Highly diastereoselective addition of phenyllithium on cis-substituted C-cyclopropylaldimines

Article abstract of DOI:10.1055/s-2007-967988

The addition of phenyllithium to cis-substituted C-cyclopropylaldimines produces in high diastereoselectivity and in good yields anti-(1-aminoalkyl) cyclopropanes as the major isomers. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-967988

LETTER
259
Highly Diastereoselective Addition of Phenyllithium on cis-Substituted
C-Cyclopropylaldimines
D
iastereoselective
a
A
ddition
o
m
f
Phenyllithium on
c
i
is
-
Sub
e
C
-C
n
yclopropylaldimin
B
es elotti, Nadim Noujeim, Janine Cossy*
Laboratoire de Chimie Organique associé au CNRS, ESPCI, 10 Rue Vauquelin, 75231 Paris Cedex 05, France
E-mail: janine.cossy@espci.fr
Received 19 September 2006
H–
R
Cl
R
Cl
Abstract: The addition of phenyllithium to cis-substituted C-cyclo-
propylaldimines produces in high diastereoselectivity and in good
yields anti-(1-aminoalkyl)cyclopropanes as the major isomers.
Ar
Ar
(1)
(2)
H
H
NR1
NHR1
B
A
C
Key words: cyclopropylaldimines, (1-aminoalkyl)cyclopropanes,
phenyllithium
R3MgBr
MgBr2
Ph
R1
H
H
Ph
R1
O–
R2
R3
N+
N
D
The stereochemical course of the addition of nucleophiles
to acyclic a-chiral aldehydes and imines has been ex-
tensively studied and predictions can be made on the basis
of the Felkin–Anh and Cram chelate model. In general,
selectivities obtained by Felkin–Anh control are moderate
while high selectivities are observed if a chelation oc-
curs.1 The addition of nucleophiles to cyclopropylketones
or cyclopropanecarboxaldehydes has found considerable
attention but only a few cases have been reported to
proceed with high diastereoselectivity.2 As (1-amino-
alkyl)cyclopropanes can be used as potent NMDA re-
ceptor antagonists,3 it is of interest to develop highly
diastereoselective methods for obtaining these products
from simple starting materials. Recently, (1-amino-
alkyl)cyclopropanes of type B were obtained by reduction
of imidoylcyclopropanes of type A but, the reduction was
not stereoselective4 [Scheme 1, (1)]. (1-Aminoalkyl)cy-
clopropanes were also synthesized by stereoselective
addition of Grignard reagents to cis-substituted C-cyclo-
propylaldonitrones of type C in the presence of a Lewis
acid.5 However, a reduction step is necessary to transform
the obtained anti-(1-hydroxylaminoalkyl)cyclopropanes
of type D to the desired (1-aminoalkyl)cyclopropanes of
type E [Scheme 1, (2)].
R2
HO
Zn
AcOH
H
Ph
R1
R3
R2
N
H
E
Scheme 1
H2NR2
H
R1O
F
H
H
H
N
H
H
R1O
THF–Et2O
r.t.
O
R2
G
RLi
Et2O
0 °C to r.t.
H
H
R
R1O
N
H
R2
H
R = alkyl, Ph
Here, we would like to report an efficient, direct and high-
ly diastereoselective synthesis of cis-substituted (1-ami-
nobenzyl)cyclopropanes of type H (R = Ph) from cis-
substituted C-cyclopropylaldimines of type G by using
phenyllithium (PhLi) without any additives (Scheme 2).
Scheme 2
MeLi, n-BuLi, s-BuLi as well as aryllithium such as PhLi
in Et2O at 0 °C in order to obtain substituted cyclopro-
panes of type H7 (Scheme 2). At first, compound 1 was
treated with MeLi, n-BuLi and s-BuLi. By using these
alkyllithium reagents in Et2O, from 0 °C to room temper-
ature, a complex mixture of products was obtained and the
expected substituted cyclopropanes of type H were only
detected by GC-MS.
The cyclopropylaldimines of type G were prepared from
the corresponding cyclopropanecarboxaldehydes of type
F6 by treatment with primary amines in a mixture of dry
Et2O–THF (5:1) overnight at room temperature. After
evaporation of the solvent, the cyclopropylaldimines of
type G were dried by azeotropic removal of water and
treated, without purification, with alkyllithium such as
As PhLi is more nucleophilic than alkyllithium reagents,
compounds 1 and 2 were treated with phenyllithium [2 M
in Bu2O (1.5 equiv)] in Et2O from 0 °C to room tempera-
ture. Under these conditions compound 1 was transformed
to 47 and 4¢ in a 98:2 ratio (87% overall yield starting from
SYNLETT 2007, No. 2, pp 0259–0262
0
1.
0
2.
2
0
0
7
Advanced online publication: 24.01.2007
DOI: 10.1055/s-2007-967988; Art ID: G25606ST
© Georg Thieme Verlag Stuttgart · New York

260
D. Belotti et al.
LETTER
Table 1 Reaction of Compounds 1–3 with PhLi/Bu2O
H
4
H
1
H
H
H
H
PhLi
H
Ph
Ph
R1O
2
3
R1O
R1O
Et2O
0 °C to r.t.
NR2
NHR2
NHR2
1–3
anti-4–6
syn-4'–6'
Entry
Starting material
R1, R2
anti:syn
Yield syn + anti (%)
1
2
3
R1 = Bn, R2 = p-Tol
1
4/4¢ (98:2)
5/5¢ (98:2)
6/6¢ (97:3)
87
71
72
R1 = Me, R2 = i-Pr
2
R1 = Bn, R2 = i-Pr
3
the aldehyde), in favor of the anti-isomer 4. Furthermore, was decreased relative to that observed previously as,
the addition of phenyllithium to 2 (R1 = methyl) occurred compounds 21/21¢ were obtained from 17 in a ratio of
stereoselectively to give compound 5 and 5¢ (71% yield) 90:10 and 22/22¢ were obtained from 18 in a 75:25 ratio.
in a 98:2 ratio in favor of the anti-compound 5. The ste- Compounds 23/23¢ were formed in a ratio of 89:11 when
reoselectivity does not depend on the alkoxy group at C4 19, which possess a sterically hindered group (R1 = t-Bu),
as the treatment of 3 (R1 = Bn) with PhLi led to 6 and 6¢ was treated with PhLi. It is worth noting that 24/24¢ were
in 72% yield in a 97:3 ratio always in favor of the anti-iso- obtained in a 50:50 anti/syn ratio from the cyclopropyl-
mer, the (1-aminobenzyl)cyclopropane 6 (Table 1).
aldimine 20, substituted by the sterically less hindered
n-propyl group. The diastereoselectivity of the addition of
PhLi to cyclopropylaldimines of type G seems sensitive to
steric hindrance (Table 3).
The reaction is general and the anti-(1-aminobenzyl)cy-
clopropanes 12–16 were obtained, as the major isomers,
from the corresponding cyclopropylaldimines derivatives
7–11. The anti/syn-(1-aminobenzyl)cyclopropanes were In order to establish the relative stereochemistry between
formed in a ratio of 98:2 in favor of the anti-products in the amino group and the cyclopropane, the bicyclo[3.1.0]
moderate to good yields (45–96%), whatever the amino compounds 25 and 25¢ were synthesized from compounds
substituent. The results are reported in Table 2.
22 (anti, major) and 22¢ (syn, minor), respectively. After
separation of 22 and 22¢, treatment of these compounds
with TBAF (THF, r.t.) and oxidation using PDC (CH2Cl2,
r.t.), 25 (69% for the 2 steps) and 25¢ (53% for the 2 steps)
were isolated, respectively. Based on previous results,4,8
As the stereoselectivity may be due to either a chelating
effect of the OR group present at C4 or to steric hindrance,
compounds 17–20 were synthesized and treated with
PhLi. The results are reported in Table 3. When the addi-
tion of PhLi to compounds 17 and 18 possessing a tert-
butyl-dimethylsilyloxy was achieved, the anti/syn ratio
1
and by analyzing the H NMR spectrum of 25 and 25¢,
we found that a coupling constant JH4–H5 = 1 Hz for 25
Table 2 Reaction of Compounds 7–11 with PhLi/Bu2O
H
H
H
H
H
H
PhLi/Bu2O
H
Ph
Ph
MeO
MeO
MeO
Et2O
NR2
NHR2
NHR2
0 °C to r.t.
7–11
anti-12–16
syn-12'–16'
Entry
Starting material
R2
anti:syn
Yield syn + anti (%)
1
2
3
4
5
R2 = p-Tol
7
12/12¢ (98:2)
13/13¢ (98:2)
14/14¢ (98:2)
15/15¢ (98:2)
16/16¢ (98:2)
96
61
80
45
45
R2 = Bn
8
R2 = Cy
9
R2 = n-Pr
10
R2 = t-Bu
11
Synlett 2007, No. 2, 259–262 © Thieme Stuttgart · New York

LETTER
Diastereoselective Addition of Phenyllithium on cis-Substituted C-Cyclopropylaldimines
261
Table 3 Reaction of Compounds 17–20 with PhLi/Bu2O
H
H
H
H
H
H
PhLi/Bu2O
H
Ph
Ph
R1
R1
syn-21'–24'
R1
anti-21–24
Et2O
NR2
NHR2
NHR2
0 °C to r.t.
17–20
Entry
Starting material
R1, R2
(Aminoalkyl)cyclopropane
anti:syn
Yield syn + anti (%)
1
2
3
4
R1 = CH2OTBDMS, R2 = p-Tol
17
21/21¢ (90:10)
22/22¢ (75:25)
23/23¢ (89:11)
24/24¢ (50:50)
90
90
97
90
R1 = CH2OTBDMS, R2 = Bn
18
R1 = t-Bu, R2 = p-Tol
19
R1 = n-Pr, R2 = p-Tol
20
one, the imine group is oriented in the cyclopropyl moiety
which increases the steric hindrance. The stereochemical
outcome of the reaction could then be understood by the
attack of the PhLi on the less hindered face of the stereo-
electronically stabilized bisected s-trans-conformer I
(Scheme 5). When the alkoxy group at C4 can chelate the
organometallic, the addition of phenyllithium to cyclopro-
pylaldimines is highly stereoselective and led also to the
anti-(1-aminobenzyl)cyclopropanes via intermediate K
(Scheme 5).
H
H5
H4
Ph
H
H
1) TBAF, THF
Ph
TBDMSO
2) PDC, CH2Cl2
O
N
NHBn
69%
J = 1 Hz
22
Bn
(major diastereomer)
25
H
H5
H
H
1) TBAF, THF
H4
Ph
Ph
TBDMSO
2) PDC, CH2Cl2
53%
O
N
NHBn
J = 6 Hz
Bn
22'
(minor diastereomer)
25'
STERIC HINDRANCE
R2
Scheme 3
H
R1
H
PhLi
N
R1
H
and JH4–H5 = 6 Hz for 25¢. These values allowed us to
determine that the major compound was the anti-isomer
(Scheme 3).
N
R2
H
s-cis J
s-trans I
We were also able to transform compound 21 to 4 in 2
steps (TBAF, THF, r.t.; then NaH, PhCH2Br, THF, r.t.)
and this compound corresponds to the major isomer which
was obtained from the addition of PhLi to 1 (Scheme 4).
Thus, whatever the protecting group of the hydroxy group
present at C4, in the C-cyclopropylaldimines of type G,
with chelating or non-chelating properties, the anti-(1-
aminophenyl)cyclopropanes were always obtained as the
major isomers.
PhLi
PhLi
H
H
H
H
Ph
NHR2
Ph
R1
R1
NHR2
syn
anti
CHELATION
H
H
O
PhLi
H
H
Ph
H
H
H
H
1) TBAF, THF
R1
NHR2
Ph
OR1
anti
Ph
Li
N
BnO
TBDMSO
2) NaH, PhCH2Br
THF, r.t.
R2
NHp-Tol
NHp-Tol
K
21
4
39%
(major diastereomer)
Scheme 5
Scheme 4
We have shown that cis-substituted (1-aminobenzyl)cy-
clopropanes can be obtained with high diastereoselec-
tivity from cis-substituted C-cyclopropylaldimines by
addition of PhLi and that chelation effects have more
influence on the diastereoselectivity of the addition of
PhLi than steric effects.
The addition of phenyllithium to cyclopropylaldimines of
type G was highly stereoselective and led to the anti-(1-
aminobenzyl)cyclopropanes. Based on previous results5
of the two possibilities, the s-trans-conformation I is pre-
ferred to the s-cis-conformation J, because in the latter
Synlett 2007, No. 2, 259–262 © Thieme Stuttgart · New York

262
D. Belotti et al.
LETTER
(7) Synthesis of 4 as Representative Procedure.
References and Notes
All the reactions were performed under an argon
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(6) Cyclopropanecarboxaldehydes of type F have been
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alcohols, which have to be prepared by Simmons–Smith–
Furukawa cyclopropanation9 of the corresponding cis-
alkenes.
atmosphere. To a stirred solution of cis-2-benzyloxymethyl-
cyclopropanecarboxaldehyde (0.38 g, 2 mmol) in a 5:1
mixture of dry Et2O (20 mL) and dry THF (4 mL), was added
p-toluidine (0.214 g, 2 mmol). The resulting solution was
stirred at r.t. for 4 h. The solvents were removed in vacuo and
the residue was dried by azeotropic evaporation to give the
pure crude imine 1 which was solubilized in dry Et2O (15
mL). To this solution, stirred at 0 °C, was added PhLi (2 M
in Bu2O, 1.5 mL, 3 mmol). The resulting light brown
solution was stirred from 0 °C to r.t. overnight and then
diluted carefully with H2O (20 mL). The organic layer was
separated and the aqueous layer was extracted with CH2Cl2
(2 × 30 mL). The combined organic layers were dried over
MgSO4 and filtered. The solvents were removed in vacuo
and the residue, which was mainly constituted by one
diastereomer (GC-MS analysis showed a ratio anti/syn >
98:2), was purified by flash column chromatography on
silica gel (90:10 PE–EtOAc) to provide anti-(1-amino-
benzyl)cyclopropane 4 as a yellow oil (0.615 g, 86% yield).
IR: 3367 (br), 1615, 1516, 1071, 809, 735, 697 cm–1.
1H NMR (CDCl3): d = 7.50–7.20 (10 H), 6.82 (d, J = 8.3 Hz,
2 H), 6.30 (m, 2 H), 4.78 (br s, 1 H), 4.43 (s, 2 H), 3.80 (dd,
J = 10.2, 5.2 Hz, 1 H), 3.65 (d, J = 9.8 Hz, 1 H), 3.27 (t, J =
10.2 Hz, 1 H), 2.17 (s, 3 H), 1.45–1.20 (2 H), 0.82 (m, 1 H),
0.48 (m, 1 H). 13C NMR (CDCl3): d = 145.9 (C), 144.6 (C),
138.1 (C), 129.3 (2 CH), 128.7 (2 CH), 128.4 (2 CH), 127.8
(2 CH), 127.6 (CH), 126.9 (CH), 126.5 (C), 126.1 (2 CH),
114.2 (2 CH), 73.3 (CH2), 70.2 (CH2), 60.5 (CH), 26.1 (CH),
20.4 (CH3), 17.1 (CH), 9.0 (CH2). MS (EI): m/z (rel. int.) =
357 (10) [M+], 196 (10), 129 (10), 107 (55), 91 (100).
(8) Benkouider, A.; Bouqaunt, J.; Pale, P. New J. Chem. 2001,
25, 676.
(9) Denmark, S. E.; Edwards, J. P. J. Org. Chem. 1991, 56,
6974.
Synlett 2007, No. 2, 259–262 © Thieme Stuttgart · New York

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