DABSO-based, three-component, one-pot sulfone synthesis

Article abstract of DOI:10.1021/ol403122a

The addition of Grignard reagents or organolithium reagents to the SO ₂-surrogate DABSO generates a diverse set of metal sulfinates, suitable for direct conversion to sulfone products. The metal sulfinates can be trapped in situ with a wide range of C-electrophiles, including alkyl, allyl, and benzyl halides, epoxides, and (hetero)aryliodoniums.

Full text of DOI:10.1021/ol403122a

Letter
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DABSO-Based, Three-Component, One-Pot Sulfone Synthesis
Alex S. Deeming,† Claire J. Russell,‡ Alan J. Hennessy,‡ and Michael C. Willis*,†
†Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA,
United Kingdom
‡Syngenta, Jealott’s Hill International Research Centre, Bracknell, Berkshire RG42 6EY, United Kingdom
S
* Supporting Information
ABSTRACT: The addition of Grignard reagents or organolithium reagents to the SO2-surrogate DABSO generates a diverse set
of metal sulfinates, suitable for direct conversion to sulfone products. The metal sulfinates can be trapped in situ with a wide
range of C-electrophiles, including alkyl, allyl, and benzyl halides, epoxides, and (hetero)aryliodoniums.
he importance of the sulfonyl unit (−SO2−) is apparent
treating an organometallic reagent with sulfur dioxide gas,11 but
this protocol is particularly unattractive due to the difficulties
in handling a toxic gaseous reagent.12 We therefore sought to
develop a one-pot process capable of delivering a diverse array
of sulfones via sulfur dioxide incorporation but employing an
amine−SO2 complex in place of SO2 gas. The complex formed
between DABCO and sulfur dioxide, DABSO, was first em-
ployed by us in a novel palladium-catalyzed aminosulfonylation
reaction13 and subsequently in a streamlined version of Barrett’s
sulfonamide synthesis.14 The use of such reagents not only
eradicates the hazards associated with the gaseous reagent but
also allows for the measured delivery of sulfur dioxide in reac-
tion systems. Consequently, the generation of metal sulfinates
from organometallic reagents and DABSO was identified as a
potentially efficient and versatile route into sulfone synthesis.
This could be achieved by exploiting the nucleophilicity of the
sulfinate intermediates with subsequent in situ trapping with a
host of different electrophiles (Scheme 1).15
T
from its ubiquity in medicinal chemistry and agrochemical
targets.1 Sulfones are an important subclass of these com-
pounds and are found in a variety of biologically active mol-
ecules. For example, they have been shown to display anti-
bacterial, anti-HIV, and antifungicidal activity (Figure 1).2,3
Figure 1. Representative biologically active sulfones.
Scheme 1. Three-Component Sulfone Synthesis Combining
an Organometallic Reagent, DABSO, and an Electrophile
From a synthetic perspective, sulfones are also versatile inter-
mediates4 and are implicit in such classic transformations as the
Ramberg−Backlund reaction5 and the Julia olefination.6
As a result of their widespread use, efficient and robust ap-
proaches toward the synthesis of sulfones are in high demand.
The most common method of forming sulfones is a two-pot
protocol from the corresponding sulfide,7 which usually re-
quires thiol substrates and oxidative conditions. The availability
of alkenyl- and heterocyclic thiols is poor, and the use of oxi-
dative conditions imposes limitations on the functional groups
that can be tolerated. Reactions of sodium sulfinates with elec-
trophiles8 and in metal-catalyzed processes9 have also been
applied in sulfone synthesis. However, the very limited com-
mercial availability of the sodium salts, and their alternative
preparation from the corresponding sulfonyl chlorides, restricts
their applicability.10 Metal sulfinates can also be formed by
We began our studies by exploring the electrophilic trapping
of alkylmagnesium sulfinates, employing benzyl bromide as
the electrophile (Table 1). With the in situ formation of the
n-butylmagnesium sulfinate from the corresponding Grignard
Received: October 30, 2013
Published: December 5, 2013
© 2013 American Chemical Society
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Table 1. Initial Screening and Optimization of Conditions
Table 2. Organometallic Substrate Scope for the One-Pot
Preparation of Benzyl Sulfones
a
for S-Alkylation of DABSO-Generated Magnesium
a
Sulfinates
entry
solvent
temp (°C)
time (h)
yield (%)
1
2
THF
THF
120
120
120
120
120
120
150
1
2
49
55
58
68
80
85
86
78
81
68
72
3
THF/H2O
THF/DMF
DMF
2
4
2
5
2
6
DMF
3
7
DMF
3
b
8
DMF
70
16
16
3
b
9
DMF
120
10
11
EtOH
120
120
DMA
3
a
n
Reaction conditions: BuMgCl (1 equiv), DABSO (1 equiv), THF,
−40 °C then benzyl bromide (3 equiv), solvent, and heat using
b
microwave. Conventional heating.
reagent and DABSO, it was found that maintaining THF as the
solvent in combination with microwave heating in the second
step could deliver the desired S-alkylated product (1a) in a
moderate 55% yield (entries 1 and 2). This was improved when
moving to more polar solvents (entries 3−9), with the ex-
ception of water as a cosolvent which resulted in a significant
amount of benzyl alcohol formation, and the product was
isolated in only 58% yield (entry 3). The optimal set of con-
ditions for sulfinate alkylation was identified as microwave heat-
ing at 120 °C in DMF for 3 h (entry 6). Employing a higher
reaction temperature (entry 7) or normal overnight heating
(entry 8) failed to deliver any improvement in sulfone yield.
O-Alkylation, leading to the sulfinic acid ester products, was not
observed in any examples.8b
With an optimal set of conditions in hand, we then explored
the range of Grignard and organolithium reagents that were
compatible with this system (Table 2). We were pleased to
find that a range of alkyl-, allyl-, alkenyl-, aryl-, and hetero-
arylmagnesium and -lithium reagents, generated using a variety
of methods, delivered the desired metal sulfinates and that
these could be efficiently alkylated in situ. For lower reactivity
sulfinates, generated from electron poor aryl- or alkenyl
organometallics, improved yields were obtained from the use
of increased reaction times and/or benzyl bromide equivalents
(see entries 6 and 9, for example). An attractive feature of the
system was that heteroaromatic compounds such as benzo-
thiazole and N-methylindole that are capable of undergoing
direct deprotonation with butyllithium can serve as simple sub-
strates yielding useful functionalized sulfone products (entries 17
and 19). For example, benzothiazol-2-yl sulfones serve as sub-
strates in the modified Julia olefination reactions where alkenes
can be generated in a single step.16 From the data obtained there
were no clear trends as to whether organomagnesium or organ-
olithium reagents were more effective; the ease of preparation
of the individual organometallic was most often the deter-
mining factor in selecting the type of reagent employed.
In order to demonstrate the versatility of this system, a range
of electrophilic coupling partners were next evaluated, with
initial studies concentrating on the use of additional alkyl
a
Reaction conditions: organometallic (1 equiv, commercial reagent
unless stated), DABSO (1 equiv), THF, −40 °C then benzyl bromide
b
(3−5 equiv), DMF, 120 °C using microwave heating, 3 h. RMgX
c
generated from the corresponding bromide and Mg. Using 5 equiv
d
of BnBr and microwave heating for 5 h. Using 5 equiv of BnBr.
e
n
t
RLi generated from the corresponding bromide and BuLi or BuLi.
f
g
i
RMgX generated from the corresponding iodide and PrMgCl. RLi
h
n
t
generated via deprotonation with BuLi or BuLi. The N−H pyrrole
product was isolated.
halides (Table 3). As anticipated, alternative benzylic halides
resulted in efficient trapping with the preparation of the
corresponding sulfones in good yields (entries 1 and 2). Allylic
(entries 3 and 4) as well as α-bromocarbonyl-derived (entry 5)
electrophiles were also effective. The use of alkyl bromide
electrophiles resulted in a reduction in sulfone yield (30−40%).
However, this could be simply overcome by employing alkyl
iodides, as demonstrated by the use of iodopropane to deliver
the corresponding dialkyl sulfone in 74% yield (entry 6).
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in good yield and with reasonable selectivity (1d, 1e). These are
the first examples of heteroaryl sulfones being prepared from the
corresponding iodonium salts. Replacing the p-methoxyphenyl
ring with a sterically encumbering mesityl group, or a dimeth-
yluracil group,18 had a detrimental impact on both yield and
selectivity.
Table 3. Extending the Substrate Scope for the in Situ
Electrophilic Trapping of Metal Sulfinates with Alternative
a
Alkyl Halides
In order to access β-hydroxy sulfone products, we next
turned our attention to the use of epoxides as electrophiles.
Sodium sulfinates have been shown to effectively ring-open
epoxides; however, the scope of such systems is significantly
limited, with phenyl- and p-tolylsulfonyl being the major
examples.19 We therefore aimed to exploit the versatile
formation of metal sulfinates using DABSO in the synthesis
of a diverse set of β-hydroxy sulfones (Scheme 3). On initial
Scheme 3. Extending the Substrate Scope for the in Situ
Electrophilic Trapping of Metal Sulfinates with Epoxides
a
n
Reaction conditions: BuMgCl (1 equiv), DABSO (1 equiv), THF,
−40 °C then electrophile (3 equiv), DMF, 120 °C using microwave
b
heating, 3 h. 5 equiv of Pr-I.
Recent work from Manolikakes has shown that aryl
hypervalent iodine reagents can be successfully employed as
electrophiles in combination with metal sulfinates to yield diaryl
sulfones.17 To extend the profile of the compatible electrophiles
in our system, an examination of iodonium salts as electrophilic
aromatic counterparts was conducted (Scheme 2). Aryliodonium
Scheme 2. Symmetrical and Unsymmetrical Iodonium Salts
as Electrophiles in a One-Pot Reaction with Magnesium
Sulfinates
examination of the in situ reaction of the n-butylmagnesium
sulfinate with cyclohexene oxide, it was found that the original
set of conditions was not applicable, with negligible conversion
in DMF observed. However, on switching to aqueous con-
ditions productivity was improved significantly. It is generally
considered that such a polar, protic solvent is integral for coor-
dination to the epoxide oxygen, activating it toward nucleo-
philic attack.19b We found that with the use of 5 equivalents of
the epoxide and heating at 90 °C in water, the anti-diastereomer
of the desired β-hydroxy sulfone (1f) could be formed in 78%
yield. Employing the corresponing organolithium reagent af-
forded a comparable result (75%). Using these optimized reac-
tion conditions we set out to evaluate the range of hydroxy
sulfones that could be accessed using this method (Scheme 3).
Pleasingly, alkyl- and arylmagnesium sulfinates performed well
in this system (1f−i). Again, electron-rich aryl sulfinates were
the more effective nucleophiles, although electron-withdrawing
groups were also shown to be compatible (1j). Several cyclic
salts were successfully employed, affording unsymmetrical alkyl
aryl and diaryl sulfones (1b, 1c). Of particular note is the
formation of pyridyl sulfones using the unsymmetrical aryl-
heteroaryl iodonium triflates. Electronically distinguishing
the two aromatic groups by using the p-methoxyphenyl- and
2-chloropyridyl constituents allowed heteroaryl group transfer
to be favored, with the corresponding pyridyl sulfones formed
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Hayter, B. R.; Willis, M. C. Angew. Chem., Int. Ed. 2013, 52
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(10) Zhou, X.; Luo, J.; Liu, J.; Peng, S.; Deng, G.-J. Org. Lett. 2011,
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2-methylglycidate we were able to demonstrate the utility of
this system with the generated sulfone (1t) providing the car-
bon backbone present in the antiandrogenic agent bicalutamide
(Casodex, Figure 1) which is used in the treatment of prostate
cancer.
In conclusion, we have developed a simple, versatile one-pot
sulfone synthesis based on the in situ electrophilic trapping of
metal sulfinates generated from organometallic reagents and
DABSO. By employing a wide range of both organometallic
substrates and electrophiles a broad class of sulfones can be
synthesized in moderate to excellent yields using this method.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and full characterization for all
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: michael.willis@chem.ox.ac.uk.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the EPSRC and Syngenta for their support of this
study.
■
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