Syntheses of c-l axial derivatives of l-menthol

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Syntheses of C-1 Axial Derivatives of l-
Menthol
Debra K. Dillner a
a Department of Chemistry, United States Naval Academy, Annapolis,
Maryland, USA
Version of record first published: 22 Apr 2009.
To cite this article: Debra K. Dillner (2009): Syntheses of C-1 Axial Derivatives of l-Menthol, Organic
Preparations and Procedures International: The New Journal for Organic Synthesis, 41:2, 147-152
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Syntheses of C-1 Axial Derivatives of L-Menthol
147
Acknowledgments
This project has been funded in part with federal funds from the National Cancer Institute,
National Institutes of Health, under contract NO1-CO-2008–00001, and in part by the
Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer
Research. The content of this article does not necessarily reflect the views or policies of the
Department of Health and Human Services, nor does mention of tradenames, commercial
products, or organizations imply endorsement by the U.S. Government.
References
1. C. A. Valdez, J. E. Saavedra, B. M. Showalter, K. M. Davies, T. C. Wilde, M. L. Citro, J. J. Barchi,
Jr., J. R. Deschamps, D. Parrish, S. El-Gayar, U. Schleicher, C. Bogdan and L. K. Keefer, J. Med.
Chem., 51, 3961 (2008).
2. M. L. Wolfrom and A. Thompson. Acetylation. In Methods in Carbohydrate Chemistry, pp. 211.
R. L. Whistler, M. L. Wolfrom, and J. N. BeMiller, eds., Academic Press, Inc., New York and
London, 1963.
3. R. S. Drago and B. R. Karstetter, J. Am. Chem. Soc., 83, 1819 (1961).
4. J.-L. Montero, J.-Y. Winum, A. Leydet, M. Kamal, A. A. Pavia and J.-P. Roque, Carbohydr. Res.,
297, 175 (1997).
5. M. L. Wolfrom and A. Thompson (1963) Deacetylation. In Methods in Carbohydrate Chemistry,
pp. 215. R. L. Whistler, M. L. Wolfrom, and J. N. BeMiller, eds., Academic Press, Inc., New York
and London, 1963.
Organic Preparations and Procedures International, 41:147–152, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print
DOI: 10.1080/00304940902802008
Syntheses of C-1 Axial Derivatives of L-Menthol
Debra K. Dillner
Department of Chemistry, United States Naval Academy, Annapolis,
Maryland, USA
Derivatives of menthol have interesting 1H NMR spectra and often, complete assignments of
the protons and determination of the configuration of substituents on the cyclohexane ring
are difficult. As part of a project to investigate the NMR properties of menthol derivatives,
several axially substituted menthanes (3–6) were prepared and their structures established.1
Submitted November 17, 2008.
Address correspondence to Debra K. Dillner, Department of Chemistry, United States Naval
Academy, Annapolis, MD 21402. E-mail: ddillner@usna.edu

148
Dillner
Menthanes containing equatorial substituents at C-1 have found use as chiral auxiliaries.2–4
Fewer examples of menthol derivatives with axial substituents at C-1 have been synthesized
and literature methods have significant difficulties.5–7 This article describes the improved
preparation of the known axial nitrile 3 and the syntheses of three isomerically pure axial
compounds 4–6. The functional groups present on the C-1 substituents are suitable for
further elaboration of these compounds as potential chiral auxiliaries.
The axial nitrile 3 had previously been prepared by Adolfsson et al. by treatment
of l-menthol tosylate8 with sodium cyanide in DMSO.9 In our hands, attempts to carry
out this procedure on a larger scale proved problematic. The yields were significantly
lower than described on scales larger than 2 mmols and the inherent safety concerns of
large scale reactions involving excess cyanide in DMSO led to the development of an
improved procedure. Extensive investigations of leaving group, solvent, temperature, ratio
of cyanide to substrate, and other factors led to the optimized conditions presented here
(Scheme 1). While the tosylate derivative gave similar results in the substitution reaction,
the mesylate derivative10 gave comparable or better yields in our hands and was more easily
prepared in pure form from l-menthol. The change of solvent from DMSO to acetonitrile
led to slightly lowered yields but allowed for easier regulation of the temperature at the
optimal 80◦C and made the reaction inherently safer. Microwave-assisted synthesis was
attempted but gave no improvements in yield. A five-fold excess of cyanide, either sodium
or potassium cyanide, and one equivalent of 18-crown-6 resulted in the optimal yields, 64%
from l-menthol The use of fewer equivalents of cyanide or 18-crown-6 lowered the yield
to 40–50% and gave significantly more E1 elimination and rearrangement products. The
yields were reproducible on scales ranging from 0.5 to 50 g of mesylate.
Scheme 1
Originally, we had intended to prepare the axial acid 6 directly by hydrolysis of the
nitrile. However, all attempts at carrying out the hydrolysis failed. Thus, the nitrile was
reduced to the aldehyde 5 with DIBAL-H in THF, which was then oxidized to the axial

Syntheses of C-1 Axial Derivatives of L-Menthol
149
acid 6 with Jones reagent in 63% yield for the two steps. Both compounds are prone
to epimerization if subjected to acidic conditions, including silica gel chromatography,
but could be chromatographed on florisil, if necessary. Generally, the compounds were
obtained in good purity without extensive purification. Finally, a derivative with an sp3
hybridized carbon at the C-1 position could be prepared by reduction of the nitrile to the
corresponding amine 4. The amine was chosen because of the frequent use of primary
amines as chiral auxiliaries. Lithium aluminum hydride reduction of the nitrile proceeded
smoothly in diethyl ether, to produce the amine in 90% yield. The free amine is somewhat
unstable but its hydrochloride salt can be stored indefinitely. The axial configuration of
1
all compounds was proven by H NMR. In all cases, the proton on C-1 is equatorial and
is consistently 0.4–0.5 ppm downfield relative to the previously described equatorially
substituted compounds.2–4
This article has described the efficient preparation of several axially substituted p-
menthane derivatives from the inexpensive, commercially available l-(-)-menthol. Each
reaction described can be carried out easily in good to excellent yield. The methods are all
robust and scalable up to 50 g. While our original interest in these compounds stemmed from
their interesting NMR spectral properties, their potential as chiral auxiliaries is currently
under investigation in our laboratories.
Experimental Section
All reagents and solvents were of reagent grade and used without further purification
unless otherwise specified. THF was dried using an Innovative Technologies PureSolv
solvent purification system. TLC was performed on silica gel 60 precoated plates with
fluorescent indicator, and compounds were visualized using aqueous vanillin/H2SO4 or
ethanolic phosphomolybdic acid solutions. Melting points were determined on a Mel-
Temp melting point apparatus and are uncorrected. IR spectra were recorded using a
Thermo IR100. GC/MS was performed with a Shimadzu QP5050A spectrometer. 1H NMR
was obtained at 400 MHz and 13C were obtained at 100 MHz with a JEOL ECX400
spectrometer and referenced to TMS. Optical rotations were measured with a JASCO DIP-
370 polarimeter. Elemental analyses were performed by Atlantic Microlabs in Norcross,
GA. Compounds 2 and 3 are known and were identical to those reported in the literature.9–11
L-Menthol Mesylate (2)
The literature procedure10 was modified as follows. To a solution of l-menthol (10.0 g, 63.9
mmol) in dichloromethane (125 mL), cooled to 0◦C, was added methanesulfonyl chloride
(9.2 g, 80.0 mmol) in one portion. The mixture was stirred for 20 minutes, followed by a
dropwise addition of triethylamine (8.4 g, 83.0 mmol) to the cold solution. The mixture
was stirred for 24 hours at 20◦C, whereupon complete consumption of starting material
was shown by TLC analysis on SiO2 using 10% ethyl acetate in hexane as eluent. The
mixture was diluted with dichloromethane (250 mL) and washed with water (2 × 100 mL),
saturated aq. NaHCO3 (100 mL) and saturated aq. NaCl (50 mL). The organic solution was
dried over MgSO4, filtered and the solvent removed in vacuo. The pale yellow residue was

150
Dillner
chromatographed on silica, using 10% ethyl acetate in hexane as eluent to give 15.0 g (99%
yield) of a colorless oil.
1H NMR (400 MHz, CDCl3): δ 0.81 (d, 3 H, CH3), 0.82–0.89 (m, 1 H, axial CHH),
0.92 (dd, 6 H, 2 CH3), 1.04 (m, 1 H, axial CHH), 1.27 (q, 1 H, axial CHH), 1.42 (m, 2
H, axial CHH), 1.69 (m, 2 H, equatorial CHH and CH(CH3)2), 2.06 (m, 1 H, equatorial
CHH), 2.26 (m, 1 H, equatorial CHH), 3.00 (s, 3 H, SO2CH3), 4.53 (td, 1 H, CHOSO2).
MS (EI, 70eV): m/z 138 (-OSO2CH3).
(1S, 2S, 5R)-1-Cyano-2-isopropyl-5-methylcyclohexane (3)
To a solution of the mesylate (3.39 g, 14.5 mmol) in acetonitrile (50 mL) was added
potassium cyanide (4.7 g, 72.3 mmol) and 18-crown-6 (3.8 g, 14.5 mmol) and the resulting
mixture was heated to reflux for 48 hours. The progress of the reaction was monitored by
GC/MS. The mixture was poured into dichloromethane (150 mL). The yellow solution was
washed with water (4 × 25 mL) to remove excess cyanide and 18-crown-6. The organic
phase was washed with saturated aqueous NaCl (50 mL) and dried over MgSO4. The
solution was filtered through silica gel and the solvents removed in vacuo. The resulting
pale yellow oil was chromatographed on silica with 5% ethyl acetate in hexanes as eluent.
A colorless oil was obtained (1.57 g, 65%).
(1S, 2S, 5R)-2-Isopropyl-5-methylcyclohexanecarboxaldehyde (5)
A solution of nitrile 2 (0.893 g, 5.4 mmol) in dry THF under argon was cooled to 0◦C.
Diisobutyl aluminum hydride (13.5 mL, 1.0 M in toluene, 13.5 mmol) was added dropwise.
The resulting solution was stirred at 0◦C for 4 hours, then allowed to warm to 25◦C, and
stirred for an additional 18 hours. GC/MS analysis showed complete consumption of starting
material. To quench, 100 mL of diethyl ether and 50 mL of 2% aq. H2SO4 were cooled
to 0◦C. The reaction mixture was added in 6 mL aliquots to the two-phase mixture with
stirring between additions. After complete addition, the two-phase mixture was acidified
further with 5 mL of 2% aq. H2SO4. The organic phase was separated and the aqueous
phase was extracted with ether (2 × 100 mL). The organic phases were combined and
washed with saturated aq. NaCl (50 mL), then dried over MgSO4, filtered, and the solvents
removed in vacuo. A colorless oil was isolated (0.88 g, 96%). Due to its instability upon
chromatography, this compound was used without further purification. [α]2D0 = −10.9 (c
0.024, CHCl3). 1H NMR (400 MHz, CDCl3): δ 0.80 (d, 3 H, CH3), 0.82–0.85 (m, 8 H, 2
CH3 and 2 axial CHH), 1.05 (m, 1 H, axial CHH), 1.19 (m, 1 H, axial CHH), 1.37 (m, 1
H, axial CHH), 1.6–1.8 (m, 3 H, equatorial CH, CH(CH3)2), 2.0 (dd, 1 H, equatorial CH),
2.67 (bs, equatorial CHCHO), 9.85 (d, 1 H, CHO). 13C NMR (100 MHz, CDCl3): δ 21.02,
21.68, 22.61, 27.19, 28.48, 29.79, 35.29, 36.01, 46.29, 48.86, 206.58. MS (EI, 70 eV): m/z
168 (M+).
(1S, 2S, 5R)-2-Isopropyl-5-methylcyclohexanecarboxylic Acid (6)
To a solution of the aldehyde 2 (0.42 g, 2.5 mmol) in 20 mL of ether and cooled to 0◦C was
added Jones reagent (5.0 mL) in 1.0 mL portions over 1 hour. After the final addition, the
dark green mixture was stirred an additional 10 minutes. The aqueous and organic phases

Syntheses of C-1 Axial Derivatives of L-Menthol
151
were separated and the aqueous phase was extracted twice with ether (50 mL). The organic
phases were combined and washed twice with water (25 mL) and dried over MgSO4. The
dried ethereal solution was filtered through florisil to remove any remaining chromium
impurities and the solvent was then removed in vacuo to give white crystals (0.306 g, 66%),
mp. 65–67◦C; [α]D20 = +3.15 (c 0.015, CHCl3).
1H NMR (400 MHz, CDCl3): δ 0.83 (m, 1 H, axial CH), 0.85 (d, 3 H, CH3), 0.90 (d,
3 H, CH3), 0.92 (d, 3 H, CH3), 0.98 (m, 1 H, axial CH), 1.41 (m, 1 H, axial CH), 1.61 (m,
1 H, axial CH), 1.66 (m, 2 H), 1.71 (m, 1 H, equatorial CH), 1.75 (m, 1 H, equatorial CH),
2.00 (dq, 1 H, equatorial CH), 2.90 (bs, 1 H, equatorial CH), 11.0 (bs, 1 H, COOH). 13C
NMR (100 MHz, CDCl3): δ 21.26, 21.50, 22.37, 25.49, 27.44, 30.21, 35.26, 37.97, 41.97,
46.38, 182.13. MS (EI, 70 eV): m/z 184 (M+).
Anal. Calcd for C11H20O2: C, 71.70; H, 10.94. Found: C, 71.85; H, 11.09.
(1S,2S,5R)-1-(Aminomethyl)-2-isopropyl-5-methylcyclohexane (4)
To a solution of nitrile 2 (0.859 g, 5.19 mmol) in diethyl ether and cooled to 0◦C under argon
was added dropwise a solution of lithium aluminum hydride (10.4 mL, 0.5 M in glyme,
5.19 mmol) over 15 minutes. The solution was stirred at 0◦C for 4 hours and then quenched
by the sequential addition of water (0.25 mL), 20% NaOH (0.25 mL) and water (1.0 mL).
The mixture was subsequently stirred at 25◦C until the salts separated. The mixture was
vacuum filtered and the white solids were washed with hexane (25 mL). The combined
organic phases were dried over MgSO4 and the solvent removed in vacuo. The amine
was isolated as a colorless oil (0.795 g, 90%) and converted to its hydrochloride salt, mp.
234–235◦ (dec.), by addition of conc. HCl (1 mL). 1H NMR (400 MHz, CDCl3): δ 0.8–1.0
(m, 12 H, 3 CH3, 3 axial CHH), 1.37 (m, 1 H, axial CHH), 1.50 (m, 1 H, CH(CH3)2), 1.68
(m, 3 H, 2 equatorial CHH, axial C5HH), 2.42 (bs, 2 H, NH2), 2.71 (bd, 2 H, CH2NH2).
13C NMR (100 MHz, CDCl3): δ 20.92, 21.84, 22.83, 25.69, 26.07, 29.44, 35.79, 36.43,
37.90, 38.06, 47.40. MS: (EI, 70 eV): m/z 169 (M+).
Anal. Calcd. for C11H24ClN: C, 64.21; H, 11.76; N, 6.81. Found: C 64.12; H, 11.79;
N, 6.57.
Acknowledgment
The author thanks Daniel J. Traficante for suggesting these classes of compounds as
interesting synthetic targets.
References
1. D. Dillner and D. Traficante, Magn. Reson. Chem., 45, 193 (2007).
2. Y. Gnas and F. Glorius, Synthesis, 1899 (2006).
3. D. A. Evans, G. Helmchen, M. Ruping and J. Wolfgang, “Asymmetric Synthesis”, p. 3, M.
Christmann and S. Braese, Eds. Wiley-VCH, Weinheim, 2007.
4. C. Spino, C. Godbout, C. Beaulieu, M. Harter, M. Topwe and L. Boisvert, J. Am. Chem. Soc.
126, 13312 (2004).

152
Xu et al.
5. M. Lebedev and M. Erman, Tetrahedron Lett., 43, 1397 (2002).
6. F. Rahm, A. Fischer and C. Moberg, Eur. J. Org. Chem., 4205 (2003).
7. M. Falorni, L. Lardicci and G. Giacomelli, J. Org. Chem., 54, 2383 (1989).
8. E. Cesaroti, H. Kagan, R. Goddard and D. Kruger, J. Organometall. Chem., 162, 279 (1978).
9. H. Adolfsson, K. Nordstrom, K. Warnmark and C. Mobert, Tetrahedron Asymm., 7, 1967 (1996).
10. A. Fischli and P. Muller, Helv. Chim. Acta, 63, 1619 (1980).
11. M. Yamashita, Y. Soeda, N. Suzuki, M. Yamada, K. Tsuenkawa, T. Oshikawa and S. Inokawa,
Bull. Chem. Soc. Jpn, 56, 1871 (1983).
Organic Preparations and Procedures International, 41:152–155, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print
DOI: 10.1080/00304940902802099
A Practical Synthesis of α-Asarone via
Iodine-catalyzed Isomerization of α/β-Asarone
Guangyu Xu,1 Chang Liu,1 Wei Zhang,2 and Gaolei Zuo1
1College of Chemistry and Chemical Engineering, Hunan Normal University,
Changsha, P. R. China
2College of Medicine, Hunan Normal University, Changsha, P. R. China
α-Asarone (1), isolated from the Guatteria guameri plant growing in southeast Mexico,
is reported to be an anti-platelet and hypolipidemic agent.1,2 In addition, it is known to
have sedating, neuroleptic, spasmolytic, anti-ulcerogenic and anti-atherogenic activity.3,4
Due to its low availability from natural sources, several synthetic approaches have been
developed for α-asarone (trans-isomer, 1), which involve Grignard, Wittig, Aldol-Grob,
Friedel-Crafts reactions.5–9 However, in the above methods, some of the unwanted toxic
β-asarone (cis-isomer, 2) was always formed, along with the desired α-asarone, which is
difficult to separate by column chromatography due to similarities in Rf values. β-Asarone
can be converted to α-asarone by fusion with KOH in good yield.10 However, this reaction
requires an excess amount of KOH (37 equiv.) and high temperature (200–220◦C). Selenium
dioxide, which can effectively convert β-asarone to α-asarone,10 is not a good choice due to
its toxicity. A recently developed palladium (II) catalyzed isomerization of cis-arylalkenes
can also be applied to the preparation of α-asarone,11,12 however, industrial applications of
this reaction on synthesis of α-asarone are challenging because the catalyst is expensive,
Submitted August 29, 2008.
Address correspondence to Guangyu Xu, Hunan Normal University, College of Chemistry and
Chemical Engineering, Changsha 410081, P. R. China. E-mail: gyxu@hunnu.edu.cn