Diastereoselective α-iminoamine rearrangement: Asymmetric synthesis of (R)-(-)- and (S)-(+)-2-benzyl-2-hydroxy-cyclohexanone

Article abstract of DOI:10.1016/S0957-4166(98)00422-4

A convenient asymmetric synthesis of both (R)-(-)- and (S)-(+)-2- benzyl-2-hydroxycyclohexanones starting from racemic 2- benzyloxycyclohexanone and the chiral auxiliary 1-phenylethylamine is reported. The route involves a [1,3]-sigmatropic shift and a ne

Full text of DOI:10.1016/S0957-4166(98)00422-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 4027–4034
Diastereoselective α-iminoamine rearrangement: asymmetric
synthesis of (R)-(−)- and (S)-(+)-2-benzyl-2-hydroxy-
cyclohexanone†
Philippe Bisel,a Gerhard Lauktien,a Edgar Weckert b and August W. Frahm a,∗
aLehrstuhl für Pharmazeutische Chemie, Pharmazeutisches Institut, Hermann-Herder-Straße 9, D-79104 Freiburg, Germany
bInstitut für Kristallographie, Universität Karlsruhe (TH), Kaiserstraße 12, D-76128 Karlsruhe, Germany
Received 30 September 1998; accepted 20 October 1998
Abstract
A convenient asymmetric synthesis of both (R)-(−)- and (S)-(+)-2-benzyl-2-hydroxycyclohexanones starting
from racemic 2-benzyloxycyclohexanone and the chiral auxiliary 1-phenylethylamine is reported. The route
involves a [1,3]-sigmatropic shift and a new diastereoselective α-iminoamine rearrangement of a 2-benzyl-2-
iminocyclohexanamine substrate. © 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
The thermal rearrangement of α-aminoketones and to a lesser extent α-hydroxyimines was studied
from a mechanistic point of view by Stevens et al.1a–d in the sixties. Since this type of rearrangement is
believed to be involved in the biosynthesis of Aristotelia-type alkaloids,2 it has gained new interest in
recent years.3 As part of a program devoted to the usefulness of the asymmetric reductive amination
sequence as a tool towards the synthesis of chiral bioactive amines4a and α-aminoalcohols,4b we
have recently prepared a series of racemic 2-alkoxycyclohexanones with the goal of synthesizing
optically active cis-2-hydroxycyclohexanamines.5 In the course of this study we have observed that 2-
benzyloxycyclohexanone 3 does not lead to the expected imine but undergoes a rearrangement when
submitted to the classical imine condensation conditions. Herein we wish to report on this rearrangement,
on our efforts to control the diastereoselectivity of the process and on its usefulness in the first asymmetric
synthesis of the acyloin 6. Even though its racemic synthesis has been described,6 to the best of our
knowledge, an enantioselective route to 6 has yet to be devised.
∗
†
Corresponding author. Fax: (0761) 203-6351; e-mail: awfrahm@sun2.ruf.uni-freiburg.de
Dedicated to Prof. Dr. F. Eiden on the occasion of the 73rd anniversary of his birthday.
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00422-4

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2. Results and discussion
Racemic 2-benzyloxycyclohexanone 3 was obtained from 2-chlorocyclohexanone 1 via the dimeric
ketal 2 and consecutive refluxing with benzyl alcohol on a Dean–Stark apparatus.7 Subsequent imine
condensation with one equivalent of either (R)-(+)- or (S)-(−)-phenylethylamine (PEA) in refluxing to-
luene and in the presence of a catalytic amount of p-toluenesulfonic acid did not lead to the condensation
product but gave a 1:1 diastereomeric mixture of the aminoketone 4 (Scheme 1) as established by homo-
and heteronuclear 2D-NMR spectroscopy. This type of rearrangement was found earlier in our laborato-
ries for the cyclohexane derivative8 and has been reported on the five membered ring and on α-allyloxy
cyclohexanimines by Desmaële et al.,9 and was interpreted as a thermal non-diastereoselective [1,3]-
sigmatropic shift. More recently, we have also observed an identical rearrangement on the cyclobutane
ring.4b However, we were able to gain the diastereomerically pure (αR,2R*)-5 and (αS,2S*)-5 in 33%
yield each by means of differentiating crystallization in acetone after treatment of the crude (αR,2RS)-4
and (αS,2RS)-4, respectively, with HCl–ether.
Scheme 1. (a) NaOH, r.t.; (b) BnOH, HCl conc., toluene, reflux, 75 min.; (c) (R)-(+)- or (S)-(−)-PEA, p-TsOH, toluene, reflux,
3 h; (d) HCl:ether
Furthermore, X-ray suitable crystals of (αR,2R*)-5 could be obtained from hot isopropanol and
thus, the (αR,2S) absolute configuration was established first by means of the three beam interaction
method10 which has been re-evaluated at low temperature (<120 K) by refining an enantiomorph
sensitive parameter according to Flack, including all Friedel related reflections and anomalous dispersion
corrections (Fig. 1).11 Since the measured [α]D values for the aminoketones obtained from (αR,2RS)-
4 and (αS,2RS)-4, respectively, are opposite, the (αS,2R) absolute configuration of the enantiomeric 5
could be deduced.
We reasoned that the hitherto unknown enantiomerically pure (R)- and (S)-2-benzyl-2-
hydroxycyclohexanones (R)-6 and (S)-6 should be accessible from (αR,2S)-5 and (αS,2R)-5,
respectively, via a subsequent aminoketone rearrangement. Indeed, this type of rearrangement has
been described along with its stereochemical pathways,12a–d the suprafacial 1,2-shift proceeding with
complete transfer of stereochemistry. Accordingly, the treatment of the corresponding free bases
(αR,2S)-4 and (αS,2R)-4, with a refluxing ethanol:water mixture led to (R)-(−)-6 and (S)-(+)-6,
respectively, in 66% yields with the chiral auxiliary being recovered (Scheme 2). The enantiomeric
excess of the respective geminal substituted acyloins 6 was determined by means of derivatization of
the carbonyl function to the corresponding ketals 7 with (2R,3R)-2,3-butandiol.13 The 1H and 13C NMR

P. Bisel et al. / Tetrahedron: Asymmetry 9 (1998) 4027–4034
4029
Figure 1. X-Ray structure of (αR,2S)-5
spectra of these ketals exhibited only one set of signal groups each accounting for a single diastereomer
and thus, an enantiomeric excess of >99% was deduced.
Scheme 2. (a) EtOH:H2O (3:1) reflux, 24 h; (b) (2R,3R)-2,3-butandiol (2 equiv.), toluene, p-TsOH, reflux
Besides offering a first convenient asymmetric synthesis of the enantiomerically pure (R)-(−)- and
(S)-(+)-6, respectively, the above findings represented an analytical tool for further studying the key
rearrangement in our route, the major issue being whether the stereochemistry can be controlled or not.
Among a series of experiments we have found that the treatment of racemic 2-benzyloxycyclohexanone
3 with two equivalents of (R)-(+)- or (S)-(−)-PEA gave rise to a non-equimolar mixture of two

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P. Bisel et al. / Tetrahedron: Asymmetry 9 (1998) 4027–4034
diastereomeric imines 8 (Scheme 3). Indeed, out of the four theoretically feasible NMR spectroscopically
differing stereoisomers, only two sets of signals could be observed in the crude 13C NMR spectra of
(αR,α0R)-8 and (αS,α0S)-8, respectively, the ratios of which were readily determined by comparing
the intensities of corresponding C-atom signals. After 4 days in refluxing toluene, a thermodynamic
equilibrium was attained with a product ratio of 78:22. Since the Z-isomers at the C_N double bond are
unlikely because of steric hindrance, we assume that the two imines must be epimers at the quaternary C-2
position. In order to confirm the diastereoselectivity (de 56%) and to establish the absolute configuration
at the C-2 carbon of the major and the minor components, we submitted the crude imine mixtures 8
to hydrolysis under the same conditions as described previously for the aminoketones 4. Theoretically,
since the hydrolysis process is completely stereoselective,12a the expected crude enantiomeric acyloin
mixtures 6a and 6b, obtained from (αR,α0R)-8 and (αS,α0S)-8, respectively, should be optically active
and should reflect the diastereomeric excesses of the parent imine mixtures 8 (Scheme 3). The [α]D values
of +55.0 and −56.2 measured for 6a and 6b, respectively, can be compared to the ones measured for the
enantiomerically pure acyloins. They indicate ee values of 50.5% and 51.2% for 6a and 6b, respectively.
One recrystallization in cyclohexane gave the acyloins 6a and 6b with enantiomeric excesses of 96.8%
and 96.7%
Scheme 3. (a) (R)-(+)- or (S)-(−)-PEA (2 equiv.), toluene, p-TsOH, reflux, 4 days; (b) EtOH:H2O (3:1) reflux, 24 h
The stereochemical issues of the iminoamine rearrangement with respect to the absolute configuration
at C-2 have been elucidated by means of analogy conclusions. Indeed, as stressed earlier, the aminoketone
(αR,2S)-4 (Scheme 2) yielded the acyloin 6 with a negative [α]D value. Therefore the major component
of the diastereomeric imine mixture 8 which leads to the acyloin with a negative [α]D value must be
S-configured at C-2. The experimental data show that the treatment of benzyloxycyclohexanone 3 with
two equivalents of (S)-(−)-PEA and subsequent hydrolysis afforded the acyloin 6 with the negative [α]D
value with the inverse counting for 3 treated with (R)-(+)-PEA. Conclusively, the major enantiomers of
the 6a and 6b mixtures are (S)-(+)-6 and (R)-(−)-6, respectively. Thus, the like induction14 at C-2 of the
imine could be established.
Since the thermal [1,3]-sigmatropic shift is not diastereoselective, our observations suggest that the
stereoselectivity has to occur during the α-iminoamine rearrangement. The stereochemical outcome was
rationalized assuming that the migrating benzyl moiety has to be placed in an axial position to attain
a certain degree of coplanarity with the developing electron deficient orbital at the imine carbon4d and
that the sterically demanding phenyl group of the phenyl ethyl imino moiety has to occupy a pseudo-
equatorial orientation. Accordingly, the observed ratio of 78:22 for (αR,α0R)-8, for example, arises from
the favored re-face attack of the migrating group at the (S)-configured C-2 epimer in comparison to the
si-face attack at the (R)-configured C-2 epimer. Indeed, if the attack is hindered by an α-proton in the first
case, it is blocked by an α-methyl group in the latter (Fig. 2) with the inverse counting for (αS,α0S)-8.

P. Bisel et al. / Tetrahedron: Asymmetry 9 (1998) 4027–4034
4031
Figure 2. Diastereoselective iminoamine rearrangement exemplified on the (αR,α0R)-8 diastereomeric imine mixture
The sequential treatment of the benzyloxycyclohexanone 3 with one equivalent of (R)-PEA for 4
h, in refluxing toluene in the presence of p-toluenesulfonic acid followed by one equivalent of the
enantiomeric (S)-PEA under the same conditions afforded the crude iminoamine as an expected 1:1
mixture of diastereomers. The absolute stereochemistry of the phenylethylimino moiety is responsible
for the stereochemical pathway of the rearrangement and the process consists of a formal ‘iminoamine–
aminoimine’ equilibrium. Thus, the (αS,α0R)-iminoamine rearranges to the (αR,α0S)-iminoamine with
the absolute stereochemistry of the key phenylethylimino group being either R- or S-configured to 50%
each. This mismatching situation finally leads to a 1:1 diastereomeric iminoamine mixture. In summary,
according to Izumi’s14 nomenclature, the reaction proceeds with diastereoface differentiation and ‘like’-
induction at C-2.
3. Experimental
3.1. General procedures
Solvents were purified according to standard procedures. Melting points are uncorrected. The given
yields are for isolated products. Column chromatography was performed on Merck silica gel (70–230
mesh ASTM). Infrared spectra were recorded on a Perkin–Elmer IR 298 spectrometer. NMR spectra
were obtained on a Varian XL 300 spectrometer at 300 MHz (1H) and 75.4 MHz (13C), respectively.
Chemical shifts are reported as δ values from TMS as internal standard. Optical rotation values were
obtained with a Perkin–Elmer 214 polarimeter. Elemental analyses were carried out on a Perkin–Elmer
DIA-CHN RS at the Analytical Laboratory, Institute for Organic Chemistry and Biochemistry, Bonn.
3.2. Dodecahydrodibenzo-1,4-dioxan-4a,9a-diol 2
140 g of sodium hydroxide (28.5%) were added within 3 h to 132.6 g (1.0 mol) of 2-chlorocyclo-
hexanone 1, whereby the reaction temperature was kept below 0°C. After this, the mixture was stirred
for 12 h at room temperature when it showed a neutral reaction. The product was filtered off, freed of
chloride with demineralized water, washed with EtOH (3×25 ml) and Et2O (3×25 ml) and finally dried
in vacuo, yielding 68.5 g (60%, 0.3 mol) of 2: mp 123–128°C [lit.15: 132.5°C]; 13C NMR (CD3OD): δ
23.5 (t), 25.5 (t), 29.0 (t), 36.6 (t), 74.1 (d), 96.4 (s).
3.3. 2-Benzyloxycyclohexanone 3
A solution of 22.8 g (0.1 mol) of 2 and 32.4 g (0.3 mol) of benzylalcohol in 40 ml of toluene and 10 ml
of conc. hydrochloric acid was refluxed for 75 min on a Dean–Stark apparatus. The reaction was stopped,

4032
P. Bisel et al. / Tetrahedron: Asymmetry 9 (1998) 4027–4034
toluene was evaporated and the oily residue was distilled in vacuo affording 28.0 g (68%, 0.14 mol) of
the ketone 3: bp1 136–138°C [lit.7: bp0.5 110–112°C]; IR (film): 1720 cm−1 (C_O); 1H NMR (CDCl3):
δ 1.65 (m, 1H, 4-H), 1.70 (m, 1H, 5-H), 1.75 (m, 1H, 3-H), 1.95 (m, 2H, 4-H, 5-H), 2.20 (m, 1H, 3-H),
2.25 (m, 1H, 6-H), 2.52 (m, 1H, 6-H), 3.87 (ddd, J=10.0, 5.5, 1.5 Hz, 1H, 2-Hax), 4.47 (d, J=10.0 Hz,
1H, H-benzyl), 4.75 (d, J=10.0 Hz, 1H, H-benzyl), 7.32 (m, 5H, aromatic H); 13C NMR (CDCl3): δ 22.7
(t), 27.2 (t), 34.1 (t), 40.2 (t), 71.2 (t), 81.3 (d), 127.6 (d), 127.7 (d), 128.3 (d), 137.9 (s), 209.6 (s).
3.4. (αR,2S)- and (αS,2R)-2-Benzyl-2-[N-(1-phenylethyl)amino]cyclohexanone hydrochloride ((αR,
2S)-5 and (αS,2R)-5)
A solution of 10.2 g (0.05 mol) of 3 and 6.2 g (0.05 mol) of (R)-(+)- and (S)-(−)-PEA, respectively,
in 50 ml of toluene containing a catalytic amount of p-TsOH was refluxed for 3.5 h on a Dean–Stark
apparatus. The solvent was removed in vacuo and the residue was treated with HCl–ether. The solvent
was removed again and the residue taken up in 50 ml acetone. The colorless crystals were filtered off and
recrystallized from isopropanol to give 5.5 g (0.016 mol) of (αR,2S)-5 and (αS,2R)-5, respectively: mp
191–194°C; IR (KBr): 1710 cm−1 (C_O); [α]D +111.6 and −111.3 (c=0.3, ethanol), respectively; 1H
30
NMR (CD3OD): δ 1.58 (m, 1H, H-5ax), 1.68 (d, J=7 Hz, 1H, H-β0), 1.79 (m, 2H, H-4), 1.95 (m, 1H, H-
5eq), 1.98 (ddd, J=12.5, 12.5, 5.5 Hz, 1H, H-3ax), 2.18 (ddd, J=12.5, 5.0, 3.0 Hz, 1H, H-3eq), 2.37 (ddd,
J=15.5, 4.0, 4.0 Hz, 1H, H-6eq), 2.66 (ddd, J=15.5, 13.0, 6.0 Hz, 1H, H-6ax), 3.44 (d, J=15.0 Hz, 1H,
H-benzyl), 3.66 (d, J=15.0 Hz, 1H, H-benzyl), 4.69 (q, J=7 Hz, 1H, H-α0), 7.2–7.5 (m, 10H, H-arom).
Anal. calcd for C21H26NOCl: C 73.30, H 7.62, N 4.10. Found: C 73.0, H 7.74, N 3.80 and C 73.40, H
7.79, N 4.20, respectively.
3.5. (αR,α0R,2RS)- and (αS,α0S,2RS)-N-(1-Phenylethyl)-1-benzyl-2-[N-(1-phenylethyl)amino]cyclo-
hexanamine ((αR,α0R)-8 and (αS,α0S)-8)
A solution of 2 g (9.8 mmol) of 3 with 2.50 g (20.58 mmol) of (R)-(+)- and (S)-(−)-PEA, in toluene
is refluxed for 4 days on a Dean–Stark apparatus in presence of a catalytic amount of p-TsOH. After
cooling, the PEA/p-toluenesulfonate salt was filtered off and the solvent evaporated in vacuo. The crude
residue was used without any further purification.
3.6. (2R)-(−)- and (2S)-(+)-2-Benzyl-2-hydroxycyclohexanone ((2R)-(−)-6 and (2S)-(+)-6)
3.6.1. Method A
The hydrochloride (688 mg, 2 mmol) of (αR,2S)-5 and (αS,2R)-5, respectively, was suspended in 20
ml of a 5% NaHCO3 solution and extracted 3 times with 20 ml ether. The solvent was removed in vacuo,
the residue taken up in ethanol:water (3:1) and refluxed for 24 h. The solvent was evaporated and the
residue purified by means of flash chromatography with ethyl acetate. The product was recrystallized
30
from cyclohexane to afford (2R)-(−)-6 and (2S)-(+)-6 (270 mg, 66%), respectively: mp 84–85°C; [α]D
−109.7 (c=1.0, CHCl3) and +109.0 (c=1.3, CHCl3), respectively. Anal. calcd for C13H16O2: C 76.40, H
7.90; Found: C 76.30, H 7.89 and C 76.30, H 8.14, respectively.
3.6.2. Method B
A solution of the crude (αR,α0R)-8 and (αS,α0S)-8 (2 g, 4.87 mmol), respectively, in ethanol:water
(3:1) was refluxed for 24 h, the solvent removed in vacuo and the residue purified by flash chromatogra-
phy with ethyl acetate to yield 6a and 6b, respectively (780 mg, 78%): mp 83°C and 82°C, respectively;

P. Bisel et al. / Tetrahedron: Asymmetry 9 (1998) 4027–4034
4033
30
[α]D +55.0 and −56.2, respectively. A single recrystallization from cyclohexane yielded (2S)-(+)-6
and (2R)-(−)-6 (435 mg, 56%), respectively: [α]D30 +105.4 (c=1.0, CHCl3) and −106.2 (c=1.0, CHCl3),
respectively.
1H NMR (300 MHz, CDCl3): δ 1.69 (m, 2H, H-5ax, H-3eq), 1.87 (m, 2H, H-4), 2.2 (m, 2H, H-5eq,
H-3ax), 2.54 (m, 1H, H-6eq), 2.70 (ddd, J=13.5, 13.5, 6.5 Hz, 1H, H-6ax), 2.97 (d, Jab=13.5 Hz, 1H,
H-benzyl), 3.14 (d, Jab=13.5 Hz, 1H, H-benzyl), 3.9 (s, 1H, OH), 7.25 (m, 5H, H-arom); 13C NMR (75
MHz, CDCl3): δ 22.7 (t), 27.3 (t), 38.5 (t), 40.3 (t), 43.2 (t), 79.2 (s), 126.9 (d), 128.1 (d), 130.0 (d),
135.3 (s), 213.1 (s).
3.7. (2R,3R,6R)- and (2R,3R,6S)-1,4-Dioxa-6-benzyl-6-hydroxy-2,3-dimethyl-spiro[4,5]-decan ((6R)-7
and (6S)-7)
A solution of 102 mg (0.5 mmol) (−)-(2R)-6 and (+)-(2S)-6, respectively, and 90 mg (1 mmol) (2R,3R)-
2,3-butandiol in 7 ml toluene was refluxed for 14 h in the presence of a catalytic amount of p-TsOH. The
solvent was removed and the residue chromatographed with cyclohexane:ethyl acetate (9:1) to give 119
1
mg (0.033 mmol, 66%) of (6R)-7 and (6S)-7, respectively: mp 86°C; H NMR (300 MHz, CDCl3): δ
1.26 (d, J=6.0 Hz, 3H, CH3), 1.30 (d, J=6.0 Hz, 3H, CH3), 1.3–2.0 (m, 8H, -CH2-), 1.78 (s, 1H, OH),
2.89 (s, 2H, H-benzyl), 3.66 (dq, J=8.5, 6.0 Hz, 1H, H-2), 3.79 (dq, J=8.5, 6.0 Hz, 1H, H-3), 7.25 (m,
5H, H-arom); 13C NMR (75 MHz, CDCl3): δ 16.1 (q), 17.7 (q), 20.3 (t), 22.9 (t), 32.8 (t), 33.4 (t), 39.3
(t), 75.2 (d), 77.9 (d), 79.8 (d), 109.9 (s), 125.4 (d), 127.8 (d), 130.8 (d), 137.2 (s) and, 16.2 (q), 17.7 (q),
20.3 (t), 23.1 (t), 32.4 (t), 32.8 (t), 40.4 (t), 75.3 (d), 78.4 (d), 79.6 (d), 110.1 (s), 126.0 (d), 127.8 (d),
130.9 (d), 137.4 (s), respectively.
3.8. X-Ray structure of (αR,2S)-5
C21H25ON·HCl, Mr=343.90, transparent crystal of size 0.25×0.4×0.6 mm3, orthorhombic, space
group P2,2,2 (No. 19 of IT16). Lattice parameters are a=8.535 (2) Å, b=11.628 (3) Å, c=18.018 (5)
Å and V=1788.2 (8) Å3 (determined from 13 211 reflections, 3°<θ<27°), Z=4, dcalc=1.277 g cm−3 and
µx (MoKα radiation, λ=0.7107 Å)=2.18 cm−1. Intensity data were collected with an image plate detector
system (MarResearch) using MoKα radiation and a graphite monochromator at T=150 K. Data collection
was carried out in the range −9≤h≤9, −14≤k≤14, −22≤l≤22 with (sinθ/λ)max=0.639. The total number
of reflections measured is 13 497, from which 3270 are unique (Rmerged=1.91%, completeness: 94%).
Data were integrated, reduced and scaled using XDS.17 3187 reflections have I(h)>3σ (I(h)) and were
retained for further analysis. The structure was solved by Direct Methods.18 All non-hydrogen atoms
were refined anisotropically using full-matrix least-squares19 based on |F| with weights 1/(σ(|F|)2 +0.1).
H-1 to H-3 were refined isotropically. The positions of all other H atoms were calculated with a C–H
distance of 0.97 Å and a hydrogen displacement parameter of 1.1 times that of the corresponding
C atoms. The shifts (∆/σ)max of the final least-square cycle were smaller than 0.01. R-values were
Rw=0.037 and R=0.028 for refined parameters. Goodness of the fit is 1.51. The final difference Fourier
is featureless (∆ρmin=−0.33, ∆ρmax=0.44 c/Å). The absolute configuration was determined by refining
an enantiomorph sensitive parameter (χ=0.02 (4)) according to Flack,20 including all Friedel related
reflections. Anomalous dispersion corrections were taken from IT Vol. IV, Table 2.3.1.16 The Cl ion is
weakly bound by a hydrogen bridge N1–H1. . .Cl1–N1, the N1–Cl1 distance is 3.118 (1) Å and the bond
angle at the H atom is 171 (2)°.
Under consideration of the measurements errors, all distances and angles are within the expected
values.21

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P. Bisel et al. / Tetrahedron: Asymmetry 9 (1998) 4027–4034
Acknowledgements
Financial support from The Fonds der Chemischen Industrie, Frankfurt a.M., Germany, is gratefully
acknowledged.
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