2124
J . Org. Chem. 1999, 64, 2124-2126
ketones. We now show that R-benzotriazole ether moi-
A Novel Syn th esis of Alk yl, Ar yl, Alk en yl,
eties can be used successively as two acyl anion synthons
to synthesize both symmetrical and unsymmetrical alkyl,
aryl, alkenyl, and alkynyl 1,6-diketones.
a n d Alk yn yl 1,6-Dik eton es
Alan R. Katritzky,*,‡ Zhizhen Huang,‡
Yunfeng Fang,‡ and Indra Prakash§
Resu lts a n d Discu ssion
Center for Heterocyclic Compounds,
Department of Chemistry, University of Florida,
Gainesville, Florida 32611-7200, and Monsanto, Nutrition
and Consumer Sector, 601 East Kensington Road,
Mt. Prospect, Illinois 60056-1300
The two acidic R-methylene protons of 1-(phenoxy-
methyl)benzotriazole (1) were used successfully in double-
lithiation techniques with considerable flexibility9 (Scheme
1). After treatment with n-butyllithium at -78 °C,
1-(phenoxymethyl)benzotriazole (1) reacted easily with
isopentyl bromide or benzyl bromide to form 1-(benzo-
triazol-1-yl)-4-methyl-1-phenoxypentane (2a ) and 1-(ben-
zotriazol-1-yl)-1-phenoxy-2-phenylethane (2b), respec-
tively, in excellent yields. Compounds 2a and 2b were
then used as alkylacyl anion synthons after their second
active proton was lithiated. Under the action of n-
butyllithium, 2 equiv of 2a or 2b reacted readily with
1,4-dibromobutane to form the corresponding bis-benzo-
triazole intermediates 4a and 4b, which undergo succes-
sive hydrolysis using dilute hydrochloric acid to produce
the symmetrical alkyl 1,6-diketones 5a and 5b, respec-
tively, in 83-84% yields.
(Benzotriazole-1-yl)methoxymethylbenzene (3a ), N-(R-
ethoxyallyl)benzotriazole (3b), and 1-(benzotriazol-1-yl)-
propargyl ethyl ether (3c) were chosen for study as
typical aryl-, alkenyl-, and alkynylacyl equivalents,
respectively.10-12 Addition of 2 equiv of n-butyllithium to
mixtures of 2 equiv of 3a -c with 1,4-dibromobutane,
followed by subsequent mild oxalic acid hydrolysis, gave
the expected symmetrical aryl 5c, alkenyl 5d , and
alkynyl 5e 1,6-diketones in 81-85% yields.
For the preparation of unsymmetrical 1,6-diketones,
compounds 3a , 2c, or 3c were reacted in the presence of
n-butyllithium with excess 1,4-dibromobutane to form
1-(benzotriazol-1-yl)-5-bromo-1-methoxy-1-phenylpen-
tane (6a ), 3-(benzotriazol-1-yl)-7-bromo-3-phenoxyhep-
tane (6b), and 3-(benzotriazol-1-yl)-7-bromo-3-ethoxy-1-
phenyl-1-heptyne (6c), respectively, in 76-91% yields
(Scheme 2). Compounds 6a -c decomposed gradually at
room temperature, and in particular, the decomposition
of 6c was accelerated by silica gel. However, 6a -c can
be stored at 0 °C. Under the action of n-butyllithium,
6a -c reacted smoothly in a second lithiation-alkylation
with a variety of benzotriazole ethers 3 to form diben-
zotriazole intermediates 7, which then underwent hy-
drolysis to give various unsymmetrical 1,6-diketones
8a -g (Table 1).
Received September 8, 1998
In tr od u ction
1,6-Diketones are somewhat more difficult to synthe-
size than other types of diketones.1 Some symmetrical
alkyl 1,6-diketones have been synthesized via bimolecu-
lar reduction of alkyl vinyl ketones using sodium or
magnesium.2 Both alkyl and aryl symmetrical 1,6-dike-
tones are obtained by reacting cadmium alkyls with
adipoyl chloride.3 Siloxycyclopropanes,4 1,2-diacylcyclo-
butanes,5 and the coupling of vinyl Grignards6 have also
been used to prepare symmetrical 1,6-diketones. Maeka-
wa et al. have made symmetrical 1,6-diketones by
electrolysis of enol acetates.7 Few methods are available
for the synthesis of unsymmetrical 1,6-diketones; in 1985,
van Leusen et al. synthesized both symmetrical and
unsymmetrical alkyl and aryl 1,6-diketones by reactions
of tosylmethyl isocyanide derivatives with 1,4-dihalides,
followed by hydrolysis.8
Recently, we have found that some R-benzotriazole
ethers can be used as masked acyl anions and can be used
to synthesize alkyl,9 aryl,10 alkenyl,11 and alkynyl12
‡ University of Florida.
§ Monsanto.
(1) For the synthesis of 1,4- and 1,5-diketones, see: (a) O’Neill, E.
T. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: Oxford, 1991; Vol 1, p 448, p 452. (b) Hassner, A.
Ibid., p 542. (c) Panek, J . S. Ibid., p 558. (d) Solladie, G. Ibid., Vol 6,
p 159. (e) Linderman, R. J . In Comprehensive Heterocyclic Chemistry
II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon
Press: Oxford, 1996; Vol. 1, p 738. (f) Varvounis, G. Ibid., Vol. 2, p
923. (g) Fan, W.-Q.; Katritzky, A. R. Ibid., Vol. 4, p 91. (h) Page, P. C.
B.; McFarland, H. L.; Millar, A. P. In Comprehensive Organic Func-
tional Group Transformation; Katritzky, A. R., Meth-Cohn, O., Rees,
C. W., Eds.; Pergamon Press: Oxford, 1995; Vol. 1, p 254. (i) Valle´e,
Y.; Bulpin, A. Ibid., Vol. 4, pp 255, 287. (j) Butters, M. Ibid., Vol. 5, p
802. (k)Waring, A. J . In Comprehensive Organic Chemistry; Barton,
S. D., Ollis, W. D., Eds.; Pergamon Press: Oxford, 1979; Vol. 1, pp
1030, 1062.
(2) Kossanyi, M. J .; Dele´pine, M. M. C. R. Hebd. Seances Acad. Sci.
1960, 3487.
For the dibenzotriazole intermediates 7, the two ends
derived from different benzotriazole ethers had different
susceptibility toward hydrolysis: a 1-alkyl substituted
moiety was more difficult to hydrolyze than that substi-
tuted with a functional group. When both ends of
dibenzotriazole intermediate 7 were alkyl substituted, the
hydrolysis was carried out using dilute hydrochloric acid
in methanol, and the unsymmetrical dialkyl 1,6-dike-
tones 8a and 8b were thus obtained in 82-86% yield.
When both ends were functional group substituted, mild
hydrolysis using a mixture of oxalic acid, water, and silica
gel in dichloromethane was applied, because hydrolysis
with dilute hydrochloric acid gave complex mixtures, and
isolation was difficult. In this manner, the unsymmetical
(3) Waight, E. S. In Rodd’s Chemistry of Carbon Compounds; Coffey,
S., Ed.; Elsevier: New York, 1965; Vol. 1, Chapter 13, p 73.
(4) Ryu, I.; Ando, M.; Ogawa, A.; Murai, S.; Sonoda, N. J . Am. Chem.
Soc. 1983, 105, 7192.
(5) Dekker, J .; Martins, F. J . C.; Kruger, J . A. Tetrahedron Lett.
1975, 29, 2489.
(6) Watanabe, S.; Suga, K.; Fujita, T.; Takahashi, Y. Can. J . Chem.
1972, 50, 2786.
(7) Maekawa, H.; Nakano K.; Hirashima, T.; Nishiguchi, I. Chem.
Lett. 1991, 1661.
(8) Leusen, A. M.; Oosterwijk, R.; Echten, E.; Leusen, D. Recl. Trav.
Chim. Pays-Bas 1985, 104, 50.
(9) Katritzky, A. R.; Lang, H.; Wang, Z.; Zhu, L. J . Org. Chem. 1996,
61, 7551.
(10) Katritzky, A. R.; Lang, H.; Wang, Z.; Zhang, Z.; Song, H. J .
Org. Chem. 1995, 60, 7619.
(11) Katritzky, A. R.; J iang, J . J . Org. Chem. 1995, 60, 6.
(12) Katritzky, A. R.; Lang, H. J . Org. Chem. 1995, 60, 7612.
10.1021/jo981823y CCC: $18.00 © 1999 American Chemical Society
Published on Web 02/25/1999