A convenient preparation of 3-isopropyl-1-methylcyclopentylmethanol and 1-isopropyl-3-methylcyclopentylmethanol via Favorskii rearrangement

Article abstract of DOI:10.1016/j.tetasy.2009.08.016

The Favorskii rearrangement of suitable α-chloro derivatives of commercially available (+)- and (-)-carvone, and (-)-menthone served efficiently to prepare the title compounds featuring delicious fruity, floral olfactory notes.

Full text of DOI:10.1016/j.tetasy.2009.08.016

Tetrahedron: Asymmetry 20 (2009) 2145–2148
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A convenient preparation of 3-isopropyl-1-methylcyclopentylmethanol
and 1-isopropyl-3-methylcyclopentylmethanol via Favorskii rearrangement
b
b
Martino Ambrosini a, Nikla Baricordi a, Simonetta Benetti a, , Carmela De Risi , Gian P. Pollini ,
*
Vinicio Zanirato b
a Dipartimento di Chimica, via L. Borsari 46, 44100 Ferrara, Italy
b Dipartimento di Scienze Farmaceutiche, via Fossato di Mortara 19, 44100 Ferrara, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 July 2009
Accepted 18 August 2009
Available online 14 September 2009
The Favorskii rearrangement of suitable
a
-chloro derivatives of commercially available (+)- and (ꢀ)-carv-
one, and (ꢀ)-menthone served efficiently to prepare the title compounds featuring delicious fruity, floral
olfactory notes.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
cyclopentanecarboxylic acid amide which can easily be transformed
into the corresponding acid through basic hydrolysis.5 The reduction
Compounds with particular fruit or flower fragrances character-
ize a large number of chemical compounds and are widely used in
the food, perfume, cosmetic, detergent and other industries. Fruity
odours are quite popular in perfumery, almost all feminine per-
fumes and more and more masculine ones possess fruity notes.
Moreover, in the fragrance industry there is a constant demand
for new compounds which could enhance or improve odour notes,
or impart new odour notes.
of the carboxylic functional group gives the odorous compound 1
(Scheme 1). Similarly, the preparationofent-1 has been accomplished
starting from (1S)-(+)-fenchone.
O
(1R)-(-)-fenchone
Accordingly, perfumers and flavourists are continually looking
for new compounds having floral and/or fruit-like qualities which
may find use in practically all fields of flavour and fragrance
applications.
In the patent literature, it has been recently reported that cer-
tain 3-isopropyl-1-methylcyclopentyl derivatives are relevant as
fragrance and flavour compounds, having floral, fruity and woody
odour notes.1,2
Cyclopentyl alcohol derivatives have for a long time been of
particular interest as perfumery and aromatic chemicals,3 as they
are relatively simple and easy to prepare starting from readily
available, inexpensive and naturally occurring starting materials.4
Most of the new compounds present interesting olfactory proper-
ties, mainly fruity character, associated in several cases with floral
and green notes. Particular attention has been devoted to [(1R,3S)-
3-isopropyl-1-methylcyclopentyl]methanol 1 and its enantiomer
ent-1, which could be prepared through elaboration of enantiome-
rically pure fenchone.1,2
1. NaNH2
2. KOH
HO
LiAlH4
HO2C
1
Scheme 1.
The cleavage of ketones by sodium amide is usually referred to
as the Haller–Bauer reaction,6,7 a transformation originally re-
ported by Semmler8 in connection with his investigations on the
structure of fenchone.
Although the cleavage reactions of non-enolisable ketones have
previously been observed under a variety of conditions, the only
thoroughly investigated general method for ketone cleavage is
the classical Haller–Bauer reaction. Gassman et al.9 systematically
investigated the C–C bond cleavage reaction in several norborna-
none derivatives and also explored various reaction media to im-
part preparative efficiency to this reaction. Thus, ring cleavage of
2-norbornanone derivatives offers a good methodology to obtain
cis-1,3-disubstituted cyclopentanes.10
Sodium amide-induced C1–C2 bond cleavage of the bicyclo[2.2.1]
heptan-2-one nucleus of (1R)-(ꢀ)-fenchone produces a substituted
* Corresponding author. Tel.: +39 0532455174; fax: +39 053240709.
E-mail address: bns@unife.it (S. Benetti).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.08.016

2146
M. Ambrosini et al. / Tetrahedron: Asymmetry 20 (2009) 2145–2148
It has also been well established that functionalized cyclopen-
O
O
tanecarboxylates can be obtained from the Favorskii rearrange-
Cl
Cl
MeONa
ment of
a-halocyclohexanone derivatives. This reaction has been
subjected to extensive mechanistic studies in order to clarify the
stereochemical outcome.11,12
Herein, we report a simple, convenient procedure for the stereose-
lective synthesis of 1-isopropyl-3-methylcyclopentylmethanol and
3-isopropyl-1-methylcyclopentylmethanol through Favorskii rear-
A
3a
O
rangementofsuitablea-chlorocyclohexanones,inturnobtainedfrom
MeO2C
commerciallyavailable starting materials, suchas(ꢀ)-menthone, and
(+)- and (ꢀ)-carvone.
4
B
2. Results and discussion
Scheme 3.
Initially, we wanted a straightforward access to [(1R,3S)-3-iso-
propyl-1-methylcyclopentyl]methanol 1 and its enantiomer ent-1
starting from both enantiomerically pure forms of carvone, one
of the most common natural monoterpene used as an attractive
chiral starting material in the synthesis of natural products.13,14
As summarized in Scheme 2, (S)-(+)-carvone was hydrogenated
to give (5S)-carvomenthone 2 as a C-2 epimeric mixture.15 The
subsequent reaction with sulfuryl chloride furnished 2-chloro-2-
methyl-(5S)-isopropylcyclohexanone 3 as a C-2 epimeric mixture
(3a/3e 4:1 ratio, estimated by 1H NMR), a result matching the al-
ready reported chlorination of (5R)-carvomenthone which led to
ent-3a (halogen axial 77%) and ent-3e (halogen equatorial 23%).16
A clean Favorskii rearrangement took place easily by treatment
of the 3a/3e mixture with sodium methoxide in ether furnishing
a 4:1 mixture of C-2 epimeric cyclopentanecarboxylic acid methyl
esters 4 and 5 (1H NMR). The major diastereomer 4 could be ob-
tained in a pure state by careful column chromatography and its
structure has been confirmed by conversion to the known cyclo-
pentyl alcohol 1, featuring the fresh clean floral tonality described
in the patent literature,1,2 by reduction with LiAlH4. The same pro-
cedure was used to obtain [(1S,3R)-3-isopropyl-1-methylcyclopen-
tyl]methanol ent-1, starting from (R)-(ꢀ)-carvone.
enolate A promoted an intramolecular displacement of the halogen
atom leading to cyclopropanone B, which underwent a regioselec-
tive ring opening to give 4.18
Accordingly, we extended this protocol to the known16
a-chloro-
cyclohexanones 6 and 7, in turn prepared from (2S,5R)-(ꢀ)-menth-
one, allowing us to obtain the structurally related cyclopentyl-
methanols 10 and 11, both possessing a pleasant floral odour with
fresh and clean notes.
In order to validate the stereospecific outcome of the Favorskii
reaction, we separated 6 and 7 subjecting them to the ring contrac-
tion/reduction sequence (Scheme 4). We found that sodium meth-
oxide-promoted Favorskii rearrangement of the two haloketones
epimeric at the halogen-bearing carbon gave rise to the formation
of different cyclopentanecarboxylic acid methyl esters. The struc-
tures of the corresponding cyclopentylmethanols obtained by
reduction with LiAlH4 were inferred on the basis of NOE-difference
experiments. In detail, a positive NOE effect observed or the lack-
ing of this effect between H-3 and hydroxymethyl group allowed
to assign the (1R,3R) absolute configuration to 11 and the (1S,3R)
configuration for the diastereomer 10, respectively. In this way
the stereochemistry of the parent cyclopentanecarboxylic acid
methyl esters 8 and 9 could also be set.
O
Cl
65%
35%
MeO2C
O
O
SO2Cl2/CCl4
94%
5
O
+
SO2Cl2
CCl4
MeONa
Et2O
3e
Cl
Cl
+
+
95%
92%
6
7
O
MeONa
Et2O
O
87%
Cl
2
MeO2C
Pd/C
H2
97%
4
MeO2C
3a
MeO2C
LiAlH4
(-)-menthone
71%
HO
LiAlH4
O
8
9
85%
(+)-carvone
1
HO
HO
Scheme 2.
10
11
The stereospecific course of the Favorskii rearrangement of 3 (a/
e 4:1) leading to the formation of a mixture of 4 and 5 in a 4:1 ratio
should be noted. Interestingly, the use of aprotic solvents as well as
of heterogeneous reaction media has been claimed17 to favour a
‘Loftfield-type’ mechanism (Scheme 3). Thus, the initially formed
Scheme 4.
These findings strongly suggest a Favorskii rearrangement
occurring through a mechanism entailing on the formation of an
intermediate cyclopropanone via an SN2-like reaction, rather than

M. Ambrosini et al. / Tetrahedron: Asymmetry 20 (2009) 2145–2148
2147
the alternative mechanism via a zwitterionic intermediate,19 the
latter requiring that both haloketones 6 and 7 produce the same
mixture of esters 8 and 9.
in dry THF (20 mL) over a period of 10 min. After the reaction mix-
ture was stirred for 2 h at room temperature, water (1 mL) was
carefully added under ice-cooling, followed by 4 M NaOH solution
(1 mL) and water (4 mL). After being stirred for 30 min the reaction
mixture was filtered to remove the inorganic salts, which were
carefully washed with dichloromethane (20 mL). The filtrate was
dried with Na2SO4, filtered and evaporated under reduced pres-
sure. Distillation gave pure 1 (1.2 g, 71%), bp 96–98 °C (10 mbar).
3. Conclusion
In conclusion, we have described an efficient and convenient
preparation of substituted cyclopentyl alcohol derivatives through
Favorskii ring contraction of the a-chloroketones in turn prepared
½
a 2D5
ꢂ
¼ ꢀ11:4 (c 1, CHCl3) {Lit.1: ½a D22
¼ ꢀ12:0 (c 1, EtOH)}; IR mmax
ꢂ
3350 cmꢀ1 1H NMR (CDCl3, 400 MHz) d 0.88 (d, 3H, J = 6.6 Hz),
;
from commercially available, optically active (+) and (ꢀ)-carvone,
0.92 (d, 3H, J = 6.6 Hz), 0.98 (s, 3H), 1.30–2.10 (m, 8H), 3.30–3.40
(m, 2H). 13C NMR (CDCl3, 100 MHz) d 18.1 (2CH3), 20.3 (CH3),
31.8 (CH2), 32.1 (CH), 35.1 (CH2), 35.5 (CH), 41.0 (CH2), 50.0 (C),
70.0 (CH2OH). Anal. Calcd for C10H20O: C, 76.86; H, 12.90. Found:
C, 76.80; H, 13.00.
and (ꢀ)-menthone.
The preparation of (1R,3S)- and (1S,3R)-3-isopropyl-1-methyl-
cyclopentylmethanol allowed for comparison of the present meth-
odology with that described in the patent literature in terms of the
starting material (carvone vs fenchone), milder reaction conditions
(sodium methoxide in diethyl ether vs sodium amide in toluene)
and easier reduction of the intermediate (ester vs carboxylic acid)
which requires less reducing agent.
4.2.3. Methyl (1S,3R)-1-isopropyl-3-methylcyclopentane-
carboxylate 8
A solution of 6 (5.38 g, 28.6 mmol) in dry ether (10 mL) was
added dropwise over a period of 10 min to an ice-cooled and stirred
suspension of NaOMe (prepared from 0.76 g of Na). After 15 min,
the ice-bath was removed and the reaction mixture stirred for 9 h
at room temperature. The ether solution was filtered, washed with
water (30 mL), dried (Na2SO4) and evaporated under reduced pres-
sure. The residual oil was purified by flash-chromatography (pen-
tane/CH2Cl2, 60:40) and the ester 8 (4.6 g, 87%) was obtained as a
4. Experimental
4.1. General remarks
1H and 13C NMR spectra were recorded on a Varian Mercury Plus
400 spectrometer with CDCl3 as a solvent. Chemical shifts (d) are
given in parts per million (ppm) downfield from TMS as an internal
standard. Multiplicities are described using the following abbrevia-
tions: s = singlet, d = doublet, t = triplet, q = quartet, sp = septuplet,
and m = multiplet. Optical rotations were carried out with a
Perkin–Elmer 241 MC polarimeter. Silica gel for column chromatog-
raphy (Merck, 230–400 mesh) was used for chromatographic
purifications. (2S,5R)-(ꢀ)-Menthone, purchased from Fluka, was
claimed to be >98% ee by GC. (S)-(+)-Carvone and (R)-(ꢀ)-carvone
were purchased from Aldrich and reduced to the corresponding
tetrahydro derivatives following literature directions.15 (1RS,5S)-
2-Chloro-2-methyl-5-isopropylcyclohexanones 3, (2R,5R)-(+)-2-
chloro-2-isopropyl-5-methylcyclohexanone 6 and (2S,5R)-(+)-2-
chloro-2-isopropyl-5-methylcyclohexanone 7 were prepared as
described in the literature.16
light yellow oil. ½a D25
ꢂ
¼ ꢀ16:3 (c 1, CHCl3); IR mmax 1730 cmꢀ1
;
1H
NMR (CDCl3, 400 MHz) d 0.80 (d, 3H, J = 6.7 Hz), 0.88 (d, 3H,
J = 6.7 Hz), 1.00 (d, 3H, J = 6.4 Hz), 1.01–1.15 (m, 1H), 1.40–1.50
(m, 1H), 1.60–1.70 (m, 1H), 1.70–1.95 (m, 3H), 1.98 (sp, 1H,
J = 6.7 Hz), 2.02–2.30 (m, 1H), 3.62 (s, 3H). 13C NMR (CDCl3,
100 MHz) d 18.4 (CH3), 18.8 (CH3), 20.2 (CH3), 33.3 (CH2), 33.7
(CH2), 33.8 (CH), 35.4 (CH), 41.4 (CH2), 51.5 (COOCH3), 59.0 (C),
178.1 (COOCH3). Anal. Calcd for C11H20O2: C, 71.70; H, 10.94. Found:
C, 71.65; H, 11.00.
4.2.4. Methyl (1R,3R)-1-isopropyl-3-methyl-cyclopentane-
carboxylate 9
Compound 9 was obtained from 7 according to the procedure
described for the preparation of 8. ½a D25
¼ þ3:8 (c 1, CHCl3); IR mmax
ꢂ
4.2. Preparation procedures
1730 cmꢀ1 1H NMR (CDCl3, 400 MHz) d 0.82 (d, 3H, J = 6.8 Hz),
;
4.2.1. Methyl (1R,3S)-3-isopropyl-1-methyl-cyclopentane-
carboxylate 4
0.86 (d, 3H, J = 6.8 Hz), 0.95 (d, 3H, J = 6.4 Hz), 1.04–1.20 (m, 1H),
1.42–1.52 (m, 1H), 1.59–1.66 (m, 1H), 1.70–1.92 (m, 3H), 1.96
(sp, 1H, J = 6.8 Hz), 2.19–2.22 (m, 1H), 3.63 (s, 3H). 13C NMR
(100 MHz, CDCl3) d 18.2 (CH3), 18.7 (CH3), 20.1 (CH3), 32.3 (CH2),
35.5 (CH), 34.9 (CH2), 35.0 (CH), 41.8 (CH2), 51.5 (C), 58.1 (CH3),
178.6 (CO). Anal. Calcd for C11H20O2: C, 71.70; H, 10.94. Found: C,
71.65; H, 11.00.
A solution of the mixture of 3a and 3e (4.2 g, 22.34 mmol) in dry
ether (10 mL) was added dropwise over a period of 10 min to an
ice-cooled and stirred slurry of NaOMe (prepared from 0.6 g of Na).
During the addition, a precipitate was formed and the temperature
of the reaction was maintained below 15 °C. The reaction mixture
was stirred for a further 15 min, then water (30 mL) was added
and the mixture was extracted with diethyl ether (3 ꢁ 30 mL). The
combined organic layers were washed with brine, dried (Na2SO4)
and evaporated under reduced pressure, to yield the crude mixture
of 4 and 5 (3.8 g, 92%) which was purified by silica gel chromatogra-
4.2.5. [(1S,3R)-3-Methyl-1-isopropylcyclopentyl]-methanol 10
To an ice-cooled suspension of LiAlH4 (0.22 g, 5.8 mmol) in dry
ether (20 mL), a solution of 8 (0.97 g, 5.27 mmol) in dry ether
(10 mL) was added dropwise over a period of 10 min. The reaction
mixture was stirred for 2 h at room temperature, then water (1 mL)
was carefully added under ice-cooling, followed by 4 M NaOH solu-
tion (4 mL). After stirring for 30 min, the reaction mixture was fil-
tered to remove the inorganic precipitate, which was carefully
washed with ether (20 mL). The dried filtrate (Na2SO4) was evapo-
rated under reduced pressure and the residual oil purified by flash-
chromatography (pentane/CH2Cl2, 60:40). Alcohol 10 (0.70 g, 85%)
phy (EtOAc/cyclohexane, 1:9) to give pure 4. ½a D25
¼ ꢀ7:8 (c 1,
ꢂ
CHCl3); IR m
max 1730 cmꢀ1. 1H NMR (CDCl3, 400 MHz): d 0.80–0.90
(m, 6H), 1.20 (s, 3H), 1.20–1.95 (m, 5H), 2.00–2.50 (m, 3H), 3.65 (s,
3H). 13C NMR (CDCl3, 100 MHz) d 20.3 (2CH3), 22.8 (CH3), 30.2
(CH2), 30.5 (CH2), 31.8 (CH), 42.7 (CH), 46.6 (CH2), 51.6 (C), 52.3
(COOCH3), 178.7 (COOCH3). Anal. Calcd for C11H20O2: C, 71.70; H,
10.94. Found: C, 71.65; H, 11.00.
was obtained as a light yellow oil. ½a D25
ꢂ
¼ þ15:6 (c 1, CHCl3); IR
4.2.2. [(1R,3S)-3-Isopropyl-1-methylcyclopentyl]-methanol 1
A solution of 4 (2 g, 10.87 mmol) in dry THF (10 mL) was added
dropwise to an ice-cooled mixture of LiAlH4 (0.45 g, 11.96 mmol)
mmax 3350 cmꢀ1
; d 0.87 (d, 3H,
1H NMR (CDCl3, 400 MHz)
J = 6.7 Hz), 0.89 (d, 3H, J = 6.7 Hz), 0.97 (d, 3H, J = 6.6 Hz), 1.00–

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M. Ambrosini et al. / Tetrahedron: Asymmetry 20 (2009) 2145–2148
1.10 (m, 1H), 1.22–1.38 (m, 1H), 1.40–1.50 (m, 1H), 1.50–1.60 (m,
2H), 1.62–1.80 (m, 2H), 1.80–1.97 (m, 1H), 3.42 (d, 1H, J = 10.7 Hz),
3.47 (d, 1H, J = 10.7 Hz). 13C NMR (CDCl3, 100 MHz) d 18.0 (2CH3),
20.2 (CH3), 31.7 (CH2), 32.0 (CH), 35.1 (CH2), 35.5 (CH), 40.9 (CH2),
50.0 (C), 69.0 (CH2). Anal. Calcd for C10H20O: C, 76.86; H, 12.90.
Found: C, 76.80; H, 13.00.
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described for the preparation of 10. ½a D25
ꢂ
¼ þ10:9 (c 1, CHCl3); IR
mmax 3350 cmꢀ1
; d 0.86 (d, 3H,
1H NMR (CDCl3, 400 MHz)
J = 6.6 Hz), 0.88 (d, 3H, J = 6.6 Hz), 0.97 (d, 3H, J = 6.6 Hz), 1.00–
1.20 (m, 2H), 1.40–1.50 (m, 3H), 1.70–1.90 (m, 3H), 3.41 (d, 1H,
J = 10.7 Hz), 3.47 (d, 1H, J = 10.7 Hz). 13C NMR (CDCl3, 100 MHz) d
18.0 (2CH3), 20.2 (CH3), 31.7 (CH2), 32.0 (CH), 35.1 (CH2), 35.5
(CH), 40.9 (CH2), 50.0 (C), 69.0 (CH2). Anal. Calcd for C10H20O: C,
76.86; H, 12.90. Found: C, 76.80; H, 13.00.
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a-
Acknowledgements
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We acknowledge the University of Ferrara for financial support
and Mr. Paolo Formaglio for his contribution to the NMR experi-
ments.
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