One-pot resolution of trans-2-iodo-cyclohexanol with O,O′-dibenzoyl- (2R,3R)-tartaric acid in solid phase

Article abstract of DOI:10.1080/00397910500501532

A one-pot, solid-state resolution of racemic-trans-2-iodo-cyclohexanol by O,O′-dibenzoyl-(2R,3R)-tartaric acid was performed. By mixing the solid racemate with half an equivalent resolving agent, the (1R,2R)-isomer of the alcohol remains uncomplexed and can be sublimated at lower temperature. By increasing the temperature, the complex decomposes and the (1S,2S)-isomer can be gained as a second fraction of the sublimation and the resolving agent remains back. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910500501532

Synthetic Communicationsw, 36: 1015–1018, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500501532
One-Pot Resolution of trans-2-Iodo-
cyclohexanol with O,O0-Dibenzoyl-(2R,3R)-
tartaric Acid in Solid Phase
C. Kassai, E. Fogassy, and D. Kozma
Department of Organic Chemical Technology, Budapest University
of Technology and Economics, Budapest, Hungary
Abstract: A one-pot, solid-state resolution of racemic-trans-2-iodo-cyclohexanol by
O,O0-dibenzoyl-(2R,3R)-tartaric acid was performed. By mixing the solid racemate
with half an equivalent resolving agent, the (1R,2R)-isomer of the alcohol remains
uncomplexed and can be sublimated at lower temperature. By increasing the tempera-
ture, the complex decomposes and the (1S,2S)-isomer can be gained as a second
fraction of the sublimation and the resolving agent remains back.
Keywords: Optical resolution, resolution by complex formation, solid-phase reactions
INTRODUCTION
Optical resolution via diastereomer formation is a rather complicated
process. An appropriate resolving agent and a solvent should be selected,
the formed diastereomeric pair can be separated by fractional crystallization,
and to regain the enantiomers and to win back the resolving agent there
are two other steps.[1] There are only very few examples of one-pot
resolutions.[2–4] They have mixed the solid resolving agent with a racemic
liquid and separated the enantiomers by distillation.
In this article we present a one-pot resolution performed by reacting
the resolving agent and the racemate in solid phase followed by separation
of the enantiomers by sublimation.
Received in the U.K. March 21, 2005
Address correspondence to D. Kozma, Department of Organic Chemical Technol-
ogy, Budapest University of Technology and Economics, Budapest, Hungary. E-mail:
koz6660@mail.iif.hu
1015

1016
C. Kassai, E. Fogassy, and D. Kozma
RESULTS AND DISCUSSION
O,O0-Dibenzoyl-(2R,3R)-tartaric acid (DBTA) can be used as a complex
forming resolving agent for the resolution of racemates having no basic
groups, such as racemic alcohols. A number of racemic alcohols were
resolved by the conventional method using hexane as solvent.[5]
The racemic trans-2-iodo-cyclohexanol (1) was selected as a model
compound for the one-pot resolution because it is solid at room temperature
(mp 43 8C) and sublimates well. DBTA monohydrate and racemic-1 was
mixed in a mortar (1:2 molar ratio) at room temperature, and after different
reaction times the solid mixture was fractionally sublimated in vacuum. At
lower temperature (50 8C) the sublimate enriches in the unreacted enantio-
meric mixture of (1R,2R)-1. By increasing the temperature (up to 100 8C),
the complex slowly decomposes, and the enantiomeric mixture of (1S,2S)-1
that was complexed can be obtained as sublimate (Figure 1). The results are
summarized in Table 1.
The reaction in the undisturbed solid mixture proceeds slowly. Although
after 1 week substantial enantiomer separation had been achieved, the equili-
brium was reached only after 3 weeks. When the solid reaction mixture was
not simply left to stand but was rubbed intensively in a mortar for 1–2 h the
same results as standing for 3–4 weeks could be achieved.
Figure 1. One-pot solid-phase resolution of racemic-1 with DBTA.

One-Pot Resolution of trans-2-Iodo-cyclohexanol
1017
Table 1. Summary of the results of solid-phase resolution of racemic-1 with DBTA
monohydrate
Results of sublimates
Reaction
time
(weeks)
Sublimation Sublimate
fraction
No.
Molar temperature
ratio
Yield
(%)a
Absolute
config.
E.e.
(%)
(8C)
S
1
2
3
4
4
1:2
50
50
1
2
3
1
2
3
1
2
3
1
2
3
1
2
3
30
58
53
56
37
53
10
77
18
15
77
26
34
28
18
(1R,2R)-(2) 68.0
(1R,2R)-(2) 86.0
(1S,2S)-(þ) 80.0
(1R,2R)-(2) 75.6
(1R,2R)-(2) 55.1
(1S,2S)-(þ) 46.2
(1R,2R)-(2) 76.2
(1R,2R)-(2) 78.7
(1S,2S)-(þ) 72.0
(1R,2R)-(2) 76.8
(1R,2R)-(2) 78.9
(1S,2S)-(þ) 58.1
(1R,2R)-(2) 40.1
(1R,2R)-(2) 23.2
(1S,2S)-(þ) 92.2
0.20
0.50
0.42
0.42
0.20
0.25
0.08
0.61
0.13
0.12
0.61
0.15
0.14
0.07
0.17
100
50
1:2
1:2
1:2
1:4
50
100
50
50
100
50
50
100
50
50
100
aYield refers to the half of the racemic-1 mass; S ¼ e.e.ꢀY (Fogassy parameter,
efficiency of the resolution).
By using 1:4 molar ratio (resolving agent–racemate) the highest e.e. value
can be attained, but because of the insufficient amounts of resolving agent,
there is no chance for a good efficiency of resolution (Table 1, row 5).
We consider this resolution one of the simplest one ever made.
EXPERIMENTAL
DBTA monohydrate was purchased from Fluka. Racemic-1 was prepared
from 1,2-epoxy-cyclohexanol.[5]
One-Pot Solid-Phase Resolution of Racemic-1 with
DBTA Monohydrate
Racemic-1, (4 ꢀ 1.00 g, 4 ꢀ 4.4 mmol) and 4 ꢀ 0.83 g (4 ꢀ 2.2 mmol) DBTA
monohydrate were mixed in a mortar for 2 min. The solid mixture was
collected and closed in a specie jar. After standing 7, 14, 21, and 28 days at
room temperature, the mixture was fractionally sublimated in a vacuum
(0.2 mmHg) at 50 8C, 70 8C, and 100 8C for 1 h. Mass, e.e., and optical
rotation of the sublimates were measured.

1018
C. Kassai, E. Fogassy, and D. Kozma
After experimenting with 1:4 molar ratio, only 0.42 g (1.1 mmol) DBTA
monohydrate was used.
A Hewlett Packard HP 5890/II instrument with flame ionization detector
(FID) detector was used for GC analysis. The column used was a
12 m ꢀ 0.100 mm i.d. fused silica open tubular column coated with Chirasil-
Dex chiral stationary phase at 0.15-mm film thickness.[6] The stationary phase
was a methylsilicone polymer substituted with permethylated b-cyclodextrin
via spacer. H2 was used as carrier gas with 1 mL/min21 speed. The injection
mode was split (1:160). Compound 1 was analyzed as an acetyl derivative at
100 8C.[7]
Optical rotation was measured with a Perkin Elmer 241 polarimeter. The
absolute configuration of 1 sublimate was determined from the sign of the
optical rotation. (1S,2S)-trans-2-Iodo-cyclohexanol (1), [a]2D3 ¼ þ33.1
(c ¼ 2.5; CHCl3).[8]
ACKNOWLEDGMENTS
The authors thank Z. Juvancz for the GC measurements. Financial support
´
´ ´
from the Orszagos Tudomanyos Kutatasi Alap (OTKA) Foundation (grant
numbers T42725 and T37342) is gratefully acknowledged.
REFERENCES
1. Kozma, D. (Ed.); Handbook of Optical Resolutions via Diastereomeric Salt
Formation; CRC Press: Boca Raton, FL, 2001.
2. Toda, F. Solid state organic chemistry: Efficient reactions, remarkable yields, and
stereoselectivity. Acc. Chem. Res. 1995, 28, 480–486.
´
3. Acs, M.; Szili, T.; Fogassy, E. New method of optical activation for racemic bases.
Tetrahedron Lett. 1991, 49, 7325–7328.
4. Kozma, D.; Fogassy, E. Solvent-free optical resolution of N-methylamphetamine by
distillation after partial diastereoisomeric salt formation. Chirality 2001, 13,
428–430.
´
5. Kassai, C.; Juvancz, Z.; Balint, J.; Fogassy, E.; Kozma, D. Optical resolution of
racemic alcohols via diastereoisomeric supramolecular compound formation with
O,O0-dibenzoyl-R,R-tartaric acid. Tetrahedron 2000, 56, 8355–8361.
6. Schurig, V.; Juvancz, Z.; Nicholson, G. J.; Schmalzing, D. Separation of enantio-
mers on immobilized polysiloxane-anchored permethyl-b-cyclodextrin
(CHIRASIL-DEX) by supercritical fluid chromatography. J. High Resol. Chroma-
torg. & Chromatogr. Comm. 1991, 14, 58–69.
7. Knapp, D. R. Handbook of Analytical Derivatization Reactions; Wiley: New York,
1979.
8. Fukuzawa, T.; Shimoji, Y.; Hashimoto, T. Synthesis of an enantiomerically pure
aminoisoquinocarbazole with antiarrhythmic activity via lipase-catalyzed enantio-
selective transesterification. Tetrahedron. Asymmetry 1996, 7, 1649–1658.