First example of axial selectivity in the nucleophilic addition to (-)-menthone-addition of cyanomethyl lithium

Article abstract of DOI:10.1016/S0957-4166(00)00099-9

The addition of cyanomethyl lithium to (-)-menthone at -78°C followed by 1.5 h stirring at room temperature and acidic workup produced exclusively the axial addition product, being the first example of preferred axial attack of an organometallic reagent t

Full text of DOI:10.1016/S0957-4166(00)00099-9

Tetrahedron: Asymmetry 11 (2000) 1513±1516
First example of axial selectivity in the nucleophilic addition
y
to (^)-menthoneÐaddition of cyanomethyl lithium
Vladimir Dimitrov* and Stefan Panev
Institute of Organic Chemistry, Bulgarian Academy of Sciences, BG-1113 So®a, Bulgaria
Received 28 January 2000; accepted 13 March 2000
Abstract
ꢀ
The addition of cyanomethyl lithium to (^)-menthone at ^78 C followed by 1.5 h stirring at room
temperature and acidic workup produced exclusively the axial addition product, being the ®rst example of
ꢀ
preferred axial attack of an organometallic reagent to menthone. In the case of hydrolysis at ^78 C after
0
.5 h reaction time the equatorial addition product was isolated as the preferably formed isomer. The axial
and equatorial cyanomethyl substituted menthol and neomenthol, respectively, were isolated in high yields.
2000 Elsevier Science Ltd. All rights reserved.
#
1
. Introduction
The addition of organometallic compounds to menthone has been described to proceed exclu-
sively from the equatorial face of the carbonyl carbon atom. We have recently prepared a chiral
1,2
3
d-aminoalcohol as a result of the equatorial attack of dimethylaminopropyl lithium to (^)-menthone,
being interested in the preparation of ligands for asymmetric syntheses. In further experiments
4
5
we investigated the addition of di€erent organometallic reagents to (^)-menthone obtaining new
chiral nonracemic compounds as a result also of exclusively equatorial attack. An equatorial
selectivity for the nucleophilic addition of the acetonitrile anion to menthone has been reported
6
by Trost et al. as an example demonstrating the limitation to the preference for axial attack of
,7
this reagent to several cyclic ketones.6
2
. Results and discussion
We were interested in the preparation of 1-hydroxy-2-isopropyl-5-methyl-cyclohex-1-yl-aceto-
nitrile for further synthetic applications and could obtain mainly the equatorial addition product
*
y
Corresponding author. E-mail: vdim@orgchm.bas.bg (present: vladimir@oci.unizh.ch).
Dedicated to Professor Dr. Manfred Hesse on the occasion of his 65th birthday.
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00099-9

1
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V. Dimitrov, S. Panev / Tetrahedron: Asymmetry 11 (2000) 1513±1516
8
ꢀ
3
and hydrolyzing the reaction mixture at this temperature (see Scheme 1 and Experimental). The
after performing the reaction between (^)-menthone and LiCH CN in THF at ^78 C for 0.5 h
2
ratio of the diastereoisomers 3 and 4 obtained was in accordance with the results published by
6
Trost et al. However, when the reaction mixture was allowed to warm to room temperature and
stirred for 1.5 h the ratio of the isomers in the crude product, obtained after hydrolytic workup,
was 3:4=1:9 (Scheme 1). To the best of our knowledge this is the ®rst example of predominantly
axial addition attack of organometallic reagent to menthone. These results indicate a higher
thermodynamic stability of compound 4 formed in the course of the reversible addition reaction
at room temperature from the initially predominant product 3. Some evidence for reversibility
has been published.1h Therefore compound 3 should be a result of a kinetically controlled addi-
tion reaction.
Scheme 1.
The di€erences in the stereochemical course of the addition reactions should not be argued
with conformational changes in menthone depending on the temperature (e.g. ring ¯ipping leading
to a conformer with axial positioned isopropyl and methyl groups), since by means of vibrational
9
10
circular dichroism, as well as NMR and molecular modelling studies, the dominant conformer
of 1 has been determined as those depicted in Scheme 1. It seems that the reagent LiCH CN is
responsible for the observed di€erences in the stereoselectivity, since with other reagents the
2
equatorial addition has always been preferred.1 LiCH CN has been suggested by theoretical
�3
2
studies to exist in solution both as solvated eight-membered ring dimers bridged by lithium and
as solvated ketimine dimers (with lithium attached to the nitrogen).11 Cyanomethyl lithium can
11
e€ectively interconvert on aggregation and solvatation into the ketimine form. The ketimine
6
form of the reagent, having a lower steric bulk, was proposed by Trost et al. to be responsible for
the reported axial attack on some cyclic ketones. However, no experimental structural informa-
ꢀ
tion is available for LiCH CN so far and it is only known for it to exist between ^108 C and
2
room temperature as a dimer, based on cryoscopy and NMR studies.11
The cyanomethyl derivative 4 could be obtained as a pure diastereoisomer after crystallization;
however, this was not possible for product 3. The observed value of the speci®c rotation for 3 is
therefore a result of the in¯uence caused by compound 4 (see Experimental).
8a
The addition of LiCH CN as a solid reagent to (^)-menthone at room temperature followed
2
by hydrolysis after 5 min provided mainly unreacted ketone 1, a small quantity of the addition
products 3 and 4, and surprisingly isomenthone (1:isomenthone:products 3/4=70:17:13; ratio
3:4=1:10; the isopropyl and the methyl groups in isomenthone are cis positioned). The observed

V. Dimitrov, S. Panev / Tetrahedron: Asymmetry 11 (2000) 1513±1516
1515
epimerization of (^)-menthone is probably the result of enolization. We tried to prove this
assumption by deuterolysis with D O of the reaction mixture after addition of LiCH CN at room
2
2
temperature. However, we could not ®nd by NMR any deuterium labelled menthone and iso-
menthone. Epimerization of (^)-menthone has also been reported to proceed easily by the
reaction with tosylhydrazine to the corresponding menthonetosylhydrazone.12
In conclusion, we have observed an unusual axial addition selectivity of acetonitrile lithium to
(^)-menthone. The variation of the reaction conditions allowed us to synthesize both axial and
equatorial addition products on a preparative scale.
3
. Experimental
3
.1. (1R,2S,5R)-1-Hydroxy-2-isopropyl-5-methylcyclohex-1-yl-acetonitrile 3
To a stirred solution of 1.80 ml (4.12 mmol) 2.29 M n-BuLi in hexane and 4 ml THF were
ꢀ
added 0.20 g (4.87 mmol) CH CN in 2 ml THF at ^78 C and the mixture was stirred for 45 min
3
at this temperature. After that 0.54 g (3.50 mmol) of 1 in 2 ml THF were added, the mixture
ꢀ
stirred for 0.5 h at ^78 C and hydrolyzed (2N HCl) at this temperature. It was extracted with
Et O (3Â15 ml), the organic layer washed with 5% aq. NaHCO , H O, dried (Na SO ) and
2
3
2
2
4
concentrated under reduced pressure. The crude product 0.68 g (quant.) was pure by TLC and
ꢀ
20
20
D
NMR (diastereoisomeric ratio 3:4=24:1). Mp 50±52 C. ‰ꢀŠ 0 (c=1.12, CHCl ), ‰ꢀŠ +1.6
D
c=1.03, EtOH). Anal. calcd for C H NO (195.30): C, 73.80; H, 10.84; N, 7.17. Found: C,
3
(
12 21
+
+
1
7
3.57; H, 10.59; N, 7.03. MS (CI: NH ) m/z (%): 213 ([M+18] , 100), 196 ([M+1] , 2). H NMR
3
(
250 MHz, CDCl , 300 K): ꢁ=0.78±0.97 (m, 1H, 4-H ), 0.92 (d, 3H, 10-H, J=6.9 Hz), 0.92 (d,
3 ax
3
1
1
2
H, 8-H, J=5.9 Hz), 0.96 (d, 3H, 9-H, J=6.9 Hz), 1.29 (t, 1H, 6-H , J=12.00 Hz), 1.31 (dm,
ax
H, 2-H ), 1.41 (qd, 1H, 3-H , J=12.5, 3.2 Hz), 1.55±1.60 (m, 1H, 3-H ), 1.57 (s, 1H, OH),
ax
ax
eq
.60±1.78 (m, 1H, 5-H ), 1.80 (dm, 2H, 4-H , 6-H ), 2.02 (quintd, 1H, 7-H, J=6.9, 1.7 Hz),
eq
ax
eq
.58 (d, 1H, 11-H , J=16.6 Hz), 2.66 (d, 1H, 11-H , J=16.6 Hz) (Table 1).
a
b
Table 1
C NMR chemical shifts for compounds 3 and 4 in CDCl
1
3
3
3
.2. (1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methylcyclohex-1-yl-acetonitrile 4
To a stirred solution of 3.32 ml (7.60 mmol) 2.29 M n-BuLi in hexane and 4 ml THF were
ꢀ
added 0.34 g (8.28 mmol) CH CN in 2 ml THF at ^78 C and the mixture was stirred for 45 min
3
at this temperature. After that 0.90 g (5.83 mmol) of 1 in 4 ml THF were added, the mixture
ꢀ
stirred for 10 min at ^78 C and then allowed to warm to rt. It was stirred for 1.5 h at rt,
hydrolyzed (2N HCl) and extracted with Et O (3Â20 ml). The organic layer was washed with 5%
2

1
516
V. Dimitrov, S. Panev / Tetrahedron: Asymmetry 11 (2000) 1513±1516
aq. NaHCO , H O, dried (Na SO ) and concentrated under reduced pressure. The crude product,
3
2
2
4
1
.17 g (3:4=1:9 by NMR), was recrystallized from hexane to give 0.77 g (68%) of pure 4 as
20
ꢀ
20
colorless crystals. Mp 105±106 C. ‰ꢀŠ ^34.4 (c=1.01, CHCl ), ‰ꢀŠ ^31.1 (c=1.04, EtOH).
D
Anal. calcd for C H NO (195.30): C, 73.80; H, 10.84; N, 7.17. Found: C, 73.71; H, 10.64; N,
3
D
12
21
+
+
1
7
.12. MS (CI: NH ) m/z (%): 213 ([M+18] , 100), 196 ([M+1] , 2). H NMR (250 MHz, CDCl ,
3
3
3
00 K): ꢁ=0.81 (d, 3H, 8-H, J=6.8 Hz), 0.88±0.98 (m, 1H, 4-H ), 0.93±1.05 (m, 1H, 3-H ), 0.95
ax
ax
(d, 3H, 10-H, J=6.6 Hz), 1.00 (d, 3H, 9-H, J=7.1 Hz), 1.09 (t, 1H, 6-H , J=12.7 Hz), 1.31 (dt,
ax
1
2
H, 2-H , J=12.0, 3.2 Hz), 1.35±1.52 (m, 1H, 5-H ), 1.72 (dm, 1H, 3-H ), 1.78 (dm, 1H, 4-H ),
ax ax eq eq
.10 (quintd, 1H, 7-H, J=6.9, 2.2 Hz), 2.15 (dm, 1H, 6-H ), 2.62 (s, 2H, 11-H).
eq
The addition of LiCH CN at rt occurred with a rapid introduction of the isolated solid
2
reagent8a to a solution of (^)-menthone in THF.
Acknowledgements
We thank Dr. S. Bienz, Organic-Chemical Institute, University of Zurich, for helpful discus-
sions. Support of this work by the Bulgarian National Fund for Scienti®c Research (project X-711)
is gratefully acknowledged.
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