A facile one-pot benzylation of sodium enolates using trifluoromethansulfonic anhydride and diphenyl sulfoxide

Article abstract of DOI:10.1246/cl.2004.8

A facile one-pot C-benzylation reaction proceeded smoothly and in good yields by treating various sodium enolates and benzyl alcohol with in situ generated alkoxy diphenyl sulfonium salt derived from trifluoromethansulfonic anhydride and diphenyl sulfoxide.

Full text of DOI:10.1246/cl.2004.8

8
Chemistry Letters Vol.33, No.1 (2004)
A Facile One-pot Benzylation of Sodium Enolates Using
Trifluoromethansulfonic Anhydride and Diphenyl Sulfoxide
Tomofumi Takuwa,y;yy Jim Yoshitaka Onishi,y;yy Jun-ichi Matsuo,y;yy and Teruaki Mukaiyamaꢀy;yy
yCenter for Basic Research, The kitasato Institute, 6-15-5 Toshima, Kita-ku, Tokyo 114-0003
yyKitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641
(Received September 19, 2003; CL-030882)
A facile one-pot C-benzylation reaction proceeded smoothly
HO
and in good yields by treating various sodium enolates and ben-
zyl alcohol with in situ generated alkoxy diphenyl sulfonium salt
derived from trifluoromethansulfonic anhydride and diphenyl
sulfoxide.
R
O
O
S
OTf
S
Tf
Tf
Base
TfOH
Ph
Ph
Ph
Ph
Ph
Ph
TfO
Nu
(1)
O
S
Nu
R
R
Alkylation of metal enolate is one of the most fundamental
and frequently employed reactions in organic synthesis. Though
alkylations of various metal enolates derived from ketones,1 es-
ters2 and ꢀ-keto esters3 with alkyl halides afforded the corre-
sponding mono-alkylated products, mixture of di- and poly-al-
kylated products are often formed even when one equivalent
of both base and alkylating reagent were used. Moreover, C-al-
kylation and O-alkylation is known to take place at the same
time depending on the nature of alkylating reagent and reaction
conditions. For example, O-monobenzylated, C-monobenzylat-
ed, and C-dibenzylated products (5:45:50) were obtained by ben-
zylation of ethyl acetoacetate with benzyl bromide in dimethyl
sulfoxide.4 Thus, to develop an efficient method for the mono-
C-alkylation of enolates still remains as an important topic in
synthetic chemistry. It was reported from our laboratory that di-
alkyl sulfide bis(trifluoromethansulfonate) reacted with styrene5
to afford the corresponding active sulfonium intermediate,
which in turn reacted with amines to afford aziridines or ꢀ; ꢁ-un-
saturated amines. Thus, alkoxy dialkyl sulfonium species would
similarly behave as an effective alkylating reagent in the reaction
with carbon nucleophiles. A similar salt derived from dialkyl
sulfoxide and trifluoromethansulfonic anhydride has been previ-
ously utilized in Swern-type oxidation,6 sulfilimine synthesis,7
and glycosylation reaction8 as an useful reagent.
O
S
TfO
Ph
Ph
(2)
Scheme 2.
carbon nucleophile attacking the benzyl carbon of the oxosulfo-
nium trifluoromethane sulfonate, where diphenyl sulfoxide acts
as a soft leaving group.
Initially, 4-methoxy benzyl alcohol and sodium methylmal-
onate was studied as a model reaction. After screening the effect
of solvent, C-benzylated product was obtained in 35% and 57%
yields when THF or toluene was used, respectively.
Next, the effect of base was examined (Table 1). The use of
pyridine or potassium carbonate was found to afford C-benzylat-
ed compound in moderate yields (Table 1, Entries 2 and 6) while
proton-sponge1 gave the best result giving C-benzylated prod-
uct in 97% yield (Table 1, Entry 7).
In order to obtain benzylated product in high yield, at least
3.0 equivalents of nucleophile was necessary. (Table 2, Entry 3).
As expected, dibenzylated or O-benzylated product was not
obtained under the above reaction condition.
The reaction was studied by using various substituted benzyl
alcohols and all of the reactions proceeded smoothly to afford
the corresponding C-benzylated products in moderate to high
yields (Table 3). It was noted that the benzylated product was
not obtained when the reaction was carried out in the absence
of diphenyl sulfoxide (Table 3, Entry 2).
Here, we would like to report a new and efficient one-pot C-
benzylation of sodium enolate with benzyl alcohol by using di-
phenyl alkoxy sulfonium salt derived from trifluoromethansul-
fonic anhydride and diphenyl sulfoxide.
Reactions with other sodium enolates derived from ꢀ-keto
A proposed reaction mechanism is shown in Scheme 2. Ini-
tially, diphenyl sulfoxide is activated with trifluoromethansul-
fonic anhydride to form an activated sulfonium complex (1).
The successive reaction of benzyl alcohol in the presence of base
affords in situ an active oxosulfonium trifluoromethanesulfonate
(2), which in turn reacts with a nucleophile to give the corre-
sponding C-benzylated product. Predominant formation of
C-alkylated product can be explained by considering the soft
Table 1. The effects of base as a scavenger in benzylation
reaction
NaCH(COOMe)2
(3.0 equiv.), THF
Tf2O (1.0 equiv.)
Base (1.2 equiv.)
COOMe
COOMe
O
S
4-MeOC6H4CH2OH
(1.2 equiv.)
−78 °C − RT
Ph
Ph
4-MeOPh
−78 °C, Toluene
Entry
Base
Yield /%
NDa
77
Entry
Base
CsCO3
K2CO3
Yield /%
58
1
2
3
4
Et3N
5
6
7
ONa
2
O
Tf O
2
R
1
Pyridine
2,6-Lutidine
CsF
65
O
S
O
S
R
1
R
R b
R
53
97
Ph
Ph
2
Proton-Sponge
HO
Proton-SpongeR
Ph
Ph
R
R
TfO
54
aDesired product was not detected. b1,8-bis(dimethylamino)-
naphthalene.
Scheme 1.
Copyright Ó 2004 The Chemical Society of Japan

Chemistry Letters Vol.33, No.1 (2004)
9
Table 2. The effect of yield on the amount of sodium enolate
Table 4. Investigation of other metal enolates
Tf2O (1.0 equiv.)
O (1.0 eq.)
Tf2
Proton-Sponge R
(1.2 equiv.)
Proton-Sponge R
(1.2 equiv.)
NaCH(COOMe)2
O
S
COOMe
COOMe
O
S
THF
Nucleophile
Nu
4-MeOC6H4CH2OH
(1.2 eq.)
−78 °C, Toluene
Ph
Ph
BnOH (1.2 equiv.)
−78 °C − RT
−78 °C − RT
Ph
Ph
4-MeOPh
−78 °C, Toluene
Product
Entry
1
Yield /%
94
Nucleophile
Nucleophile
Equivalent
Yield /%
Entry
COOMe
1
2
3
1.5
2.0
3.0
25
68
97
COOMe
Na
COOMe
Na
COOMe
COMe
COOMe
Ph
Ph
COOMe
COMe
Na
2
3
96
Table 3. Study of verious benzyl alcohols derivatives in benzy-
lation reaction
COOMe
COiPr
COOMe
COiPr
Tf2O (1.0 equiv.)
COOMe
Na
quant
Proton-Sponge R
NaCH(COOMe)2
COOEt
COOEt
CN
Ph
Ph
Ph
Ph
O
(3.0 equiv.), THF
(1.2 equiv.)
CN
Na
COOMe
S
R
70a
78c
4
Ph
Ph
Alcohol (1.2 equiv.)
−78 °C − RT
COOMe
COOMe
−78 °C, Toluene
ONa
O
O
5b
Entry
Alcohol
BnOH
BnOH
Yield /% Entry
Alcohol
Yield /%
Ph
Ph
Ph
1
94
NDb
97
7
8
9
1-Naphthalenmethanol 83
2a
4-NO2-C6H4CH2OH
4-Cl-C6H4CH2OH
74
88
74
84
76
ONa
95c,d
6
7
3
4-MeO-C6H4CH2OH
3-MeO-C6H4CH2OH
4-Me-C6H4CH2OH
Ph
4
88
10 3-Cl-C6H4CH2OH
ONa
O
O
95a,d
5
85
11
2-Cl-C6H4CH2OH
Ph
Ph
Ph
Ph
4-iPr-C6H4CH2OH
6
85
12
2-F-C6H4CH2OH
aThe reaction was carried out without diphenyl sulfoxide.
ONa
bDesired product was not detected.
84d,e
98a,d
8
9
esters, ꢂ-cyano esters, esters and ketones were also investigated
(Table 4). The desired products were obtained in good yields
when ꢀ-keto esters were used (Table 4, Entries 2 and 3). Simi-
larly, the reaction proceeded smoothly with ꢂ-aromatic or ꢂ-ali-
phatic enolates derived from ketones (Table 4, Entries 5–8).
Furthermore, enolates derived from esters could also be used
as a nucleophile in this reaction (Table 4, Entry 9). However,
the desired product was not obtained when lithium enolates were
used (Table 4, Entry 5).
A typical experimental procedure is as follows: to a solution
of diphenyl sulfoxide (0.20 mmol) in toluene (1.0 mL) under an
argon atmosphere was added a trifluoromethansulfonic anhy-
dride (0.20 mmol) at ꢁ78 ꢂC. After stirring for 30 min. A solu-
tion of benzyl alcohol (0.24 mmol) and proton-sponge1
(0.24 mmol) in toluene (0.8 mL) was added, and the reaction
was stirred for a further 30 min. Fleshly prepared sodium salt9
of methyl malonate dissolved in THF (0.4 M, 1.5 mL) was added
and the reaction mixture was slowly warmed to room tempera-
ture. After stirring for 2 h, the reaction mixture was quenched
with water (5.0 mL) and the aqueous layer was extracted with
ethyl acetate (30 mL). The organic layers were collected and
dried (MgSO4). After filtration and evaporation, the resulted
residue was purified by preparative TLC to afford the corre-
sponding benzylated product.
ONa
O
O
O
Ph
a4 equiv. of nucleophile was used. bNo reaction was observed
when lithium enolate of acetophenone was used as a nucleo-
phile. 5 equiv. of nucleophile was used. Yields were deter-
c
d
mined by 1HNMR. 6 equiv. of nucleophile was used.
e
Century COE Program, Ministry of Education, Culture, Sports,
Science and Technology (MEXT) and the JSPS postdoctoral
fellowship for foreign researchers.
References and Notes
1
A. J. Waring, in ‘‘Comprehensive Organic Chemistry,’’ ed. by
J. F. Stoddart, University of Sheffield (1979), pp 1017–1104.
I. O. Sutherland, in ‘‘Comprehensive Organic Chemistry,’’
ed. by I. O. Sutherland, University of Livarpool (1979),
pp 869–956.
J. M. Brown, in ‘‘Comprehensive Organic Chemistry,’’ ed. by
I. O. Sutherland, University of Livarpool (1979), pp 779–814.
W. J. le. Noble and J. E. Puerta, Tetrahedron Lett., 7, 1087
(1966).
a) J. Matsuo, H. Yamanaka, A. Kawana, and T. Mukaiyam,
Chem. Lett., 32, 392 (2003). b) H. Yamanaka, J. Matsuo, A.
Kawana, and T. Mukaiyama, Chem. Lett., 32, 626 (2003).
J. B. Henderson and S. M. Schwartzman, Tetrahedron Lett.,
16, 273 (1975).
M. D.Coburn and H. H. Hayden, Synthesis, 1986, 490.
B. A. Garcia and J. L. Poole, J. Am. Chem. Soc., 119, 7597
(1997).
2
3
4
5
6
Thus, a new and efficient method for C-benzylation of var-
ious sodium enolates was established by using a new benzylating
reagent generated in situ from diphenyl sulfoxide, trifuluoro-
methansulfonic anhydride and benzyl alcohols. Further study
on this type of alkylation reaction is currently in progress.
7
8
9
Sodium enolates were prepared by adding sodium hydride in
THF (Table 4, Entries 1–4) or sodium hexamethyldisilaza-
nide in THF (Table 4, Entries 5–8) to THF solution of the
corresponding carbonyl compounds.
This study was supported in part by the Grant of the 21st
Published on the web (Advance View) December 1, 2003; DOI 10.1246/cl.2004.8