Catalyst Selection Facilitates the Use of Heterocyclic Sulfinates as General Nucleophilic Coupling Partners in Palladium-Catalyzed Coupling Reactions

Article abstract of DOI:10.1021/acs.orglett.7b02944

A range of 5- and 6-membered heterocycle-derived sulfinates are shown to be effective nucleophilic coupling partners with aryl chlorides and bromides using Pd(0) catalysis. The use of optimal reaction conditions, specifically incorporating a P(t-Bu)₂Me-derived Pd catalyst, allowed reactions to be performed at moderate temperatures and enabled the inclusion of a variety of sensitive functional groups. Challenging heterocyclic sulfinates, including pyrazine, pyridazine, pyrimidine, pyrazole, and imidazole, were all shown to perform well.

Full text of DOI:10.1021/acs.orglett.7b02944

Letter
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
pubs.acs.org/OrgLett
Catalyst Selection Facilitates the Use of Heterocyclic Sulfinates as
General Nucleophilic Coupling Partners in Palladium-Catalyzed
Coupling Reactions
†
‡
‡
‡
,†
Tim Markovic, Benjamin N. Rocke, David C. Blakemore, Vincent Mascitti, and Michael C. Willis*
†Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, U.K.
‡Medicine Design, Pfizer Inc., Eastern Point Road, Groton, Connecticut 06340, United States
*
S Supporting Information
ABSTRACT: A range of 5- and 6-membered heterocycle-derived sulfinates are shown to be effective nucleophilic coupling
partners with aryl chlorides and bromides using Pd(0) catalysis. The use of optimal reaction conditions, specifically incorporating
a P(t-Bu) Me-derived Pd catalyst, allowed reactions to be performed at moderate temperatures and enabled the inclusion of a
2
variety of sensitive functional groups. Challenging heterocyclic sulfinates, including pyrazine, pyridazine, pyrimidine, pyrazole,
and imidazole, were all shown to perform well.
he ability to use cross-coupling methods to access
substituted heteroaromatics is crucial to medicinal
Scheme 1. Heterocylic Boronic Acids vs Heterocyclic
Sulfinates in Coupling Reactions and an Example Pyridine-2-
sulfinate Coupling Reaction
T
chemistry, where functionalized heterocycles are key compo-
1
nents of many target structures. However, heteroaromatic
reactants are notoriously challenging substrates for a variety of
cross-coupling reactions. One of the most documented
challenges is the poor performance of heterocycle-derived
boronic acids, and related boronates, in palladium-catalyzed
2
Suzuki−Miyaura reactions. Several factors contribute to these
difficulties, but the propensity of heteroaryl boronic acid
3
derivatives to undergo rapid proto-deboronation is the major
4
problem. N-Heterocycles are notorious in this regard. To
address these issues, we recently reported on the preparation
and use of pyridine sulfinates as replacements for pyridine
boronates in palladium-catalyzed coupling reactions with aryl
5
halides. Pyridine sulfinates are straightforward to prepare,
stable under extended storage times, and conductive to high-
yielding coupling reactions when combined with a broad range
of aryl halides (Scheme 1). Despite the success of this
chemistry, there were some notable constraints due to the
elevated reaction temperature required (150 °C) and the
We hypothesized that a more active catalyst would permit
lower reaction temperatures and, with our previous results in
hand, selected for further screening a set of seven ligands
including and close-in to the existing high-performers as well as
seven ligands that represented unexplored. We also selected for
evaluation (1) a range of solvents with boiling points above the
screening temperature, (2) bases and Pd sources having shown
promise in our previous screening campaign, and (3) a phase
transfer catalyst (PTC) to understand its possible influence on
this heterogeneous reaction. Screening was conducted against
both chloro and bromo electrophiles in plate format at 100 °C,
a temperature that we considered to be reasonable for use in
6
corresponding functional group compatibility limitations. The
use of elevated temperatures has also been noted by others as
being a potential drawback from a process chemistry
7
perspective. In this paper, we show how the use of an
alternative catalyst allows the reaction temperature to be
dramatically reduced, thus delivering improved functional
group tolerance. We also report the preparation and successful
coupling chemistry of a broad range of 5- and 6-membered-ring
heteroaromatic sulfinates.
In order to address the stated limitations, we undertook a
systematic evaluation of all reaction parameters (Scheme 2).
Received: September 20, 2017
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02944
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Catalyst and Reaction Optimization
reactions were comparable to those achieved with our earlier,
higher temperature, conditions.
5
Having validated these new reaction conditions, we then
wanted to test our hypothesis that a more active catalyst and
milder reaction conditions would allow for greater functional
group tolerance. Accordingly, a trifluoromethyl-substituted
pyridine-2-sulfinate and a methoxy-substituted pyridine-3-
sulfinate were combined with a selection of functionalized
coupling partners, all of which had failed under our original
reaction conditions (Scheme 4). Pleasingly, a broad range of
Scheme 4. Demonstration of Functional Group
a
Compatibility
both array and large-scale reactions. Analysis of the screening
results identified P(t-Bu) Me (used as its HBF salt) as a highly
2
4
8
active ligand, affording analytical yields up to 87%. Despite the
thorough screening, we resettled on Pd(OAc) , K CO , and
2
2
3
dioxane. Validation of these results in singleton experiments
performed on preparative scale (0.2 mmol) delivered isolated
yields of 90% for coupling with the aryl bromide, and 85% for
the chloride, respectively. A 1.0 mmol scale reaction using the
Br-quinoline coupling partner delivered the coupled product in
8
7% yield.
To test the generality of these newly optimized reaction
conditions and ligand selection, we evaluated the coupling of 10
pyridine 2-sulfinates, featuring a variety of substitution patterns,
with simple aryl halides (Scheme 3). High-yielding reactions
were achieved in all cases, with both aryl chloride and aryl
bromide coupling partners performing well under these new
conditions. Importantly, the yields obtained in these coupling
Scheme 3. Evaluation of Pyridine-2-sulfinate Coupling
a
Partners
a
Reaction conditions: pyridine sulfinate (1.5 equiv), aryl halide (1.0
equiv), Pd(OAc) (5 mol %), P(t-Bu) Me (10 mol %), K CO (1.5
2
2
2
3
b
equiv), 1,4-dioxane, 100 °C, 18 h. Isolated yields. Isolated as the
methyl ester after treatment with TMSCH N due to isolation
2
2
c
difficulties with the free acid. Lithium sulfinate used.
reactive functional groups were shown to be compatible with
the reaction conditions, delivering coupled products in good to
excellent yields. Specifically, acidic OH and NH groups, present
in phenol (2l), carboxylic acid (2m), carbamate (2n),
sulfonamide (2o), and amide (2p) substituted arenes, were
all tolerated. Sulfone (2q) and cyano-containing substrates (2r,
2
s) also performed well. A 4-bromo-N-methylpyrazole coupling
partner could also be employed (2t), although in this case a
reaction temperature of 130 °C was needed. 2,2′-Bipyridine 2u
was obtained in 73% yield, establishing the validity of these new
conditions to promote challenging heterocycle−heterocycle
coupling reactions. Medicinally relevant pentafluorosulfide
groups were also tolerated (2v). Finally, a sterically demanding
2
(
,6-dimethyl-substituted benzene underwent efficient coupling
2w).
Although the challenges of using pyridine-derived boronic
a
Reaction conditions: pyridine sulfinate (1.5 equiv), aryl halide (1.0
equiv), Pd(OAc) (5 mol %), P(t-Bu) Me (10 mol %), K CO (1.5
2
2
2
3
equiv), 1,4-dioxane, 100 °C, 18 h. Isolated yields.
acids and related boronates in Suzuki−Miyaura coupling
B
DOI: 10.1021/acs.orglett.7b02944
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
reactions are well documented, a number of other heterocyclic2
partners are also known to be particularly problematic.
Consequently, we evaluated the preparation and coupling
chemistry of a variety of 5- and 6-membered heterocyclic
AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: michael.willis@chem.ox.ac.uk.
ORCID
9
sulfinates (Scheme 5). The sulfinates were prepared from
Michael C. Willis: 0000-0002-0636-6471
Notes
Scheme 5. 5- and 6-Membered Heterocyclic Sulfinates As
Nucleophilic Coupling Partners with Aryl Bromides
a
The authors declare the following competing financial
interest(s): B.N.R., D.C.B., and V.M. are employees of Pfizer,
Inc. and may own stock in the company.
ACKNOWLEDGMENTS
■
We thank Pfizer and EPSRC for support of this study. In
addition, we acknowledge Greg Steeno, Usa Reilly, and Neal
Sach, all of Pfizer Medicine Design, for assistance with reaction
screening.
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2
2
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10
either oxidation of the corresponding thiol or using SMOPS
11
chemistry from the corresponding halide. All of the sulfinates
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4
(
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(
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2
(
3j) substituted sulfinates all delivering efficient reactions.
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(8) See the Supporting Information for full details.
(9) For thiophene, benzothiophene, furan, and benzofuran sulfinates
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medicinally relevant 5- and 6-membered heterocyclic sulfinates.
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corresponding boronic acids, we anticipate that these reagents
will find wide use in discovery chemistry.
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ASSOCIATED CONTENT
■
*
S
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02944.
Experimental procedures and full characterization for all
compounds (PDF)
C
DOI: 10.1021/acs.orglett.7b02944
Org. Lett. XXXX, XXX, XXX−XXX