Highly stereoselective reactions of γ-sulfinyl carbanions with achiral imines

Article abstract of DOI:10.1080/10426500590910800

Lithium 2-p-tolylsulfinylbenzyl carbanions react with different N-substituted imines affording 1,2-diaryl ethyl (and propyl) amines with a high stereoselectivity control at both benzyllic (only dependent of the sulfur configuration) and iminic carbons. The anti:syn ratio, ranging between >96:<4 and <2:>98, dependent on the electronic density at nitrogen. Copyright Taylor & Francis Inc.

Full text of DOI:10.1080/10426500590910800

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Highly Stereoselective
Reactions of γ-Sulfinyl
Carbanions with Achiral Imines
José Luis García Ruano a , José Alemán a & Alejandro
Parra a
a Departamento de Química Orgánica, Universidad
Autónoma de Madrid, Cantoblanco, Madrid, Spain
Version of record first published: 16 Aug 2006
To cite this article: José Luis García Ruano, José Alemán & Alejandro Parra (2005):
Highly Stereoselective Reactions of γ-Sulfinyl Carbanions with Achiral Imines,
Phosphorus, Sulfur, and Silicon and the Related Elements, 180:5-6, 1209-1215
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Phosphorus, Sulfur, and Silicon, 180:1209–1215, 2005
Copyright © Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500590910800
Highly Stereoselective Reactions of γ-Sulfinyl
Carbanions with Achiral Imines
´
´
Jose Luis Garcıa Ruano
´
´
Jose Aleman
Alejandro Parra
Departamento de Qu´ımica Orga´nica, Universidad Auto´noma de Madrid,
Cantoblanco, Madrid, Spain
Lithium 2-p-tolylsulfinylbenzyl carbanions react with different N-substituted
imines affording 1,2-diaryl ethyl (and propyl) amines with a high stereoselectiv-
ity control at both benzyllic (only dependent of the sulfur configuration) and iminic
carbons. The anti:syn ratio, ranging between >96:<4 and <2:>98, dependent on
the electronic density at nitrogen.
Keywords 1,4- and 1,5-Asymmetric induction; asymmetric benzylation; remote stereo-
control with sulfoxides
INTRODUCTION
There are a large number of recent publications involved in the search
for new and efficient methods for synthesizing enantiomerically pure
2-arylethyl and propylamines. They are relevant structural subunits
because of their frequent occurrence in natural products and their im-
portance as valuable synthetic intermediates.1 Otherwise enantiomer-
ically pure β-amino alcohols are even more important as key interme-
diates for the synthesis of biologically active compounds,2 as stationary
phases in HPLC,3 and as chiral ligands or auxiliaries in asymmetric
reactions.4 Interestingly, the C C bond disconnection represents the
most direct retrosynthetic route for simultaneously creating both chi-
ral centers. In this sense, the nucleophilic addition of organometallic
reagents to iminic C N double bonds5 is one of the most direct routes
Received July 9, 2004; accepted October 5, 2004.
We thank the Spanish Government for financial support (Grant BQU2003-04012).
J. A. thanks the Spanish Government for a predoctoral fellowship.
Address correspondence to Jose´ Alema´n, Departamento de Qu´ımica Orga´nica, Uni-
versidad Auto´noma de Madrid, Cantoblanco, 28049 Madrid, Spain. E-mail: jose.aleman@
uam.es
1209

1210
J. L. Garc´ıa Ruano et al.
to chiral amine derivatives. Thus the use of the N-sulfinylimines as
starting compounds has been shown to be highly efficient in the
asymmetric addition of organometallic reagents, except for benzylic
nucleophiles.6 In this communication we describe different procedures
to achieve the benzylation of C N in a completely stereocontrolled
manner.
RESULTS AND DISCUSSION
We first studied the benzylation of N-sulfinylimines by using the
enantiomerically pure benzylcarbanion derived from 2-p-tolylsulfinyl-
2-ethylbenzene (1a)7 as electrophile. Reactions were completely
stereoselective8 even when two new chiral centers are simultaneously
created in the formation of 2-arylethyl and propylamines (Scheme 1
and Table I).
TABLE I Yields and de Obtained
for Reactions at Scheme 1
R2
de
Yield (%)
Ph
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
81
78
74
72
89
71
77
68
76
82
84
60
85
88
89
88
75
87
p-MeOC6H4
p-CNC6H4
Bu
i-Bu
o-BrC6H4
2-Py
Napht
p-CIC6H4
Ph
p-MeOC6H4
p-CNC6H4
Bu
i-Bu
t-Bu
PhCH2
Naph
o-BrC6H4
SCHEME 1

γ -Sulfinyl Carbanion Reactions
1211
Starting from benzylcarbanions derived from 2-p-tolylsulfinyl ben-
zyl alcohol (1b), we could also prepare the anti 1,2-aminoalcohols
(Scheme 1), making use of the same procedure.9 Desulfinylation with
Raney–Nickel afforded the corresponding free amines.
Both reactions are good examples of double asymmetric induction
processes with the sulfinyl group acting as a chiral inductor at both
electrophile and nucleophile, each one controlling the configuration of
their closer chiral center. The matched pairs (formed by compounds
with S configuration) yield the anti compounds with diastereomeric
excess (de) >98% and very high yields. The reactions are efficient from
aliphatic and aromatic aldimines (Scheme 1).
The next step in this research was the study of the reactions of 1a
with N-p-tolylsulfinylketimines (4). The results indicate that the stere-
oselectivity is also completely controlled in most of the cases, yielding
the anti compounds 5 (Scheme 2 and Table II). However, the reaction
with the N-p-tolylsulfinyl methyl p-cyanophenylidenimine (4e) evolves
into a 75:25 mixture of anti-5e and syn-5e, thus evidencing a significant
influence of the electronic density on the stereoselectivity control.
SCHEME 2
These results prompted us to study the behavior of the anions de-
rived from 1a and 1b with achiral imines. Our aim was to explore
the influence of the steric and electronic factors at the electrophile on
the stereochemical course of the reaction and eventually obtain the
TABLE II Results Obtained for
Reaction at Scheme 2
R2
dr (anti:syn)
Yield (%)
Ph
>99:1<
>99:1<
>99:1<
75:25
No reaction
No reaction
73
64
69
27
—
—
p-MeOC6H4
p-MeC6H4
p-CNC6H4
n-Bu
i-Bu

1212
J. L. Garc´ıa Ruano et al.
TABLE III Structure of the Studied N-Benzylidenanilines
1
2
==
(Ar -CH N-Ar )
Imine
Ar1
Ar2
Imine
Ar1
Ar2
6a
6b
6c
6d
6e
6f
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
6i
6j
6k
6l
6m
6n
6o
p-CN-C6H4
p-Me-C6H4
p-MeO-C6H4
3,4-di-MeO-C6H4
2,4-di-MeO-C6H4
2,4,6-tri-MeO-C6H4
p-MeO-C6H4
Ph
Ph
Ph
Ph
Ph
Ph
p-CN-C6H4
p-Cl-C6H4
p-Me-C6H4
p-MeO-C6H4
3,4-di-MeO-C6H4
2,4-di-MeO-C6H4
2,4,6-tri-MeO-C6H4
6g
6h
p-MeO-C6H4
syn-compounds by modulating their features. It would make the
reaction stereodivergent and much more versatile from a synthetic
point of view.
We first synthesized the N-benzylidenaniline 6a and their deriva-
tives 6b–o (Table III) containing electron-withdrawing and electron-
donating groups at the two phenyl rings, by reacting substituted ani-
lines with benzaldehydes under the presence of molecular shieves.
The reaction of 1a with the imine 6a yielded a 91:9 epimeric mix-
ture of anti-7a and syn-7a, both exhibiting the same configuration at
benzylic carbon (Scheme 3). It demonstrates that this is completely
controlled by the sulfinyl group at 1a, which also has a significant in-
fluence on the configuration induced at the nitrogenated center. Both
compounds can be easily obtained in an optically pure form after chro-
matographic purification.
SCHEME 3
At this point we evaluated the influence of the substituent at the N-
aryl group. Electron-withdrawing substituents increased the anti/syn
relationship whereas electron-donating groups decreased and even in-
verted it. The reaction of 1 with 6h is completely stereoselective, only
yielding compound syn-7h (Scheme 4 and Table IV).
A similar influence is exerted by the substituent when they are
located at the aromatic ring of the arylideneimine (Scheme 5 and
Table V), except for 6n, where the presence of two MeO groups at both

γ -Sulfinyl Carbanion Reactions
1213
TABLE IV Results Obtained for
Reaction at Scheme 4
6
anti-7b,h
syn-7b,h
6b(p-CN)
6c(p-Cl)
6d(p-Me)
6e(p-MeO)
6f(3,4-di-MeO)
6g(2,4-di-MeO)
6h(2,4,6-tri-MeO)
96
85
66
36
23
1
4
15
33
64
77
99
99
1
TABLE V Results Obtained for
Reaction at Scheme 5
6
anti-7i,n
syn-7i,n
6i(p-CN)
6j(p-Me)
6k(p-MeO)
6l(3,4-di-MeO)
6m(2,4-di-MeO)
6n(2,4,6-tri-MeO)
99
78
41
33
1
1
22
59
67
99
66
34
SCHEME 4
SCHEME 5

1214
J. L. Garc´ıa Ruano et al.
ortho positions has a negative influence on the stereoselectivity that
must be due to a steric inhibition of the resonance that is not present
when such groups are in the N-aryl ring (see 6h in Table IV).
To illustrate the scope of this powerful methodology, we have applied
it to the synthesis of the amine-alcohols starting from 1b. Its reaction
with the imine 6b yielded only the anti diastereoisomer 8, whereas
the syn-9 was exclusively formed in the reaction with the imine 6o,
with both aromatic rings substituted with electron donating groups
(Scheme 6).
SCHEME 6
As conclusion we have found that γ -sulfinyl carbanions derived from
2-p-tolylsulfinyl ethyl and hydroxymethyl benzenes are quite efficient
to control the stereoselectivity of the reactions with N-sulfinylimines,
yielding the corresponding anti derivatives. N-arylimines derived from
benzaldehydes yielded syn or anti isomers depending on the electronic
density at iminic nitrogen.10
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