Direct C-H amidation of benzoic acids to introduce meta- and para-amino groups by tandem decarboxylation

Article abstract of DOI:10.1002/chem.201500331

The Ir-catalyzed mild C-H amidation of benzoic acids with sulfonyl azides was developed to give reactions with high efficiency and functional-group compatibility. Subsequent protodecarboxylation of ortho-amidated benzoic acid products afforded meta- or para-substituted (N-sulfonyl)aniline derivatives, the latter being inaccessible by other C-H functionalization approaches. The decarboxylation step was compatible with the amidation conditions, enabling a convenient one-pot, two-step process. Without a trace: Carboxylic acids are used as traceless directing groups in the Ir-catalyzed direct C-H amidation of arenes with sulfonyl azides under mild conditions. The tandem protodecarboxylation of the ortho-amidated benzoic acid products afforded meta- or para-substituted (N-sulfonyl)anilines, which are difficult to obtain by other C-H functionalization approaches.

Full text of DOI:10.1002/chem.201500331

DOI: 10.1002/chem.201500331
Communication
&
Organic Synthesis
Direct CÀH Amidation of Benzoic Acids to Introduce meta- and
para-Amino Groups by Tandem Decarboxylation
Donggun Lee[a, b] and Sukbok Chang*[a, b]
Abstract: The Ir-catalyzed mild CÀH amidation of benzoic
acids with sulfonyl azides was developed to give reactions
with high efficiency and functional-group compatibility.
Subsequent protodecarboxylation of ortho-amidated ben-
zoic acid products afforded meta- or para-substituted (N-
sulfonyl)aniline derivatives, the latter being inaccessible by
other CÀH functionalization approaches. The decarboxyla-
tion step was compatible with the amidation conditions,
enabling a convenient one-pot, two-step process.
Preparation of aryl amines is one of the most important reac-
tions in organic synthesis because they are omnipresent as
a key unit in natural products, synthetic intermediates, phar-
maceuticals, agrochemicals, and electronic materials.[1] As
a result, significant research progress has been made in the
past few decades, enabling the development of efficient CÀN
bond forming procedures.[2] Among these, the Buchwald–Hart-
wig N-arylation[3] represents one of the most well-established
methods for this purpose. Its broad applicability is unprece-
dented; the reaction employs aryl (pseudo)halides as starting
materials to react with amines, however, it also generates stoi-
chiometric amounts of byproducts such as halide salts. In this
regard, direct CÀH amination[4] has attracted special attention
as (hetero)arenes can be directly employed. Because control of
regioselectivity in the CÀH amination approach is a challenge,
chelation-assisted CÀH bond activation is the most widely uti-
lized route, thus giving rise to ortho-aminated products.[5] Be-
cause of this, the installation of amino groups at the meta-po-
sition relative to the existing arene substituents has been
much less exploited and only a few examples have been re-
ported. For instance, Hartwig and co-workers devised an ele-
gant tandem process for the synthesis of 3,5-disubstituted aryl-
amines that involves Ir-catalyzed borylation of arenes followed
by a Cu-catalyzed Chan–Lam type amination (Scheme 1a).[6] Al-
though this method displays high efficiency and excellent se-
Scheme 1. Synthetic approaches to meta- or para-substituted anilines.
lectivity, substrates are limited to 3,5-disubstituted arenes for
securing meta-selective borylation. Another creative strategy
was disclosed by the Dong group, in which the Pd-catalyzed
Catellani-type CÀH amination of aryl halides is achieved in the
presence of a norbornene cocatalyst (Scheme 1b).[7] This pro-
cedure of employing specially designed amino sources allows
selective CÀH amination to occur ortho to the traceless halide
substituents, and, interestingly, the Buchwald–Hartwig type N-
arylation was not observed.
meta-Substituted arenes can be accessed by employing re-
movable directing groups to guide the selective CÀH bond ac-
tivation, and these are cleaved after the desired CÀH function-
alization.[8] In fact, this approach to combine ortho-functionali-
zation and subsequent removal of directing groups has been
successfully applied to reactions using carboxylic acids as
a traceless directing group by several research groups.[9] For in-
stance, formal meta CÀH olefination or arylation was reported
independently by Miura and Larrosa.[9a–d] More recently,
Gooßen and co-workers developed a synthetic route to aryl
[a] D. Lee, Prof. S. Chang
Department of Chemistry
Korea Advanced Institute of Science and Technology (KAIST)
Daejeon 305-701 (Republic of Korea)
E-mail: sbchang@kaist.ac.kr
[b] D. Lee, Prof. S. Chang
Center for Catalytic Hydrocarbon Functionalizations
Institute for Basic Science (IBS), Daejeon 305-701 (Republic of Korea)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201500331.
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ethers from carboxylic acids by
using this strategy.[9f] In these re-
ports, however, only carbon or
oxygen groups were introduced
ortho to the carboxylic acids to
obtain meta-substituted arenes.
Although ortho CÀH amida-
tion of benzoic acids was previ-
ously reported by Yu,[10] CÀN
bond formation at the meta-po-
sition of substituted arenes
through this approach has not
been reported to the best of
our knowledge. Moreover, the
traceless CÀH functionalization
method has never been applied
to the synthesis of para-substi-
tuted amino arenes. In this con-
text, described herein is an ad-
vance to access to meta- and
para-substituted (N-sulfonyl)ani-
lines through a tandem process,
that is, Ir-catalyzed ortho CÀH
Table 1. Optimization of CÀH amidation of benzoic acid.[a]
Entry
Catalytic system (mol%)
Additives (mol%)
Solvent
T [8C]
Yield [%][b]
1
[IrCp*Cl2]2 (4)
–
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,4-dioxane
DMSO
80
80
80
25
50
50
50
50
50
50
50
50
50
50
N.R.
35
95
75
92
78
55
91
<5
32
2
3
4
5
6
7
8
9
10
11
12
13
14
[IrCp*Cl2]2 (4)/AgNTf2 (16)
[IrCp*Cl2]2 (4)/AgNTf2 (16)
[IrCp*Cl2]2(4)/AgNTf2 (16)
[IrCp*Cl2]2 (2)/AgNTf2 (8)
[IrCp*Cl2]2 (2)/AgNTf2 (8)
[IrCp*Cl2]2 (2)/AgNTf2 (8)
[IrCp*Cl2]2 (2)/AgNTf2 (8)
[IrCp*Cl2]2 (2)/AgNTf2 (8)
[IrCp*Cl2]2 (2)/AgNTf2 (8)
[IrCp*Cl2]2 (1)/AgNTf2 (4)
[RhCp*Cl2]2 (2)/AgSbF6 (8)
[Ru(p-cymene)Cl2]2 (2)/AgNTf2 (8)
[Pd(OAc)2]
–
LiOAc (30)
LiOAc (30)
LiOAc (30)
NaOAc (30)
KOAc (30)
LiOAc (30)
LiOAc (30)
LiOAc (30)
LiOAc (30)
LiOAc (30)
LiOAc (30)
–
DMF
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
63
N.R.
N.R.
N.R.
[a] Reaction conditions: 1a (0.20 mmol) and 2a (1.2 equiv) in solvent (0.5 mL). [b] 1H NMR yield of crude reac-
tion mixture (Cl2CHCHCl2 as an internal standard). N.R.=no reaction.
amidation of benzoic acids and the subsequent protodecar-
boxylation by Pd or Cu catalysts (Scheme 1c). As the second
stage is compatible with the initial CÀH amidation conditions,
this tandem procedure could be optimized to be conveniently
carried out in one pot.
Table 2. Substrate scope of carboxylic acids in the CÀH amidation.[a]
We commenced our studies by optimizing an amidation re-
action of 2-methylbenzoic acid (1a) with p-toluenesulfonyl
azide (2a, 1.2 equiv) under various catalytic conditions
(Table 1).[11] A moderate yield (35%) of the ortho-amidated
toluic acid (3a) was obtained when [IrCp*Cl2]2 was used in the
presence of AgNTf2 additive for the in situ generation of a cat-
ionic iridium species, whereas no reaction took place with
a neutral precursor only (entries 1–2). To our delight, the ami-
dation occurred almost quantitatively in the presence of lithi-
um acetate at 808C (entry 3). Remarkably, the desired reaction
took place even at room temperature, albeit with slightly
lower efficiency (entry 4). Optimal conditions were established
with 2 mol% of dimeric iridium precursor [IrCp*Cl2]2 at 508C in
1,2-dichloroethane (1,2-DCE) to afford the desired product 3a
in high yield (entry 5). LiOAc turned out to be most effective:
the use of other acetates resulted in lower efficiency (en-
tries 6–7, and see the Supporting Information for details). The
reaction was also found to be sensitive to the choice of sol-
vents: 1,4-dioxane was similar to 1,2-DCE in efficiency, but the
reaction was sluggish in polar solvents (entries 8–10). Although
the amidation was still significant even with lower amounts of
iridium catalyst (entry 11), other previously known catalytic sys-
tems such as rhodium, ruthenium, and palladium, were not ef-
fective (entries 12–14).[5,10]
With the optimized conditions in hand, we explored the
scope of substrates in the reaction with p-toluenesulfonyl
azide (Table 2). Benzoic acids bearing alkyl, aryl, or alkoxy
groups at the ortho-position underwent the desired amidation
in moderate to high yields (3a–3e). The reaction of mono- or
[a] Reaction conditions: 1 (0.20 mmol) and 2 (1.2 equiv) in 1,2-dichloro-
ethane (0.5 mL). Yields of isolated products are given. [b] AgOAc was
used instead of LiOAc at 258C.
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disubstituted halide-containing substrates was also facile (3 f–
3j), indicating that the amidation was not significantly influ-
enced by the electronic variation of substrates. The sulfonami-
dated product of tetrahydronaphthalene carboxylic acid was
formed in high yield (3k), a product that is known to be
a potent inhibitor of methionine aminopeptidase-2 (MetAP-
2).[12] Reactions with naphthoic acids also proceeded smoothly
(3l–3m). Significantly, olefinic CÀH bonds could also be ami-
dated in acceptable yields by using carboxylic acid as a direct-
ing group (3n–3o). It is noteworthy that the amidation of
tiglic acid took place at room temperature (3o). In addition,
the scope of sulfonyl azides that underwent reaction was
broad enough to include alkyl, naphthyl, camphor, and halide-
substituted phenyl derivatives, and all of which were found to
be highly suitable amido sources (3p–3s). On the other hand,
other amino sources such as alkyl-, aryl-, and phosphoryl
azides were not reactive, leading to negligible product yields
(<5%), only acyl azides showed moderate reactivity, but still
with insufficient efficiency (~30% yields).
better than those obtained from two separate reactions by iso-
lating the amidated intermediates. As a result, a tandem pro-
cess consisting of two catalytic reactions could be applied to
a wide range of carboxylic acid substrates (Table 4).
Table 4. Substrate scope for the tandem CÀH amidation and decarboxy-
lation.[a]
As a proof of concept, we were curious to see whether de-
carboxylation of amidated products could be achieved. Consid-
ering the fact that amidated products obtained in this study
have an intramolecular hydrogen-bond between the carboxylic
acid and sulfonamide groups (the X-ray structure of 3g is
shown in Table 3), it was uncertain at the initial stage if the de-
Table 3. Optimization of protodecarboxylation.[a]
Entry
Catalyst (mol%)
Additive
T [oC]
Yield [%][b]
1
2
3
4
5
[Pd(OAc)2] (15)
[Pd(OAc)2] (15)
[Pd(O2CCF3)2] (10)
Ag2CO3 (10)
–
–
100
120
120
120
120
52
84
24
<5
<5
TFA (10.0 equiv)
–
K2CO3 (15 mol%)
AgOAc (20)
[a] Reaction conditions: 1) 1 (0.20 mmol) and 2 (1.2 equiv) in 1,2-dichloro-
ethane (0.5 mL) at 508C for 24 h; 2) 1208C for 12 h. Yields of isolated
products are given.
[a] Reaction conditions: 3a (0.10 mmol) in 1,2-dichloroethane (0.5 mL).
[b] 1H NMR yield of crude reaction mixture (Cl2CHCHCl2 as an internal
standard).
sired defunctionalization would indeed take place.[13] We were
delighted to observe that protodecarboxylation of 3a was
mediated efficiently by a [Pd(OAc)2] catalyst at 1208C (Table 3,
entry 2).[14] However, known procedures using silver species
were not successfully adapted (entries 4–5).[15]
The one-pot protocol of CÀH amidation and subsequent
protodecarboxylation proceeded smoothly with most of the
substrates examined in good to excellent product yields. Elec-
tronic variation of substrates was not influential on the reac-
tion efficiency, and both electron-donating and -withdrawing
groups were compatible in each step of the amidation and de-
carboxylation (4a–4g). The one-pot procedure was successful-
ly applied to 2,4-disubstituted benzoic acids, leading to 3,5-dis-
ubstituted (N-sulfonyl)anilines in high yields regardless of the
electronic properties (4h–4k). It should be mentioned that al-
though these products could also be obtained by using the
Hartwig tandem process of borylation and amidation, mono-
substituted anilines cannot be accessed by this approach.
Naphthoic acids were reacted under the optimized conditions
to give naphthalene sulfonamides bearing various substituents
The Pd-mediated protodecarboxylation procedure was then
examined to see whether it is compatible with the Ir-catalyzed
CÀH amidation conditions. We were pleased to find that the
two reactions could be carried out in one pot without the
need to isolate the amidated products for the subsequent de-
carboxylation process. Indeed, the decarboxylation occurred
smoothly just by adding the palladium catalyst (15 mol%) to
the amidation reaction mixture and then allowing the reaction
to occur for 12 h at 1208C. It should be noted that the overall
yields for the one-pot, two-step procedure were similar or
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one pot with a slight modification of the second re-
action: 1,2-dichloroethane, used in the amidation,
was replaced by dimethylacetamide (DMA) for the
subsequent decarboxylation step. With this com-
bined protocol, para-substituted (N-sulfonyl)aniline
products (7a–7c) were obtained in satisfactory over-
all yields (Scheme 2, bottom). It is worthwhile to
mention that, to our best knowledge, this is the first
example preparing para-substituted amidated com-
pounds by using CÀH functionalization approaches.
In fact, neither the Hartwig or Dong’s approaches
can provide this type of products.[6,7]
In conclusion, we have developed a new approach
to meta- and para-substituted (N-sulfonyl)anilines.
Carboxylic acids were utilized as traceless directing
groups in the Ir-catalyzed direct CÀH amidation of
arenes with sulfonyl azides under mild conditions.
Subsequent protodecarboxylation of the carboxylic
acid group in the amidated products was catalyzed
Scheme 2. Amidation of 3-substituted benzoic acids and tandem one-pot procedure to
afford para-substituted (N-sulfonyl)anilines. Reaction conditions: 1) 5 (0.20 mmol) and 2a
(1.2 equiv) in 1,2-dichloroethane (0.5 mL); 2) after amidation was complete, the solvent
was removed and replaced with DMA (0.5 mL). Yields of isolated products are given.
(4l–4n). Again, a labile bromo group was well tolerated under
the Pd-catalyzed decarboxylation conditions (4n). We were
also curious to see whether this tandem process would work
with various types of sulfonyl azides. Both arene and alkane
sulfonamides were completely compatible with the Pd-cata-
lyzed protodecarboxylation conditions (4o–4v). In addition,
the reaction efficiency was not influenced by the electronic
property of the arene sulfonamide moiety (4o–4r).
by palladium or copper species. The two tandem reactions
were optimized to enable them to be carried out conveniently
in one pot without need to isolate the ortho-amidated benzoic
acid intermediates.
Experimental Section
Representative tandem procedure
With successful results in obtaining meta-substituted (N-sul-
fonyl)anilines, we were next curious to extend this approach to
the formation of para-substituted (N-sulfonyl)anilines.
ortho-Toluic acid (1a, 0.20 mmol), p-toluenesulfonyl azide (2a,
0.24 mmol), [IrCp*Cl2]2 (3.2 mg, 2.0 mol%), AgNTf2 (6.2 mg,
8.0 mol%), LiOAc (4.0 mg, 30 mol%) and 1,2-dichloroethane
(0.5 mL) were placed in a screw-capped vial equipped with a Spin-
vane triangular stir bar. The reaction mixture was stirred at 508C in
a pre-heated oil bath for 24 h. After cooling to room temperature,
[Pd(OAc)2] (6.6 mg, 15 mol%) was added and the resulting mixture
was stirred at 1208C for an additional 12 h. Upon cooling, the mix-
ture was filtered through a pad of Celite and washed with EtOAc
(3ꢁ10 mL). Solvents were removed under reduced pressure, and
the residue was purified by silica-gel chromatography (n-hexane/
EtOAc=8:1, v/v) to give 4a (37 mg, 71%).
It was envisioned that the key to success would be regiose-
lective CÀH amidation of meta-substituted benzoic acids.
Unlike 2-substituted benzoic acids, there are two reactive CÀH
bonds present for possible amidation in the case of 3-substi-
tuted benzoic acids. In this regard, we anticipated that the dif-
ference in steric congestion between the two CÀH bonds in 3-
substituted benzoic acids would lead to the preferential activa-
tion at the less sterically hindered site, thus leading to regiose-
lective amidation. We were quite pleased to observe that this
prediction turned out to be the case (Scheme 2, top). Indeed,
Ir-catalyzed amidation of 3-methylbenzoic acid with p-toluene-
sulfonyl azide proceeded exclusively at the 6-position without
reacting at the sterically more congested 2-position (6a). This
reactivity and selectivity were maintained in other substrates
bearing C-3 substituents, such as phenyl (6b), trifluoromethyl
(6c), bromo (6d), and iodo groups (6e). In all the cases exam-
ined, the desired products were obtained in satisfactory yields
by using 2 mol% of iridium catalyst at 508C.
We next examined the feasibility of a tandem one-pot pro-
cess consisting of CÀH amidation followed by protodecarbox-
ylation of the obtained products, 6. Although a palladium cata-
lyst system had been successfully applied to amidated com-
pounds obtained from ortho-substituted benzoic acids
(Table 4), we found that Cu2O (0.5 equiv) was required to medi-
ate the protodecarboxylation process of amidated products
derived from 3-substituted benzoic acids.[16] More pleasingly,
the two separate reactions could be conveniently carried in
Acknowledgements
This research was supported by the Institute for Basic Science
in Korea (IBS-R010-D1).
Keywords: CÀH amidation · decarboxylation · meta- and para-
substituted anilines · tandem processes · traceless directing
groups
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Received: January 26, 2015
Published online on && &&, 0000
Chem. Eur. J. 2015, 21, 1 – 6
www.chemeurj.org
5
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Communication
COMMUNICATION
&
Organic Synthesis
D. Lee, S. Chang*
&& – &&
Direct CÀH Amidation of Benzoic
Acids to Introduce meta- and para-
Amino Groups by Tandem
Decarboxylation
Without a trace: Carboxylic acids are
used as traceless directing groups in the
Ir-catalyzed direct CÀH amidation of
arenes with sulfonyl azides under mild
conditions. The tandem protodecarbox-
ylation of the ortho-amidated benzoic
acid products afforded meta- or para-
substituted (N-sulfonyl)anilines, which
are difficult to obtain by other CÀH
functionalization approaches.
&
&
Chem. Eur. J. 2015, 21, 1 – 6
www.chemeurj.org
6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!