140
J. Org. Chem. 1981,46, 140-143
Ar and NH), 6.6 (d, J = 9 Hz, 2 H, Ar), 4.3 (m, 2 H, CH2). Anal. Calcd for ClSH14N203:C, 66.71; H, 5.19; N, 10.37. Found: C, 67.09; H, 5.37; N, 10.51.
Acknowledgment. We are grateful to our service support staff for expertly performing spectroscopic and combustion analyses and their helpful discussions. Registry No. 5,99-92-3; 6, 2719-21-3;7,73549-48-1; 7 (E-oxime derivative), 75626-40-3;8,15535-99-6; 9,75626-41-4; lla, 75626-42-5; l l a (E-oxime derivative), 75626-43-6; l l a (2-oxime derivative), 75626-44-7; 12, 75626-45-8; 13, 75626-46-9; 14, 75626-47-0; 16, 75626-48-1; 17, 75626-49-2; 18, 75626-50-5; 19, 75626-51-6; 19 (Eoxime derivative), 75626-52-7; 19 methyl ester (E-oxime derivative),
75626-53-8; 19 methyl eater (2-oxime derivative), 75626-54-9; 20, 75626-55-0; 21, 75626-56-1; 22, 75626-57-2; 23, 75626-68-3; 24, 75626-59-4; 25, 75626-60-7; 26a, 75626-61-8; 26b, 75626-62-9; 26c, 75640-91-4; 26d, 75626-63-0; 26e, 75626-64-1; 27a. 75626-65-2;27b, 75626-66-3; 2 7 ~75626-67-4; , 27d, 75626-68-5; 3Oa,75626-69-6,30b, 75626-70-9;31,75626-71-0; 32,75626-72-1; l,l’-carbonyldiimidazole, 530-62-1; aniline, 62-53-3; 4-[[(benzyloxy)carbonyl]amino]acetophenone, 72531-10-3; dihydropyran,110-87-2; (tetrahydropyran-2yl)hydroxylamine, 6723-30-4; furoyl chloride, 527-69-5; benzoyl chloride, 98-88-4; 0-acetylmandeloyl chloride, 1638-63-7; trifluoro[(benacetic anhydride, 407-25-0; benzyl (-)-(R)-4-chloro-4-oxo-2-[ zyloxy)carbonyl]amino]butyrate, 7562873-2; benzaldehyde, 100-52-7; benzyl 4-oxo-24[(be~loxy)carbonyl]am~o]butanoate, 75626-74-3; 2-aminobutyrolactone hydrobromide, 6306-38-0; sodium 2-(benzyloxy)carbonyl]amino]-4-hydroxybutanoate, 75626-75-4.
Transannular Reactions of Dibenzo[ a,d]cycloalkenes. 3.’ Nature of the Amine to Olefin Ring Closure Ben E. Evans* and Paul S. Anderson Merck Sharp & Dohme Research Laboratories, West Point, Pennsylvania 19486 Received J u l y 29, 1980
An efficient, regiospecific, intramolecular amine to olefin addition is described. Evidence is presented which suggests that the reaction pathway has radical character and involves nitrogen participation. Factors considered are the structure of the substrate, the initiating base, the effect of reagent addition order, sensitivity to oxygen and other radical inhibitors, the ESR signature, and the fate of hydrogen at key reaction centers as determined by deuterium labeling.
The direct addition of amines to simple olefins is an infrequently utilized synthetic reaction. In those cases where addition is observed, conditions sufficently basic for formation of the amide anion? elevated temperatures, and protracted reaction times are required! These conditions usually produce low yields of product mixtures. In the course of synthetic studies on bridged ring cyclic imines,lP6we observed a regiospecific amine to olefin addition which took place rapidly at room temperature in excellent yield. The characteristics of this reaction indicated it was not a nucleophilic addition, and we, therefore, undertook a closer study of its mechanism. Reported here are the results of that study.
1 -
Results Our earlier work on bridged ring cyclic imines’ revealed that the amino olefins 1 and 3 could be converted in high yield to the cyclic structures 2 and 4, respectively. Ad-
cx3
3 -
(1) B. E. Evans, P. s. Anderson, M. E. Christy, C. D. Colton, D. C. Remy, K. E. Rittle, and E. L. Engelhardt, J. Org. Chem., 44,3127 (1979). ( 2 ) March3 describes the addition of amines to olefins as “...nearly always nucleophilic”, noting that “...basic catalysts are sometimes used, so that RN-H or b N - is the actual nucleophile”. (3) J. March, “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure”, 2nd ed., McGraw-Hill, New York, 1977, pp 704-705. (4) A recent statement of the generally held view is provided by Barton and Ollis:6 “Nucleophilic addition of ammonia and amines to simple alkenes is difficult but is possible with catalystsat high temperatures and pressures”. (5) D. H. R. Barton and W. D. Ollis, “Comprehensive Organic Chemistry: The Synthesis and Reactions of Organic Compounds”, Vol. 2, Pergamon Press, New York, 1979, p 11. (6) (a) D. C. Remy, P. S. Anderson, M. E. Christy, and B. E. Evans, J. Org. Chem., 43, 4311 (1978); (b) M. E. Christy, P. S. Anderson, S. F. Britcher, C. D. Colton, B. E. Evans, D. C. Remy, and E. L. Engelhardt, ibid.,44, 3117 (1979).
0022-3263/81/1946-0140$01.00/0
-4
dition of 0.2 equiv of butyllithium to a stirred T H F solution of 1 or 3 maintained under nitrogen at room temperature rapidly gave 2 or 4, respectively. The mechanism initially considered (Scheme I) involved formation of the amide anion 5 followed by intramolecular nucleophilic addition to the olefin. However, this formulation proved inadequate to explain all of the characteristics of the reaction. For example, successful reactions were always accompanied by a persistent deep bronze color. Exposure of the reaction mixture to air caused the bronze color to fade and the reaction to stop. In THF dried over molecular sieves, the amount of butyllithium required varied considerably (0.5-1.2 equiv) from run to run. If this solvent was distilled from ben0 1981 American Chemical Society
Transannular Reactions of Dibenzo[a,d]cycloalkenes
J. Org. Chem., Vol. 46, No. 1, 1981 141
Scheme I
Scheme I1
+ Bu
L
zophenone ketyl, however, the butyllithium requirement was reduced to approximately 0.2 equiv. Substitution of N-benzyl, N-phenyl, or N-hydrogen for N-methyl in 3 thwarted the reaction completely. The deep bronze color of the reaction, the sensitivity to oxygen or other trace impurities, and the effect of changes in N substitutent all appeared inconsistent with the nitrogen anion addition mechanism and suggested instead that a radical process might be involved.lJ In agreement with this proposal, the reaction was found to be inhibited by as little as 0.07 equiv of the radical scavengers p-(or m-)dinitr~benzene.~Repeated additions of butyllithium eventually overcame this inhibition, but not until a substantial excess of the organometallic had been added. Further support for a radical mechanism was provided by an ESR experiment. When the butyllithium-mediated cyclization of 3 to 4 in T H F was carried out at -180 “C in the probe of an ESR spectrometer, a strong, broad ( 100 G ) signal was observed, the intensity of which initially increased and then decreased with time. The signal (g = 2) was indicative of a radical intermediate present in significant concentration during the reaction. Additional evidence against the anion mechanism was provided by the failure of the strong base lithium diisopropylamide (LDA) to induce cyclization. While 0.2 equiv of butyllithium brought about complete cyclization of 3 in ca. 15 min, 0.2-1.0 equiv of LDA under identical conditions failed to produce any trace of product after 2 h. Subsequent addition of butyllithium to this reaction mixture caused rapid (
