Reaction of α-benzenesulfonylphenylacetic acid with alkyl halides. Decarboxylative alkylation vs. decarboxylative protonation

Article abstract of DOI:10.1080/10426500490463592

The reaction of α-benzenesulfonylphenylacetic acid with some alkyl halides, using as base NaH in DMSO, leads to decarboxylative protonation to give benzylphenylsulfone. Decarboxylative alkylation occurs only when CO₂ is expelled by flushing with nitrogen. The mechanism of the decarboxylative protonation is investigated.

Full text of DOI:10.1080/10426500490463592

Phosphorus, Sulfur, and Silicon, 179:1403–1409, 2004
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ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500490463592
REACTION OF
α-BENZENESULFONYLPHENYLACETIC ACID WITH
ALKYL HALIDES. DECARBOXYLATIVE ALKYLATION
VS. DECARBOXYLATIVE PROTONATION
Blanka Wladislaw, Fernando Perna,
Regina Maria de Almeida Neves, Liliana Marzorati,
and Claudio Di Vitta
Instituto de Qu´ımica da Universidade de Sa˜o Paulo,
Sa˜o Paulo, Brazil
(Received October 29, 2003; accepted November 7, 2003)
The reaction of α-benzenesulfonylphenylacetic acid with some alkyl
halides, using as base NaH in DMSO, leads to decarboxylative proto-
nation to give benzylphenylsulfone. Decarboxylative alkylation occurs
only when CO2 is expelled by flushing with nitrogen. The mechanism
of the decarboxylative protonation is investigated.
Keywords: Alkylation; decarboxylation; protonation; sodium hydride
In the course of our investigations on the decarboxylative electrophilic
substitution of carboxylic acids containing an activated methylene
group, in aprotic media,1,2 we became interested in the decarboxyla-
tive alkylation of α-sulfonyl carboxylic acids.
Our studies were initiated by the reaction of α-benzenesul-
fonylphenylacetic acid, 1, with NaH in DMSO, followed by reaction
with benzyl bromide at room temperature (r.t.). However, surprisingly,
instead of the expected decarboxylative alkylation, decarboxylative
protonation took place to give benzylphenylsulfone, 2, as the only
reaction product. However, it was observed that, upon flushing the
We are grateful to the Fundac¸a˜o de Amparo a` Pesquisa do Estado de Sa˜o Paulo
(FAPESP) for financial support and to the Conselho Nacional de Desenvolvimento
Cient´ıfico e Tecnolo´gico (CNPq) for scholarships. We thank Professor F. H. Quina for
revising the manuscript.
Address correspondence to Blanka Wladislaw, Instituto de Qu´ımica, Universidade de
Sa˜o Paulo, Av. Prof. Lineu Prestes, 748-C.P. 26007, Sa˜o Paulo, S.P., 05513-970, Brazil.
E-mail: bwlad@iq.usp.br
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B. Wladislaw et al.
reaction mixture with nitrogen, decarboxylative alkylation does occur,
yielding the benzyl substituted sulfone 2a (Scheme 1).
SCHEME 1
The same reaction, performed using other alkyl halides to obtain the
α-alkylsubstituted sulfones 2b–d, was successful only when nitrogen
was flushed through the reaction mixture (Table I).
Assuming an equilibrium between the sodium carboxylate and the
sulfonyl carbanion, with the equilibrium constant favouring the car-
boxylate, sulfone 2 could be formed in the absence of nitrogen by decar-
boxylative protonation during the work-up. Upon flushing the reaction
mixture with nitrogen, this equilibrium would be shifted toward the
sulfonyl carbanion, which could then undergo alkylation (Scheme 2).
SCHEME 2
However, this possibility was disproved by the results of compar-
ative experiments in which benzylphenylsulfone, 2, and benzenesul-
fonylphenylacetic acid, 1, were treated with 1 equiv. of NaH in DMSO.
Sulfone 2 formed a deep yellow carbanion solution, as demonstrated
by the desapearance of the methylene signal in the 1HNMR spectrum.

Reactions of α-Benzenesulfonylphenylacetic Acid
1405
TABLE I Reaction of Benzenesulfonylphenylacetic Acid 1
with Some Alkyl Halides,a Flushing the Reaction Mixture
with Nitrogen
Entry
RX
C6H5SO2CH(R)C6H5
Yield (%)
1
2
3
p-CH3 C6H5CH2Br
CH3I
C2H5I
2b
2c
2d
41
43
41
aNaH/DMSO, r.t.
However, in the case of the benzenesulfonylphenylacetic acid, 1, a color-
less solution of sulfone 2 was obtained. The latter was stable in the pres-
ence of NaH, affording the corresponding yellow carbanion solution only
after flushing with nitrogen. As expected, subsequent treatment with
methyl tosylate yielded sulfone 2c in admixture with benzylphenylsul-
fone 2 (2:1).
As for the mechanism of formation of benzylphenylsulfone, 2, from
the sulfonyl acid 1, an unimolecular mechanism in which the carban-
ion is formed by departure of CO2 from carboxylate may be excluded.
A bimolecular mechanistic description similar to that proposed to ex-
plain the retention of chirality in the protonation of S,S-benzenesulfonyl
α-phenylpropionic acid3 seems to be more appropriate (Scheme 3).
SCHEME 3
In our case, this mechanism proved to be operative as demonstrated
by an experiment, in the presence of a catalytic amount of NaH in
DMSO in which benzenesulfonylphenylacetic acid, 1, underwent de-
composition, in only a few minutes, to give benzylphenylsulfone, 2. It
is noteworthy that, in the absence of NaH, the decomposition also oc-
curred, but took ca. 50 min.

1406
B. Wladislaw et al.
The catalytic nature of this decarboxylation conflicts with the lack
of formation of the carbanion when sulfonyl acid 1 is treated with one
equiv. of NaH. The observed inhibition of carbanion formation could
be due to the presence of the evolved CO2. In fact, in an experiment
in which benzylphenylsulfone 2 was added to a suspension of NaH in
1
DMSO, previously saturated with CO2, the HNMR spectrum of the
resulting colourless solution showed that no deprotonation took place.
Additionally, no methylation occurred upon addition of methyl iodide.
It is interesting to note that this bimolecular mechanism can also
explain the decarboxylative protonation, observed previously in this
laboratory,4 in the reaction of α, α’-dimethyl malonate half ester, 3, in
the presence of NaH/DMSO with a sulfenylating agent, to give ester 4
(Eq. 1).
(1)
Furthermore, it was verified that the lack of formation of the car-
banion in the presence of CO2 is not limited to benzylphenylsulfone, 2.
Indeed phenylacetonitrile and ethyl phenylacetate, when treated with
NaH in DMSO, afforded a violet and a yellow solution, respectively,
of the corresponding carbanion, as evidenced by 1HNMR. However,
lighter coloured mixtures, containing mainly unreacted starting ma-
terials, were formed when CO2 saturated DMSO was employed.
It was also verified that the lack of reactivity of NaH toward ben-
zylphenylsulfone, 2, in the presence of CO2 is not limited to DMSO,
which is known to interact with CO2,5 but is also observed with other
solvents, such as DMF and THF.
The possibility that formation of sodium formate,6 is responsible for
deactivation of NaH was eliminated by showing that a solution of ben-
zylphenylsulfone, 2, in DMSO, containing sodium formate, did not be-
come yellow upon flushing with nitrogen.
Therefore, it seems reasonable to attribute the lack of reactivity of
NaH as deprotonating agent in the presence of CO2 to deactivation of
the hydride surface or to a decrease of its solubility.
In summary, protonative decarboxylation of benzenesulfonylpheny-
lacetic acid, in the presence of NaH in DMSO, occurs via a cat-
alytic bimolecular non-carbanion mechanism. NaH deactivation, in the

Reactions of α-Benzenesulfonylphenylacetic Acid
1407
presence of CO2, precludes carbanion formation and further alkylation.
However, this drawback can be circumvented by flushing the reaction
mixture with nitrogen.
EXPERIMENTAL
General
Microanalysis was performed on a Perkin-Elmer 240B Elemental Anal-
yser. m.p.s are uncorrected and were determined on a Kofler hot-stage
apparatus.
1HNMR spectra were recorded on a Varian Inova 300 spectrometer
with SiMe4 as internal standard. Chemical shifts (δ) are expressed in
ppm relative to SiMe4. NMR spectra for samples dissolved in DMSO
or DMF were recorded using a sealed capillary tube containing DMSO-
d6 for internal lock. Gravity chromatography was performed on Merck
Kieselgel 60 (70–230 mesh).
Starting Materials
Benzenesulfonylacetic acid, 1, was prepared by carbonation of ben-
zylphenylsulfone, 2, according to a described procedure7 and was dried
by lyophilization; sulfone 2 was prepared by oxidation of the correspond-
ing sulfide.8
Reaction of Benzenesulfonylphenylacetic Acid, 1, with
Benzyl Bromide Without Nitrogen Flushing
A solution of acid 1 (0.100 g, 0.362 mmol) in 1.0 mL of DMSO was
added dropwise via syringe to a suspension of oil-free NaH (0.035 g,
0.792 mmol, 50% in mineral oil) in DMSO (1.0 mL). After stirring for
1 h at r.t., benzyl bromide (0.062 g, 0.362 mmol) was added dropwise
via syringe, further stirring for 3 h. The mixture was poured into water,
yielding quantitatively sulfone 2. 1HNMR, CDCl3, δ = 4.25 (s; 2H), 6.84–
7.70 (m, 10H).
Decarboxylative Alkylation of
Benzenesulfonylphenylacetic Acid, 1
General Procedure
To a suspension of oil-free NaH (0.0550 g, 50% in mineral oil,
1.15 mmol) in 2.0 mL of dry DMSO was added, at r.t., a solution of acid

1408
B. Wladislaw et al.
1 (1.08 mmol) in 1.0 mL of DMSO, continuously purging the reaction
mixture with nitrogen. After 1 h, the alkylating agent (1.14 mmol) was
added dropwise via syringe and the solution was stirred at r.t. for an
additional period of time (see below) before being poured into 20 mL of
saturated aqueous ammoniun chloride solution. When solid, the crude
product was filtered or, when oily, extracted with dichloromethane.
1-Methyl-4-[(2-phenyl-2-(phenylsulfonyl)ethyl]
benzene, 2b
Using p-methylbenzylbromide and stirring for 5 h, a pale yellow solid
was obtained. Recrystallization from ethanol yielded 2b (41%) as white
1
crystals. m.p. 169–171◦C. HNMR, CDCl3, δ = 2.20 (s, 3H), 3.35 (dd,
1H, J = 13.8 and 11.6Hz), 3.78 (dd, 1H, J = 13.8 and 3.2 Hz), 4.21 (dd,
1H, J = 11.6 and 3.2Hz), 6.83 (d, 2H, J = 8Hz), 6.91 (d, 2 H, J = 8Hz),
7.03–7.56 (m, 10 H). Calcd. for C21H20O2S: C, 75.0; H, 6.0. Found: C,
74.9; H, 5.9.
[(1-Phenylethyl)sulfonyl]benzene, 2c
Using methyl iodide and stirring for 1 h, an oil was obtained after the
work-up. Crystallization from ethyl ether yielded 2c as a pale yellow
solid (43%). m.p. 108–114◦C (Lit.9 113◦C). 1HNMR, CDCl3, δ = 1.77 (d,
3H, J = 7.2Hz), 4.24 (q, 1H, J = 7.2Hz), 7.09–7.57 (m,10H).
[(1-Phenylpropyl)sulfonyl]benzene, 2d
Using ethyl iodide and stirring for 1 h, a yellow oil was obtained which
solidified on standing. After column chromatography using hexane-
ethyl acetate (4:1), sulfone 2d was isolated (41%). m.p. 91–95◦C (Lit.10
1
99.5–100◦C). HNMR, CDCl3, δ = 0.87 (t, 3H, J = 7.4 Hz), 2.07–2.24
(m,1H), 2.43–2.56 (m, 1H), 3.94 (dd, 1H, J = 11.4 and 3.8 Hz), 7.06–7.57
(m, 10 H).
Attempts to Prepare the Benzylphenylsulfonyl Carbanion
From Benzylphenylsulfone 2
A solution of sulfone 2 (0.040 g, 1.7 mmol) in DMSO (0.5 mL) was in-
troduced via syringe into a NMR tube containing oil-free NaH (0.007 g,
60% in mineral oil, 1.8 mmol). Evolution of gas and formation of a yel-
1
low colored solution was observed. HNMR, DMSO, δ = 4,50 (bs, 1H),
6.6–7.8(m, 10H); 13CNMR, DMSO, δ = 60 (bs). Addition of excess methyl

Reactions of α-Benzenesulfonylphenylacetic Acid
1409
iodide to this mixture afforded a colorless solution with a 1HNMR spec-
trum identical to that of sulfone 2c.
From Benzenesulfonylphenylacetic Acid, 1
A solution of benzenesulfonylphenylacetic acid, 1 (0.030 g, 1.1 mmol),
in 0.5 mL of DMSO was added to a suspension of oil-free NaH (0.003 g,
1
1.3 mmol) in DMSO. The HNMR spectrum of the resulting colorless
solution was identical to that obtained for sulfone 2. Addition of excess
1
methyl iodide did not afford sulfone 2c, as verified by HNMR spec-
troscopy. Using the same procedure described above, but purging the
reaction mixture with nitrogen for 1 h before adding methyl iodide, sul-
fone 2c was formed in admixture (2:1) with sulfone 2, as verified by
1HNMR spectroscopy.
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[3] J .E. Taylor and F. H. Verhoek, J. Am. Chem. Soc., 81, 4537 (1959).
[4] B. Wladislaw, L. Marzorati, and C. L. Donnici, unpublished results.
[5] P. Raveendran and S. L. Wallen, J. Am. Chem. Soc., 124, 12590 (2002).
[6] H. Moissan, Ann. Chim. Phys., 6, 297 (1905).
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