Novel synthesis of sulfones from α,α-dibromomethyl aromatics

Article abstract of DOI:10.1016/S0040-4039(02)02769-7

A novel, high yielding preparation of sulfones from α,α-dibromomethyl aromatics through reaction with a sulfinate salt is reported.

Full text of DOI:10.1016/S0040-4039(02)02769-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1283–1286
Novel synthesis of sulfones from a,a-dibromomethyl aromatics
Feng Xu,* Kimberly Savary, J. Michael Williams, Edward J. J. Grabowski and Paul J. Reider
Department of Process Research, Merck Research Laboratory, Rahway, NJ 0706, USA
Received 18 October 2002; revised 4 December 2002; accepted 5 December 2002
Abstract—A novel, high yielding preparation of sulfones from a,a-dibromomethyl aromatics through reaction with a sulfinate salt
is reported. © 2003 Published by Elsevier Science Ltd.
Sulfones are widely used intermediates in organic syn-
thesis.1 Many procedures can be applied in the prepara-
tion of sulfones.1 One of the most commonly used
methods involves formation of the CꢀS bond by react-
ing an alkyl halide with a sulfinate salt. As part of
synthetic efforts to support a drug development pro-
gram at Merck, a practical synthesis of the key interme-
diate sulfone 1 was required. The initial synthesis of 1 is
shown in Scheme 1.
and conversion in the bromination step heavily
depended on the NBS charge, reaction temperature,
and solvents. The overall yield in the synthesis of 1 is
limited by the bromination step. Table 1 illustrates
some selected bromination results. To date, the best
selectivity/conversion achieved is about 90:5:5 (2:3:4)
with 80–85% isolated yield. Full conversion could be
achieved by treatment of 3 with 1.4 equiv. of NBS in
PhCl in the presence of 10 mol% of Vazo® 672 at 70°C,
but selectivity suffered (2:4=70:30).
The by-product 4, which resulted from bromination of
the desired product competitive with bromination of 3,
was separated as waste in isolation of 2. The selectivity
Although extensive studies have been carried out in the
past, selectivity clearly remains a common problem in
radical bromination.3 a,a-Dibromomethyl aromatics
are often observed in the radical bromination of methyl
aromatics used to prepare monobromomethyl aromat-
ics.3 It is also known that a-bromomethyl sulfones can
be reduced to the corresponding sulfones in the pres-
ence of suitable reducing reagents such as cat. (PhSe)2/
NaBH4.4 In principal, the oxidation state of sulfur in a
sulfinic acid allows it to act as a reducing agent. How-
ever, one-step synthesis of sulfones from a,a-dibro-
momethyl aromatics in the presence of sulfinate salt has
not been reported. Therefore, we initiated studies to
determine the potential for converting the a,a-dibro-
momethyl quinoline 4 into the desired sulfone 1 using
MeSO2Na.
No reaction was observed between the tribromide 4 and
MeSO2Na in aqueous DMAc at ambient temperature.
However, the bromosulfone 5 was observed as an inter-
mediate in the formation of the desired sulfone 1 when
the reaction was carried out at higher temperature. The
bromosulfone 5 was isolated and characterized. At
70–90°C, 4 was completely converted to the desired
sulfone product 1 in 95% yield. Figure 1 illustrates the
conversion versus time for sulfone formation at 70°C.
Scheme 1. Initial synthesis of sulfone 1.
* Corresponding author. Tel.: 732-594-3211; fax: 732-594-1499;
e-mail: feng xu@merck.com
–
0040-4039/03/$ - see front matter © 2003 Published by Elsevier Science Ltd.
PII: S0040-4039(02)02769-7

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F. Xu et al. / Tetrahedron Letters 44 (2003) 1283–1286
Table 1. Bromination of 3: selectivity versus conversion
Entry
Reagents
Temp. (°C)
Solvents
Conversion/selectivity 3:2:4
1
2
3
4
5
6
7
8
1.05 equiv. NBS/AIBN
1.4 equiv. NBS/Vazo® 672
1.2 equiv. NBS/(BzO)2
1.2 equiv. NBS/(BzO)2
1.2 equiv. NBS/(BzO)2
65–70
70
65
65
65
65
50–55
65–70
PhCl
PhCl
EtOAc
t-BuCO2Me
MeCO2Bu-t
i-PrOAc
i-PrOAc
12:77:11
0:70:30
10:80:10
8:75:17
5:83:12
10:80:10
5:90:5
1.2 equiv. NBS/(BzO)2
1.05 equiv. NBS/Vazo® 522
1.05 equiv. NBS/AIBN or (BzO)2
CF3CO2Pr-i or CF3CO2Pr-i/CF3Ph
5:90:5
Applying this new approach coupled with sulfone for-
mation from monobromomethyl quinoline 2, the
improved synthesis of sulfone 1 turns out to be robust
and allows the use of a mixture of 2,4, and succinimide
as isolated directly from the bromination reaction. The
presence of succinimide does not affect the reaction.
Thus, bromination of 2 (1.4 equiv. NBS, 5–10 mol%
Vazo® 672/PhCl/70°C) is carried out in nearly full
conversion (entry 2, Table 1). Then, heptane is added to
the reaction mixture and a solid mixture of 2,4, and
succinimide is isolated in 94% yield. The above mixture
(typical mole ratio of 2:4 is about 2.5:1; succinimide is
about 30 wt%) is treated with MeSO2Na (1.1 equiv. for
2 and 2.5 equiv. for 4) at ambient temperature in
DMAc containing 20% water in the presence of 2.5
equiv. NaHCO3. Sulfone formation can be carried out
in aqueous DMAc without suffering hydrolysis of a-
mono/a,a-dibromides. The reaction solution is aged at
ambient temperature until all the a-monobromide 2 is
consumed (about 2 h). The reaction solution is then
heated at 90°C for approximately 10 h to convert 4 to
1. The crystalline sulfone product 1 is isolated in 92%
yield and 98 A% purity by adding water at the end of
the reaction.6
Figure 1. Plot of conversion versus time for sulfone formation
at 70°C.
−
During the reaction, 1 equiv. of sulfinate salt (RSO2 ) is
oxidized to sulfonic acid (RSO3H) (Scheme 2), the
The scope of the new sulfone formation reaction was
examined with commercially available or easily pre-
pared a,a-dibromomethyl compounds.7 Table 2 sum-
marizes the results for the reactions using various
a,a-dibromomethyl aromatics and sulfinate salts. In a
typical experiment, 2.5 equiv. of the sulfinate salt and
NaHCO3 are charged. The reaction is typically run in
DMAc containing 20% water at elevated temperature
(70–110°C). In most of the cases, the product is crystal-
lized by addition of water at the end of the reaction.
detailed mechanism for reduction of a-bromosulfone to
−
sulfone with sulfinate salt (RSO2 ) has not been further
investigated. Sulfinic acid is a weaker acid and is not
stable under acidic conditions,5 therefore, addition of a
base such as NaHCO3 is required to improve efficiency
−
in use of the sulfinate salt (RSO2 ) and prevent forma-
tion of sulfinic acid during the reaction. A plausible
reaction pathway is shown in Scheme 2.
As shown in Table 2, the sulfone formation works
extremely well when the aromatics bear electron-with-
drawing groups. The reduction of the corresponding
a-bromosulfone is faster relative to displacement. In
fact, the displacement competition product, a,a-disul-
fonylmethyl aromatics, was not observed.8 Without
having an electron-withdrawing group, the reduction of
a-bromosulfone slows down and requires going to
higher reaction temperatures, while the formation of
the bromosulfone is still fast. The displacement
product, a,a-disulfonylmethyl aromatics, starts to form
as the reaction temperature is increased so that the
Scheme 2. Reaction pathway for formation of sulfone.

F. Xu et al. / Tetrahedron Letters 44 (2003) 1283–1286
1285
Table 2. Synthesis of sulfones from dibromides
reduction reaction could take place. In entry 7, a,a-
dibromotoluene was allowed to reacted with NaSO2Me
at 110°C for 1 day to give a mixture of the monosul-
fone and the displacement product a,a-disulfone (2.5:1).
If the reaction is carried out at 70°C, the bromosulfone
is the only product. Aromatic sulfinate salt PhSO2Na
works as well as MeSO2Na, as shown in entries 3 and
4.

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F. Xu et al. / Tetrahedron Letters 44 (2003) 1283–1286
Schneider, H. Ger. Offen. 19917025, 2000; (c) Lehmann, B.
Ger. Offen. 19757995, 1999; (d) Awano, H.; Shimoda, A.;
Kubo, M. Jpn. Kokai Tokkyo Koho 11130708, 1999; (e)
Kikichi, D.; Sakaguchi, S.; Ishii, Y. J. Org. Chem. 1998,
63, 6023; (f) Shaw, H.; Perlmutter, H. D.; Gu, C. J. Org.
Chem. 1997, 62, 236; (g) Yoneda, Y.; Yamamoto, Y.;
Okamura, S.; Ataka, K. Jpn. Kokai Tokkyo Koho
09031059, 1997; (h) Kleiner, H.-J.; Regnat, D. Ger. Offen.
9531164, 1997; (i) Waykole, L.; Prashad, M.; Palermo, S.;
Repic, O.; Blacklock, T. J. Synth. Commun. 1997, 27, 2159.
4. Yashimatsu, M.; Ohara, M. Tetrahedron Lett. 1997, 38,
5651.
Scheme 3. Proposed reaction pathway for formation of 1,2-
bis[(methylsulfonyl)methyl]benzene.9
5. (a) Oae, S.; Kunieda, N. Organic Chemistry of Sulfur; Oae,
S., Ed.; Plenum: New York, 1977; Chapter 11; (b) Truce,
W. E.; Murphy, A. M. Chem. Rev. 1951, 48, 69.
For o-methyl a,a-dibromo-o-xylene (entry 6) the reac-
tion proceeds via a different pathway, formation of the
disulfone product is believed to take place via an elimi-
nation–addition sequence (Scheme 3). Formation of the
trisulfone product in entry 2 is believed to involve a
combination of elimination–addition and reduction
pathway.
6. Interestingly, at elevated temperature the O-alkylated by-
product 6 (typically 3–4 A%, generated from 2) was also
converted to the desired sulfone 1. This was confirmed by
subjecting the isolated 6 to the reaction conditions. Sulfi-
nate ester is a by-product often observed by reacting an
alkyl bromide with a sulfinate salt. For mechanistic studies
on converting sulfinate esters to sulfones, see: Hendrick-
son, J. B.; Skipper, P. L. Tetrahedron 1976, 32, 1627.
a,a-Dichloromethyl aromatics are easily converted to
the chlorosulfone, but the chlorosulfone is not reduced
to the sulfone.
In conclusion, a novel method for high yielding prepa-
ration of sulfones simply by reacting a,a-dibro-
momethyl aromatics with sulfinate salts has been
demonstrated. The new method makes it possible to use
mixtures of mono- and dibromomethyl aromatics to
prepare sulfones in high yields. Since a,a-dibro-
momethyl aromatics are often obtained in the radical
bromination used to prepare monobromomethyl aro-
matics, this discovery eliminates the need to achieve
high selectivity in the bromination.
7. a,a-Dibromomethyl compounds can be prepared in vari-
ous ways, see: (a) Hoffmann, R. W.; Bovicelli, P. Synthesis
1990, 657; (b) Guo, W.; Duann, Y. F. Org. Prep. Proced.
Int. 1990, 23, 85; (c) Lansinger, J. M.; Ronald, R. C.
Synth. Commun. 1979, 9, 341; (d) Hase, T. Acta Chem.
Scand. 1970, 24, 2263.
8. For a recent review on reactivity and application of a-halo
sulfonyl compounds, see: Paquette, L. A. Synlett 2001, 1.
9. Spectral data for new compounds:
References
1 - [Bis(methylsulfonyl)methyl] - 2 - [(methylsulfonyl)methyl]-
1
benzene: H NMR (CDCl3): l 8.05 (m, 1H), 7.58 (m, 2H),
1. For recent reviews, see: (a) Najera, C.; Sansano, J. M.
Recent Res. Dev. Org. Chem. 1998, 637; (b) Simpkins, N.
S. Sulphones in Organic Synthesis; Baldwin, J. E.; Magnus,
P. D., Eds.; Tetrahedron Org. Chem. Series, Vol. 10;
Pergamon Press: Oxford, 1993.
7.43 (m, 1H), 6.43 (s, 1H), 4.62 (s, 2H), 3.26 (s, 3H), 2.90
(s, 3H), 1.57 (s, 3H); 13C NMR (DMSO-d6): l 134.2,
131.1, 130.7, 130.5, 129.3, 125.9, 80.0, 55.8, 42.4.
1
1,2-Bis[(methylsulfonyl)methyl]benzene: H NMR (CDCl3):
l 7.44 (m, 4H), 4.66 (s, 4H), 2.94 (s, 6H); 13C NMR
(CDCl3): l 133.5, 129.9, 128.5, 58.4, 40.4.
2. Vazo® is a DuPont registerted name for free radical
sources. Vazo® 67: 2,2%-azobis(2-methylbutanenitrile);
Vazo® 52: 2,2%-azobis(2,4-dimethylpentanenitrile).
1-[Bis(methylsulfonyl)methyl]-4-methylbenzene: 1H NMR
(CDCl3): l 7.52 (d, J=8 Hz, 2H), 7.29 (d, J=8.0 Hz, 2H),
5.25 (s, 1H), 3.20 (s, 6H), 2.40 (s, 3H); 13C NMR (CDCl3):
l 141.5, 130.7, 130.4, 121.6, 86.2, 41.0, 21.4.
3. For recent examples, see: (a) Noda, K.; Matsui, N.;
Miyazaki, H. Jpn. Kokai Tokkyo Koho 20020522, 2002; (b)