Dimsyl anion in the monoalkylation of solid-phase alkyl sulfones

Article abstract of DOI:10.1016/S0040-4039(02)00423-9

Polymer-bound α-sulfonyl monocarbanions can be generated very effectively with dimsyl anion. The highly efficient and convenient protocols presented here report the preparation of α,β-unsaturated ketones and vinylaryl compounds using dimsyl anion to achie

Full text of DOI:10.1016/S0040-4039(02)00423-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2967–2970
Dimsyl anion in the monoalkylation of solid-phase alkyl sulfones
a
b
a,
Wei-Chieh Cheng, Chu-Chung Lin and Mark J. Kurth *
a
Department of Chemistry, University of California, One Shields Avenue, Davis, CA 95616-5295, USA
b
Taigen Biotechnolog 7F, 138 Shin Ming Rd., Neihu Dist., Taipei 114, Taiwan, ROC
Received 12 February 2002; revised 27 February 2002; accepted 28 February 2002
Abstract—Polymer-bound a-sulfonyl monocarbanions can be generated very effectively with dimsyl anion. The highly efficient
and convenient protocols presented here report the preparation of a,b-unsaturated ketones and vinylaryl compounds using dimsyl
anion to achieve the key solid-phase a-sulfonyl monocarbanion alkylation step. © 2002 Elsevier Science Ltd. All rights reserved.
The solution-phase geminal dialkylation of a,a-sulfonyl
Preliminary solution-phase studies were undertaken to
survey reaction conditions and establish the modifica-
tions required for SPOS. LDA was the first base
employed in our trial and, to mimic solid-phase condi-
tions, excess base (2 equiv.) and electrophile (epoxide, 3
equiv.) were employed at various temperatures to per-
form the epoxide-alkylation reactions (Scheme 1, Table
1). At lower temperature (e.g. −78°C), the reaction
proceeds best (78% yield of 4), but the yield was poor at
room temperature (18%) and unreacted starting mate-
rial (3) was recovered (50% recovery; presumably due
to LDA decomposition at room temperature in THF).
These results led us to select LDA at −78°C for our
investigation of solid-phase monoalkylation.
dicarbanions with various electrophiles has been stud-
1
2
ied by Kaiser and others. According to those proto-
1
,2
cols, the a,a-dilithiosulfone is typically generated by
two equivalents of BuLi in THF and subsequently
n
undergoes smooth geminal dialkylation. In solid-phase
organic synthesis (SPOS), excess reagents are often
employed to drive reactions to completion; thus, poly-
mer-bound a,a-dilithiosulfones can be readily prepared
8,9
n
3
with excess BuLi. In contrast, given the vagaries of
stoichiometry and reaction rates on solid-phase, it is
difficult to perform a controlled generation of an a-
n
monolithiosulfone on resin using BuLi (Fig. 1). More-
over, functional groups such as amides and aryl halides
n
are incompatible with the use of BuLi. Even though
the solution-phase preparation of a-sulfonyl monocar-
banions can be accomplished by the use of stoichiomet-
n
4
ric BuLi or LDA, the efficient solid-phase production
of a-monolithiosulfones for use in monoalkylations has
not been explored.
As part of an investigation of the feasibility of solid-
phase sulfone monoalkylation, we set out to prepare
5
a,b-unsaturated ketones via a four-step process con-
sisting of (i) sulfinate S-alkylation; (ii) sulfone
monoalkylation with epoxides; (iii) g-hydroxy sulfone“
g-ketosulfone oxidation, and (iv) polymer-bound
Figure 1.
6
benzenesulfinate elimination with release of the desired
a,b-unsaturated ketone product from the resin (Fig. 2).
While these a,b-unsaturated ketones can be prepared
via the Claisen–Schmidt base-catalyzed aldol condensa-
7
tion, they have not, to our knowledge, been prepared
3,7
via SPOS using a traceless sulfone linker strategy.
*
Corresponding author. Tel.: +1-(530)-752-8192; fax: +1-(530)-752-
995; e-mail: mjkurth@ucdavis.edu
8
Figure 2. Benzenesulfinate 1“a,b-unsaturated ketones 2.
0
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00423-9

2
968
W.-C. Cheng et al. / Tetrahedron Letters 43 (2002) 2967–2970
Ph SO2
Ph SO2 OH
O
base,
THF
Me
Me
3
4
Scheme 1. Solution-phase monoalkylation with propylene
oxide.
Table 1.
Entry
Basea
Temp.
Yield of 4 (%)
Scheme 2. Loading of 1=0.5 mmol/g. Reagents and condi-
tions: (a) 4-bromobenzyl bromide, THF/DMF, 80°C. (b) Base
b
1
2
3
4
LDA
LDA
LDA
Rt
18
67
78
93
b
b
−30°C
−78°C
Rt
(
5 equiv.), THF; propylene oxide (7 equiv.), THF. (c) Swern
Dimsylc
oxidation.
a
12
−
+
Two equivalents of base and three equivalents of propylene oxide
the use of dimsyl anion [CH S(O)CH M ; DMSO,
3
2
were used.
i
pK =35] in place of LDA [( Pr) NH, pK =36] for the
a
2
a
b
c
i
LDA=( Pr) NLi.
13
2
generation of solid-phase a-sulfonyl monocarbanions.
Dimsyl=CH S(O)CH Li.
3
2
In solution-phase studies, treatment of 3 with dimsyl
14
anion (2 equiv.) at room temperature followed by
addition of propylene oxide gave 4 in 93% yield
In the event, treatment of sulfone resin 5a (see Scheme
; 1“5a) with LDA (now, 5 equiv.) at −78°C followed
(
Scheme 1). We next extended this encouraging result
2
to solid-phase, now employing dimsyl anion for a-sul-
by addition of propylene oxide (now, 7 equiv.) gave
resin 6a. Since this transformation exhibited no reliably
diagnostic absorption peaks in the single bead FTIR
spectrum, we decided to release the target molecule
fonyl monocarbanion formation—now at room temper-
15
ature. Following the protocol outlined in Scheme 2,
monocarbanion formation and alkylation of 5a with
propylene oxide followed by oxidation of intermediate
10
from the solid support via Swern oxidation of 6a with
6
a led to the a,b-unsaturated ketone via concomitant
concomitant linker cleavage by sulfinate elimination
linker cleavage by sulfinate elimination. Enone 7a was
11
following our published protocol. The resulting a,b-
unsaturated ketone (7a) was produced smoothly in 72%
overall yield from starting resin 1.
obtained in 90% overall yield for this three-step process.
To further illustrate the merits of employing dimsyl
anion for solid-phase sulfone monoalkylation, polymer-
bound benzyl phenyl sulfones 5a (R=Br) and 5b (R=
Me) together with propylene and styrene oxides were
Although the solid-phase monoalkylation of 5a using
LDA was viable, we realized that the low temperature
1
6
(
−78°C) requirement as well as the relative instability of
utilized to build a small library of enones (7a–d), as
illustrated in Scheme 3. Monocarbanion formation and
alkylation delivered resins 6a–d which, upon Swern
LDA would be inconvenient in combinatorial library
production. These considerations led us to investigate
Scheme 3. Loading of 1=0.5 mmol/g. Reagents and conditions: (a) 4-bromobenzyl bromide or 4-methylbenzyl chloride,
THF/DMF, 80°C. (b) CH S(O)CH Li (5 equiv.), THF; propylene or styrene oxide (7 equiv.), THF. (c) Swern oxidation.
3
2

W.-C. Cheng et al. / Tetrahedron Letters 43 (2002) 2967–2970
2969
oxidation with concomitant sulfinate elimination, deliv-
ered a,b-unsaturated ketones 7a–d in excellent overall
yields from starting resin 1 (82–90%).
tion to trigger elimination of polymer-bound benzene-
sulfinate. Thus, treating resin 9 with floride anion
18
(TBAF)
in THF for 6 h delivered the target
molecules—vinylaryl compounds 10a–c—in high yields
(80–89%; Scheme 5).
In addition to sulfone aninon opening of epoxides, we
also examined the use of chloromethyltrimethylsilane as
our alkylation reagent. We again started in solution-
phase by reacting 3 with bases (2 equiv.) followed by
addition of chloromethyltrimethylsilane to afford 8
In summary, polymer-bound a-sulfonyl monocarban-
ions can be generated by LDA (−78°C) or dimsyl anion
(room temperature) and undergo alkylation with epox-
ides to generate g-hydroxy sulfones (6) or
chloromethyltrimethylsilane to generate b-silyl sulfones
(
Scheme 4, Table 2). As hoped, monoalkylation pro-
duced 8 in high yield (95%) when dimsyl anion was
used as base. In contrast, the conversion was sluggish
with LDA as base at −78°C (entries 1 and 2), but
improved in the presence of added crown ether (15-
(
9). In each case, the more convenient and efficient
protocol employs dimsyl anion as base.
1
7
crown-5; entry 3).
Acknowledgements
Following the solid-phase monoalkylation protocols
shown in Schemes 2 and 3, monocarbanions of resins
5
a–c were generated by treatment with dimsyl anion at
We thank the National Science Foundation and Cystic
Fibrosis Foundation for financial support of this
research. C.-C.L. thanks Taigen Biotechnology for the
opportunity to do a sabbatical study at the University
of California, Davis. The 400 and 300 MHz NMR
spectrometers used in this study were funded in part by
a grant from NSF (CHE-9808183).
room temperature. Subsequent monoalkylation by
treatment with chloromethyltrimethylsilane generated
resins 9a–c. This transformation exhibited reliably diag-
nostic absorption peaks in the single bead FTIR spec-
−
1
trum (SiꢀC bond at 1250 cm ). To release our target
molecules from the resin, we chose a new cleavage
strategy that employed the silane moiety at the b posi-
Ph SO2
Ph SO2
References
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Scheme 4. Solution-phase monoalkylation with propylene
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Temp./time
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b
Entry
1
2
3
4
LDA
−78°C/2 h
−78°C/5 h
−78°C/3 h
Rt/2 h
55
75
89
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(
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Scheme 5. Solid-phase monoalkylation with ClCH SiMe .
2
3

2
970
W.-C. Cheng et al. / Tetrahedron Letters 43 (2002) 2967–2970
8
. Similar epoxide opening reactions have been reported by
Julia and Uguen with the use of BuLi (1 equiv., −78°C)
as base. See: Julia, M.; Uguen, D. Bull. Soc. Chim. Fr.
added to DMSO (10 equiv., 0.3 g) in THF (10 mL) at
n
0°C and stirred for 5 min. The resulting dimsyl anion
solution was transferred to a suspension of polymer 5a
(0.8 g, 0.38 mmol) in THF (6 mL) at room temperature;
the resin color changed from pale yellow to yellow. After
30 min, propylene oxide (7 equiv., 0.16 g) was added to
this mixture; the color turned light orange. The reaction
was quenched with 10% HCl (aq.) after 1 h and the resin
was filtrated, washed, and dried to afford resin 6a as pale
yellow beads: IR (single bead reflectance) 1600, 1492,
1
976, 513.
9
. Attempts to separate the diastereomeric mixture of 4 are
not feasible with flash column chromatography. Oxida-
tion (Jones’ reagent) of 4 delivers 4-benzenesulfonyl-4-(p-
tolyl)butan-2-one in quantitative yield: IR (neat) 1718,
−
1 1
1
3
4
314, 1145 cm ; H NMR l 2.13 (s, 3H), 2.27 (s, 3H),
.24 (dd, 1H, J=18, 9 Hz), 3.56 (dd, 1H, J=18, 4.2 Hz),
.69 (dd, 1H, J=9, 4.2 Hz), 6.95–7.54 (m, 9H); C NMR
13
−1
1452, 1310, 1138 cm .
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6
1
1
2
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5
73.
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1
1
3. Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456.
4. Dimsyl anion was prepared by addition of BuLi to
DMSO (1/2 molar ratio) in THF at 0°C.
n
1
5. Typical procedure for the transformation (5a“6a) with
n
dimsyl anion as base: BuLi (5 equiv., 1.2 mL, 1.6 M) was