Diastereoselectivity in the Overman rearrangement of O-cyclohexylideneethylimidates

Article abstract of DOI:10.1016/j.tetlet.2006.03.174

Conformationally biased cyclohexylideneethanols were prepared and converted to trichloroacetimidates, which then were subjected to the thermal Overman rearrangement. The rearrangement of axially unshielded imidates was unselective, providing isomeric amid

Full text of DOI:10.1016/j.tetlet.2006.03.174

Tetrahedron Letters 47 (2006) 3885–3887
Diastereoselectivity in the Overman rearrangement of
O-cyclohexylideneethylimidates
a,b
b,
b
a,b
*
Ieva Jaunzeme, Aigars Jirgensons, Valerjans Kauss and Eduards Liepins
a
Faculty of Material Science and Applied Chemistry, Riga Technical University, Riga LV-1048, Latvia
b
Latvian Institute of Organic Synthesis, Riga LV-1006, Latvia
Received 1 February 2006; revised 17 March 2006; accepted 29 March 2006
Available online 27 April 2006
Abstract—Conformationally biased cyclohexylideneethanols were prepared and converted to trichloroacetimidates, which then were
subjected to the thermal Overman rearrangement. The rearrangement of axially unshielded imidates was unselective, providing iso-
meric amides in equal ratio. The axial face shielding in the 3,3,5-trimethylcyclohexylidene system resulted in highly selective nitrogen
attack from the equatorial side.
Ó 2006 Elsevier Ltd. All rights reserved.
The aza-Claisen rearrangement of O-allyltrichloroacet-
imidates to N-allyltrichloroacetamides (the Overman
rearrangement), performed thermally or catalyzed by
soft Lewis acids, is a convenient method to prepare allyl
equatorial face favored axial attack of the imidate
nitrogen, while simultaneous axial and equatorial shield-
ing resulted in the undesired 1,3-rearrangement prod-
2
d–f
uct.
Limited information on the stereochemical
1
amine derivatives. The thermal Overman rearrange-
aspects of the Overman rearrangement prompted our
investigations in this field.
ment constitutes one of the few alternatives for intro-
2
ducing an amino group at a tertiary carbon atom. We
found it to be the method of choice for the synthesis
of 1-vinylaminocyclohexanes as NMDA receptor antag-
onists. However, in imidates of type 1 nitrogen can
attack the double bond from either the axial or the
equatorial side resulting in isomeric amides 2 (Fig. 1).
We chose the 4-tert-butyl- and 4-phenylcyclohexylidene
systems as conformationally biased models for axially
unshielded attack, and the 3,3,5-trimethylcyclohexyl-
idene system for axially shielded attack of the nucleo-
3
4
phile at C-1.
The stereochemical outcome of the rearrangement was
difficult to predict, since only a few examples have been
reported where remarkable selectivity was induced by
Cyclohexylideneethanols 4a–c were prepared from
cyclohexanones 3a–c by converting them into unsatu-
rated esters, which were subsequently reduced (Scheme
1). 3,3,5-Trimethylcyclohexanone (3c) gave a mixture
of isomeric alcohols E-4c and Z-4c in the ratio 2:1.
These were converted to a mixture of the corresponding
4-nitrobenzoates which were resolved by crystallization.
Cleavage of the 4-nitrobenzoyl group provided allylic
alcohols E-4c and Z-4c with de’s of 73% and 68%,
2
b–f
remote substituent effects.
The closest example was
the stereoselective introduction of an amido group in a
conformationally biased cyclohexene in Isobe’s total
synthesis of tetrodotoxin. In this case, shielding of the
O
5
respectively. The diastereomeric purity of alcohols E-
R
CCl3
O
reflux
O
HN
CCl3
4c and Z-4c was sufficient to evaluate the effect of the
double bond geometry on the stereoselectivity of the
Overman rearrangement (vide infra). The double bond
geometry in isomer Z-4c was determined based on the
NOE studies.
+
HN
R
N
H
R
CCl3
1
eq-2
ax-2
Figure 1. Formation of isomeric amides eq-2 and ax-2 from imidates 1.
Allylic alcohols 4a,b and E-4c, Z-4c were converted to
trichloroacetimidates 1a,b and E-1c, Z-1c, which were
*
Corresponding author. Tel.: +371 7543535; fax: +371 7553142;
e-mail: aigars@osi.lv
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.174

3886
I. Jaunzeme et al. / Tetrahedron Letters 47 (2006) 3885–3887
O
i, ii
Me
O
H
R
R
Me
H
OH
H
Me
i
N
H
CCl3
Me
3
a,b
4a,b
NH
*
HCl
Me
2
a, R = 4-t-Bu
Me
b, R = 4-Ph
eq-2c
5
Me
Scheme 3. Reagents and conditions: (i) (a) NaOH, DMSO; (b) HCl,
Me
68%.
OH
OH
Me
Me
O
i-iv
Me
E-4c
between 4-CHax and 6-CHax (J = 12.5 Hz) indicated
the chair conformation of compound 5. The amino
HH
Me
7
3c
Me
H
group is cis oriented with respect to 5-CH , as was indi-
3
Me
H
cated by NOE measurements.
H
Me
Z-4c
Scheme 1. Reagents and conditions: (i) (EtO)
The high selectivity in the rearrangement of conforma-
tionally biased imidates E-1c and Z-1c confirmed that
axial face shielding of the cyclohexane directs nitrogen
attack from the equatorial side. Kinetic control was
proved by the fact that the ratio of the trichloroacet-
amides eq-2c and ax-2c (enriched with minor isomer
ax-2c, 2:1) remained unchanged after heating the mix-
ture for 10 h. This suggests that the isomer distribution
depends on the energy differences of the diastereomeric
transition states. Axial face shielding by 3-CH3ax occurs
provided that nitrogen attacks C-1 nondistorted from
2
P(O)CH
1.2 equiv), NaOEt, EtOH, rt; (ii) DIBAL-H (2.2 equiv), Et O, 0 °C,
COCl, Py,
2 2
CO Et
(
2
4
a 70%, 4b 71%, 4c 80% over two steps; (iii) o-NO
2 6 4
C H
0
°C, 89%; (iv) K CO , MeOH, rt, 2 h, 78%.
2
3
isolated and immediately subjected to thermal rearrange-
ment (Scheme 2). The ratio of the resulting trichloro-
acetamidocyclohexanes eq-2a–c and ax-2a–c was
determined by GC–MS analysis prior to workup, and
the products were then isolated as mixtures of isomers
2
sp geometry—a situation that is similar to nucleophilic
addition to cyclohexanones. This is the case if the rear-
rangement is concerted and proceeds through an early
(
1
Table 1). The rearrangement of trichloroacetimidates
a,b derived from 4-phenyl- and 4-tert-butylcyclohexyl-
(
reactant-like) transition state, as supported by the evi-
ideneethanols (3a,b) was unselective, providing isomeric
amides eq-2a,b and ax-2a,b in equal ratios. However, the
rearrangement of trichloroacetimidates E-1c and Z-1c
gave predominantly amide eq-2c. Notably, the geometry
of the double bond in imidates E-1c and Z-1c had little
impact on the ratio of isomers eq-2c and ax-2c.
1
b
dence of exothermic nature of the process. A planar
allylic part in an ion-pair transition state for the Over-
man rearrangement was proposed by semi-empirical
8
calculations and could also be used to explain the
observed stereochemical results.
In summary, we have demonstrated that axial face
shielding induces stereoselective nitrogen attack from
the equatorial side during the Overman rearrangement
of trichloroacetimidates derived from 2-cyclohexylidene-
ethanols. With this information in hand, we have
prepared a series of 1,3,3,5-tetrasubstituted aminocyclo-
hexanes possessing an equatorially positioned amino
group as NMDA receptor antagonists, the studies of
which will be reported elsewhere.
To determine the configuration of the major trichloro-
acetamide eq-2c, it was hydrolyzed to amine 5 (Scheme
3
), crystallized to give a de >95% and studied by
6
NMR spectroscopy. Large vicinal coupling constants
O
CCl3
i, ii
HN
CCl3
R
R
O
+
N
H
OH
R
4
a-c
eq-2a-c
ax-2a-c
Acknowledgements
a, R = 4-t-Bu
b, R = 4-Ph
The work was supported by Merz Pharmaceuticals, a
Grant from Latvian Council of Science and the Euro-
pean Social Fund within the National Programme ‘Sup-
port for Carrying Out Doctoral Study Programmes and
Post-Doctoral Research’. We also wish to thank Dr. R.
Zemribo for valuable comments during the preparation
of the manuscript.
c, R = 3,3,5-triMe
Scheme 2. Reagents and conditions: (i) Cl
10 mol %), Et
3
CCN (1.1 equiv), NaH
(
2
O, ꢀ10 °C; (ii) o-xylene, reflux, 10 h.
Table 1. Stereochemical results of the Overman rearrangement
a
Alcohol 4
Ratio eq-2:ax-2
Yield (%)
a
1:1
1:1
12:1
19:1
70
72
58
References and notes
b
E-c
Z-c
1
. (a) Overman, L. E. J. Am. Chem. Soc. 1974, 96, 597–599;
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(c) Overman, L. E. Acc. Chem. Res. 1980, 13, 218–224; (d)
6
28
(
a
Isolated yields in two steps from alcohol 4.

I. Jaunzeme et al. / Tetrahedron Letters 47 (2006) 3885–3887
3887
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2
3
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5-CH3eq), 0.85–1.05 (m, 1H, 4-CHax), 0.94 (s, 3H, 3-CH3eq),
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eq ax ax
J = 6.8 Hz, 2H, CH
2
O), 5.33 (t, J = 7.0 Hz, 1H, @CH).
(
6. The low isolated yield of amide 2c from Z-4c may be due to
the very small scale. The rearrangement of the imidate
derived from the mixture of isomeric alcohols E-4c and
Z-4c (E/Z = 3:1) gave trichloroacetamides eq-2c and ax-2c
(
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Ohyabu, N.; Nishikawa, T.; Isobe, M. J. Am. Chem. Soc.
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2
003, 125, 8798–8805.
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3
3
4
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CH ), 0.95 (s, 3H, 3-CH3ax), 1.31–1.38 (m, 2H, 2-CHax and
3
2
3
003166634, September, 2003; Chem. Abstr. 2003, 138,
79247.
4-CHeq), 1.67 (d, 1H, J = 13.2 Hz, 6-CHax), 1.70 (m, 1H, 5-
CH ), 1.97 (d, 1H, J = 13.2 Hz, 2-CH ), 2.30 (d, 1H,
ax
eq
. Devant, R. M.; Radunz, H.-E. In Formation of C–C bonds
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J = 12.3 Hz, 6-CHeq), 5.41 (d, 1H, J = 10.5 @CH2trans),
5.62 (d, 1H, J = 17.6 Hz, @CH2cis), 6.02 (dd, 1H, J = 17.6,
þ
13
10.5 Hz, @CH), 8.25 (3H, br s, NH3
;
C NMR
(150 MHz, CDCl ): 22.07 (5-CH ), 25.14 (5-CH), 26.66
3
3
Vol. 2, Chapter 1.3, pp 1151–1334.
. Z-4c: H NMR (600 MHz, CDCl
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(3-CH3ax), 31.99 (3-C), 33.89 (3-CH3eq), 40.86 (4-CH
2
),
1
5
3
): d = 0.77 (s, 3H, 3-
3
47.23 (2,6-CH
(@CH).
2
), 57.67 (1-C), 119.27 (@CH
2
), 138.28
1
H, 4-CHax), 0.96 (s, 3H, 3-CH3eq), 1.36–1.42 (m, 2H, 4-
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CHeq and 6-CHax), 1.56 (d, J = 13.7 Hz, 1H, 2-CHax), 1.61