Direct Copper-Catalyzed Three-Component Synthesis of Sulfonamides

Article abstract of DOI:10.1021/jacs.8b04532

First introduced into medicines in the 1930s, the sulfonamide functional group continues to be present in a wide range of contemporary pharmaceuticals and agrochemicals. Despite their popularity in the design of modern bioactive molecules, the underpinning methods for sulfonamide synthesis are essentially unchanged since their introduction, and rely on the use of starting materials with preinstalled sulfur-functionality. Herein we report a direct single-step synthesis of sulfonamides that combines two of the largest monomer sets available in discovery chemistry, (hetero)aryl boronic acids and amines, along with sulfur dioxide, using a Cu(II) catalyst, to deliver a broad range of sulfonamides. Sulfur dioxide is provided by the surrogate reagent DABSO. The reaction tolerates broad variation in both coupling partners, including aryl, heteroaryl and alkenyl boronic acids, as well as cyclic and acyclic alkyl secondary amines, and primary anilines. We validate the method by showing that a variety of drugs, and drug-fragments, can be incorporated into the process.

Full text of DOI:10.1021/jacs.8b04532

Article
pubs.acs.org/JACS
Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Direct Copper-Catalyzed Three-Component Synthesis of
Sulfonamides
Yiding Chen, Philip R. D. Murray, Alyn T. Davies, and Michael C. Willis*
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, United
Kingdom
S
* Supporting Information
ABSTRACT: First introduced into medicines in the 1930s,
the sulfonamide functional group continues to be present in a
wide range of contemporary pharmaceuticals and agro-
chemicals. Despite their popularity in the design of modern
bioactive molecules, the underpinning methods for sulfona-
mide synthesis are essentially unchanged since their
introduction, and rely on the use of starting materials with preinstalled sulfur-functionality. Herein we report a direct single-
step synthesis of sulfonamides that combines two of the largest monomer sets available in discovery chemistry, (hetero)aryl
boronic acids and amines, along with sulfur dioxide, using a Cu(II) catalyst, to deliver a broad range of sulfonamides. Sulfur
dioxide is provided by the surrogate reagent DABSO. The reaction tolerates broad variation in both coupling partners, including
aryl, heteroaryl and alkenyl boronic acids, as well as cyclic and acyclic alkyl secondary amines, and primary anilines. We validate
the method by showing that a variety of drugs, and drug-fragments, can be incorporated into the process.
of allowing the exploration of new chemical space,8 which is an
INTRODUCTION
■
important consideration in discovery chemistry.9
For a functional group with negligible presence in nature, the
A conceptually attractive route to sulfonamides, which
widespread occurrence of sulfonamides in medicinal and
avoids the use of sulfur-containing starting materials, involves
agrochemical agents is remarkable.1 The favorable physi-
the insertion of a molecule of sulfur dioxide between
ochemical profile, chemical and metabolic stability, three-
appropriate carbon and nitrogen fragments. To be synthetically
dimensional topology, heteroatom-rich nature, and often
useful, particularly for discovery chemistry, these two frag-
crystalline form, combine to propel sulfonamides to the
ments would ideally be simple organic feedstocks, preferably
forefront of functional groups employed in the design of
modern bioactive molecules.2 The resulting molecules are used
with wide commercial availability. The last eight years has seen
the use of sulfur dioxide in catalysis become an established
in myriad applications, ranging from antibiotics, treatments for
migraines and HIV, to herbicides (Scheme 1a).1 Despite the
technology for introducing sulfonyl-derived functional groups,
with the 2010 report from our laboratory of the Pd-catalyzed
advances made in their application, the most common method
of sulfonamide synthesis3 remains unchanged from that used
synthesis of N-aminosulfonamides from the combination of
aryl iodides, sulfur dioxide and hydrazines, providing the key
for the preparation of the first “sulfa drug”, Prontosil, in the
advance (Scheme 1b).10 This report was the first to show that
1930s.4 The key reaction combines an amine with a
cross-coupling type reactions with sulfur dioxide incorporation
corresponding activated sulfonyl derivative, most commonly
were possible, and that the use of a sulfur dioxide surrogate,11
a sulfonyl chloride, and although this is robust methodology, it
in this case the double adduct of sulfur dioxide with the amine
DABCO, offered significant advantages over the use of sulfur
is limited by the stability and availability of specific sulfonyl
chlorides.5 These sulfonyl chlorides are most usually prepared
dioxide gas.12 Several closely related procedures in which the
starting substrate,13 catalyst13c or the SO2-source14 were
changed have been subsequently reported; however, all of
these intermolecular processes maintain the restriction to the
use of hydrazine nucleophiles, thus providing esoteric N-
aminosulfonamide products, which have few applications in
medicinal chemistry. Simple amine coupling partners, which
are required for the preparation of the parent sulfonamides,
cannot be used in these reactions, although an intramolecular
process which is specific for the formation of 5-membered
by the electrophilic chlorosulfonylation of the parent arene,6 or
by oxidative chlorination of an aryl organosulfur compound.7
Electrophilic aromatic substitution processes often require
harsh acidic conditions, limiting functional group compati-
bility, and are only effective for the preparation of specific
substitution patterns as determined by the electronic character-
istics of the starting arene. Similarly, oxidative chlorination
procedures place strict limits on tolerable functionality, and
frequently require the use of odorous thiol substrates. These
issues could be avoided if a direct route to sulfonamides was
possible from readily available starting materials that did not
require preinstalled sulfur-functionality. Employing starting
materials of increased diversity would have the added benefit
Received: April 30, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.8b04532
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
synthesis of these valuable molecules. In particular, we wished
to avoid the requirement for a final S−N bond-forming
reductive elimination from a Pd-center. Copper(II) catalysts
have been used to promote coupling between aryl boronic
acids and a broad range of heteroatom nucleophiles, including
amines,22 phenols23 and sulfinates,24 and this chemistry,
initially developed by Chan, Lam and Evans, has now been
applied in a multitude of settings (Scheme 2a).25 Inspired by
Scheme 1. (a) Examples of Biologically Relevant
Sulfonamides; (b) Catalytic Syntheses of Sulfonamides
Using Sulfur Dioxide, and the Target Transformation
Scheme 2. (a) Cu(II)-Catalyzed Chan−Lam Reactions; (b)
Reaction Design; (c) Optimized Conditions for the
Formation of Sulfonamide 4a
sulfonamides has demonstrated the use of amine nucleo-
philes.15 A number of intermolecular Pd-catalyzed sulfinate
syntheses have been developed, and these have been applied to
sulfonamide preparation in the form of two-step procedures
using in situ derivatization of the sulfinates (Scheme 1b).16
The Buchwald group have reported a related strategy, and
employed Pd-catalysis to convert aryl boronic acids into
sulfonyl chlorides using phenyl chlorosulfate as the coupling
partner.17 A small number of direct sulfonamide syntheses
based on sulfur dioxide insertion are known, but these employ
activated, or noncommercial substrates; for example, the
Cu(I)-catalyzed combination of aryl hydrazines, DABSO and
amines,18 the Cu(II)-catalyzed union of aryl diazonium salts,
DABSO and N-chloro amines,19 and the catalyst-free
combination of N-tosylhydrazones, DABSO and amines,20 all
deliver sulfonamides. Despite these advances, and others,21
a
catalytic single-step sulfonamide synthesis which employs
amines, a readily available arene substrate class, and sulfur
dioxide or an equivalent, remains elusive. In this study, we
provide a solution to this challenge, and show that by using a
Cu(II) catalyst it is possible to achieve the efficient union of
aryl boronic acids, sulfur dioxide (from DABSO), and amines,
to deliver sulfonamides in a direct single step process (Scheme
1b).
the success and scope of these reactions, in particular the
sulfone syntheses using sulfinate nucleophiles, we postulated
that a three-component system, comprising an aryl boronic
acid, sulfur dioxide and an amine, could, in the presence of a
copper(II) catalyst, lead to sulfonamide formation (Scheme
2b). The direct coupling of the boronic acid and amine would
be a competing process, although we speculated that rapid
formation of “amino-sulfinate” (sulfuramidite) intermediates
RESULTS AND DISCUSSION
■
Given the failure to achieve a direct and general sulfonamide
synthesis using palladium-catalysis, we considered alternative
mechanistic scenarios and catalysts to achieve a single-step
B
DOI: 10.1021/jacs.8b04532
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
a
Table 1. Scope of the Boronic Acid Coupling Partner
a
Reaction conditions: morpholine (1.0 equiv), aryl boronic acid (2.0 equiv), copper(II) triflate (10 mol %), L1 (10 mol %), DABSO (2.0 equiv),
cesium carbonate (1.0 equiv), DMSO, 130 °C, 16 h. Isolated yields.
(1)26 should limit this pathway. The challenge would be to
engage amino-sulfinates 1 in cross-coupling.
that the use of alternative oxidants (to DMSO)27 was not
successful.28
To explore this concept we chose the coupling of phenyl
boronic acid (2a), morpholine (3a), and sulfur dioxide. We
selected the Lewis adduct formed between DABCO and sulfur
dioxide, DABSO, as our sulfur dioxide source,12 as it is an easy
to handle solid reagent that has been shown to be effective in a
number of catalytic processes (Scheme 2c).10,16a,c,f,18,19
Pleasingly, initial results employing Cu(OAc)2, the catalyst
used in the majority of Chan−Lam reactions,25a delivered a
17% yield of sulfonamide 4a. An extensive optimization study
was then undertaken and delivered reaction conditions based
on the use of Cu(OTf)2 in combination with a supporting
bipyridine ligand in DMSO as solvent (see Supporting
Information for full details). Specific variations from these
optimized conditions, and their effect on reaction efficiency,
are also provided. Key observations were that DABSO was the
optimal SO2 source, the use of base was advantageous (but not
essential), boronic acids were the boron reagent of choice, and
With optimal conditions for the preparation of sulfonamide
4a in hand, a full substrate scope was explored with respect to
the boronic acid, using morpholine as the amine coupling
partner (Table 1). A broad range of para-substituted aromatics
could be tolerated, delivering the expected sulfonamides in
good yields (4b−k), as could meta-substituted substrates (4l−
u). These examples showed that both electron-donating and
electron-withdrawing groups could be employed, although
substrates bearing electron-withdrawing substituents provided
reduced yields in some cases, with the mass balance comprising
unreacted amine and protodeborylated arene. These examples
also demonstrate the excellent functional group tolerance of
the process, with reactive groups such as alcohols, amines,
esters and halides all being unaffected by the reaction
conditions. It is notable that oxidation-sensitive sulfides are
compatible with the reaction (4e,o). A variety of more
complex di- (4w,x) and trisubstituted aryl boronic acids
C
DOI: 10.1021/jacs.8b04532
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
a
Table 2. Scope of the Amine Coupling Partner
a
Reaction conditions: amine (1.0 equiv), aryl boronic acid (2.0 equiv), copper(II) triflate (10 mol %), L1 (10 mol %), DABSO (2.0 equiv), cesium
carbonate (1.0 equiv), DMSO, 130 °C, 16 h. Isolated yields.
D
DOI: 10.1021/jacs.8b04532
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
a
Table 3. Incorporation of Pharmaceutical APIs, and Related Fragments, into a Single-Step Sulfonamide Synthesis
a
Reaction conditions: amine (1.0 equiv), aryl boronic acid (2.0 equiv), copper(II) triflate (10 mol %), L1 (10 mol %), DABSO (2.0 equiv), cesium
carbonate (1.0 equiv), DMSO, 130 °C, 16 h. Isolated yields.
(4aa,ab), as well as naphthyls (4y,z), and examples fused with
saturated heterocycles (4ac−ae), were also shown to work
well. Importantly, a selection of heteroaromatic boronic acids
were successfully converted into sulfonamides, including
benzofuran (4af), pyridines (4ag−aj), indoles (4ak−am)
and indazole (4an). The indole example 4ak was scaled to
deliver >1.0 g of product without issue. Finally, a group of
alkenyl boronic acids were also shown to be effective substrates
(4ao−aq).
Variation of the amine fragment was evaluated next, using N-
methylindole-5-boronic acid as the coupling partner (Table 2).
Disubstituted acyclic amines, exemplified by a series of N-
methyl amines, performed well in the reactions, providing the
corresponding sulfonamides in good yields (5a−e). Disub-
stituted acyclic amines that were more sterically demanding
provided the sulfonamides in significantly reduced yields (poor
yielding substrates are documented in the Supporting
Information). Amines based on the piperidine ring-system
were excellent substrates (5f−v), and this scaffold was
consequently used to probe the functional group tolerance of
the transformation with respect to the amine. Pleasingly, a
broad range of reactive functional groups, including alcohols,
amines, esters, ketones, sulfides, and nitriles, were readily
tolerated. Tertiary alcohol (5s), spirocyclic ketal (5t) and
spirocyclic azetidine (5v) examples further validate the high
tolerance of the reaction to potentially sensitive functionality.
In addition, the tetrahydroisoquinoline example (5u) demon-
strates that oxidation-sensitive functionality is also tolerated
under the oxidative conditions that are employed. Piperazine
rings are common motifs in medicinal agents, and pleasingly a
range of these cyclic amines substituted with carbamate (5w),
aryl (5x) and heteroaryl (5y−aa) groups were converted into
sulfonamides in an efficient manner. Cyclic amines of different
ring-sizes and composition, including azetidines, were also
effective substrates (5ab−ae). Although simple primary alkyl
amines were not effective substrates (see Supporting
Information), the less nucleophilic aniline class of amines
were well tolerated, and examples featuring a variety of
substituents (5af−ak), including saturated heterocycles (5al−
ao), were effective. Indole (5ap) and pyridine-derived (5aq)
aromatic amines were also successfully used. A set of
representative amine nucleophiles, comprising a piperadine, a
piperazine and an aniline, were also combined successfully with
the less reactive arene components benzene boronic acid and
4-fluoro-benzene boronic acid (5ar−aw).
We anticipate that this chemistry will find wide application
in discovery medicinal and agrochemistry, and accordingly
wanted to demonstrate that coupling-fragments of established
value in these communities could be incorporated. The
examples presented in Table 3 show that a variety of amines
that are either actual active pharmaceutical ingredients (APIs),
or closely related derivatives, can be effectively converted into
sulfonamides. For example, a series of complex substituted
piperidine derivatives performed well, and allowed the
E
DOI: 10.1021/jacs.8b04532
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
incorporation of amine fragments from antihistamine (Lor-
atidine, 6a), antiplatelet (Clopidogrel, 6b) and antipsychotic
(Haloperidol, 6c) agents, as well as the actual API of the
antidepressant Paroxetine (6d). Piperazines that feature in the
atypical antipsychotics Perospirone and Ziprasidone (6e), and
the anti-Parkinson’s compound Piribedal (6f), all performed
well, in addition to the piperazine moiety that is the API in the
antidepressant Amoxapine (6g). A pyrrolo-pyrrole fused
heterocycle that is part of reported treatments for cardiac
arrhythmias (6h),29 the acyclic N-methylamine that is the API
in the antidepressant Fluoxetine (6i), and a tropane used as a
CCR1 antagonist (6j)30 complete the bioactive amines that
were used. We were also able to employ appropriate boronic
acids to allow the formation of sulfonamides featuring the
sulfonylarene fragment from the COX2 inhibitor Celecoxib
(6k), and the arene core of the sedative Zolpidem (6l).
Importantly, modification of our optimized reaction conditions
was not needed for any of these more complex examples.
When considering the potential mechanism of our
developed single-step sulfonamide synthesis, we were aware
of a report from Jiang and co-workers,31 who had shown that
aryl sodium sulfinates could be converted into the correspond-
ing aryl sulfonamides by treatment with an amine and a
copper-catalyst under oxidative conditions, raising the
potential of the involvement a sulfinate intermediate in our
system. Reaction of isolated sodium benzenesulfinate (7) with
morpholine, under our reaction conditions delivered no
sulfonamide product (Scheme 3, eq 1). Similarly, the inclusion
nylethylene, respectively, delivered good yields of sulfonamides
(eq 2). We have similarly considered the possible formation of
a sulfinamide intermediate that then undergoes oxidation to
the desired sulfonamide product.15 However, a coupling
reaction doped with sulfinamide 8 resulted in the formation
an approximate 1:1 mixture of sulfonamides 5t and 4ak (eq 3).
Sulfonamide 4a, the oxidation product of sulfinamide 8, was
not observed. Sulfonamides 5t and 4ak are presumed to arise
from amine exchange with sulfinamide 8. The requirement to
use DMSO as solvent is key in our process, and is consistent
with this simple sulfoxide acting as an oxidant and allowing
substoichiometric amounts of a Cu(II) complex to be used as a
catalyst.32 Direct coupling of the amines and aryl boronic acids,
to give anilines, was not observed. These mechanistic
investigations are only preliminary in nature, and a detailed
mechanistic investigation is underway.
CONCLUSIONS
■
The examples collected in Tables 1−3 demonstrate the broad
scope and high functional group tolerance of the developed
single-step sulfonamide synthesis. They also establish the
ability of the method to process established bioactive
fragments. Amines and boronic acids are both popular and
widely available monomer sets used extensively by chemists in
the pharmaceutical and agrochemical industries; DABSO is a
commercially available and convenient to use sulfur dioxide
surrogate, and copper(II) triflate and bipyridine ligand L1 are
also items of commerce, are widely used in other catalytic
reactions, and are readily encountered in many synthetic
chemistry laboratories. Given the availability of these
substrates and reagents, and the widespread use of
sulfonamides in discovery chemistry, we anticipate the rapid
take-up and application of the methodology disclosed in this
report.
Scheme 3. Preliminary Mechanistic Control Experiments
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.8b04532.
Experimental procedures and supporting characteriza-
tion data and spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*michael.willis@chem.ox.ac.uk
ORCID
Michael C. Willis: 0000-0002-0636-6471
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the EPSRC.
REFERENCES
■
of two equivalents of 4-F-phenylboronic acid to this system
failed to deliver any sulfonamide product. The Jiang chemistry
is susceptible to radical trapping;31 however, this is not the case
for the transformations reported here, as reactions carried out
in the presence of two different radical scavengers, (2,2,6,6-
tetramethylpiperidin-1-yl)oxidanyl (TEMPO) and 1,1-diphe-
(1) Scott, K. A.; Njardarson, J. T. Top. Curr. Chem. (Z) 2018, 376,
376.
(2) Kalgutkar, A. S.; Jones, R.; Sawant, A. In Metabolism,
Pharmacokinetics and Toxicity of Functional Groups: Impact of the
Building Blocks of Medicinal Chemistry on Admet; Smith, D. A., Ed.;
Royal Society of Chemistry: Cambridge, 2010; p 210.
F
DOI: 10.1021/jacs.8b04532
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
(3) Schmitt, A.-M. D.; Schmitt, D. C. In Synthetic Methods in Drug
Discovery; Blakemore, D. C., Doyle, P. M., Fobian, Y. M., Eds.; Royal
Society of Chemistry: Cambridge, 2016; Vol. 2, p 123.
(4) Domagk, G. Klin. Wochenschr. 1936, 15, 1585.
(5) Gabriel, S.; Dambergis, A. K. Ber. Dtsch. Chem. Ges. 1880, 13,
1408.
(6) Bassin, J. P.; Cremlyn, R. J.; Swinbourne, F. J. Phosphorus, Sulfur
Silicon Relat. Elem. 1991, 56, 245.
(7) Wright, S. W.; Hallstrom, K. N. J. Org. Chem. 2006, 71, 1080.
(8) Reymond, J.-L.; van Deursen, R.; Blum, L. C.; Ruddigkeit, L.
MedChemComm 2010, 1, 30.
(29) Bjoersne, M.; Ponten, F.; Strandlund, G.; Svensson, P.;
Wilstermann, M. Preparation of 3,7-diazabicyclo[3.3.0]octanes for the
treatment of cardiac arrhythmias. Patent WO2002060902A1, 2002.
(30) Blumberg, L. C.; Brown, M. F.; Gaweco, A. S.; Gladue, R. P.;
Hayward, M. M.; Lundquist, G. D.; Poss, C. S.; Shavnya, A.
Preparation of bicyclic piperidine derivatives as antagonists of the
CCR1 chemokine receptor. Patent WO2004039376, 2004.
(31) Tang, X.; Huang, L.; Qi, C.; Wu, X.; Wu, W.; Jiang, H. Chem.
Commun. 2013, 49, 6102.
(32) The characterertic odour of Me2S is apparent at the end of the
reactions.
(9) Chow, S. Y.; Nelson, A. J. Med. Chem. 2017, 60, 3591.
(10) Nguyen, B.; Emmett, E. J.; Willis, M. C. J. Am. Chem. Soc. 2010,
132, 16372.
(11) Emmett, E. J.; Willis, M. C. Asian J. Org. Chem. 2015, 4, 602.
(12) Woolven, H.; Gonzalez-Rodriguez, C.; Marco, I.; Thompson,
A. L.; Willis, M. C. Org. Lett. 2011, 13, 4876.
(13) (a) Ye, S. Q.; Wu, J. Chem. Commun. 2012, 48, 7753.
(b) Zheng, D. Q.; An, Y. Y.; Li, Z. H.; Wu, J. Angew. Chem., Int. Ed.
2014, 53, 2451. (c) Wang, X.; Xue, L.; Wang, Z. Org. Lett. 2014, 16,
4056. (d) Liu, N. W.; Liang, S.; Manolikakes, G. Adv. Synth. Catal.
2017, 359, 1308.
(14) Ye, S. Q.; Wu, J. Chem. Commun. 2012, 48, 10037.
(15) Konishi, H.; Tanaka, H.; Manabe, K. Org. Lett. 2017, 19, 1578.
(16) (a) Emmett, E. J.; Hayter, B. R.; Willis, M. C. Angew. Chem., Int.
Ed. 2014, 53, 10204. (b) Shavnya, A.; Coffey, S. B.; Smith, A. C.;
Mascitti, V. Org. Lett. 2013, 15, 6226. (c) Deeming, A. S.; Russell, C.
J.; Willis, M. C. Angew. Chem., Int. Ed. 2016, 55, 747. (d) Shavnya, A.;
Hesp, K. D.; Mascitti, V.; Smith, A. C. Angew. Chem., Int. Ed. 2015,
54, 13571. (e) Johnson, M. W.; Bagley, S. W.; Mankad, N. P.;
Bergman, R. G.; Mascitti, V.; Toste, F. D. Angew. Chem., Int. Ed. 2014,
53, 4404. (f) Zhu, H.; Shen, Y.; Deng, Q.; Huang, C.; Tu, T. Chem. -
Asian J. 2017, 12, 706.
(17) DeBergh, J. R.; Niljianskul, N.; Buchwald, S. L. J. Am. Chem.
Soc. 2013, 135, 10638.
(18) Du, B.; Wang, Y.; Sha, W.; Qian, P.; Mei, H.; Han, J.; Pan, Y.
Asian J. Org. Chem. 2017, 6, 153.
(19) Zhang, F.; Zheng, D.; Lai, L.; Cheng, J.; Sun, J.; Wu, J. Org.
Lett. 2018, 20, 1167.
(20) Tsai, A. S.; Curto, J. M.; Rocke, B. N.; Dechert-Schmitt, A.-M.
R.; Ingle, G. K.; Mascitti, V. Org. Lett. 2016, 18, 508.
(21) (a) Frost, C. G.; Hartley, J. P.; Griffin, D. Synlett 2002, 2002,
1928. (b) Caddick, S.; Wilden, J. D.; Judd, D. B. J. Am. Chem. Soc.
2004, 126, 1024. (c) Moon, S.-Y.; Nam, J.; Rathwell, K.; Kim, W.-S.
Org. Lett. 2014, 16, 338. (d) Wang, Q.; Tang, X. Y.; Shi, M. Angew.
Chem., Int. Ed. 2016, 55, 10811.
(22) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters, M.
P.; Chan, D. M. T.; Combs, A. Tetrahedron Lett. 1998, 39, 2941.
(23) (a) Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett. 1998,
39, 2937. (b) Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters,
M. P. Tetrahedron Lett. 1998, 39, 2933.
(24) (a) Kar, A.; Sayyed, I. A.; Lo, W. F.; Kaiser, H. M.; Beller, M.;
Tse, M. K. Org. Lett. 2007, 9, 3405. (b) Huang, F.; Batey, R. A.
Tetrahedron 2007, 63, 7667. (c) Beaulieu, C.; Guay, D.; Wang, Z.;
Evans, D. A. Tetrahedron Lett. 2004, 45, 3233.
(25) (a) Qiao, J.; Lam, P. Synthesis 2011, 2011, 829. (b) Lam, P. Y.
S. In Synthetic Methods in Drug Discovery; Blakemore, D. C., Doyle, P.
M., Fobian, Y. M., Eds.; The Royal Society of Chemistry: Cambridge,
2016; Vol. 1, p 242.
(26) (a) Hill, A. E. J. Am. Chem. Soc. 1931, 53, 2598. (b) Wong, M.
W.; Wiberg, K. B. J. Am. Chem. Soc. 1992, 114, 7527.
(27) Wu, X.-F.; Natte, K. Adv. Synth. Catal. 2016, 358, 336.
(28) When performed in the absence of a copper catalyst there is a
slow background reaction that delivers 12% of sulfonamide product,
presumably via a mechanistically distinct pathway. Efforts to fully
understand this interesting, but synthetically nonproductive process,
are ongoing.
G
DOI: 10.1021/jacs.8b04532
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX