High-Throughput Discovery and Evaluation of a General Catalytic Method for N-Arylation of Weakly Nucleophilic Sulfonamides

Article abstract of DOI:10.1021/acs.orglett.9b03380

Through targeted high-throughput experimentation (HTE), we have identified the Pd/AdBippyPhos catalyst system as an effective and general method to construct densely functionalized N,N-diaryl sulfonamide motifs relevant to medicinal chemistry. AdBippyPhos is particularly effective for the installation of heteroaromatic groups. Computational steric parametrization of the investigated ligands reveals the potential importance of remote steric demand, where a large cone angle combined with an accessible Pd center is correlated to successful catalysts for C-N coupling reactions.

Full text of DOI:10.1021/acs.orglett.9b03380

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
High-Throughput Discovery and Evaluation of a General Catalytic
Method for N‑Arylation of Weakly Nucleophilic Sulfonamides
†
,‡
‡
‡
§
Joseph Becica, Damian P. Hruszkewycz, Janelle E. Steves, Jennifer M. Elward,
,
‡,¶
,†
David C. Leitch,*
and Graham E. Dobereiner*
†
Department of Chemistry, Temple University, Philadelphia, Pennsylvania 19122, United States
Chemical Development, GlaxoSmithKline, Collegeville, Pennsylvania 19426, United States
‡
§
Molecular Design, Data & Computational Sciences, GlaxoSmithKline, Collegeville, Pennsylvania 19426, United States
¶
Department of Chemistry, University of Victoria, Victoria, British Columbia V8P 5C2, Canada
S Supporting Information
*
ABSTRACT: Through targeted high-throughput experimentation (HTE), we have
identified the Pd/AdBippyPhos catalyst system as an effective and general method to
construct densely functionalized N,N-diaryl sulfonamide motifs relevant to medicinal
chemistry. AdBippyPhos is particularly effective for the installation of heteroaromatic
groups. Computational steric parametrization of the investigated ligands reveals the
potential importance of remote steric demand, where a large cone angle combined with an
accessible Pd center is correlated to successful catalysts for C−N coupling reactions.
he sulfonamide functional group, a metabolically stable
hydrogen bond acceptor, is commonly found in bio-
∼6000 have the N,N-diaryl substructures shown in Figure 2.
We attribute this to the difficulty of N-sulfonylation at a poorly
T
17
logically active molecules including many active pharmaceut-
nucleophilic diarylamine and the difficulty of arylation at a
poorly nucleophilic secondary sulfonamide. Herein we describe
a simple yet highly effective palladium/AdBippyPhos catalyst
system that enables access to a wide range of N,N-diaryl
sulfonamides with pharmaceutically relevant functionality. We
believe this methodology will open unexplored chemical space
and further the development of new potential therapeutics,
agrochemicals, and materials.
1
−4
ical ingredients.
Sulfa drugs such as sulfamethoxazole have
5
been used for decades as inexpensive antimicrobial agents,
while more complex sulfonamides find uses as anticancer
6
7
8
agents, antiretroviral agents, in hepatitis C treatment, and in
9
various crop protection methods.
Through our work on GSK8175 (Figure 1), an NS5B
8
,10
inhibitor for treatment of hepatitis C,
we discovered that
17−21
efficient access to the N,N-diarylsulfonamide motif is a
We employed high throughput experimentation (HTE)
11−14
significant challenge using current synthetic methods.
to explore the coupling of sulfonamide 1 with either aryl
bromide 2a or pyridyl bromide 2b using a number of Pd
sources, six phosphine ligands (Figure 3), and carbonate
Medicinal chemistry routes to prepare N,N-diarylsulfonamides
analogous to GSK8175 focused on nucleophilic aromatic
substitution and low yielding Cu-catalyzed Chan-Lam
22
bases. This screen was designed to comprehensively evaluate
structural variations of JackiePhos (L1) and BippyPhos (L6),
ligands that were found to be the most promising in
preliminary trials. L1 is a successful ligand in C−N coupling
10
couplings with aryl boronic acids. The initial scale-up route
to GSK8175 itself relied on a multiday S Ar reaction that
N
required the toxic solvent HMPA. Attempts to replace this step
with Pd-catalyzed coupling of the secondary mesylaniline to
simple aryl halides were unsuccessful, as was sulfonylation of
the analogous diarylamine with mesyl chloride. Instead,
development focused on optimization of the Chan-Lam
approach, employing an aryl boronate ester and a cationic
14b
reactions of amides, JackiePhos variants (L2 and L3) in C−
23
N coupling of hindered amines, and BippyPhos-type ligands
2
4−29
as a broad ligand class for C−N coupling reactions.
When
employing high catalyst loadings (>5 mol % [Pd(crotyl)Cl] ),
2
all of the ligands screened enabled coupling with aryl bromide
1
5,16
2
a; in contrast, only BippyPhos-type ligands enabled
Cu precatalyst.
appreciable coupling of heteroaryl bromide 2b, with
AdBippyPhos (L6) providing the highest conversion to
The difficulties encountered during this program alerted us
to a broader gap in practical synthetic methods for accessing
these compounds. A search of the CAS compound database
revealed a striking paucity of reported N,N-diarylsulfonamides:
of the nearly one million reported tertiary sulfonamides, only
30
Received: September 24, 2019
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03380
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Figure 1. GSK8175, inspiration for developing C−N bond coupling
for synthesis of N,N-diarylsulfonamides; prior catalytic approaches to
arylation of N-arylsulfonamides; Pd coupling described in the present
work.
Figure 4. Selected results from high-throughput screening for N-
arylation of N-phenylmethanesulfonamide. Reaction conditions: 96-
well plate; 0.02 mmol 1, 0.02 mmol 2, 0.06 mmol K CO , 0.0013
2
3
mmol [Pd(crotyl)Cl] , 0.004 mmol L1−L6, 0.1 mL CPME (0.2 M in
2
1
), 100 °C. See SI for full table of results.
Table 1. Dependence of Sulfonamide N-Arylation on Pd
Loading, Ligand Identity, and Loading for 1 mmol Scale
a
Reactions
entry
ligand
Pd (mol %)
L (mol %)
yield (%)
1
2
3
4
5
BippyPhos (L5)
BippyPhos (L5)
AdBippyPhos (L6)
AdBippyPhos (L6)
AdBippyPhos (L6)
AdBippyPhos (L6)
5
1
0.5
1
1
10
2
1
2
4
59
<2%
6
14
52
b
6
1
4
59
Figure 2. Reported and commercially available tertiary sulfonamides
in the CAS compound database, separated into compound classes.
a
Reaction conditions: 1 mmol 1, 1 mmol 2, 3 mmol K CO ,
2
3
[
Pd(crotyl)Cl] , L5 or L6, CPME (0.2 M), 100 °C. Yield is
2
b
determined by LC−MS. 3 Å molecular sieves are used.
mitigated decomposition of the aryl halide (observed to
occur via dehalogenation, hydroxylation, and etherification),
14b,22
leading to a 59% yield of 3b (entry 6).
Higher yields are
obtained when performing the reaction with an excess of aryl
halide (vide infra).
A microscale array was designed to evaluate the [Pd(crotyl)-
Figure 3. Phosphine ligands screened in high throughput
experimentation.
Cl] /L6 catalyst system against a large number of substrate
2
combinations (Figure 5). The sulfonamides (S1−S12) were
selected to reflect a variety of S- and N-substituents and
different steric and electronic properties. One primary
sulfonamide (S11) was included for comparison. The
heteroaryl halides (A1−A24) were sourced from the GSK
compound library to form a diverse set of pharmaceutically
relevant heterocyclic structures. The reaction outcome was
evaluated by LC−MS analysis; the presence of cross-coupled
products was initially assessed by MS, and the area percent of
the corresponding LC peak (LCAP) provided a semi-
quantitative metric of reaction performance.
product (Figure 4). Decreasing the catalyst loading was
essential for enabling the practicality of a broad substrate
screen in which >300 individual substrate combinations were
targeted. During attempts to decrease Pd and ligand loadings
for larger scale reactions, other ligands failed to promote the
coupling reaction (Table 1), whereas the reaction of 1 (1
31
mmol) and 2b (1 mmol) with [Pd(crotyl)Cl] (1 mol %) and
2
L6 (4 mol %) resulted in 52% yield of 3b (entry 5). Further
experiments revealed that adding 3 Å molecular sieves
B
DOI: 10.1021/acs.orglett.9b03380
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Figure 5. Selected results from evaluation of aryl halides (A1−A24) and sulfonamides (S1−S12) in microscale array experiments. See SI for details.
Left: Values represent the LC area percent of various sulfonamide/aryl halide combinations. Reaction conditions: 0.04 mmol aryl halide, 0.04 mmol
sulfonamide, 0.08 mmol K CO , 3 Å mol sieves, [Pd(crotyl)Cl] (3 mol %), L6 (12 mol %), 0.5 mL of CPME, 100 °C, 1000 rpm tumble stirring.
2
3
2
Right: Compounds in red gave no desired products under any conditions. Sulfonamide S8 undergoes direct arylation at C2 of the benzothiophene
22
instead of N-arylation.
Figure 6. Tertiary sulfonamides isolated by preparative HPLC. Yield corresponds to solution yield versus 1,3,5-trimethoxybenzene by comparison
1
to H NMR spectrum of purified material. Reaction conditions: 0.4 mmol aryl halide, 0.2 mmol sulfonamide, 0.6 mmol K CO , 3 Å mol sieves,
[
2
3
a
Pd(crotyl)Cl] (3 mol %), L6 (12 mol %), 0.75 mL of CPME, 100 °C, 1000 rpm tumble stirring. Reaction conditions: 4 mmol aryl halide, 2
2
mmol sulfonamide, 6 mmol K CO , 3 Å mol sieves, [Pd(crotyl)Cl] (1 mol %), L6 (4 mol %), 10 mL CPME, 100 °C, yield corresponds to isolated
2
3
2
yield.
The microscale array enabled us to survey >280 substrate
combinations and identify potential targets for preparative-
scale reactions. In particular, we wished to rapidly determine
the viability of different heterocyclic structures that are
32,33
ordinarily challenging in C−N coupling reactions.
High
yielding reactions (>50% LCAP coupling product) were
C
DOI: 10.1021/acs.orglett.9b03380
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
3
4
observed with six-membered heterocycles (such as substituted
pyridines and pyrazines), five-membered heterocycles (such as
furans, thiazoles, and thiophenes), and fused heterocycles
the percentage of the Pd center shielded by ligand atoms.
The JackiePhos series (L1−L3, entries 5−7) features
progressively larger cone angles and lower G(Pd) values, and
the BippyPhos series (L4, entry 4; L5, entry 3; and L6, entry
1) exhibits large cone angles (196−210°) and low G(Pd)
(19.3−21.4%). Although not tested experimentally in this
study beyond preliminary trials, AdBrettPhos, Me tBuXPhos,
tBuBrettPhos, and tBuXPhos exhibit higher G(Pd) (>24%;
entries 2, 8−10).
(
7
such as quinolones, azindoles, and benzothiazoles). In total,
0 of these microscale reactions resulted in >10% LCAP of
cross-coupled product. Within the substrate sets, only five of
the 24 aryl halides and four of the 12 sulfonamides failed to
give any products in the array. Several of these are substrates
containing five-membered azoles (A8, A16−A18, S12), which
remain challenging for many Pd-catalyzed reactions. Sulfona-
mides with electron-deficient aryl substituents (in particular,
S4 and S10) gave little or no conversion in most cases.
To confirm the viability of this method for practical
synthesis, a representative set of sulfonamide products was
isolated on preparative scale (0.2 to 2 mmol) (Figure 6).
Product 3a was formed quantitatively using the optimized
conditions, giving excellent isolated yield at lower Pd loading
4
While further study is required to thoroughly assess this
correlation, our working hypothesis is that ligands with a low
G(Pd) provide a binding pocket for the weakly coordinating
sulfonamide substrates, while a large ligand cone angle
promotes the challenging C−N reductive elimination through
36
remote steric pressure. Prior work has implicated both N-
metalation and reductive elimination as potentially rate-
limiting for Pd-catalyzed C−N couplings of amides and
17,37−39
sulfonamides.
Thus, while previous catalyst develop-
(
[
2 mmol 1, 4 mmol 2, 2 equiv K CO , 1 mol %
2 3
ment efforts focused on generating a more electron-deficient
Pd center to improve amide/sulfonamide binding and
reductive elimination, we propose that steric effects are
likely to be critical in expanding the scope of this coupling
reaction.
Pd(crotyl)Cl] , 4 mol % L6, 3 Å mol sieves, 0.2 M CPME,
2
17
1
00 °C, 2 h). 3b−3s were synthesized on a 10-fold smaller
40
scale (0.2 mmol 1, 0.4 mmol 2, 2 equiv K CO , 3 mol %
2
3
[
Pd(crotyl)Cl] , 12 mol % L6, 3 Å mol sieves, 0.2 M CPME,
2
1
00 °C, 24 h) and isolated by mass-directed preparative
In conclusion, we have identified a superior Pd catalyst
system for challenging N-arylations of secondary sulfonamides.
While several ligands are suitable for the synthesis of simple
tertiary sulfonamides, AdBippyPhos (L6) is particularly adept
at installing pharmaceutically relevant heteroaromatic moieties.
By using an array of microscale experiments, we were able to
simultaneously determine the catalyst’s amenability to different
heterocyclic electrophiles and various sulfonamide structures.
Compatible heterocycles include substituted pyridines, pyr-
azines, thiazoles, thiophenes, furans, benzothiazoles, and
azindoles, while five-membered N-containing heterocycles
such as pyrroles or pyrazoles remain challenging. A number
of tertiary sulfonamide products have been isolated on 0.2−2
mmol scale in good to excellent yields. We propose that the
success of L6 is related to specific steric properties, as
evidenced by the large ECA and G(Pd) determined through
the steric modeling of Pd−phosphine complexes. This
interplay of ligand cone angle and G(Pd) provide a set of
criteria for evaluating new potential ligand scaffolds for
sulfonamide arylations; work to test this hypothesis is currently
HPLC. N-Arylation proceeded chemoselectively in the
presence of a tert-butylcarbamate-protected N−H bond
22
(
3h−3k) as indicated by NMR analysis. High yields of
products with ortho-substituted N-arylsulfonamides can be
obtained using these conditions (3k−3m), though sulfona-
mides with less electron-rich S-substituents (3n−3p) generally
result in lower yields (i.e., S-Tol versus S-Me).
Having found bipyrazolylbis(alkyl)phosphine-based ligands
are more effective than conventional biarylbis(alkyl)phosphine
or biarylbis(aryl)phosphine ligands for the arylation of
secondary sulfonamides, we turned to steric modeling using
DFT optimized geometries (PBE0/6-31+g*) to identify
specific ligand features that are correlated with high-yield
couplings. The steric character of palladium−phosphine
complexes is determined using methods developed by Guzei
3
4
35
and co-workers and previously used by Sigman. Relevant
features derived from the maximum-cone angle conformations
are shown in Table 2. Of the ligands investigated in our initial
screens (Figure 4), those able to promote the synthesis of 3b
in >50% solution yield all have estimated cone angles (ECAs)
41
underway.
>
195°; however, those that give the highest solution yields
also result in comparatively lower G(Pd), which is defined as
ASSOCIATED CONTENT
Supporting Information
■
*
S
Table 2. Steric Parameters for Biaryl and Bis(pyrazolyl)
Phosphine Ligands
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03380.
a
b
entry
ligand
ECA (deg)
G(Pd) (%)
1
2
3
4
5
6
7
8
9
AdBippyphos (L6)
AdBrettPhos
Bippyphos (L5)
CyBippyphos (L4)
JackiePhos (L1)
209.7
217.9
202.7
195.8
163.4
193.7
190.5
173.0
175.5
205.8
19.34
24.56
20.78
21.40
19.34
19.35
20.60
28.00
26.59
24.78
Experimental procedures, CAS structure search results,
characterization, computational methods, chromato-
graphic and spectral data; data and structures for trace
products 3s, 4a, and 4b (PDF)
JackiePhos-NMe (L2)
2
AUTHOR INFORMATION
Corresponding Authors
JackiePhos-OiPr (L3)
■
*
*
Me tBuXPhos
4
tBuBrettPhos
tBuXPhos
E-mail: dob@temple.edu
E-mail: dcleitch@uvic.ca
10
a
b
ORCID
ECA = Estimated cone angle. G(Pd) = % Pd shielded by ligand
atoms.
David C. Leitch: 0000-0002-8726-3318
D
DOI: 10.1021/acs.orglett.9b03380
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
treatment of alzheimer’s disease. Patent WO2004080376A2, 2004. (c)
Eickmeier, C.; Fuchs, K.; Peters, S.; Dorner-Ciossek, C.; Handschuh,
N. H. S.; Klinder, K.; Kostka, M. Substituted 1,2-ethylendiamines,
medicaments comprising said compound; their use and their method of
manufacture. Patent WO2006103038A1, 2006.
Graham E. Dobereiner: 0000-0001-6885-2021
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(14) For Pd-catalyzed coupling examples, see: (a) Wu, Y.-J.; Zhang,
Y.; Good, A. C.; Burton, C. R.; Toyn, J. H.; Albright, C. F.; Macor, J.
E.; Thompson, L. A. Synthesis and SAR of hydroxyethylamine based
phenylcarboxyamides as inhibitors of BACE. Bioorg. Med. Chem. Lett.
■
This work was supported by the National Science Foundation
CHE-1565721). Support for the NMR facility at Temple
University by a CURE grant from the Pennsylvania Depart-
ment of Health is gratefully acknowledged.
(
2009, 19, 2654−2660. (b) Hicks, J. D.; Hyde, A. M.; Martinez
Cuezva, A.; Buchwald, S. L. Pd-Catalyzed N-Arylation of Secondary
Acyclic Amides: Catalyst Development, Scope, and Computational
Study. J. Am. Chem. Soc. 2009, 131, 16720−16734.
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