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Synlett 2006(3): 0369-0374  
DOI: 10.1055/s-2006-926259
LETTER
© Georg Thieme Verlag Stuttgart · New York

Michael-Induced Ring Closure to 2-Azidocyclopropane-1,1-dicarboxylates and their Staudinger Reduction to 5-Alkoxy-3-(alkoxycarbonyl)pyrrolidin-2-ones

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

Publication History

Received 8 November 2005
Publication Date:
06 February 2006 (online)

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Abstract

An easy and short synthesis of new β-azidocyclo­propanedicarboxylates, a rather unexplored class of conformationally constrained N-protected β-aminocyclopropanecarboxylic acid derivatives, is described. Michael-induced ring closure (MIRC) of sodium azide to 2-bromoalkylidenemalonates in alcoholic solvents leads to 3,3-dialkyl-2-azidocyclopropane-1,1-dicarboxylates, whereas other polar solvents give increasing amounts of competitive 2-azidoalkylidenemalonates. The reactivity of the azidocyclopropanes was investigated under reducing conditions, giving an easy access to diastereomeric mixtures of 5-alkoxy-3-(alkoxy­carbonyl)pyrrolidin-2-ones.

Key words

Michael-induced ring closure - cyclopropanes - β-azido acids - Staudinger reduction - ring expansion

12

General Procedure for the Synthesis of 3-Azido-2,2-dialkyl-1,1-dicarboxylates 9.
To a solution of 2-bromoalkylidenemalonate 8 13 (5 mmol) in MeOH (5 mL) (or EtOH for 9b) was added NaN3 (6 mmol). The reaction mixture was stirred at reflux for 14-16 h. The reaction mixture was then evaporated, diluted with dry Et2O, filtered and concentrated. The pure cyclopropanes 9a-c, γ-azido-α,β-unsaturated diesters 10a,b and olefin 11 13 were obtained by column chromatography (silica gel, PE-EtOAc, 4:1) for 9a and 10a; (silica gel, PE-Et2O, 9:1) for 9b and 10b; (silica gel, hexane-Et2O, 95:5) for 9c and 11.
Cyclopropanes 9a,b and γ-azido-α,β-unsaturated diesters 10a,b are reported as representative examples.
Dimethyl 3-Azido-2,2-dimethylcyclopropane-1,1-dicarboxylate (9a): colourless oil. R f = 0.47 (PE-EtOAc, 4:1). 1H NMR (270 MHz, CDCl3): δ = 1.24 (s, 3 H), 1.26 (s, 3 H), 3.70 (s, 1 H), 3.75 (s, 3 H), 3.79 (s, 3 H). 13C NMR (68 MHz, CDCl3): δ = 17.9, 19.6, 31.1, 42.3, 51.9, 52.5, 52.9, 165.8, 167.7. IR (NaCl): ν = 2113, 1732 cm-1. MS (ES, pos. mode): m/z (%) = 200(19) [M - N2 + H+], 173 (100) [M - CHN3 + H+]. Anal. Calcd for C9H13N3O4: C, 47.57; H, 5.77; N, 18.49. Found: C, 47.32; H, 5.69; N, 18.65.
Dimethyl (2-Azido-2-methylpropylidene)malonate (10a): colourless oil. R f = 0.32 (PE-EtOAc, 4:1). 1H NMR (270 MHz, CDCl3): δ = 1.49 (s, 6 H), 3.80 (s, 3 H), 3.87 (s, 3 H), 6.80 (s, 1 H). 13C NMR (68 MHz, CDCl3): δ = 26.5, 52.6, 52.8, 60.7, 127.2, 148.0, 164.0, 166.2. IR (NaCl): ν = 2110, 1737, 1654 cm-1. MS (EI, 70 eV): m/z (%) = no [M+], 196 (2), 185 (59), 184 (10), 168 (3), 154 (5), 153 (53), 125 (10), 124 (11), 88 (11), 86 (73), 84 (100), 59 (10). Anal. Calcd for C9H13N3O4: N, 18.49. Found: N, 18.21.
Diethyl 3-Azido-2,2-dimethylcyclopropane-1,1-dicarboxylate (9b): colourless oil. R f = 0.39 (PE-Et2O, 4:1). The 1H NMR and 13C NMR data are in good agreement with reported data, with the exception that in the 1H NMR the signals at δ = 1.23 and 1.27 ppm are two times a singlet and not doublet of doublet, and in the 13C NMR, the signals for CHN3 (δ = 51.6 ppm) and CMe2 (δ = 30.7 ppm) were mistakenly attributed.11 1H NMR (300 MHz, CDCl3): δ = 1.23 (s, 3 H), 1.27 (s, 3 H), 1.27 (t, J = 7.15 Hz, 3 H), 1.31 (t, J = 7.15 Hz, 3 H), 3.68 (s, 1 H), 4.11-4.31 (m, 4 H). 13C NMR (75 MHz, CDCl3): δ = 14.1, 17.9, 19.6, 30.7, 42.8, 51.6, 61.4, 61.9, 165.2, 167.4. IR (NaCl): ν = 2112, 1729 cm-1. MS (ES, pos. mode): m/z (%) = 228 (17) [M - N2 + H+], 201 (100) [M - CHN3 + H+]. Anal. Calcd for C11H17N3O4: C, 51.76; H, 6.71; N, 16.46. Found C, 51.46; H, 6.65; N, 16.33.
Diethyl (2-Azido-2-methylpropylidene)malonate (10b): colourless oil. R f = 0.20 (PE-Et2O, 4:1). 1H NMR (300 MHz, CDCl3): δ = 1.30 (t, J = 7.15 Hz, 3 H), 1.36 (t, J = 7.15 Hz, 3 H), 1.49 (s, 6 H), 4.25 (q, J = 7.15 Hz, 2 H), 4.34 (q, J = 7.15 Hz, 2 H), 6.76 (s, 1 H). 13C NMR (75 MHz, CDCl3): δ = 13.97, 14.05, 26.6, 60.7, 61.7, 61.9, 128.0, 147.2, 163.6, 165.7. IR (NaCl): ν = 2111, 1735, 1655 cm-1. MS (ES, pos. mode): m/z (%) = 228 (52) [M - N2 + H+], 213 (100). Anal. Calcd for C11H17N3O4: C, 51.76; H, 6.71; N, 16.46. Found: C, 51.53; H, 6.63; N, 16.38.

15

Methyl 4-Azidobut-3-enoate (13): colourless oil. R f = 0.37 (PE-EtOAc, 4:1). 1H NMR (300 MHz, CDCl3): δ
(Z-isomer) = 3.14 (dd, J = 7.15 Hz, J = 1.65 Hz, 2 H), 3.70 (s, 3 H), 5.06 (dt, J = 7.43 Hz, J = 7.15 Hz, 1 H), 6.32 (dt, J = 7.43 Hz, J = 1.65 Hz, 1 H); δ (E-isomer) = 3.07 (dd, J = 7.43 Hz, J = 1.38 Hz, 2 H), 3.70 (s, 3 H), 5.45 (dt, J = 13.76 Hz, J = 7.43 Hz, 1 H), 6.03 (dt, J = 13.76 Hz, J = 1.38 Hz, 1 H). 13C NMR (75 MHz, CDCl3): δ
(Z-isomer) = 31.0, 52.0, 111.4, 128.3, 171.6; δ (E-isomer) = 34.5, 52.1, 111.8, 129.9, 171.6. IR (NaCl): ν = 2111, 1739, 1648 cm-1. MS (ES, pos. mode): m/z (%) = 283 (100)
[2 M + H+]. Anal. Calcd for C5H7N3O2: C, 42.55; H, 5.00; N, 29.77. Found: C, 42.35; H, 5.15; N, 29.63.

26

General Procedure for the Synthesis of Alkyl 5-Alkoxy-4,4-dialkyl-2-oxopyrrolidine-3-carboxylates (15).
To a solution of azidocyclopropane 9 (1 mmol) in dry THF (4 mL) under nitrogen atmosphere was added Ph3P (0.275 g, 1.05 mmol). The reaction mixture was stirred for 3 h at r.t. The reaction mixture was poured into H2O (10 mL) and extracted with CH2Cl2. After drying of the organic layer (MgSO4), filtration and evaporation, the pure pyrrolidin-2-ones 15 were obtained as diastereomeric mixtures after column chromatography (silica gel, PE-EtOAc).
Pyrrolidinone 15a is reported as a representative example.
Methyl 5-Methoxy-4,4-dimethyl-2-oxopyrrolidine-3-carboxylate (15a): amorphous white solid. R f = 0.29 and 0.22 (PE-EtOAc, 1:3). Mp 73.8-74.7 °C. Spectral data obtained from the mixture of two isomers (ratio 4:1). 1H NMR (300 MHz, CDCl3): δ = 1.09 (s, 3 H), 1.25 (s, 3 H), 2.98 (s, 1/5 H), 3.34 (s, 12/5 H), 3.36 (s, 3/5 H), 3.37 (s, 4/5 H), 3.73 (s, 3/5 H), 3.76 (s, 12/5 H), 4.31 (d, J = 1.24 Hz, 4/5 H), 4.33 (d, J = 1.10 Hz, 1/5 H), 8.62 (br s, 4/5 H), 8.67 (br s, 1/5 H). 13C NMR (75 MHz, CDCl3): δ (for the major isomer) = 22.1, 23.5, 44.2, 52.1, 55.9, 56.7, 93.2, 168.8, 174.4; δ (for the minor isomer) = 19.1, 29.5, 43.3, 52.2, 56.1, 59.0, 94.0, 169.1, 174.7. IR (KBr): ν = 3218, 3116, 1733, 1698 cm-1. LCMS (ES, pos. mode): m/z (for the major isomer, %) = 425 (7) [2 M + Na+], 202 (100) [M + H+]; m/z (for the minor isomer, %) = 425 (7) [2 M + Na+], 170 (100) [M - MeOH + H+]. Anal. Calcd for C9H15NO4: C, 53.72; H, 7.51; N, 6.96. Found: C, 53.47; H, 7.58; N, 6.88.

31

5-Methoxy-3-(methoxycarbonyl)-4,4-dimethyl-1-(triphenylphosphonio)-4,5-dihydro-1 H -pyrrol-2-olate (20a): hygroscopic white crystals; mp 76.5-78.0 °C. 1H NMR (300 MHz, CDCl3): δ = 1.32 (s, 3 H), 1.46 (s, 3 H), 2.65 (s, 3 H), 3.63 (s, 3 H), 3.87 (s, 1 H), 7.50-7.80 (m, 15 H). 13C NMR (75 MHz, CDCl3): δ = 20.4, 28.5, 46.5 (d, 3 J P,C = 9.2 Hz), 49.4, 56.5, 79.9 (d, 3 J P,C = 8.1 Hz), 97.0 (d, 2 J P,C = 3.5 Hz), 122.3 (d, 1 J P,C = 105.0 Hz), 129.4 (d, 3 J P,C = 13.9 Hz), 133.9 (d, 4 J P,C = 2.3 Hz), 134.1 (d, 2 J P,C = 11.5 Hz), 165.5, 167.6. 31P NMR (121 MHz, CDCl3): δ = 34.8. IR (KBr): ν = 1667, 1615 cm-1. MS (ES, pos. mode): m/z (%) = 462 (100) [M + H+].