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Synlett 2002(6): 0879-0882
DOI: 10.1055/s-2002-31906
LETTER
© Georg Thieme Verlag Stuttgart · New York

Functionalized Aminocyclopropanes From Functionalized Organozinc Compounds and N,N-Dialkylcarboxamides [1]

Stefan Wiedemanna, Ilan Marekb, Armin de Meijere*a
a Institut für Organische Chemie der Georg-August-Universität Göttingen, Tammannstrasse 2, 37077 Göttingen, Germany
Fax: +49(551)399475; e-Mail: Armin.deMeijere@chemie.uni-goettingen.de;
b Department of Chemistry and Institute of Catalysis Science and Technology, Technion-Israel Institute of Technology, Technion City, Haifa, 32000 Israel
Further Information

Publication History

Received 15 February 2002
Publication Date:
07 February 2007 (online)

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Abstract

Inter- as well as intramolecular competition experiments have been performed to demonstrate that N,N-dialkylcarboxamides react faster than tert-butyl esters with the titanium intermediates formed from ethylmagnesium bromide and methyltitanium triisopropoxide to selectively yield cyclopropylamines rather than cyclopropanols. Thus, functionalized organozinc reagents including a series with tert-butyl ester functionalities could be employed under newly developed conditions to transform N,N-dialkylformamides into chloroalkyl-substituted N,N-dialkylcyclopropylamines (55-67%) and tert-butyl (N,N-dialkylaminocyclopropyl)alkanoates (24-63% yield).

Key words

cyclopropanes - organometallics - amino acids - organo­titanium intermediates - cyclopropylamines

    References

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13

The added isopropoxide most probably helps to form a zincate which can more rapidly transfer one of its ethyl groups to titanium. Wiedemann, S. Part of the forthcoming Dissertation, Universität Göttingen, 2002.

14

Wiedemann, S.; Frank, D.; Winsel, H.; de Meijere, A. unpublished results.

17

All new compounds were fully characterized by spectroscopic methods (IR, 1H and 13C NMR, MS) and elemental analyses. General Procedure B (GPB): To a solution of Cl2Ti(O-i-Pr)2 (1043 mg, 4.0 mmol) in THF (5 mL) kept at -30 °C, was added 5.3 mL of a 1.65 M solution of methyllithium (8.8 mmol) in hexane. Then 1.5 mL of a 3 M solution of methylmagnesium chloride (4.5 mmol) in THF was added, and the mixture was stirred for
1 h at this temperature. After that the previously prepared solution of the organozinc compound in THF and the N,N-dialkylcarboxamide (4 mmol) were added, the mixture was slowly warmed up to r.t. until gas evolution ceased, and stirred for an additional 8 h. The reaction was quenched by addition of 2 mL of H2O, and stirring of the mixture continued until the color of the suspension had turned yellow. The mixture was filtered, and the solid was washed with diethyl ether (2 × 10 mL). The combined organic phases were dried over Na2SO4. The crude products were purified by column chromatography. For example (2-Dibenzylaminocyclopropyl)acetic Acid tert -Butyl Ester (17aa): From tert-butyl 4-iodobutyrate and N,N-dibenzylformamide, following GPB as above, two diastereomeric products were isolated by column chromatography (70 g of silica gel, diethyl ether/pentane 1:10).
Fraction I (Rf = 0.83): 300 mg (21%) of cis-(2-dibenzyl-aminocyclopropyl)acetic acid tert-butyl ester (cis-17aa) as a colorless oil. IR(film): ν = 3063, 2977, 2928, 1733, 1494, 1454, 1367, 1152, 1028, 749, 698 cm-1. 1H NMR (250 MHz, CDCl3): δ = 0.13 (ddd, 3 J = 4.5, 3 J = 4.9, 2 J = 5.1 Hz, 1 H, 3′-H), 0.73 (ddd, 2 J = 5.1, 3 J = 6.9, 3 J = 8.6 Hz, 1 H, 3′-H), 1.14 (ddddd, 3 J = 4.9, 3 J = 6.8, 3 J = 7.0, 3 J = 7.2, 3 J = 8.6 Hz, 1 H, 1′-H), 1.34 [s, 9 H, C(CH3)3], 1.96 (ddd, 3 J = 4.5, 3 J = 6.9, 3 J = 7.0 Hz, 1 H, 2′-H), 2.41 (dd, 3 J = 6.8, 2 J = 16.4 Hz, 1 H, 2-H), 2.48 (dd, 3 J = 7.2, 2 J = 16.4 Hz, 1 H, 2-H), 3.50 (d, 2 J = 13.8 Hz, 2 H, CHHPh), 3.69 (d, 2 J = 13.8 Hz, 2 H, CHHPh), 7.35-7.21 (m, 10 H, Ph-C). 13C NMR (62.9 MHz, CDCl3, DEPT): δ = 12.1 (-, C-3′), 15.1 (+, C-1′), 28.0 [+,OC(CH3)3], 33.9 (-, C-2), 40.1 (+, C-2′), 57.5 (-, NCH2), 80.0 [Cquat, OC(CH3)3], 126.8 (+, Ph-C), 128.0 (+, Ph-C), 129.4 (+, Ph-C), 138.1 (Cquat, Ph-C), 173.5(Cquat, C=O). MS (EI, 70 eV): m/z (%) = 351(6) [M+], 278(9), 260(4), 236(9), 204(100), 181(2), 158(5),106(4), 91(81). Anal. Calcd for C23H29NO2: C, 78.60; H, 8.32; N, 3.99. Found: C, 78.44; H, 8.34; N, 4.04.
Fraction II (Rf = 0.58): 542 mg (39%) of trans-(2-dibenzyl-aminocyclopropyl)acetic acid tert-butyl ester (trans-17aa) as a colorless oil. IR(film): ν = 3063, 3028, 2978, 2929, 1732, 1602, 1494, 1454, 1392, 1367, 1257, 1154, 1076, 1029, 955, 750, 699, 620 cm-1. 1H NMR (250 MHz, CDCl3): δ = 0.34 (ddd, 2 J = 5.3, 3 J = 5.3, 3 J = 6.7 Hz, 1 H, 3′-H), 0.61 (ddd, 3 J = 3.3, 2 J = 5.3, 3 J = 8.0 Hz, 1 H, 3′-H), 1.04 (ddddd, 3 J = 3.4, 3 J = 5.3, 3 J = 7.2, 3 J = 7.2, 3 J = 8.0 Hz, 1 H, 1′-H), 1.42 [s, 9 H, C(CH3)3], 1.68 (ddd, 3 J = 3.3, 3 J = 3.4, 3 J = 6.7 Hz, 1 H, 2′-H), 2.02 (dd, 3 J = 7.2, 2 J = 14.6 Hz, 1 H, 2-H), 2.07 (dd, 3 J = 7.2, 2 J = 14.6 Hz, 1 H, 2-H), 3.64 (d, 2 J = 13.5 Hz, 2 H, CHHPh), 3.71 (d, 2 J = 13.5 Hz, 2 H, CHHPh), 7.35-7.22 (m, 10 H, Ph-C). 13C NMR (62.9 MHz, CDCl3, DEPT): δ = 14.2 (-, C-3′), 17.6 (+, C-1′), 28.1 [+, OC(CH3)3], 38.6 (-, C-2), 43.1 (+, C-2′), 57.7 (-, NCH2), 80.2 [Cquat, OC(CH3)3], 126.8 (+, Ph-C), 128.0 (+, Ph-C), 129.4 (+, Ph-C), 138.6 (Cquat, Ph-C), 172.2 (Cquat, C=O). MS (EI, 70 eV): m/z (%) = 351(6) [M+], 294(6), 260(5), 250(14), 236(8), 204(100), 186(3), 158(6), 131(4), 106(6), 91(81). Anal. Calcd for C23H29NO2: C, 78.60; H, 8.32; N, 3.99. Found: C, 78.81; H, 8.10; N, 3.96.