An improved and efficient process for the scalable preparation of optically pure trans-2-aminocyclohexanols

Article abstract of DOI:10.3184/174751914X13977299691549

An improved and efficient process has been developed for a green and scalable preparation of optically pure (1R,2R) - and (1S,2S) -trans-2-aminocyclohexanols. The process utilised hot water to promote the aminolysis of cyclohexene oxide by benzylamine to afford racemic trans-2-(benzylamino)cyclohexanols, which were resolved by sequential and repeated use of (R)- and (S)-mandelic acid. Finally, after treatment of the two salts sequentially with HCl and NaOH and recovery of mandelic acid, liberation was achieved of the optically pure trans-2-benzylaminoaminocyclohexanols which were smoothly debenzylated using a low loading of a Pd/C catalyst to the trans-2-aminocyclohexanols. The synthetic route has been successfully applied to large-scale (1 mol) preparations in good yield.

Full text of DOI:10.3184/174751914X13977299691549

322 RESEARCH PAPER
VOL. 38 MAY, 322–324
JOURNAL OF CHEMICAL RESEARCH 2014
An improved and efficient process for the scalable preparation of optically
pure trans-2-aminocyclohexanols
Feng Xue*, Chang-Gong Li, Yong Zhu and Tian-Jun Lou
Key Laboratory of Functional Organic Molecules of Xinxiang City Henan Province, College of Chemistry and Chemical Engineering, Henan
Institute of Science and Technology, Xinxiang Henan, 453002, P.R. China
An improved and efficient process has been developed for a green and scalable preparation of optically pure (1R,2R)- and
(1S,2S)-trans-2-aminocyclohexanols. The process utilised hot water to promote the aminolysis of cyclohexene oxide by
benzylamine to afford racemic trans-2-(benzylamino)cyclohexanols, which were resolved by sequential and repeated use of
(R)- and (S)-mandelic acid. Finally, after treatment of the two salts sequentially with HCl and NaOH and recovery of mandelic
acid, liberation was achieved of the optically pure trans-2-benzylaminoaminocyclohexanols which were smoothly debenzylated
using a low loading of a Pd/C catalyst to the trans-2-aminocyclohexanols. The synthetic route has been successfully applied to
large-scale (1 mol) preparations in good yield.
Keywords: trans-2-(benzylamino)cyclohexanol, chiral resolution, enantiopure (1R,2R)-trans-2-aminocyclohexanol, enantiopure
(1S,2S)-trans-2-aminocyclohexanol
Enantiopure trans-1,2-amino alcohols are versatile synthetic
intermediates for the preparation of a wide variety of natural
products and biologically active compounds,1 as well as
chiral auxiliaries and ligands in asymmetric synthesis.2
Despite the impressive success in the preparation of optically
pure vicinal amino alcohols, there are only a few efficient
procedures for the preparation of highly enantiomerically
involving formation of the amine hydrochlorides with aqueous
HCl and subsequent liberation of the free bases with NaOH
permitted on the one hand the almost quantitative recovery
of the (R)- and (S)-mandelic acids and on the other hand the
isolation of enantiopure (1R,2R)-2 and (1S,2S)-2 in 78–80%
yields and in analytically pure form. Finally, the enantiopure
trans-2-aminocyclohexanols 4 were smoothly obtained by
debenzylation through hydrogenolysis at room temperature
with a Pd/C catalyst. We found that a low loading of 20.5 mg
mmol–1 Pd/C catalyst was economical and satisfactory, which
was a decrease from 80 mg mmol–1 used previously.9
In conclusion, we report an improved and efficient process for
the scalable preparation of optically pure (1R,2R)- and (1S,2S)-
trans-2-aminocyclohexanols with smooth and simplified
reaction procedures. The advantages of this improved method
are its preparative ease and its efficiency in large scale
resolutions delivering both amino alcohol enantiomers with
99% ee. Compared with the reported procedures, the overall
process is more environmentally friendly as well as cost-
effective, which will satisfy both laboratory and industrial
operations.
enriched aminocyclohexanols which are suitable for
a
broad variety of further derivatisations.3 Typical examples
include Overman’s aminolysis of cyclohexene oxide with an
aluminium amide stemming from enantiomerically enriched
methylbenzylamine and trimethylaluminum,4 Jacobsen’s
Cr(III)/salen-catalysed enantioselective ring-opening reaction
of cyclohexene oxide by azidosilanes,5,6 as well as the resolution
of racemic 2-azidocyclohexanol7,8 and 2-aminocyclohexanol
derivatives.9,10 Although these procedures have shown some
practical applications in synthesis, their application on a
preparative scale has been limited and deficient in view of
laborious synthetic processes and harsh reaction conditions.
To overcome these problems, we now describe an improved
and efficient process for the scalable preparation of optically
pure (1R,2R)-trans-2-aminocyclohexanol, enantiopure (1S,2S)-
trans-2-aminocyclohexanol.
Experimental
Solvents and reagents were purchased from the Sigma-Aldrich
company and used without further purification. Melting points
were determined on a Mettler FP5 melting point apparatus and
are uncorrected. NMR spectra were recorded on a Bruker DRX
400 MHz spectrometer in DMSO-d6 orCDCl3 with tetramethylsilane
(TMS) as internal standard. Optical rotations were measured with a
JASCO P-1020 automatic polarimeter. High resolution mass spectra
were recorded on an Applied Biosystems Mariner System 5303.
Enantiomeric excess (ee) determination was carried out using HPLC
with a Chiralcel AS-H and AD-H column on an Agilent 1100 Series
HPLC instrument.
A. Racemic trans-2-(benzylamino)cyclohexanol(rac-2): A 1-L
autoclave equipped with mechanical stirring, a thermometer and a
refluxing condenser was charged with cyclohexene oxide (1) (100.0 g,
1.02 mol 1.1 equiv.) and benzylamine (99.2 g, 0.927 mol, 1 equiv.)
in water (158 g, 9.5 equiv.). The reaction mixture was heated at 95°C
for 3.5 h, then cooled to ambient temperature, diluted with EtOAc
(150 mL), and transferred into a 1000-mL separatory funnel, then
rinsed with EtOAc (3×50 mL). Amino alcohol rac-2 (97% purity) in
EtOAc solution was obtained, which was suitable for use in the next
step without further purification.
Results and discussion
Following literature precedents,11 Qu and co-workers proposed
that hot water acted as a weak acid catalyst and solvent in the
aminolysis of epoxides.12 Indeed, these authors reported that
racemic trans-2-(benzylamino)cyclohexanol (rac-2) was easily
available by aminolysis of cyclohexene oxide by benzylamine
in hot water in 3.5 h.12 We adopted these gentle conditions, in
contrast to the previously reported protocol9 in which harsh
reaction conditions of high temperature (250 °C) and high
pressure were used. This made the reactions safe and practical
for large-scale synthesis. When the aminolysis reaction was
completed, simple extraction of the aqueous reaction mixture
with ethyl acetate (EtOAc) yielded a solution of relatively
pure rac-2, which was directly used in the resolution step.
The resolution was achieved by sequential treatment of rac-2
with 0.5 equiv. (S)- and (R)-mandelic acid (Scheme 1) as
reported previously.9 Subsequently, a simple work-up sequence
* Correspondent. E-mail: fxuehist@sina.com
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JOURNAL OF CHEMICAL RESEARCH 2014 323
OH
OH
_
+
O
precipitate
NHBn
(S)-mandelic acid
H
O
OH
benzylamine
hot H2O
(0.5 equiv)
3
O
EtOAc
NHBn
rac-
1
2
OH
+
filtrate
OH
_
O
+ (R)-mandelic acid
NHBn
(0.5 equiv)
H
O
en -
t 3
OH
OH
Pd/C
MeOH
NHBn
NH2
1. HCl (aq.), EtOAc
2. NaOH (aq.), EtOAc
2
(1R,2R)-
4
(1R,2R)-
3
3
or ent-
(recovery of mandelic acid)
OH
OH
Pd/C
MeOH
n
NHB
NH2
2
(1S,2S)-
4
(1S,2S)-
Scheme 1 Preparation of optically pure (1R,2R)- and (1S,2S)-trans-2-aminocyclohexanols 4.
B. (S)-Mandelic acid salt of (1R,2R)-2-trans-2-(benzylamino)
cyclohexanol (3) and (R)-Mandelic acid salt of (1S,2S)-2-trans-2-
(benzylamino)cyclohexanol (ent-3): A 1-L single-necked, round-
bottomed flask containing equipped with a mechanical stirrer and a
pressure-equalising addition funnel was charged with the prepared
ethyl acetate solution (300 mL) containing amino alcohol rac-2, and a
solution of (S)-mandelic acid (70.4 g, 0.46 mol, 0.5 equiv.) in EtOAc
(150 mL) was added via the addition funnel over a period of 2 h at
room temperature. After the addition was complete the dropping
funnel was rinsed with EtOAc (2×5 mL) and the reaction mixture was
stirred overnight at ambient temperature, followed by 5 h at 0 °C. The
precipitated ammonium salt was collected by suction filtration, washed
with ethyl acetate (2×50 mL), and dried under reduced pressure at room
temperature over 1 h to afford the (S)-mandelic acid salt of (1R,2R)-2-
trans-2-(benzylamino)cyclohexanol (3) as a colourless solid (131.8 g,
0.37 mol), yield 80% based on mandelic acid, m.p. 147–149°C (lit.10
acetate (3×100 mL). The combined organic phases were dried, filtered
and concentrated under reduced pressure to give the corresponding
mandelic acid enantiomer (23.7–24.3 g, 93–94%), which showed an
identical value for the optical rotation in comparison with the starting
material to fully satisfy the next use. To a mixture of the acidic aqueous
phase and ethyl acetate (200 mL) in the same separatory funnel, 5 N
NaOH (300 mL) was added carefully in small portions over a period
of 45–60 minutes. After separation, the aqueous layer was extracted
with ethyl acetate (4×100 mL) and the combined organic phases were
dried, filtered, and concentrated under reduced pressure to yield the
corresponding
trans-2-(benzylamino)cyclohexanol
enantiomers
(1R,2R)-2 and (1S,2S)-2 as white solids (31.3–32.5 g, 90–93%).
The products had the following physicochemical characteristics:
[α]D25 =–78.4 (c=1.12, MeOH) for (1R,2R)-2,ꢀ [α]D25 =+80.2 (c= 1.05,
MeOH) for (1S,2S)-2; m.p. 89–90 °C (lit.10 91 °C); ee >99%
[HPLC analysis: Chiralcel AD-H at room temperature, n-heptane/
ethanol=80:20, 0.8 mL min–1, 220 nm, tR(1R,2R)-2=7.75 min, tR
(1S,2S)-2=ꢀ14.52ꢀmin];ꢀ1H NMR (CDCl3)ꢀδꢀ0.92–1.04ꢀ(m,ꢀ1ꢀH),ꢀ1.14–1.30ꢀ
(m, 3 H), 1.63–1.78 (m, 2 H), 1.99–2.07 (m, 1 H), 2.11–2.24 (m, 1 H),
2.30–2.36 (m, 1H), 3.17–3.22(m, 1 H), 3.70 (d, J=12.9 Hz, 1 H), 3.96 (d,
J=12.9 Hz, 1 H), 7.29–7.52 (m, 5 H).
D. Trans-2-aminocyclohexanol enantiomers (1R,2R)-4 and (1S,2S)-
4: A solution of the trans-2-(benzylamino)cyclohexanol enantiomers
(1R,2R)-2 or (1S,2S)-2 (60.00 g, 292.3 mmol) in dry MeOH (119 mL)
was hydrogenated over 10% Pd/C (6.0 g, 20.5 mg mmol–1) for 1–2 h
at room temperature and at 3 atm. After the reaction was completed,
the catalyst was removed by filtration through Celite®, washed with
MeOH and the filtrate was evaporated to give the corresponding trans-
2-aminocyclohexanol enantiomers (1R,2R)-4 (32.6 g, 97%) yield or
(1S,2S)-4 (32.9 g, 98% yield) as colourless solids. The products had
theꢀfollowingꢀphysicochemicalꢀcharacteristics:ꢀ[α]D25 =+40.3 (c=1.15,
MeOH) for (1S,2S)-4, [α]D25 =–39.8 (c=2.0, MeOH) for (1R,2R)-
4; m.p. 69–70 °C (lit.9 68 °C); ee >99% [HPLC analysis: Chiralcel
AD-H at room temperature, n-heptane/ethanol=80:20, 0.8 mL min–1,
220 nm, tR(1R,2R)-4=10.50 min, tR (1S,2S)-4=ꢀ14.50ꢀmin];ꢀ 1H NMR
(DMSO-d6) δꢀ0.96–1.17ꢀ(4ꢀH,ꢀm),ꢀ1.55–1.74ꢀ(4ꢀH,ꢀm),ꢀ2.10–2.25ꢀ(1ꢀH,ꢀm),ꢀ
2.74–2.89 (1 H, m).
1
146ꢀ°C);ꢀ[α]D25 =+14.7 (c=2.0, CHCl3); H NMR (CDCl3)ꢀδꢀ0.96–1.29ꢀ
(m, 4 H), 1.58–1.73 (m, 3 H), 1.90 (d, J=12.6 Hz, 1 H), 2.53 (dt, J=4.0,
J=12.0 Hz, 1 H), 3.03 (dt, J=4.3, 10.6 Hz, 1 H), 3.46 (d, J=12.9 Hz, 1
H), 3.89 (d, J=12.6 Hz, 1 H), 4.90 (s, 1 H), 7.19–7.35 (m, 8 H), 7.49–7.52
(m, 2H). The filtrate from the above procedure was concentrated under
reduced pressure to give a pale yellow oily residue (518.2 g) which was
dissolved in EtOAc (200 mL), transferred into a 1-L flask, and treated
with a solution of (R)-mandelic acid ((70.4 g, 0.46 mol, 0.5 equiv.) in
ethyl acetate (100 mL) similar to the above described procedure, to
deliver the (R)-mandelic acid salt of (1S,2S)-2-trans-2-(benzylamino)
cyclohexanol (ent-3) as a colourless solid (132.8 g, 0.36 mol), yield 78%
basedꢀonꢀmandelicꢀacid),ꢀ[α]D25 =–15.3 (c=2.0, CHCl3). The analytical
data were in accordance with those observed for the corresponding
enantiomer of opposite configuration.
C. Liberation of the amino alcohols and recovery of mandelic acid:
In a 1-L separatory funnel, the mandelic acid ammonium salt 3 or ent-3
(60.0 g, 0.17 mol) was partitioned between ethyl acetate (500 mL) and
2N aq. HCl solution (220 mL). Then, the mixture was manually and
vigorously shaken until the salt was completely dissolved. The organic
layer was additionally washed with 2 N aq. HCl solution (2×30 mL)
and the combined aqueous phases were back-extracted with ethyl
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324 JOURNAL OF CHEMICAL RESEARCH 2014
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L.E. Martinez, J.L. Leighton, D.H. Carsten and E.N. Jacobsen, J. Am.
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Received 4 March 2014; accepted 26 March 2014
Paper 1402506 doi: 10.3184/174751914X13977299691549
Published online: 6 May 2014
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