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Synlett 2008(9): 1394-1398  
DOI: 10.1055/s-2008-1072747
LETTER
© Georg Thieme Verlag Stuttgart · New York

2-(Dichloromethylene)azetidines: Stable Strained Cyclic Enamines

Sven Mangelinckx, Marc Boeykens, 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 5 February 2008
Publication Date:
07 May 2008 (online)

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Abstract

2-(Dichloromethylene)azetidines constitute a new class of stable exocyclic enamines. The synthesis of these inductively stabilized N-alkyl-2-methyleneazetidines entails the imination of β-halo ketones, followed by α′,α′-dichlorination and subsequent 1,4-dehydrohalogenation. The synthesis of these azetidines is easy and can be performed on multigram scale in good yield. 2-(Dichloro­methylene)azetidines undergo smooth reactions towards electrophilic reagents as evidenced by the ready alkoxyhalogenation and hydrolysis to pyrrolidin-3-ones.

Key words

imines - methyleneazetidines - enamines - cyclizations - heterocycles

1

Postdoctoral Fellow of the Research Foundation - Flanders (FWO-Vlaanderen).

10

General Procedure
To a solution of imine 1 (3 mmol) in CCl4 (10 mL) was added NCS (0.84 g, 6.3 mmol) and the heterogeneous mixture was stirred under reflux for 1.5-4 h. Filtration and evaporation of the solvent in vacuo afforded the trichloroketimines 2 in high purity (>96%), which were used as such in the next step.
N-(1,1,4-Trichloro-3,3-dimethyl-2-butylidene)isopropyl-
amine (2b): yield 95-97%; mp 42 °C.1H NMR (270 MHz, CDCl3): δ = 1.18 [d, 6 H, J = 6 Hz, (CH 3)2CH], 1.28 [s, 6 H, (CH3)2], 3.67 (s, 2 H, CH2Cl), 4.70 [sept, 1 H, J = 6 Hz, CH(CH3)2], 6.23 (s, 1 H, CHCl2). 13C NMR (68 MHz, CDCl3): δ = 22.8, 23.4, 44.8, 50.9, 53.7, 59.3, 161.2. IR (KBr): νC=N = 1655 cm-1. MS (EI, 70 eV): m/z (%) = 242/4/6/8(1) [M+], 228/30/2/4 (1), 208/10/2 (2), 207/9/11/3 (1), 192/4/6/8 (1), 166 (1), 160/2 (19), 152/4/6 (3), 130/2 (1), 118/20 (100), 110 (2), 91/3 (36), 82 (7), 77 (3), 75 (7), 69 (7), 68 (4), 67 (3), 66 (3), 65 (4), 63 (4), 56 (11), 55 (34), 54 (4), 53 (6), 51 (4), 49 (4), 44 (6), 43 (70), 42 (13), 41 (41), 40 (4), 39 (19).

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General Procedure
Trichloroketimine 2 (0.005 mol) was dissolved in 2 M NaOMe in MeOH (12.5 mL, 0.025 mol). The solution was stirred under reflux for 4 h, after which the reaction mixture was poured into a mixture of H2O (30 mL) and CH2Cl2 (20 mL). The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (2 × 15 mL). The combined organic layers were dried (K2CO3), filtered, and evaporated under reduced pressure to afford the 2-methyleneazetidine 3 (purity >96%). Distillation under vacuum afforded the analytically pure 2-methyleneazetidine 3.
1-Ethyl-2-(dichloromethylene)-3,3-dimethylazetidine (3a): yield 58-64%; bp 40-43 °C (0.075 mmHg). 1H NMR (270 MHz, CDCl3): δ = 1.06 (t, 3 H, J = 7.2 Hz, CH2CH 3), 1.37 [s, 6 H, (CH3)2], 3.18 (s, 2 H, CH2), 3.22 (q, 2 H, J = 7.2 Hz, CH 2CH3). 13C NMR (68 MHz, CDCl3): δ = 12.0, 23.2, 41.2, 41.9, 60.4, 86.5, 152.8. IR (NaCl): νC=C = 1665 cm-1. MS (EI, 70 eV): m/z (%) = 193/5/7 (30) [M+], 178/80/2 (7), 158/60 (8), 137/9/41 (12), 109/11/3 (36), 101/3 (30), 97 (100), 69 (94), 65 (15), 58 (15), 57 (24), 56 (18), 55 (13), 54 (9), 42 (76), 41 (27), 39 (21). Anal. Calcd (%) for C8H13Cl2N: C, 49.50; H, 6.75; N, 7.22. Found: C, 49.32; H, 6.98; N, 7.16.

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Synthesis of 1-Ethyl-2-(dichloromethyl)-3,3-dimethylazetidine (6)
To an ice-cooled solution of 1-ethyl-2-(dichloromethylene)-3,3-dimethylazetidine (3a, 3.9 g, 20 mmol) in MeOH was added NaCNBH3 (2.5 g, 40 mmol), followed by AcOH (1.2 g, 20 mmol). The mixture was stirred for 1 h at 0 °C, poured into H2O, and extracted with CH2Cl2. The combined organic extracts were dried (MgSO4) and evaporated under reduced pressure to yield 3.81 g (97%) of 2-(dichloromethyl)-3,3-dimethylazetidine (6). Purification can be performed by means of flash chromatography: R f = 0.47 (Et2O-pentane, 1:2). 1H NMR (270 MHz, CDCl3): δ = 0.95 (d × d, 3 H, J = 7.03, 7.41 Hz, CH2CH 3), 1.19 and 1.26 [each s, each 3 H, (CH3)2], 2.31 [d × q, 1 H, J = 11.41, 7.03 Hz, CH(H)CH3], 2.46 [d, 1 H, J = 6.56 Hz, CH(H)N], 3.07 (d, 1 H, J = 9.84 Hz, CHN), 3.11 [d, 1 H, J = 6.58 Hz, CH(H)N], 3.19 [d × q, 1 H, J = 11.41, 7.41 Hz, CH(H)CH3], 5.70 (d, 1 H, J = 9.84 Hz, CHCl2). 13C NMR (68 MHz, CDCl3): δ = 11.6, 21.6, 28.2, 35.4, 52.4, 62.7, 73.3, 79.4. IR (NaCl): ν = 2965, 2825, 1463, 1382, 1368, 1350, 1252, 1208, 1163, 1142, 1108, 1012, 790, 730 cm-1. MS (EI, 70 eV): m/z (%) = 195/7/9 (4) [M+], 180/2/4 (2), 160/2 (2), 140/2/4 (12), 112 (63), 103/5 (6), 75 (3), 67 (5), 58 (31), 57 (31), 56 (100), 55 (8), 43 (5), 42 (63), 41 (21). Anal. Calcd (%) for C8H15Cl2N: C, 48.99; H, 7.71; N, 7.14. Found: C, 48.76; H, 7.90; N, 7.01.

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Synthesis of 1-Ethyl-3,3-dimethoxy-4,4-dimethylpyrrolidin-2-one (11)
To a solution of 1-ethyl-2-(dichloromethylene)-3,3-dimethylazetidine (3a, 0.97 g, 5 mmol) in MeOH was added PhSeBr (1.3 g, 5.5 mmol) followed after 30 min by Hg(OAc)2 (3.18 g, 10 mmol). The mixture was stirred for
17 h, filtered, and the solvent evaporated partially under reduced pressure. The residue was poured into H2O and extracted with CH2Cl2. The combined organic extracts were dried (MgSO4) and evaporated in vacuo. The residual oil is chromatographed on silica gel to yield 0.52 g (52%) of pyrrolidin-2-one (11). R f = 0.17 (EtOAc-hexane, 1:1). 1H NMR (270 MHz, CDCl3): δ = 1.09 (t, 3 H, J = 7.08 Hz, CH2CH 3), 1.15 [s, 6 H, (CH3)2], 2.89 (s, 2 H, CH2N), 3.33 (q, 2 H, J = 7.08 Hz, CH 2CH3), 3.37 [s, 6 H, C(OMe)2]. 13C NMR (68 MHz, CDCl3): δ = 12.3, 21.5, 37.4, 41.3, 50.7, 56.6, 101.6, 168.3. IR (NaCl): νC=O = 1700 (br) cm-1. MS (EI, 70 eV): m/z (%) = no [M+], 171 (63), 156 (86), 116 (36), 115 (30), 102 (70), 101 (47), 99 (91), 88 (13), 87 (20), 85 (26), 75 (84), 74 (35), 73 (2), 70 (13), 69 (31), 67 (13), 59 (96), 58 (14), 57 (11), 56 (100), 55 (69), 45 (15), 44 (22), 43 (41), 42 (61), 41 (87), 40 (70). Anal. Calcd (%) for C10H19NO3: C, 59.68; H, 9.52; N, 6.96. Found: C, 59.65; H, 9.38; N, 7.04.

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Synthesis of 1-Isopropyl-2-(dichloromethylene)-3,3-dimethoxyazetidine (21)
To a solution of KOt-Bu (3.37 g, 0.03 mol) in t-BuOH (50 mL) was added N-(4-bromo-1,1-dichloro-3,3-dimethoxy-2-butylidene)isopropylamine (20, 4.82 g, 0.015 mol) and the resulting mixture was stirred at reflux for 17 h. After cooling, pentane (100 mL) was added as a result of which a fine suspension was formed. The suspension was stored at
-20 °C for 15 h, decanted, and the residue washed again with some pentane (20 mL). The pentane fractions are combined and the solvent was evaporated in vacuo. The residue, still containing some t-BuOH, was distilled, affording 2.15 g (60%) of pure 1-isopropyl-2-(dichloromethylene)-3,3-dimethoxyazetidine (21); bp 65-67 °C (0.01 mmHg). 1H NMR (270 MHz, CDCl3): δ = 1.08 [d, 6 H, J = 6.60 Hz, CH(CH 3)2], 3.41 [s, 6 H, (OCH3)2], 3.43 (s, 2 H, NCH2), 4.10 (sept, 1 H, J = 6.60 Hz, NCH). 13C NMR (68 MHz, CDCl3): δ = 18.8, 45.8, 51.8, 53.6, 89.5, 100.4, 145.1. IR (NaCl): νC=C = 1663 cm-1. MS (EI, 70 eV): m/z (%) = 239/41/43 (55) [M+], 224/6/8 (63), 208/10/12 (29), 182/4/6 (100), 166/68/70 (11), 151/3/5 (23), 150/2/4 (60), 139/41/43 (13), 133/5 (33), 125 (13), 124 (21), 123 (23), 122 (29), 109/11/13 (51), 88 (35), 87 (19), 59 (25), 58 (23), 57 (19), 56 (15), 45 (38), 44 (10), 42 (27), 41 (46), 40 (21). Anal. Calcd (%) for C9H15Cl2NO2: C, 45.02; H, 6.30; N, 5.83. Found: C, 44.83; H, 6.51; N, 5.71.