Facile synthesis of isodamascone and its analogs

Article abstract of DOI:10.1080/00397910601038988

Synthesis of isodamascone and its analogs, the commercially important aroma compounds, have been accomplished from the readily available 1,5,5-trimethyl-2-cyclohexen-1-ol via a short, facile, and simple sequence of reactions in excellent yield. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910601038988

This article was downloaded by: [Washington University in St Louis]
On: 04 October 2014, At: 02:30
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office:
Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International
Journal for Rapid Communication of
Synthetic Organic Chemistry
Publication details, including instructions for authors and subscription
information:
http://www.tandfonline.com/loi/lsyc20
Facile Synthesis of Isodamascone and Its
Analogs
Dinesh W. Rangnekar a , Vikas S. Kulkarni a , Prasad V. Ranade a & Ram W.
Sabnis b
a Dyes Research Laboratory , Institute of Chemical Technology, University of
Mumbai , Matunga, Mumbai, India
b Ascadia Inc. , Eagan, Minnesota, USA
Published online: 06 Feb 2007.
To cite this article: Dinesh W. Rangnekar , Vikas S. Kulkarni , Prasad V. Ranade & Ram W. Sabnis (2007) Facile
Synthesis of Isodamascone and Its Analogs, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 37:3, 425-430, DOI: 10.1080/00397910601038988
To link to this article: http://dx.doi.org/10.1080/00397910601038988
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”)
contained in the publications on our platform. However, Taylor & Francis, our agents, and our
licensors make no representations or warranties whatsoever as to the accuracy, completeness, or
suitability for any purpose of the Content. Any opinions and views expressed in this publication
are the opinions and views of the authors, and are not the views of or endorsed by Taylor &
Francis. The accuracy of the Content should not be relied upon and should be independently
verified with primary sources of information. Taylor and Francis shall not be liable for any
losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities
whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or
arising out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any substantial
or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or
distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use
can be found at http://www.tandfonline.com/page/terms-and-conditions

Synthetic Communicationsw, 37: 425–430, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910601038988
Facile Synthesis of Isodamascone
and Its Analogs
Dinesh W. Rangnekar, Vikas S. Kulkarni,
and Prasad V. Ranade
Dyes Research Laboratory, Institute of Chemical Technology,
University of Mumbai, Matunga, Mumbai, India
Ram W. Sabnis
Ascadia Inc., Eagan, Minnesota, USA
Abstract: Synthesis of isodamascone and its analogs, the commercially important
aroma compounds, have been accomplished from the readily available 1,5,5-trimethyl-
2-cyclohexen-1-ol via a short, facile, and simple sequence of reactions in excellent yield.
Keywords: facile synthesis, Kondakov reaction, isodamascone, perfume
The kingdom of blooms is the domain of monoterpenoids and C-13 degraded
carotenoids. Damascones are important class of aroma compounds having a
more raspberry-like, fruity, and exotic note. Damascones have attained promi-
nence with the discovery of their occurrence in rose and geranium oils.[1] They
are used in perfume compositions, especially in rose perfumes, and in flavor
compositions, to which they impart naturalness and brilliance.[2–4] Klein[5]
reported isodamascone (1), one of the major derivative of damascone. In
recent years, isodamascone has attracted special attention on account of
their applications in hair cosmetics,[6] skin-care products,[7] and laundry deter-
gents.[8] Klein[5] prepared isodamascone using crotonic anhydride and Lewis
acid. The process was complex, involving multiple steps with poor yields and
Received in the USA June 30, 2006
Address correspondence to Ram W. Sabnis, Ascadia Inc., 3947 Thames Avenue,
Eagan, MN 55123, USA. E-mail: ramsabnis@yahoo.com
425

426
D. W. Rangnekar et al.
low purity. We have reported facile synthetic routes[9–11] for a wide variety of
novel organic compounds.
In this communication, we report a facile synthesis of isodamascone from
readily available and economical key starting material 1,5,5-trimethyl-2-
cyclohexen-1-ol (1) in excellent yield by a simple method. The cyclic
alcohol (1) has three methyl groups of the target molecule as well as
suitable functionality for subsequent transformations, which prompted us to
investigate a new route to the titled compounds (6) using compound (1).
We have developed a facile synthetic route that involved the synthesis of
cyclogeraniolene (3) first from 1,5,5-trimethyl-2-cyclohexen-1-ol (1) and
later developed a proper side chain yielding isodamascone and its analogs (7).
Wharton[12] reported the synthesis of cyclic tertiary alcohol (2) from
1,5,5-trimethyl-2-cyclohexen-1-ol (1) using platinum oxide in ethanol as
hydrogenating agent. Because platinum oxide is an expensive ingredient,
the method cannot be used for commercial applications. We have developed
the most economical method of hydrogenation, which involves the hydrogen-
ation of 1,5,5-trimethyl-2-cyclohexe-1-ol (1) using 5% palladium/carbon,
giving excellent yield (95%) and high-purity cyclic tertiary alcohol (2).

Facile Synthesis of Isodamascone and Its Analogs
427
Owing to a high sublimation rate of the low melting solid tertiary alcohol
(2), it was immediately subjected to next step, dehydration. Heating (2) with
p-toluene sulphonic acid (PTSA) in refluxing toluene furnished the insepar-
able isomeric mixture of a- and b-cyclogeraniolenes (3a and 3b),[13,14]
which was confirmed by gas chromatography analysis.
The isomeric mixture of a- and b-cyclogeraniolenes (3a and 3b) on
treatment with acetic anhydride and anhydrous zinc chloride under
Kondakov reaction conditions[15] gave pure ketone (4) in high yield and
high purity. The structure of the ketone (4) was confirmed on the basis of
1
infrared spectra, H NMR spectra, and elemental analysis.
The homologation of the side chain was achieved by reacting (4) with
N-methylanilino magnesium bromide and then with aldehydes, namely, acet-
aldehyde and propionaldehyde. The resulting aldol was converted in situ
using p-toluenesulfonic acid in refluxing toluene to give isodamascone (6a)
and its analog, methyl isodamascone (6b).
In conclusion, 1,5,5-trimethyl-2-cyclohexen-1-ol (1), an economical
starting material, was used as a precursor for the synthesis of isodamascone
as well as its analog by following a simple sequence of reactions as
described. Moreover, it offers the advantage over the earlier report[16] of
getting access to synthesis of isodamascone analogs.
EXPERIMENTAL
All melting points and boiling points are uncorrected. The infrared spectra
were recorded on Bomen MB spectrophotometer. The 1H NMR spectra
were recorded on a Varian 300 MHz instrument using tetramethylsilane as
the internal standard, and the chemical shifts are given in d (ppm).
Elemental analysis was performed on a Fison EA 1108 elemental analyzer.
1,3,3-Trimethyl cyclohexan-1-ol (2)
In a Parr autoclave, a mixture of allyl alcohol (1) (24.5g, 0.175 mol) in ethanol
(350 mL) was stirred with 5% palladium on carbon (1.25 g) under 50-psi H2
pressure at room temperature for 1 h. The reaction mixture was filtered
through celite-521. The solvent was evaporated on Buchi rotary evaporator,
dried to give (2) in 95% yield; mp 748C (lit. 748C).[12]
a-Cyclogeraniolene (3a) and b-Cyclogeraniolene (3b)
To a stirred solution of (2) (21.3 g, 0.15 mol) in dry toluene (300 mL), p-tolue-
nesulfonic acid (0.82 g, 0.0043 mol) was added. The reaction mixture was
refluxed and the water formed was removed azeotropically using a

428
D. W. Rangnekar et al.
Dean–Stark water separator. When no more water was separated, the reaction
was stopped after 2 h. The mixture was allowed to cool to room temperature
and washed successively with water (50 mL), 10% aqueous sodium carbonate
(3 Â 50 mL), and again with water. The toluene layer was dried over
anhydrous sodium sulfate, and the solvent was evaporated on Buchi rotary
evaporator. Residual oil was distilled under reduced pressure to give the
isomeric mixture of cyclogeraniolenes (3a and 3b) in 88% yield; bp
104–1068C/200 mm (lit. 137–1388C).[13,14]
1-(2,4,4-Trimethyl-2-cyclohexen-1-yl)-ethanone (4)
A mixture of cyclogeraniolenes (3a and 3b) (12.4 g, 0.1 mol) and anhydrous
zinc chloride (2.72 g, 0.02 mol) was stirred followed by dropwise addition of
acetic anhydride (22 mL, 0.23 mol) over a period of 1 h at room temperature.
Acetic anhydride was added to a mixture of olefin and zinc chloride to avoid
polymerization. The reaction mixture was heated to 708C in a water bath for
an additional 2 h. The reaction mixture was allowed to cool to room tempera-
ture and slowly added to an ice–water mixture (50 mL). The resulting solution
was extracted with ether (3 Â 25 mL). The combined ethereal extracts were
washed with saturated aqueous sodium bicarbonate until no further
evolution of a gas was observed. The organic layer was separated and dried
over sodium sulfate, and the solvent was evaporated on a Buchi rotary evap-
orator. Residual oil was distilled under reduced pressure to give ketone (4) in
1
79% yield; bp 568C/3 mm; IR (Oil film): n 1712, 1685 cm21; H NMR
(CDCl3) d: 5.38 (s, 1H, CH55C,), 2.98 (t, 1H, 55C-CH-CO), 2.15 (s, 3H,
CH3-CO), 1.76–1.88 (m, 2H, ring -CH2-), 1.6 (s, 3H, CH3-C55), 1.34 to
1.42 (m, 2H, ring -CH2-, 0.9 (s, 3H, methyl), 1.0 (s, 3H, methyl); anal.
calcd. for C11H18O: C, 79.46; H, 10.91. Found: C, 79.39; H, 10.96.
General Procedure for Compounds (6a and 6b)
A solution of ethyl magnesium bromide in dry ether was prepared by reacting
ethyl bromide (0.033 mol) with magnesium turnings (0.033 mol). The solution
was cooled to 258C followed by addition of a solution of monomethyl aniline
(0.033 mol) in sodium dried toluene (5.0 mL). The reaction mixture was
stirred at 158C for 15 min. A solution of ketone (4) (0.3 mol) in sodium-
dried toluene (5.0 mL) was added to the reaction mixture at 258C and was
stirred at 258C for 30 min. The reaction mixture was cooled to 258C
followed by slow addition of aldehyde (0.036 mol) (5) in sodium-dried
toluene (10 mL) over a period of 20 min. The mixture was stirred further
for 1 h at 258C and slowly added to ice–water mixture followed by
addition of 10% HCl (75 mL). The solution was extracted with toluene
(3 Â 25 mL); combined extracts were washed with 10% HCl (3 Â 25 mL)

Facile Synthesis of Isodamascone and Its Analogs
429
followed by water (3 Â 25 mL) and dried over anhydrous sodium sulfate.
Solvent was distilled out to give crude oil, which was diluted with
dry toluene to about 125 mL. p-Toluenesulfonic acid (0.20 g) was
added, and the mixture was refluxed. The water formed was removed
azeotropically using Dean–Stark water separator. When no more water was
separated, reaction was stopped. The reaction mixture was cooled to room
temperature, washed successively with water (25 mL), 10% aqueous sodium
carbonate (3 Â 25 mL), and again with water (2 Â 25 mL). The toluene
layer was dried with anhydrous sodium sulfate. Toluene was vacuum
distilled to give (6). Structure was confirmed on the basis of its spectral
data.[15]
Trans 1-(2,4,4-Trimethyl-2-cyclohexen-1-yl)-2-buten-1-one
(Isodamascone) (6a)
1
Yield 65%; bp 104–1068C/3 mm; IR (neat): 1685, 1642 cm21; H NMR
(CDCl3) d: 6.8 (d/q, 1H, 55CH-CH3), 6.12 (d/q, 1H, -CO-CH55), 5.18
(s, 1H, -CH55C,), 2.98 (t, 1H, 55C-CH-CO), 1.86 (d/d, 3H, CH3-
CH55CH-), 1.72 to 1.84 (m, 2H, ring -CH2-), 1.5 (s, 3H, CH3-C55), 1.3 to
1.38 (m, 2H, ring -CH2-), 0.9 (s, 3H, methyl), 1.0 (s, 3H, methyl).
Trans 1-(2,4,4-Trimethyl-2-cyclohexen-1-yl)-2-penten-1-one (Methyl
Isodamascone) (6b)
1
Yield 59.67%; bp 116–1188C/3mm; IR (neat): 1685, 1642 cm21; H NMR
(CDCl3) d: 6.82 (d/t, 1H, 55CH-CH2-), 6.12 (d/t, 1H, -CO-CH55), 5.2
(s, 1H, -CH55C,), 3.00 (t, 1H, 55C-CH-CO), 1.9(m, 2H, -CH2-CH55CH-),
1.72 to 1.84 (m, 2H, ring -CH2-), 1.5 (s, 3H, CH3-C55), 1.3 to 1.38 (m, 2H,
ring -CH2-), 1.1(t, 3H, CH3-CH2-C55), 0.9 (s, 3H, methyl), 1.0 (s, 3H,
methyl).
REFERENCES
1. Demole, E.; Enggist, P.; Sauberli, U.; Stoll, M.; Kovats, E. Structure et synthese da
le damascenone. Helv. Chim. Acta 1970, 53, 541–551.
2. Kawasaki, K. Fruit-like flavor compositions. Jpn. Kokai Tokkyo Koho JP
2005015686, Chem. Abstr. 2005, 142, 154629.
3. Bara, I.; Buet, D. Fragrance compositions comprising decamethyltetrasiloxane.
U.S. Patent Appl. Publ. US 2005245430, Chem. Abstr. 2005, 143, 446276.
4. Bauer, K.; Garbe, D.; Surburg, H. Common Fragrance and Flavor Materials;
Wiley-VCH: Weinheim, Germany, 2001.
5. Klein, E. Trans-2,4,6-trimethyl-1-crotonoyl-2-cyclohexene. Ger. Offen. 2120413.
Chem. Abstr. 1972, 78, 29325.

430
D. W. Rangnekar et al.
6. Kawasaki, K. Odor masking compositions containing fragrant substances for hair
cosmetics. Jpn. Kokai Tokkyo Koho JP 2003137758. Chem. Abstr. 2003, 138,
390526.
7. Granger, S. P.; Scott, I. R.; Donovan, R. M.; Iobst-Teklits, S.; Licameli, L. Skin
conditioning compositions containing compounds for mimicking the effect of
retinoic acid on skin. PCT Int. Appl. WO 2002002074. Chem. Abstr. 2002, 136,
90707.
8. Wevers, J.; Smets, J.; Rosaldo, R. T.; Van Steenwinckel, P. C. A. Laundry
detergent comprising
a pro-perfume composition containing suspending
material, an amino-functional component, and ketone and/or aldehyde perfume
ingredient. PCT Int. Appl. WO 2001051599. Chem. Abstr. 2001, 135, 108977.
9. Rangnekar, D. W.; Kamat, P. Y.; Mavlankar, S. V. A facile synthesis of 2-substi-
tuted-8-dicyanovinylindeno[2,1-d]thiazoles. Synth. Commun. 1990, 20, 2447–2552.
10. Phadke, R. C.; Rangnekar, D. W. A novel one step synthesis of pyrazolo
[1,5-a]pyridine derivatives. Synthesis 1987, 484–485.
11. Phadke, R. C.; Rangnekar, D. W. A novel one step synthesis of [1,2,4]triazolo
[1,5-a]pyridine derivatives. Synthesis 1986, 860–862.
12. Wharton, P. S.; Bohlen, D. H. Hydrazine reduction of a,b-epoxy ketones to allylic
alcohols. J. Org. Chem. 1961, 26, 3615–3616.
13. Arai, A.; Yao, C.; Ichikizaki, I. The gas chromatographic separation and character-
ization of d-cyclogeraniolene and a-cyclogeraniolene formed from isophorone by
Wolff–Kishner reaction. Bull. Chem. Soc. Japan 1963, 36, 1432–1434.
14. Zaidlewicz, M. Synthesis of a- and y-damascones. Tetrahedron Lett. 1986, 27,
5135–5138.
15. Klein, E.; Rojahn, W. Die Knodakov-reaktion mit crotonsaureanhydrid. Tetra-
hedron Lett. 1971, 12, 3607–3609.
16. Ayyar, K. S.; Cookson, R. C.; Kagi, D. A. J. Chem. Soc., Perkin Trans. 1 1975,
1727–1736.