Iridium-catalyzed direct ortho-C-H amidation of benzoic acids with sulfonylazides

Article abstract of DOI:10.1016/j.cclet.2015.08.009

A mild and efficient iridium-catalyzed ortho-C-H amidation with sulfonyl azides by weakly coordinating carboxylic acid was demonstrated, which provided a novel approach to anthranilic acid derivatives.

Full text of DOI:10.1016/j.cclet.2015.08.009

Chinese Chemical Letters 26 (2015) 1336–1340
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Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
Iridium-catalyzed direct ortho-C–H amidation of benzoic acids with
sulfonylazides
*
Ming-E Wei, Lian-Hui Wang, Yu-Dong Li, Xiu-Ling Cui
Engineering Research Center of Molecular Medicine, Ministry of Education, the Key Laboratory of Xiamen Marine and Gene Drugs, Institute of Molecular
Medicine and School of Biomedical Sciences, Huaqiao University, Xiamen 361021, China
A R T I C L E I N F O
A B S T R A C T
Article history:
A mild and efficient iridium-catalyzed ortho-C–H amidation with sulfonyl azides by weakly coordinating
carboxylic acid was demonstrated, which provided a novel approach to anthranilic acid derivatives.
ß 2015 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
Received 29 June 2015
Received in revised form 24 July 2015
Accepted 4 August 2015
Available online 20 August 2015
Keywords:
Ir-catalysis
Benzoic acid
Sulfonyl azides
C–H bond amination
1. Introduction
which afforded sulfonamide and anthranilic acid derivatives
[32]. Notably, the products obtained from this protocol as an
C–N bond construction has been one of the most important
research topic in organic synthesis, accompanied by the develop-
ment of Ullmann reaction [1,2] and Buchwald–Hartwig amination
[3,4]. However, their high cost and environmental toxicity, such as
stoichiometric amounts of halogen salt as by-product, prevent the
large-scale syntheses in industrial applications. Recently, the direct
C–H bond functionalization has been more facility, straightforward
and environment friendly protocols to construct carbon–carbon [5]
and carbon–heteroatom bonds [6–8]. However, most of transition-
metal-catalyzed C–H amination reactions require stoichiometric
external oxidants and the harsh reaction conditions. Organic azides,
which is an environmental amino source and also as an internal
oxidant via N–N2 bondcleavage, would bekeytodevelopanefficient
C–H amination and the sole byproduct is molecular nitrogen (N2)
[9,10]. Recently, Chang reported elegant works on azides as nitrogen
source for transition-metal-catalyzed direct C–H amidations [11–
21]. Miura [22], Daugulis [23] and Yu [24–31] have independently
achieved direct ortho-C–H amidation of benzoic acids. Along with
our continuing efforts to explore novel C–N bond formations [7], we
herein independently reported an iridium-catalyzed carboxylic
acid-directedC–Haminationswithsulfonylazidesasaminosources,
important structural unitswidely existin pharmaceutical molecules
and natural products, such as the potent inhibitor of methionine
aminopeptidase-2 (MetAP-2) (Fig. 1, left), and sulfonamide deriva-
tives with efficiently anti-inflammatory and aldose reductase
inhibitory activities (Fig. 1, right) [33,34].
2. Experimental
To a screw capped vial with a spinvane triangular-shaped Teflon
stir bar were added benzoic acids (1, 0.20 mmol), azide (2,
0.20 mmol), [IrCp*Cl2]2 (3.2 mg, 4 mol%), AgNTf2 (6.2 mg, 8 mol%),
Li2CO3 (2.2 mg, 15 mol%), AcOH(1.8 mg, 15 mol%) and 1,2-dichloro-
ethane (2.0 mL) under N2 atmosphere. The reaction mixture was
stirredinapre-heatedoilbathattheindicatingtemperaturefor12 h.
Then,thereactionmixturewascooledtoroomtemperatureincaseof
heating, filteredthrougha padofceliteand thenwashedwithCH2Cl2
*
Corresponding author.
Fig. 1. Examples illustrating the importance of 2-sulfonylamido benzoic acids.
E-mail address: cuixl@hqu.edu.cn (X.-L. Cui).
http://dx.doi.org/10.1016/j.cclet.2015.08.009
0933-3657/$ – see front matter1001-8417/ß 2015 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V.
All rights reserved.

M.-E. Wei et al. / Chinese Chemical Letters 26 (2015) 1336–1340
1337
Table 1
Optimization of various reaction parameters.a
Entry
Catalyst
Silver salt
Additive
Solvent
T (8C)
3aa (%)
1
2
–
AgNTf2
–
HOAc + Li2CO3
HOAc + Li2CO3
–
DCE
80
80
80
50
50
50
50
50
50
50
50
50
25
60
70
80
80
80
80
80
80
80
80
80
80
0
0
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[RhCp*Cl2]2
[Ru(p-cymene)Cl2]2
Pd(OAc)2
DCE
3
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNO3
AgBF4
DCE
0
4
NaOAc
DCE
39
22
60
68
10
25
0
5
Li2CO3
DCE
6
LiOAc
DCE
7
HOAc + Li2CO3
HOAc + Li2CO3
HOAc + Li2CO3
HOAc + Li2CO3
HOAc + Li2CO3
HOAc + Li2CO3
HOAc + Li2CO3
HOAc + Li2CO3
HOAc + Li2CO3
HOAc + Li2CO3
HOAc + Li2CO3
HOAc + Li2CO3
HOAc + Li2CO3
HOAc + Li2CO3
HOAc + Li2CO3
HOAc + Li2CO3
HOAc + Li2CO3
HOAc + Li2CO3
HOAc + Li2CO3
DCE
8
THF
9
1,4-Dioxane
DMA
t-AmylOH
Acetonitrile
DCE
10
11
12
13
14
15
16
17b
18
19
20
21
22
23
24
25
0
0
15
80
85
95
72
20
5
DCE
DCE
DCE
DCE
DCE
DCE
Ag2CO3
Ag2O
DCE
50
41
56
0
DCE
AgCF3SO4
AgNTf2
AgNTf2
AgNTf2
DCE
DCE
DCE
0
DCE
0
a
Reaction conditions: 1a (0.2 mmol), 2a (0.2 mmol), [IrCp*Cl2]2 (2 mol%), AgNTf2 (8 mol%), additives (15 mol%), solvent (2 mL), 12 h, isolated yields.
b
[IrCp*Cl2]2 (1 mol%), AgNTf2 (4 mol%).
(5 mL ꢀ 3). Thesolventswereremovedinvacuo, andtheresiduewas
NaOAc (15 mol%) or LiOAc (15 mol%) could evidently promote this
amidation. HOAc and Li2CO3 as co-additives make the yield increase
to 68% (entries 3–7). The solvent also played a crucial role. Among
the solvents tested (DCE, THF, 1,4-dioxane, DMA, t-AmylOH and
acetonitrile), DCE was proved to be the best for this transformation
(entries 7–12). It is noteworthy that reaction temperature was
critical for this transformation as well. Lower reaction temperatures
resulted in decreasing reactivity. The yields were gradually
improved to 95% by continuous increasing to 80 8C (entries 6, 13–
16). Notably, this catalytic system also provided satisfactory yields
even with a lower loading of iridium catalyst (1 mol%) (entry 17).
purified by column chromatography on silica gel (PE/EtOAc/
HCOOH = 30:1:0.1–25:5:0.1, v/v/v) to give the target product 3.
3. Results and discussion
Attheoutsetofourstudies,themodelreactionof2-fluorobenzoic
acid (1a) with para-methylphenylsulfonyl azide (2a) in the presence
of [IrCp*Cl2]2 was chosen to screen the reaction parameters
(Table 1). The reaction did not proceed in the absence of AgNTf2
or Ir(III) catalyst (entries 1–2). To our delight, LiOAc (15 mol%),
Scheme 1. Amidation of benzoic acids (1) with TsN3 (2a).

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M.-E. Wei et al. / Chinese Chemical Letters 26 (2015) 1336–1340
Scheme 2. Amidation of benzoic acid (1b) with sulfonyl azides (2).
Furthermore, we examined various silver salt, AgNTf2 was proved to
be the best (entries 18–22). In addition, no conversion was observed
with [RhCp*Cl2]2, [Ru(p-cymene)Cl2]2 or Pd(OAc)2 as catalyst
(entries 23–25).
such as 2-nitrobenzoic acids (3ea), behaved less active. For meta-
substituted benzoic acids, there are two different C–H bonds could
be aminated. The electron-donating substituents (OMe) promoted
the reaction producing the di-amidation products (3fa). For meta-
nitrobenzoic acid only gave mono-amidated product because of its
lower activity (3ga). meta-Bromobenzoic acid (1h) could generated
isolatable mono- and di-amidation products 3ha and 4ha in totally
excellent yield.
3.1. Amidation of benzoic acids with TsN3
With the optimal reaction conditions in hand, we firstly
investigated various ortho-benzoic acids 1 with para-methylphe-
nylsulfonyl azide (2a) (Scheme 1). Benzoic acids with weakly
electron-withdrawing and electron-donating groups at ortho
position could be smoothly converted to the target products in
excellent yields (3aa–3da, Scheme 1). Deficient sulfonyl azide,
3.2. Amidation of benzoic acid with sulfonyl azides
The scope of sulfonyl azides 2 was then examined in the
amidation of 2-methylbenzoic acid (1b) (Scheme 2). Various
Scheme 3. Amidation of para-benzoic acids (1) with TsN3 (2a).

M.-E. Wei et al. / Chinese Chemical Letters 26 (2015) 1336–1340
1339
the azide to C formed the intermediate D. Finally, the desired
amidated product 3 was generated with the formation of C–N bond
and the release of N2.
4. Conclusion
In summary, we have developed an iridium-catalyzed direct C–H
amidation of weakly coordinating benzoic acids with sulfonyl
azides. The protocol exhibited a broad substrate scope and
proceeded under mild conditions with excellent functional group
tolerance. Carboxylic acids are more available compared to other
traditional coupling reagents and easy to save, the process of
carboxylic acid-directed C–H amination herein has a great signifi-
cance on synthetic organic products and medicinal intermediates.
Acknowledgment
This work was supported by Minjiang Scholar Program (No.
10BS216), Xiamen Southern Oceanographic Center (No.
13GYY003NF16) and Huaqiao University.
Appendix A. Supplementary data
Scheme 4. Proposed reaction mechanism.
Supplementarymaterialrelatedtothisarticlecanbefound, inthe
online version, at http://dx.doi.org/10.1016/j.cclet.2015.08.009.
functional groups, such as F, Cl and NO2, were well tolerated under
the standard reaction conditions. Benzenesulfonyl azide (2b)
resulted in the target product 3bb in excellent yield. For para-
substituted benzenesulfonyl azides, electron-donating substitu-
ents (3ba, 3bc) promoted the reaction much more rapidly than the
electron-withdrawing groups (3bd, 2bf). Methyl substituent at
ortho-position of the arene ring (3bg) led to a much lower yield
than the meta-methyl benzenesulfonyl azide (3bh) due to the
steric hindrance. Moreover, alkane sulfonyl azides 3bi and 3bj
were readily amidated under the standard reaction conditions.
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