One-Pot Sulfoxide Synthesis Exploiting a Sulfinyl-Dication Equivalent Generated from a DABSO/Trimethylsilyl Chloride Sequence

Article abstract of DOI:10.1021/acs.orglett.6b00712

A one-pot process for the synthesis of unsymmetrical sulfoxides using organometallic nucleophiles is described. Sulfur dioxide, delivered from the surrogate DABSO (DABCO-bis(sulfur dioxide)), acts as the initial electrophile and combines with the first organometallic reagent to generate a sulfinate intermediate. In situ conversion of the sulfinate to a sulfinate silyl ester, using TMS-Cl (trimethylsilyl chloride), generates a second electrophile, allowing addition of a second organometallic reagent. Organolithium or Grignard reagents can be employed, delivering sulfoxides in good to excellent yields.

Full text of DOI:10.1021/acs.orglett.6b00712

Letter
pubs.acs.org/OrgLett
One-Pot Sulfoxide Synthesis Exploiting a Sulfinyl-Dication Equivalent
Generated from a DABSO/Trimethylsilyl Chloride Sequence
Danny C. Lenstra, Vincent Vedovato, Emmanuel Ferrer Flegeau, Jonathan Maydom,
and Michael C. Willis*
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA, United
Kingdom
S
* Supporting Information
ABSTRACT: A one-pot process for the synthesis of unsym-
metrical sulfoxides using organometallic nucleophiles is
described. Sulfur dioxide, delivered from the surrogate
DABSO (DABCO-bis(sulfur dioxide)), acts as the initial
electrophile and combines with the first organometallic reagent
to generate a sulfinate intermediate. In situ conversion of the
sulfinate to a sulfinate silyl ester, using TMS-Cl (trimethylsilyl chloride), generates a second electrophile, allowing addition of a
second organometallic reagent. Organolithium or Grignard reagents can be employed, delivering sulfoxides in good to excellent
yields.
he sulfoxide moiety is a fundamental functional group
found in many biologically active molecules.1 For
example, omeprazole, a gastric acid inhibitor, is listed as an
essential medicine by the World Health Organization (Figure
1).2 In addition, sulfoxides are used as ligands in organometallic
Scheme 1. Common Strategies for the Synthesis of
Sulfoxides, DABSO in a Three-Component Sulfone
Synthesis, and the Proposed DABSO-Based Sulfoxide
Synthesis
T
Figure 1. Medicinally relevant sulfoxides.
chemistry,3 as organocatalysts,4 and as intermediates in a variety
of organic transformations, such as the Pummerer and Evans−
Mislow rearrangements, and syn-eliminations.5
The most widely employed method for the synthesis of
sulfoxides is by oxidation of the corresponding sulfides, for
which a wide variety of reagents have been reported (Scheme 1,
eq 1).6 Drawbacks of these procedures are the requirement for
stoichiometric amounts of oxidant, the resultant limited
functional group compatibility, and overoxidation to give
sulfone products. In addition, the sulfide starting materials are
most usually prepared from the corresponding thiols, which are
commonly foul smelling. Sulfoxides can also be obtained by
nucleophilic displacement on sulfinyl derivatives, such as
sulfinamides, and sulfinic esters, with organometallic reagents
(Scheme 1, eq 2).7,8 However, these starting materials are often
of limited availability. The modification of existing sulfoxides,
including the use of palladium-catalyzed protocols,9 has also
emerged as a useful tool.10 Despite these advances, general,
efficient methods to access sulfoxides, ideally employing readily
available starting materials, remain in demand.
Received: March 11, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00712
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
We have recently reported a three-component one-pot route
to sulfones,11a in which an intermediate sulfinate salt (1),
generated from an organometallic reagent and the sulfur
dioxide surrogate DABSO (DABCO-bis(sulfur dioxide)),12−14
undergoes S-alkylation to deliver sulfone products (Scheme 1,
eq 3). In this process, SO2 is effectively functioning as a sulfonyl
cation/anion synthon. Following the success of the sulfone
chemistry, we wished to develop a related route to sulfoxides,
for which the key goals would be to achieve an operationally
simple one-pot process, employ readily available substrates,
avoid the use of thiols, and allow the preparation of sulfoxides
possessing varied substitution patterns.
To achieve these goals, and in particular to access the correct
S-oxidation state, we would need to employ a reagent, or
reagent combination, that reacts as a sulfinyl dication synthon.15
We speculated this should be possible if we could engineer a
polarity reversal of the key intermediate (relative to our sulfone
synthesis), and deliver an electrophilic species, which would
allow the addition of a second nucleophilic organometallic
reagent (Scheme 1, eq 4). To achieve the desired polarity
reversal we focused on the ambidentate nature of the initially
formed sulfinate, reasoning that if we could identify a suitable
electrophile to favor O-alkylation we would generate a sulfinate
ester (1 → 2, Scheme 1, eq 4). The sulfinate ester would then
undergo reaction with a second organometallic reagent, to
deliver the desired sulfoxide product. The combination of SO2,
delivered from the solid, bench stable surrogate DABSO, and
an O-alkylated sulfinate would provide the targeted sulfinyl
dication equivalent. This Letter documents the successful
realization of this process.
Table 1. Optimization of the Synthesis of Sulfoxide 5a
b
DABSO
(equiv)
t1/t3
(min)
TMSCl
(equiv)
t2
yield (%)/
b
entry
4 (equiv) (min)
(5a:6a)
1
0.40
0.50
0.60
0.50
0.50
0.50
0.50
0.50
0.50
0.50
90
90
90
90
90
90
90
90
45
45
1.30
1.30
1.30
1.30
1.30
1.30
1.30
1.50
1.50
1.50
1.20
1.20
1.20
1.00
0.95
0.75
0.50
0.50
0.50
0.75
90
90
90
90
90
90
90
90
45
45
91 (3:1)
2
83 (6:1)
3
89 (7:1)
4
75 (10:1)
87 (17:1)
98 (18:1)
96 (14:1)
96 (>25:1)
97 (>25:1)
97 (>25:1)
5
6
7
8
9
10
a
b
Reaction conditions: 3 (1.0 equiv) and as in table. Isolated yields.
1
Ratio of 5a:6a determined by H NMR spectroscopy.
conditions involved all steps of the process being performed at
room temperature, with only a 45 min delay between each stage
of the reaction.
We began our investigation by attempting the synthesis of
diaryl sulfoxide 5a, from the combination of the two relevant
aryl Grignard reagents, the SO2-surrogate DABSO, and a
suitable electrophile, with the identification of the electrophile
being the initial challenge. Meerwein’s reagent, triethyloxonium
tetrafluoroborate, is one of the few examples of a C-electrophile
reported to react through the oxygen atom of a sulfinate.16
Unfortunately, Meerwein’s reagent is also known to react with
ethereal solvents, in which organometallic reagents are typically
stored and used, and as such we considered its use impractical.
Inspired by Vogel’s silyl sulfinate chemistry,17 we surmised that
a Si-electrophile should allow the formation of a suitable
sulfinate ester. Turks has also recently shown that silyl sulfinate
esters, formed using ene chemistry, do combine effectively with
Grignard reagents.18 In the event, the use of the simplest and
most cost-effective silyl reagent, TMS-Cl (trimethylsilyl
chloride), proved to be effective. Optimization of the basic
process, employing Grignard reagents 3 and 4, DABSO, and
TMS-Cl, is shown in Table 1.
Initial reactions quickly established that the main issue with
the proposed synthesis of sulfoxide 5a was concomitant
formation of the symmetrical sulfoxide 6a (Table 1, entry 1).
However, variation of the stoichiometries of the process,
including increasing the equivalents of DABSO (entries 1−3),
reducing the equivalents of the second Grignard reagent (4,
entries 4−7), and then slightly increasing the amount of TMS-
Cl (entries 7−8), improved the selectivity of the reaction
considerably. Finally, in order to deliver the most practically
straightforward process we also reduced the times for each step
of the one-pot reaction and were pleased to find that this in
turn allowed an increase in the amount of the second Grignard
reagent used, meaning that the first Grignard reagent was not
used in large excess (entries 9 and 10). The optimized
With the optimized conditions in hand, we set out to explore
the scope of the reaction (Scheme 2). A diverse set of
commercially available and in situ generated Grignard reagents
were used to synthesize a variety of sulfoxides. We were pleased
to find that aromatic Grignard reagents bearing electron-
donating, -neutral, and -withdrawing groups could be
combined, to afford unsymmetrical diaryl sulfoxides in good
yields (5a−d). The initial addition of an aryl Grignard reagent
could be partnered effectively with primary (5e), secondary
(5f,g), and tertiary alkyl Grignard reagents (5h) to deliver
mixed arylalkyl sulfoxides.
The order of addition of the organometallic reagents could
also be reversed, with a range of primary, secondary alkyl, and
benzylic Grignard reagents partnering effectively with the
secondary addition of aryl reagents, to deliver good yields of the
targeted sulfoxides (5i−n). The combination of two different
alkyl Grignard reagents was also effective (5o), as were allyl/
aryl (5p) and alkenyl/aryl (5q) combinations. Several hetero-
cycle-derived Grignard reagents were successfully used (5r−t).
The preparative utility of the chemistry was demonstrated by a
larger scale synthesis of sulfoxide 5f; starting from 2.0 g of
DABSO (8.5 mmol) allowed sulfoxide 5f to be isolated in 92%
yield (2.65 g).
Next, we moved on to investigate whether the reaction was
compatible with alternative organometallic reagents (Table 2).
Entries 1 and 2 demonstrate the effective use of an alkyl or aryl
Grignard reagent as the first nucleophile, partnered with an
organolithium reagent as the second; in both cases the desired
sulfoxides were obtained in good yields. Employing organo-
lithium reagents as the first component, followed by Grignard
reagents as the second, was also successful, providing good
yields of sulfoxides (entries 3 and 4). Disappointingly, the use
of organolithium reagents as both nucleophilic components
B
DOI: 10.1021/acs.orglett.6b00712
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Scope of Sulfoxide Synthesis Employing Grignard
Reagents, DABSO, and TMS-Cl
Table 2. Sulfoxide Synthesis Employing Varied
Organometallic Reagents
a
a
a
Reaction conditions: R1-M (1.0 equiv), DABSO (0.5 equiv), TMSCl
b
(1.50 equiv), R2-M (0.75 equiv) 0.33 M. Isolated yields. 1:1 mixture
of diastereomers.
sulfinate 7, generated from 4-F−C6H4−MgBr, DABSO, and
PhMe2Si−Cl, was isolated in 99% yield (Scheme 3). Treatment
Scheme 3. Preparation of Silyl Sulfinate 7, and the
Conversion of 7 into Sulfoxide 5f
of silyl sulfinate 7 with cyclohexyl magnesium chloride
delivered sulfoxide 5f in 66% yield, providing good support
for the proposed reaction intermediate. A one-pot sequence
employing PhMe2Si−Cl in place of Me3Si−Cl was also
evaluated, and in this case sulfoxide 5f was obtained in 76%
yield.
a
Reaction conditions: R1−MgX (1.0 equiv), DABSO (0.5 equiv),
TMSCl (1.50 equiv), R2−MgX (0.75 equiv), 0.33 M. Isolated yields.
In conclusion, we have developed a general one-pot
procedure for the preparation of sulfoxides from organometallic
reagents, DABSO, and trimethylsilyl chloride. This protocol is
applicable to commercially available and in situ generated
Grignard and organolithium reagents, and combinations
thereof. A wide variety of sulfoxides were obtained in good
to excellent isolated yields. The use of room temperature
conditions, short reaction times, and readily available starting
materials is notable.
only delivered the sulfoxide products in poor yields; a
representative example is shown in entry 5.
Our initial reaction design invokes the formation of an in situ
generated silyl sulfinate ester (2, Scheme 1). To investigate this
hypothesis we attempted to isolate such a silyl sulfinate.
Unfortunately, trimethylsilyl variants of sulfinate ester 2 were
unstable; however, the corresponding dimethylphenylsilyl
esters could be isolated in good yield. For example, silyl
C
DOI: 10.1021/acs.orglett.6b00712
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Emmett, E. J.; Richards-Taylor, C. S.; Willis, M. C. Synthesis 2014, 46,
2701.
(13) For a recent review of SO2 surrogates, see: Emmett, E. J.; Willis,
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00712.
M. C. Asian J. Org. Chem. 2015, 4, 602.
(14) For recent uses of DABSO, see: (a) An, Y.; Xia, H.; Wu, J. Org.
Biomol. Chem. 2016, 14, 1665. (b) Tsai, A. S.; Curto, J. M.; Rocke, B.
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2016, 18, 508. (c) Deeming, A. S.; Russell, C. J.; Willis, M. C. Angew.
Chem., Int. Ed. 2016, 55, 747. (d) Flegeau, F.; Harrison, J. M.; Willis,
M. C. Synlett 2016, 27, 101. (e) Skillinghaug, B.; Rydfjord, J.; Odell, L.
R. Tetrahedron Lett. 2016, 57, 533. (f) Deeming, A. S.; Russell, C. J.;
Willis, M. C. Angew. Chem., Int. Ed. 2015, 54, 1168. (g) Emmett, E. J.;
Hayter, B. R.; Willis, M. C. Angew. Chem., Int. Ed. 2014, 53, 10204.
(h) Richards-Taylor, C. S.; Blakemore, D. C.; Willis, M. C. Chem. Sci.
2014, 5, 222. (i) Zheng, D.; An, Y.; Li, Z.; Wu, J. Angew. Chem., Int. Ed.
2014, 53, 2451. (j) Ye, S.; Wang, H.; Xiao, Q.; Ding, Q.; Wu, J. Adv.
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Angew. Chem., Int. Ed. 2013, 52, 12679. (m) Emmett, E. J.; Richards-
Taylor, C. S.; Nguyen, B.; Garcia-Rubia, A.; Hayter, B. R.; Willis, M. C.
Experimental procedures and full characterization for all
compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: michael.willis@chem.ox.ac.uk.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Stichting Fundatie van de Vrijvrouwe van
Renswoude and Stichting Nijmeegs Universiteits Fonds
(SNUF, to D.C.L.), GlaxoSmithKline (to V.V.), and the
EPSRC for support of this study.
́
Org. Biomol. Chem. 2012, 10, 4007. (n) Woolven, H.; Gonzalez-
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Chem. Soc. 2010, 132, 16372.
(15) A number of preformed sulfinyl dications based on cyclic
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DOI: 10.1021/acs.orglett.6b00712
Org. Lett. XXXX, XXX, XXX−XXX