J. Org. Chem., Vol.39, No. 7, 1974 881
Thermal Cyclization of Aryl Propargyl Ethers l,l-difluoro-2-(m-trifluoromethylphenyl)ethane, 50562-17-9; p-fluoro-cr,cu,cu-trifluoroacetophenone, 655-32-3; l-phenyl-2,2,2-trifluoroethanol, 340-04-5; 1-(m-tolyl)-2,2,2-trifluoroethanol tosylate, 655-32-3; l-(p-fluorophenyl)-2,2,2-trifluoroethanol, 50562-19-1, 50562-20-4 (tosylate); l-(m-trifluoromethylphenyl)-2,2,2-trifluoroethanol tosylate, 50562-21-5; l,l,l-trifluoro-2-(m-trifluoromethylphenyl)ethane, 50562-22-6; 2,2-difluoro-l-phenylethanol-l-d~, 50562-23-7, 50562-24-8 (tosylate).
References a n d Notes C. H . DePuy and C. A. Bishop, J. Amer. Chem. SOC..82, 2535 (1960).
E. D. Bergmann and I . Shahak, Chem. Ind. (London),157 (1958). S. A. Fuqua, W. G . Duncan, and R. M . Silverstein, J. Org. Chem., 30, 1027 (1965). H. F. Koch and A. (1970).
J. Kielbania, Jr., J. Amer. Chem. SOC.,9 2 , 729
W. H . Saunders and R. A. Williams, J. Amer. Chem. SOC.,79, 3712 (1957).
H . F. Koch, D. B. Dahlberg, A. G. Toczko, and R. L. Solsky, J. Amer. Chem. SOC.,95,2029 (1973). H . C. Brown and B. C. S. Rao, J. Amer. Chem. SOC.. 82, 681 (1960). J . W. Corse, R. G. Jones, Q. F. Soper, C. W. Whitehead, and 0. K. Behrens, J. Amer. Chem. SOC.,70, 2837 (1948). R. S. Tipson, J. Org. Chem., 9, 235 (1944). L. Ruzicka and L. Ehmann, Helv. Chim. Acta, 15, 140 (1932).
D. Nasipuri and D. N . Roy, J. Indian Chem. SOC.,40, 327 (1963). G. Baddeleyand G. M . Bennett, J. Chem. SOC., 1819 (1935). G. B. Bachman and L. L. Lewis, J. Amer. Chem. SOC.,69, 2022 (1947). C. H. DePuy and D. H. Froemsdorf, J. Amer. Chem. SOC., 79, 3710 (1957). K. T. Dishart and R. Levine, J. Amer. Chem. SOC.. 78, 2268 (1956). E. D. Bergmann. 2 . Pelchowicz, and A. Shani, lsrael J. Chem., 1, 129 (1963). J. H. Simons and D. F. Herman, J. Amer. Chem. SOC., 65, 2064 (1943). M . Prober, J. Amer. Chem. SOC.,75,968 (1953). K. B. Wiberg, "Laboratory Techniques in Organic Chemistry," McGraw-Hill. New York, N. Y., 1960, p 228. J. H . Simons and E. 0. Ramler, J. Amer. Chem. SOC., 65, 389 (1943). J. D. Park, H . A. Brown, and J. R. Lacher, J. Amer. Chem. SOC., 73, 709 (1951). E. T. McBee, S. Resconich, L. R. Belohlav, and H . P. Braendlin, J. Org. Chem.. 28, 3579 (1963). F. E. Herkesand D. J. Burton, J. Org. Chem., 32, 1311 (1967). R. Fuchs and G . J. Park, J. Org. Chem., 22, 993 (1957). E. T. McBee, 0. R. Pierce, and J. F. Higgins, J. Amer. Chem. SOC., 74, 1736 (1952). W. H . Saunders, Jr., and D. H. Edison, J. Amer. Chem. Soc.. 82, 138 (1960). W. H. Saunders, Jr., S. Asperger, and D. H. Edison, J. Amer. Chem. Soc., 80, 2421 (1958). D. L. Storm, Ph.D. Thesis, Iowa State University, 1967.
Steric and Electronic Factors Which Effect the Thermal Cyclization of Meta-Substituted Aryl Propargyl Ethers. Synthesis of 5- and 7-Substituted 3-Chromenesl Wayne K. Anderson,* Edmond J. LaVoie, and Peter G. Whitkop Department of Medicinal Chemistry, School of Pharmacy, State University of New York at Buffalo, Buffalo, New York 14214 Received October 30, 1973 The thermal cyclization of meta-substituted phenyl propargyl ethers (1 and 4) proceeded to yield a mixture of 5- and 7-substituted 3-chromenes. The ratio of chromene isomers was somewhat dependent upon the nature
of the starting materials. Thus, terminal acetylenes (1) gave a mixture of 2 and 3 (resulting from para and ortho cyclization, respectively) with the latter product usually in slight excess. Nonterminal acetylenes (4) also gave a mixture of ortho- and para-cyclized products (6 and 5, respectively); however, para cyclization was found to be favored. Regioselective cyclization was greatest for 4d, which gave a mixture of 4,7- and 4,5-di(16) also promethyl-3-chromene in a ratio of 2: 1. The cyclization of 3-(3-methoxyphenyloxy)-3-methylbutyne ceeded with little regioselectivity to give a mixture of 17 and 18. The effects of electron-donating and electronwithdrawing meta substituents were also studied.
In our initial studies2 on the thermal cyclization of aryl propargyl ethers we found that the cyclization of la did not proceed in the regioselective manner previously rep ~ r t e d Instead, .~ the cyclization of la led to the formation of both 2a and 3a where, in fact, the previously unreported 5-methoxy isomer (3a) was the more abundant prod-
I
R'
R' 1,
2, R' = H 5, R' = CHB
R = H
4, R' = CHB a,
R
= OCHj
b, R = COCHB C,
R
=
R
R'
3, R'= H 6, R' = CH,
d, R = CH3 e,
R = OCOCHS
N(C,H,)S
uct. Our interest in the use of certain substituted chromenes as intermediates in the synthesis of tumor-inhibitory trichothecan mycotoxins4 prompted us to further examine those factors which influence regioselectivity in this
reaction and to study the effects of various substituents on the aromatic ring. The aryl propargyl ethers used in this study were synthesized by a Williamson reaction using the appropriately substituted phenols and propargyl bromides.2 The cyclization of the aryl propargyl ethers was carried out in N,N-diethylaniline a t 210-215";2 the isolated yield of the cyclized products, boiling points, reaction times, and product ratios are given in Table I. The structures of the various chromene isomers were determined by comparison of nmr spectra. Typical 1,2,3and 1,2,4-trisubstituted benzene patterns were generally evident in the nmr spectra of the 5 and 7 isomers (Jo Y 8 and Jm GZ2 Hz). In the nmr spectra of the various chromenes the C-2 protons always appeared at slightly higher field in the 5substituted isomer compared to the 7-substituted isomer. Similarly, the C-3 proton appeared at slightly lower field in the 5 isomer compared to the 7 isomer. The C-4 proton (or the C-4' methyl protons) generally appeared a t lower field in the nmr spectra of the 5-substituted compound compared to the 7 isomer. One exception to this latter
Anderson, LaVoie, and Whitkop
882 J . Org. Chem., Vol. 39, No. 7, 1974
Table I Thermal Cyclization of Meta-Substituted Aryl Propargyl E t h e r s (1or 4) Compd
Reaction time, hr
R
la2 4a
Ortho:para" Yield, %
BP, O
C
ratio
(mm)
51 54 :46 54 (0.6) 47 :53 30 86 9 3 . 5 (0.4) Pbb 15
