Synthesis of sulfones from organozinc reagents, DABSO, and alkyl halides

Article abstract of DOI:10.1021/ol4031233

Organozinc reagents react with the SO₂ surrogate DABSO, and the resulting zinc sulfinate salts are alkylated in situ to afford sulfones. This transformation has a broad scope and is compatible with a wide range of structural motifs of medicinal

Full text of DOI:10.1021/ol4031233

Letter
pubs.acs.org/OrgLett
Synthesis of Sulfones from Organozinc Reagents, DABSO, and Alkyl
Halides
Benjamin N. Rocke,* Kevin B. Bahnck, Michael Herr, Sophie Lavergne, Vincent Mascitti,
Christian Perreault,† Jana Polivkova, and Andrei Shavnya
Pfizer Worldwide Medicinal Chemistry, Eastern Point Road, Groton, Connecticut 06340, United States
S
* Supporting Information
ABSTRACT: Organozinc reagents react with the SO2
surrogate DABSO, and the resulting zinc sulfinate salts are
alkylated in situ to afford sulfones. This transformation has a
broad scope and is compatible with a wide range of structural
motifs of medicinal chemistry relevance including nitrile,
secondary carbamates, and nitrogen-containing heterocycles.
ulfones constitute a diverse structural class associated with
medicinal chemistry due to the limited practicality associated
Simportant applications. In organic synthesis, such mole- with their current synthesis (synthesis of precursors,4b,h,i harsh
conditions,4a,f,g side reactions,5 the propensity of their
conjugate acids to disproportionate,6 and the use of SO2, a
toxic gas).
cules are intermediates in the Julia olefination1a−c and
Ramberg−Backlund rearrangement,1c−f two transformations
̈
routinely used to construct olefins. Furthermore, as demon-
strated by the antimigraine medicine eletriptan (Relpax, 1),2
sulfones are found in numerous medicines and drug candidates
under development for the treatment of a host of diseases
impacting human health worldwide (Figure 1).3
Recent publications from Willis7 highlighted the discovery of
the reagent DABSO (DABCO·2SO2) as a surrogate for SO2
and its application to sulfonamide, N-aminosulfonamide,
sulfamide, and sulfone synthesis. We envisioned that sulfones
could be advantageously obtained in a one pot reaction of
Scheme 1. Sulfone Synthesis via Sulfinate Salts
Figure 1. Biologically active sulfones.
Sulfones are prepared by a variety of methods. Thiol building
blocks are typically employed, and the desired oxidation state is
subsequently achieved via redox chemistry3a,c−e using protocols
often lacking practicality. Because speed to establish structure−
activity relationships (SAR) is critical in medicinal chemistry
programs, we sought to facilitate access to this chemotype by
developing a method that would be conducive to rapid
analogue generation. Such a reaction would need to be
operationally simple, mild (for functional group tolerance),
and of broad scope while using readily available and easily
handled reactants. Although the use of sulfinate salts addresses
this goal,4 these intermediates have been underutilized in
organozinc reagents, DABSO, and alkyl halides (Scheme 1).
Organozinc reagents are (1) available commercially or are
mildly prepared (vs sulfonyl chlorides4b,i), (2) they do not
necessarily require prefunctionalization, and (3) their decreased
reactivity (vs organolithium and Grignard reagents4a,f,g,7b) was
expected to increase functional group tolerance, decrease side
reactions during sulfinylation, and improve operational
Received: October 30, 2013
Published: December 5, 2013
© 2013 American Chemical Society
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Letter
simplicity for potential parallel chemical synthesis applications.
To the best of our knowledge, the addition of organozinc
reagents to SO2 has not been described.8
Table 2. Scope of the Reaction between DABSO and
Organozinc Reagents
Initial experiments were designed to establish standard
conditions for this transformation. Cyclohexylzinc bromide
(5a) was selected as an unfunctionalized, commercially
available organozinc reagent. We quickly determined that
good yields were achieved when sulfinylation was conducted in
the presence of only 0.55 equiv of DABSO for 15 min at room
temperature (21 °C). Although colder temperatures or shorter
reaction times seemed feasible, we found further optimization
to be unnecessary. In situ alkylation of the resulting zinc
sulfinate intermediate9 was probed with tert-butyl bromoace-
tate, a reagent in which we had particular interest for one of our
programs and which we observed to afford purely S-alkylated
Table 1. Optimization of Zinc Sulfinate Alkylation
a
entry
alkylation conditions
yield (%)
1
2
3
4
BrCH2CO2-t-Bu (1.1 equiv), 70 °C, 1 h
BrCH2CO2-t-Bu (1.1 equiv), 21 °C, 17 h
BrCH2CO2-t-Bu (2 equiv), 70 °C, 1 h
BrCH2CO2-t-Bu (2 equiv), 21 °C, 17 h
BrCH2CO2-t-Bu (2 equiv), 70 °C, 1 h
46
59
78
81
<5
b
5
a
b
Yields are for products isolated after chromatography. DMSO was
not added.
products10 (Table 1). Although alkylation was accomplished in
a moderate yield at 21 °C with as little as 1.1 equiv of alkylating
agent (entries 1 and 2), we observed significant improvements
by employing 2 equiv of alkylating agent at either 70 °C for 1 h
(entry 3) or at 21 °C overnight (entry 4). Addition of DMSO
as a cosolvent was required to effect alkylation (entry 5), likely
to solubilize the intermediate zinc sulfinate (many of which are
insoluble in THF). Although alkyl halides are known to
undergo Kornblum oxidation11 in DMSO at elevated temper-
atures, we did not observe detrimental effects on the intended
reaction.12 Thus, we selected the 1 h, 70 °C reaction using 2
equiv of alkylating reagent as our standard conditions.
With optimized reaction conditions in hand, we investigated
the reactivity of a series of commercially available organozinc
reagents (Table 2). Using tert-butyl bromoacetate as the
alkylating agent, we obtained good yields of the corresponding
sulfone products from primary (entries 1−2) and cyclic
secondary (entry 4) alkylzinc reagents. Reformatsky-type
reagents (entries 5−6) afforded sulfone products in modest
yields. A range of arylzinc reagents also reacted under the
standard conditions to afford the desired sulfones (entries 7−
17). The highest yields were obtained when electron-with-
drawing substituents (entries 11−13 and 17) were present in
the organozinc reagent; electron-neutral (entries 8−10) and
electron-rich (entries 14−16) substrates afforded products in
lower yields (31−44%). Using the reaction to sulfone 6n (entry
14) as an example, anisole was observed to account for greater
than 80% of the remaining mass balance.13 Ortho substitution
(entries 10, 13, and 16) appeared to have little effect on the
reaction. In addition, heterocyclic zinc reagents (entries 18 and
19) were competent substrates in this reaction. In all of the
above cases, only S-alkylation was observed.
a
b
Yields are for products isolated after chromatography. The reaction
was conducted under similar but nonstandard conditions. See the
c
Supporting Information for details. SO2 gas was substituted for
DABSO. Products estimated to be 90−95% pure. Product estimated
to be 90−95% pure. Product estimated to be 80−85% pure.
d
e
As illustrated with compound 6c, DABSO (entry 2) proved
superior in a direct comparison to SO2 gas (entry 3), leading to
higher isolated yields (75% vs 62%).
With organozinc sulfinylation established, a range of
additional alkyl halide electrophiles were selected to probe
the scope of the in situ alkylation of the zinc sulfinate
intermediates (Table 3). Suitable electrophiles included
primary alkyl iodides (entries 1 and 2) and benzyl bromide
(entry 3), producing sulfones 6t−v in 68−89% yield. A
secondary alkyl iodide (entry 4) returned sulfone 6w in modest,
yet useful, yield whereas the corresponding secondary alkyl
bromide (entry 5) proved ineffective. As already demonstrated
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Letter
Table 3. Electrophile Scope in the Alkylation of Zinc
Sulfinate Salts
Table 4. One-Pot Conversion of Alkyl and Aryl Halides to
Sulfones
a
b
Yields are for products isolated after chromatography. Product
estimated to be 90−95% pure.
a
b
Yields are for products isolated after chromatography. Calculated
elsewhere, chloroacetonitriles4c and epoxides4i are also
competent electrophiles in reactions with zinc sulfinate salts.
To expand the utility of this protocol beyond commercially
available organozinc reagents and explore its potential for
parallel medicinal chemistry applications, we investigated a
series of tandem reactions converting alkyl and aryl iodides of
medicinal chemistry relevance into sulfones (Table 4). Zinc
insertion was accomplished according to standard procedures.14
Sulfinylation in the presence of 0.55 equiv of DABSO and
subsequent alkylation produced sulfones 6x−z and 6bb in 77−
90% yield. Addition of DMSO was unnecessary when the
reaction was conducted in a polar aprotic solvent. Yields were
consistent with the results in Table 2, although a lower yield
was observed in the case of 6aa, where the highly sensitive
acetophenone substrate (5aa) was used.
using a titrated16 organozinc solution as the limiting reagent.
c
Calculated using the starting halide as the limiting reagent.
d
Sulfinylation was conducted with similar but nonstandard conditions.
See the Supporting Information.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, compound characterization data, and
1H and 13C NMR spectra for compounds 6a−bb. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
In contrast to methods employing organolithium and
Grignard reagents,4a,f,g,7b the present method is notable for its
functional group tolerance and operational simplicity. Halides,
esters, nitriles, and even weakly acidic secondary carbamates
can be incorporated into products with high yields, and
sulfinylation is smooth at 21 °C. Of particular note, (1) ester
homoenolates react productively, allowing a synthesis of β-
sulfonyl esters (e.g., 6f) complementary to the traditional 1,4-
addition to an enone;4a,g (2) although obtained in low yield,
product 6aa would not be readily accessible by methods such as
Mg/I exchange15a or electrophilic aromatic substitution;15b and
(3) the compatibility of secondary carbamate functionality with
organozinc reagents allows for the synthesis of unnatural amino
acid derivatives (e.g., 6z).
In conclusion, we have established the reaction between
organozinc reagents, DABSO, and alkyl halides as an important
route to mixed dialkyl and alkyl aryl sulfones. This method will
prove useful in subsequent studies for transition-metal-
mediated sulfone synthesis,4c−e,7e oxidative sulfonamide
synthesis,4f,7b and C−C bond-forming reactions.1
*E-mail: benjamin.n.rocke@pfizer.com.
Present Address
†Currently affiliated with Paraza Pharma, Laval, QC, Canada.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank Jason Ramsay of Pfizer Worldwide Medicinal
Chemistry, Groton, CT, for HRMS determinations.
■
REFERENCES
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