An expeditious entry to benzylic and allylic sulfones through byproduct-catalyzed reaction of alcohols with sulfinyl chlorides

Article abstract of DOI:10.1021/jo901974h

(Chemical Equation Presented) In the absence of external catalysts and additives, a broad range of benzylic and allylic alcohols react with various sulfinyl chlorides to afford structurally diversified benzylic and allylic sulfones in moderate to excellen

Full text of DOI:10.1021/jo901974h

pubs.acs.org/joc
corresponding sulfides and the coupling of sulfinate salts
An Expeditious Entry to Benzylic and Allylic Sulfones
through Byproduct-Catalyzed Reaction of Alcohols
with Sulfinyl Chlorides
with benzylic and allylic carbon electrophiles.4 Although
several new methods have recently been reported to improve
the synthesis of benzylic and allylic sulfones, they require
expensive reagents/catalysts and/or harsh reaction condi-
tions.5
Hai-Hua Li, De-Jun Dong, Yin-Huan Jin, and
Shi-Kai Tian*
As early as 1930, Braun and Weissbach disclosed the
condensation reaction of alcohols with aliphatic sulfinyl
chlorides to yield sulfinate esters without requiring external
catalysts and additives (Scheme 1).6 More than 20 years later,
Douglass and Farah found, however, that alkyl chlorides
rather than sulfinate esters were obtained as the major
products when similar reaction mixtures were subjected to
high temperatures.7 Particularly, they noted that benzyl
alcohol (1.6 equiv) and methanesulfinyl chloride were re-
fluxed together to give benzyl chloride in 83% yield together
with benzyl methyl sulfone in 8% yield. In the course of
developing new reactions with carbocations,8 we investi-
gated the reaction of benzylic and allylic alcohols with
sulfinyl chlorides and found, to our surprise, that milder
reaction conditions could predominantly lead to the forma-
tion of benzylic and allylic sulfones (Scheme 1). Herein, we
wish to describe the synthesis of benzylic and allylic sulfones
from the corresponding alcohols and sulfinyl chlorides in
the absence of external catalysts and additives, wherein
byproduct HCl plays a vital role to accelerate the sulfone
synthesis.
Department of Chemistry, University of Science and
Technology of China, Hefei, Anhui 230026, China
tiansk@ustc.edu.cn
Received September 14, 2009
In the absence of external catalysts and additives, a broad
range of benzylic and allylic alcohols react with various
sulfinyl chlorides to afford structurally diversified
benzylic and allylic sulfones in moderate to excellent
yields, and importantly, a catalysis with byproduct HCl
is involved in this new protocol for sulfone synthesis.
SCHEME 1. Reactions of Alcohols with Sulfinyl Chlorides in
the Absence of External Catalysts and Additives
Benzylic and allylic sulfones serve as versatile building
blocks for a number of important carbon-carbon bond-
forming reactions owing to the useful reactivity of R-sulfonyl
carbanions under various reaction conditions.1 Moreover,
they are the necessary constituents of some biologically
important compounds that have potential for the treatment
of Alzheimer’s disease,2 cancer, and abnormal cell prolifera-
tion diseases.3 Therefore, much attention has been paid
to the synthesis of benzylic and allylic sulfones, for which
the general approaches include the oxidation of the
We investigated the possibility to obtain a benzylic sulfone
from the corresponding alcohol and a sulfinyl chloride under
milder reaction conditions relative to those reported by
Douglass and Farah.7,9 To our delight, the reaction of
4-methoxybenzyl alcohol (1a) with benzenesulfinyl chloride
proceeded smoothly in chloroform at room temperature to
afford 4-methoxybenzyl phenyl sulfone (2a) in 63% yield.
Notably, 4-methoxybenzyl benzenesulfinate was not obtained
at all, though 4-methoxybenzyl chloride was identified as a
minor product, the molar ratio of which to sulfone 2a was
(1) For reviews, see: (a) Simpkins, N. S. Sulfones in Organic Synthesis;
Pergamon Press: New York, 1993. (b) Blakemore, P. R. J. Chem. Soc., Perkin
Trans. 1 2002, 2563.
(2) Churcher, I.; Beher, D.; Best, J. D.; Castro, J. L.; Clarke, E. E.;
Gentry, A.; Harrison, T.; Hitzel, L.; Kay, E.; Kerrad, S.; Lewis, H. D.;
Morentin-Gutierrez, P.; Mortishire-Smith, R.; Oakley, P. J.; Reilly, M.;
Shaw, D. E.; Shearman, M. S.; Teall, M. R.; Williams, S.; Wrigley, J. D. J.
Bioorg. Med. Chem. Lett. 2006, 16, 280 and references therein.
(3) Neamati, N.; Kabalka, G. W.; Venkataiah, B.; Dayam, R.
WO2007081966, 2007.
(4) For a review, see: Solladie, G. In Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 6, pp 133.
(5) For some recent examples, see: (a) Reddy, L. R.; Hu, B.; Prashad, M.;
Prasad, K. Angew. Chem., Int. Ed. 2009, 48, 172. (b) Jegelka, M.; Plietker, B.
Org. Lett. 2009, 11, 3462. (c) Liu, C.-R.; Li, M.-B.; Cheng, D.-J.; Yang, C.-F.;
Tian, S.-K. Org. Lett. 2009, 11, 2543. (d) Chandrasekhar, S.; Saritha, B.;
Jagadeshwar, V.; Narsihmulu, C.; Vijay, D.; Sarma, G. D.; Jagadeesh, B.
Tetrahedron Lett. 2006, 47, 2981. (e) Liao, M.; Duan, X.; Liang, Y. Tetra-
hedron Lett. 2005, 46, 3469. (f) Felpin, F.-X.; Landais, Y. J. Org. Chem. 2005,
70, 6441. (g) Chandrasekhar, S.; Jagadeshwar, V.; Saritha, B.; Narsihmulu,
C. J. Org. Chem. 2005, 70, 6506. (h) Kabalka, G. W.; Venkataiah, B.; Dong,
G. Tetrahedron Lett. 2003, 44, 4673.
(6) v. Braun, J.; Weissbach, K. Ber. 1930, 63B, 2836. The authors
mentioned a warm reaction mixture but did not specify the temperature.
(7) Douglass, I. B.; Farah, B. S. J. Org. Chem. 1958, 23, 805.
(8) (a) Liu, C.-R.; Li, M.-B.; Yang, C.-F.; Tian, S.-K. Chem.;Eur. J.
2009, 15, 793. (b) Li, H.-H.; Jin, Y.-H.; Wang, J.-Q.; Tian, S.-K. Org. Biomol.
Chem. 2009, 7, 3219. (c) Li, H.-H.; Dong, D.-J.; Tian, S.-K. Eur. J. Org.
Chem. 2008, 3623. (d) Liu, C.-R.; Li, M.-B.; Yang, C.-F.; Tian, S.-K. Chem.
Commun. 2008, 1249.
(9) For the preparation of sulfinyl chlorides, see: (a) Whitesell, J. K.;
Wong, M.-S. J. Org. Chem. 1991, 56, 4552. (b) Peyronneau, M.; Roques, N.;
ꢀ
Mazieres, S.; Roux, C. L. Synlett 2003, 631.
DOI: 10.1021/jo901974h
r
Published on Web 11/13/2009
J. Org. Chem. 2009, 74, 9501–9504 9501
2009 American Chemical Society

Li et al.
JOCNote
determined to be 2:98 by 1H NMR analysis of the reaction
mixture. The yield for sulfone 2a was further improved to
75% by heating the reaction mixture at 60 °C.10 In addition,
there was no need to exclude air and moisture for this
reaction, and the yield for sulfone 2a decreased significantly
when chloroform was replaced with another common organic
solvent such as 1,2-dichloroethane (57%), toluene (30%),
ethyl acetate (43%), tetrahydrofuran (16%), dioxane (61%),
acetonitrile (44%), or nitromethane (34%).
SCHEME 2. Proposed Reaction Pathways Involving a Cataly-
sis with Byproduct HCl
TABLE 1. Synthesis of Benzylic Sulfonesa
that the present reaction conditions successfully avoided the
sulfinylation reaction toward the electron-rich aromatic
(or heteroaromatic) moieties of substrates such as alcohols
1a-e, 1g, 1i, and 1l (Table 1, entries 1-5, 7, 9, and 12).11 To
our delight, no isomerization occurred in the reaction with
benzylic propargylic alcohol 1n, the hydroxy group of which
was simply substituted to afford sulfone 2n in 86% yield
(Table 1, entry 14). Nevertheless, the reaction of benzyl
alcohol (1p) with benzenesulfinyl chloride in chloroform at
60 °C did not yield the corresponding sulfone but gave benzyl
benzenesulfinate in 65% yield (Table 1, entry 20). Moreover,
we did not obtain a sulfone product from the reaction with a
tertiary alcohol such as triphenylmethanol (1q) under similar
reaction conditions (Table 1, entry 21).
Optically active (R)-1-(4-methoxyphenyl)ethanol [(R)-1d,
> 99% ee] reacted with benzenesulfinyl chloride at room
temperature for 4 h to give sulfone 2d in nearly racemic form
(6% ee). This result suggests that a carbocation intermediate
is involved in the reaction. On the basis of the above
experiments and the results reported in the literature,
we propose the following reaction pathways to account for
the formation of sulfones (Scheme 2). The condensation
reaction of alcohol 1 with a sulfinyl chloride proceeds first
to give sulfinate ester A and byproduct HCl,6 and then the
former is promoted by the latter to undergo carbon-oxygen
bond cleavage. The resulting sulfinic acid C acts as a sulfur
nucleophile to couple with carbocation B to yield sulfone 2
(Scheme 2, path a). The rearrangement of sulfinate esters to
sulfones under acidic conditions was reported previously12
and was further confirmed by the following experiment.
Treatment of 4-methoxybenzyl benzenesulfinate with HCl
(1.2 equiv) in chloroform at 60 °C for 2 h resulted in the
formation of sulfone 2a in 92% yield. Alternatively, byproduct
HCl promotes the conversion of alcohol 1 to carbocation B,13
and the released water further decomposes the sulfinyl chloride
to give sulfinic acid C (Scheme 2, Path b). This byproduct
aReaction conditions: alcohol 1 (0.25 mmol), sulfinyl chloride (0.30
mmol), chloroform (0.25 mL). bIsolated yield. cBenzyl benzenesulfinate
was obtained in 65% yield. d2q = phenyl triphenylmethyl sulfone.
In the absence of external catalysts and additives, a broad
range of benzylic alcohols reacted with aromatic and alipha-
tic sulfinyl chlorides in chloroform at room temperature or at
60 °C to give the corresponding benzylic sulfones in good to
excellent yields (Table 1, entries 1-19). It should be noted
(11) (a) Chasar, D. W.; Pratt, T. M. Phosphorus, Sulfur, Silicon 1978, 5,
35. (b) Chasar, D. W.; Pratt, T. M.; Shockcor, J. P. Phosphorus, Sulfur,
Silicon 1980, 8, 183. (c) Chasar, D. W.; Hunt, D. J.; Lupyan, D. A.
Phosphorus, Sulfur, Silicon 1981, 12, 55. (d) Jung, M. E.; Kim, C.; von dem
Bussche, L. J. Org. Chem. 1994, 59, 3248.
(12) Wragg, A. H.; McFadyen, J. S.; Stevens, T. S. J. Chem. Soc. 1958,
3603.
(13) At an early stage of the reaction, a significant portion of alcohol was
converted to the corresponding ether that could serve as another source for
(10) This reaction was carried out on a 0.25-mmol scale, and the yield was
improved to 87% when performing the reaction on a 10-mmol scale.
carbocation B under acidic conditions. For a relevant study, see ref 8c
.
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Li et al.
JOCNote
TABLE 2. Synthesis of Allylic Sulfonesa
c
aReaction conditions: alcohol 3 (0.25 mmol), PhSOCl (0.30 mmol), chloroform (0.25 mL). bDetermined by 1H NMR analysis. Isolated yield.
d1,2-Dichloroethane was used as the solvent. eTotal yield of isomers 4 and 5. fThe E/Z ratios of allylic sulfones 5c,d are shown in parentheses.
catalysis was substantially supported by the following experi-
ments.14 While alcohol 1a could react with benzenesulfinic acid
in chloroform at 60 °C for 7 h to give sulfone 2a in 46% yield,
the addition of HCl (1.2 equiv) increased the yield to 58%. The
removal of byproduct HCl with an organic base, such as
pyridine or triethylamine, from the reaction of benzylic alco-
hols with sulfinyl chlorides has been reported to result in the
formation of the corresponding sulfinate esters rather than
secondary allylic alcohol 3c, wherein an allylic rearrange-
ment took place in addition to a simple hydroxy substitution
(Table 2, entry 3). While the replacement of the phenyl group
of allylic alcohol 3c with a 4-methoxyphenyl group favored
an allylic rearrangement (Table 2, entry 4), similar replace-
ment with a 4-chlorophenyl group predominantly led to a
simple hydroxy substitution with a regioselectivity of 94:6
(Table 2, entry 5). Interestingly, the reaction with secondary
allylic alcohol 3f, a regioisomer of allylic alcohol 3c, furn-
ished a mixture of allylic sulfones 4c (an allylic rearrange-
ment product) and 5c (a hydroxy substitution product) in
nearly the same ratio as that for the reaction with alcohol 3c
(Table 2, entry 6 versus entry 3). It should be noted that both
allylic sulfones 4 and 5 were obtained in all cases with
exclusive E selectivity (Table 2, entries 2-6).
The product distribution can be accounted for by the
relative steric demands of the R1 and R2 groups in allylic
alcohol 3 and the relative stability of the two major reso-
nance structures, D and E, of an allylic carbocation inter-
mediate generated from alcohol 3 during the reaction
(Scheme 3). While a phenyl group is superior to a methyl
group in stabilizing an allylic carbocation, the former
exhibits a steric demand larger than that of the latter toward
the nucleophilic attack of a sufinic acid. The balance of these
two factors allows the reaction with either allylic alcohol 3c
or its regioisomer 3f to afford a nearly 1:1 mixture of an SN
1-type hydroxy substitution product and an SN10-type allylic
rearrangement product. When the phenyl group of allylic
sulfones.15 Moreover, the use of molecular sieves (4 A) to
˚
sequester byproduct HCl in the reaction of alcohol 1l with
benzenesulfinyl chloride decreased the yield for the formation
of sulfone 2l from 99% to 18%.16
The sulfone synthesis catalyzed by byproduct HCl was
successfully extended to a wide variety of acyclic and cyclic
allylic alcohols (Table 2). Although the hydroxy group of
primary allylic alcohol 3b was simply substituted in the
presence of benzenesulfinyl chloride to give allylic sulfone
4b as a single product (Table 2, entry 2), a 49:51 mixture of
allylic sulfones 4c and 5c was obtained from the reaction with
(14) For some recent examples of the acidic byproduct co-catalyzed
reactions, see: (a) Nishimoto, Y.; Yasuda, M.; Baba, A. Org. Lett. 2007, 9,
4931. (b) Yang, B.-L.; Tian, S.-K. Eur. J. Org. Chem. 2007, 4646. (c) Song,
Q.-Y.; Yang, B.-L.; Tian, S.-K. J. Org. Chem. 2007, 72, 5407.
(15) (a) Braverman, S.; Steiner, S. Isr. J. Chem. 1967, 5, 267. (b) Coulomb,
^
J.; Certal, V.; Fensterbank, L.; Lacote, E.; Malacria, M. Angew. Chem., Int.
Ed. 2006, 45, 633. (c) Evans, J. W.; Fierman, M. B.; Miller, S. J.; Ellman, J. A.
J. Am. Chem. Soc. 2004, 126, 8134.
(16) For an example, see: Weinstock, L. M.; Karady, S.; Roberts, F. E.;
Hoinowski, A. M.; Brenner, G. S.; Lee, T. B. K.; Lumma, W. C.; Sletzinger,
M. Tetrahedron Lett. 1975, 16, 3979.
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Li et al.
JOCNote
SCHEME 3. Proposed Reaction Pathways for the Formation of
Allylic Sulfones 4c-e and 5c-e
reactive conformation G, which is energetically favored
relative to reactive conformation F by relieving allylic
1,2-strain (Scheme 4).5a,c,19,20 Similarly, the attack of a
chloride anion to reactive conformation G accounts for
the exclusive Z selectivity for the formation of a trisub-
stituted allyl chloride as a minor product.
SCHEME 4. Proposed SN20-Type Process for the Formation of
Allylic Sulfone 6 (R1 = H)
In summary, we have developed a convenient synthesis of
benzylic and allylic sulfones through the reaction of alco-
hols with sulfinyl chlorides. In the absence of external
catalysts and additives, a broad range of benzylic alcohols
react with various sulfinyl chlorides to afford structurally
diversified benzylic sulfones in good to excellent yields.
Notably, byproduct HCl can accelerate the sulfone syn-
thesis by catalyzing the formation of carbocation inter-
mediates from the corresponding alcohols. This bypro-
duct-catalyzed sulfone synthesis has further been extended
to a wide variety of acyclic and cyclic allylic alcohols,
and importantly, exquisite regioselectivity and stereo-
selectivity has been achieved from an SN20-type reaction
with 2-acylallylic alcohols, which provides a convenient
access to trisubstituted allyl sulfones with exclusive
Z selectivity.
alcohol 3c bears an electron-donating group, the resulting
larger energetic gap between resonance structures D and E
shifts the balance to favor an SN10-type allylic rearrange-
ment. Otherwise, an SN1-type hydroxy substitution is
favored when the phenyl group of alcohol 3c bears an
electron-withdrawing group.
To our great delight, only allylic rearrangement pro-
ducts were obtained from the reaction with allylic alco-
hols bearing activated terminal carbon-carbon double
bonds. The reaction of 2-acetylallylic alcohols with ben-
zenesulfinyl chloride proceeded smoothly at room tem-
perature to afford a range of trisubstituted allyl sulfones
with exclusive Z selectivity (Table 2, entries 8-13).17 The
exquisite regioselectivity and stereoselectivity suggest a
reaction pathway different from the aforementioned ones
involving carbocations that should be disfavored by the
presence of acyl groups. To gain insight to the mecha-
Experimental Section
General Procedure for the Synthesis of Benzylic and Allylic
Sulfones. To a solution of a benzylic or allylic alcohol (0.25
mmol) in chloroform (0.25 mL) at room temperature was
added a sulfinyl chloride (0.30 mmol). The resulting mixture
was stirred at the temperature specified in Table 1 or 2 until
no further transformation was detected by TLC analysis and
was then purified directly by silica gel column chromatog-
raphy, eluting with petroleum ether/ethyl acetate (20:1 to
5:1), to give a benzylic or allylic sulfone.
1
nism, we carried out H NMR analysis of the reaction
mixture of alcohol 3h with benzenesulfinyl chloride and
observed the formation of benzenesulfinic acid and (Z)-
trisubstituted allyl chloride 7h, the molar ratio of which
to sulfone 6h was determined to be 5:95 when the reaction
proceeded at room temperature for 1 h (eq 1).18 Notably,
treatment of allylic chloride 7h with benzenesulfinic acid
in chloroform at room temperature for 24 h could afford
sulfone 6h in 33% yield, which is, however, significantly
lower than that for the reaction of alcohol 3h with
benzenesulfinyl chloride (77%, Table 2, entry 8). Thus,
we propose that the reaction involves an SN20-type pro-
cess that is allowed to take place by the activation of a
terminal carbon-carbon double bond with the acetyl
group and by the activation of a hydroxy group with a
sulfinyl group or a proton (vide supra) and the Z selectiv-
ity for the formation of trisubstituted allyl sulfones
originates from the attack of benzenesulfinic acid to
Acknowledgment. We are grateful for the financial sup-
port from the National Natural Science Foundation of
China and the Chinese Academy of Sciences.
Supporting Information Available: General information,
detailed experimental procedures, characterization data, and
copies of 1H and 13C NMR spectra for products. This material is
available free of charge via the Internet at http://pubs.acs.org.
(19) Lee, H. J.; Seong, M. R.; Kim, J. N. Tetrahedron Lett. 1998, 39, 6223.
(20) Our results are inconsistent with the [2,3]-sigmatropic rearrangement
of an allylic sulfinate, which should favor the formation of allylic sulfone 5
(R1 = H) rather than its stereoisomer 6 (R1 = H). For the rearrangement of
allylic sulfinates to yield allylic sulfones, see: (a) Knight, D. J.; Whitham, G.
H.; Williams, J. G. J. Chem. Soc., Perkin Trans. 1 1987, 2149. (b) Braverman,
S. Int. J. Sulfur Chem. C 1971, 149. (c) Braverman S. In The Chemistry of
Sulfinic Acids, Esters and Their Derivatives; Patai, S., Ed.; John Wiley and
Sons: New York, 1990; pp. 297.
(17) For reviews of such highly functionalized alcohols, see: (a) Masson,
G.; Housseman, C.; Zhu, J. Angew. Chem., Int. Ed. 2007, 46, 4614. (b)
Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. Rev. 2003, 103, 811.
(18) Benzenesulfinic acid could also be generated through the decom-
position of benzenesulfinyl chloride with moisture.
9504 J. Org. Chem. Vol. 74, No. 24, 2009