Synthesis of anthranilic acid derivatives through iron-catalyzed ortho amination of aromatic carboxamides with N-chloroamines

Article abstract of DOI:10.1021/ja412521k

Arenes possessing an 8-quinolinylamide group as a directing group are ortho aminated with N-chloroamines and N-benzoyloxyamines in the presence of an iron/diphosphine catalyst and an organometallic base to produce anthranilic acid derivatives in high yield. The reaction proceeds via iron-catalyzed C-H activation, followed by the reaction of the resulting iron intermediate with N-chloroamine. The choice of the directing group and diphosphine ligand is crucial for obtaining the anthranilic acid derivative with high yield and product selectivity.

Full text of DOI:10.1021/ja412521k

Communication
pubs.acs.org/JACS
Synthesis of Anthranilic Acid Derivatives through Iron-Catalyzed
Ortho Amination of Aromatic Carboxamides with N‑Chloroamines
Tatsuaki Matsubara, Sobi Asako, Laurean Ilies,* and Eiichi Nakamura*
Department of Chemistry, School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
S
* Supporting Information
Scheme 1. Stoichiometric C−H Activation of N-(Quinolin-8-
ABSTRACT: Arenes possessing an 8-quinolinylamide
group as a directing group are ortho aminated with N-
chloroamines and N-benzoyloxyamines in the presence of
an iron/diphosphine catalyst and an organometallic base
to produce anthranilic acid derivatives in high yield. The
reaction proceeds via iron-catalyzed C−H activation,
followed by the reaction of the resulting iron intermediate
with N-chloroamine. The choice of the directing group
and diphosphine ligand is crucial for obtaining the
anthranilic acid derivative with high yield and product
selectivity.
yl)benzamide (1a) and Amination with N-
Chloromorpholine
he direct conversion of a C−H bond of an arene1 to the
2
Tcorresponding C−N bond
is an attractive synthetic
approach to substituted anilines3important compounds in
industry, medicinal chemistry, and materials science. The most
straightforward method is the oxidative coupling of an amine
with an arene; this has been achieved with copper4 or
palladium5 catalysts6 under high-temperature conditions. An
alternative ortho-amination method using a more reactive
electrophilic aminating or amidating reagent employs late
transition metal catalysts (rhodium,7−9 ruthenium,10 palla-
dium,11 or iridium12) under milder conditions.13 We report
here that reactive first-row iron14 can effect catalytic ortho-
amination15 of aromatic carboxamides with N-chloroamines at
65 °C to produce anthranilic acid derivatives16 in up to 100%
yield. Iron has become a popular catalyst for C−H activation
chemistry because of its high reactivity, abundance, and low
toxicity.14,17
chlorinated product, sometimes even predominantly, instead of
an aminated product,20 suggesting that A is an organoiron
species rather than a Grignard species. As discussed later, the
quinolin-8-yl group (Q) and the diphosphine ligand are
important factors that effectively retard the undesired C−C
bond formation. We note that PhMgBr is the best among the
other Grignard reagents investigated (Supporting Information
(SI)), and organozinc reagents were completely ineffective and
mainly produced the phenylated product such as 3a.
The reaction was rendered catalytic by careful tuning of the
reaction conditions (eq 1). To a mixture of naphthalene-
We developed the catalytic ortho-amination reaction on the
basis of the stoichiometric formation and amination of a
putative iron intermediate A18 from N-(quinolin-8-yl)-
benzamide (1a) that we optimized first (Scheme 1). Treatment
of a mixture of 1a and 1 equiv each of Fe(acac)3 and dppbz
with 3 equiv of PhMgBr in THF at 65 °C gave the intermediate
A. In agreement with the catalytic oxidative C−C bond
formation via a similar intermediate,19 oxidation of A with 1,2-
dichloroisobutane slowly produced a phenylated product 3a in
12% yield. Quenching A with D2O resulted in 67% deuterium
incorporation at the ortho position of the benzamide (product
1D) without the formation of 3a. Thus, A is stable and does not
undergo thermal reductive elimination. The reaction of A with
N-chloromorpholine occurs much faster than the oxidative C−
C bond formation and gave the desired ortho-aminated product
2a in 60% yield with <1% of 3a. Note that the reaction of a
Grignard reagent (PhMgBr) with a chloroamine also gives a
carboxamide 1b (60 mg, 0.2 mmol), Fe(acac)3 (10 mol %), and
1,2-bis[bis(4-fluorophenyl)phosphino]benzene (F-dppbz, 15
mol %) was added 1.2 equiv of PhMgBr, and the mixture
was heated at 65 °C. This operation results in deprotonation of
the amide (with 1.0 equiv of PhMgBr) and the formation of a
small amount of A (0.2 equiv). A solution of PhMgBr in THF
Received: December 10, 2013
Published: December 31, 2013
© 2013 American Chemical Society
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(0.67 mL, 0.89 mol/L, 0.60 mmol) and a solution of freshly
distilled N-chloromorpholine in THF (0.54 mmol in 0.72 mL)
were added simultaneously using a dual syringe pump at 65 °C
over 60 min. The reaction was quenched just after the addition
finished and gave 2b in 99% yield after isolation. The procedure
was amenable to scaling up, and we obtained 2b in 89% yield
on a 1 mmol scale and 82% yield on a gram scale (with 20 mol
% catalyst). We note that the purity of the chloroamine was
crucial for the large scale reaction, because a trace impurity due
to decomposition of the N-chloroamine impedes the catalytic
cycle.
Table 1. Iron-Catalyzed Reaction of Various Carboxamides
with N-Chloromorpholine
a
The synchronization of the formation of A (addition of
PhMgBr) with the slow addition of the aminating reagent is
necessary to prevent the direct reaction between PhMgBr and
N-chloroamine20 that prevents catalytic turnover. As with the
stoichiometric reaction (Scheme 1), formation of the ortho-
phenylated 3b was mostly suppressed (<1%). Note that 1 equiv
of PhMgBr takes up the ortho hydrogen of 1b, and the rest was
consumed for biphenyl formation through iron-catalyzed
homocoupling.19
The directing group and the ligand are crucial for the success
of this reaction (Figure 1). The bidentate 8-quinolinylcarbox-
a
Reaction conditions: PhMgBr in THF (1.2−1.4 equiv) was added to
a THF solution of carboxamide (1.0 equiv), Fe(acac)3 (10 mol %),
and F-dppbz (15 mol %), and then PhMgBr in THF (3.0 equiv) and
N-chloromorpholine in THF (2.7 equiv) were added slowly at 65 °C.
b
See the Supporting Information for details. Q = 8-quinolinyl.
c
d
Determined by isolation. Debrominated compound was obtained in
e
9%. 20 mol % of catalyst was used.
quinolyn-8-yl amide products can be readily hydrolyzed to the
corresponding carboxylic acid.4e In all cases, only the
monoaminated product was obtained selectively without
diamination. In agreement with this observation, an ortho
substituent was found to completely shut off the reaction (entry
12), while para- and meta-substituted carboxamides reacted
well. We speculate that steric interactions disturb the formation
of the ferracycle intermediate A.19d For meta-substituted
carboxamides (entries 8−11), the reaction proceeded exclu-
sively at the less hindered ortho position. Electron-rich
substrates reacted quickly (over 20−60 min), while electron-
deficient ones reacted more slowly (over 60−120 min; see the
SI for details). Halides such as chloride and bromide were
tolerated under the reaction conditions (entries 6 and 7,
debromination product was obtained in 9% at entry 7). 2-
Naphthalenecarboxamide also reacted well (entry 13).
Heteroaromatic substrates such as thiophene- and indole-
carboxamide (entries 14 and 15) also reacted, albeit in lower
yield, to give heteroaromatic amino acid derivatives. For these
substrates, the phenylation product accounted for a significant
Figure 1. Effect of the directing group and ligand on the amination of
arenes with N-chloromorpholine.
amide directing group21 was uniquely effective (Figure 1a). A
monodentate carboxamide such as N-phenyl- or N-methyl-
carboxamide resulted in recovery of the amide, as did 2-
phenylpyridine or N-phenylpyrazole (SI). Increasing the
flexibility of the directing group, as with picolinylcarboxamide,
resulted in increased phenylation. 2-Methylquinolin-8-yl amide
entirely failed to participate in the reaction, suggesting the
sensitivity of the chelation formation to steric hindrance. An N-
methylated amide also did not react at all.
The electronic property of the diphosphine ligand strongly
affects the product selectivity (Figure 1b).22 Thus, a more
electron-rich ligand favors the phenylated product, and a less
electron-rich ligand favors the desired amination product.
With the optimized conditions in hand, we next investigated
the scope of the carboxamide substrate (Table 1). Most of the
substrates we examined reacted with high yield (>90%). These
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portion of the reaction outcome (thiophene substrate, 6%;
indole substrate, 24%).
dialkylamine could also be introduced to produce an unsym-
metrical N-dialkylaniline derivative (entry 6). Benzylamines
(entries 7−9), including sterically demanding dibenzylamine
(entry 9), and diallylamine (entry 10) were well tolerated and
introduced to the substrate in high yield. A bromide substituent
on the benzylic amine (entry 8) was well tolerated.
In conclusion, we have developed an iron-catalyzed directed
amination of a C(sp2)−H bond with chloroamines to produce
anthranilic acid derivatives in up to 100% yield. The structure
of the directing group and the control of the electronic
properties of the diphosphine ligand allowed selective
formation of the aminated product, by balancing the rate of
the C−H activation step with the stability of the forming iron
intermediate. Further understanding of this balance will lead to
efficient iron-catalyzed C−H bond functionalization.
The reaction proceeded well (>90% yield) with the common
N-chloroamines (Table 2). We could also use N-benzoyloxy-
morpholine, which gave the corresponding aminated product in
89% yield (entry 2). However, other N-benzoyloxyamines
reacted in poor yield (SI). Cyclic and acyclic chloroamines
reacted equally well. Morpholine (entry 1), protected
piperidine (entry 3), and six- and seven-membered amines
(entries 4 and 5) could be introduced in high yield. A
Table 2. Iron-Catalyzed Reaction of N-(Quinolin-8-
yl)naphthaleneamide with N-Chloro- and N-
a
benzoyloxyamines
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and physical properties of the
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Authors
*laur@chem.s.u-tokyo.ac.jp
*nakamura@chem.s.u-tokyo.ac.jp
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank MEXT for financial support (KAKENHI Specially
Promoted Research No. 22000008 to E.N., and Grant-in-Aid
for Scientific Research on Innovative Areas No. 25105711 to
L.I.). T.M. was supported by the Japan Society for the
Promotion of Science through the Program for Leading
Graduate Schools (MERIT). S.A. thanks the Japan Society
for the Promotion of Science for Young Scientists for a
Research Fellowship (No. 23-8207).
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