Hydrolysis of β,γ-unsaturated aldehyde dimethylhydrazones with copper dichloride: A new synthesis of lavandulol

Full text of DOI:10.1021/jo9613242

734
J . Org. Chem. 1997, 62, 734-735
Sch em e 1
Hyd r olysis of â,γ-Un sa tu r a ted Ald eh yd e
Dim eth ylh yd r a zon es w ith Cop p er
Dich lor id e: A New Syn th esis of
La va n d u lol†
Takashi Mino, Satoru Fukui, and Masakazu Yamashita*
Department of Molecular Science and Technology,
Faculty of Engineering, Doshisha University,
Tanabe, Kyoto 610-03, J apan
Received J uly 12, 1996
Lavandulol (1), a constituent of lavender oil,1 possesses
an unusual monoterpene skeleton and is used as an
important additive in the perfume industry. This com-
pound has also been isolated as a defensive pheromone
of the red-lined carrion beetle.2 Because of its impor-
tance, several syntheses of this compound have been
reported.3 However, these have required a complicated
starting material3b or employed reaction of low regio-
selectivity.3f
Ta ble 1. Hyd r olysis of Dim eth ylh yd r a zon e 4
In this paper, we wish to report on a new and
convenient synthesis of lavandulol (1) by regioselective
alkylation of 3-methyl-2-butenal dimethylhydrazone (3)
with 1-bromo-3-methyl-2-butene and hydrolysis of the
product, 2-isopropenyl-5-methyl-4-hexenal dimethylhy-
drazone (4), with copper dichloride without double bond
migration from â,γ to R,â (Scheme 1). We also report
additional examples of this mild hydrolysis procedure.
3-Methyl-2-butenal dimethylhydrazone (3) was easily
prepared in 86% yield from 3-methyl-2-butenal (2) and
N,N-dimethylhydrazine by using trifluoroacetic acid as
a catalyst. After deprotonation of the dimethylhydrazone
3 with lithium diisopropylamide (LDA) in THF, the
azaenolate of 3 was alkylated by 1-bromo-3-methyl-2-
butene to give 2-isopropenyl-5-methyl-4-hexenal dimeth-
ylhydrazone (4) in 65% yield.4 2-Isopropenyl-5-methyl-
4-hexenal (5) was obtained from the dimethylhydrazone
4 in 68% yield by hydrolysis in the presence of copper
dichloride.5 Reduction of 5 with sodium borohydride gave
lavandulol (1) in 66% yield.
a
Isolated yield.
Sch em e 2
In this synthesis, one of the key steps is the hydrolysis
of the dimethylhydrazone 4. Although a variety of
methods, such as using MMPP (magnesium monoper-
phthalate hexahydrate),6 are available for the cleavage
† Dedicated to Prof. Yoshito Kishi on the occasion of his 60th
birthday.
(1) (a) Schinz, H.; Seidel, C. F. Helv. Chim. Acta 1942, 25, 1572. (b)
Schinz, H.; Bourquin, J . P. Helv. Chim. Acta 1942, 25, 1591. (c)
Bohlmann, F.; Zdero, C.; Faass, U. Chem. Ber. 1973, 106, 2904.
(2) Eisner, T.; Deyrup, M.; J acobs, R.; Meinwald, J . J . Chem. Ecol.
1986, 12, 1407.
(3) (a) Schinz, H.; Scha¨ppi, G. Helv. Chim. Acta 1947, 30, 1483. (b)
Bertrand, M.; Gil, G.; Viala, J . Tetrahedron Lett. 1977, 1785. (c) Ueno,
Y.; Aoki, S.; Okawara, M. J . Chem. Soc., Chem. Commun. 1980, 683.
(d) Cookson, R. C.; Mirza, N. A. Synth. Commun. 1981, 11, 299. (e)
Babin, D.; Fourneron, J . D.; Harwood, L. M.; J ulia, M. Tetrahedron
1981, 37, 325. (f) Majewski, M.; Mpango, G. B.; Thomas, M. T.; Wu,
A.; Snieckus, V. J . Org. Chem. 1981, 46, 2029. (g) Kramer, A.; Pfander,
H. Helv. Chim. Acta 1982, 65, 293. (h) Takano, S.; Tanaka, M.; Seo,
K.; Hirama, M.; Ogasawara, K. J . Org. Chem. 1985, 50, 931. (i)
Celebuski, J .; Rosenblum, M. Tetrahedron 1985, 41, 5741. (j) J ulia,
M.; Schmitz, C. Bull. Soc. Chim. Fr. 1986, 630. (k) Cardillo, G.;
D’Amico, A; Orena, M.; Sandri, S. J . Org. Chem. 1988, 53, 2354. (l)
McCullough, D. W.; Bhupathy, M.; Piccolino, E.; Cohen, T. Tetrahedron
1991, 47, 9727. (m) Piva, O. J . Org. Chem. 1995, 60, 7879.
(4) Yamashita, M.; Matsumiya, K.; Nakano, K. Bull. Chem. Soc. J pn.
1993, 66, 1759.
of ketone dimethylhydrazones,7 few are satisfactory when
applied to aldehyde dimethylhydrazones.
We investigated the hydrolysis of 2-isopropenyl-5-
methyl-4-hexenal dimethylhydrazone (3) under various
conditions. Hydrochloric acid, which was previously used
at room temperature in the synthesis of 7h ,4 caused
double-bond migration from â,γ to R,â in the case of 4
(entry 1, Table 1). At 0 °C (entry 2, Table 1), aldehyde 5
was found from 4 without double bond migration, but the
yield was only 16%. On the other hand, when copper
dichloride was used at room temperature, aldehyde 5 was
obtained in good yield (entry 3, Table 1).
To test the generality of the method, various â,γ-
unsaturated aldehyde dimethylhydrazones 6 were ex-
amined (Scheme 2). The results are listed in Table 2.
(5) To our knowledge, the hydrolysis of aldehyde dimethylhydrazone
with copper dichloride was only applied to the cyclohexanecarboxal-
dehyde dimethylhydrazone and cinnamaldehyde dimethylhydrazone.9
(6) Enders, D.; Plant, A. Synlett 1990, 725.
(7) Greene, T. W.; Wuts, P. G. M. In Protective Groups in Organic
Synthesis; J ohn Wiley & Sons, Inc.: New York, 1991; p 212 and
references cited therein.
S0022-3263(96)01324-2 CCC: $14.00 © 1997 American Chemical Society

Notes
J . Org. Chem., Vol. 62, No. 3, 1997 735
performed on silica gel 60 plates F254 THF was dried and
Ta ble 2. Hyd r olysis of Dim eth ylh yd r a zon e 6 w ith Cu Cl2
.
deoxygenated by distillation from potassium-benzophenone
under an argon atmosphere just before use. Copper dichloride
and sodium borohydride were commercial reagents of the highest
available purity. Hydrazones 3, 4, and 6 were prepared accord-
ing to methods reported previously.4,8
Hyd r olysis of Dim eth ylh yd r a zon e 4 w ith Hyd r och lor ic
Acid . To a solution of aqueous 1 N HCl (15 mL) was added a
solution of hydrazone 4 (0.97 g, 5.0 mmol) in THF (15 mL) at
room temperature. After being stirred for 8 h at room temper-
ature, the reaction mixture was quenched with saturated
NaHCO3 (aq), diluted with ether, washed with brine, and dried
over MgSO4. Removal of solvents and column chromatography
gave 2-isopropylidene-5-methyl-4-hexenal (8) (23%, 0.17 g, 1.11
1
mmol): IR (neat) 1670 (CdO) cm-1; H NMR (60 Mz, CDCl3) δ
1.70 (s, 6H), 2.00 (s, 3H), 2.20 (s, 3H), 2.80-3.10 (m, 2H), 4.70-
5.10 (m, 1H), 9.62-9.82 (m, 1H); MS m/z 152 (M+, 74). Anal.
Calcd for C10H16O: C, 78.90; H, 10.59. Found: C, 78.67; H,
10.59.
Gen er a l P r oced u r e for th e Hyd r olysis of Dim eth ylh y-
d r a zon es w ith Cu Cl2. To a solution of CuCl2 (1.1 mmol, 0.15
g) in water (10.0 mL) was added a solution of hydrazone 4 or 6
(1.0 mmol) in THF (15 mL) at room temperature. After being
stirred for 2.5 h at room temperature, the reaction mixture was
quenched with aqueous 3 N NH4OH, diluted with ethyl acetate,
washed with brine, and dried over MgSO4. Removal of the
solvents and column chromatography gave the pure aldehyde 5
or 7.
2-Isop r op en yl-5-m eth yl-4-h exen a l (5): IR (neat) 1742
(CdO) cm-1 1H NMR (60 Mz, CDCl3) δ 1.52 (s, 3H), 1.68 (s,
;
3H), 1.75 (s, 3H), 2.10-2.61 (m, 2H), 2.82-2.89 (m, 1H), 4.89
(s, 1H), 4.90-5.25 (m, 2H), 9.48 (s, 1H); 13C NMR (100 Mz,
CDCl3) δ 17.88, 21.27, 25.74, 25.99, 60.69, 115.34, 120.64, 133.67,
140.27, 201.26; MS m/z 152 (M+, 12). Anal. Calcd for C10H16O:
C, 78.90; H, 10.59. Found: C, 79.04; H, 10.74.
2-Ben zyl-3-m eth yl-2-h exen a l (7a ): IR (neat) 1722 (CdO)
cm-1; 1H NMR (60 Mz, CDCl3) δ 1.70 (s, 3H), 2.63-3.08 (m, 1H),
3.10-3.42 (m, 2H), 4.78 (s, 1H), 5.08 (s, 1H), 7.02-7.44 (br, 5H),
9.52 (s, 1H); 13C NMR (100 Mz, CDCl3) δ 21.36, 33.42, 62.03,
116.16, 126.31, 128.43, 128.84, 139.05, 139.74, 200.19; MS m/z
174 (M+, 10). Anal. Calcd for C12H14O: C, 82.72; H, 8.10.
Found: C, 82.58; H, 8.10.
La va n d u lol (1). To a solution of aldehyde 5 (1.0 mmol, 0.152
g) in 10.0 mL of EtOH was added
a solution of sodium
borohydride (0.50 mmol, 0.02 g) in 1.0 mL of EtOH at room
temperature. After 4 h, the reaction mixture was quenched with
water, diluted with ethyl acetate, washed with brine, and dried
over MgSO4. After removal of the solvent, the residue was
purified by silica gel column chromatography to give lavandulol
(1) (0.66 mmol, 0.10 g, 66%): IR (neat) 3370 (OH) cm-1; 1H NMR
(60 Mz, CDCl3) δ 1.52 (br, 1H), 1.62 (s, 3H), 1.75 (s, 6H), 1.92-
2.48 (m, 3H), 3.45-3.63 (m, 1H), 4.83 (s, 1H), 4.94 (s, 1H); MS
m/z 136 (M+ - H2O, 8); TMS ether MS m/z 226 (M+, 23).
a
b
Isolated yield. Value in parentheses is the yield using
hydrochloric acid.
After workup and purification by flash column chroma-
tography, â,γ-unsaturated aldehydes 7 were obtained in
acceptable to good yields without double bond migration
(entries 1-5, Table 2). As shown in entry 8 (Table 2),
the copper dichloride method is more useful than the
hydrochloric acid method even for the hydrolysis of â,γ-
unsaturated aldehyde hydrazones, which have a quater-
nary carbon atom at the R-position.
Registr y n u m ber s p r ovid ed by th e a u th or : 1,
1845-51-8; 3, 16713-48-7; 4, 119045-78-2; 5, 75697-98-2;
7a , 66730-46-9; 7f, 68620-37-1; 7h , 119045-67-9; 8, 3304-
28-7.
Su p p or tin g In for m a tion Ava ila ble: Characterization
data of compounds 7b-h and copy of 13C NMR spectra of 7f
(3 pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
Exp er im en ta l Section
Gen er a l P r oced u r es. 1H and 13C NMR spectra were taken
(at 400 MHz or 60 MHz) in CDCl3 solvent and recorded in parts
per million (ppm, δ) downfield from internal tetramethylsilane
(Me4Si). Column chromatography was performed on silica gel
60 (230-400 mesh), and thin-layer chromatography (TLC) was
J O9613242
(8) Mino, T.; Yamashita, M. J . Org. Chem. 1996, 61, 1159.
(9) Corey, E. J .; Knapp, S. Tetrahedron Lett. 1976, 3667.