The Direct Rh(III)-Catalyzed C-H Amidation of Aniline Derivatives Using a Pyrimidine Directing Group: The Selective Solvent Controlled Synthesis of 1,2-Diaminobenzenes and Benzimidazoles

Article abstract of DOI:10.1021/acs.orglett.0c01126

The regioselective Rh(III)-catalyzed C-H amidation of aniline derivatives with dioxazolones as an amidating reagent with a pyrimidine as a directing group leading to the production of 1,2-diaminobenzene derivatives or benzimidazole derivatives is describe

Full text of DOI:10.1021/acs.orglett.0c01126

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Letter
The Direct Rh(III)-Catalyzed C−H Amidation of Aniline Derivatives
Using a Pyrimidine Directing Group: The Selective Solvent
Controlled Synthesis of 1,2-Diaminobenzenes and Benzimidazoles
Shrikant M. Khake and Naoto Chatani*
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ABSTRACT: The regioselective Rh(III)-catalyzed C−H amida-
tion of aniline derivatives with dioxazolones as an amidating
reagent with a pyrimidine as a directing group leading to the
production of 1,2-diaminobenzene derivatives or benzimidazole
derivatives is described. The product distribution is controlled by
the nature of solvent used. The reaction provides a broad substrate
scope for aniline derivatives with various important functional
groups including dioxazolones.
Scheme 1. Transition Metal Catalyzed C−H Bond Amidation
ecause nitrogen-containing heteroarenes are fundamental
Bunits of a variety of naturally occurring compounds,
biologically active compounds, agricultural products, pharma-
ceutical drug molecules, and polymers, C−N bond forming
reactions are of great importance in synthetic chemistry.1
Traditional reactions for the formation of C−N bond include
the Ullmann−Goldberg reaction, Chan−Lam coupling, and the
Buchwald−Hartwig amination reaction, but these reactions
have drawbacks in that a stoichiometric amount of metal species
is required, resulting in the formation of a stoichiometric amount
of byproducts such as hydrogen halides or their base salts.2
Transition metal catalyzed C−N bond formation reactions via
C−H bond activation are currently the most powerful and
versatile synthetic tool in synthetic chemistry.3 Direct C−H
bond amidation by transition metal catalysis would be highly
desirable because it is highly atom-economical and is an efficient
alternative route to conventional cross-coupling reactions.
Various amidating reagents such as N-tosylates,4 N-carboxylate,5
N-fluorobenzenesulfonimide,6 organic azides,7 and others8 have
been used in C−H amidation reactions. Dioxazolones have
recently been explored as amidating reagents because they are
easily handled and strongly coordinate to a metal, and only CO2
is produced as a byproduct.9 In 2015, Chang used dioxazolones
as an amidating reagent for the Rh-catalyzed C−H amidation of
2-phenylpyridines, and a DFT study showed dioxazolones
strongly coordinate to rhodium compared to sulfonyl azide as
amidating reagent. Since then, a number of reports have
appeared on the use of Ir(III), Rh(III), and Co(III) catalysts in
C−H amidation reactions with dioxozolones via a directing
group strategy (Scheme 1a).9b−x Various substrates, such as 2-
arylpyridines, azobenzene, indole derivatives, benzamides,
azoles, and arylpyrozolopyrimidine, have been used, but aniline
derivatives have been less explored for use in amidation
reactions, although the amidation of aniline derivatives is an
with Dioxazolones
attractive route to the synthesis of 1,2-aminobenzene deriva-
tives.
While the use of a pyrimidine directing group in C−H bond
alkylation,10 alkynylation,11 and sulfenylation12 of aniline
derivatives has been widely explored, C−H bond amidation
has been less explored. In 2017, Cui developed the Ir(III)-
catalyzed C−H amidation of anilines with sulfonyl azides as an
amidating reagent.13 This method, however, involves the use of a
Received: March 31, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01126
© XXXX American Chemical Society
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hazardous and heat-sensitive amidating reagent, and the reaction
has only a limited scope. In the same year, Li reported the
Ir(III)-catalyzed synthesis of benzimidazole via C−H amidation
of aniline derivatives using a pyridine as directing group wherein
the first step is amidation which upon cyclization forms
benzimidazole.9o We herein report the Rh(III)-catalyzed C−H
amidation of various aniline derivatives with dioxazolones using
a pyrimidine directing group (Scheme 1b). It should be noted
that this protocol can be used for the amidation of various aniline
derivatives with aromatic as well as aliphatic dioxazolones as
amidating reagents with functional groups. Most importantly,
the product distribution between 1,2-diaminobenzene deriva-
tives or benzimidazole derivatives can be controlled by the
nature of solvents used.
Scheme 2. Scope of Aniline Derivatives and Dioxazolones for
the C−H Amidation
a b
,
We started optimizing the reaction conditions for C−H bond
amidation using N-(2-tolyl)pyrimidin-2-amine (1a) as a model
substrate with 3-phenyl-1,4,2-dioxazol-5-one (2a) as an
amidating reagent (see Table S1 in Supporting Information
(SI)). The optimal reaction conditions were determined to be as
follows: 1a (0.15 mmol), 2a (0.3 mmol), [Cp*RhCl2]2 (5 mol
%), and AgSbF6 (10 mol %) in HFIP (1 mL) at 100 °C for 8 h
(entry 12 in Table S1).
Having the optimized conditions in hand, we employed this
method for the C−H amidation of substituted aniline derivatives
1 (Scheme 2). The reaction of an aniline substrate without any
substituent 1b afforded the expected monoamidated product
3ba as a major product. While a diamidating product was not
formed, instead, 4ba was formed, the structure of which was
confirmed by X-ray diffraction. The reaction path for 4ba will be
discussed below. Important functional groups, such OMe, Cl,
Br, and CF3 substituents, were tolerated in the backbone of the
aniline substrates to give the corresponding products 3ca−3fa.
In the case of 1-naphthylaniline 1g, the C−H bond at the 2-
position was exclusively amidated to give 3ga and no C−H
amidation at the 8-position was detected. The reaction of meta-
substituted aniline 1l gave the expected product 3la exclusively
in 77% yield, in which the less hindered C−H bond was
selectively amidated. The reaction of the 3,5-dimethyl-
substituted aniline 1n did not give the desired amidated product
3na because of the steric hindrance at the ortho-position. We
further extended the scope of the reaction with respect to the
amidating reagent. Various dioxazolones 2 bearing alkyl, aryl,
and heteroaryl substituents were examined for the C−H bond
amidation of 1a. Dioxazolone bearing a methyl group 2b on the
phenyl ring efficiently afforded 3ab in 69% yield. In addition, aryl
dioxazolones 2 having electron-withdrawing groups such as F,
Cl, and Br substituents at the para-position of the phenyl ring
gave the desired products 3ac, 3ad, and 3ae, respectively.
Similarly, a substituent at the ortho-position of a phenyl ring of
dioxazolone derivatives afforded excellent yields of 3af and 3ag.
The alkyl substituted dioxazolone 2j−2m reacted efficiently
with 1a to afford 3aj−3am in high yields. The cyclohexyl-
substituted dioxazolone 2n also participated in the reaction.
As shown in Scheme 2, we observed that the benzimidazole
derivative 4ba was formed as a minor product. The formation of
4ba could occur through monoamidation followed by
cyclization and further C−H amidation. If it were possible to
stop the reaction at the cyclized product stage, this would be a
convenient route to prepare C2-arylated benimidazole deriva-
tives, which are a fundamental unit of many pharmaceutical
compounds as well as naturally occurring heterocycles.14 We
therefore screened various solvents in attempts to obtain the
cyclized product and avoid further amidation (Scheme 3).
a
Reaction conditions: 1 (0.15 mmol), dioxazolone 2a (0.3 mmol),
[Cp*RhCl2]2 (5 mol %), AgSbF6 (10 mol %) in HFIP (1 mL) at 100
b
c
°C for 8 h under N2 atmosphere. Isolated yield. 3 mmol scale
synthesis.
Scheme 3. Selective Formation of Cyclized Product
Gratifyingly, the use of trifluoroethanol (TFE) as a solvent gave
5ba as a single product in 71% isolated yield, while other
solvents, such 1,4-dioxane (20%), DCE (35%), and toluene
(32%), gave 4ba selectively, along with a trace amount of 5ba.
TFE has a more acidic nature than HFIP which makes carbonyl
groups more electrophilic in nature by donating a proton to a
carbonyl group. Because of this, it would facilitate an
intramolecular nucleophilic attack of NH to the amide carbonyl
group and the subsequent elimination of water would result in
the formation of the cyclized product 5. This is a possible reason
B
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for why changing the solvent from HFIP to TFE changes the
selectivity for product formation.
rich alkyl group decreases the electrophilic nature of a carbonyl
group, which disfavors or slows down the nucleophilic attack of
the NH group to the amide carbonyl, resulting in a pyrimidine
group for directing the second C−H amidation.
With the optimized conditions for the cyclized product 5 in
hand, we then employed this method for the C−H amidation/
cyclization of the aniline derivative 1b with various aryl-
substituted dioxazolones (Scheme 4). The reaction shows broad
substrate scope for dioxazolone derivatives bearing halides, such
as F, Cl, and Br. The heteroaryl substituted dioxazolone 2i also
gave 5bi.
Some control experiments were performed to gain some
insights into the reaction mechanism (Scheme 6; see also SI for
Scheme 6. Control Experiments
a b
,
Scheme 4. Scope of Cyclized Products 5 and 6
a
Reaction conditions: 1b (0.15 mmol), 2a (0.45 mmol),
[Cp*RhCl2]2 (5 mol %), AgSbF6 (30 mol %) in CF3CH2OH (1
b
mL) at 120 °C for 18 h. Isolated yield.
When the alkyl-substituted dioxazolone 2j was used for the
C−H amidation/cyclization of 1b, the double amidated and
cyclized product 6bj was selectively formed (Scheme 4). In the
case of the cyclohexyl-substituted dioxazolone 2n, the reaction
stopped at monoamidation/cyclization stage to give 5bn due to
steric hindrance. The use of 3-(3-chloropropyl)-1,4,2-dioxazol-
5-one (2o) gave 7, the formation of which occurs through C−H
amidation followed by a nucleophilic attack of the free NH to the
alkyl chloride to form an eight-membered ring.
There are two possible paths for the formation of 6: (i) 1b
undergoes diamidation followed by cyclization or (ii) 1b
undergoes monoamidation and cyclization to give benzimida-
zole 5 which undergoes further C−H amidation at the 7-
position. To examine the operative reaction pathway, we
examined the C−H amidation reaction of 5bj with 2j (Scheme
5). However, no C7 amidation took place, indicating that the
diamidation of 1b at both the 2- and 6-positions occurs, followed
by cyclization to form product 6. In the monoamidation product
from alkyl-substituted dioxazolone, the presence of an electron-
details). When the reaction was performed in the presence of a
radical scavenger TEMPO (1 and 3 equiv), 3aa was formed in
77% and 30% yields, respectively (Scheme 6a). This observation
ruled out the involvement of free-radical species in the present
reaction. Intermolecular competition experiments were carried
out between the electron-rich aniline 1c and the electron-
deficient aniline 1f with 2a (Scheme 6b). The ratio of product
distribution between 3ca and 3fa was 19.2/1, indicating that an
electron-donating group facilitates the reaction. This finding
suggests that a cationic rhodium species acts as an electrophile
during the catalytic cycle.13 To gain additional information
regarding the initial rates of the reaction, reactions using
substrate 1a and [D]-1a were conducted, and the kinetic isotope
effect kH/kD = 0.93 was determined (Scheme 8c; see Figure S1 in
SI), which indicates that C−H activation is not involved in the
rate-determining step. When 1a was treated with HFIP/CD3OD
under the standard reaction conditions in the absence of 2a, a
36% D-incorporation was observed only at the ortho-position,
which indicates that C−H bond metalation is a reversible step
(Scheme 6d).
Scheme 5. Control Experiment
Based on the experimental data obtained from control
experiments and previous reports on Rh-catalyzed C−H
b o n d a m i d a t i o n r e a c t i o n s r e p o r t e d t h u s
far,3d,5a,9a,l,n,o,3d,5a,9a,l,n,o,v−x,10h,15 a plausible catalytic cycle for
the present amidation reaction is shown in Scheme 7. First, the
reaction of [Cp*RhCl2]2 with AgSbF6 forms a cationic Rh(III)-
complex A. The coordination of a N(sp2) atom of the aniline
C
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and benzimidazole derivatives which are important scaffolds in
synthetic chemistry. Preliminary mechanistic studies ruled out
the involvement of a free-radical species in the reaction. A
deuterium scrambling experiment indicated that C−H bond
metalation is a reversible process.
Scheme 7. Proposed Catalytic Cycle
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01126.
Experimental procedures and characterization data of all
new compounds (PDF)
Accession Codes
CCDC 1961840, 1983469−1983472, 1983474−1983476, and
1984360 contain the supplementary crystallographic data for
this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
substrate 1a to A then undergoes reversible C−H activation to
give the six-membered rhodacycle B. The coordination of
dioxazolone 2a to the rhodacycle B generates intermediate C,
which, upon migratory insertion, forms complex D with the
concomitant generation of CO2. Complex D upon proto-
derhodation in the presence of HSbF6 affords the desired
product 3aa and with the regeneration of the cationic Rh(III)
species A.
AUTHOR INFORMATION
Corresponding Author
■
Naoto Chatani − Department of Applied Chemistry, Faculty of
Engineering, Suita, Osaka 565-0871, Japan; orcid.org/0000-
0001-8330-7478; Email: chatani@chem.eng.osaka-u.ac.jp
The chemoselective deprotection of amide 3aa was
accomplished by treating it with KOH in ethanol, which gives
the free amine 8 (Scheme 8). Further, the treatment of 5bd, 5be,
Author
Shrikant M. Khake − Department of Applied Chemistry, Faculty
of Engineering, Suita, Osaka 565-0871, Japan
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01126
Scheme 8. Chemoselective Deprotection
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by Grant in Aid for Specially Promoted
Research by MEXT (No. 17H06091).
■
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