Application of fundamental organometallic chemistry to the development of a gold-catalyzed synthesis of sulfinate derivatives

Article abstract of DOI:10.1002/anie.201400037

The development of a gold(I)-catalyzed sulfination of aryl boronic acids is described. This transformation proceeds through an unprecedented mechanism which exploits the reactivity of gold(I)-heteroatom bonds to form sulfinate anions. Further in situ elaboration of the sulfinate intermediates leads to the corresponding sulfones and sulfonamides, two pharmacophores routinely encountered in drug discovery. A la mode: A gold(I)-catalyzed synthesis of sulfinates has been accomplished. Preparation of proposed intermediates, X-ray studies, and a number of mechanistic experiments suggest that an unprecedented mode of reactivity for gold(I) has been achieved. The resulting sulfinates from this reaction can be functionalized in situ to form sulfones and sulfonamides.

Full text of DOI:10.1002/anie.201400037

Angewandte
Chemie
DOI: 10.1002/anie.201400037
Sulfination
Application of Fundamental Organometallic Chemistry to the
Development of a Gold-Catalyzed Synthesis of Sulfinate Derivatives**
Miles W. Johnson, Scott W. Bagley, Neal P. Mankad, Robert G. Bergman, Vincent Mascitti,* and
F. Dean Toste*
Abstract: The development of a gold(I)-catalyzed sulfination
of aryl boronic acids is described. This transformation
proceeds through an unprecedented mechanism which exploits
the reactivity of gold(I)–heteroatom bonds to form sulfinate
anions. Further in situ elaboration of the sulfinate intermedi-
ates leads to the corresponding sulfones and sulfonamides, two
pharmacophores routinely encountered in drug discovery.
ment over the last decade of palladium- and copper-catalyzed
methods[7] to access sulfonyl motifs, and the importance of
such pharmacophores in drug discovery, a gold-mediated
sulfination would be of great interest from both a fundamental
organometallic and synthetic organic chemistry standpoint.
Herein we report the first gold(I)-catalyzed synthesis of
sulfinate salts from aryl and heteroaryl boronic acid deriva-
tives.[8]
G
old complexes, often associated with the activation of p-
We initially explored sulfur dioxide insertion into
a number of gold–carbon bonds with the metal center
supported by the robust N-heterocyclic carbene (NHC)
bonds toward nucleophiles,[1] have rarely been employed in
reactions with traditional coupling reagents such as boronic
acids.[2] We envisioned that incorporation of a boronic acid
into an X-type heteroatom ligand[3] for gold(I) might provide
an alternative to the oxidative addition/transmetalation/
reductive elimination pathway often associated with this
class of reagents. In this context, we were inspired by the
formation of gold–SO2 bonds from gold(I) aryl complexes,
which have largely been unexplored since the seminal works
of Johnson and Puddephatt,[4] and Aresta and Vasapollo.[5,6]
Based on the literature precedent for SO2 insertion into gold–
carbon bonds, we posited that this elementary step could be
coupled with the more recent discovery of gold alkoxides and
hydroxides and their ability to transmetalate with boronic
acids[3b] to establish a redox neutral catalytic cycle for the
synthesis of sulfinate salts [Eq. (1)]. Given the rapid develop-
1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene
(IPr;
Figure 1).[9] Upon treatment with SO2 (1 atm), the NHC-
Figure 1. Synthesis of gold(I) sulfinate complexes.
supported gold sulfinates were formed in high yield when the
2
À
starting material possessed a Au C bond with an sp -
hybridized carbon atom (1) or activated benzylic carbon
atom (2). The complexes 1 and 2 were characterized crystallo-
graphically and the sulfinate ligand was found to be sulfur-
bound to the metal center (Figure 2).[10] No reaction was seen
with the analogous phenylacetylide and ethyl gold complexes,
[*] M. W. Johnson, Prof. R. G. Bergman, Prof. F. D. Toste
Department of Chemistry, University of California, Berkeley
Berkeley, CA 94720 (USA)
À
and thus parallels the established reactivity of Au C bonds to
electrophilic attack.[10,11]
E-mail: fdtoste@berkeley.edu
S. W. Bagley, Dr. V. Mascitti
Pfizer Worldwide Medicinal Chemistry
Groton, CT 06340 (USA)
E-mail: vincent.mascitti@pfizer.com
Prof. N. P. Mankad
Department of Chemistry, University of Illinois at Chicago (USA)
[**] This research was supported in part by a grant from the NIHGMS
(RO1 GM073932). M.W.J. is grateful to the National Science
Foundation (no. DGE1106400) and UC Berkeley for pre-doctoral
research fellowships. N.P.M. acknowledges the National Institute of
Health for a Kirchstein-NRSA postdoctoral fellowship. S.W.B. thanks
Andrei Shavyna, Aaron Smith, and Kevin Hesp for helpful dis-
cussions. William J. Wolf (UC Berkeley) and Brian Samas (Pfizer)
are thanked for assistance with X-ray crystallographic studies.
Figure 2. Solid-state structures of the sulfinate complexes 1 (left) and
2 (right). Thermal ellipsoids shown at 50% probability. Hydrogen
atoms and solvent molecules have been omitted for clarity.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201400037.
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With these promising initial results, we began to construct
a catalytic cycle which would incorporate the elementary
steps necessary to synthesize sulfinates (Scheme 1). Thus,
Scheme 2. Subjection of proposed intermediates to reaction condi-
tions. [a] Yield determined by NMR spectroscopy versus 1,3,5-tri-
methoxybenzene as an internal standard.
reaction was observed without the catalyst (Table 1, entry 2)
and other catalysts able to effect sulfonylation proved inferior
to gold (entries 3–7). A bulky amine base was required for the
Table 1: Variation from optimized reaction conditions.
Scheme 1. Stoichiometric reactions in a plausible catalytic sulfinate
synthesis. [a] Yield of isolated product. [b] Yields were determined by
1H NMR spectroscopy with 1,3,5-trimethoxybenzene as an internal
standard.
Entry
Variation from standard conditions
Yield [%][a]
1
2
none
no catalyst
51
0
3
4
5
6
7
8
9
10
11
10 mol% Pd(OAc)2 as catalyst
10 mol% Pd(OAc)2/[HPtBu3][BF4] as catalyst
10 mol% Pd(PPh3)4 as catalyst
10 mol% Cu2O as catalyst
10 mol% CuCl as catalyst
Et3N in place of DIPEA
no base
trace
9
trace
10
3
treatment of the model gold(I) phenyl sulfinate (1) with
NaOtBu led to precipitation of NaSO2Ph and formation of the
gold alkoxide IPrAuOtBu,[3c] which regenerated IPrAuPh
when treated with phenyl boronic acid.
7
trace
4
9
Establishment of a closed synthetic cycle in a stoichio-
metric fashion provided the impetus for rendering the net
transformation truly catalytic. Potassium metabisulfite
(K2S2O5) was chosen as the SO2 surrogate because of its
ease of handling and accessibility.[7c] Benzyl bromide was
employed as an electrophile to trap the sulfinate intermediate
as the corresponding sulfone. Screening of solvents and bases
revealed that a 1:1 MeOH/toluene mixture with 2 equivalents
N,N-diisopropylethyl amine (DIPEA) provided the highest
yields. Initial use of IPrAuCl as the precatalyst provided some
product, albeit in low yield (21%). It was determined that
bulky electron-rich phosphines were superior supporting
ligands for the desired transformation, with tBu3PAuCl
being the best [66%, Eq. (2)].[13]
addition of 10%-by-volume H2O
under SO2(g) (1 atm) in place of air
[a] Yield determined versus 1,3,5-trimethoxybenzene as an internal
standard.
reaction to proceed (entries 8 and 9). Though no special
precautions are needed for the exclusion of air or moisture
from the reaction mixture, large quantities of water did shut
down catalysis (entry 10). The yield decreased significantly
when the reaction was conducted under an atmosphere of SO2
(entry 11), which we attribute to the removal of DIPEA from
the catalytic cycle through formation of an SO2–amine
adduct.[15]
A brief survey of boronic acids supports our mechanistic
hypothesis [Eq. (3)]. Boronic acids that are electronically
unbiased or electron-rich (5–9, 11) provide yields comparable
to those observed in the model reaction, whereas electron-
poor boronic acids show no reactivity (10). The lack of
reactivity of this latter boronic acid may be attributed to the
To determine the viability of our proposed catalytic cycle,
we synthesized the putative gold aryl 3 and sulfinate 4
intermediates (Scheme 2).[14] These complexes were then
subjected to standard reaction conditions as substitutes for
tBu3PAuCl. The results showed comparable yields for the
catalytic reaction regardless of the starting gold source. These
data suggest that gold aryl and sulfinate complexes may be
reasonably proposed as catalytic intermediates.
We next surveyed reaction conditions to determine the
role of the reagents involved in the transformation. No
2
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electron-deficient intermediate gold(I) aryl complex being
less susceptible to electrophilic attack by SO2. Of importance
for potential applications in the context of drug discovery,
nitrogen-containing aromatic heterocycles, such as indazole,
appeared compatible with the reaction conditions (12).
The lack of reactivity of 4-cyanophenyl boronic acid
motivated us to examine this limitation. The organometallic
intermediate for reaction with this boronic acid, 13, was
prepared independently and subjected to catalytic conditions
with the well-established coupling partner p-tolylboronic acid
[Eq. (4)]. The sulfone 8 was observed in only 7% yield, less
than a single turnover. Additionally, treatment of 13 with
SO2(g) at 1008C led to no reaction, unlike the facile synthesis
of gold sulfinate 4.[16] This result suggests that electron-
deficient boronic acids may be capable of the transmetalation
step of the catalytic cycle, but the subsequent intermediate
shows little reaction toward SO2, thus precluding the use of
these coupling partners in catalysis.
Scheme 3. Divergent synthesis of sulfonyl compounds.
Experimental Section
A 2-dram vial with a stir bar was charged with 4-methylphenyl
boronic acid (50 mg, 0.37 mmol), K2S2O5 (167 mg, 0.74 mmol), and
tBu3P-AuCl (16 mg, 0.037). The reagents were suspended in 1:1
PhCH3/MeOH (2 mL) and treated with diisopropylethylamine
(128 mL, 0.74 mmol) and benzyl bromide (88 mL, 0.74 mmol). The
vial was sealed with a septum-lined cap and heated in an aluminum
block at 1008C for 18 h. The reaction was cooled to room temperature
and the volatiles were removed in vacuo. The resultant solids were
partitioned between EtOAc (30 mL) and water (30 mL) treated with
sat. aq. NH4Cl (3 mL). The organic phase was dried over Na2SO4,
filtered, and concentrated. The resultant crude product was purified
by flash chromatography (0–60% EtOAc/heptanes gradient, 4 g silica
gel) to yield 60 mg (66% yield) of the desired product 1-(benzylsul-
fonyl)-4-methylbenzene (8).
The final aspect of the sulfinate functionalization, liber-
ation of the sulfinate salt and its trapping, was confirmed to
occur independently of the gold catalyst by the simple
alkylation of p-tolylsulfinate under standard reaction con-
ditions, but without catalyst (see the Supporting Information).
This late addition allows introduction of diversity and
provides a powerful tool for chemical space exploration in
the context of drug discovery. Indeed, short analoguing
sequences from a common modular intermediate, the use of
readily available classes of monomers or reagents (such as
boronic acids, amines, alkylating agents), and robust exper-
imental conditions are hallmarks of a reaction suitable for
rapid structure–activity relationship studies. These criteria are
demonstrated in the construction of two targeted libraries
consisting of 24 sulfones and sulfonamides based on the
medicinally relevant indazole framework (Scheme 3).[17,18]
This latter set of experiments not only reaffirmed the fate
of our catalytic cycleꢀs product but demonstrated the utility of
this reaction in making divergent products, sulfones and
sulfonamides, from a common versatile sulfinate intermedi-
ate.
In summary, we have advanced our understanding of the
fundamental reactivity of gold(I)–heteroatom bonds and used
that information to construct a catalytic cycle for the synthesis
of sulfinates from boronic acids. Preparation of new sulfinato
complexes, stoichiometric reactions representing elementary
steps, and subjection of proposed intermediates to reaction
conditions informed the development of this system. Addi-
tionally, this method is complementary to established meth-
ods in that it forms sulfinates directly, which in turn can be
elaborated in situ into more complex sulfonyl compounds of
broad interest, such as sulfones and sulfonamides.
Received: January 2, 2014
Published online: && &&, &&&&
Keywords: gold · heterocycles · structure elucidation ·
.
sulfonamides · synthetic methods
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Sulfination
M. W. Johnson, S. W. Bagley,
N. P. Mankad, R. G. Bergman,
V. Mascitti,* F. D. Toste*
&&&& — &&&&
ꢀ la mode: A gold(I)-catalyzed synthesis
of sulfinates has been accomplished.
Preparation of proposed intermediates,
X-ray studies, and a number of mecha-
nistic experiments suggest that an
unprecedented mode of reactivity for
Application of Fundamental
gold(I) has been achieved. The resulting
sulfinates from this reaction can be
functionalized in situ to form sulfones
and sulfonamides.
Organometallic Chemistry to the
Development of a Gold-Catalyzed
Synthesis of Sulfinate Derivatives
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