Preparation of enantiopure trans-1,2-cyclohexanediol and trans-2-aminocyclohexanol

Article abstract of DOI:10.1080/00397910701266075

Trans-1,2-cyclohexanediol and trans-2-aminocycloxexanol are useful chiral auxiliaries. Simple chemical resolution procedures for these molecules are presented. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701266075

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Preparation of Enantiopure
trans‐1,2‐Cyclohexanediol and
trans‐2‐Aminocyclohexanol
A. Chatterjee a , M. Sasikumar, a & N. N. Joshi a
a Division of Organic Synthesis , National Chemical Laboratory , Pune, India
Published online: 22 May 2007.
To cite this article: A. Chatterjee , M. Sasikumar, & N. N. Joshi (2007) Preparation of Enantiopure
trans‐1,2‐Cyclohexanediol and trans‐2‐Aminocyclohexanol, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:10, 1727-1733, DOI:
10.1080/00397910701266075
To link to this article: http://dx.doi.org/10.1080/00397910701266075
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Synthetic Communicationsw, 37: 1727–1733, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701266075
Preparation of Enantiopure trans-1,2-
Cyclohexanediol and trans-2-
Aminocyclohexanol
A. Chatterjee, M. Sasikumar, and N. N. Joshi
Division of Organic Synthesis, National Chemical Laboratory,
Pune, India
Abstract: Trans-1,2-cyclohexanediol and trans-2-aminocycloxexanol are useful chiral
auxiliaries. Simple chemical resolution procedures for these molecules are presented.
Keywords: chemical resolution, chiral auxiliaries, epoxide-cleavage
INTRODUCTION
Chiral 1,2-diols[1] and b-amino alcohols[2] are versatile tools because of their
use as chiral ligands, auxiliaries, structural motifs, and so on. A variety of pro-
cedures have been developed for the preparation of these compounds in
optically pure form.[3] However, chemical resolution, an age-old procedure,
has remained an attractive methodology, particularly in the large-scale prep-
aration of these compounds.[4]
RESULTS AND DISCUSSION
One such important diol is trans-1,2-cyclohexanediol (1). This diol has been
used successfully in a variety of reactions.[5] Although, a voluminous litera-
ture is available for the preparation of this compound, most of them deal
with chemoenzymatic methods.[6] Considering the exorbitant cost of these
enzymes and limitations for large-scale preparations, we planned to develop
Received October 17, 2006
Address correspondence to N. N. Joshi, Division of Organic Synthesis, National
Chemical Laboratory, Pune 411008, India. E-mail: nn.joshi@ncl.res.in
1727

1728
A. Chatterjee, M. Sasikumar, and N. N. Joshi
Scheme 1. Resolution of cyclohexane-1,2-diol. Reagents and conditions: (a) AcCl,
reflux, 2 h; (b) (+)-1, DCC, DMAP, DCM, 2108C, 6 h; (c) NaOH, MeOH.
a chemical resolution procedure for this diol. After screening a variety of
optically active acids such as hydratropic acid, v-camphanic acid, N-car-
bethoxy proline, and N-tosyl proline, we found O-acetyl mandelic acid to
be an appropriate resolving agent. Although the separation of the diastereo-
meric mixture of the monoester (2a/2b) was achieved through column chrom-
atography, crystallization from a mixed solvent of petroleum ether/diethyl
ether was found equally effective when performed on a multigram scale.
The only drawback of this resolution was the partial racemization of
mandelic acid during workup (Scheme 1).
trans-2-Aminocyclohexanol (3) is another important compound and finds
wide application in the literature.[7] The most popular method for the prep-
aration of this compound includes stereoselective ring opening of the
epoxide,[8] kinetic resolution,[9] or resolution of its derivatives.[7] All these
procedures suffer some drawback or the other.
Herein we report a novel resolution procedure for this compound using a
cheap proline derivative. Initially, a variety of optically active acids were
examined to separate the diastereomeric salt through fractional recrystalliza-
tion. Unfortunately, none of them proved to be successful. Finally, we
succeeded in obtaining a diastereomerically pure salt using N-pivaloyl
proline. Three successive crystallizations from EtOH/EtOAc were required
to realize the purity. Subsequent hydrolysis of the salt provided the amino
alcohol (3) in moderate yield and high optical purity (Scheme 2).
EXPERIMENTAL
1H and 13C NMR spectra were recorded in CDCl3, and the chemical shift
values were reported in parts per million (ppm) downfield to TMS (d ¼ 0)
1
for H and relative to the central CDCl3 resonance (d ¼ 77) for 13C NMR

Preparation of Enantiopure
1729
Scheme 2. Resolution of 2-aminocyclohexanol. Reagents and conditions: (a) NaOH,
TBABr (cat.), H2O–DCM, rt, 4 h; (b) (i) three crystallization from EtOAc/EtOH;
(ii) aqueous NaOH.
on AC 200-MHz or DRX 500-MHz spectrometer. The abbreviations s, bs, d, t,
and m refer to singlet, broad singlet, doublet, triplet, quartet, and multiplet
respectively. Melting points were determined on a Yamaco micromelting-
point apparatus and are uncorrected. Optical rotations were measured with a
Bellingham-Stanley ADP220 digital polarimeter using a sodium lamp
(l ¼ 589 nm) at 248C. IR spectra were recorded on a Shimadzu FTIR-8400
spectrophotometer with NaCl as optics. Thin-layer chromatography (TLC)
was carried out on 0.25-mm E-Merck silica-gel plates (60F254) with UV
light / I2 / anisaldehyde as viewing methods. All solvents and reagents
were purified and dried according to procedures given in D. D. Perin’s Puri-
fication of Laboratory Reagents. All reactions were carried out under argon
atmosphere using freshly distilled solvents under anhydrous conditions
unless otherwise specified. Yields refer to isolated product, purified by chrom-
atography or distillation. (+)-Cyclohexane-1,2-diol (1) was prepared as
described in the literature.[10]
Resolution of (+)-trans-Cyclohexane-1,2-diol (1)
Preparation of (S)-O-Acetylmandelic Acid
The reported procedure was modified as follows.[11] A flame-dried, 100-mL,
two-necked, round-bottomed flask was equipped with a stirring bar and a
dropping funnel. S-(þ)-Mandelic acid (15.2 g, 100 mmol) was placed inside
the flask, and acetylchloride (35.5 mL, 500 mmol) was added slowly with
vigorous stirring. The stirring was continued initially at room temperature
and then under reflux for 2 h. Excess acetylchloride was removed on a
rotary evaporator, and the semisolid mass was suspended in a minimum
volume of water. The acid was extracted with dichloromethane (DCM)
(3 ꢀ 40 mL), and the combined organic layer was washed with brine

1730
A. Chatterjee, M. Sasikumar, and N. N. Joshi
(2 ꢀ 20 mL). It was dried over anhydrous Na2SO4 and evaporated under
reduced pressure. The sticky mass obtained after keeping it in a high
vacuum for 2 h at 508C solidified slowly in the refrigerator (2 days). The
solid was crystallized from a combination of petroleum ether and diethyl
ether to give white crystals of (S)-(þ)-O-acetylmandelic acid. White solid
(12.3 g, 63%); mp 103–1058C [lit.[11] 95–97.58C]; [a]D ¼ þ152 (c 1,
acetone) [lit.[11] þ148 (c 1.87, acetone)].
Preparation of Monoesters 2a and 2b
A flame-dried, two-necked, round-bottomed flask was charged with dicyclo-
hexylcarbofiimide (DCC) (9.06 g, 44 mmol), (+)-1,2-cyclohexanediol (1)
(4.65 g, 40 mmol), and NN-dimethylaminopyridine (DMAP) (0.48 g,
4 mmol) under an argon atmosphere. Freshly distilled DCM (80 mL) was
introduced into the flask, and the solution was cooled to 2108C. (S)-(þ)-O-
Acetylmandelic acid (7.76 g, 40 mmol) was added slowly as a solution in
DCM (20 mL). Stirring was continued for 6 h until the completion of the
reaction (TLC). The reaction mixture was filtered to remove the urea deriva-
tive, and the filtrate was evaporated to obtained a pasty mass, which was chro-
matographed using 230 to 400-mesh silica gel and 10% EtOAc/petroleum
ether as eluent. The solid monoester (2a) was crystallized from a combination
of petroleum ether and ethylacetate. Monoester 2a: White solid (4.1 g, 35%
overall); Rf ¼ 0.25 (EtOAc/ petroleum ether 1:4); mp 101–1038C;
1
[a]D ¼ þ78.3 (c 1.2, acetone); IR (CHCl3) cm21: 3544, 2943, 1741; H
NMR (CDCl3) d 1.17–1.39 (m, 4H, CH2), 1.66–1.74 (m, 3H, CH2, OH),
1.90–2.08 (m, 2H, CH2), 2.21 (s, 3H, CH3), 3.39–3.50 (m, 1H, CH), 4.58–
4.64 (m, 1H, CH), 5.91 (s, 1H, CHPh), 7.37–7.50 (m, 5H, HAr); 13C NMR
(CDCl3) d 20.3, 23.1, 23.3, 29.2, 32.0, 71.6, 74.6, 79.0, 127.3, 128.5, 128.9,
133.8, 168.2, 170.3. Monoester 2b: Liquid (4.65 g, 40%); Rf ¼ 0.22 (EtOAc/
petroleum ether 1:4); [a]D ¼ þ40.8 (c 1.2, acetone); IR (CHCl3) (cm21):
1
3523, 2943, 1741; H NMR (CDCl3) d 1.14–1.39 (m, 4H, CH2), 1.60–1.73
(m, 2H, CH2), 1.77–1.85 (m, 2H, CH2, OH), 2.0–2.10 (m, 1H, CH2), 2.20
(s, 3H, CH3), 3.57–3.64 (m, 1H, CH), 4.66–4.74 (m, 1H, CH), 5.85 (s, 1H,
CHPh), 7.36–7.52 (m, 5H, HAr); 13C NMR (CDCl3) d 20.3, 23.2, 23.3, 28.9,
32.1, 71.6, 74.6, 78.9, 127.3, 128.4, 128.9, 133.5, 168.5, 170.4.
Preparation of (S,S)-(þ)-1,2-Cyclohexanediol (1)
The solid monoester (2a) (4.1 g) was stirred in 1 N methanolic NaOH solution
(36 mL) at room temperature for 4 h. When the TLC showed the disappear-
ance of the ester, MeOH was evaporated, and the diol was extracted with
DCM (4 ꢀ 20 mL). The crude product was purified through Kugelrohr distil-
lation (1208C at 4 mm Hg) to obtain (S,S)-(þ)-1 in 97% optical purity. White
solid (1.5 g, 92%); mp 115–1168C [lit.[6e] 107.5–108.5]; [a]D ¼ þ 40 (c 1.6,
H2O) [lit.[6b] 236.9 (c 1.4, H2O) for 89% ee].

Preparation of Enantiopure
1731
Preparation of (R,R)-(-)-1,2-Cyclohexanediol (1)
Compound (R,R)-(-)-1 was obtained in a similar way from liquid monoester
(2b). The diol was recrystallized from ethylacetate. White solid (1.5 g,
81%); mp 110–1128C [lit.[6e] 107.5–108.5]; [a]D ¼ 239.4 (c 1.6, H2O)
(96% ee) [lit.[6b] 236.9 (c 1.4, H2O) for 89% ee].
Resolution of (+)-trans-2-Aminocyclohexanol (3)
Preparation of (+)-trans-2-Azidocyclohexanol
To a solution of cyclohexene oxide (22 mL, 200 mmol) in EtOH (300 mL),
NaN3 (26 g, 400 mmol) and NH4Cl (21.2 g, 400 mmol) were added. The het-
erogeneous mixture was refluxed for 24 h. Most EtOH was evaporated on a
rotavapor, and the solid was triturated with THF and finally filtered. After eva-
porating the solvent, the crude azidoalcohol was obtained, which was purified
through Kugelrohr distillation. Colorless liquid at room temperature (26.33 g,
93%); bp 908C at 4 mm of Hg (lit.[12] 70–718C at 1.5 mm of Hg).
Preparation of (+)-trans-2-Aminocyclohexanol
(+)-trans-2-Azidocyclohexanol (14 g, 100 mmol) was reduced using 5% Pd/
C (1 g) in MeOH (100 mL). The solution was shaken at 50 psi of hydrogen for
8 h in a Parr apparatus. The reaction mixture was filtered through a short bed
of Celitew, and MeOH was evaporated on a rotary evaporator. The crude
compound was distilled in a Kugelrohr to obtain the (+)-trans-2-aminocyclo-
hexanol as a white hygroscopic solid (10.35 g, 90%); mp 608C (lit.[13] 658C);
bp 1208C at 10 mm of Hg (lit.[12] 708C at 2 mm of Hg); IR (CHCl3) (cm21):
3359, 2860, 2931.
Resolution of (+)-trans-2-Aminocyclohexanol
Preparation of N-pivaloyl Proline
To a solution of L-proline (25.3 g, 220 mmol) in water (100 mL), NaOH
solution (17.6 g dissolved in 50 mL of H2O) was added slowly at 08C. TBABr
(3.5 g, 11 mmol) was added to the solution, and the stirring was continued for
an hour. Pivaloylchloride (24.6 mL, 200 mmol) dissolved in 70 mL of DCM
was added slowly to the vigorously stirred reaction mixture at such a rate so
that the addition completed in 1 h. After the addition, stirring continued at
08C for 1 h. It was further stirred for 4 h at room temperature. The aqueous
layer was separated and washed with DCM (1 ꢀ 30 mL) to remove neutral
impurities. It was then acidified to pHꢀ3 with concentrated HCl and
extracted with DCM (3 ꢀ 50 mL). The combined organic layer was washed
with brine (1 ꢀ 30 mL) and kept over anhydrous Na2SO4. The pasty mass

1732
A. Chatterjee, M. Sasikumar, and N. N. Joshi
obtained after evaporating the solvent partly solidified when kept under
vacuum for a long time. However, the material was kept in a refrigerator
for 24 h after adding 10 mL of petroleum ether, where it solidified completely.
It was crystallized twice from EtOAc to obtain N-pivaloyl proline. White
solid. (28.6 g, 72%); mp 130–1358C [lit.[14] 138–1408C]; [a]D ¼ 273 (c 1,
EtOH) [lit[14] –15 (c 0.36)]; IR (CHCl3) (cm21): 3294, 2981, 1749; 1H
NMR (CDCl3) d 1.28 (s, 9H, CH3), 1.90–2.22 (m, 4H, CH2), 3.66–3.83
(m, 2H, CH2), 4.51–4.63 (m, 1H, CH), 10.01 (bs, 1H, COOH); 13C NMR
(CDCl3) d 25.5, 26.7, 27.0, 38.4, 47.9, 60.8, 175.8, 177.4. Anal. calcd. for
C10H17NO3: C, 60.26; H, 8.62; N, 7.03. Found: C, 60.01; H, 8.69; N, 7.09.
Preparation of the Diastereomeric Salt
To a solution of (+)-trans-2-aminocyclohexanol (8.06 g, 70 mmol) in
MeOH (25 mL), a solution of (S)-(-)-N-pivaloyl proline (13.9 g, 70 mmol)
in MeOH (25 mL) was added slowly. After few minutes of stirring, the
solvent was evaporated on a rotavapor, and the white salt was recrystallized
from a mixture of EtOAc/EtOH (three times) to obtain diastereomeric pure
salt (7.15 g, 32.5% overall); mp 188–1948C; [a]D ¼ 230.4 (c 1, H2O).
Hydrolysis of the Salt
To an aqueous solution of the aforementioned salt (7.15 g in 5 mL of
H2O), a NaOH solution (1.6 g in 10 mL of H2O) was added slowly at 08C.
The resulting amino alcohol was extracted with a solvent mixture of THF/
diethyl ether (1:4, 4 ꢀ 20 mL). The combined organic layer was washed
with brine (1 ꢀ 10 mL) and then kept over anhydrous K2CO3. On evaporating
the solvent, a viscous liquid was obtained, which was distilled in a Kugelrohr
at 1408C at 4 mm of Hg. After cooling, the (S,S)-(þ)-2-aminocyclohexanol
(3) solidified as hygroscopic mass (2.1 g, 80%); mp 92–948C (lit.[8d] 88–
898C); [a]D ¼ þ 49.01 (c 1, MeOH) [lit.[8d] þ 48.2 (c 1, MeOH) for 96% ee].
ACKNOWLEDGMENTS
We are thankful to the Department of Science and Technology for financial
support of the research, and two of us (A. C. and M. S.) are grateful to
Council of Scientific and Industrial Research (CSIR) for research fellowships.
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