Divergent C-H functionalizations directed by sulfonamide pharmacophores: Late-stage diversification as a tool for drug discovery

Article abstract of DOI:10.1021/ja201708f

Modern drug discovery is contingent on identifying lead compounds and rapidly synthesizing analogues. The use of a common pharmacophore to direct multiple and divergent C-H functionalizations of lead compounds is a particularly attractive approach. Herein, we demonstrate the viability of late-stage diversification through the divergent C-H functionalization of sulfonamides, an important class of pharmacophores found in nearly 200 drugs currently on the market, including the non-steroidal anti-inflammatory blockbuster drug celecoxib. We developed a set of six categorically different sulfonamide C-H functionalization reactions (olefination, arylation, alkylation, halogenation, carboxylation, and carbonylation), each representing a distinct handle for further diversification to reach a large number of analogues. We then performed late-stage, site-selective diversification of a sulfonamide drug candidate containing multiple potentially reactive C-H bonds to synthesize directly novel celecoxib analogues as potential cyclooxygenase-II (COX-2)-specific inhibitors. Together with other recently developed practical directing groups, such as CONHOMe and CONHC₆F₅, sulfonamide directing groups demonstrate that the auxiliary approach established in asymmetric catalysis can be equally effective in developing broadly useful C-H activation reactions.

Full text of DOI:10.1021/ja201708f

ARTICLE
pubs.acs.org/JACS
Divergent CꢀH Functionalizations Directed by Sulfonamide
Pharmacophores: Late-Stage Diversification as a Tool for Drug
Discovery
Hui-Xiong Dai,† Antonia F. Stepan,‡ Mark S. Plummer,§ Yang-Hui Zhang,† and Jin-Quan Yu*,†
†Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
‡Neuroscience Medicinal Chemistry and §Antibacterials Medicinal Chemistry, Pfizer Global Research and Development, Groton,
Connecticut 06340, United States
S Supporting Information
b
ABSTRACT: Modern drug discovery is contingent on identify-
ing lead compounds and rapidly synthesizing analogues. The
use of a common pharmacophore to direct multiple and
divergent CꢀH functionalizations of lead compounds is a
particularly attractive approach. Herein, we demonstrate the
viability of late-stage diversification through the divergent CꢀH
functionalization of sulfonamides, an important class of phar-
macophores found in nearly 200 drugs currently on the market,
including the non-steroidal anti-inflammatory blockbuster drug celecoxib. We developed a set of six categorically different
sulfonamide CꢀH functionalization reactions (olefination, arylation, alkylation, halogenation, carboxylation, and carbonylation),
each representing a distinct handle for further diversification to reach a large number of analogues. We then performed late-stage,
site-selective diversification of a sulfonamide drug candidate containing multiple potentially reactive CꢀH bonds to synthesize
directly novel celecoxib analogues as potential cyclooxygenase-II (COX-2)-specific inhibitors. Together with other recently
developed practical directing groups, such as CONHOMe and CONHC6F5, sulfonamide directing groups demonstrate that the
auxiliary approach established in asymmetric catalysis can be equally effective in developing broadly useful CꢀH activation
reactions.
Therefore, late-stage, divergent CꢀH functionalizations directed
1. INTRODUCTION
by sulfonamides could provide a unique method for diversity-
Among the many hurdles in identifying promising drug
oriented synthesis (DOS) of drug candidates (Figure 1).
Herein, we report the design and discovery of six different
candidates, rapidly accessing molecular diversity is recognized
as one of the potential bottlenecks.1,2 Among many reported
catalytic systems to effect the efficient CꢀH functionalization of
sulfonamides. Importantly, exclusive site-selectivity was achieved in
the presence of multiple reactive CꢀH bonds, a traditionally
challenging problem for late-stage diversification via CꢀH activa-
tion. In an effort to maximize access to different classes of analogues
of existing aryl- and benzylsulfonamide skeletons, we developed six
categorically different types of Pd(II)-catalyzed CꢀH functionaliza-
tion reactions to install new carbon and heteroatom units. In terms
of operational ease, the procedure of installation and removal of the
appended directing groups is comparable to a common protec-
tionꢀdeprotection sequence.7 The utility of these reactions was also
demonstrated by preparation of celecoxib analogues.
approaches,3 site-selective replacement of inert CꢀH bonds of
bioactive skeletons represents a unique strategy for accessing
new pools of functionalized analogues.4 To demonstrate the
viability of this approach in drug discovery, we embarked on an
investigation to develop a set of divergent CꢀH functionaliza-
tion reactions directed by a privileged pharmacophore. Sulfon-
amide functional groups have long been acclaimed as essential
structural motifs in medicinal chemistry since the early discovery
of a series of sulfonamide-containing antibacterial drugs in 1932
(e.g., sulfamethoxazole).5,6 Numerous sulfonamide-based med-
icines were subsequently found to be effective as diuretics
(e.g., azosemide), anti-migraine agents (e.g., sumatriptan), and
cyclooxygenase-II (COX-2)-specific anti-inflammatory drugs
(e.g., celecoxib) (Figure 1). In the vast majority of cases, the
sulfonamide moiety is thought to play a key role in the primary
pharmacology and disposition characteristics of these marketed
drugs. The introduction of a sulfonamide group represents an
attractive tactic in medicinal chemistry for increasing pharmaco-
logic potency and/or the absorption, distribution, metabolism,
and excretion (ADME) attributes of the lead chemical matter.
2. RESULTS AND DISCUSSION
2.1. Discovery of an Effective Sulfonamide Directing
Group for CꢀH Olefination. Recently, substantial progress
Received: February 23, 2011
Published: April 13, 2011
r
2011 American Chemical Society
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Figure 1. Site-selective diversification of sulfonamide drugs.
Table 1. Discovery of a Sulfonamide Directing Group for
Table 2. Ligand-Enabled CꢀH Olefination of Sulfonamidesa
CꢀH Activationa
yield (%)
entry
ligand
mono
di
1
none
40
35
48
15
31
37
4
20
57
19
79
65
59
89
78
56
20
57
2
Boc-Val-OH
3
Bz-Val-OH
4
Ac-Val-OH
5
Fmoc-Val-OH
(þ)-menthyl(O2C)-Leu-OH
Ac-Leu-OH
6
7
8
Boc-Leu-OH
16
36
46
33
9
Boc-Phe-OH
a Reaction conditions: 1 (0.125 mmol), Pd(OAc)2 (10 mol %), AgOAc
(4 equiv), 2a (4 equiv), DMF (10 equiv), CH2Cl2, 80 °C, 36 h. 1H NMR
yield with CH2Br2 as internal standard.
10
Boc-Thr(t-Bu)-OH
11
Boc-Tyr(t-Bu)-OH
a Reaction conditions: 1h (0.125 mmol), Pd(OAc)2 (10 mol %), ligand
(20 mol %), AgOAc (4 equiv), 2a (4 equiv), DMF (10 equiv), CH2Cl2,
80 °C, 36 h. 1H NMR yield with CH2Br2 as internal standard.
has been made toward the development of Pd-catalyzed ortho-
CꢀH functionalization reactions using simple functional groups
(carboxyl,8a,b acidic amide,8cꢀe hydroxyl,8f carbonyl8g) to direct
CꢀH cleavage through weak coordination. For instance, Pd(II)-
catalyzed coupling of sp3 CꢀH bonds with organoboronic acids
has been employed to diversify bioactive natural products such as
adipic acids.4b Pd(0)-catalyzed CꢀH arylation reactions have
also been used to make anti-inflammatory ibuprofen analogues.4c
To date, these reactions have not been demonstrated to be
compatible with a major class of drug molecules due to lack of
reactivity or selectivity. Keeping in mind that the directing group
would need to be either part of the existing pharmacophore or
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Table 3. CꢀH Olefination of Benzylsulfonamides and Benzenesulfonamidesa
a Reaction conditions: 1 (0.125 mmol), Pd(OAc)2 (10 mol %), Ac-Leu-OH (20 mol %), AgOAc (4 equiv), 2 (4 equiv), DMF (10 equiv), CH2Cl2, 80
°C, 36 h.
readily converted to the targeted drug molecule via simple
synthetic operations, such as those that utilize a practical
protecting group or Evans auxiliary,9 we began our efforts by
devising a generally applicable sulfonamide-based directing
group capable of efficiently promoting divergent metal-catalyzed
CꢀH activation reactions. Despite the pioneering Rh-catalyzed
alkoxysulfonamide-directed nitrene insertion reactions,10 sulfo-
namides have not been shown to direct palladation of CꢀH
bonds. We first examined several benzylsulfonamide derivatives
using a Pd(II)-catalyzed CꢀH olefination protocol as a screening
assay for reactivity (Table 1). [Notably, a benzylsulfonamide is
the key pharmacophore in sumatriptan.5,6] While the majority of
commonly encountered sulfonamides were not sufficiently active
in promoting CꢀH olefination, we found that the more acidic
N-arylsulfonamide displayed encouraging reactivity, affording a
mixture of mono- and di-olefinated products in 60% combined
yield (entry 8).
This olefination protocol was then applied to variety of
benzylsulfonamide substrates (Table 3). CꢀH olefination of
ortho- and meta-substituted benzylsulfonamides gave mono-
olefinated products in good yields (3aꢀ3e, Table 3). The
presence of an electron-donating meta-OMe group enhanced
the reactivity to give mainly the di-olefinated product (3g).
Olefination of unsubstituted or para-substituted substrates af-
forded mainly the di-olefinated products accompanied by less
than 5% of the mono-olefinated products, which could be readily
separated by column chromatography (3hꢀ3j). Moderate yield
was obtained when styrene was used as the coupling partner
(3k). It is noteworthy that the presence of electron-withdrawing
groups (CF3 and halides) on the aryl ring was also well-tolerated
(3aꢀ3f, 3i, 3j).
With this catalytic olefination protocol in hand, we then went
on to test the applicability of this methodology to another
important motif in drug molecules, benzenesulfonamides
(Table 3). We were pleased to find that the reaction of
benzenesulfonamide 1l gave exclusively the mono-olefinated
product 3l in 56% isolated yield. The presence of an electron-
donating group increased the yield to 68% (3n). Electron-with-
drawing groups, such as halides and CF3, decreased the yield
Guided by our previous studies on ligand-accelerated CꢀH
olefination,11 we extensively screened mono-N-protected amino
acid ligands (Table 2). We found that the use of Ac-Leu-OH as a
ligand enhanced the reactivity drastically to produce predomi-
nantly the di-olefinated product in 89% yield (entry 7).
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Scheme 1. Divergent CꢀH Functionalization Reactions of Sulfonamide 1ma
a Reaction conditions: (1) 1m (0.125 mmol), Pd(OAc)2 (10 mol %), Ac-Leu-OH (20 mol %), AgOAc (4 equiv), ethyl acrylate 2a (4 equiv), DMF
(10 equiv), CH2Cl2, 80 °C, 36 h; yield 51%. (2) 1m (0.125 mmol), Pd(OAc)2 (10 mol %), AgOAc (2 equiv), TEMPO (2 equiv), KH2PO4 (2 equiv),
n-hexane, CO (1 atm), 130 °C, 24 h; yield 66%. (3) 1m (0.125 mmol), Pd(OAc)2 (10 mol %), AgOAc (2 equiv), KH2PO4 (2 equiv), n-hexane, CO
(1 atm), 130 °C, 24 h; yield 96%. (4) 1m (0.125 mmol), Pd(OAc)2 (10 mol %), PhI(OAc)2 (3 equiv), I2 (3 equiv), DMF, 90 °C, 48 h; yield 62%. (5) 1m
(0.125 mmol), Pd(OAc)2 (10 mol %), BQ (10 mol %), pinacol phenylboronate (2 equiv), K2HPO4 (1 equiv), Ag2CO3 (2 equiv), t-AmylOH, 110 °C,
24 h; yield 64% (mono:di = 3:1). (6) 1m (0.125 mmol), Pd(OAc)2 (10 mol %), BQ (10 mol %), MeB(OH)2 (2 equiv), K2HPO4 (1 equiv), Ag2CO3
(2 equiv), t-AmylOH, 110 °C, 24 h; yield 82% (mono:di = 4.5:1).
(3p, 3q). An extremely electron-withdrawing nitro group de-
creased the yield to 36% (3r). Interestingly, olefination of
naphthalenesulfonamide proceeded with high selectivity at the
3-position to give the mono-olefinated product in 65% yield (3s).
The relatively low reactivity of benzenesulfonamides (compared
to benzylsulfonamides) is unsurprising because sulfonyl groups
tend to significantly decrease the electron density of arenes.
Although further improvement of this olefination can be ex-
pected through optimization of conditions and ligands, this
reactivity encouraged us to move forward to develop a broad
range of reactions in order to achieve diversification as
described below.
2.2. Development of Divergent CꢀH Functionalizations
Directed by Sulfonamides. To establish the sulfonamide group
as a powerful handle for DOS, the next important challenge was
to apply this newly uncovered CꢀH activation reactivity to
develop a broad range of carbonꢀcarbon and carbonꢀheteroa-
tom bond-forming processes. Drawing upon our accumulated
experience in developing Pd(II)-catalyzed CꢀH functionaliza-
tion reactions,11,12 extensive screening and optimizations were
carried out to develop several new ortho-CꢀH functionalization
processes. Thus far, we have successfully developed new catalytic
conditions to perform a diverse range of reactions directed by
the same sulfonamide functionality, including olefination,11
carboxylation,12a carbonylation,12b iodination,12c arylation,8a
and alkylation12d (Scheme 1). Excellent yields of the carbonyla-
tion and methylation were obtained, 96% and 82%, respectively.
Notably, the majority of previously reported directing groups
have only been shown to promote a limited set of CꢀH
activation transformations. The availability of these unprece-
dented transformations demonstrates the power of the sulfon-
amide group to diversify a privileged skeleton in a manner that
was previously impossible. The N-aryl moiety in the product can
be kept as part of the pharmacophore or readily removed by
hydrolysis with TFA in order to prepare other sulfonamide
derivatives (Scheme 1). In terms of ease, the procedure for
removing this directing group is comparable to a common
deprotection step.
2.3. Preparation of Celecoxib Analogues via Late-Stage
Diversifications. Finally, we performed this divergent CꢀH
functionalization technique on celecoxib analogue 1t, which is
readily available in large quantities from the Pfizer sample bank
and only differs from the blockbuster celecoxib by an OMe group
in place of a Me group (Scheme 2). We chose celecoxib analogue
1t in order to examine the viability of our late-stage diversification
approach in complex settings. In this case, site-selective CꢀH
bond functionalization must occur in the presence of multiple
reactive CꢀH bonds that could be cleaved through competitive
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Scheme 2. Preparation of Celecoxib Analogues through Divergent CꢀH Functionalizationa
a Reaction conditions: (1) 1t (0.0625 mmol), Pd(OAc)2 (20 mol %), Ac-Leu-OH (40 mol %), AgOAc (4 equiv), ethyl acrylate 2a (4 equiv), DMF
(10 equiv), HOAc (2 equiv), CH2Cl2, 100 °C, 48 h; yield 45%. (2) 1t (0.0625 mmol), Pd(OAc)2 (20 mol %), AgOAc (2 equiv), TEMPO (2 equiv),
KH2PO4 (2 equiv), n-hexane, CO (1 atm), 130 °C, 24 h; yield 67%. (3) 1t (0.0625 mmol), Pd(OAc)2 (20 mol %), AgOAc (2 equiv), KH2PO4 (2 equiv),
n-hexane, CO (1 atm), 130 °C, 24 h; yield 79%. (4) 1t (0.0625 mmol), Pd(OAc)2 (20 mol %), PhI(OAc)2 (3 equiv), I2 (3 equiv), DMF, 110 °C, 48 h;
yield 56%. (5) 1t (0.0625 mmol), Pd(OAc)2 (20 mol %), BQ (20 mol %), pinacol phenylboronate (2 equiv), K2HPO4 (1 equiv), Ag2CO3 (2 equiv),
t-AmylOH, 110 °C, 24 h; yield 39%. (6) 1t (0.0625 mmol), Pd(OAc)2 (20 mol %), BQ (20 mol %), MeB(OH)2 (2 equiv), K2HPO4 (1 equiv), Ag2CO3
(2 equiv), t-AmylOH, 110 °C, 24 h; yield 71%.
reaction pathways. For instance, the CꢀHb bond could undergo
pyrazole-directed CꢀH activation,13 or alternatively, the elec-
tron-donating OMe group on the anisole ring in 1t could render
the CꢀHc or CꢀHd bonds reactive enough to undergo Fujiwara-
type electrophilic palladation14 or electrophilic bromination.
Furthermore, the CꢀHe bond could also be brominated with
Br2/HOAc15 or arylated following treatment with Pd(0)/ArBr
by known procedures.16 Thus, we were pleased to find that
treatment of celecoxib analogue 1t under our six reactions
conditions (olefination, carboxylation, etc.) yielded exclusively
the corresponding products (3t and 10ꢀ14) from sulfonamide-
directed functionalization of the CꢀHa bond; other CꢀH
functionalization pathways were not observed. Each of these
newly installed carbon or heteroatom units represents a distinct
handle for further diversification to access a large number of
previously unavailable celecoxib analogues for biological screen-
ing as potential COX-2-selective inhibitors.15 For instance, CꢀC
cross-coupling could be performed with a wide range of alkyl and
aryl boron reagents. The newly installed iodide, carboxyl, and
vinyl groups, on the other hand, can readily be converted to many
other functional groups. It is noteworthy that selective bromina-
tion of CꢀHe in the functionalized products also provides a
handle for further diversification (Scheme 2). It should be noted
that de novo syntheses of these analogues would not only be
laborious but could also be problematic, as the newly installed
functional groups may not necessarily be compatible with a
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particular synthetic sequence. Additionally, some of the substi-
tuted sulfonamide building blocks require multiple steps to
synthesize.
and heated to 130 °C for 24 h under vigorous stirring. The reaction
mixture was cooled to room temperature, diluted with ethyl acetate, and
filtered through a small pad of Celite. The filtrate was concentrated in
vacuo and purified by a silica-gel-packed flash chromatography column,
using ethyl acetate/methanol as the eluent. The product 4 was obtained
as a white amorphous solid (32 mg, 66% yield).
3. CONCLUSION
In summary, we have successfully employed key sulfonamide
pharmacophores to direct a diverse range of CꢀH functionaliza-
tion reactions. The directing power of the sulfonamide group
overrides a common heterocycle directing group, affording
exclusive site-selectivity in the presence of multiple potentially
reactive CꢀH bonds. This combination of selectivity and
versatility paves the way for late-stage diversifications of drug
molecules. The utility of divergent CꢀH functionalization in
drug discovery is demonstrated by the rapid preparation of six
categorically distinct analogues of the blockbuster celecoxib as
potential COX-2-selective inhibitors. Together with other re-
cently developed practical directing groups, such as CONHOMe
and CONHC6F5, this sulfonamide directing group further
showcases the feasibility and potential of developing “Evans
auxiliary equivalents” for assisting practical CꢀH activation
reactions.
4.4. General Procedure for the CꢀH Carbonylation of
Benzenesulfonamides. A 50 mL Schlenk-type tube (with a Teflon
high-pressure valve and side arm) equipped with a magnetic stir bar was
charged with Pd(OAc)2 (2.8 mg, 0.0125 mmol, 10 mol %) followed by
sulfonamide 1m (42 mg, 0.125 mmol, 1.0 equiv), AgOAc (42 mg,
0.25 mmol, 2.0 equiv), KH2PO4 (34 mg, 0.25 mmol, 2.0 equiv), and
n-hexane (2 mL). The reaction tube was evacuated, back-filled with CO
(five times, balloon), and heated to 130 °C for 24 h under vigorous
stirring. The reaction mixture was cooled to room temperature, diluted
with ethyl acetate, and filtered through a small pad of Celite. The filtrate
was concentrated in vacuo and purified by a silica-gel-packed flash
chromatography column, using ethyl acetate/hexane as the eluent.
The product 5 was obtained as a white amorphous solid (43 mg, 96%
yield).
4.5. General Procedure for the CꢀH Iodination of Benze-
nesulfonamides. In a 20 mL sealed tube, 1m (42 mg, 0.125 mmol,
1.0 equiv), Pd(OAc)2 (2.8 mg, 0.0125 mmol, 10 mol %), PhI(OAc)2
(121 mg, 0.375 mmol, 3.0 equiv), and I2 (96 mg, 0.375 mmol, 3.0 equiv)
were dissolved in DMF (2 mL) under air. The reaction mixture was then
stirred at 90 °C for 48 h. The reaction mixture was cooled to room
temperature, diluted with ethyl acetate, and filtered through a small pad
of Celite. The filtrate was concentrated in vacuo and purified by a silica-
gel-packed flash chromatography column, using ethyl acetate/hexane as
the eluent. The product 6 was obtained as a pale yellow amorphous solid
(36 mg, 62% yield).
4.6. General Procedure for the CꢀH Arylation of Benze-
nesulfonamides. In a 20 mL sealed tube, 1m (42 mg, 0.125 mmol,
1.0 equiv), Pd(OAc)2 (2.8 mg, 0.0125 mmol, 10 mol %), 1,4-benzoqui-
none (BQ) (1.5 mg, 0.0125 mmol, 10 mol %), Ag2CO3 (69 mg,
0.25 mmol, 2 equiv), pinacol phenylboronate (51 mg, 0.25 mmol, 2.0
equiv), and K2HPO4 (22 mg, 0.125 mmol, 1.0 equiv) were dissolved in
t-AmylOH (2 mL) under air. The reaction mixture was then stirred at
110 °C for 24 h. The reaction mixture was cooled to room temperature,
diluted with ethyl acetate, and filtered through a small pad of Celite. The
filtrate was concentrated in vacuo and purified by a silica-gel-packed flash
chromatography column, using ethyl acetate/hexane as the eluent. The
products 7 (25 mg, 48% yield) and 70 (9 mg, 16% yield) were obtained as
pale yellow oils.
4.7. General Procedure for the CꢀH Methylation of Ben-
zenesulfonamides. In a 20 mL sealed tube, 1m (42 mg, 0.125 mmol,
1.0 equiv), Pd(OAc)2 (2.8 mg, 0.0125 mmol, 10 mol %), 1,4-benzoqui-
none (BQ) (1.5 mg, 0.0125 mmol, 10 mol %), Ag2CO3 (69 mg,
0.25 mmol, 2.0 equiv), MeB(OH)2 (15 mg, 0.25 mmol, 2.0 equiv),
and K2HPO4 (22 mg, 0.125 mmol, 1.0 equiv) were dissolved in
t-AmylOH (2 mL) under air. The reaction mixture was then stirred at
110 °C for 24 h. The reaction mixture was cooled to room temperature,
diluted with ethyl acetate, and filtered through a small pad of Celite. The
filtrate was concentrated in vacuo and purified by a silica-gel-packed flash
chromatography column, using ethyl acetate/hexane as the eluent. The
products 8 (29 mg, 67% yield) and 80 (7 mg, 15% yield) were obtained as
pale yellow amorphous solids.
4. EXPERIMENTAL SECTION
4.1. General Information. Anhydrous solvents were obtained by
purification according to standard methods,17 and all other solvents were
used as received from commercial sources without further purification.
With the exception of 3-methoxylbenzylsulfonyl chloride18 and 4-(5-
(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzene-1-sulfo-
nyl chloride,19,20 all the other sulfonyl chlorides, olefin coupling
partners, and reagents used to prepare the sulfonamide substrates were
purchased from Acros, Sigma-Aldrich, TCI, Oakwood, and Alfa-Aesar
and were used as received without further purification. Palladium acetate
was purchased from Sigma-Aldrich and used without further purifica-
tion. The amino acid ligands were purchased from Bachem and
Novabiochem. 1H NMR and 13C NMR spectra were recorded on
Bruker-AV (400 and 100 MHz, respectively), Bruker DRX (500 and
125 MHz, respectively), and Bruker-DRX (600 and 150 MHz, re-
spectively) instruments and are reported relative to the SiMe4 or residual
undeuterated solvent signals. High-resolution mass spectra were re-
corded at the Center for Mass Spectrometry, The Scripps Research
Institute.
4.2. General Procedure for the CꢀH Olefination of Ben-
zylsulfonamides and Benzenesulfonamides. In a 20 mL sealed
tube, benzylsulfonamide 1a (45 mg, 0.125 mmol, 1.0 equiv), Pd(OAc)2
(2.8 mg, 0.0125 mmol, 10 mol %), Ac-Leu-OH (4.5 mg, 0.025 mmol, 20
mol %), AgOAc (82 mg, 0.50 mmol, 4 equiv), ethyl acrylate 2a (53 μL,
0.50 mmol, 4 equiv), and DMF (0.1 mL, 1.25 mmol, 10 equiv) were
dissolved in CH2Cl2 (2 mL) under air. The reaction mixture was then
stirred at 80 °C for 36 h. The reaction mixture was cooled to room
temperature, diluted with ethyl acetate, and filtered through a small pad
of Celite. The filtrate was concentrated in vacuo and purified by a silica-
gel-packed flash chromatography column, using ethyl acetate/hexane as
the eluent. The product 3a was obtained as a white amorphous solid (42
mg, 74% yield).
4.3. General Procedure for the CꢀH Carboxylation of
Benzenesulfonamides. A 50 mL Schlenk-type tube (with a Teflon
high-pressure valve and side arm) equipped with a magnetic stir bar was
charged with Pd(OAc)2 (2.8 mg, 0.0125 mmol, 10 mol %) followed by
sulfonamide 1m (42 mg, 0.125 mmol, 1.0 equiv), AgOAc (42 mg,
0.25 mmol, 2.0 equiv), KH2PO4 (34 mg, 0.25 mmol, 2.0 equiv),
TEMPO (39 mg, 0.25 mmol, 2.0 equiv), and n-hexane (2 mL). The
reaction tube was evacuated, back-filled with CO (five times, balloon),
4.8. Hydrolysis of Sulfonamide 8. Sulfonamide (8, 22 mg,
0.0626 mmol) was dissolved in trifluoroacetic acidꢀH2O (10:1,
2.2 mL), and the mixture was heated to 100 °C for 24 h before cooling
to room temperature. After the solvent was removed in vacuo, the residue
was dissolved in H2O (5 mL) and washed with ethyl acetate (5 mL ꢁ 3).
H2O was removed in vacuo to obtain sulfonyl acid 96 (14 mg, 87% yield)
as a white amorphous solid. 1H NMR (400 MHz, D2O): δ 7.60
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4.9. Bromination of Sulfonamide 11. To a solution of 11
(11 mg, 0.0187 mmol) in CH2Cl2 (1 mL) at room temperature was
added a solution of 1.0 M Br2/CH2Cl2 (95 μL, 0.0935 mmol) dropwise.
The mixture was then stirred at 50 °C for 24 h. The reaction mixture was
cooled to room temperature, diluted with ethyl acetate (50 mL), and
extracted with saturated NaHCO3 (2 ꢁ 50 mL) followed by brine (2 ꢁ
50 mL). The organic layer was dried over Na2SO4, filtered, and
concentrated in vacuo to give a yellow oil. The crude product was
purified by a silica-gel-packed flash chromatography column, using ethyl
acetate/hexane (1:4) as the eluent. The product 15 was obtained as a
white amorphous solid (7.3 mg, 59% yield).
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’ ASSOCIATED CONTENT
S
Supporting Information. Detailed experimental proce-
b
dures, characterization of new compounds, and complete ref 15.
This material is available free of charge via the Internet at http://
pubs.acs.org.
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’ AUTHOR INFORMATION
Corresponding Author
yu200@scripps.edu
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128, 12634. (b) Desai, L. V.; Stowers, K. J.; Sanford, M. S. J. Am. Chem.
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’ ACKNOWLEDGMENT
We gratefully acknowledge The Scripps Research Institute,
Pfizer, and the U.S. National Science Foundation (NSF CHE-
0910014) and National Science Foundation under the Center of
Chemical Innovation in Stereoselective CꢀH Functionalization
(CHE-0943980) for financial support.
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