Nickel(II)-Catalyzed Synthesis of Sulfinates from Aryl and Heteroaryl Boronic Acids and the Sulfur Dioxide Surrogate DABSO

Article abstract of DOI:10.1021/acscatal.9b04363

We report a redox-neutral Ni(II)-catalyzed sulfination of readily available aryl and heteroaryl boronic acids. Using the combination of commercially available, air-stable NiBr₂·(glyme), a commercially available phenanthroline ligand, and DABSO, boronic acids are efficiently converted to the corresponding sulfinate salts, which can be further elaborated to valuable sulfonyl-containing groups, including sulfones, sulfonamides, sulfonyl fluorides, and sulfonate esters. The catalyst loading can be reduced to 2.5 mol ?% on a gram scale. This practically simple protocol tolerates an unprecedented range of pharmaceutically relevant and electron-poor (hetero)aryl boronic acids, allowing the direct synthesis of active pharmaceutical ingredients.

Full text of DOI:10.1021/acscatal.9b04363

Letter
pubs.acs.org/acscatalysis
Cite This: ACS Catal. 2019, 9, 10668−10673
Nickel(II)-Catalyzed Synthesis of Sulfinates from Aryl and Heteroaryl
Boronic Acids and the Sulfur Dioxide Surrogate DABSO
Pui Kin Tony Lo, Yiding Chen, and Michael C. Willis*
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, United
Kingdom
S
* Supporting Information
ABSTRACT: We report a redox-neutral Ni(II)-catalyzed
sulfination of readily available aryl and heteroaryl boronic
acids. Using the combination of commercially available, air-
stable NiBr2·(glyme), a commercially available phenanthroline
ligand, and DABSO, boronic acids are efficiently converted to
the corresponding sulfinate salts, which can be further
elaborated to valuable sulfonyl-containing groups, including
sulfones, sulfonamides, sulfonyl fluorides, and sulfonate esters.
The catalyst loading can be reduced to 2.5 mol % on a gram scale. This practically simple protocol tolerates an unprecedented
range of pharmaceutically relevant and electron-poor (hetero)aryl boronic acids, allowing the direct synthesis of active
pharmaceutical ingredients.
KEYWORDS: nickel, catalysis, sulfinates, boronic acids, sulfones, sulfonamides, sulfonyl fluorides, sulfur dioxide
ulfonyl-containing (−SO2−) compounds such as sulfones
sulfonamides,8,14 sulfonyl fluorides,8e,15 and sulfonate esters.8f
Sand sulfonamides have broad applications in fields ranging Sulfinates can also be employed as reaction partners in
desulfinylative cross-coupling processes,16 and as radical
precursors.17 Later, aryl boronic acids were also employed in
place of aryl halides, and these substrates have also been used
in combination with Au(I),18 Pd(II),8c,10b,19 and Cu(I)8d
catalysts (see Figure 1d). Despite these advances in sulfinate
synthesis, signficant challenges remain unsolved. For example,
the scope of these processes is generally limited to electron-
rich or neutral aryl systems. Electron-poor aryl and heteroaryl
boronic acids commonly provide only low yields of products,
or fail completely.8c,d,f,g,18−20 An exception to this is the
palladium-catalyzed system reported by Chen and Tu, in which
a bespoke N-heterocyclic carbene ligand enables some success
with these substrates for the synthesis of simple sulfone
products. However, a general catalytic system that employs
commerical reaction components and is able to tolerate a
broad range of electronically varied boronic acids is as yet
unknown.
from synthetic chemistry,1 pharmaceuticals, and agrochemicals,
to materials science (see Figures 1a−c).2 Conventional
approaches to synthesize these valuable functional groups
can often require multistep sequences. For example, sulfones
are usually synthesized by oxidation of the corresponding
sulfides, which, in turn, are commonly prepared from alkylation
of thiols.3 The use of thiols is a limitation because of their
often unpleasant odor, and their relatively limited availability
from commercial vendors. Aryl sulfonamides, meanwhile, are
most usually available from the combination of sulfonyl
chlorides and amines.4 However, the preparation of the former
via the electrophilic aromatic substitution (SEAr) of arenes
requires harsh acidic reaction conditions, which limits
functional group tolerance.5 In addition, the high levels of
regiocontrol often observed in SEAr processes makes access to
all isomers of these products challenging.
Catalytic methods for the sulfination of abundant feedstocks,
such as aryl halides and boronic acids, have had a tremdous
impact of the synthesis of sulfonyl-containing molecules.6 In
2010, our laboratory reported the use of DABCO·(SO2)2
(DABSO) as a convenient sulfur dioxide surrogate.7 This air-
stable, easy-to-handle, and now commercially available solid
has been employed by us,8 and others,9 to access a wide range
of sulfonyl-containing products using metal catalysis. Inorganic
sulfur dioxide surrogates such as K2S2O5 and Na2S2O5 have
also been used,10 as have noncatalytic methods.11
In recent years, a focus of both academic and industrial
communities has been the use of abundant base-metal catalysts
in synthetic chemistry. In particular, the replacement of
precious metal catalysts with these lower-cost, more-sustain-
able metals that are less susceptible to risk of supply, has
attracted significant attention.21 Nickel catalysis features
prominently in this field, not only because of its significantly
lower cost, relative to palladium, but also because it frequently
provides alternative, often complementary, reactivity.22 For
The direct palladium-catalyzed synthesis of sulfinate salts
from aryl halides represented a signficant advance,8a,12 as these
versatile intermediates could be readily transformed to a
variety of valuable functional group, such as sulfones,13
Received: October 9, 2019
Revised: October 22, 2019
© XXXX American Chemical Society
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Table 1. Optimization of Reaction Conditions for the
a
Formation of Sulfinate 1a from Phenylboronic Acid
a
Reaction conditions: phenylboronic acid (0.2 mmol, 1.0 equiv),
NiBr2·(glyme) (10 mol %), tmphen (10 mol %), DABSO (0.12 mmol,
0.6 equiv), LiOt-Bu (0.2 mmol, 1.0 equiv), DMI (1.0 mL, 0.2 M).
Yields were calculated from HPLC analysis using acetophenone as an
internal standard.
With the optimized conditions in hand, we examined the
scope, with respect to boronic acids, by reacting the in situ
formed sulfinates with tert-butyl bromoacetate as the electro-
phile, to prepare the corresponding sulfones in a one-pot two-
step sequence (see Table 2). Generally, a wide range of aryl
boronic acids could be effectively converted to sulfinates and
then to sulfones. Boronic acids bearing different electronic
substitutions were well-tolerated, with electronically neutral
phenyl (2a) and p-trimethylsilyl (2b), and electron-rich p-
methoxy (2c) and p-thiomethyl (2d) substituents delivering
excellent isolated yields. Previously challenging substrates with
electron-withdrawing groups could also be incorporated in the
arene unit, including sensitive functional groups such as nitrile
(2g), ketone (2i), and ester (2j), as well as the first example of
a trifluoromethylated aryl boronic acid being used in catalytic
sulfination chemistry (2f). Boronic acids substituted with all
four halogens (2k−2o) were well-tolerated under the reaction
conditions, with the caveat that using NiI2 as the catalyst was
necessary when p-iodophenyl boronic acid (2o) was the
substrate. For this example, using the original NiBr2·(glyme)
catalyst resulted in a degree of bromo/iodo substitution in the
product. The catalyst loading could be lowered to 2.5 mol %,
delivering 70% isolated yield of sulfone (2m) on a 0.2 mmol
scale, and a 71% yield when performed on a gram scale (7
mmol) at a slightly elevated temperature (110 °C). Further
reducing the catalyst loading to 1 mol % resulted in diminished
yields. Methylthio (2d)- and methanesulfonyl (2h)-substituted
examples showcase the potential utility of this reaction,
demonstrating how it is possible to access mixed-oxidation-
state S-centers, as well as disparate sulfonyl functional groups.
Meta-substituted boronic acids were also reacted well, giving
identical yields compared to the para-substituted counterpart
(2g and 2q). However, ortho-substituted (2r) and alkenyl
boronic acid (2s) were less successful, with only poor to
modest product yields isolated even at elevated temperature.
Figure 1. (a−c) Applications of sulfones and sulfonamides; and (d)
catalytic synthesis of sulfinates from boronic acids.
example, nickel undergoes ready oxidative addition with less-
reactive and more-abundant electrophiles such as aryl
chlorides, ethers, and carbamates.22a−c In addition, it can be
used, in combination with photoredox catalysts, to deliver
modes of reactivity23 that are challenging to achieve with
palladium systems. Given these advantages, we speculated that
nickel catalysis could deliver new reactivities in sulfination
chemistry and address the limitations of earlier catalytic
methods (see Figure 1d).
We selected the addition of phenylboronic acid to DABSO
as a test platform and evaluated a range of Ni(II) catalysts (see
Table 1). We were pleased to find that using 10 mol % of
commercially available and air-stable NiBr2·(glyme), in
combination with 10 mol % of 3,4,7,8-tetramethyl-1,10-
phenanthroline (tmphen) as ligand, was sufficient to promote
the reaction, providing the targeted sulfinate in 91% yield. The
reaction used DMI as a solvent at 100 °C and required only 0.6
equiv of DABSO and 1 equiv of LiOt-Bu (Table 1, entry 1). A
lower reaction temperature (90 °C), higher loading of ligand,
or base, or increasing the concentration, all provided less-
efficient reactions (Table 1, entries 2−6). We also found that
using a strong base was crucial in this transformation, with
LiOt-Bu being optimal; using a weaker base or KOt-Bu
resulted in diminished yields (Table 1, entries 7 and 8).
Substituting DABSO for an inorganic source of sulfur dioxide
(K2S2O5), or replacing phenylboronic acid with potassium
phenyltrifluoroborate was unproductive (Table 1, entries 9 and
10). Full details of the reaction optimization are provided in
the Supporting Information.
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a
Table 2. Scope of the Boronic Acid Reaction Component
a
Reaction conditions: (hetero)aryl boronic acid (0.2 mmol, 1.0 equiv), NiBr2·(glyme) (10 mol %), tmphen (10 mol %), DABSO (0.12 mmol, 0.6
equiv), LiOt-Bu (0.2 mmol, 1.0 equiv), DMI (1.0 mL, 0.2 M), 100 °C, 16 h, then tert-butyl bromoacetate (2.0 equiv), rt, 1 h. bNiI2 used as catalyst.
d
e
f
g
h
c120 °C. 110 °C. 6 h for second step. 2 h for second step. 1 h for first step. 2 h for first step.
We were pleased to find that several pharmaceutically relevant
boronic acids reacted smoothly under the optimized
conditions, delivering the sulfonylarene core of the COX2
inhibitor Celecoxib (2u), antiulcer drug Zolimidine (2v) and
CrtN inhibitor NP16 (2w).2b A range of heteroaryl boronic
acids were also suitable substrates, including O- (2x, 2y) and S-
heterocycles (2z, 2aa), as well as a variety of challenging
substituted pyridyl groups (2ab−2af). Imidazopyridine (2ag),
indazole (2ah), and azaindole (2ai) groups were also included,
delivering the desired sulfones in good yields. It is also worth
noting that, in previous reported sulfinations of aryl boronic
acids using Au(I),18 Pd(II),8c,19,20 or Cu(I)8d catalytic systems,
electron-deficient aryl (e.g., nitrile, trifluoromethyl) and
pyridine-derived boronic acids generally reacted poorly or
failed completely. However, these substrates reacted smoothly
under the Ni(II) catalytic systems reported here, highlighting
the utility of the present chemistry.
We then explored alternative derivatization processes for the
sulfinate intermediates. p-Chlorophenylboronic acid was
selected as the model substrate. Table 3a outlines the sulfones
prepared by combining the sulfinates with a variety of carbon-
based electrophiles, including alkyl halides (3a), heteroaryl
halides (3b), diaryliodonium salts (3c), and epoxides. The
antiulcer drug Zolimidine (3d) was prepared conveniently
using methyl iodide as the alkylating agent. In situ alkylation of
the sulfinate intermediates with allyl bromide afforded allyl
sulfones (3e−3h), which are a class of sulfone with established
utility in desulfinative cross-coupling and aromatic sulfonyla-
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Letter
sulfones in good yields (3i−3m) and allowed the direct
synthesis of the antiandrogen pharmaceutical Casodex (3m).
The examples in Table 3b show that sulfonamides are
accessible if N-electrophiles are used. Secondary and tertiary
sulfonamides are available using an electrophile generated from
the combination of an appropriate amine and N-chlorosucci-
nimide (NCS).14b The conditions can tolerate both secondary
(4a−4c) and primary (4f) amines, including amino acids (4d)
and anilines (4e), as well as other biologically relevant amines
(4c, 4g). Different boronic acid reaction partners were also
employed, allowing the preparation of an analogue of
Celecoxib (4h) and the CrtN inhibitor NP16 (4i). Primary
sulfonamides were available by combining the in-situ-
generated sulfinates with hydroxylamine-O-sulfonic acid
(H2NOSO3H).25 Several pyridyl (4k, 4l) examples were
prepared in good yield, as was the primary sulfonamide
Celecoxib (4m).
Table 3. Scope of Carbon- and Nitrogen-Based
Electrophiles To Form Sulfones and Sulfonamides
a
Sulfonyl fluorides have recently received increased recog-
nition in the field of chemical biology, because of their
unconventional balance between reactivity and stability under
physiological conditions.26 Table 4 shows that, by using N-
fluorobenzenesulfonimide (NFSI) as the electrophilic compo-
nent, we are able to prepare a selection of sulfonyl fluorides in
good to modest yields.
Table 4. Preparation of Sulfonyl Fluorides, Using NFSI as
a
the Electrophilic Reagent
a
Reaction conditions for sulfinate derivatization step: aqueous
b
workup, then DIPEA (3 equiv), NFSI (1.5 equiv), rt, 1 h. NFSI (1
equiv) used.
Pentafluorophenyl (PFP) sulfonate esters are often crystal-
line and bench-stable replacements for sulfonyl chlorides.8f,27
Our laboratory has recently reported the preparation of PFP
sulfonate esters using copper-catalyzed oxidative coupling of
sulfinates and pentafluorophenol.8f Here, we show that the
copper-catalyzed PFP sulfonate ester synthesis can be
combined with nickel-catalyzed sulfinate formation. Accord-
ingly, PFP-ester 6 was prepared in 52% yield from the
corresponding boronic acid (see Scheme 1).
In conclusion, we have developed the first examples of
nickel-catalyzed sulfination. The developed chemistry is redox-
neutral and combines (hetero)aryl boronic acids and DABSO
a
Reaction conditions for sulfinate derivatization step: E+ (2 equiv), rt
or 100 °C, 1 h. For epoxides: aqueous workup, DIPEA (3 equiv),
epoxide (5 equiv), H2O, 100 °C, 48 h. For sulfonamides: R1R2NH
(1.5 equiv), NCS (1.5 equiv), 0 °C to rt, 1 h; H2N-OSO3H (2 equiv),
rt, H2O, 24 h. For individual variations, see the Supporting
Scheme 1. Synthesis of a PFP Sulfonate Ester
b
Information. For products 3i−3l, dr >20:1.
tion processes.16d,24 Notably, pyridine- (3f, 3g) and Celecoxib-
derived (3h) allyl sulfones were prepared in good yields.
Epoxide ring opening delivered the corresponding β-hydroxy
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
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Palladium(II)-Catalyzed Synthesis of Sulfinates from Boronic Acids
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With DABSO. Org. Chem. Front. 2016, 3, 693−696. (e) Wang, K.;
Wang, G.; Duan, G.; Xia, C. Cobalt(II)-Catalyzed Remote C5-
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Halides, Potassium Metabisulfite, and Hydrazines. Chem. Commun.
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■
S
Experimental procedures and supporting characteriza-
tion data and spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: michael.willis@chem.ox.ac.uk.
■
ORCID
Michael C. Willis: 0000-0002-0636-6471
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the EPSRC (EP/K024205/1) for support of this
study.
■
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