Agric. Biol. Chem.

, 48 (2), 461 -464, 1984 461

New Synthesis of y-Homocyclogeranial, y-Dihydroionone

and Their Derivatives
Tsuneo Kawanobe, Kunio Kogami, Kazuo Hayashi
and MasanaoMatsui*
Kawasaki Research Center, T. Hasegawa Co., Ltd.,
335 Kariyado, Nakahara-ku, Kawasaki 211, Japan
*Nodai Research Institute, Setagaya-ku, Tokyo 156, Japan
Received August 9, 1983

A new and efficient synthesis of y-homocyclogeranial (4), y-dihydroionone (3) and their
derivatives, 5, 6, 7 and 8, volatile components of ambergris, is described. Their compoundswere
synthesized via Claisen rearrangement of (3,3-dimethylcyclohexenyl)methyl vinyl ether (14).

Ambergris, an intestinal concretion of homocyclogeranyl acetate (6), y-homocyclo-

spermwhale, is extensively utilized in the geranyl chloride (7), and a-ambrinol (8), have
perfumery industry for its characteristic odor already been found toin ambergris and contrib-
and fixative power. A major component of uted importantly the ambergris odor.3)
ambergris is the odorless triterpene alcohol, Since these compounds are not readily avail-
ambrein (1), oxidative degradation of which able from natural sources, muchattention has
produces many odorous substances.1} Oxi- been paid to the synthesis of 2~8. In partic-
dation of the central trans double bond of 1 ular, various synthesis of 3~8 from such dif-
results in an ambreinolide (2) group and ferent startingand materials as geranyl acetone,4)
y-dihydroionone (3) group.2) The oxidative a-ionone5) 3-methyl-2-cyclohexenone6)
have been reported.
Here we wish to describe a newand efficient
synthesis of 3 and 4 via the same intermediate,
allylic alcohol (13), and their conversion to
1 2 3
5 ~7 and 8. Claisen rearrangement of the vinyl
Fig. 1. ether (14) from 13 was applied to prepare 4,
which was transformed to 3 by employing
substances belonging to the latter, y-homo- Darzen's condensation and subsequent
cyclogeranial (4), y-homocyclogeraniol (5), y- decarboxylation.

6-&-&
"Oy0^ 'CHO
"

6:X=OAc
H {*J Ji ^ . 7=x-a
462 T. Kawanobe et al.

Table
(ju
13, cjO
14 4,

15
>
OEt

q kf f *vv r t TemP- Time Yield(%> Yield(%)

No. Substrate E.V.E. Cat. ^ ^ , 4 15

1 14 - - 200 2 88 -
2 13.- 2.0eq JW 200 3 10, 75

3 13 2.0 ^CH 220 2 Trace 85

4 13 2.0 '

5 13 2.0 ;o?)"COOH 220 3 79

The starting material, hydroxymethylene pyridine at roomtemperature to give the ace-

cyclohexanone (10), was prepared from 2- tate (6) in a 88% yield. Furthermore, chlori-
methyl cyclohexanone (9) by an improved nation of 5 with SOCl2-pyridine at 70C for
method of Bailey's procedure.7* Protection of 2hr gave the chloride (7) in a 65% yield.
the hydroxy group of 10 was achieved by In order to elongate the side chain of 4,
treating 10 with ethyl vinyl ether in the pres- Darzen's condensation was employed, and the
ence of H3PO4at room temperature to give intermediate (16) was selected for the synthesis
the acetal (ll) in a quantitative yield. of 3. Condensation of 4 with ethyl a-bromo-
Reduction of ll with NaBH4 in EtOH, fol- propionate was carried out in the presence of
lowed by treatment with 20% aqueous H2SO4, NaOEt at 5C and then decarboxylated with a
yielded the aldehyde (12), which was reduced catalytic amount of AcONaat 200C under a
with NaBH4 in EtOH at 10C to give the key reduced pressure to afforded the ketone (3) as
intermediate, allylic alcohol (13), in an 85%
a pure
Finally,
product in a 65%yield from 4.
conversion of 3 to a-ambrinol (8)
yield from ll.
Subsequently, in order to obtain the al-
was achieved by treating with 20%aqueous
dehyde (4), Claisen rearrangement was exam- sulfuric acid-THF in a 78% yield.8)
ined, the results of which are shownin the Thus a short and efficient synthesis of the
table. Refluxing of 13 with ethyl vinyl ether in several important constituents in ambergris,
the presence of Hg(OAc)2gave the vinyl ether 3~8, was established.
(14) in a 91% yield, which was then rearranged
at 200C for 2hr in an autoclave to afford the EXPERIMENTAL
desired aldehyde (4) in an 88% yield. Further
heating of 13 with ethyl vinyl ether in the All bps were uncorrected. IR were determined on a
JASCO-2spectrometer. NMRspectra were recorded at
presence ofpivalic acid at 220C for 3 hr in an 60 MHzwith TMSas an internal standard on a Hitachi R-
autoclave directly afforded 4 in a 79% yield. 24A spectrometer. MSspectra were obtained on a Hitachi
However, the reaction 13 with ethyl vinyl ether RMU-5MGC-MSspectrometer.
in the presence of H3PO4 and AcOHyielded
the acetal (15) as a major product. 2,2-Dimethyl-6-hydroxymethylene cyclohexanone (10).
Reduction of 4 with NaBH4 in EtOH at To a stirred suspension of NaH (58g of 60% mineral oil
dispersion) in dry toluene (1.8 liters) was added dropwise
room temperature gave the alcohol 5 in a 92% 2-methyl cyclohexanone (135g) during 2hr at 100C, the
yield, which was then acetylated with Ac2O- mixture being stirred throughout this period. To this was
 463
NewSynthesis of y-Homocyclogeranial and y-Dihydroionone
added dropwise Mel (206g) during 2hr at 60C, and the (80), 81 (100), 67 (45), 55 (32), 41 (38). The vinyl ether (14)
mixture was stirred for a further 2hr at 60C. After (50g) was stirred under N2 at 200C for 2hr in an
cooling, a mixture of NaOMe (110g) and HCO2Me autoclave. After cooling, the reaction mixture was distilled
(163g) was added to the mixture at 5C, and the reaction to afford 4 (44g, 88%): bp 58-62C/2mmHg). IR v
mixture stirred for a further 12hr at room temperature cm"1: 2700, 1730, 1640, 895. NMR (CDC13) <S: 0.80 (3H,
before being poured into ice cooled water. The aqueous s), 0.98 (3H, s), 1.1-2.3 (7H), 2.45 (2H, d, J=2Hz), 4.50

layer was acidified with 10% HC1 aq. and extracted with (1H, s), 4.77 (1H, s), 9.58 (1H, t, 7=2Hz). MS m/z: 166
ether. The extract was washed with brine, dried over (M+, 0.7), 151 (16), 122(19), 109(22), 95(18), 81 (32), 69

MgSO4and concentrated. The residue was distilled to give (100), 67 (20), 55 (19), 41 (64).
10 (95g, 51%): bp 85-87C/15mmHg. IR v^ cm"1: b) A mixture of 13 (35g), ethyl vinyl ether (35g) and
3150, 1625, 1580, 895. NMR (CDC13) S: 1.18 (6H, s),
pivalic acid (5g) was stirred at 220C for 3hr in an
1.5-2.4 (6H), 8.54 (1H, s), 14.40 (1H, broad s). MS rn/z: autoclave. After cooling, the reaction mixture was washed
154(M+, 27), 111 (65), 70 (44), 69 (100), 55 (51), 43 (42),
41(82).
with NaHCO3aq., dried over MgSO4, and concentrated.
The residue was distilled to give 4 (32.8 g, 79%).
c) A mixture of 13 (5 g), ethyl vinyl ether (5 g) and acetic
2,2-Dimethyl-6-(l-ethoxy ethoxy) methylene cyclohe- acid (l g) was stirred at 220C for 2hr in an autoclave.
xanone (ll). To a mixture of ethyl vinyl ether (250g) and After the same work-up as above, the residue was distilled
10 (lOOg) was added H3PO4 (3g). After stirring for 12hr togive 15(6.4g, 85%): NMR (CDC13) S: 0.98 (6H, s), 1.21
(3H, t, 7=7Hz), 1.30 (3H, d, J=6Hz), 1.4-2.1 (6H),
at room temperature, the reaction mixture was poured
into NaHCO3aq. and extracted with ether. The extract 3.3-3.8 (2H, m), 3.89 (2H, s), 4.68 (1H, q,.7=6Hz), 5.40
was washed with brine, dried over MgSO4 and con- (1H,s).
centrated to yield crude ll (145g, 99%): IR v"" cm"1:
1670, 1378, 1340, 1110.NMR(CDC13)S: 1.10(6H,s), 1.20 y-Homocyclogeraniol (5). To a stirred suspension of
(3H, t, 7=8Hz), 1.40 (3H, d, 7=6Hz), 1.6-2.7 (6H), NaBH4 (4.5g) in 95% EtOH (40ml) was added dropwise a
3.4-3.9 (2H, m), 5.20 (1H, q, 7=6Hz), 7.61 (1H, t, 7= solution of 4 (20g) in 95% EtOH (40ml) during 1hr at
2Hz). 10C, the mixture being stirred for a further 1 hr at room
temperature. After the usual work-up, the residue was
3,3-Dimethyl-l-hydroxymethyl-l-cyclohexene (13). To a distilled to give 5 (18.6g, 92%): bp 78-80C/0.2mmHg.
stirred suspension of NaBH4 (25 g) in 95% EtOH (300ml) IR v cm"1: 3350, 1640, 1050, 895. NMR (CDC13) S:
was added dropwise ll (153.5 g) during 1 hr at 10C. After 0.87 (3H, s), 0.93 (3H, s), 1.1-2.2 (9H), 2.90 (1H, s), 3.50
stirring for 1 hr, 20% aq. H2SO4 (325g) was added drop- (2H, t, J=1Hz), 4.58 (1H, d, 7=2Hz), 4.73 (1H, d, J=

wise to the reaction mixture during 1 hr at room tempera- 2Hz). MSm/z: 168 (M+, 1.3), 153 (15), 123 (23), 109(46),
ture. The mixture was neutralized with 25%aq. NaOH, 81 (47), 69 (100), 55 (25), 41 (60).
and to the reaction mixture of the crude aldehyde (12) was
then added NaBH4(25g) during 30 min at 10C. After y-Homocyclogeranyl acetate (6). To a solution of Ac2O
stirring for 2 hr at room temperature, the reaction mixture (12.4g) in pyridine (14ml) was added dropwise 4 (10g)
was poured into water and extracted with ether. The during 30 min at 10C, and the mixture was stirred at
extract was washed with brine, dried over MgSO4and room temperature for 12 hr. After the usual work-up, the
concentrated. The residue was distilled to give 13 (81 g, residue was distilled to give 6 (llg, 88%): bp 78-80C/
85% from ll): bp 78~82C/2mmHg. IR vcm"1: 3325, 0.2mmHg. IR vEcm"1: 1742, 1640, 895. NMR(CDC13)
1368, 1360, 1030. NMR (CDC13) 3: 0.96 (6H, s), 1.1-2.1 S: 0.89 (3H, s), 0.93 (3H, s), 1.1-2.0 (9H), 2.02 (3H, s),
(6H), 2.96 (1H, broad s), 3.91 (2H, s), 5.36 (1H, s). MS 3.8-4.2 (2H, m), 4.65 (1H, s), 4.82 (1H, s). MS m/z: 150
m/z: 140(M+, 17), 125 (29), 109 (100), 107(40), 95 (47), 79 (28), 135 (32), 107 (28), 81 (26), 79 (25), 69 (100), 43 (63),
(41), 67 (40), 55 (60), 41 (55). 41(47).
12: NMR (CDC13) d: 1.10 (6H, s), 1.2-2.3 (6H), 6.45
(1H, s), 9.36 (1H, s).
y-Homocyclogeranyl chloride (7). To a stirred solution of
5 (10g) in pyridine (6.4g) was added dropwise SOC12
y-Homocyclogeranial (4).
(9.6 g) during 30 min at 15C, the mixture being stirred for
a) A mixture of 13 (65g), ethyl vinyl ether (2 liters) and a further 2hr at 70C. The mixture was then cooled,
Hg(OAc)2 (25 g) was refluxed for 12 hr. After cooling, the diluted with water and extracted with ether. The extract
reaction mixture was washed with NaHCO3aq. and brine, was washed with brine and NaHCO3 aq., dried over
dried over MgSO4,and concentrated. The residue was MgSO4, and concentrated. The residue was distilled to
distilled to give the vinyl ether (14) (70g, 91%): bp give 7 (7.2g, 65%): bp 58-60C/lmmHg. IR vS cm"1:
42-45C/2mmHg. IR vJJlS cm'1: 3100, 1635. NMR
1642, 895, 660. NMR (CDC13) S: 0.86 (3H, s), 0.94 (3H, s),
(CDCI3)6: 0.96(6H, s), 1.1-2.1 (6H), 3.93 (1H, d-d, 7=2,
1.1-2.2 (9H), 3.2-3.7 (2H, m), 4r60 (1H, broad s), 4.80
8Hz), 4.00 (2H, s), 4.17 (1H, d-d, 7=2, 16Hz), 5.43 (1H, (1H, broads). MSm/z: 188 (M+, 1.3), 186(M+, 3.9), 173
s),6.42(lH,d~d,7=8, 16Hz). MSm/z: 166(M+, 1.4), 123 (2.7), 171 (8), 145 (6.7), 143 (20), 109 (12), 95 (ll), 81 (29),
464 T. Kawanobe et al.
69 (100), 55 (12), 41 (67).
brine, dried over MgSO4, and concentrated. The residue
was distilled to give 8 (7g, 78%): bp 81 ~82C/0.8mmHg.
Ethyl 4- (2-methylene-6,6-dimethylcyclohexyl) -2-methyl- IR vS cm"1: 3450. NMR (CDC13) S: 0.87 (3H, s), 0.92
(3H,s), 1.21 (3H,s), 1.1-2.1 (llH), 1.84(1H,s), 5.45(1H,
2,3-epixybutyrate. To a stirred suspension of NaOEt,
prepared from NaH (21in g,dry60%toluene
mineral (500ml),
oil dispersion) and t,J=2Hz). MSm/z: 194(M+, 8), 176(16), 161 (13), 136
abs. EtOH (27g) was added (88), 121 (56), 105 (39), 95 (52), 71 (42), 43 (100), 41 (42).
dropwise a mixture of 4 (60g) and ethyl a-bromopro- These data for synthetic 8 were identical with those of the
pionate (97g) during 1 hr at 5C. After stirring at room authentic sample.
temperature for a further 12hr, the mixture was washed
with water, dried over MgSO4, and concentrated. The Acknowledgments. We thank Mr. O. Takazawa, T.
residue was distilled to give a mixture of cisltrans 16 (82 g, Hasegawa Co., Ltd., for the gift of authentic a-ambrinol
86%) in a 1:1 ratio: bp'll5~118C/0.2mmHg. IR v"a" and for his useful suggestions. Our thanks are also due to
cm"1: 1742, 1730, 1640, 895. NMR (CDC13) 6: 0.85 (3H, Mr. T. Yanai, T. Hasegawa Co., Ltd., for GC-MS
s), 0.95 (3H, s), 1.1~2.3 (9H), 1.27 (3H, t, 7=7Hz), 1.50 analysis.
(3H, s), 2.85 and 3.10 (1H, t, J=7Hz), 4.0~4.4 (2H, m),
4.62 (1H, broad s), 4.80 (1H, broad s). MS m/z: 193 (ll), REFERENCES
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was extracted with ether and the extract was washed with 1990 (1957).
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centrated. The residue was distilled in the presence of Congress of Essential Oils, Kyoto, Japan, 1977, p.
NaOAc (2g) in vacuo to give 3 (25g, 76%): bp 82~84C/ 479.
0.5mmHg. IR v"a" cm"1: 1720, 1642, 895. NMR(CDC13) 4) G. Ohloff and G. Schade, Chem. Ber., 91, 2017
3: 0.88 (3H, s), 0.93 (3H, s), 1.1-2.6 (llH), 2.12 (3H, s), (1958).
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(100ml) in THF (60ml) was added dropwise 3 (9 g) during 1593 (1955).
10 min at 20C. After stirring for a further 2 hr at 40C, the b) A. G. Armour, G. Buchi, A. Eschenmoser and A.
reaction mixture was poured into water, and extracted Storni, Helv. Chim. Acta, 42, 2233 (1959).
with ether. The extract was washed with NaHCO3aq. and