Mechanistic Insight Enables Practical, Scalable, Room Temperature Chan-Lam N-Arylation of N-Aryl Sulfonamides

Article abstract of DOI:10.1021/acscatal.8b03238

Sulfonamides are profoundly important in pharmaceutical design. C-N cross-coupling of sulfonamides is an effective method for fragment coupling and structure-activity relationship (SAR) mining. However, cross-coupling of the important N-arylsulfonamide pharmacophore has been notably unsuccessful. Here, we present a solution to this problem via oxidative Cu-catalysis (Chan-Lam cross-coupling). Mechanistic insight has allowed the discovery and refinement of an effective cationic Cu catalyst to facilitate the practical and scalable Chan-Lam N-arylation of primary and secondary N-arylsulfonamides at room temperature. We also demonstrate utility in the large scale synthesis of a key intermediate to a clinical hepatitis C virus treatment.

Full text of DOI:10.1021/acscatal.8b03238

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Article
Mechanistic insight enables practical, scalable, room
temperature Chan-Lam N-arylation of N-aryl sulfonamides
Julien Vantourout, Ling Li, Enrique Bendito-Moll, Sonia Chabbra, Kenneth Arrington,
Bela Ernest Bode, Albert Isidro-Llobet, John A. Kowalski, Mark Nilson, Katherine
Wheelhouse, John L. Woodward, Shiping Xie, David C. Leitch, and Allan J. B. Watson
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b03238 • Publication Date (Web): 06 Sep 2018
Downloaded from http://pubs.acs.org on September 7, 2018
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ACS Catalysis
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Mechanistic insight enables practical, scalable, room temperature
Chan–Lam N-arylation of N-aryl sulfonamides
Julien C. Vantourout,a,b,‡ Ling Li,c,‡ Enrique BenditoꢀMoll,a,b Sonia Chabbra,d Kenneth Arrington,c Bela
E. Bode,d Albert IsidroꢀLlobet,b John A. Kowalski,c Mark G. Nilson,c Katherine M. P. Wheelhouse,b
John L. Woodard,c Shiping Xie,c David C. Leitch,c,* and Allan J. B. Watsond,*
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a Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow, G1 1XL, U.K.
b GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.
c GlaxoSmithKline, Medicines Research Centre, 709 Swedeland Rd #1539, King of Prussia, PA 19406, U.S.A.
d EaStCHEM, School of Chemistry, University of St Andrews, North Haugh, St Andrews, KY16 9ST, U.K.
In celebration of the 20th anniversary of the Chan–Lam reaction
ABSTRACT: Sulfonamides are profoundly important in pharmaceutical design. CꢀN crossꢀcoupling of sulfonamides is an effecꢀ
tive method for fragment coupling and SAR mining. However, crossꢀcoupling of the important Nꢀarylsulfonamide pharmacophore
has been notably unsuccessful. Here, we present a solution to this problem via oxidative Cuꢀcatalysis (Chan–Lam crossꢀcoupling).
Mechanistic insight has allowed the discovery and refinement of an effective cationic Cu catalyst to facilitate the practical and scalꢀ
able Chan–Lam Nꢀarylation of primary and secondary Nꢀarylsulfonamides at room temperature. We also demonstrate utility in the
large scale synthesis of a key intermediate to a clinical HCV treatment.
KEYWORDS: boronic acid, boronic ester, catalysis, Chan–Lam, copper, sulfonamide
(a) Sulfonamides in pharmaceutical agents
The Nꢀaryl sulfonamide functional group is ubiquitous in
medicinal chemistry, with the value of this motif demonstrated
OMe
H
O
N
Me
S
O
N
O
in marketed drugs for many different disease indications
(Scheme 1a).1 The broad utility of this group arises from the
tetrahedral geometry, permitting control of Hꢀbond doꢀ
nor/acceptor directionality to more effectively interact with a
target ligand, and the imbued modulation of physicochemical
properties that can be used to influence pharmacokinetics.1
O
O
HO
HN
N
NH
S
O
N
t-Bu
OMe
O
N
O
t-Bu
N
bosentan
(cadriovascular disease)
dasabuvir
(HCV)
O
O
S
N
t-Bu
F
O
F
N
N
O
NꢀArylation of Nꢀarylsulfonamides is an attractive approach
to target synthesis, enabling an alternative fragment coupling
to Nꢀsulfonylation (which is not always straightforward due to
the poor nucleophilicity of diarylamines), and also providing a
platform for rapid SAR analysis. Despite its appeal, this has
been a challenging process to realize via transition metal caꢀ
talysis.2 To the best of our knowledge, only two examples of
Pdꢀcatalyzed arylation of Nꢀarylsulfonamides have been reꢀ
ported (Scheme 1b),3 with ligand development usually reꢀ
quired for substrates of impaired Lewis basicity.4 Ullmanꢀ
based approaches are generally limited to simple substrates
based on the forcing conditions required.5 Oxidative crossꢀ
coupling using Cuꢀcatalysis (Chan–Lam crossꢀcoupling) offers
an appealing alternative based on the generally inexpensive,
ligandꢀfree, and mild reaction conditions prevalent in this area,
as well as the availability and variety of organoboron coupling
partners.6 However, Chan–Lam Nꢀarylation of Nꢀ
arylsulfonamides is particularly underdeveloped: only scatꢀ
tered examples are reported in the patent literature, with either
low or no yields disclosed.7,8 Perhaps more importantly, the
origin of the problem is unknown. Here, we provide a mechaꢀ
nistically informed rationally designed system for practical
and scalable Chan–Lam Nꢀarylation of sulfonamides at room
temperature (Scheme 1c).
O
H
S
Me
N
S
S
N
H
O
O
F
N
H2N
NH2
N
sulfamethoxzaole
(antibiotic)
dabrafenib
(oncology)
(b) Pd- and Cu-based N-arylsulfonamide N-arylation
Buchwald–Hartwig (Pd, X = halogen):
56-77% yield (2 examples)
O
O
O
O
Pd or Cu
Ar1
Ullmann (Cu, X = halogen):
harsh conditions, simple substrates
S
Ar1
Ar2
X
R1
N
S
R1
N
H
Ar2
Chan–Lam (Cu, X = B(OR)2):
16-26% or unreported yield
(c) This work: Chan-Lam N-arylation by rational design
O
O
S
R2
O
O
R1
N
24 examples (1 mmol)
scalable to >20 mmol
RB(OH)2 and RBpin
37-98% yield
B(OR)2
Cu(MeCN)4PF6 (0.5 equiv)
S
R2
R3
R1
N
N-methylpiperidine or K3PO4
H
R3
MeCN, RT, air
Scheme 1. (a) Exemplar sulfonamides in active pharmaceutical
ingredients. (b) Previous Pdꢀ and Cuꢀmediated Nꢀarylsulfonamide
Nꢀarylation. (c)
A mechanisticallyꢀinformed Chan–Lam Nꢀ
arylation of Nꢀarylsulfonamides.
We recently reported a functional description of Chan–Lam
amination (Scheme 2).9 The description was based on the most
common reaction conditions using Cu(OAc)2 and Et3N as a
base. The process is initiated by denucleation of the paddleꢀ
wheel dimer to the catalytically active monomeric
Cu(II)(R2NH) complex 1. Transmetalation of the organoboron
reagent delivers Cu(II)(Ar)(R2NH) complex 2, which is oxiꢀ
1
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dized via disproportionation to Cu(III) complex 3.10 Reductive
Page 2 of 6
lation efficiency problem under standard conditions (entry 1).
Moving to Cu(MeCN)4PF6 with Et3N immediately improved
the reaction to deliver 57% and 18% yield using 6a and 6b,
respectively (entry 2). Use of a stronger amine base (Nꢀ
methylpiperidine) delivered a highly effective process using
6a (80%) and increasing base stoichiometry improved the
yield further to 98% (entry 4). As expected from our previous
work,9 amine bases gave a notably poorer performance with
6b, due to catalyst inhibition by pinacol (ca. 20%; entries 3
and 4). However, K3PO4 delivered 7a in 50% using 6b (entry
5) with increased stoichiometry improving to 80% (entry 6).
As anticipated, K3PO4 was significantly detrimental to the
reaction of 6a (entries 5 and 6). All of these reaction parameꢀ
ters were further investigated in multivariate arrays, confirmꢀ
ing the optimal conditions from Table 1 (see Supporting Inꢀ
formation (SI) for full details). Several points are worth notꢀ
ing: (1) the use of 0.5 equiv Cu was necessary for efficiency
since Cu is required as catalyst and oxidant (oxidation of
Cu(II)→Cu(III) and Cu(I)→Cu(II)); (2) the organoboron was
required in excess to maintain efficiency with respect to the
expected competing side reactions (i.e., protodeboronation,
oxidation, and homocoupling); (3) selected inorganic bases
were effective for reactions of 6a when used in in conjunction
with Cu(OAc)2; however, these were not transferable to 6b.
1
2
3
4
5
6
7
8
elimination liberates the product and Cu(I). Completion of the
catalytic cycle requires oxidation of Cu(I) to Cu(II), typically
achieved by O2.
pinacol
Reaction deconstruction:
Major substrate-dependent events
2–
[Cu(pin)2
]
[Cu(OAc)2]2•2H2O
4
R2NH
AcO–
(a) Denucleation (R2NH dependent)
–AcOH•Et3N
R2NH
S
OAc
Cu
S
OAc
[Cu(OAc)2]2•2H2
O
HO
NHR2
Cu
1
O2 + R2NH
+ AcOH Et3N
AcO–
1
HO
NHR2
Ar B(OR)2
HOB(OR)2
Cu(II)
•
Cu(II)
(b) Oxidative turnover (R2NH dependent)
9
S
OAc
O2, R2NH
AcOH Et3N
S
OAc
LnCuOAc
Cu(I)
Cu
Cu
2
LnCuOAc Cu(I)
Cu(II)
HO
NHR2
•
Ar
NHR2
1
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Cu(II)
(c) Catalyst inhibition (Bpin specific)
LnCu(II)X2
LnCu(I)X2
Ar NR2
Cu(III)
pinacol
S
OAc
2–
Cu
[Cu(pin)2
]
[Cu(OAc)2]2•2H2
O
+
HX
Ar
NR2
4
3
Scheme 2. Key mechanistic considerations for reaction design.
From mechanistic analysis, two Nꢀsubstrateꢀdependent
events were identified as critical: (1) the initial paddlewheel
denucleation is highly dependent on the Lewis basicity of the
Nꢀsubstrate (Scheme 2a).9 (2) Similarly, Nꢀsubstrate associaꢀ
tion facilitates the oxidative turnover of the Cu catalyst
(Scheme 2b).9 Efficient Cu(I) oxidation is essential not only
for turnover but also to avoid organoboron oxidation, protodeꢀ
boronation, and homocoupling, which are driven by Cu(I).9 (1)
and (2) were anticipated to be the difficult steps in sulfonaꢀ
mide Nꢀarylation based on the poor Lewis basicity of the Nꢀ
arylsulfonamide. From the organoboron perspective, no speꢀ
cific issues were anticipated with arylboronic acids; however,
use of BPin derivatives could lead to catalyst inhibition by
pinacol (forming 4), generated from transmetalation byprodꢀ
ucts (Scheme 2c).9
Table 1. Reaction optimization.
O
O
O
O
conditions
S
Ph
S
Ph
Ph B(OR)2
Me
N
Me
N
H
MeCN, RT, air
B(OH)2 = 6a
Bpin = 6b
2 equiv
Ph
7a
5
1 equiv
Entry Conditions
7a from 7a from
6a (%)a
6b (%)a
Our reaction design was based on several considerations:
(1) To aid paddlewheel denucleation, we selected a Cu(I) cataꢀ
lyst without competing ligating anions (e.g., AcO–);
Cu(MeCN)4PF6.11 This catalyst also served to reduce the quanꢀ
tity of uncontrolled H2O in the system ([Cu(OAc)2]2 is usually
the dihydrate), avoiding the need for rigorous drying and comꢀ
peting organoboron oxidation.12 (2) Bolstering substrate ligaꢀ
tion would aid productive catalysis, avoid organoboron homoꢀ
1
2
Cu(OAc)2 (0.5 equiv), Et3N (6 equiv)
43
13
Cu(MeCN)4PF6 (0.5 equiv), Et3N (6 57
equiv)
18
3
4
5
6
Cu(MeCN)4PF6 (0.5 equiv), Nꢀ 80
methylpiperidine (6 equiv)
21
17
50
80
coupling,
and
facilitate
oxidative
turnover.9
Nꢀ
Cu(MeCN)4PF6 (0.5 equiv), Nꢀ 98
methylpiperidine (8 equiv)
Arylsulfonamide deprotonation was identified as a simple
solution. However, base selection would be crucial: the base
must deprotonate without causing competing processes – diꢀ
merꢀforming anionic bases would therefore be incompatible
based on the points above. A second concern was inhibition of
transmetallation by boron speciation, which would be a greater
problem for boronic acids than BPin esters based on the proꢀ
pensities for hydroxyꢀ and ternary boronate formation.13,14 As
such, we excluded anionic Oꢀbases for boronic acid couplings
and instead focused on amine bases. Anionic Oꢀbases have
shown some potential utility for Chan–Lam amination of
Bpin,9 and are anticipated to be tolerated for Bpin due to a
lower propensity for boronate formation.14 A greater base
strength would help to avoid catalyst inhibition by pinacol by
providing a greater solution concentration of substrate anion.
Finally, adventitious desiccant effects using hygroscopic inorꢀ
ganic bases would lower organoboron oxidation further.15
Based on all of these considerations, we selected K3PO4 for
Bpin processes.
Cu(MeCN)4PF6 (0.5 equiv), K3PO4 (3 40
equiv)
Cu(MeCN)4PF6 (0.5 equiv), K3PO4 (8 32
equiv)
a Conversion to product determined by HPLC. See SI.
The origin of the efficiency gain from a mechanistic perꢀ
spective was reinforced by spectroscopy (Figure 2). EPR analꢀ
ysis confirmed the denucleation problem (Figure 2a). Effective
denucleation only takes place upon inclusion of a base capable
of deprotonating 5. NꢀMethylpiperidine and K3PO4 were sigꢀ
nificantly more effective than Et3N. Similarly, UVꢀVis analysis
showed that Cu(I) oxidation is more effective with 5 in the
presence of Nꢀmethylpiperidine and K3PO4 due to greater elecꢀ
tronꢀdensity at Cu(I) (Scheme 2b). It is worthwhile noting that
the oxidation using K3PO4 is slower than Nꢀmethylpiperidine
due to the formation of some Cu(I)PO4 in situ.16 This further
highlights the need to consider all potential substrateꢀcatalyst
and reagentꢀcatalyst interactions in the design of these proꢀ
cesses (Figure 2b).
This mechanistic rationalization was successful on applicaꢀ
tion (Table 1). Using sulfonamide 5 as a benchmark substrate,
control reactions with Cu(OAc)2 and Et3N confirmed the aryꢀ
2
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ACS Catalysis
O
O
(a) Denucleation event: EPR studies
S
R2
R1
N
B(OR)2
Cu(MeCN)4PF6 (0.5 equiv)
O
O
1
Cu(OAc)2
R3
S
R2
R1
N
Cu(OAc)2 + 5 + K3PO4
Cu(OAc)2 + 5
base (8 equiv), MeCN, RT, air
2
3
4
R3
H
Cu(OAc)2 + 5 + Et3
N
1 equiv
(a) Boronic acid scope
2 equiv
ArB(OH)2: base = N-methylpiperidine
ArBPin: base = K3PO4
Cu(OAc)2 + 5 + NMP
7a-x
5
6
O
O
O
O
O
O
O
O
S
S
Me
N
S
S
Me
N
Me
N
Me
N
7
Me
8
9
(b) Cu(I) oxidation event: UV-vis studies
CF3
Br
7a, 96%
7b, 77%
7c, 82%
7d, 89%
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O
O
O
S
O
O
O
S
O
O
S
Me
N
Ph
N
Ph
Me
N
S
Me
N
Me
Cu(MeCN)4PF6
Cu(MeCN)4PF6 + 5
Cu(MeCN)4PF6 + 5 + Et3
NC
N
Ph
Ph
F
Cu(MeCN)4PF6 + 5 + NMP
7e, 46%
7f, 35%
7g, 94%
7h, 84%
Cu(MeCN)4PF6 + 5 + K3PO4
Cu(MeCN)4PF6 + 5 + NMP + KOAc
Br
O
O
O
O
O
O
O
O
N
S
Me
S
S
N
N
S
Me
N
Me
N
Me
Me
Cl
N
N
N
NHBoc
N
MeO
7i, 68%
7j, 41%
7k, 78%
7l, 37%
(b) BPin scope
O
O
O
O
O
O
O
O
Figure 2. (a) Denucleation EPR analysis. (b) Cu(I) oxidation UVꢀ
Vis analysis. NMP = Nꢀmethylpiperidine.
S
N
S
S
N
S
Me
NH
Me
N
Me
Me
N
N
I
CN
The generality of the protocols was assessed by application
to a series of substrates on 1 mmol scale (Scheme 3). Both
protocols were broadly tolerant of functionality on the organoꢀ
boron partner including variation of regiochemistry and elecꢀ
tronic character, as well as the functionality on the Nꢀaryl sulꢀ
fonamide arene and the sulfonyl group. In particular, halide
substituents (e.g., 7l, 7n, 7x) reinforce the orthogonality of the
Chan–Lam amination with respect to redox neutral Pd and Cu
methods, retaining these handles for subsequent manipulation.
This key feature was important to the subsequent application
of this method in target synthesis (vide infra). Notably, this
protocol was chemoselective for the sulfonamide Nꢀarylation
vs. carbamate Nꢀarylation (7k). While the focus of this study
was to enable Nꢀaryl sulfonamide Nꢀarylation, we found the
protocol amenable to arylation of both primary and Nꢀalkyl
sulfonamides, thereby establishing a broadly applicable methꢀ
od for sulfonamide arylation. Important to our focus on develꢀ
oping a practical methodology, the reaction operates at ambiꢀ
ent temperature and using O2 from air (instead of, for example,
a saturated O2 atmosphere). Yields were synthetically useful in
the main, with sensitive organoborons (e.g., heterocyclic exꢀ
amples 7j, 7l, 7v, 7w) and primary sulfonamides (7p, 7s, 7t)
the most challenging.
7m, 79%
7n, 73%
7o, 81%
7p, 57%
O
O
O
O
O
O
S
O
O
S
NH
S
Me
N
S
N
Me
NH
Me
N
Me
Me
N
CO2Me
Ph
7q, 70%
7r, 51%
7s, 53%
7t, 47%
O
O
N
O
S
O
O
O
O
S
O
S
Me
S
Me
N
Me
N
Me
N
N
N
Me
Me
Me
N
N
MeO
Br
7u, 63%
7v, 56%
7w, 43%
7x, 69%
Scheme 3. NꢀArylation scope. 1 mmol scale (sulfonamide), exꢀ
cept for 7a and 7q, which are on 20 mmol scale. Isolated yields.
Similarly, our objectives required the development of a
scalable process. To this end, the method was found to operate
effectively on 20 mmol (3.4 g sulfonamide) scale for two exꢀ
amples (7a and 7q, Scheme 3). The products were isolated in
high purity (>98% purity), with the reaction to form 7a requirꢀ
ing only a simple aqueous wash (NH4OH, NH4Cl) procedure.
These results demonstrate the potential power of this Chan–
Lam protocol not only for medicinal chemistry analogue genꢀ
eration and SAR, but also for eventual scaleꢀup of potential
clinical candidates.
As a final demonstration of utility, we report the use of this
Chan–Lam coupling as a key transformation in the synthesis
of the NS5B inhibitor GSK8175 (Scheme 4).7c NS5B inhibiꢀ
tors block the RNA polymerase activity of the NS5B viral
enzyme and are an important class of hepatitis C (HCV) theraꢀ
peutics.17 HCV is a lifeꢀthreatening condition with no known
vaccine affecting approximately 2% of the global population,18
with the majority of cases occurring in the developing world.
Accordingly, the development of effective treatments for HCV
3
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Page 4 of 6
Experimental procedures, spectroscopic data (EPR, UV), characꢀ
is a major international goal. A key structural feature of
GSK8175 is the N,Nꢀdiarylsulfonamide, and the accompanyꢀ
ing boronate ester moiety. Application of this Chan–Lam
chemistry as an orthogonal coupling approach allows use of
the halogenated aryl substrate 9 to access compound 10, which
can be quickly elaborated to the API.7c While our general conꢀ
ditions were found to be broadly effective on 1ꢀ20 mmol scale
(Scheme 3), some optimization was necessary on this more
challenging substrate. Specifically, targeted optimization led to
several modifications for this specific transformation, includꢀ
ing use of NEt3 (to generate a soluble triethylammonium carꢀ
boxylate in situ) and a dilute 5% O2 stream as the terminal
oxidant (to maintain a basis of safety on large scale). With
these modifications to our general protocol, we have achieved
63% isolated yield of 10 on 15 g scale after crystallization of
the methylammonium salt.19
terization data, copies of NMR spectra. The Supporting Inforꢀ
mation is available free of charge on the ACS Publications webꢀ
site.
1
2
3
4
5
6
7
8
ACKNOWLEDGMENT
We thank the EPSRC and GSK for a studentship (JCV). LL, KA,
JAK, MGN, JLW, SX, and DCL thank all of the members of the
GSK8175 team, and the members of the Global Chemical Catalyꢀ
sis group.
9
ABBREVIATIONS
10
11
12
13
14
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16
17
18
19
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29
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EPR, electron paramagnetic resonance spectroscopy; HCV, hepaꢀ
titis C virus; NMP, Nꢀmethylpiperidine; pin, pinacol/pinacolate;
SAR, structureꢀactivity relationahips;
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nal Chemist’s Toolbox: An Analysis of Reactions Used in the Pursuit
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G. L. An Introduction to Medicinal Chemistry, 5th ed.; Oxford Uniꢀ
versity Press: Oxford, 2013.
(2) For alternative approaches, see: (a) Scherrer, R. A.; Beatty, H. R.
Preparation of oꢀSubstituted Benzoic Acids by the Copper(II)ꢀ
catalyzed Reaction of Diphenyliodoniumꢀ2ꢀcarboxylate with Anilines
and Other Nucleophiles. J. Org. Chem. 1980, 45, 2127–2131; (b)
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Coupling Reaction: Copperꢀpromoted C−Element Bond Oxidative
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Scheme 4. NꢀArylsulfonamide Nꢀarylation en route to GSK8175.
Isolated yield.
In summary, rational methodological design enabled by
mechanistic insight has allowed the development of an effecꢀ
tive protocol for Chan–Lam arylation of a variety of primary
and secondary sulfonamides. The mild reaction conditions
operate effectively on small (1 mmol) scale and can be readily
scaled (20 mmol and above). This methodology is facilitating
the largeꢀscale production of a clinical HCV therapy and we
expect similar utility to be found in other applications in
pharmaceutical development.
AUTHOR INFORMATION
Corresponding Author
* david.c.leitch@gsk.com
* aw260@stꢀandrews.ac.uk
Author Contributions
All authors have given approval to the final version of the manuꢀ
script.
‡These authors contributed equally.
Funding Sources
Engineering and Physical Sciences Research Council (EPSRC).
GlaxoSmithKline.
Notes
The authors declare no competing financial interest.
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H. S.; Klinder, K.; Kostka, M. Substituted 1,2ꢀethylendiamines,
medicaments comprising said compound; their use and their method
ASSOCIATED CONTENT
Supporting Information
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(19) For the synthesis of 8 see ref 16b.
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Poor substrate-catalyst
interactions
O
O
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B(OR)2
O
O
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R
Ar
R
N
Cu(I)
Cu(III)
H
Ar
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Mechanistic insight
• RB(OH)2 and RBpin • 24 examples •Scalable to >20 mmol
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