Nickel-Catalyzed Cross-Coupling of Sulfonamides With (Hetero)aryl Chlorides

Article abstract of DOI:10.1002/anie.202002392

The development of Ni-catalyzed C?N cross-couplings of sulfonamides with (hetero)aryl chlorides is reported. These transformations, which were previously achievable only with Pd catalysis, are enabled by use of air-stable (L)NiCl(o-tol) pre-catalysts (L=P

Full text of DOI:10.1002/anie.202002392

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Accepted Article
Title: Nickel-Catalyzed Cross-Coupling of Sulfonamides With
(Hetero)aryl Chlorides
Authors: Ryan McGuire, Connor Simon, Arun Yadav, Michael
Ferguson, and Mark Stradiotto
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202002392
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10.1002/anie.202002392
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Nickel-Catalyzed Cross-Coupling of Sulfonamides With
(Hetero)aryl Chlorides
Ryan T. McGuire,[a] Connor M. Simon,[a] Arun A. Yadav,[b] Michael J. Ferguson,[c] and Mark Stradiotto*,[a]
Abstract: The development of Ni-catalyzed C-N cross-couplings of
sulfonamides with (hetero)aryl chlorides is reported. These
transformations, which were previously achievable only with Pd
catalysis, are enabled by use of air-stable (L)NiCl(o-tol) pre-catalysts
(L = PhPAd-DalPhos and PAd2-DalPhos), without photocatalysis.
challenging, (hetero)aryl (pseudo)halide electrophile classes
(Figure 1B).[7] A modest number of publications documenting Cu
or Pd-catalyzed cross-couplings of sulfonamides with (hetero)aryl
bromides or iodides have appeared.[5, 8] By comparison, no such
Cu-catalyzed cross-couplings of chloride or phenol derivatives
The collective scope of (pseudo)halide electrophiles (X = Cl, Br, I, OTs, have been published, and Pd-catalyzed cross-couplings of this
and OC(O)NEt2) demonstrated herein is unprecedented for any
reported catalyst system for sulfonamide C-N cross-coupling (Pd, Cu,
Ni, or other). Preliminary competition experiments and coordination
chemistry studies, which provide insight into the reactivity behavior of
the catalysts employed herein, are also presented.
type (i.e., (hetero)aryl sulfonate[8j, 9] or chloride[5, 8d, 8f, 8i, 8j, 9a, 10]
reaction partners) are limited.
Sulfonamides have figured prominently in medicinal chemistry for
over ninety years, and there is sustained interest in their synthesis
and modification owing to their diverse biological[1] and reactivity[2]
properties. While pharmaceuticals based on primary (e.g.,
celecoxib,[3] Figure 1A), secondary (e.g., tipranavir), and tertiary
(e.g., sildenafil) sulfonamides each have proven efficacy,
secondary N-(hetero)aryl sulfonamides represent a particularly
common and highly sought-after structural motif. Beyond their
desirable bioactivity,[1] secondary N-(hetero)aryl sulfonamides
can serve as isosteres of carboxylic acids,[4] whereby the N-H
acidity and other properties can be modified by the choice of N-
(hetero)aryl group.
Secondary N-(hetero)aryl sulfonamides are commonly
prepared via reaction of a sulfonyl chloride with a primary
(hetero)aniline; however, the potentially genotoxic nature of these
synthons[5] and the ongoing desire for diversified disconnection
strategies provides motivation for the identification of
complementary synthetic routes.[6] While the metal-catalyzed
C(sp2)-N (herein ‘C-N’) cross-coupling of (hetero)aryl
electrophiles with primary sulfonamides offers an alternative and
more modular approach, such transformations have proven to be
stubbornly difficult, especially in comparison to reactions of more
nucleophilic NH substrates such as alkylamines. The difficulty
posed by metal-catalyzed sulfonamide C-N cross-coupling is
amplified when using (hetero)aryl chlorides or phenol derivatives
– arguably the most inexpensive and/or widely available, yet
Figure 1. N-Arylation of sulfonamides with (hetero)aryl (pseudo)halides. A.
The structure of celecoxib. B. Metal-catalyzed C-N cross-couplings of
sulfonamides. C. DalPhos ligands used in Ni-catalyzed cross-couplings.
The relatively abundant and inexpensive nature of Ni, paired
with its propensity to engage in oxidative addition, offers
advantages in the quest to develop new and useful alternatives to
Cu and Pd in C-N cross-coupling catalysis.[11] One approach that
has been employed to address potentially rate-limiting C-N
reductive elimination with Ni is the application of ‘ligand free’
photoredox protocols,[12] with a notable limitation of this strategy
being poor catalytic performance with (hetero)aryl chlorides and
phenol derivatives. Such an approach is employed in the only
report of Ni-catalyzed sulfonamide N-arylation chemistry (Figure
1B),[13] whereby (glyme)NiCl2 (5 mol%) in the presence of an Ir
photocatalyst (in some cases with 4,4'-di-tert-butyl-2,2'-bipyridine,
dtbbpy) enabled the C-N cross-coupling of primary sulfonamides
[a]
R. T. McGuire, C. M. Simon, Prof. Dr. M. Stradiotto
Department of Chemistry
with (hetero)aryl bromides.
A similar protocol was used
subsequently by Roizen and co-workers in the N-arylation of
sulfamate esters.[14]
Dalhousie University
Halifax, Nova Scotia B3H 4R2 (Canada)
E-mail: mark.stradiotto@dal.ca
Dr. A. A. Yadav
Paraza Pharma, Inc.
2525 Avenue Marie-Curie
We have adopted
a complementary ‘photoredox-free’
approach that exploits ancillary ligand design[15] as a means of
enabling Ni-catalyzed C-N and related cross-couplings,
particularly involving (hetero)aryl chlorides and phenol derivatives
for which photoredox-promoted methods are generally ineffective.
One aspect of this research involves the development and/or
application of sterically demanding and modestly electron-
donating bisphosphines[16] (including the DalPhos series, Figure
1C[17]), which we envisioned might promote C-N reductive
[b]
[c]
Montreal, Quebec, H4S 2E1 (Canada)
Dr. M. J. Ferguson
X-Ray Crystallography Laboratory, Department of Chemistry
University of Alberta
Edmonton, Alberta T6G 2G2 (Canada)
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.202YXXXXX.
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10.1002/anie.202002392
Angewandte Chemie International Edition
COMMUNICATION
elimination within a putative Ni(0/II) catalytic cycle,[18] while
circumventing catalyst deactivation arising from bis-chelation
and/or comproportionation.[19] Notably, the catalytic performance
in C-N[17] and C-O[20] cross-coupling of Ni catalysts supported by
these DalPhos ligands is in many cases competitive with, or
superior to, the best metal catalysts known (Pd, Cu, Ni, or other).
Herein we report that use of the air-stable pre-catalyst
(PhPAd-DalPhos)NiCl(o-tol)[17e] enables the cross-coupling of
structurally diverse primary sulfonamides, including celecoxib,
with an unprecedentedly broad scope of (hetero)aryl-X
electrophiles (X = Cl, Br, I, OTs, OC(O)NEt2, Figure 1B), without
the aid of photocatalysis. Preliminary investigations also
demonstrate the utility of air-stable (PAd2-DalPhos)NiCl(o-tol)[17f]
for cross-couplings of N-methylsulfonamides. Preparation of
(PhPAd-DalPhos)Ni(o-tol)(NH(SO2(p-anisyl))),
an
isolable
putative intermediate within a Ni(0/II) cycle that is capable of
engaging in C-N reductive elimination, is also disclosed.
The cross-coupling of p-toluenesulfonamide (1a) and 1-
chloronaphthalene employing Ni(COD)2/L (5 mol%, Figure 2A),
was examined in an effort to identify an ancillary ligand that might
enable such hitherto unknown Ni-catalyzed transformations of
(hetero)aryl chlorides. In surveying a selection of ligands with
proven utility in other Ni-catalyzed C-N cross-couplings, including
IPr,[21] DPEPhos,[22] DPPF,[23] and several DalPhos ligands, only
PhPAd-DalPhos provided substantial conversion to 2a (70%,
Figure 2A). In turn, application of (PhPAd-DalPhos)NiCl(o-tol) as
a pre-catalyst allowed for improved conversion to 2a under similar
conditions (95% isolated yield, 5 mol% Ni; Figure 2B). No change
in conversion to 2a was observed in cross-couplings using this
pre-catalyst, either when ambient light was excluded, or when the
reaction was conducted on a larger scale (4.8 vs. 0.48 mmol).
However, our efforts to use alternative bases such as Cs2CO3 or
K3PO4 in the cross-couplings reported herein were unsuccessful.
In testing the scope of (pseudo)halide compatibility (Figure 2B),
1-bromo and 1-iodonaphthalene each proved to be suitable
substrates, as did a 1-napthol-derived carbamate; in all cases,
>80% conversion to 2a was achieved. Notably, the collective
scope of compatible electrophile classes demonstrated herein (X
= Cl, Br, I, and OC(O)NEt2; also OTs for 2m, vide infra), is
unprecedented in sulfonamide C-N cross-coupling catalysis.
In examining the scope of reactivity involving (hetero)aryl
chlorides and primary sulfonamides (affording 2b-2t, Figure 2B),
such electrophiles bearing electron-donating and electron-
withdrawing groups spanning methyl, trifluoromethyl, methoxy,
pinacolatoboron, and ketone functionalities proved compatible
when using (PhPAd-DalPhos)NiCl(o-tol), as did electrophiles
featuring quinoline, quinaldine, and pyridine core structures.
Conversely, electron-rich 4-chloroanisole was a problematic
Figure 2. Catalyst screening and substrate scope for the Ni-catalyzed N-
arylation of primary sulfonamides. A. Estimated conversion on the basis of
GC data (monitoring consumption of 1-chloronaphthalene and formation of
2a). B. 0.48 mmol scale in (het)aryl-X. Where noted, conversion to product
(2) determined on the basis of response-factor calibrated GC data using
authentic material (0.12 mmol scale for 2q and 2r); control experiments
confirm <5% conversion to product under the reported conditions in the
absence of the Ni catalyst.
methoxy, trifluoromethoxy, cyano, pyridyl, and pyrazolyl
functionalities were successfully employed, affording the desired
secondary N-(hetero)aryl sulfonamides in synthetically useful
isolated yields. Although less well explored in our study and more
challenging, (tBu)S(O)2NH2 and (cyclopropyl)S(O)2NH2 were also
used with success (2q-2s, Figure 2B). Co-elution during
chromatographic separation with the starting sulfonamides
contributed to a less-than-optimal isolated yield of 2q-2s (as well
as 4e, Figure 3B).
electrophile,
as
were
3-chloropyridine
and
2-
chlorobenzothiophene. What are typically challenging ortho-
hindered (hetero)aryl chlorides proved successful (Figure 2B),
leading to 2c, 2d, 2g, 2t, and 2u, with 2t being the first product of
C-N cross-coupling with celecoxib (Figure 1A). Despite potential
applications of such derivatives, only one N-(hetero)aryl variant of
celecoxib (prepared from a sulfonyl chloride and a primary
(hetero)aniline) has been reported, for use in imaging COX-2
over-expression in cancer.[24]
Having addressed our main goal of developing the Ni-
catalyzed C-N cross-coupling of primary sulfonamides with
(hetero)aryl chlorides, and given the dearth of documented Ni-
Amongst the cross-couplings depicted in Figure 2, primary
(hetero)arylsulfonamides featuring methyl, trifluoromethyl,
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10.1002/anie.202002392
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catalyzed cross-couplings of secondary sulfonamides, we turned
our attention to assessing the viability of such transformations.
Test screening involving the cross-coupling of N-methyl-p-
toluenesulfonamide (3a) with 2-chloro-6-methoxypyridine to give
4a (Figure 3A) led to the identification of PAd2-DalPhos as a
viable choice for enabling such transformations. Subsequent
application of (PAd2-DalPhos)NiCl(o-tol) allowed for a selection
of cross-couplings involving N-methylsulfonamides and
(hetero)aryl chlorides to be achieved (4a-4e, Figure 3B). This
success notwithstanding, our efforts to extend this chemistry to
of excess primary sulfonamide and/or the need to employ excess
base relative to sulfonamide in order to achieve conditions
favoring catalysis. In the competitive cross-coupling of N-methyl-
p-toluenesulfonamide (3a, 1.1 equiv) versus indole (1.1 equiv)
with 2-chloroquinoline (1 equiv) using NaOtBu (2 equiv) and
(PAd2-DalPhos)NiCl(o-tol) (5 mol%) as depicted in Figure 4B,
exclusive indole N-arylation leading to 6 is observed. While
control experiments confirm that background reactivity not
involving Ni catalysis contributes to the production of 6 under the
conditions employed, the competition nonetheless establishes the
clear preference of the PAd2-DalPhos ligated Ni catalyst system
for indole over 3a.
substrates
such
as
N-cyclohexyl
or
N-phenyl-p-
toluenesulfonamide (for example with 2-chloroquinoline), instead
afforded complex reaction mixtures from which the desired N-
arylated sulfonamides could not be isolated in suitably high yields.
Figure 3. Catalyst screening and substrate scope for the Ni-catalyzed N-
arylation of N-methylsulfonamides. A. Estimated conversion on the basis
of GC data (monitoring consumption of 2-chloro-6-methoxypyridine and
formation of 4a). B. 0.48 mmol scale in (het)aryl-Cl. Where noted,
conversion to 4b determined on the basis of response-factor calibrated GC
data using authentic material.
Figure 4. Nucleophile competition experiments (A,B) and coordination
chemistry studies (C). Conversion to product (2b, 2u, 4b, 5, and 6)
determined on the basis of response-factor calibrated GC data using
authentic material. For the single-crystal X-ray structure of C1, 30%
thermal ellipsoids are shown, and selected H-atoms have been omitted.
Selected distances (Å) and angles (º): Ni-P1 2.2340(5), Ni-P2 2.1223(5),
Ni-N1 1.9036(17), Ni-C(aryl) 1.9450(19), P1-Ni-P2 87.517(19), P2-Ni-
C(aryl) 84.37(6), P1-Ni-N1 95.02(5), N1-Ni-C(aryl) 93.32(7). aIn the
absence of added (p-tolyl)S(O)2NHMe and Ni pre-catalyst, 43%
conversion to 6 and ~60% remaining (hetero)aryl chloride observed.
Previous reports from our group established (PhPAd-
DalPhos)NiCl(o-tol) as being effective for challenging C-N cross-
couplings of sterically demanding alkylamines including
tBuNH2,[17e] whereas (PAd2-DalPhos)NiCl(o-tol) exhibited a
marked propensity for otherwise difficult indole N-arylation,[17g]
each in combination with (hetero)aryl chlorides. Given the utility
of these pre-catalysts demonstrated herein for the N-arylation of
sulfonamides (Figures 2 and 3), we conducted competition
experiments so as to better understand the relative reactivity
preferences of these pre-catalysts. The competitive Ni-catalyzed
C-N cross-coupling of p-toluenesulfonamide (1a, 1.1 equiv)
versus tBuNH2 (3 equiv) with 7-chloroquinaldine (1 equiv) using
NaOtBu (2 equiv) and (PhPAd-DalPhos)NiCl(o-tol) (5 mol%)
under the conditions outlined in Figure 4A afforded high
conversion of the electrophile and produced the primary
sulfonamide-derived product 2b preferably (~3:1) relative to the
alkylamine product 5, despite the relative excess of tBuNH2 that
was used in an effort to compensate for the volatility of this amine.
However, in analogous experiments conducted using 2.2 equiv of
1a without tBuNH2, no conversion was observed. These two
experiments highlight the favorability of 1a over tBuNH2 as a
nucleophile for Ni-catalyzed C-N cross-couplings under these
conditions, while also underscoring the possible inhibitory effect
Encouraged by the catalytic performance of (PhPAd-
DalPhos)NiCl(o-tol) in C-N cross-couplings involving primary
sulfonamides (Figure 2B), we sought to explore the synthetic
feasibility of derived (PhPAd-DalPhos)Ni(o-tol)(NH(SO2aryl))
complexes, which represent putative catalytic intermediates
within Ni(0/II) catalytic cycles leading to 2. While reductive
elimination from L2NiII(aryl)(amido) species is routinely invoked as
part of Ni-catalyzed C-N cross-coupling cycles, examples of such
elementary steps involving isolated complexes are rare.[25]
Exposure of (PhPAd-DalPhos)NiCl(o-tol) to (p-anisolyl)S(O)2NH2
and NaOtBu (Figure 4C) afforded the isolable sulfonamido
complex C1 (57%). The NMR spectroscopic and X-ray
crystallographic features of C1 parallel those of (PhPAd-
DalPhos)NiCl(o-tol),[17e] with the chiral (racemic) PCg group
residing trans to the o-tol moiety, and where hindered Ni-C
rotation affords major and minor diastereomers on the NMR
timescale at room temperature (see the SI for details). The
formation of 2u (27%) arising from apparent C-N reductive
elimination from C1 (0.012 M in dioxane, 110 ºC, 0.5 h), and 2,2’-
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10.1002/anie.202002392
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COMMUNICATION
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dimethylbiphenyl (6%), were each confirmed on the basis of
response-factor calibrated GC data using authentic samples. Our
observation of negligible stoichiometric conversion of C1 to 2u or
2,2’-dimethylbiphenyl under more mild conditions (0.012 M in
THF, 80 ºC, 0.5 h) is in keeping with the poor catalytic conversion
achieved when using (PhPAd-DalPhos)NiCl(o-tol) as a pre-
catalyst (5 mol%) in the attempted cross-coupling leading to 2u
(6%, THF, 80 ºC, 18 h; see Figure 2 and the SI). While we are
hesitant to comment definitively regarding the mechanism of the
Ni-catalyzed C-N cross-couplings reported herein, the observed
formation of 2u from C1 supports the viability of a Ni(0/II) pathway;
2,2’-dimethylbiphenyl likely forms from (PhPAd-DalPhos)Ni(o-
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chloronaphthalene leading to 2a (Figure 2B).
In summary, the utility of deploying appropriate
bisphosphine ancillary ligation as a means of enabling new and
otherwise challenging Ni-catalyzed C-N cross-couplings is
showcased herein in the development of sulfonamide N-arylation
chemistry that accommodates inexpensive and abundant
(hetero)aryl chloride electrophiles, and beyond (X = Cl, Br, I, OTs,
and OC(O)NEt2). In addition to offering a competitive alternative
to Pd and Cu catalysis, the ‘ligand-enabled’ approach to Ni-
catalyzed C-N cross-coupling exploited herein affords access to
substrate scope (in both sulfonamide nucleophile and (hetero)aryl
electrophile) that has thus far proven to be beyond the reach of
complementary photoredox-promoted protocols. Future work will
focus on developing our understanding of the mechanistic
underpinnings of the Ni-catalyzed C-N cross-couplings disclosed
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We are grateful to the NSERC of Canada (Discovery Grant
RGPIN-2019-04288 and Engage Grant NSERC EGP 542827-19
for M.S.; CGS-M Scholarship for R. T. M.), Paraza Pharma Inc.
(in particular Claudio Sturino and Arshad Siddiqui), the Province
of Nova Scotia (Graduate Scholarship for R. T. M.), and Dalhousie
University for their support of this work. We also thank Dr. Michael
Lumsden and Mr. Xiao Feng (Dalhousie) for technical assistance
in the acquisition of NMR and MS data.
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Keywords: amination • cross-coupling • ligand design • nickel •
sulfonamides
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Entry for the Table of Contents
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Ryan T. McGuire, Connor M. Simon,
Arun A. Yadav, Michael J. Ferguson,
and Mark Stradiotto*
Page No. – Page No.
Nickel-Catalyzed Cross-Coupling of
Sulfonamides With (Hetero)aryl
Chlorides
Ancillary Ligation: The development of the first nickel-catalyzed protocols for the
cross-coupling of sulfonamides with inexpensive and abundant (hetero)aryl chlorides
and phenol derivatives is enabled by use of appropriate bisphosphine ligation.
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