An efficient synthesis of geminal di-sulfones

Article abstract of DOI:10.1016/S0040-4039(02)00023-0

A simple and efficient method for the synthesis of gem-disulfones is reported. This method is based on protection of one of the central acidic hydrogens of bis(methylsulfonyl)methane as a thioether followed by formation of the dianion and selective alkylation of the methyl group. Alkylation of one of the methyl groups was demonstrated as well as alkylation of both methyl groups with the same or different alkyl groups. Removal of the thioether moiety furnished the desired substituted disulfones.

Full text of DOI:10.1016/S0040-4039(02)00023-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1377–1379
An efficient synthesis of geminal di-sulfones
Yimin Zhu and Dale G. Drueckhammer*
Department of Chemistry, State University at Stony Brook, Stony Brook, NY 11794, USA
Received 28 November 2001; revised 19 December 2001; accepted 20 December 2001
Abstract—A simple and efficient method for the synthesis of gem-disulfones is reported. This method is based on protection of
one of the central acidic hydrogens of bis(methylsulfonyl)methane as a thioether followed by formation of the dianion and
selective alkylation of the methyl group. Alkylation of one of the methyl groups was demonstrated as well as alkylation of both
methyl groups with the same or different alkyl groups. Removal of the thioether moiety furnished the desired substituted
disulfones. © 2002 Elsevier Science Ltd. All rights reserved.
The pyrophosphate moiety is a common structural
motif in many biologically important compounds
including the prenyl pyrophosphates, dinucleotide coen-
zymes, and nucleoside diphosphate sugars. The lability
of the pyrophosphate moiety to phosphatase enzymes
and the inability of such ionic compounds to cross cell
membranes necessitates the modification of this moiety
in the design of analogs of these compounds for poten-
tial in vivo use as enzyme inhibitors and biological
probes.1 A number of surrogates of the pyrophosphate
moiety have thus been prepared including various phos-
phonates, though these compounds maintain the ionic
characteristics.2–4 Neutral analogs include a carbonyl
sulfonamide,5 derivatives of malonic and tartaric acid,
and structures based on monosaccharide moieties.6
Sulfones7 and sulfonate esters8 have been proposed as
neutral mimics of the phosphodiester linkage in nucleic
acids and more recently the disulfone moiety has been
proposed as a neutral mimic of the diphosphate func-
tionality.9–12 However, efforts to synthesize the appro-
priately substituted disulfones have had limited success.
Castro and Spencer studied the alkylation of bis-
(methylsulfonyl)methane 1 as a possible route to disul-
fones.9,10 They showed that reaction with 2 equiv. of
base resulted in double deprotonation of the central
methylene group to form the geminal dianion 2, as
demonstrated by alkylation and deuteration experi-
ments (Scheme 1). Reaction with 3 equiv. of base
formed the trianion 3, alkylation of which formed
products 4 and 5 resulting from alkylation of both the
central and terminal carbons. Yields of the desired
terminal alkylation products 5 were only 25–35%. This
mirrored earlier results observed in alkylation of the
trianion of trifluoromethylsulfonyl methyl sulfone.13
Subsequent alkylation with a second alkyl group was
not demonstrated. Gervay-Hague and co-workers
recently reported a novel reagent 6 that reacts with
aldehydes to form a,b-unsaturated gem-disulfones 7 by
a Horner–Emmons–Wadsworth type reaction (Scheme
2).11 Non-symmetrical products were obtained in good
yields based on the initial aldehyde if an excess of the
disulfone reagent 6 was used in the first step.
O
O
O
O
O
O
1 eq. R-X
O
O
O
O
O
nBuLi
O
O
O
O
2 eq. nBuLi
O
S
S
S
S
S
S
S
S
-
=
3
=
2
R
4
1
O
O
O
O
+
S
S
R
5
Scheme 1.
Keywords: disulfone; alkylation; pyrophosphate mimic.
* Corresponding author. Tel.: 631-632-7923; fax: 631-632-7960; e-mail: dale.drueckhammer@sunysb.edu
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00023-0

1378
Y. Zhu, D. G. Drueckhammer / Tetrahedron Letters 43 (2002) 1377–1379
O
C
O
O
O
O
O
O
O
P
iPrO
O
O
O
O
R'
H
R C
H
S
S
S
S
P OiPr
OiPr
iPrO
R
R'
iPr2NEt
iPr2NEt
7
6
Scheme 2.
Presented here is a newly developed method for the
synthesis of unsymmetrical geminal disulfones. The key
feature of this method is ‘protection’ of one of the
central methylene hydrogens of bis(methylsul-
fonyl)methane 1 as a thioether. Thus, initial reaction of
the disulfone 1 with N-ethylthio phthalimide 8 under
basic conditions as previously described for several
active methylene compounds formed the thioketal 9 in
97% yield (Scheme 3).14 Compound 9 was converted to
the thioether 10 in 87% yield upon reaction with
ethanethiolate with excess sodium hydride, again fol-
lowing the general method previously described
(Scheme 3).14 The thioether prevents formation of a
dianion at the central carbon, thus reaction of 10 with
2 equiv. of butyllithium formed the dianion 11. Alkyla-
tion of this dianion with iodopentane formed 12. Using
1.67 equiv. of 11 relative to iodopentane, a 76% yield of
12 was obtained based on iodopentane along with 17%
yield of the dialkylation product 13. The formation of
13 is consistent with the expectation that proton
exchange between 11 and the monoanion of 12 should
be more rapid than the alkylation reaction, as has been
observed in the alkylation of methyl phenyl sulfone.15
When 3 equiv. of 11 were used, the yield of 12 was
essentially unchanged, though no dialkylation product
was observed. Removal of the ethylthio group from 12
was accomplished by reaction with ethanethiolate in the
presence of ethanethiol in ethanol to form 14 in quanti-
tative yield.14
Synthesis of a symmetrically disubstituted disulfone was
accomplished as shown in Scheme 4. Reaction of 10
with 3 equiv. of n-butyllithium followed by addition of
2 equiv. of pentyl iodide formed the disubstitution
product 13 in 63% yield. Removal of the ethylthio
group was accomplished as before to form 15 in quanti-
tative yield. For synthesis of an unsymmetrically disub-
stituted disulfone, the monosubstituted product 12 was
converted to the dianion which was reacted with benzyl
bromide to form 16 in 87% yield (Scheme 5). Removal
of the ethylthio group formed the unsymmetrical disul-
fone 17 quantitatively. Interestingly, no product from
O
O
O
O
NaSEt, EtSH
EtOH
1. 2 eq. nBuLi
2. PhCH2-Br
S
S
(CH2)4-CH3
12
Ph
SEt
16
O
O
O
O
S
S
(CH2)4-CH3
Ph
17
Scheme 5.
O
N SEt
O
O
O
O
O
O O
S
O
O
O
O
O
2 eq. nBuLi
NaSEt, NaH
THF
8
O
S
S
S
S
S
1
-
-
Et3N, CH2Cl2
SEt
11
SEt
EtS SEt
9
10
O
O O
O
O
O
O
O
NaSEt, EtSH
EtOH
S
S
S
+
S
(CH2)4-CH3
(CH2)4-CH3
14
SEt
O
I-(CH2)4-CH3
12
O
O
O
CH3-(CH2)4
S
S
(CH2)4-CH3
SEt
13
Scheme 3.
Scheme 4.
O
O
O
O
3 eq. nBuLi
2 eq. I-(CH2)4-CH3
NaSEt, EtSH
EtOH
CH3-(CH2)4
S
S
10
13
(CH2)4-CH3
15

Y. Zhu, D. G. Drueckhammer / Tetrahedron Letters 43 (2002) 1377–1379
1379
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the reactions. This is in contrast to alkylation reactions
of the anion of phenyl methyl sulfone, in which signifi-
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This work was supported by National Institutes of
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