Rhodium(iii)-catalyzed sulfonamide directed ortho C-H carbenoid functionalization via metal carbene migratory insertion

Article abstract of DOI:10.1039/c8cc08837c

A rhodium(iii)-catalyzed sulfonamide directed ortho C-H carbenoid functionalization has been developed with good yields. This method is attractive due to its broad substrate scope, and enables derivation of diverse biologically active sulfonamide structures and late-stage modification of sulfa drugs.

Full text of DOI:10.1039/c8cc08837c

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Rhodium(III)-catalyzed sulfonamide directed
ortho C–H carbenoid functionalization via metal
carbene migratory insertion†
Cite this:DOI: 10.1039/c8cc08837c
Received 6th November 2018,
Accepted 5th December 2018
ab
ab
Yi Dong,
Jiajing Chenab and Heng Xu
*
DOI: 10.1039/c8cc08837c
rsc.li/chemcomm
A rhodium(III)-catalyzed sulfonamide directed ortho C–H carbenoid carboxylation, carbonylation and arylation, the palladium-
functionalization has been developed with good yields. This method catalyzed sulfonamide group directed C–H activation method
is attractive due to its broad substrate scope, and enables derivation could become an efficient tool for the late-stage functionaliza-
of diverse biologically active sulfonamide structures and late-stage tion of N-pentafluorophenyl (–C6F5) substituted sulfonamide
modification of sulfa drugs.
pharmacophores (Fig. 2C).5 In addition to Pd-catalyzed C–H
activation, Rh- and Co-catalyzed C–H activation reactions have
Aryl sulfonamides, as ubiquitous functional groups in biologically been well investigated with alkenes, allenes and alkynes by
active compounds, often exhibit a variety of pharmacological using sulfonamide as a directing group (Fig. 2D).6 It is note-
effects such as antibiotic, antitumor, hypoglycemic, diuretic, worthy that carbenoid functionalization enables the synthesis
and antihypertensive activities.1 Among them, a number of ortho of natural products and other complex molecules.7 However, to
modified aryl sulfonamide analogues are of great value in drug the best of our knowledge, the sulfonamide functionality has
discovery owing to their potent and diverse biological activities not been utilized as a directing group for ortho C–H insertion
(Fig. 1).2 In the traditional synthetic method for ortho modified carbenoid functionalization, while other directing groups such
aryl sulfonamides, ortho-halo or ortho-silicon substituted sulfon- as heterocycle, imine, amide and diazene have been recently
amides are commonly needed as pre-functionalized starting investigated for this type of reaction.8,9 Herein, we report that
materials (Fig. 2A).3 Recently, sulfonamide-directed C–H activa- sulfonamide directed ortho C–H insertion carbenoid function-
tion was proven to be a more efficient synthetic method for the alization can be achieved using a RhIII catalyst with a broad
preparation of ortho modified aryl sulfonamide analogues (Fig. 2B).4
Having been successfully demonstrated for C–H olefination,
Fig. 1 Selected sulfonamide drugs and biological molecules.
a State Key Laboratory of Bioactive Substance and Function of Natural Medicines,
Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking
Union Medical College, Beijing 100050, China. E-mail: xuheng@imm.ac.cn
b Beijing Key Laboratory of Active Substances Discovery and Druggability
Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and
Peking Union Medical College, Beijing 100050, China
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
Fig. 2 Metal-catalyzed sulfonamide directed ortho C–H activation.
c8cc08837c
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Table 1 Optimal conditionsa
Entry
R
Additive
Solvent
Yieldb/%
1
2
3
4
5
6
7
8
H
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgSbF6
AgBF4
NaOAc
CsOAc
—
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
Toluene
MeOH
DCE
DCE
DCE
DCE
DCE
0
0
0
0
83
0
Me
OMe
tBu
Ac
Boc
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
0
0
9
21
19
Trace
81
18
30
79
77
Trace
0
10
11
12
13
14c
15d
16e
17 f
18g
a
1 (0.25 mmol), 2a (0.5 mmol), [RhCp*Cl2]2 (5 mol%), AgSbF6 (20 mol%),
solvent (2.5 mL), and 60 1C. b Isolated yield. c Room temperature. d 2.5 mol%
[RhCp*Cl2]2 was used. 1.1 equivalents of 2a were used. DCE =
1,2-dichloroethane. 5.0 mmol% [IrCp*Cl2]2 was used. 10 mmol%
CoCp*(CO)I2 was used.
e
f
g
scope of substrates and this functionalization enables deriva-
tion of diverse biologically active sulfonamide structures and
late-stage modification of sulfa drugs (Fig. 2E).
Initially, this sulfonamide directed C–H carbenoid function-
alization was begun by testing the substrates with different
N-auxiliary groups in the presence of 5 mol% [RhCp*Cl2]2 and
20 mol% AgOAc in DCE at 60 1C for 5 h (Table 1). Except for
t
acetyl, other protecting groups, including Me, OMe, Bu, and
Boc substituted sulfonamides and amino free sulfonamides,
were noneffective (entries 1–6). AgSbF6 and AgBF4 were selected
for testing, but dissatisfactory results were obtained (entries 7 and 8).
Screening of the acetate salts showed that OAcÀ was essential
for this transformation, and AgOAc was more suitable for
this C–H carbenoid functionalization than NaOAc and CsOAc
(entries 9 and 10). When the reaction was carried out without
AgOAc, only a trace amount of desired compound 3 was
obtained (entry 11). Further investigation showed that toluene
Scheme 1 Substrate scope. [RhCp*Cl2]2 (5 mol%), AgOAc (20 mol%),
sulfonamides (0.25 mmol), 2 (0.5 mmol), DCE (2.5 mL), 60 1C, and 5 h.
Isolated yield; brsm yield in the parentheses. brsm = based on the
recovered starting material. a Overnight. b 0.375 mmol 2a. c 2.5 mol%
[RhCp*Cl2]2 and 10 mol% AgOAc. d 0.25 mmol 2a. e 1 h.
was also an effective solvent, but MeOH gave a low yield with alkyl, alkenyl, phenyl, furyl, thienyl, carboxylic ester and
(entries 12 and 13). When the carbenoid reaction was carried ketone functional groups were tested and the corresponding
out at room temperature, C–H bond functionalization occurred, monoalkylated products were obtained in good yields (4–11). It
but with incomplete conversion, to afford the C–H activated is notable that the ortho-substituted substrates performed well
product 3 in 30% yield (entry 14). Upon decreasing the amount of in this C–H functionalization reaction to yield the desired
[RhCp*Cl2]2 and 2a to 2.5 mol% and 1.1 equivalents, respectively, alkylated products (12–18), regardless of the substituent being
slightly declined yields were obtained (entries 15 and 16). It is electron-rich (methyl and alkoxyl) or electron-deficient (carboxylic
worthy to note that no desired product was obtained when the ester and nitro). Gratifyingly, this catalytic system was also efficient
[RhCp*Cl2]2 catalyst was replaced with [IrCp*Cl2]2 or CoCp*(CO)I2 for multi-substituted substrates (19–24). When para-substituted
(entries 17 and 18).
substrates were used in this reaction, dialkylated products were
Next, the scope of sulfonamides for this Rh-catalyzed arene obtained (30–34). Further investigation revealed that thiophene-2-
C–H carbenoid functionalization was investigated under the sulfonamide could be also successfully converted into the corres-
optimal conditions (Scheme 1). meta-Substituted sulfonamides ponding product 25. In addition to dimethyl 2-diazomalonate,
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Scheme 2 Substrate scope. [RhCp*Cl2]2 (5.0 mol%), AgOAc (20 mol%),
sulfonamides (0.25 mmol), 2a (0.5 mmol), DCE (2.5 mL), 60 1C, and
overnight. Isolated yield. a2.5 mol% [RhCp*Cl2]2 and 10 mol% AgOAc.
Scheme 4 Synthetic application. Isolated yield; brsm yield in the
parentheses.
substrates containing phosphate ester, sulfone ester and ketone
ester diazo compounds also gave satisfactory results (26–29).
Generally, transition-metal catalyzed C–H activation reactions
are challenging for nitrogen-containing substrates, because nitrogen
usually can coordinate with the metal to interfere with the metal
catalyst.10 In this RhIII-catalyzed C–H carbenoid functionaliza-
tion, it is worthy to note that this method was suitable for some
nitrogen-containing substrates, and the catalytic performance of
the Rh-catalyst was not affected by the nitrogen atom under
these standard conditions (Scheme 2).
It is worthy to note that N-heterocycle directed ortho C–H
carbenoid functionalization mainly occurred and mixed C–H
activated products were obtained when strongly coordinating
N-heterocycles, such as 2-pyridyl and 2-pyrazolyl, were in a
competitive position (Scheme 3).
derivative 51 was prepared under reduction conditions in
excellent yield (Scheme 4A). In addition, the acetylated deriva-
tive of indane-5-sulfonamide (a carbonic anhydrase inhibitor)
underwent this carbenoid functionalization to afford ortho C–H
activated product 52, and further removal of the acetyl group
under acidic conditions resulted in a free sulfonamide group
(Scheme 4B). Sulfonamide group directed ortho C–H carbenoid
functionalization of parecoxib, a COX-2 selective inhibitor,
could be accomplished with tolerance of isoxazole interference
(Scheme 4C).
(1)
To enhance the application of this method in the synthesis
and further modification of sulfa drugs, some important transfor-
mations were investigated and shown in Scheme 4. Essentially,
this Rh-catalyzed ortho C–H carbenoid functionalization can
support gram-scale synthesis with excellent yields. Further
decarboxylation in the presence of LiCl in DMSO at 150 1C
gave 49 in 56% yield, and subsequent refluxing in a cat. amount
of p-TsOH in toluene afforded cyclic compound 50 in 96% yield.
It is worthy to note that benzofused six-ring sultam skeleton
As is shown in eqn (1), an H/D exchange experiment was
conducted to explore the mechanism. When the reaction of 1g
was carried out in the presence of 2.5 mol% [RhCp*Cl2]2 and
10 mol% AgOAc in DCE with [D4]-MeOH, 77% deuteration was
observed at the ortho position of the sulfonamide group. This result
suggested that the first C–H activation step was reversible.
A proposed mechanism of this C–H carbenoid functionaliza-
tion directed by the sulfonamide group is depicted in Scheme 5.
First, ligand exchange of [RhCp*Cl2]2 gives the active rhodium
species RhCp*(OAc)2, which undergoes C–H bond cleavage with
substrate 1a to form rhodacycle I, followed by coordination
with diazo compound 2a and extrusion of N2 to result in the
carbene intermediate II, and subsequent migratory insertion
would generate intermediate III, which undergoes protonolysis
to lead the desired product and the RhCp*(OAc)2 to start a new
catalytic cycle.
In summary, a RhIII-catalyzed sulfonamide directed ortho
C–H carbenoid functionalization was developed with good
yields. A broad substrate scope makes this method more
attractive and derivation of diverse biological sulfonamide
structural units and late-stage modification of sulfa drugs
Scheme 3 Competitive C–H carbenoid functionalization of sulfonamide
containing N-heterocycles. Isolated yield. a Determined by the 1H NMR
analysis of the crude reaction mixture before separation.
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Scheme 5 Proposed mechanistic cycle.
render this method a good application prospect in drug
discovery.
We gratefully acknowledge the financial support from the
National Natural Science Foundation of China (81703329), the
CAMS Innovation Fund for Medical Sciences (2017-I2M-3-011),
and the Non-profit Central Research Institute Fund of Chinese
Academy of Medical Sciences (2018PT35003).
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Conflicts of interest
The authors declare no conflict of interest.
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