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J . Org. Chem., Vol. 43, No. 15, 1978
Caramella et al.
m o n i t o r e d by measurement o f t h e UV absorption a t 399 nm. T h e technique was essentially t h a t reported earlier,23 except t h a t each rate was t h e result o f only a single trial. A d d u c t s (17 a n d 18) of A c r i d i z i n i u m T e t r a f l u o r o b o r a t e w i t h 2-Stilbazole. T h e standard procedure was followed except t h a t only a 3:l r a t i o o f stilbazole to acridizinium salt was used (46-h reflux) a n d most of t h e adduct crystallized f r o m t h e reaction m i x t u r e (overall yield 96%).T h e IH NMFl spectrum o f the crude p r o d u c t showed t h a t t h e major regioisomer ('17; -66%) h a d t h e p h e n y l group a t p o f , i t i o n 12 a n d indicated t h a t the m i n o r isomer (18) consisted o f almost equal parts of t h e t w o possible geometrical isomers. Recrystallization frorn acetronitrile afforded a colorless powder w h i c h was analyzed as a n isomeric mixture: mp 247-255 "C; lH NMR ((CD&SO) 6 3.89-4.72 (m, 2, C-12, C-13), 5.43 (m, 0.6, C-11 of 171, 5.55 (d, 0.2, J = 2 Hz, C-11 o f 18),5.79 (d, 0.2, J = 2 Hz, C-11 o f la), 6.70-9.27 (m, 17), a n d 9.53 (m, 1, C-4); 'H NMR (CF~COZH) 8 3.91-4.93 (m, 2, (2-12, C-13),5.36 (m, 0.7, C-11 o f 17), 5.70 (m, 0.3, C-11 of l a ) , 6.52 (m, 0.3, C-6 o f l a ) , 6.56-9.01 (m, 17), a n d 9.30 (m, 1,
c-4).
Anal. Calcd for C ~ ~ H ~ ~ BC, F 69.66; ~ N ZH, : 4.72; N, 6.25. Found: C, 69.70; H, 4.95; N, 6.07. R e g i s t r y No.-1 BF4, 32865-43-3; 1 picrate, 66357-78-6; 1 Br, 7547-88-8; 3 (isomer 1:i, 66357-80-0; 3 (isomer 2), 66511-02-2; 4, 66357-82-2; 5,66357-84-4; 6 Br (isomer l ) , 66357-85-5; 6 Br (isomer 2), 66511-03-3; 6 Clod (isomer l),66511-05-5; 6 Clod (isomer 2), 66537-15-3; 9, 80-62-6; 12 (isomer l), 66357-87-7; 12 (isomer 21, 66511-07-7; 13 (isomer ,).I 66357-89-9; 13 (isomer 2), 66511-09-9; 14 (isomer l),66357-91-3;1.4 (isomer 2), 66511-11-3; 15,66357-93-5;16, 66357-95-7; 17,66357-97-9; 18,66357-99-1; indene, 95-13-6; anethole, 104-46-1; cis-8-methoxystyrene, 14371-19-8; l-methoxy-1,3-butadiene, 3036-66-6; e t h y l acrylate, 140-88-5; cis-crotononitrile, 119076-7: 2-stilbazole. 714-08-9.
References and Notes
K. Fukui and H. Kujimoto, Bull. Chem. SOC.Jpn., 42, 3399 (1969). K. N. Houck, J. Am. Chem. SOC.,95,4092,4094, 7287 (1973). K. N. Houck, Acc. Chem. Res., 6, 361 (1975). R. R. Schmidt, Angew. Chem., Int. Ed. Engl., 12, 212(1973). C. K. Bradsher, Adv. Heterocycl. Chem., 16, 289 (1974). All of these reports of regiospecificity were based on 'H NMR data, but a reviewer has questioned whether a regioisomer originally present might have been lost in the mother liquor during crystallization. In a few instances this suggestion can be refuted on the basis of the very high yield of pure product. Of this original list of 20 adducts we have carefully reexamined only those from acrylonitrile, styrene, and pmethyl- and pmethoxystyrene, but none of these gives an indication of regioisomerism. Should some future investigation of the remaining 16 adducts show an example of regioisomerism, we would be surprised but would not consider the electrophilic addition model invalidated. (15) C. K. Bradsher and F. H. Day, J. Heterocycl. Chem., 11, 23 (1974). (16) F. H. Day, C. K. Bradsher, and T.-K. Chen, J. Org. Chem., 40, 1195 (1975). (17) C. K. Bradsher, C. R. Miles, N. A. Porter, and I. J. Westerman, Tetrahedron Lett., 4969 (1972). (18) D. L. Fields, T. L. Regan, and J. C. Dignan, J. Org. Chem., 33, 390 (1968). (19) C. K. Bradsher and J. A. Stone, J. Org. Chem., 33, 519 (1968). (20) R. R . Schmidt, Chem. Ber., 103, 3242 (1970). (21) For example, C. F. Koelsch and V. Boekelheide, J. Am. Chem. SOC.,66, 412 (1944); C. S.Rondestvedt, Org. React., 11, 193 (1960). (22) For example, H. Schechter, F. Conrad, A. L. Daulton, and R . B. Kaplan, J. Am. Chem. SOC.,74,3052 (1952). (23) I. J. Westerman and C. K. Bradsher, J. Org. Chem., 36, 969 (1971). (24) I. Fleming, "Frontier Orbitals and Organic Chemical Reactions", Wiley, London, 1976, p 129. We are indebted to Professor K. N. Houk for bringing this reference to our attention. (25) Although the relative magnitudes of the alkene HOMO coefficients in acrylonitrile vary according to the specific procedure used for the MO calculation, photoelectron spectroscopic data indicate that the 6 coefficient is larger. For a thorough discussion of this question, see K. N. k u k , J. Sims, R. E. Duke, Jr., R . W. Strozier, and J. K. George, J. Am. Chem. SOC., 95, 7299 (1973). See also N. D. Epiotis, J. Am. Chem. SOC.,95, 5624 (1973), and ref 23, pp 115 and 124. (26) J. G. Traynham and 0. S.Pascual, Tetrahedron, 7, 165 (1959). (27) G. F. Bloomfield, E. H. Farme, and C. G. 8. Hose, J. Chem. SOC., 800 (1933). ---, (28) K. A. Oglobolin and V. P. Semenov, Zh. Org. Khim., 1, 27 (1965); Chem. Abstr., 62, 16035 (1965). (29) S. S. Novikov, G. A. Shvekhgeimer, and N. V. Pyatakov, lzv. Akad. Nauk SSSR, Ser. Khim., 914 (1961): Chem. Absb., 55, 22121 (1961). (30) R. R. Schmidt, Tetrahedron Lett., 5279 (1969), has reported the formation of regioisomefs when a protonated ogulnonemethide is added to cis-2pentene, an ethylene in which the substituents are both alkyl groups. (31) C. K. Bradsher and J. A. Stone, J. Org. Chem.. 34, 1700 (1969). (32) C. K. Bradsher, G. L. B. Carlson, N. A. Porter, I. J. Westerman, and T. G. Wallis, J. Org. Chem., 43, 822 (1978). (33) W. S.Burnham and C. K. Bradsher, J. Org. Chem., 37, 355 (1972).
(9) (10) (11) (12) (13) (14)
\
(1) This research was supported by Public Health Service Research Grant No. HL 02170 of the National Heart and Lung Institute of the National Institutes of Health. (2) J. Feuer, W. C . Herndon, and L. C. Hall, Tetrahedron, 24, 2575 (1968). (3) N. D. Epiotis, J. Am. (:hem. Soc., 94, 1925 (1972). (4) A. Devaquet and L. Salem, J. Am. Chem. Soc., 91, 3796 (1969). (5) R. A. Firestone, J. Org. Chem., 37, 2181 (1972). (6) W. C. Herndon, Chem. Rev., 72, 157 (1972). (7) J. Sauer, Angew. Chem., lnt. Ed. Engl., 6, 16 (1967). (8) R. B. Woodward and 13. Hoffmann, Agnew. Chem., lnt. Ed. Engl., 8, 781 (1969).
Selectivity in Cycloadditions. 6. Cycloadditions of Nitrile Oxides to Benzofuran. Regiochemistryl P. Caramella,*2a,bG. Cellerino,2c K. N. Houk,*2a F. Marinone Albini,2c and Cielo Santiagoza Department of Chemistry, Louisiana State Uniuersity, Baton Rouge, Louisiana 70803, and Institute of Organic Chemistry, Uniuersity of Pauia, 27100 P ~ u i aItaly , Receioed January 6, 1978 Cycloaddition o f benzonitrile oxide a n d mesitonitrile oxide t o benzofuran yields t h e t w o regioisomeric cycloadducts 1 and 2 in a 70:30 a n d 26:74 ratio, respectively. F r o n t i e r o r b i t a l considerations, using a b i n i t i o STO-3G calculations, and a comparison w i t h the regioselectivitres observed w i t h indene a n d styrene allow elucidation o f t h e inversion of regiochemistry o f t h e cycloadditions o f the t w o n i t r i l e oxides t o benzofuran.
Although much is known about the physical properties of heteroaromatic compounds and the reactivities of these molecules in electrophilic substitution reaction^,^ the study of the dipolarophilic reactivities of these molecules toward 1,3 dipoles is by far less developed. The reluctance of heteroaromatics to undergo addition reactions is well known and usually rationalized in terms of loss of aromaticity in the addition step. The study of cycloaddition reactions of heteroaromatics is
of interest for mechanistic reasons, since the concerted cycloaddition is expected to be slowed down, so that diradical and zwitterionic pathways, which are normally of no importance in 1,3-dipolar cycloadditions,4 may become competitive. The previous paper of this series dealt with the cycloadditions of nitrile oxides to ~yclopentadiene,~ indene,5 and furan.lb In the case of furan a competition between the concerted pathway and a minor two-step pathway was described.
0022-326317811943-3006$0100/0 0 1978 American Chemical Society
Selectivity in Cycloadditions
J . Org. Chem., Vol. 43, No. 1,5, 1978 3007
Table I. Chemical Shiftsu and Coupling Constants of Cycloadductsc
Compd
Registry no.
la lb 2a 2b 3a 3b
66303-77-3 66357-75-3 66303-78-4 66303-79-5 61495-72-5 66303-80-8
4-Hd
5-Hd
543
6.21 d 6.18 d 5.35 d 5.11 d
6.30 d 6.30 d 7.03 d 6.91 d 8.53 s 9.03 s
8.7 8.6 7.4 7.1
Other o-Me 2.14 s, p-Me 2.27 s o-Me, p-Me 2.29 s 0He.f o-Me 2.02 s, p-Me 2.32 s, OH 6.79 sf
Chemical shifts in parts per million ( 6 ) from internal Me&. Multiplicity: s, singlet; d, doublet; m, multiplet. Solvent: CDC13. In Hz. Satisfactory combustion analytical data C, H, N (f0.4%)have been obtained for these compounds. Numbering refers to the isoxazoline (isoxazole)ring. e Occurs under phenyl multiplet. f Exchanges with D20. This paper reports a study of the cycloaddition of benzo. and mesitonitrile oxide to benzofuran. The reactions of benzofuran6 in 1,3-dipolar cycloadditions with diphenylnitrilimine: and with 3,5-dichloro-2,4,6-trimethylbenzonitrile oxide8 have been reported recently. Results Benzofuran reacts slowly with benzonitrile oxide (BNO). Generation of BNO in situ in ether in the presence of 10 equiv of benzofuran afforded a 14%yield of cycloadducts l a and 2a (Scheme I) in a ratio of 70:30, along with the dimerization products of BNO. On performing the reaction in benzofuran (100 equiv) as solvent, the dimerization of BNO decreases and the yield of cycloadducts improves to 24%. The reactivity of benzofuran is 180 times less than that of indene, as determined by competition experiments. No other products could be detected or isolated from the reaction mixtures. The known oximes 49 and 5,1° which are the formal products of 1,3 addition, have been obtained by oximation of the ketones. The oximes are stable under the reaction and separation conditions and could not be detected by TLC or GLC of the reaction mixtures. The cycloadducts were separated by column chromatography. The structure proofs are based on chemical and NMR evidence (Table I). In adduct 2a the isoxazoline C-5 proton is deshielded by two adjacent oxygens and occurs as a doublet a t low field, 6 7.03, whereas the doublet of the other isoxazoline proton is well separated a t 6 5.35, in the usual range reported for isoxazoline C-4 pr0tons.l' In adduct la both the isoxazolinic protons experience the deshielding effect of an oxygen and have similar chemical shifts, appearing as an AB system. The easy acidic hydrolytic cleavage of 5-alkoxyisoxazolines1zJ~ further supports this structural assignment. Adduct 2a has
Scheme I Ar
