C. C. Silveira et al. / Tetrahedron Letters 45 (2004) 4077–4080
Table 1. Synthesis of 4-methyl-b-tetralones
4079
Entry
1
Acyl chloride Allylsilane (equiv)
b-Tetralone
5 þ 15a (2:1)b
R1
R2
R3
R4
R5
Yield (%)a
13a
14a (1.6)
5: H
15a: –
CH3
H
CH3O
CH3O
H
H
H
25c
16
47d
CH3
H
H
2
13b
14a (1.6)
15b þ 15c (2:1)b 15b: H
CH3
H
H
15c: –
H
CH3
H
H
3
4
5
6
7
13c
13d
13e
13f
13f
14a (3.0)
14a (1.6)
14a (1.6)
14a (1.6)
14b (5.0)
15d
15e
15f
15g
15h
H
H
Cl
H
H
H
CH3
Br
H
23
35
60
71
34
H
H
H
H
H
H
H
H
H
H
H
nPentyl
H
H
H
a After purification by silica gel column chromatography.
b Determined by GC and 1H NMR of the crude reaction and compared after purification.
c Purified by crystallization from petroleum ether.
d Yield of the mixture.
(petroleum ether, 25% yield). A similar behavior was
observed during the cyclization of 13b (Table 1, entries 1
References and notes
1. (a) Miles, D. H.; Lho, D. S.; de la Cruz, A. A.; Gomez, E.
D.; Weeks, J. A.; Atwood, J. L. J. Org. Chem. 1987, 52,
2930; (b) Miles, D. H.; Chitttawong, A.; Ly, V.; de Ia
Cruz, A. A.; Gomez, E. D. J. Nat. Prod. 1989, 52, 896.
2. Luitgards-Moura, J. F.; Bermudez, E. G. C.; Rocha, A. F.
I.; Tsouris, P.; Rosa-Freitas, M. G. Mem. Inst. Oswaldo
Cruz 2002, 97, 737.
3. (a) Irie, H.; Matsumoto, R.; Nishimura, M.; Zhang, Y.
Chem. Pharm. Bull. 1990, 38, 1852; (b) Ayyangar, R. N.;
Chavan, P. S.; Zubaidha, K. P.; Racherla, S. U. Tetrahe-
dron 1991, 47, 5759; (c) Chavan, P. S.; Zubaidha, K. P.;
Govande, C. A.; Rao, T. S. Y. J. Chem. Soc., Chem.
Commun. 1994, 1101; (d) Subhash, P.; Chavan, S. P.;
Govande, C. A. Green Chem. 2002, 4, 194.
4. (a) Silveira, C. C.; Lenardo, E. J.; Araujo, M. A.; Braga,
A. L.; Dabdoub, M. J. Synthesis 1995, 1305; (b) Silveira,
C. C.; Machado, A.; Fiorin, G. L.; Braga, A. L.;
Dabdoub, M. J. Tetrahedron Lett. 1996, 37, 9173; (c)
Silveira, C. C.; Bernardi, C. R.; Braga, A. L.; Kaufman, T.
S. Tetrahedron Lett. 1999, 40, 4969; (d) Silveira, C. C.;
Bernardi, C. R.; Braga, A. L.; Kaufman, T. S. Tetrahedron
Lett. 2001, 42, 8947; (e) Silveira, C. C.; Bernardi, C. R.;
Braga, A. L.; Kaufman, T. S. Tetrahedron Lett. 2003, 44,
6137.
5. (a) Craig, J. C.; Torkelson, S. M.; Findell, P. R.; Weiner,
R. L. J. Med. Chem. 1989, 32, 961; (b) Hacksell, U.;
Johanson, A. M.; Arvidsson, L. E.; Nilsson, J. L. G.;
Hjorth, S.; Carlsson, A.; Wikstrm, H.; Sanchez, D.;
Lindberg, P. J. J. Med. Chem. 1984, 27, 1003.
and 2). Yields of b-tetralones prepared as shown in
Scheme 3 are satisfactory, compared to those arising
from cyclization of b,c-unsaturated ketones with AlCl3.16
Moreover, the aryl acetic acids and allyltrimethylsilane
are easily available, the method described here allows
the preparation of several 4-methyl-b-tetralones in a
short sequence, and acyl chlorides with electron with-
drawing groups can be used (entry 5).
A reaction that exploits the ability of the selenium atom
in stabilizing an adjacent carbocation, which is part of
an extensive study of selenocarbenium ions developed
by our group,4 served for the synthesis of the butenolide
unit of (ꢀ)-heritonin (1). Thus, silyl enol ether 9 was
prepared in 76% yield from the b-tetralone 5 and treated
with a-chloro-a-phenylseleno-ethyl propionate in the
presence of ZnBr2,4b furnishing c-keto ester 10. Reac-
tion of crude ester 10 with mCPBA at ꢁ78 ꢁC provided
41% of a,b-unsaturated ester 11,17 together with 16% of
its isomeric trans ester, easily separated by silica gel
column chromatography (hexane/EtOAc, 95:5). Finally,
ester 11 was cyclized upon reduction with NaBH4 and
acid hydrolysis to give 75% of (ꢀ)-heritonin 1 and (ꢀ)-
epi-heritonin 12 as a 1.5:1 diastereomeric mixture
(Scheme 2), purified by fractional crystallization
(petroleum ether). Isomer 12 was the first to crystal-
lize, while (ꢀ)-1 was obtained from the mother
liquors, as described in the literature.3b Spectral data of
1 and 12 perfectly agreed with those reported.3
Demethylation of (ꢀ)-1 to (ꢀ)-heritol (2) with BCl3 or
BBr3 is well established and can be achieved in 59–81%
yield.3b;d
6. Kanao, M.; Hashizume, Y.; Ichikawa, K.; Irie, K.; Isoda,
S. J. Med. Chem. 1982, 25, 1358.
7. For a review on 1,2-carbonyl transposition, see: Kane,
V. V.; Singh, V.; Martin, A. Tetrahedron 1983, 39, 345.
8. (a) Shishido, K.; Goto, K.; Miyoshi, S.; Takaishi, Y.;
Shibuya, M. J. Org. Chem. 1994, 59, 406; (b) Johansson,
A. M.; Mellin, C.; Hacksell, U. J. Org. Chem. 1986, 51,
5252; (c) Covarrubias-Ziga, A.; Cant, F.; Maldonado, L.
A. J. Org. Chem. 1998, 63, 2918.
9. (a) Oikawa, Y.; Yonemitsu, O. J. Org. Chem. 1976, 41,
1118; (b) Cannon, J. G.; Lee, T.; Goldman, H. D.; Costall,
B.; Naylor, R. J. Med. Chem. 1977, 20, 1111.
In conclusion, we described here a new method for the
synthesis of 4-alkyl-b-tetralones and a new route to (ꢀ)-
heritonin 1, which constitutes a good alternative to
other described protocols, especially if the easy access of
the b-tetralone intermediate is considered.
10. (a) Kanao, M.; Hashizume, Y.; Ichikawa, K.; Irie, K.;
Isoda, S. J. Med. Chem. 1982, 25, 1358; (b) Nevy, J. B.;
Hawkinson, D. C.; Grzegorz, B.; Yao, X.; Pollack, R. M.
J. Am. Chem. Soc. 1997, 119, 12722.
11. Meyers, A. I.; Henry, S. S.; Pryde, D. C. Tetrahedron Lett.
1996, 37, 3243.
Acknowledgements
12. 1,2-Carbonyl transposition of 7: 1,6-dimethyl-7-methoxy-
1,2-dihydro-4-naphthylcyanide 8. Me3SiCN (1.38 mL,
We thank FAPERGS and CNPq for financial support.