Arenesulfinamides as new reagents for the synthesis of allylic sulfoxides

Article abstract of DOI:10.1055/s-2004-820054

Reaction of arenesulfinamides with alkenes bearing allylic hydrogens in the presence of Yb(OTf)₃/TMSC1 led to the corresponding allylic sulfoxides in good yields.

Full text of DOI:10.1055/s-2004-820054

LETTER
995
Arenesulfinamides as New Reagents for the Synthesis of Allylic Sulfoxides
Arenesulfinamides
as
N
a
ewReage
t
e
the Synthe
s
o
is of
A
llylic Sulfox
A
ides lajarín,* Aurelia Pastor,* José Cabrera
Departamento de Química Orgánica, Facultad de Química, Universidad de Murcia, Campus de Espinardo, 30100 Murcia, Spain
Fax +34(968)364149; E-mail: alajarin@um.es
Received 12 February 2004
∆, SnCl4
or TiCl4
Ph
Ar
Abstract: Reaction of arenesulfinamides with alkenes bearing
allylic hydrogens in the presence of Yb(OTf)3/TMSCl led to the
corresponding allylic sulfoxides in good yields.
H
N
Tol-p
O
S
Tol-p
S
N
O
Ph
Key word: alkenes, sulfinamides, lanthanides, regioselectivity,
sulfoxides
2
+
Ar
1
Yb(OTf)3
TMSCl
/
Ph
(Ar = 4-NO2C6H4)
Tol-p
A growing number of organosulfur compounds are widely
used reagents in organic synthesis.1 In particular, N-
sulfinimines are versatile intermediates especially for the
preparation of amine derivatives. They display unique
reactivity and the presence of the chiral electron with-
drawing sulfinyl group makes possible to control addition
reactions to the C-N double bond in a highly diastereo-
selective manner. Besides, N-sulfinimines can be easily
prepared in enantiopure form and are stable and isolable.2
Browsing through the reported chemistry of this species
we were drawn to the fact that the use of sulfinimines in
imino ene reactions, one of the most attractive methodol-
ogies for the functionalization of olefins,3 has not been ex-
ploited to date. The only work along these lines dates back
one year, in which F. A. Davis and co-workers4 reported
the reaction of N-sulfinyl imino esters with allyl benzene.
In this case they isolated an unexpected isothiazolidine-
carboxylate. To explain the formation of this heterocycle
the authors speculated on the possibility of an imino ene
reaction followed by cyclization of the corresponding g,d-
unsaturated a-amino ester intermediate, but the mecha-
nism of this reaction remains unknown. For these reasons,
we decided to investigate the behavior of sulfinimines 1 as
iminoenophiles.
S
O
3a
Scheme 1 The treatment of a-methyl styrene with the sulfinimine 1
under Lewis acid catalysis led to the allylic sulfoxide 3a as the only
reaction product
4a and a-methyl styrene takes place by the attachment of
the sulfoxide functionality to the less substituted carbon
atom of the C-C double bond, with the removal of one
hydrogen atom from the allylic position of the alkene,
probably in an NH3 molecule.
Aryl allyl sulfoxides such as 3a are versatile and valuable
building blocks in organic synthesis6 which proved their
remarkable synthetic utility in the syntheses of a variety of
functionalized compounds7 and natural products.8 Hence,
efficient and convenient methods for their preparation are
still in demand and a challenging goal. A careful literature
survey reveals that the main approach to allylic sulfoxides
is the oxidation of allylic sulfides with electrophilic oxi-
dants which features serious drawbacks as the lack of
chemoselectivity.9 Snider10 and Moissenkov11 have both
reported synthetic methodologies for the preparation of
allylic sulfoxides by reacting alkenes with sulfinyl chlo-
rides in the presence of EtAlCl2 and ZnCl2, respectively.
Nevertheless, these methodologies are rather less conve-
nient due to the use of the highly moisture sensitive sulfi-
nyl halides12 as starting materials. On the contrary,
arenesulfinamides 4 are very stable and isolable com-
pounds.13 Therefore, we focused our attention on the use
of this new reaction as a potentially valuable process for
the synthesis of aryl allyl sulfoxides.
Unfortunately, the reaction of sulfinimine 1 with a-methyl
styrene under thermal conditions or in the presence of the
classical Lewis acids for catalyzing ene reactions (SnCl4
and TiCl4) led to complex mixtures of products where the
imino ene adduct 2 was not detected (Scheme 1). Unex-
pectedly, when the reaction was accomplished in the pres-
ence of a mixture of Yb(OTf)3 and TMSCl,5 the allylic
sulfoxide 3a was isolated in 32% yield. The formation of
3a was rationalized in terms of the reaction of the alkene
with the sulfinamide 4a (Equation 1), which could be
formed in situ by hydrolysis of 1 under the reaction con-
ditions. This hypothesis was independently proved by re-
acting 4a and a-methyl styrene in the presence of the same
catalytic system. The formation of the sulfoxide 3a from
To optimize the synthesis of 3a, sulfinamide 4a was react-
ed with a-methyl styrene under different reaction condi-
tions (solvent, temperature and Lewis acid) (Equation 1,
Table 1).
First, the reaction was conducted without Lewis acid at
room temperature or under heating but the unchanged
starting materials or a complex mixture of products were
obtained respectively (Table 1; entries 1 and 2). Lewis
acids such as TiCl4, SnCl4 or ZnCl2 only led to complex
SYNLETT 2004, No. 6, pp 0995–0998
0
6.
0
5.
2
0
0
4
Advanced online publication: 25.03.2004
DOI: 10.1055/s-2004-820054; Art ID: D03604ST
© Georg Thieme Verlag Stuttgart · New York

996
M. Alajarín et al.
LETTER
Ph
O
Ar
Ph
∆ or LA
S
H2N
Tol-p
H
+
Tol-p
S
O
S
solvent, T
[– NH3]
Yb(OTf)3 / TMSCl
CH2Cl2, 20 °C
S
O
+
H2N
Ar
O
4a
3
3a
4a (Ar = p-Tol)
4b (Ar = Ph)
Equation 1 The reaction of a-methyl styrene with the sulfinamide
4a was tested under different reaction conditions
Equation 2 The reaction of alkenes bearing allylic hydrogen atoms
with the sulfinamides 4 yielded the corresponding sulfoxides 3 (see
Table 2)
mixtures of products or to 3a but in low yields (entries 3–
5). The best results were obtained for the catalytic system
Yb(OTf)3/TMSCl, in particular, when the reaction was
conducted in CH2Cl2 at room temperature and 0.5 equiv-
alents and 1 equivalent of both reagents were used,
respectively (entry 10). In this case, the sulfoxide 3a was
obtained in excellent yield (90%). Other stoichiometries,
solvents or temperatures also provided 3a although in
significantly lower yields (entries 6–9). The presence of
TMSCl turned to be essential as the yield of the final prod-
uct dropped to 33% when the reaction was conducted
without this additive (entry 11). Finally, TMSOTf was
also a good Lewis acid (entry 12) although not so efficient
as Yb(OTf)3/TMSCl.
of alkenes. As it is shown in Table 2 this process is highly
regioselective since the sulfoxide functionality is always
introduced at the less substituted carbon atom of the orig-
inal alkene C-C double bond.
The E/Z-stereoselectivity was poor (Table 2; entries 4 and
5). Besides, when different types of allylic protons are
available (entries 5 and 6) the reaction led to mixtures of
regioisomeric allylic sulfoxides (3e–3e¢, 3f–3f¢).
Nevertheless, highly site- and regioselective terminal
functionalization of acyclic monoterpenes was carried out
by using this new methodology (Table 2; entries 8–10).
Thus, their treatment with sulfinamide 4b under our stan-
dard conditions afforded the allylic sulfoxides 3h–j in
good yields. When more than one C-C double bond was
present the more electron-rich terminal isopropylidene
group was always preferably functionalized over the other
olefinic portions (entries 9, 10). The potential usefulness
of terminally functionalized olefins of this type has re-
ceived much attention from the viewpoint of C-C bond
formation with highly geometric and positional control.15
Table 1 Reaction Conditions and Yields for 3a
Entry Solvent T (°C) Lewis acid (equiv)
Yield 3a
(%)a
1
2
CHCl3
20
–
0b
0c
Toluene Reflux
CH2Cl2 20
–
3
TiCl4 (1)
0c
Taking into account the potential stereogenic nature of the
sulfur atom in sulfoxides, poor diastereoselectivities were
generally achieved in those cases where more than one
diastereomer could be obtained (Table 2; entries 6–10)
with the exception of 3g (entry 7), for which a dr of 94:6
was measured and the R,R/S,S-diastereomer was the
major component.16 Although the formation of the two
diastereomers are expected also in this case, they can
interconvert through a [2,3]-sigmatropic sulfoxide/
sulfenate rearrangement (Mislow–Braverman–Evans re-
arrangement; Scheme 2).17 As it has been previously
described this equilibrium is shifted towards the more
stable R,R/S,S-diastereoisomer as the aryl group is away
from the cyclohexene ring (‘exo’) in the transition state of
the rearrangement leading to it.16
4
Toluene Reflux SnCl4 (2)
19
30
67
58
81
23
5
CH2Cl2 Reflux ZnCl2 (1)
6
Toluene Reflux Yb(OTf)3 (1)/TMSCl (1)
Toluene Reflux Yb(OTf)3 (0.5)/TMSCl (1)
7
8
Toluene 20
CH2Cl2 20
CH2Cl2 20
Yb(OTf)3 (0.5)/TMSCl (1)
Yb(OTf)3 (0.1)/TMSCl (1)
9
10
11
12
Yb(OTf)3 (0.5)/TMSCl (1) 90
Toluene Reflux Yb(OTf)3 (1)
CH2Cl2 20 TMSOTf (1)
33
67
a After chromatography (%).
b No conversion.
c Complex mixture of products.
Tol-p
p-Tol
S
S
O
O
The generality of this procedure was tested by reacting a
series of relatively simple alkenes bearing allylic protons
with the two sulfinamides 4a and 4b under our standard
reaction conditions (Equation 2).14 The results are com-
piled in Table 2 (entries 1–7) and reveal that the reaction
is quite versatile, proceeding in good yields with a variety
OSTol-p
(R,R/S,S)-3g
(S,R/R,S)-3g
Scheme 2 The interconversion equilibrium between the two dia-
stereomers takes place through a sulfenate intermediate and it is
shifted to the R,R/S,S one
Synlett 2004, No. 6, 995–998 © Thieme Stuttgart · New York

LETTER
Arenesulfinamides as New Reagents for the Synthesis of Allylic Sulfoxides
997
Table 2 Yields, Regio- and Diastereomeric Ratio of Allylic Sulfoxides 3
Entry
1
Alkene
Sulfinamide 4 Allylic sulfoxide 3
Yield of 3 (%)a
4a
90
Ph
Ph
SOTol-p
3a
3b
2
3
4a
4a
79
60
SOTol-p
SOTol-p
3c
4
5
4a
4a
18
Ph
SOTol-p
SOTol-p
Ph
Ph
(E)-3d:(Z)-3d
56:44
(E)-3d
(E)-3e
3f
(Z)-3d
93
SOTol-p
SOTol-p
(E)-3e:(Z)-3e:3e¢
34:20:46
p-TolOS
3e¢
(Z)-3e
6
4a
79
3f:3f¢
85:15
dr 3f
68:32
dr 3f¢
73:27
SOTol-p
SOTol-p
3f¢
7
8
4a
4b
31
SOTol-p
dr
94:6b
3g
75
dr
25:25:25:25c
SO
SO
SO
Ph
CN
CN
3h
9
4b
4b
62
dr
59:41
OAc
Ph
OAc
3i
10
63
dr
59:41
Ph
AcO
OAc
3j
a The regio- and diastereoisomeric ratios were calculated after chromatography by integration of characteristic signals in the corresponding 1H
NMR spectra; error 5% of the stated value.
b Configuration of the major diastereoisomer (R,R/S,S; see ref.16).
c The diastereomeric ratio was approximately determined due to the overlapping of all the signals.
The chemistry of sulfinamides has not been thoroughly in- action with b-pinene gave a complex mixture of products
vestigated. However, it is well-known that they react with suggests the intermediacy of a carbenium ion intermedi-
nucleophiles at the sulfur atom.13 In this case, the electro- ate.
philicity of the sulfinamide is enhanced by activation
In summary, here we disclose the preparation of aryl allyl
through coordination with the catalytic system Yb(OTf)3/
sulfoxides from alkenes and sulfinamides in the presence
TMSCl favoring the attack of the nucleophilic alkene. Al-
of the catalytic system Yb(OTf)3/TMSCl. The main ad-
though the mechanism of the reaction remains unknown,
vantage of the present methodology compared to those
the regiochemistry of the reaction and the fact that the re-
Synlett 2004, No. 6, 995–998 © Thieme Stuttgart · New York

998
M. Alajarín et al.
LETTER
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previously reported is the use of easily available and sta-
ble sulfinylating reagents, N-unsubstituted sulfinamides
4, for which no applications in C-S bond forming reac-
tions have been reported before.
Acknowledgment
This work was supported by MCYT-FEDER (Project BQU2001-
0010) and Fundación Séneca-CARM (Project PI-1/00749/FS/01).
A. P. thanks to the European Comission for a Marie Curie fel-
lowship (contract HPMF-CT-1999-00126). J. C. is grateful to the
Ministerio de Educación, Cultura y Deporte of Spain for a predoc-
toral fellowship. Finally, we thank Acedesa-Takasago (El Palmar,
Spain) for a generous gift of the monoterpenes.
References
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chlorides with NH3, see: (a) Andersen, K. K. In
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(14) Typical Procedure for the Synthesis of Allylic Sulfoxides
3: To a solution of p-toluenesulfinamide 1a (0.15 g; 0.966
mmol) in dry CH2Cl2 (20 mL), Yb(OTf)3 (0.30 g; 0.483
mmol), a-methyl styrene (0.34 g; 2.899 mmol) and TMSCl
(0.11 g; 0.966 mmol) were sequentially added. After the
addition, the reaction mixture was stirred at r.t. for 16 h. The
inorganic salts were removed by filtration and the filtrate
was collected. The solvent was evaporated to dryness and
the residue purified by silica gel chromatography eluting
with 1:3 to 1:1 EtOAc–hexanes. An analytically pure sample
was obtained by recrystallization from Et2O/n-pentane
(white prisms). Yield (0.22 g, 90%); mp 63–65 °C. IR (neat):
1620, 1597, 1494, 1085, 1045, 810, 778, 701 cm–1. 1H NMR
(200 MHz, CDCl3): d = 2.38 (s, 3 H, CH3), 3.82 (d, 1 H,
2J = 12.7 Hz, CH2SO), 4.07 (d, 1 H, 2J = 12.7 Hz, CH2SO),
5.09 (s, 1 H, = CH2), 5.53 (s, 1 H, = CH2), 7.23–7.49 (m, 9
H, aromatics). 13C {1H} NMR (50 MHz, CDCl3): d = 21.3
(q), 64.7 (t), 119.7 (t), 124.3 (2 × d), 126.0 (2 × d), 128.0 (d),
128.4 (2 × d), 129.5 (2 × d), 137.5 (s), 138.9 (s), 140.2 (s),
141.6 (s). Anal. Calcd for C16H16SO: C, 74.96; H, 6.29; S,
12.51. Found: C, 74.72; H, 6.47; S, 12.20.
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Synlett 2004, No. 6, 995–998 © Thieme Stuttgart · New York