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Synlett 2005(6): 0976-0980  
DOI: 10.1055/s-2005-864800
LETTER
© Georg Thieme Verlag Stuttgart · New York

Functionalized 2-Chlorocyclopropanecarboxylates through the MIRC Reaction

Nicola Giubellina, 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 15 December 2004
Publication Date:
23 March 2005 (online)

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Abstract

Addition of 3,3-dichloro-1-azaallylic anions to acrylates smoothly gave cis-2-chloro-2-imidoylcyclopropanecarboxylates with complete diastereoselection. The resulting cyclopropanes are reduced to 2-(aminomethyl)-2-chlorocyclopropanecarboxylates or hydrolyzed to afford 2-acyl-2-chlorocyclopropylcarboxylates.

Key words

halogenated cyclopropane - activated olefin - 3,3-di­halo-1-azaallylic anion - MIRC reaction - γ-amino acid

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2-Chloro-2-[( N -isopropylimino)(phenyl)methyl]cyclo-propanecarboxylate 2a as Representative Procedure.
Diisopropylamine (6.0 mmol, 0.61 g) is placed in a 100 mL round-bottomed flask along with 50 mL of dry THF, and n-BuLi 2.5 N solution in hexane (5.5 mmol, 2.2 mL) is added at 0 °C under nitrogen atmosphere. Then, α,α-dichloroimine 1a (5.0 mmol, 1.15 g) is added dropwise in 5 mL of THF and the resulting red-brown solution is stirred for 20-30 min at 0 °C. The temperature is lowered to -78 °C and the acrylate (5.5 mmol, 0.47 g) is quickly added in 5 mL of THF, then the solution is kept at the same temperature for 1.5 h. Upon quenching with 1 mL of 0.5 N NaOH at -78 °C, the solution is washed with an additional 50 mL of 0.5 N NaOH solution and extracted with Et2O (50 mL × 3). The combined organic layers are dried over MgSO4 and evaporated to afforded a red-brown residue that is purified by recrystallization (Et2O) to yield 0.94 g of cyclopropylimine 2a (67 %) as yellow crystals. Flash chromatography of the mother liquor (petroleum ether-EtOAc, 9:1) additionally gave 0.14 g (10%) of compound 2a, along with 0.03 g of 5-phenylpen-tanoate 3a (2 %) and 0.18 g of pentane-1,5-dioate 4a (9%).
Methyl cis -2-Chloro-2-[( E , Z )-( N -isopropylimino)(phen-yl)methyl]cyclopropanecarboxylate ( 2a).
Anal. Calcd for C15H18ClNO2: C, 64.40; H, 6.49; N, 5.01. Found: C, 64.67; H, 6.59; N, 4.70. Spectral data of the pure E isomer: 1H NMR (270 MHz, CDCl3): δ = 0.99 (d, 3 H, J = 6.3 Hz, CH3), 1.04 (d, 3 H, J = 6.3 Hz, CH3), 1.89 (dd, 1 H, J = 5.7, 7.5 Hz, CH A H), 2.07 (dd, 1 H, J = 5.7, 9.3 Hz, CHH B ), 2.65 (dd, 1 H, J = 7.5, 9.3 Hz, CHCq), 3.40 [sept, 1 H, J = 6.3 Hz, CH(CH3)2], 3.76 (s, 3 H, OCH3), 7.15-7.19 (m, 2 H, CH), 7.38-7.42 (m, 3 H, CH) ppm. 13C NMR (68 MHz, CDCl3): δ = 21.1 (CH2), 23.6 (CH3), 23.7 (CH3), 29.2 (CHCq), 49.7 (C qCl), 52.3 (CHN), 52.5 (OCH3), 127.2 (CHarom. × 2), 128.4 (CHarom. × 2), 128.7 (CH), 135.6 (Cq), 164.1 (Cq), 168.9 (Cq) ppm. IR (KBr): ν = 1742 (C=O), 1635 (C=N) cm-1. MS (ES+): m/z = 280/282 [MH+]. Mp 79.3-80.4 °C (Et2O); yield 77 %, yellow crystals.
The spectral data of the Z-isomer are obtained from a 4:1 E/Z isomer mixture. 1H NMR (300 MHz, CDCl3): δ = 1.25 (d, 3 H, J = 6.0 Hz, CH3), 1.29 (d, 3 H, J = 6.0 Hz, CH3), 1.45 (dd, 1 H, J = 5.9, 8.2 Hz, CH A H), 2.06-2.15 (m, 2 H, CHH B and CHCq), 3.85 (s, 3 H, OCH3), 4.47 [sept, 1 H, J = 6.0 Hz, CH(CH3)2], 7.15-7.19 (m, 2 H, CH), 7.38-7.42 (m, 3 H, CH), 7.79-7.82 (m, 2 H, CH) ppm. 13C NMR (68 MHz, CDCl3): δ = 21.5 (CH2), 23.1 (CH3), 23.2 (CH3), 28.2 (CHCq), 39.3 (C qCl), 52.4 (CHN), 52.7 (OCH3), 127.7 (CHarom. × 2), 128.2 (CHarom. × 2), 129.8 (CH), 137.3 (Cq), 160.0 (Cq), 168.4 (Cq) ppm. Yield 10 % (flash chromatography, petroleum ether-EtOAc, 9:1, R f = 0.25).
Methyl ( E )-4,4-Dichloro-5-( N -isopropylimino)-5-phenylpentanoate ( 3a). Anal. Calcd for C15H19Cl2NO2: C, 56.97; H, 6.06; N, 4.43. Found: C, 57.16; H, 6.25; N, 4.31. 1H NMR (270 MHz, CDCl3): δ = 0.98 (d, 6 H, J = 6.3 Hz, CH3 × 2), 2.73-2.83 (m, 2 H, CH2), 2.91-3.01 (m, 2 H, CH2), 3.17 [sept, 1 H, J = 6.3 Hz, CH(CH3)2], 3.71 (s, 3 H, OCH3), 7.24-7.28 (m, 2 H, CH), 7.39-7.42 (m, 3 H, CH) ppm. 13C NMR (68 MHz, CDCl3): δ = 23.3 (CH3 × 2), 31.0 (CH2), 40.1 (CH2), 51.9, 53.3, 91.2 (CqCl2), 127.9 (CHarom. × 2), 128.7 (CHarom.), 129.1 (CHarom. × 2), 133.7 (Cq), 163.9 (C=N), 173.1 (C=O) ppm. IR (NaCl): ν = 1742 (C=O), 1645 (C=N) cm-1. MS (ES+): m/z = 316/318/320 [MH+]. Yield 21% (flash chromatography, petroleum ether-EtOAc 9:1, R f = 0.45).

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Upon recrystallization in Et2O, the cyclopropanecarboxylate 2a could be isolated in 67 % yield. A 1H NMR spectrum of the pure E isomer can be recorded in CDCl3 when the sample is freshly prepared. Leaving the compound in CDCl3 at r.t. resulted in a slow isomerization, affording a 4:1 mixture of E/Z after 4 d in solution. No changes in the equilibrium were observed, upon heating the CDCl3 solution at 70 °C for 30 min, or flushing with HCl gas through the CDCl3 solution, or by addition of 1 N NaOH aqueous solution. On the other hand, the crude reaction mixture of cyclopropane-carboxylate 2b afforded a 65:35 E/Z mixture, that slowly recrystallized in Et2O (1 week) in 15 % yield. The 1H NMR analysis of the crystals gave a spectrum identified as the nearly pure Z isomer (98-99 %, along with 1-2 % of E), converted in CDCl3 after 45 h at r.t. to a mixture of E/Z = 66:34.

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Procedure A: chlorocyclopropylimine 2a (0.5 mmol, 0.14 g) was dissolved at 0 °C in 2 mL of MeOH, then NaBH3CN (0.75 mmol, 47 mg) was added portionwise, followed by dropwise addition of HOAc (0.75 mmol, 45 mg). The reaction is brought to r.t. and stirred up to consumption of starting products (3-6 h, TLC, petroleum ether-EtOAc, 9:1).
Procedure B: chlorocyclopropylimine 2b (0.5 mmol, 0.16 g) was dissolved at 0 °C in 2 mL of MeOH, then NaBH4 (0.55 mmol, 21 mg) was added portionwise. The reaction mixture is brought at r.t. and stirred up to consumption of starting product (3-6 h, TLC, petroleum ether-EtOAc, 9:1).
Methyl 2-Chloro-2-[( N -isopropylamino)(phen-yl)methyl]cyclopropanecarboxylate ( 6a). Anal. Calcd for C15H20ClNO2: C, 63.94; H, 7.15; N, 4.97. Found: C, 63.99; H, 7.18; N, 4.95. Spectral data obtained from a 60:40 = syn/anti isomer mixture, underlined the major isomer. 1H NMR (300 MHz, CDCl3): δ = 1.03 and 1.04 (each d, 3 H, J = 6.2 Hz, CH3), 1.04 and 1.05 (each d, 3 H, J = 6.2 Hz, CH3), 1.25 (br s, 1 H, NH), 1.35 (dd, 1 H, J = 6.3 and 9.4 Hz, CH A H) and 1.45 (dd, 1 H, J = 6.6, 9.1 Hz, CH A H), 1.66 (dd, 1 H, J = 6.6 and 7.1 Hz, CHH B ), 1.76 (dd, 1 H, J = 6.3 and 7.2 Hz, CHH B ), 2.11 (dd, 1 H, J = 7.1 and 9.1 Hz, CHCO), 2.19 (dd, 1 H, J = 7.2 and 9.4 Hz, CHCO), 2.77 and 2.78 [each sept, 1 H, J = 6.2 Hz, CH(CH3)2], 3.69 and 3.77 (each s, 3 H, OCH3), 3.70 and 3.75 (each s, 1 H, Cq CHN), 7.28-7.39 (m, 10 H, CHarom.) ppm. 13C NMR (75 MHz, CDCl3 as internal standard): δ = 18.1 and 20.0 (CH2), 22.6 and 22.7 (CH3), 23.6 and 23.7 (CH3), 24.7 and 27.3 (CHCq), 46.2 and 46.4 (Cq CHN), 51.6 (CqCl × 2), 52.3 and 52.4 (OCH3), 65.7 and 66.0 (CHN), 127.9, 127.9 and 128.0, 128.0, 128.5, 140.3 (Cq), 169.5 (C=O) and 169.6 (C=O) ppm. IR (NaCl): ν = 3332 (NH), 1733 and 1739 (C=O) cm-1. MS (ES+): m/z = 282/284 [MH+]. Yield 78 % (flash chromatography, petroleum ether-EtOAc, 4:1, R f = 0.47).

17

Cyclopropane 2a (1.0 mmol, 0.28 mg) is dissolved in 5.0 mL of THF-H2O = 1:1, 2 N HCl solution (1.5 equiv, 0.75 mL) is added and the reaction is stirred up to completion (TLC). Upon usual work up, the corresponding benzoylated cyclopropane is purified via flash chromatography to give 76% of pure 5a.
Methyl cis -2-Benzoyl-2-chlorocyclopropanecarboxylate ( 5a).
Anal. Calcd for C12H11ClO3: C, 60.39; H, 4.65. Found: C, 60.45; H, 4.69. 1H NMR (270 MHz, CDCl3): δ = 2.00 (m, 2 H, CH2), 2.65 (dd, 1 H, J = 7.9, 8.9 Hz, CHCO), 3.85 (s, 3 H, OCH3), 7.43-7.58 (m, 3 H, CH), 7.96-7.99 (m, 2 H, CH) ppm. 13C NMR (68 MHz, CDCl3): δ = 19.83 (CH2), 27.64 (CHCq), 46.68 (CqCl), 52.76 (OCH3), 128.66 (CHarom. × 2), 129.07 (CHarom. × 2), 132.53 (CHarom.), 132.87 (Cq), 167.74 (Cq), 191.28 (C=O) ppm. IR (NaCl): ν = 1741 (OC=O), 1687 (C=O) cm-1. MS (EI): m/z (%) = 238/240 (3) [M+], 203 (42), 178 (9), 105 (100), 77 (38), 51 (8). Yield 76% (flash chromatography, petroleum ether-EtOAc, 9:1, R f = 0.35).