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

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).

cyclopropanes - organometallics - amino acids - organo­titanium intermediates - cyclopropylamines

References

1 Part 76 in the series Cyclopropyl Building Blocks for Organic Synthesis, Part 75 see: Nötzel MW. Labahn T. Rauch K. de Meijere A. Org. Lett.  2002,  4:  839 

2 Review: Salaün J. Top. Curr. Chem.  2000,  207:  1 

3 Kulinkovich OG. Sviridov SV. Vasilewski DA. Pritytskaya TS. J. Org. Chem. USSR (Engl. Transl.)  1989,  25:  2027 ; Zh. Org. Khim. 1989, 25, 2244

4 Review: Kulinkovich OG. de Meijere A. Chem. Rev.  2000,  100:  2789 

5 Chaplinski V. de Meijere A. Angew. Chem., Int. Ed. Engl.  1996,  35:  413 ; Angew. Chem. 1996, 108, 491

6 Chaplinski V. Winsel H. Kordes M. de Meijere A. Synlett  1997,  111 

7 Kordes M. Winsel H. de Meijere A. Eur. J. Org. Chem.  2000,  3235 

8 Kordes M. Dissertation   Universität; Göttingen: 1999. 

9 Handbook of Grignard Reagents, Silverman G. S., Rakita P. E.   Dekker; New York: 1996. 

10 Review: Knochel P. Singer RD. Chem. Rev.  1993,  93:  2117 

11 The functionally substituted dialkylzinc reagents were prepared from the corresponding alkyl iodides and excess diethylzinc according to a published protocol. Cf.: Rozema MJ. Sidduri AR. Knochel P. J. Org. Chem.  1992,  57:  1956 

12 Winsel H. Diplomarbeit   Universität; Göttingen: 1997. 

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Wiedemann, S.; Frank, D.; Winsel, H.; de Meijere, A. unpublished results.

15 It has been shown that i-PrMgBr reacts faster with RZnX than with Ti(i-PrO)₄. Cf.: Averbuj C. Kaftanov J. Marek I. Synlett  1999,  1939 

16 Reetz MT. Westermann J. Steinbach R. Wenderoth B. Peter R. Ostarek R. Maus S. Chem. Ber.  1985,  118:  1421 

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 (R_f = 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 [C_quat, OC(CH₃)₃], 126.8 (+, Ph-C), 128.0 (+, Ph-C), 129.4 (+, Ph-C), 138.1 (C_quat, Ph-C), 173.5(C_quat, 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 (R_f = 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 [C_quat, OC(CH₃)₃], 126.8 (+, Ph-C), 128.0 (+, Ph-C), 129.4 (+, Ph-C), 138.6 (C_quat, Ph-C), 172.2 (C_quat, 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.

18 Diastereomerically pure (E)-1-(2-chloroethyl)-2-ethyl-cyclopropanols can be obtained from β-chloropropionates and unsubstituted butylmagnesium bromide. Cf.: Sylvestre I. Ollivier J. Salaün J. Tetrahedron Lett.  2001,  42:  4991