Sulfonamidation of Aryl and Heteroaryl Halides through Photosensitized Nickel Catalysis

Article abstract of DOI:10.1002/anie.201800699

Herein we report a highly efficient method for nickel-catalyzed C?N bond formation between sulfonamides and aryl electrophiles. This technology provides generic access to a broad range of N-aryl and N-heteroaryl sulfonamide motifs, which are widely represented in drug discovery. Initial mechanistic studies suggest an energy-transfer mechanism wherein C?N bond reductive elimination occurs from a triplet excited Ni^II complex. Late-stage sulfonamidation in the synthesis of a pharmacologically relevant structure is also demonstrated.

Full text of DOI:10.1002/anie.201800699

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Accepted Article
Title: Sulfonamidation of Aryl and Heteroaryl Halides via
Photosensitized Nickel Catalysis
Authors: Taehoon Kim, Stefan McCarver, Chulbom Lee, and David
William MacMillan
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201800699
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10.1002/anie.201800699
Angewandte Chemie International Edition
COMMUNICATION
Sulfonamidation of Aryl and Heteroaryl Halides via
Photosensitized Nickel Catalysis**
Taehoon Kim, Stefan J. McCarver, Chulbom Lee, and David W. C. MacMillan*
Abstract: Herein we report
a highly efficient nickel-catalyzed
method for C–N bond formation between sulfonamides and aryl
electrophiles. This technology provides generic access to a broad
range of N-aryl and N-heteroaryl sulfonamide motifs which are
widely represented in drug discovery. Initial mechanistic studies
suggest an energy transfer mechanism wherein C–N bond reductive
elimination occurs from a triplet excited Ni(II) complex. Late-stage
sulfonamidation in the synthesis of a pharmacologically relevant
structure is also demonstrated.
2016 – Development of a Photocatalyzed Approach to Amination
H
Ir Ni
Br
N
H2N
This work – General Approach to Photocatalyzed Sulfonamidation
Rapid Access to Important Pharmacophores
t-Bu
H2N
F
Aniline synthesis by means of C–N bond formation is a widely
used transformation in medicinal chemistry and pharmaceutical
synthesis.[1] Key structural motifs within this important class of
compounds are N-aryl and -heteroaryl sulfonamides, which are
F
N
H
H
S
N
N
S
S
Me
O
O
O
O
N
F
O
N
sulfamethoxazole
dabrafenib
N
NH2
represented in
a significant portion of widely prescribed
antibacterial agent
kinase inhibitor
pharmaceuticals (Scheme 1).[2] Indeed, the sulfonamide motif
has been known to exhibit high levels of bioactivity for almost a
century, forming the basis of a series of antibacterial drugs,
some of which are still in use to this day.[3] In addition to a range
of valuable biochemical properties, secondary sulfonamides can
be readily exploited as carboxylic acid isosteres, wherein the
inherent N–H pKa can be readily modulated via pendent aryl
and heteroaryl groups.[4] Access to sulfonamides traditionally
involves amine nucleophiles in combination with sulfonyl
chlorides, reagents which are often toxic and non-trivial to
prepare. While the development of technologies to directly
cross-couple amines with aryl halides has proceeded rapidly in
recent years, the attenuated nucleophilicity of sulfonamides
relative to alkyl amines presents an additional challenge.[5]
O
O
O
O
O
*
S
O
S
S
H2N
N
L
L
NH
H
NiII
L
L
Br
sulfonamide
product
excited state NiII
complex
abundant
enabled by energy
transfer mechanism
starting materials
Ir Ni
The utility and scope of C–N bond-forming reactions have
increased dramatically over the last several decades, mainly
arising from the advent of the Buchwald-Hartwig aryl-amination
cross-coupling protocol.[6] A central feature enabling the success
of this technology is the now-ubiquitous family of dialkyl biaryl
phosphine ligands carefully designed to prevent Pd dimer
formation and accelerate reductive elimination steps.[7] In
contrast to the large body of literature describing C–N bond
formation via Pd and Cu catalysis, the use of Ni catalysis
remains largely underdeveloped, an unfortunate circumstance
given the relative abundance and economic advantages
Scheme 1. Nickel-Catalyzed Synthesis of Aryl Sulfonamides.
afforded by nickel.[8] The lack of success for nickel in this area
has long been attributed to the fact that Ni(II) C–NR2 reductive
elimination is a high barrier step, a mechanistic feature that has
curtailed broad application.[9]
Recently, however, it has been demonstrated that a number
of fundamental steps in nickel cross-coupling processes can be
generically “switched on” via the modulation of oxidation states
or electronic energy levels using photocatalysis. In this context,
our laboratory has described several different transformations
that employ photocatalyst excited states with nickel to enable
otherwise disfavored reductive elimination steps involving C–O
and C–N bonds (Figure 1).[10] Moreover, recent reports from Fu
and Peters, Nocera, Molander, and Doyle describing direct
photoexcitation of transition metal catalysts provide elegant
demonstrations of this paradigm.[11] Our laboratory has also
demonstrated that energy-transfer photosensitization can be
used to access triplet excited states of Ni(II) complexes,
specifically in the context of C–O bond formation between
carboxylic acids and aryl halides.[10b] A key benefit of this
methodology is the separation of light- harvesting and cross-
coupling roles between two different transition metal complexes.
Indeed, utilization of a discrete energy-transfer catalyst
[*]
S. J. McCarver[+], Prof. Dr. D. W. C. MacMillan
Merck Center for Catalysis at Princeton University
Washington Road, Princeton, NJ 08544, (USA)
E-mail: dmacmill@princeton.edu
Homepage: http://www.princeton.edu/chemistry/macmillan/
T. Kim[+], Prof. Dr. C. Lee
Department of Chemistry, Seoul National University
Seoul 08826, South Korea
[+]
[**]
These authors contributed equally to this work.
The authors are grateful for financial support provided by the NIH
General Medical Sciences (Grant NIHGMS (R01 GM103558-05),
Seoul National University, the NRF (2017 R1A2B3002869) of Korea,
and kind gifts from Merck, BMS, Janssen, and Eli Lilly.
Supporting Information for this article can be found under:
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10.1002/anie.201800699
Angewandte Chemie International Edition
COMMUNICATION
Figure 1. Proposed Mechanism of Sulfonamidation.
presence of benzophenone, an organic sensitizer. This
observation demonstrates that formation of a Ni(II) excited state
species can induce reductive elimination, which is consistent
with an energy transfer mechanism being operative in the
presence of the photocatalyst.[14] Moreover, the improved
efficiency observed under dual catalytic conditions (cf. light-only
direct excitation) highlights the important role of light-harvesting
by the photocatalyst. As further evidence for photosensitization
of the nickel catalyst, additional experiments revealed that the
efficiency of product formation is correlated with the triplet
energy of the photocatalyst (see Supporting Information).
Having determined optimal conditions for C–N bond formation,
we set out to determine the substrate scope of this
photocatalytic protocol (Table 2). As a general design principle,
we sought to examine the proposed transformation in the
presence and absence of bipyridine ligands, given that our
recent studies demonstrated the possibility of C–N coupling
using “ligand-free” conditions. Notably, the inclusion of dtbbpy (1
mol%) in DMSO as solvent enabled the reaction to be
conducted at ambient temperature and displayed high efficiency
for electron-rich aryl halide substrates. In the absence of ligand,
the amination protocol was also successful at elevated reaction
temperatures (68 ºC), presumably to facilitate oxidative addition,
and the reaction could be conducted with reduced photocatalyst
loading (0.05 mol%). Given the inherent advantages of each
system, we have elected to report the results of both protocols
(Table 2).
L
L
ArBr (2)
L
L
L
L
Br
Ar
Ni0
NiII
3
1
H
O
N
O
Ar
NH2
S
Ph
S
O
Ph
Nickel Catalytic
Cycle
O
N-aryl
4
sulfonamide
H
N
H
N
*
9
L
L
L
L
NiII
SO2Ph
NiII
8
SO2Ph
Ar
Ar
5
energy transfer
singlet
ground
state
triplet
IrIII (6)
*IrIII (7)
Photosensitization
Cycle
excited
state
S0
T1
visible light
bypasses the question of whether an organometallic complex
can efficiently undergo direct visible light excitation, the capacity
for which often varies on a case-by-case basis.
Recently,
we
hypothesized
that
photosensitized
A large number of electron-neutral and electron-rich halides
provided excellent yields, despite a potentially challenging nickel
oxidative addition step in these cases (10 to 17, 41–86% yield
organometallic catalysis might enable C–N bond formation
between aryl halides and sulfonamides in a general sense. The
proposed mechanism for this sulfonamidation protocol is
outlined in Figure 1. This dual catalysis process begins with
oxidative addition of Ni(0) complex 1 into aryl halide electrophile
2 to generate Ni(II)-aryl complex 3. At this stage, ligand
exchange with benzenesulfonamide (4) and deprotonation would
form Ni(II)-aryl amido complex 5. At the same time, irradiation of
Table 1. C–N Sulfonamidation Control Experiments.[a]
Ir(ppy)2(bpy)PF6
Ni(cod)2, TMG
H
N
Br
Ph
O
O
S
S
O
O
Ph
NH2
CO2Me
aryl bromide
MeCN, 35 ºC
CO2Me
34 W LED, 2 h
sulfonamide
aniline
iridium(III)
photocatalyst
Ir(ppy)2(bpy)PF6
(ppy
=
2-
yield[b]
entry
conditions
phenylpyridine; bpy = bipyridine) (6) with visible light would
produce the long-lived triplet photoexcited state *IrIII 7 (τ = 0.3
µs).[12] Based on our previous studies, we hypothesized that
nickel complex 5 and excited state Ir system 7 would undergo
triplet-triplet energy transfer to form excited nickel complex 8.
The resulting triplet excited state species 8 should readily
1
2
3
4
5
6
as shown
no light
99%
0%
no nickel
0%
no photocatalyst
11%
18%
0%
benzophenone (0.5%) as photocatalyst
no photocatalyst, no light
undergo
a
reductive elimination step to deliver N-aryl
sulfonamide product 9 and regenerate Ni(0) catalyst 1.
To our delight, initial studies revealed that the proposed C–N
bond-forming reaction was indeed possible via the use of
Ir(ppy)2(bpy)PF6 (1), NiCl2·glyme, tetramethylguanadine (TMG)
as base, and MeCN as solvent (see Supporting Information for
optimization studies). At this juncture, we sought to evaluate our
hypothesis that an energy transfer pathway was operative, as
outlined in our mechanistic scheme (Fig 1). Indeed, control
experiments revealed that the presence of both nickel and
visible light were critical to product formation (Table 1).[13]
However, in the absence of photocatalyst a significant amount of
product was still obtained via direct irradiation with blue LED
light, and UV-vis studies support the formation of a nickel
complex capable of visible light absorption (see Supporting
Information). Efficiency of this process is increased in the
O
*
Ir
O
O
99%
O
S
S
L
L
prod.
NH2
NH
Photo-
sensitization
NiII
L
L
+
Br
Ni
11%
excited state
NiII complex
prod.
Direct
excitation
Photosensitization manifold – energy transfer leads to *Ni(II) formation
Direct excitation manifold – photon absorption leads to *Ni(II) formation
[a]Performed with Ir(ppy)2(bpy)PF6 (0.05 mol%), Ni(cod)2 (5 mol%), TMG (1.5
equiv), aryl halide (1.0 equiv), and benzenesulfonamide (1.5 equiv). [b]Yields
were obtained by 1H NMR analysis.
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10.1002/anie.201800699
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COMMUNICATION
Table 2. Scope of Photosensitized Nickel Catalyzed Cross-Coupling.[a]
0.05 mol% Ir(ppy)2(bpy)PF6
0.5 mol% Ir(ppy)2(dtbbpy)PF6
H
O
Br
O
N
NiCl2•glyme
NiCl2•glyme, 1 mol% dtbbpy
NH2
S
- or -
S
R
R
R
R
O
O
TMG, MeCN, 68 ºC
blue LED, 24 h
TMG, DMSO, 25 ºC
blue LED, 48 h
X
X
aryl halide
“ligand-free” Ni (A)
ligated Ni (B)
N-aryl sulfonamide
sulfonamide
Aryl Halide Scope
H
H
H
H
H
H
O
O
O
O
O
O
N
N
SMe
N
OMe
N
N
OMe
N
S
S
S
S
S
S
Ph
Ph
Ph
Ph
Ph
Ph
O
O
O
O
O
O
N
OMe
Boc
OMe
10 A: 82% yield
B: 96% yield
11 A: 80% yield
B: 97% yield
12 A: 76% yield
B: 96% yield
13 A: 41% yield
B: 66% yield
14 A: 56% yield
B: 92% yield
15 A: 48% yield
B: 95% yield
Me
F
H
O
H
O
H
O
H
O
H
O
H
O
N
S
N
S
N
S
Cl
N
S
N
S
F
N
S
Ph
Ph
Ph
Ph
Ph
Ph
O
O
O
O
O
O
t-Bu
CONHMe
16 A: 61% yield
B: 74% yield
17 A: 86% yield
B: 98% yield
18 A: 84% yield
B: 94% yield
19 A: 54% yield
B: 72% yield
20 A: 81% yield
B: 94% yield
21 A: 88% yield
B: 96% yield
CN
H
H
H
H
H
H
O
O
O
O
O
O
N
N
CF3
N
N
N
N
S
S
S
S
S
N
S
N
Ph
Ph
Ph
Ph
Ph
Ph
O
O
O
O
O
O
N
CF3
Cl
CF3
22 A: 84% yield
B: 93% yield
23 A: 85% yield
B: 87% yield
24 A: 50% yield
B: 83% yield
25 A: 90% yield
B: 0% yield
26 A: 89% yield
B: 73% yield
27 A: 80% yield
B: 71% yield
H
O
H
O
H
O
H
O
H
O
H
O
N
N
N
N
N
N
N
N
N
Cl
N
S
S
N
S
S
S
S
S
Ph
Ph
Ph
Ph
Ph
Ph
O
O
N
O
O
O
O
N
N
N
N
Ph
28 A: 56% yield
B: 20% yield
29 A: 83% yield
B: 15% yield
30 A: 55% yield
B: <5% yield
31 A: 49% yield
B: 10% yield
32 A: 62% yield
B: <5% yield
33 A: 55% yield
B: 15% yield
Sulfonamide Scope
Me
Me
H
H
H
H
O
O
O
O
O
N
N
N
N
N
S
S
S
S
S
S
4-MePh
O
O
O
O
O
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
Me
F3C
34 A: 86% yield
B: 98% yield
35 A: 82% yield
B: 97% yield
36 A: 19% yield
B: 63% yield
37 A: 74% yield
B: 96% yield
38 A: 66% yield
B: 99% yield
H
H
H
H
H
O
O
O
O
O
N
N
N
N
N
S
S
Ph
S
S
Me
Me
S
Me
O
O
O
O
O
t-Bu
t-Bu
t-Bu
t-Bu
Me
t-Bu
AcHN
39 A: 91% yield
B: 99% yield
40 A: 90% yield
B: 97% yield
41 A: 73% yield
B: 99% yield
42 A: 76% yield
B: 98% yield
43 A: 41% yield
B: 98% yield
[a]All yields are isolated. Performed with Ir photocatalyst (0.5 or 0.05 mol%), NiCl2·glyme (5 mol%), aryl bromide (1.0 equiv), sulfonamide (1.5 equiv), and
tetramethylguanadine (1.5 equiv). For detailed experimental procedures, see Supporting Information.
without ligand, 66–98% yield with ligand). As expected, the
ligand-added conditions were generally more effective for
electron-rich arenes. Notably, ortho-substituted aryl rings were
readily tolerated (16, 19, and 24, 50–83% yield). Furthermore, a
number of electron-deficient aryl halides containing fluoro, amido,
trifluoromethyl, and cyano functionalities were successful
coupling partners (18 to 24, 50–88% yield without ligand, 72–
96% yield with ligand). It is important to note that good to
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10.1002/anie.201800699
Angewandte Chemie International Edition
COMMUNICATION
F
O
O
sulfonamide
common nucleophile
in cross-coupling
heteroaryl amine
common nucleophile
in cross-coupling
Keywords: sulfonamides • energy transfer • heterocycles •
S
F
N
NH2
nickel • photocatalysis
N
NH2
[1]
[2]
Fischer, C.; Koenig, B. Belstein J. Org. Chem. 2011, 7, 59–74.
(a) Feng, M.; Tang, B.; Liang, S. H.; Jiang, X. Curr. Top. Med. Chem.
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Supuran, C. T. Curr. Med. Chem. 2003, 10, 925–953.
F
F
O
O
S
F
t-Bu
O
NH2
S
O
F
N
S
F
HN
[3]
(a) Drews, J. Science 2000, 287, 1960–1964. (b) Kalgutkar, A. S.;
Jones, R.; Sawant, A. Sulfonamide as an Essential Functional Group in
Drug Design. In Metabolism, Pharmacokinetics and Toxicity of
Functional Groups; Smith, D. A., Ed.; Royal Society of Chemistry:
Cambridge, 2010; pp 210–274.
+
t-Bu
N
F
N
high throughput
evaluations
Br
S
N
N
NH2
45
dabrafenib
Ir Ni
[4]
[5]
(a) Ballatore, C.; Huryn, D. M.; Smith, A. B. III ChemMedChem 2013, 8,
385–395. (b) Şanli, N.; Şanli, S.; Özkan, G.; Denizli, A. J. Braz. Chem.
Soc. 2010, 21, 1952–1960.
57% yield
N
NH2
44
B-Raf kinase inhibitor
antitumor activity
4 steps from commercial
For reports on aryl halide sulfonamidation with Cu and Pd see: (a)
Wolfe, J. P.; Rennels, R. A.; Buchwald, S. L. Tetrahedron, 1996, 52,
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complete selectivity for C–N bond formation with sulfonamide nucleophile
Figure 3. Synthesis of Dabrafenib.
excellent yields were observed with a range of heteroaryl halide
electrophiles including pyridine, pyrimidine, and pyrazine (25 to
31, 49–90% yield without ligand, 5–73% yield with ligand).
[6]
Importantly, 5-membered ring heterocyclic aryl halides
–
notoriously difficult cross-coupling partners in general – also
provided good yields of the desired C–N coupled products (32
and 33, 62% and 55% yield, respectively). Among this class of
substrates, “ligand-free” conditions were uniformly more
effective. We next turned our attention to the scope of the
sulfonamide nucleophile. Gratifyingly, a number of aryl and
heteroaryl sulfonamides were tolerated (34 to 39, 19–99% yield).
It should also be noted that complete selectivity for bond
formation at the primary sulfonamide moiety versus alternative
N–H sites was observed (39, 91% and 99% yields). Moreover,
efficient coupling was achieved with a range of alkyl sulfonamide
examples (40 to 43, 41–99% yield).
Finally, as a demonstration of this new C–N bond-forming
protocol and its potential application to the preparation of drug-
like molecules, we have undertaken a synthesis of dabrafenib, a
selective B-Raf kinase inhibitor.[15] As shown in Figure 3, the
drug precursor 44 incorporates both an aryl halide and an
[7]
[8]
Fors, B. P.; Watson, D. A.; Biscoe, M. R.; Buchwald, S. L. J. Am. Chem.
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353, 279–283. (c) Ge, S.; Green, R.; Hartwig, J. F. J. Am. Chem. Soc.
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Commun. 2016, 7, 11073.
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unprotected anilinic nitrogen on
a
pyrimidine ring.
By
implementing high-throughput evaluation (96-well plate format)
we were able to find optimal conditions for the desired C–N bond
formation (see Supporting Information). Indeed, photosensitized
nickel cross-coupling between 2,6-difluorobenzenesulfonamide
and aryl bromide 44 using ligated nickel provided dabrafenib
(45) in a useful level of efficiency (57% yield) without the
requirement for protection/deprotection sequences.
[12] Ochola, J. R.; Wolf, M. O. Org. Biomol. Chem. 2016, 14, 9088–9092.
[13] The use of Ni(cod)2 for these mechanistic experiments is critical in that
it circumvents the necessary initial reduction of the Ni(II) precatalyst to
Ni(0).
[14] Stern-Volmer experiments rule out the involvement of N-centered
sulfonamidyl radicals generated by a proton-coupled electron transfer
mechanism, see Supporting Information.
Acknowledgement
[15] Rheault, T. R.; Stellwagen, J. C.; Adjabeng, G. M; Hornberger, K. R.;
Petrov, K. G.; Waterson, A. G.; Dickerson, S. H.; Mook, R. A. Jr.;
Laquerre, S. G.; King, A. J.; Rossanese, O. W.; Arnone, M. R.;
Smitheman, K. N.; Kane-Carson, L. S.; Han, C.; Moorthy, G. S.; Moss,
K. G.; Uehling, D. E. ACS Med. Chem. Lett. 2013, 4, 358–362.
The authors thank Professor Stephen Buchwald for helpful
discussions.
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10.1002/anie.201800699
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COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Taehoon Kim, Stefan J. McCarver,
Chulbom Lee, and David W. C.
MacMillan
Page No. – Page No.
Sulfonamidation of Aryl and
Heteroaryl Halides via
Photosensitized Nickel Catalysis
We report method for C–N bond formation between sulfonamides and aryl
electrophiles. This technology provides generic access to a broad range of N-aryl
and N-heteroaryl sulfonamide motifs which are widely represented in drug
discovery. Initial mechanistic studies suggest an energy transfer mechanism
wherein C–N bond reductive elimination occurs from a triplet excited Ni(II) complex.
This article is protected by copyright. All rights reserved.