro[2.5]octane-1,1-dicarboxylate ( 4c).
White crystals. R f (silica gel, hexane-Et2O, 2:1) = 0.29. Mp 92.8-94.2 °C. 1H NMR (270 MHz, CDCl3): δ = 1.41-2.11 (m, 10 H), 3.50 (s, 1 H), 3.68 (s, 3 H), 3.72 (s, 3 H), 7.26-7.57 (m, 10 H). 13C NMR (67.5 MHz, CDCl3): δ = 25.3, 25.5, 26.1, 28.7, 30.1, 41.2, 47.1, 52.2, 52.5, 54.9, 128.0, 128.3, 128.4, 128.5, 128.8, 129.9, 136.2, 139.5, 166.9, 168.3, 168.7. IR (KBr): ν = 1749, 1728, 1623 cm-1. MS (ES, pos. mode): m/z (%) = 406 (100) [M + H+]. Anal. Calcd for C25H27NO4: C, 74.05; N, 3.45. Found: C, 73.91; N, 3.41.
Diethyl 3-[(Diphenylmethylidene)amino]-2,2-dimethylcyclopropane-1,1-dicarboxylate ( 4d).
White crystals. R f (silica gel, hexane-Et2O, 9:1) = 0.08. Mp 56.2-58.6 °C. 1H NMR (300 MHz, CDCl3): δ = 1.14 (s, 3 H), 1.16 (t, J = 7.15 Hz, 3 H), 1.23 (t, J = 7.15 Hz, 3 H), 1.59 (s, 3 H), 3.46 (s, 1 H), 4.06-4.23 (m, 4 H), 7.21-7.61 (m, 10 H). 13C NMR (75 MHz, CDCl3): δ = 14.1, 14.2, 18.5, 20.5, 34.2, 46.4, 55.6, 60.8, 61.3, 127.9, 128.4, 128.8, 129.9, 136.3, 139.4, 166.4, 168.1, 169.1. IR (KBr): ν = 1738, 1716, 1619 cm-1. MS (ES, pos. mode): m/z (%) = 394 (100) [M + H+]. Anal. Calcd for C24H27NO4: C, 73.26; N, 3.56. Found: C, 73.04; N, 3.44.

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These new compounds 7 and 8 gave satisfactory analytical and spectral data. Selected characterisation data.
Dimethyl {2-Methoxy-1,1-dimethyl-2-[(diphenylmethylidene)amino]ethyl}malonate ( 7).
Viscous oil. R f (petroleum ether-EtOAc, 4:1) = 0.24. 1H NMR (270 MHz, CDCl3): δ = 1.01 (s, 3 H), 1.31 (s, 3 H), 3.16 (s, 3 H), 3.50 (s, 3 H), 3.67 (s, 3 H), 3.81 (s, 1 H), 4.46 (s, 1 H), 7.16-7.19 (m, 2 H), 7.31-7.47 (m, 6 H), 7.66-7.70 (m, 2 H). 13C NMR (67.5 MHz, CDCl3): δ = 20.3, 20.9, 42.7, 51.7, 51.8, 56.0, 56.6, 94.9, 128.0, 128.1, 128.2, 128.4, 129.0, 130.6, 136.4, 139.2, 168.7, 168.8, 170.8. IR (NaCl): ν = 1756, 1732, 1620 cm-1. MS (70 eV): m/z (%) = no M+, 365 (60), 223 (83), 216 (72), 192 (81), 181 (44), 180 (100), 166 (57), 165 (78), 104 (39), 77 (38). Anal. Calcd for C23H27NO5: C, 69.50; N, 3.52. Found: C, 69.38; N, 3.44.
Dimethyl 4,4-Dimethyl-2,2-diphenyl-2,4-dihydro-3 H -pyrrole-3,3-dicarboxylate ( 8).
White crystals. R f (silica gel, petroleum ether-EtOAc, 7:3) = 0.22. Mp 112.6-113.6 °C. 1H NMR (300 MHz, CDCl3): δ = 1.27 (s, 6 H), 3.46 (s, 6 H), 7.12-7.26 (m, 6 H), 7.64 (br d, J = 7.71 Hz, 4 H), 7.71 (s, 1 H). 13C NMR (75 MHz, CDCl3): δ = 23.6, 51.9, 55.7, 75.2, 89.1, 126.8, 127.4, 128.9, 143.4, 169.7, 170.8. IR (KBr): ν = 1737, 1719, 1652 cm-1. MS (ES, pos. mode): m/z (%) = 366 (100) [M + H+]. Anal. Calcd for C22H23NO4: C, 72.31; N, 3.83. Found: C, 72.07; N, 3.75.

38

General Experimental Procedure.
To a mixture of cyclopropane 4 (0.5 mmol) and MeOH (3 mL) was added NaCNBH3 (1.25 mmol) and HOAc (0.6 mmol). The reaction mixture was stirred at r.t. (12a: 17 h; 12b: 42 h; 12c: 4 h; 12d and 11d: 48 h). The reaction mixture was poured into aq NaOH (0.5 N, 10 mL) and extracted with CH2Cl2 (3 × 5 mL). After drying of the organic layer (MgSO4), filtration and evaporation, the pure pyrrolidin-2-ones 12a-c, or the mixture of 12d and 11d was obtained. Analytically pure samples could be obtained upon recrystallisation (Et2O-hexane) for 12a; flash column chromatography (silica gel, petroleum ether-EtOAc, 4:1) for 12b,c; flash column chromatography (silica gel, hexane-Et2O, 4:1) for 12d and 11d.

39

All compounds gave satisfactory analytical and spectral data.
Methyl 1-Benzhydryl-4,4-dimethyl-2-oxopyrrolidine-3-carboxylate ( 12a).
White crystals. Mp 83.3-83.7 °C. 1H NMR (270 MHz, CDCl3): δ = 1.04 (s, 3 H), 1.11 (s, 3 H), 2.82 (d, J = 9.6 Hz, 1 H), 3.15 (s, 1 H), 3.23 (d, J = 9.6 Hz, 1 H), 3.72 (s, 3 H), 6.65 (s, 1 H), 7.21-7.35 (m, 10 H). 13C NMR (67.5 MHz, CDCl3): δ = 22.6, 28.6, 36.8, 52.0, 56.1, 58.8, 60.8, 127.4, 127.6, 128.3, 128.4, 128.5, 128.8, 138.0, 138.5, 169.4, 170.3. IR (KBr): ν = 1749, 1694 cm-1. MS (ES, pos. mode): m/z (%) = 338 (100) [M + H+], 167 (9). Anal. Calcd for C21H23NO3: C, 74.75; N, 4.15. Found: C, 74.36; N, 4.14.
Methyl 1-Benzhydryl-4,4-diethyl-2-oxopyrrolidine-3-carboxylate ( 12b).
Viscous oil. R f (silica gel, petroleum ether-EtOAc, 4:1) = 0.18. 1H NMR (300 MHz CDCl3): δ = 0.68 (t, J = 7.4 Hz, 3 H), 0.76 (t, J = 7.4 Hz, 3 H), 1.26-1.56 (m, 4 H), 2.87 (d, J = 10 Hz, 1 H), 3.23 (d, J = 10 Hz, 1 H), 3.25 (s, 1 H), 3.73 (s, 3 H), 6.64 (s, 1 H), 7.22-7.49 (m, 10 H). 13C NMR (75 MHz, CDCl3): δ = 7.6, 8.1, 24.8, 28.3, 43.4, 52.0, 53.0, 58.9, 59.1, 127.4, 127.8, 128.2, 128.4, 128.6, 129.1, 138.0, 138.6, 169.7, 170.6. IR (NaCl): ν = 1734, 1694 cm-1. MS (ES, pos. mode): m/z (%) = 366 (100) [M +H+], 167 (52). Anal. Calcd for C23H27NO3: C, 75.59; N, 3.83. Found: C, 75.34; N, 3.78.
Methyl 2-Benzhydryl-3-oxo-2-azaspiro[4.5]decane-4-carboxylate ( 12c).
Viscous oil. R f (silica gel, petroleum ether-EtOAc, 4:1) = 0.17. 1H NMR (300 MHz, CDCl3): δ = 1.11-1.57 (m, 10 H), 2.98 (d, J = 10 Hz, 1 H), 3.21 (d, J = 10 Hz, 1 H), 3.24 (s, 1 H), 3.72 (s, 3 H), 6.65 (s, 1 H), 7.15-7.44 (m, 10 H). 13C NMR (75 MHz, CDCl3): δ = 22.0, 22.5, 25.4, 32.1, 36.3, 40.7, 52.0, 53.1, 58.8, 60.2, 127.4, 127.7, 128.4, 128.5, 128.8, 138.1, 138.7, 169.4, 170.5. IR (NaCl): ν = 1736, 1694 cm-1. MS (ES, pos. mode): m/z (%) = 378 (100) [M + H+], 167 (35). Anal. Calcd for C24H27NO3: C, 76.36; N, 3.71. Found: C, 76.05; N, 3.61.
Ethyl 1-Benzhydryl-4,4-dimethyl-2-oxopyrrolidine-3-carboxylate ( 12d).
White crystals. R f (silica gel, hexane-Et2O, 4:1) = 0.27. Mp 94.9-96.1 °C. 1H NMR (300 MHz, CDCl3): δ = 1.06 (s, 3 H), 1.12 (s, 3 H), 1.26 (t, J = 7.15 Hz, 3 H), 2.81 (d, J = 9.63 Hz, 1 H), 3.12 (s, 1 H), 3.24 (d, J = 9.63 Hz, 1 H), 4.20 (q, J = 7.15 Hz, 2 H), 6.65 (s, 1 H), 7.21-7.38 (m, 10 H). 13C NMR (75 MHz, CDCl3): δ = 14.2, 22.6, 28.8, 36.9, 56.2, 58.9, 61.0, 61.2, 127.5, 127.8, 128.4, 128.6, 128.8, 138.1, 138.7, 169.0, 170.5. IR (KBr): ν = 1737, 1683 cm-1.
MS (ES, pos. mode): m/z (%) = 352 (100) [M + H+]. Anal. Calcd for C22H25NO3: C, 75.19; N, 3.99. Found: C, 74.98; N, 3.93.
Diethyl [2-(Benzhydrylamino)-1,1-dimethylethyl]malon-ate ( 11d).
Viscous oil. R f (silica gel, hexane-Et2O, 1:1) = 0.23. 1H NMR (300 MHz, CDCl3): δ = 1.11 (s, 6 H), 1.22 (t, J = 7.15 Hz, 6 H), 1.63 (br s, 1 H), 2.53 (s, 2 H), 3.69 (s, 1 H), 4.14 (q, J = 7.15 Hz, 4 H), 4.72 (s, 1 H), 7.17-7.37 (m, 10 H). 13C NMR (75 MHz, CDCl3): δ = 14.1, 24.0, 37.5, 57.4, 57.6, 60.9, 67.8, 126.9, 127.4, 128.4, 144.2, 168.7. IR (NaCl): ν = 3351, 1755, 1732 cm-1. MS (ES, pos. mode): m/z (%) = 398 (100) [M + H+]. Anal. Calcd for C24H31NO4: C, 72.52; N, 3.52. Found: C, 72.28; N, 3.43.