p-Tolylsulfinyl Amides: Reagents for Facile Electrophilic Functionalization of Olefins

Article abstract of DOI:10.1021/jo035518a

A variety of olefins were found to react with sulfinyl amides in the presence of POCl₃ to give β-chlorosulfides and β-hydroxysulfides in good yields. In the absence of nucleophiles, p-tolylsulfinyl amides were found to react with olefins with the formation of allylsulfoxides.

Full text of DOI:10.1021/jo035518a

SCHEME 1
p-Tolylsu lfin yl Am id es: Rea gen ts for F a cile
Electr op h ilic F u n ction a liza tion of Olefin s
Larissa B. Krasnova and Andrei K. Yudin*
Davenport Building, Department of Chemistry,
University of Toronto, 80 St. George Street, Toronto,
Ontario, M5S 3H6, Canada
SCHEME 2
ayudin@chem.utoronto.ca
Received October 14, 2003
Abstr a ct: A variety of olefins were found to react with
sulfinyl amides in the presence of POCl3 to give â-chloro-
sulfides and â-hydroxysulfides in good yields. In the absence
of nucleophiles, p-tolylsulfinyl amides were found to react
with olefins with the formation of allylsulfoxides.
were found to react with phenylsulfinyl chloride in the
presence of SnCl4.6 An intramolecular version of the
sulfinyl chloride addition to the double bond was applied
by Eli Lilly in the synthesis of Cefaclor-cephalosporin
family of antibiotics.7
Sulfinyl amides are relatively stable compounds com-
pared to the other sulfur(IV) derivatives. We were
intrigued by the prospects of their application in olefin
functionalization. There appear to be no reported ex-
amples of reactions between unsaturated hydrocarbons
and sulfinyl amides. Our initial goal was to perform an
asymmetric version of the multicomponent ene reaction
between tolylsulfinyl amide, aldehyde, and R-methylsty-
rene, analogous to that reported for the tolylsulfonyl
amide (Scheme 1).8
However, when tolylsulfonyl amide was replaced by
p-tolylsulfinyl amide, no reaction was detected by TLC
after 1 h. After 48 h, the only isolated product was
allylsulfoxide 1 in a disappointing 25% yield. The alde-
hyde was not consumed in the reaction. In a control
experiment, the premade p-tolylsulfinyl phenyl imine did
not react under these conditions (Scheme 2), which
indicated to us that the low yield of sulfoxide 1 was not
the result of a background ene reaction.
The survey of reaction conditions is summarized in
Table 1. The reaction does not take place without Yb-
(OTf)3 (Table 1, entry 4). Although the role of TMSCl is
presently unclear, its absence substantially increases the
reaction time (Table 1, entry 5). The use of TMSOTf
instead of TMSCl does not influence the yield of the
process. Other Lewis acids such as TiF4, TiCl4, Ti(Oi-Pr)4,
and BF3‚Et2O were found to be inefficient in promoting
the addition.
The general utility of sulfur-containing substituents in
terms of subsequent elimination, reduction, and substitu-
tion makes them broadly applicable in organic synthesis.1
The compounds containing S(IV) centers possess an
additional feature of chirality at sulfur, which makes
them targets for stereoselective synthesis. Several pro-
tocols with a sulfinyl group as a chiral auxiliary have
been developed and utilized in the asymmetric synthesis
of biologically active compounds.2
Considerable efforts have been devoted to oxidation of
sulfides using catalytic amounts of metal complexes that
give sulfoxides in good yields and with high enantiomeric
excesses.3 Sulfoxides can also be obtained by direct
addition of the sulfinyl group to the double bond. For
instance, phenylsulfinyl chloride is known to add to
olefins with the formation of â-chlorosulfoxides.4 Despite
several literature precedents for this strategy, the chem-
istry remains underdeveloped mainly because of the low
stability of arenesulfinyl chlorides. These compounds are
air- and moisture-sensitive and are normally used di-
rectly upon preparation. Moreover, the reaction has fairly
limited scope: only aromatic olefins react with arene-
sulfinyl chlorides. It has been postulated that the sulfinyl
group reacts with olefins with the formation of a sulfoxo-
nium cation, stabilized by resonance effects at sulfur.1
Only a few examples of the electrophilic addition of
sulfinyl chlorides to olefins under Lewis acid activation5
are known. Electron-rich olefins such as silylated enols
(1) For the chemistry of the S(II) compounds: Gundermann, K. D.;
Humke, K. In Methoden Der Organischen Chemie (Houben-Weyl);
Klamann, D., Ed.; George Thieme Verlag Stuttgart: New York, 1985;
Bd. E11 T.1, pp 158-187. Chemistry of S(IV): Kresze, G. In Methoden
Der Organischen Chemie (Houben-Weyl); Klamann, D., Ed.; George
Thieme Verlag Stuttgart: New York, 1985; Bd. E11 T.1, pp 669-886.
Chemistry of S(VI): Schank, K. In Methoden Der Organischen Chemie
(Houben-Weyl); Klamann, D., Ed.; George Thieme Verlag Stuttgart:
New York, 1985; Bd. E11 T.2, pp 1129-1298.
To investigate the plausible mechanism, enantiomeri-
cally pure p-tolylsulfinyl amide was synthesized from (S)-
tolylsulfinyl menthyl ester according to the literature
(2) Polezshaeva, I. Russ. Chem. Rev. 2000, 69 (5), 367-408.
(3) Palucki, M.; Hanson, P.; J acobsen, E. N. Tetrahedron Lett. 1992,
33 (47), 7111-7114. Node, K.; Hosoya, N.; Iric, R.; Yamashita, Y.;
Katsuki, T. Tetrahedron 1994a , 50 (32), 9609-9618. Bolm, C.; Bi-
enewald, F. Angew. Chem., Int. Ed. Engl. 1995, 34 (23), 2640-2642.
Liu, G.; Cogan, D. A.; Ellman, J . A. J . Am. Chem. Soc. 1997, 119, 9913-
9914.
(5) Krauthausen, E. In Methoden Der Organischen Chemie (Houben-
Weyl); Klamann, D., Ed.; George Thieme Verlag Stuttgart: New York,
1985; Board E11, T.1, pp 614-664.
(6) Meanwell, N. A.; J ohnson, C. R. Synthesis 1982, 283-284.
(7) PCT Int. Appl. 2001, 060828, 13 Aug, 2001.
(8) Yamanaka, M.; Nishida, A.; Nakayama, M. Org. Lett. 2000, 2
(2), 159-161.
(4) Glaros, G.; Sullivan, S. Synth. Comm. 1976, 6 (7), 495-501.
10.1021/jo035518a CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/26/2004
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J . Org. Chem. 2004, 69, 2584-2587

TABLE 1. Rea ction Con d ition s for th e Allylsu lfoxid e F or m a tion
entry
NR2
Lewis acid (equiv)
TMSX (equiv)
TMSCl (0.5)
TMSCl or TMSOTf (1 or 2.5)
TMSCl (2.5)
time (h)
yield (%)
1
2
3
4
5
-NH2
-NH2
-NH2
Yb(OTf)3 (0.5)
Yb(OTf)3 (0.1) or Sc(OTf)3 (0.1)
Yb(OTf)3 (0.1)
48
48
48
12
12
25
10
34
0
<10
-CH2(CH2)3CH2-
-CH2(CH2)3CH2-
TMSCl (1)
Yb(OTf)3 (1)
SCHEME 3
TABLE 2. Syn th esis of â-Ch lor osu lfid es fr om Olefin s
a
Ratios of 10a /10b as well as 11a /11b were determined by 1H NMR.
SCHEME 4
procedure9 and was submitted to the standard conditions.
The product sulfoxide was found to be racemic. On the
basis of this observation, the following mechanism can
be formulated (Scheme 3). In the presence of a Lewis acid,
p-tolylsulfinyl amide forms sulfinyl cation 2, which reacts
with the olefin to form an episulfonium salt 3. The last
step of the sequence is deprotonation with the amide
anion liberated in situ during the reaction.
In the course of our further investigations into selective
functionalization of olefins, we discovered that p-tolyl-
sulfinyl piperidine reacts with olefins at 0-4 °C in the
presence of POCl3. Surprisingly, the product of the
reaction with R-methylstyrene was found to be â-sulfide
alcohol in 75% yield (Scheme 7).10 This unexpected
(9) Cogan, D. A.; Liu, G.; Kim, K.; Backers, B. J .; Ellman, J . A. J .
Am. Chem. Soc. 1998, 120 (32), 8011-8019.
(10) Node, M.; Nishide, K.; Shigeta, Y.; Obata, K.; Shiraki, H.;
Kunishige, H. Tetrahedron 1997, 53 (38), 12883-12894.
J . Org. Chem, Vol. 69, No. 7, 2004 2585

SCHEME 5
SCHEME 6
reduction of the sulfinyl functionality warranted inves-
tigation of the process in more detail.
We established that p-tolylsulfinyl piperidine reacts
with cyclohexene at 0-4 °C in the presence of POCl3 as
a Lewis acid and a source of chloride (Scheme 4). 1H NMR
spectrum of the reaction mixture after 3 h indicated 100%
conversion of the sulfur reagent and corresponded to the
formation of trans-1-chloro-2-p-tolylsulfenylcyclohexane
4a . The trans configuration of 4a was confirmed by
converting it into sulfone 4b, for which the value of the
1
vicinal H-1H coupling constant is known.11
nyl piperidine (5), tolyl sulfinyl amide (6), and tolyl
sulfinyl phthalimide (7). The results of the reactions with
these reagents are summarized in Scheme 5. As the data
indicate, the piperidine derivative is the amide of choice.
It was found that 0-4 °C (ice-water mixture bath) was
the optimal reaction temperature. Decreasing the tem-
perature to -10 °C dramatically slowed the reaction rate.
Increasing the temperature to 20 °C decreased the yield
and purity of the product. Dichloromethane was found
to be the best reaction medium. No reaction was observed
using hexanes as a solvent. The conversion in acetonitrile
was found to be only 45% after 12 h.
The best results were achieved using 1-1.2 equiv of
POCl3 and 2-5 equiv of olefin relative to the sulfinyl
amide (0.33 M concentration of the amide reagent in
anhydrous dichloromethane). These conditions were ap-
plied to a range of substrates (Table 2).
Alkyl-â-chlorosulfides can be obtained by addition of
sulfinyl chlorides to the olefins. Better yields can be
achieved by generating sulfinyl chloride in situ from
symmetrical disulfides and Cl2 or SO2Cl2.13 Alterna-
12
tively, alkyl-â-chlorosulfides can be prepared from DMSO
and SOCl2 or TMSCl.14 Well-known difficulties in han-
dling chlorine as well as sulfides and disulfides are
among the notable disadvantages of these methods. In
addition, in the case of sulfoxide-based reagents, copo-
lymerization of the evolved SO2 with olefins is known to
occasionally take place.15 This fact explains the limited
scope of the olefins that participate in chlorosulfinylation.
To optimize the reaction conditions, other chlorine-
containing Lewis acids were screened. Neither ZnCl2 nor
SOCl2 induced any reaction, whereas the use of AlCl3 and
TiCl4 caused decomposition of the sulfur reagent. The
best additive, POCl3, gave â-chlorosulfide 4a in 85%
isolated yield. Attempts to increase the yield by varying
the amount of POCl3 were not successful. The use of 0.5
equiv as well as the use of 3 equiv of POCl3 reduced the
yield. We first assumed that sulfinyl chloride formed in
situ was responsible for the product formation. To
investigate this possibility, sulfinyl chloride was synthe-
sized and was reacted with cyclohexene at room temper-
The reaction with cyclic olefins gave â-chlorosulfides
in good yields. For instance, norbornene was converted
into endo-3-chloro-exo-2-norbornyl-p-tolylthioether 9 (Table
2, entry 3). The relative stereochemistry of 9 was
determined by ROESY and HSQC (see Supporting In-
formation). In the case of unsymmetrical olefins, the
reaction was also found to be regioselective, controlled
by electronic rather than steric factors (Markovnikov
addition). For instance, 1-hexene and allylbromide gave
mixtures of regioisomers in 73:27 and 86:14 ratios,
1
ature. The reaction mixture was monitored by H NMR,
and after 48 h, conversion of the sulfur reagent was found
to be only 25%. Attempts to generate sulfinyl amide in
situ by adding piperidine to the reaction mixture also
yielded only traces of product and unreacted olefin.
The following sulfur reagents were synthesized and
compared in their reaction with cyclohexene: tolyl sulfi-
1
respectively (as determined by H NMR).
Electron-rich olefins such as trimethylsilyl enol ether
reacted under the reaction conditions with the formation
of â-ketosulfide in 67% yield, whereas the olefins pos-
sessing electron-withdrawing groups (methyl ester of
trans-cinnamic acid) did not react at all (Scheme 6). In
the case of styrene and R-methylstyrene, â-chlorosulfides
were easily hydrolyzed into the corresponding alcohols
on the silica gel column. Otherwise, the hydroxylated
products were obtained upon quenching the reaction
mixture with saturated aqueous NaHCO3 (Scheme 7).
To interpret the observed results, a mechanism that
involves reduction of the sulfinyl group with POCl3 can
be proposed. Similar reduction of the sulfonyl group with
(11) Bairamov, A. A.; Mursakulov, I. G.; Guseinov, M. M.; Zefirov,
N. S. J . Org. Chem. USSR 1978, 14 (5), 903-906.
(12) Martin, L. R.; Perozzi, E. F.; Martin, J . C. J . Am. Chem. Soc.
1979, 101, 3595-3598.
(13) Bordwell, F. G.; Pitt, B. M. J . Am. Chem. Soc. 1955, 77, 572-
578.
(14) Bellesia, F.; Ghelfi, V.; Pagnoni, U. M.; Pinetti, A. J . Chem.
Res., Synop. 1987, 238-239.
(15) Bellesia, F.; Boni, M.; Ghelfi, F.; Pagnoni, U. M.; Pinnetti, A.
Synth. Commun. 1992, 22 (8), 1101-1108.
2586 J . Org. Chem., Vol. 69, No. 7, 2004

SCHEME 7
sulfides and aryl-â-hydroxysulfides can be obtained upon
reaction with olefins in good yields. The reaction was
applied to a series of olefins and can be used as a new
method for the preparation of alkyl-â-chlorosulfides and
aryl-â-hydroxysulfides.
Exp er im en ta l Section
1-Meth yl-4-[(2-p h en yl-p r op en yl)su lfin yl]-ben zen e (1). A
flame-dried Schlenk flask was charged with 4-methyl-benzene-
sulfinyl amide (1 mmol), dichloromethane (4 mL), Yb(OTf)3/THF
solution (62 mg of Yb(OTf)3, 10 mol % in 1 mL of THF), and 650
µL (5 mmol) of R-methylstyrene under nitrogen. Then, 125 µL
(1 mmol) of TMSCl was added to the reaction mixture dropwise
at room temperature. After 12 h, no starting material was
detected by TLC (hexane/EtOAc ) 6/4; Rf ≈ 0.4). The reaction
mixture was concentrated and purified by column chromatog-
raphy on silica gel (hexane/EtOAc ) 6/4). A colorless oil was
obtained (87 mg; 34%): 1H NMR δ (CDCl3) 2.38 (s, 3H), 3.96
(AX, dd, 2J ) 1.2 Hz, J ) 17.2 Hz, 2H), 5.08 (d, 2J ) 0.8 Hz,
1H), 5.52 (d, 2J ) 0.8 Hz, 1H), 7.22-7.47 (m, 9H); 13C NMR δ
(CDCl3) 21.8, 65.1, 119.8, 124.5, 126.1, 128.1, 128.6, 129.7, 137.6,
139.0, 140.3, 141.7;17 EI MS, m/e (relative intensity) 78(31), 115-
(60), 139(13), 256(M+); HRMS calcd for C16H16OS (M+) 256.0922,
found 256.0921.
SCHEME 8
P r oced u r e for â-Ch lor osu lfid e Syn th esis fr om Olefin s.
A flame-dried Schlenk flask was charged with 4-methyl-ben-
zensulfinyl amide (1 mmol), olefin (1 or 2 mmol depending on
the olefin; see Table 2 and Scheme 7), and dichloromethane (3
mL) under nitrogen. To the reaction mixture was then added
93 µL (1 mmol) of POCl3 at 0-4 °C. The reaction mixture was
stirred at 0-4 °C temperature for 3-6 h depending on the
substrate. Completion of the reaction was determined by the
disappearance of 4-methyl-benzenesulfinyl amide on TLC (hex-
ane/EtOAc ) 8/2). The reaction mixture was purified without
concentration using flash chromatography on silica gel (pentane/
ether ) 8/2). In the case of aromatic olefins, â-chlorosulfoxides
were easily hydrolyzed to the corresponding alcohols on the
column (hexane/EtOAc ) 8/2).
TiCl4 was recently reported.16 It is likely that POCl3
coordinates to the oxygen of TolS(O)NR2 (15) followed by
attack of the chloride ion at the electrophilic sulfur center
(Scheme 8). The oxygen atom is eliminated as part of the
dichlorophosphate. Tolylsulfenyl chloride 17 is then
attacked by the olefin with the formation of the episul-
fonium salt 18. The episulfonium cation can be opened
with the chloride nucleophile to give trans-â-chlorosulfide
4a . The opening of this cationic intermediate with water
results in trans-â-hydroxysulfide.
The new reactivity of sulfinyl amides was uncovered.
It was found that tolylsulfinyl piperidine reacts with
olefins in the presence of Lewis acids to give allylsul-
foxides. It was also found that the sulfinyl group can be
reduced in the presence of POCl3 and valuable â-chloro-
Ack n ow led gm en t. We thank the Natural Sciences
and Engineering Research Council (NSERC), Canada
Foundation for Innovation, ORDCF, and University of
Toronto for financial support. Andrei K. Yudin is a
Cottrell Scholar of Research Corporation. Dr. Igor
Titaniouk is acknowledged for helpful discussions.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of the compounds 1, 4a , 4b, 8, 9, 10a /10b, 11a /11b,
and 12-14 and procedures for the preparation of sulfinyl
amides 5-7 and their 1H and 13C NMR. This material is
available free of charge via the Internet at http://pubs.acs.org.
(16) Morgan, P. E.; McCague, R.; Whiting, A. Tetrahedron Lett. 1999,
40, 4857-4860.
(17) Berlan, J .; Koosha, K.; Battioni, J .-P. Bull. Chem. Soc. Fr. 1978,
11-12 (pt. 2), 575-580.
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