ring deformation); uv (HC1 salt) A,, (methanol) 261 nm ( E 531); mass spectrum: m/e 207 (M+); mp (HC1 salt) 190191'1 and 3-benzyl-6-endo-chloro-3-azabicyclo[3.1.0]hexane (4) [(8.6% yield); PMR (CDCl3) 6 1.79 (2 H, d of m, = 7 Hz), 2.80 (2 H, d, 2J = 10 Hz), 3.03 (2 H, d of m, *J= 10 Hz), 3.40 (1 H, t, 3J = 7 Hz), 3.66 (2 H, s), 7.31 ( 5 H, s); ir (film) 2790 (9, tertiary alkylamine), 1010 cm-l (w, cyclo(methanol) propyl ring deformation); uv (HCl salt) A,, 261 nm ( t 259); mass spectrum: m/e 207 (M+); mp (HC1 salt) 158-158.5'1. Addition of n-butyllithium solution (2 M in hexane) to a stirred solution of 3 in ether under nitrogen a t 25' gave a product in 51% yield identified as 3-phenyl-4-azatricy( 5 ) on the basis of its CMR, PMR, ir, cl0[2.2.1.0~~~]heptane
Synthesis and Reactions of Some Bicyclic Piperidine Analogs. Formation of the 4-Azatricycl0[2.2.1.0~~~]heptane Ring System Summary: The reaction of n- butyllithium with 3-benzyl6-exo-chloro-3-azabicyclo[3.l.0]hexane (3) produced 3phenyl-4-azatricyclo[2.2.1.0z~6] heptane ( 5 ) , a new heterotricyclic ring system.
Sir: We are reporting the synthesis of several novel 3-azabicyclo[3.1.0]hexane derivatives and a new heterotricyclic ring system.' Dichlorocarbene added to 1,4-dichloro-cis-2butene to produce 1,l-dichloro-cis-2,3-bis(chloromethyl)cyclopropane (1, 45% yield): bp 123-126' (22 Torr); PMR (CDC13) 6 2.22 (2 H, m), 3.67 (4 H, m); ir (film) 1255 (-CHZCl wagz), 988 cm-l (cyclopropyl ring deformation3); uv (methanol) A,, 239 nm ( t 87.5); mass spectrum m/e 171 (M - Cl). The dichlorocarbene was generated from CHCl3 and 50% aqueous NaOH solution using the phase transfer reaction reported by Makosza.* Reaction at room temperature over a period of 2-3 days5 using cetyltrimethylammonium bromide (CTABr)6 as a catalyst gave the best yield (44.5%). When 1, benzylamine, and sodium bicarbonate were stirred together in 1-butanol and heated a t reflux for 16-30 ( 2 ) was hr, 3-benzyl-6,6-dichloro-3-azabicyclo[3.l.O]hexane obtained. Chromatography on Florisil using increasing ram-
PhCH,WH,
PhCH2.=D(r1
c1
C1
2
1
tios of acetone to benzene gave pure 2 (51% yield): PMR (CDC13) 6 2.23 (2 H, m), 2.97 (4 H, m), 3.62 (2 H, s), 7.29 ( 5 H, s); ir (film) 2800 (s, tertiary alkylamine7), 1018 cm-l (m, (HC1 cyclopropyl ring deformation); uv (methanol) A,, salt) 261 nm ( e 260); mass spectrum m/e 241 (M+); nip (HC1 salt) 198-199'. Reduction of 2 with zinc dust in refluxing acetic acid8 yielded the exo-monochloro isomers 3 and the endo- monochloro isomer 4 in a 4:l ratio. Reduction of 2 with zinc dust 2 -
Zn
PhCH,N
mcl
Dh
5
and mass spectra: PMR (CDC13) 6 1.46 (3 H, m), 2.28 (2 H, d of d, 3 J = 9.5, 11 Hz, 2J = 13 Hz), 2.70 (2 H, d of d, 3J= 9.5, 11 Hz, 2J = 14 Hz) 3.80 (1H, s), 7.40 ( 5 H, m); ir (film) 1020 cm-I (w, cyclopropyl ring deformation); uv (oxalate (methanol) 261 nm ( t 396); mass spectrum m/e salt) A, 171 (M+); mp (oxalate salt) 155-156'. The 25.2-MHz I3C proton decoupled spectrum of the oxalate salt of 5 in deuteriomethanol shows three carbons at 9.973, 10.708, and 2.160 ppm for the cyclopropyl carbons. The other ring carbons appear at 51.924, 58.489, and 71.56 ppm. The aromatic carbons give peaks at 129.892,130,914, and 132.313 ppm. The single frequency off resonance (SFOR) spectrum of the salt shows each of the cyclopropyl carbons to give a doublet (coupled with one proton each), triplets for each of the pyrrolidine ring carbons with two protons, and a doublet for the bridging carbon which has only one proton. A multiplet absorption pattern appears for the aromatic carbons. T o our knowledge, this is the first reported synthesis ring system. of the 4-azatricycl0[2.2.l.O~~~]heptane The endo isomer 4 failed to give 5 when treated with nbutyllithium in ether. Reaction of 2 with n-butyllithium in ether produced 5 in a low yield. Compound 5 would most probably be formed by an intramolecular C-H insertion via a carbene or carbenoid formed by reaction of butyllithium on 3. To test this hypothesis, 2 was reduced with zinc and H
1
iPhCH,N
3
4
in refluxing ethanolic KOH9 also yielded the same isomers but with the endo-monochloro isomer 4 being the major refluxing deuterioacetic acid to yield the two monochloro deuterated isomers 6 and 7. These isomers were separated product. The isomers obtained from reduction in acetic acid were separated by column chromatography on silica gel using increaoing ratios of ethyl acetate to benzene to D 'C I elute the isomers 3-benzyl-6-exo-chloro-3-azabicyclo[3.1.0]hexane (3) [(75%yield); PMR (CDClB), 6 1.70 (2 H, q, 3J = 1.8 Hz), 2.35 (2 H, d of m, 2J = 9 Hz), 3.07 (2 H, d, 2J = 9 Hz), 3.31 (1 H, m), 3.55 (2 H, s), 7.27 ( 5 H, s); ir (film), 6 7 2790 (s, tertiary alkylamine), 1020 cm-' (w, cyclopropyl 2419
2420 J. Org. Chem., Vol. 40,No.16,1975 by chromatography on silica gel to give 3-benzyl-6-ezochloro-6-d-3-azabicyclo[3.l.0]hexane(6)(55% yield) [PMR (CDC13) 6 1.69 (2, H, m), 2.35 (2 H, d of m, 2J = 9 Hz), 3.07 (2 H, d, 2J = 9 Hz), 3.53 (2 H, s), 7.28 (5 H , s); ir (film) 2790 (s, tertiary alkylamine), 1020 cm-l (cyclopropyl ring defor(methanol) 261 nm ( E 267); mation); uv (HC1 salt) A,, mass spectrum m/e 208 (M+);mp (HC1 salt) 190-191°] and 3-benzyl-6-endo-chloro-6-d-3-azabicyclo[3.l.O]hexane(7) (-10% yield) [PMR (CDC13) 6 1.75 (2 H, s), 2.80 (2 H, d, 2J = 10 Hz), 3.02 (2 H, d of m, 2J = 10 Hz), 3.62 (2 H, s), 7.30 (5 H, s); ir (film) 2780 (s, tertiary alkylamine), 1020 cm-l (m, cyclopropyl ring deformation); uv (HC1 salt),,,A (methanol) 261 nm ( E 474); mass spectrum: m/e 208 (M+); mp (HC1 salt) 157-158'1. Reaction of the exo-chloro deuterated isomer 6 with n butyllithium in ether yielded 5 with no deuterium incorporation, indicating that the cyclopropyl proton at position 2 of the tricyclic structure came from insertion in a benzylic C-H bond. Frazer-Reid has reported that treating 4-phenyl-8,8-dichloro-3,5-dioxobicyclo[5.l.0]hexanewith n-butyllithium resulted in a tricyclic product formed by benzylic C-H intramolecular insertion. Reaction of butyllithium with 4-d4-phenyl-8,8-dichloro-3,5-dioxobicyclo[5.l.O]hexane in ether gave a tricyclic product containing deuterium.1° These results supports our interpretation.
Acknowledgment. The authors appreciate the support of this research by the A. H. Robins Co., Richmond, Va.
Communications Supplementary Material Available. Experimental procedures for preparation of substances 1-7 will appear following these pages in the microfilm edition of this volume of this journal. Photocopies of the supplementary material from this paper only or microfiche (105 X 148 mm, 24X reduction, negatives) containing all of the supplementary material for the papers in this issue may be obtained from the Journals Department, American Chemical Society, 1155 16th St., N.W., Washington, D.C. 20036. Remit check or money order for $4.50 for photocopy or $2.50 for microfiche, referring to code number JOC-75-2419.
References and Notes (1) All compounds gave satisfactory elemental analyses for C, H, N. (2) R. M. Silverstein and G. C. Bassler. "Spectrometric Identification of Organic Compounds", 2nd ed, Wiley, New York, N.Y., 1967, p. 102. (3) L J. Bellamy, "The Infrared Spectra of Complex Molecules", 2nd ed, Methuen, London, 1958, p 29. (4) M. Makosza and M. Wawrzyniewicz, Tetrahedron Lett., 4659-4652 (1969). (5) G. C. Josh1 et al., Tetrahedron Lett., 1461-1464 (1972). (6) W. Kraus eta/., Synthesis, 485-487 (1972). (7) (a) J. A. Richmond, Jr., Master's Thesis, Universlty of Richmond, Richmond, Va., 1967. (b) K. Nakanishi, "Infrared Absorption SpectroscopyPractical", Holden-Day, San Francisco, Calif., 1962, p 40-41. (c) L. H.
Bellamy, "Advances in Infrared Group Frequencies", Methuen, Suffolk, 1968, p 5. (8) K. L. Williamson et al., Tetrahedron, 24, 6007-6015 (1968). (9) H. Yamanaka et al., J Org. Chem., 37, 1734-1737 (1972). (IO) B. Frazer-Reid et al., Tetrahedron Lett., 2775 (1962); ibid., 2779 (1962).
Department of Chemistry Richmond, Virginia 23284 Virginia Commonwealth University Received May 27,1975
R. F. Boswell
R.G.Bass*
