[RhIII(Cp*)]-catalyzed ortho-selective direct C(sp 2)-H bond amidation/amination of benzoic acids by N-chlorocarbamates and N-chloromorpholines. A versatile synthesis of functionalized anthranilic acids

Article abstract of DOI:10.1002/chem.201304855

A Rh^III-catalyzed direct ortho-C-H amidation/amination of benzoic acids with N-chlorocarbamates/N-chloromorpholines was achieved, giving anthranilic acids in up to 85 % yields with excellent ortho-selectivity and functional-group tolerance. Successful benzoic acid aminations were achieved with carbamates bearing various amide groups including NHCO₂Me, NHCbz, and NHTroc (Cbz=carbobenzyloxy; Troc=trichloroethylchloroformate), as well as secondary amines, such as morpholines, piperizines, and piperidines, furnishing highly functionalized anthranilic acids. A stoichiometric reaction of a cyclometallated rhodium(III) complex of benzo[h]quinoline with a silver salt of N-chlorocarbamate afforded an amido-rhodium(III) complex, which was isolated and structurally characterized by X-ray crystallography. This finding confirmed that the C-N bond formation results from the cross-coupling of N-chlorocarbamate with the aryl-rhodium(III) complex. Yet, the mechanistic details regarding the C-N bond formation remain unclear; pathways involving 1,2-aryl migration and rhodium(V)- nitrene are plausible. Put an N to the ring! Carbamates with amides including NHCO₂Me, NHCbz, and NHTroc, as well as secondary amines, such as morpholines, piperdines, and piperizines, were coupled to benzoic acids to furnish functionalized anthranilic acids in up to 85 % yield (see scheme; Boc=tert-butoxycarbonyl; Cbz=carbobenzyloxy; Cp=pentamethylcyclopentadienyl; Troc=trichloroethylchloroformate).

Full text of DOI:10.1002/chem.201304855

DOI: 10.1002/chem.201304855
Full Paper
&
Organic Synthesis
[RhIII(Cp*)]-Catalyzed ortho-Selective Direct C(sp2)ÀH Bond
Amidation/Amination of Benzoic Acids by N-Chlorocarbamates
and N-Chloromorpholines. A Versatile Synthesis of Functionalized
Anthranilic Acids**
Fo-Ning Ng, Zhongyuan Zhou, and Wing-Yiu Yu*[a]
Abstract: A RhIII-catalyzed direct ortho-CÀH amidation/ami-
nation of benzoic acids with N-chlorocarbamates/N-chloro-
morpholines was achieved, giving anthranilic acids in up to
85% yields with excellent ortho-selectivity and functional-
group tolerance. Successful benzoic acid aminations were
achieved with carbamates bearing various amide groups in-
cluding NHCO2Me, NHCbz, and NHTroc (Cbz=carbobenzy-
loxy; Troc=trichloroethylchloroformate), as well as secon-
dary amines, such as morpholines, piperizines, and piperi-
dines, furnishing highly functionalized anthranilic acids. A
stoichiometric reaction of a cyclometallated rhodium(III)
complex of benzo[h]quinoline with a silver salt of N-chloro-
carbamate afforded an amido–rhodium(III) complex, which
was isolated and structurally characterized by X-ray crystal-
lography. This finding confirmed that the CÀN bond forma-
tion results from the cross-coupling of N-chlorocarbamate
with the aryl–rhodium(III) complex. Yet, the mechanistic de-
tails regarding the CÀN bond formation remain unclear;
pathways involving 1,2-aryl migration and rhodium(V)–
nitrene are plausible.
Introduction
these apparent successes, direct aminations are limited to sub-
strates bearing N-donor directing groups (DG=pyridines,
amides, oximes; Scheme 1); related examples involving oxygen
donors are sparse.[8]
Transition-metal-catalyzed CÀN bond formation by C(sp2)ÀH
bond activation is currently receiving attention for the devel-
opment of atom-economical syntheses of arylamines.[1,2] While
significant advances have been accomplished in Pd-catalyzed
intra- and intermolecular arene CÀH amidations, these exam-
ples are mainly limited to amides as coupling partners.[3,4] Re-
cently, extensive investigations have been directed to
Anthranilic acids (AAs) are important precursors to many
medicinally active heterocycles, such as indoles, acridines, and
quinolines.[9] Prompted by our earlier work on the direct CÀH
amidation of anilides,[3 g] we pursued a rapid synthesis of AAs
by Pd-catalyzed ortho-CÀH amidation of benzoic acids with sul-
fonyloxycarbamates.[3f] However, the Pd-catalyzed reactions
suffered from moderate yields and were limited to the mesityl-
sulfonyloxycarbamate reagents for effective reactions. Since
prior derivatization of the benzoic acids to their lithium salts
was required for effective transformations, the moderate prod-
uct yields were attributed to the incompatibility of the mesityl-
sulfonyloxycarbamate with the alkaline medium.
Previously,[10] we achieved the [RhIII(Cp*)]-catalyzed carbe-
noid C(sp2)ÀH bond insertion to benzoic acids under alkaline-
free conditions.[8n] In our study, when reacting 2,4-dimethylben-
zoic acid (0.1 mmol) with [Rh(Cp*)(OAc)2] (5 mol%) in
[D4]methanol at 608C for 20 min, 44% ortho-deuteriated ben-
zoic acid was observed. This result suggests that [Rh(Cp*)-
(OAc)2] can effect ortho-CÀH bond activation of benzoic acids
without prior derivatization. Motivated by this finding, we
herein disclosed a Rh-catalyzed direct ortho-CÀH amination of
benzoic acids for the synthesis of functionalized anthranilic
acids.
[RhIII(Cp*)]-catalyzed
(Cp*=pentamethylcyclopentadienyl)
direct arene CÀH aminations.[5,6] With [RhCl2(Cp*)]2 and deriva-
tives as catalysts, the aminations should initially involve ortho-
selective arene CÀH bond cleavage to form reactive aryl–
rhodium(III) complexes.[7] The Glorius group and ours have al-
ready independently reported the coupling of the aryl–
rhodium(III) complexes with N-chloroamines to afford N-aryla-
mines.[5a–c] Other aminating reagents, such as arylsulfonyla-
zides, arylazides, alkyl azides,[5d–i] aroyloxycarbamates,[5j] N-are-
nesulfonated imides,[5k] and N-fluorobenzenesulfonimide
(NFSI)[5l] are shown to be effective coupling partners. Despite
[a] F.-N. Ng, Prof. Dr. Z. Zhou, Prof. Dr. W.-Y. Yu
State Key Laboratory of Chirosciences
Department of Applied Biology and Chemical Technology
The Hong Kong Polytechnic University
Hung Hom, Kowloon (Hong Kong)
Fax: (+852)2364-9932
E-mail: wing-yiu.yu@polyu.edu.hk
[**] Cp*=pentamethylcyclopentadienyl.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201304855.
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study were transformed to their
corresponding anthranilic acids
3ba–3ea in 40–85% yields with
excellent ortho-selectivities. The
amidation
reactions
exhibit
good tolerance to the OAc, Br, I,
and F substituents, which are
useful functional groups for late-
stage cross-coupling reactions.
Notably, when the amidation of
2-bromobenzoic acid (1c) was
performed by the Pd-catalyzed
conditions (Li salt of 1c
(0.2 mmol),
ethyl
mesityl-
sulfonyloxycarbamate
(1.5 equiv), Pd(OAc)2 (10 mol%),
and KOAc (1 equiv) in dioxane
(1 mL) at 908C for 4 h), 2-[(ethox-
ycarbonyl)amino]benzoic
acid
(debrominated product) was
formed exclusively in 20% yield
(i.e., no 3ca was obtained).
The meta-substituted trifluoro-
methyl- and phenoxy-benzoic
acids were amidated at the less-
Scheme 1. Recent examples in RhIII-catalyzed direct CÀH aminations/amidations.
Results and Discussion
Table 1. Reaction optimization.[a]
To begin, 2,4-dimethylbenzoic acid 1a (0.2 mmol) was treated
with [RhCl2(Cp*)]2 (3 mol%), AgOAc (1.5 equiv), and methyl N-
chlorocarbamate (2a) (1.5 equiv) in MeOH (2 mL) at 608C for
12 h, and 3aa was obtained in 68% yield (Table 1, entry 1). In
this work, employing phenylazide and sulfonyloxycarbamates
as reagents failed to effect significant transformations, and the
desired AAs were obtained in <5% yield (entries 2–4). No
product formation was observed with AgOAc alone in the ab-
sence of the Rh catalyst (entry 5). When CsOAc (1.5 equiv) was
used, 3aa was formed in 5% yield (entry 6). According to our
Entry
Reagent [equiv]
Additives [equiv] Solvent
Yield [%][b,c]
1
2
3
2a
AgOAc (1.5)
–
CsOAc (0.3)
MeOH
DCE
MeOH
(68)
0
0
phenylazide (2)
N-nosyloxy
carbamate (1.2)
4
N-mesitylsulfonyl CsOAc (0.3)
MeOH
5
previous report,
a substoichiometric amount of CsOAc
oxycarbamate
(1.2)
2a
2a
2a
2a
(30 mol%) was needed for the Rh-catalyzed amination of ace-
tophenone oximes.[5c] In this work, a combination of AgSbF6
(1.5 equiv) and CsOAc (0–2 equiv) was examined. Unlike our
previous finding, employing 0–0.3 equivalents of CsOAc result-
ed in negligible 3aa formation (entries 7 and 8). When 1–
2 equivalents of CsOAc was utilized, 3aa was furnished in ap-
proximately 40% yield (entries 9 and 10). This finding suggest-
ed that a stoichiometric amount of acetate is required for ef-
fective catalytic turnovers. Low product yields were obtained
with silver trifluoroacetate (AgTFA) (entry 11) and Ag2CO3
(entry 12) as additives. Up to 85% of 3aa formation was ac-
complished when AgOAc was used along with tBuOH as sol-
vent (entry 13). With MeOH as the solvent, the methyl ester of
1a (~10%) was obtained as a side product. Employing nonal-
coholic solvents, such as 1,2-dichloroethane (DCE), DMF, diox-
ane, and toluene, resulted in 25–42% product yields (en-
tries 14–17).
5[d]
6
7
8
AgOAc (1.5)
CsOAc (1.5)
AgSbF6 (1.5)
AgSbF6 (1.5)
CsOAc (0.3)
AgSbF6 (1.5)
CsOAc (1)
MeOH
MeOH
MeOH
MeOH
0
5
0
0
9
2a
2a
MeOH
MeOH
50
40
10
AgSbF6 (1.5)
CsOAc (2)
11
2a
2a
2a
2a
2a
2a
2a
AgTFA (1.5)
Ag2CO3 (1.5)
AgOAc (1.5)
AgOAc (1.5)
AgOAc (1.5)
AgOAc (1.5)
AgOAc (1.5)
MeOH
MeOH
tBuOH
DCE
DMF
dioxane
toluene
30
36
(85)
26
42
28
12
13[e]
14
15
16
17
25
[a] Reaction conditions: 1a (0.2 mmol), 2a (1.5 equiv), [RhCl2(Cp*)]2
(3 mol%), additives (0.3–2 equiv), solvent (2 mL), 608C for 12 h under a N2
atmosphere. [b] NMR spectroscopic yields. [c] Isolated yields in parenthe-
ses. [d] The reaction ran without [RhCl2(Cp*)]2. [e] Same result was ob-
tained when 2a (1.2 equiv) was used. DCE=1,2-dichloroethane.
Table 2 depicts the results of a substrate-scope study. Under
the optimized conditions, all benzoic acids employed in this
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cally incompatible to the Rh-catalyzed arene amidation reac-
tions.
Table 2. Substrate scope studies.[a,b]
The diversity of the N-coupling partners has been examined.
For instance, reactions of benzyl N-chlorocarbamate (2b) and
2,2,2-trichloroethyl N-chlorocarbamate (2c) with 1a under the
Rh-catalyzed conditions afforded 3ab and 3bc in 77 and 75%
yields. Notably, the OAc and NHTroc (Troc=trichloroethylchlor-
oformate) groups can be selectively deprotected under orthog-
onal conditions for further transformations.[12] For the coupling
of 1a with 2c, we obtained a mixture of N-Troc AA and a cy-
clized product 3ac (combined yield=50%). When the reaction
was repeated with the presence of PivOH (0.5 equiv), 3ac was
obtained exclusively in 55% yield (mass balance=70%). A sim-
ilar cyclization reaction was also reported by Glorius and co-
workers in the RhIII-catalyzed CÀH amidation of O-methylben-
zohydroxamic acids with aroyloxycarbamates.[5j]
Direct CÀH bond couplings of benzoic acids with N-chloro-
morpholines were also achieved (Table 3). Treatment of 2,4-di-
methylbenzoic acid (0.2 mmol), N-chloromorpholine (1.2 equiv;
[a] Reaction conditions:
1
(0.2 mmol),
2
(1.2 equiv), [RhCl2(Cp*)]2
Table 3. Amine scope.[a–c]
(3 mol%), AgOAc (1.5 equiv), tBuOH (2 mL), 608C under a N2 atmosphere.
[b] Isolated yields. [c] 0.5 equiv PivOH was added. [d] Isolated as the cor-
responding methylester.
hindered ortho-CÀH bond to give 3 fa (50%) and 3ga (47%)
with a mass balance of >90%. The analogous reaction of 4-
bromobenzoic acid afforded 2,6-diamidated benzoic acid 3ha
exclusively in 54% yield with a >90% mass balance. Yet, dou-
bling the quantity of 2a failed to improve the yield of 3ha
even with an extended reaction time of 24 h. A similar diami-
dation was also reported by Glorius and co-workers in the
study of the Rh-catalyzed amination of O-methylbenzohyroxa-
mic acids.[5j] Facile reactions were also achieved for disubstitut-
ed benzoic acids bearing alkyl, halogen, and ethereal substitu-
ents to furnish 3ia–3ka in 50–70% yields (mass balance of
3ka=85%).
[a] Reaction conditions:
1
(0.2 mmol),
2
(1.2 equiv), [RhCl2(Cp*)]2
(3 mol%), AgOAc (1.5 equiv), tBuOH/MeOH (1:1), 608C under a N2 atmos-
phere. [b] Isolated yields. [c] Chloroamines were added dropwise by using
MeOH as a solvent; rate=0.11 equiv/h.
According to our previous report, the Pd-catalyzed amida-
tion of 1-naphthoic acid (1l) suffered low product yield (~
30%). In this work, when 1-naphthoic acid was reacted with
2a under the Rh-catalyzed conditions, 3la was formed in 67%
yield. Similarly, the analogous reaction of 3-thiophencarboxylic
acid (1m) furnished 3mb in 40% yield (mass balance=80%).
However, we found that treating the lithium salt of 1m
(0.2 mmol) with ethyl mesitylsulfonyloxycarbamate (1.5 equiv),
Pd(OAc)2 (10 mol%), and KOAc (1 equiv) in dioxane (1 mL) at
908C for 4 h did not produce any amide products. Thus, the
Rh-catalyzed amidation appeared to be more general than the
Pd-catalyzed reactions. Notwithstanding, carboxylic acids bear-
ing some heteroaryl motifs, such as benzofuran, indole, and
pyridine, were found to be poor substrates, which were fully
recovered at the end of the reactions. The amidation of 2-ben-
zylbenzoic acid occurred exclusively at the arene-CÀH bond to
furnish 3na in 73% yield; products due to amidation at the
benzyl-CÀH bond were not obtained.[11] This result suggests
that the outer-sphere nitrene-mediated CÀH insertion is kineti-
0.11 equiv/h), [RhCl2(Cp*)]2 (3 mol%), and AgOAc (1.5 equiv) in
tBuOH/MeOH (1:1) at 608C for 12 h afforded 3ad in 70% yield.
No prior derivatization of the carboxylic acid group to an
amide group is needed. Likewise, other N-chloroamines were
successfully coupled to 2,4-dimethylbenzoic acid to give 3ae
(67%), 3af (81%), and 3ag (69%) under Rh catalysis. When 2-
(acetyloxy)benzoic acid (1b) was reacted with N-chloro-N’-Boc-
piperizine (2 f) (Boc=tert-butoxycarbonyl),
a deacetylated
product 3bf was obtained exclusively in 50% yield after
workup. In this work, N-chloroamines derived from N-chlorocy-
clopentylamine were found to be ineffective coupling partners,
and no desirable amination product was obtained with >90%
recovery of the starting benzoic acid.
A cross-dehydrogenative coupling (CDC) between benzoic
acids and amines involving twofold NÀH and CÀH activations
has been developed (Scheme 2). In this work, the NÀH activa-
tion was achieved by treating morpholines (0.24 mmol) with
tert-butyl hypochlorite (0.24 mmol) in dioxane at room temper-
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Based on the single-crystal X-ray diffraction study,
complex 6 was confirmed to be a metallacyclic
amido–rhodium(III) complex that features
a
Rh(1)ÀN(2) bond length of 2.061 ꢁ. This bond length
value is comparable to corresponding values ob-
served in some defined amido–rhodium(III) com-
plexes (Scheme 4): sulfonamido–rhodium(III) complex
7: 2.108 ꢁ; cationic isopropylcarbamato–rhodium(III)
complex 8: 2.090 ꢁ; tetrakis(carboxamidates)dirhodiu-
m(II) complex: 2.018 ꢁ; and a 1,2-bis(2-pyridinecar-
boxamido)benzene rhodium(III) complex: 1.971 ꢁ.[16,5i]
Scheme 5 depicts a plausible reaction mechanism.
[Rh(Cp*)(OAc)2][17] should be the active catalyst and
Scheme 2. Cross-dehydrogenative amination of benzoic acids involving in situ twofold
NÀH and CÀH activations.
ature for 5 min to generate N-chloromorpholine in situ.[15] And
it was directly employed without isolation for the RhIII-cata-
lyzed direct-CÀH amination of benzoic acids. For instance,
treating 2,4-dimethylbenzoic acid (1a), N-chloromorpholine (in
situ; 0.11 equiv/h), [RhCl2(Cp*)]2 (3 mol%), AgOAc (1.5 equiv) in
MeOH at 608C for 12 h furnished 3ad in 70% yield. Similarly,
other amines, such as piperidine and N’-Boc-piperizine, were
coupled to 2,4-dimethylbenzoic acid to give 3ae (62%) and
3af (55%).
In this study, anthranilic acid 3aa was readily converted to
the corresponding 4H-3,1-benzoxain-4-one (4aa) in 90% yield
Scheme 3. Synthetic applications.
by N,N-dicyclohexylcarbodiimide (DCC) treatment (Scheme 3).
Compound 4aa was known to exhibit human leukocyte elas-
tase inhibitory activities.[13] With the choice of the NHCbz
group, 3ab can be selectively derivatized to 4ab bearing
a free NH group by a sequence of esterification and hydroge-
nolysis. It is conceivable that the free NH group is open for the
Buchwald–Hartwig arylation to
undergoes an irreversible rate-limiting CÀH bond cleavage to
form a cyclometallated benzoate complex (A).[7c] This is sup-
ported by the observed notable primary kinetic isotope effect
(KIE) kH/kD =3.1.[18] Furthermore, upon treating 1a (0.2 mmol),
afford the flufenamic acid deriva-
tives.[14]
To ascertain the role of the
aryl–rhodium(III) complex in the
amination reaction, we prepared
well-characterized aryl–rhodium-
(III) complex
[RhCl2(Cp*)]2 (0.2 mmol) with
benzo[h]quinoline (0.2 mmol)
5
by reacting
and NaOAc (0.44 mmol) in
CH2Cl2 under room temperature
for 24 h.[7b] When 5 (0.1 mmol)
was subjected to the amidation
conditions (i.e., methyl N-chloro-
carbamate (2a; 0.12 mmol) and
AgSbF6 (0.1 mmol) in CH2Cl2),
a complicated mixture was ob-
tained. Attempts to purify the
mixture were unsuccessful. Yet,
when 5 was reacted with a silver
salt of 2a in CH2Cl2,[15] an
amido–rhodium(III) complex
6
Scheme 4. Characterization of the amido–rhodium(III) complex 6 (representative bond lengths: Rh(1)ÀN(1):
2.103 ꢁ; Rh(1)ÀN(2): 2.061 ꢁ) and selected examples of well-defined amido–rhodium(III) complexes.
[Rh2(5R-MEPY)4]=dirhodium(II) tetrakis(methyl 2-oxopyrrolidine-5-carboxylates); H2bpb=1,2-bis(2-pyridinecarbox-
amido)benzene; py=pyridine.
was obtained in 95% yield
(Scheme 4).
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Experimental Section
General procedures for the RhIII-catalyzed
ortho-CÀH amidation of benzoic acids
For N-chloroamides as a coupling partner: One-batch
addition of reagent
2 (method A): Benzoic acids
1
(0.2 mmol), [RhCl2(Cp*)]2 (3 mol%), and AgOAc
(1.5 equiv) were added to a vial (8 mL) that was sealed
with a Teflon liner cap. The vial was evacuated and back-
filled with N2 three times. Freshly distilled tBuOH (2 mL)
was added to the reaction vial, followed by the addition
of 2 (1.2 equiv) with a 50 mL-syringe in one portion (re-
agents 2b and 2c, which are solids at room tempera-
ture, were added to the reaction vial along with the ben-
zoic acids). The reaction was stirred at 608C for 12 h.
After cooling to room temperature, EtOAc (4 mL) and
2m HCl (2 mL) were added. The organic layer was col-
lected and the aqueous layer was washed with EtOAc
(4 mLꢂ2). The combined organic fractions were dried
over Na2SO4 and then filtered through a plug of glass-
wool. Solvents were removed by rotary evaporation and
the residue was redissolved in a small amount of di-
chloromethane. The dissolved mixture was then purified
by flash column chromatography on silica gel by gradi-
ent elution with 10% EtOAc in hexanes with 5% incre-
ment until 50% EtOAc in hexanes was reached, at which
point the anthranilic acid products were eluted.
Scheme 5. Proposed mechanism.
[RhCl2(Cp*)]2 (3 mol%), AgOAc (1.5 equiv), and 2a in
[D4]methanol at 608C for 20 min, no ortho-deuteriated benzoic
acid was detected with 3aa formed in 14% yield. On the con-
trary, when the analogous experiment was performed in the
absence of 2a, ortho-deuteriated benzoic acid was obtained in
54% based on 1H NMR spectroscopic analysis. This result
shows CÀH bond cleavage in the Rh-catalyzed amidation reac-
tion is irreversible.[19] Based on our stoichiometric studies, the
CÀN bond formation should be mediated by the coupling of
the aryl–rhodium(III) complex and the N-chloroamidate anion,
which is likely to be formed by reacting 2 with AgOAc. We hy-
pothesized that the CÀN bond formation may occur by 1,2-aryl
migration with the cleavage of the NÀCl bond. However, an al-
ternative pathway involving the formation of RhV nitrenoid
species is also possible. In a computation study by Xia and co-
workers on the [RhIII(Cp*)]-catalyzed cycloaddition of benzohy-
droxamic acids with alkenes, formation of RhV nitrene inter-
mediate from a seven-membered rhodacycle containing a N-
OPiv moiety by an acyloxy migration process was proposed.[20]
Yet, both pathways should afford the same amido–rhodium(III)
intermediate (B). Protodemetalation should regenerate the
[Rh(Cp*)(OAc)2] catalyst with release of the anthranilic acid
products.
For N-chloroamines as a coupling partner: Slow addition of re-
agent 2 (method B): A mixture of benzoic acids (0.2 mmol), [RhCl2-
(Cp*)]2 (3 mol%), and AgOAc (1.5 equiv) were dissolved in freshly
distilled tBuOH (1 mL) in a 10 mL-Schlenk tube under a N2 atmos-
phere. Chloroamine 2 was dissolved in MeOH (1 mL) and was
added dropwise to the reaction tube by a syringe pump (rate=
0.11 equiv/h). The reaction was stirred at 608C for 12 h. After cool-
ing to room temperature, the reaction was diluted with EtOAc
(4 mL). Saturated NaHCO3 and 1m HCl were added to adjust the
pH of the crude mixture to 5. The organic layer was collected, and
the aqueous layer was washed with EtOAc (4 mLꢂ2). The com-
bined organic fractions were dried over Na2SO4 and then filtered
through a plug of glasswool. Solvents were removed by rotary
evaporation, and the residue was re-dissolved in a small amount of
dichloromethane. The dissolved mixture was then purified by flash
column chromatography on silica gel by gradient elution with
10% EtOAc in hexanes with 5% increment until 50% EtOAc in hex-
anes was reached, at which point the anthranilic acid products
were eluted.
Cross-dehydrogenative coupling reaction between benzoic
acids and amines
A mixture of 2,4-dimethylbenzoic acid (0.2 mmol), [RhCl2(Cp*)]2
(3 mol%), and AgOAc (1.5 equiv) were dissolved in freshly distilled
MeOH (1 mL) in a 10 mL-Schlenk tube under a N2 atmosphere. In
a separate 4 mL-vial, secondary amines (0.24 mmol) were mixed
with tert-butyl hypochlorite (0.24 mmol) in dioxane (1 mL) for
5 min. To the Schlenk tube containing RhIII and the benzoic acids,
the secondary amine solution mixture in the vial was added drop-
wise by a syringe pump (rate=0.11 equiv/h). The reaction mixture
was stirred at 608C for 12 h, and then was treated by the same
workup procedures as in method B.
Conclusion
To conclude, a RhIII-catalyzed direct CÀH amidation/amination
of benzoic acids is developed. The amidation offers a direct
route for the synthesis of functionalized anthranilic acids,
which are important building blocks to many medicinally
active heterocycles. The amidation/amination reactions exhibit
excellent regioselectivities and functional-group tolerance.
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8480; b) 28 amines and benzoyl peroxide: E. J. Yoo, S. Ma, T.-S. Mei,
K. S. L. Chan, J.-Q. Yu, J. Am. Chem. Soc. 2011, 133, 7652; c) sulfonamide
and N-fluoro-2,4,6-trimethyl-pyridinium triflate: B. Xiao, T.-J. Gong, J. Xu,
Z.-J. Liu, L. Liu, J. Am. Chem. Soc. 2011, 133, 1466; d) N-methoxybenza-
mide and AgO: G.-W. Wang, T.-T. Yuan, D.-D. Li, Angew. Chem. 2011, 123,
1416; Angew. Chem. Int. Ed. 2011, 50, 1380; e) amides and K2S2O8: H.-Y.
Thu, W.-Y. Yu, C.-M. Che, J. Am. Chem. Soc. 2006, 128, 9048; f) arylsulfo-
nyloxycarbamates: K.-H. Ng, F.-N. Ng, W.-Y. Yu, Chem. Commun. 2012,
48, 11680; g) K.-H. Ng, A. S. C. Chan, W.-Y. Yu, J. Am. Chem. Soc. 2010,
132, 12862; h) N-fluorobenzenesulfonimide: G. B. Boursalian, M.-Y. Ngai,
K. N. Hojczyk, T. Ritter, J. Am. Chem. Soc. 2013, 135, 13278; i) K. Sun, Y. Li,
T. Xiong, J. Zhang, Q. Zhang, J. Am. Chem. Soc. 2011, 133, 1694; j) Pd-
catalyzed intramolecular CÀH amidations/aminations: Y. Tan, J. F. Hart-
wig, J. Am. Chem. Soc. 2010, 132, 3676; k) T.-S. Mei, X. Wang, J.-Q. Yu, J.
Am. Chem. Soc. 2009, 131, 10806; l) M. Wasa, J.-Q. Yu, J. Am. Chem. Soc.
2008, 130, 14058; m) J. A. Jordan-Hore, C. C. C. Johansson, M. Gulias,
E. M. Beck, M. J. Gaunt, J. Am. Chem. Soc. 2008, 130, 16184; n) W. C. P.
Tsang, N. Zheng, S. L. Buchwald, J. Am. Chem. Soc. 2005, 127, 14560.
[4] Selected examples of Pd-catalyzed directing-group assisted C(sp3)ÀH
bond aminations: a) G. He, Y. Zhao, S. Zhang, C. Lu, G. Chen, J. Am.
Chem. Soc. 2012, 134, 3; b) ꢃ. Iglesias, R. ꢃlvarez, ꢃ. R. de Lera, K. MuÇiz,
Angew. Chem. 2012, 124, 2268; Angew. Chem. Int. Ed. 2012, 51, 2225;
c) C. Tsukano, M. Okuno, Y. Takemoto, Angew. Chem. 2012, 124, 2817;
Angew. Chem. Int. Ed. 2012, 51, 2763; E. T. Nadres, O. Daugulis, J. Am.
Chem. Soc. 2012, 134, 7; J. J. Neumann, S. Rakshit, T. Drçge, F. Glorius,
Angew. Chem. 2009, 121, 7024; Angew. Chem. Int. Ed. 2009, 48, 6892.
[5] Recent examples in Rh-catalyzed C(sp2)ÀH amidation/aminations with
N-chloroamines: a) K.-H. Ng, Z. Zhou, W.-Y. Yu, Chem. Commun. 2013,
49, 7031; b) C. Grohmann, H. Wang, F. Glorius, Org. Lett. 2012, 14, 656;
c) K.-H. Ng, Z. Zhou, W.-Y. Yu, Org. Lett. 2012, 14, 272; d) arylsulfonyl
azides, arylazides, or alkylazides: Y. Lian, J. R. Hummel, R. G. Bergman,
J. A. Ellman, J. Am. Chem. Soc. 2013, 135, 12548; e) D.-G. Yu, M. Suri, F.
Glorius, J. Am. Chem. Soc. 2013, 135, 8802; f) K. Shin, Y. Baek, S. Chang,
Angew. Chem. 2013, 125, 8189; Angew. Chem. Int. Ed. 2013, 52, 8031;
g) J. Shi, B. Zhou, Y. Yang, Y. Li, Org. Biomol. Chem. 2012, 10, 8953; h) J.
Ryu, K. Shin, S. H. Park, J. Y. Kim, S. Chang, Angew. Chem. 2012, 124,
10042; Angew. Chem. Int. Ed. 2012, 51, 9904; i) J. Y. Kim, S. H. Park, J.
Ryu, S. H. Cho, S. H. Kim, S. Chang, J. Am. Chem. Soc. 2012, 134, 9110;
j) N-aroyloxycarbamates: C. Grohmann, H. Wang, F. Glorius, Org. Lett.
2013, 15, 3014; k) N-arenesulfonated imides: S. Yu, B. Wan, X. Li, Org.
Lett. 2013, 15, 3706; l) N-fluorobenzenesulfonimide: R.-J. Tang, C.-P. Luo,
L. Yang, C.-J. Li, Adv. Synth. Catal. 2013, 355, 869; m) sodium azide and
hypervalent iodine: F. Xie, Z. Qi, X. Li, Angew. Chem. Int. Ed. 2013, 52,
11862; n) arylsulfonamides and hypervalent iodine: H. Zhao, Y. Shang,
W. Su, Org. Lett. 2013, 15, 5106; o) an example for RhIII-catalyzed intra-
molecular allylic CÀH amination: T. Cochet, V. Bellosta, D. Roche, J.-Y. Or-
tholand, A. Greiner, J. Cossy, Chem. Commun. 2012, 48, 10745.
Kinetic isotope effect (KIE) experiment
In a parallel experiment, benzoic acids 1a (0.1 mmol) and [D2]2,4-
dimethyl-6-benzoic acid ([D2]1a) (0.1 mmol) were added separately
into two 8 mL-vials sealed with a Teflon liner cap. [RhCl2(Cp*)]2
(3 mol%) and AgOAc (1.5 equiv) were added into the two separate
reaction vials, and the vials were evacuated and back-filled with N2
three times. Freshly distilled MeOH (2 mL) was added to the two
reaction vials, followed by the addition of 2 (1.2 equiv) with
a 50 mL-syringe in one portion. The two reactions were stirred at
608C for 20 min. After cooling to room temperature, EtOAc (4 mL)
and 2m HCl (2 mL) were added. The organic layer was collected
and the aqueous layer was washed with EtOAc (4 mLꢂ2). The
combined organic fractions were dried over Na2SO4 and then fil-
tered through a plug of glasswool. Solvents were removed by
rotary evaporation to dryness. The residue was redissolved in
[D]chloroform followed by the addition of internal standard (dibro-
momethane, 0.1 mmol). The conversions of 1a and ([D2]1a) were
1
determined by H NMR spectroscopy. The same set of experiments
was repeated three times to obtain an average KIE value.
Synthesis of amido–rhodium(III) complex 6
Cyclometallated complex 5 (0.1 mmol) and the silver salt of 2a
(0.1 mmol) were added to a 10 mL-Schlenk tube. The tube was
evacuated and back-filled with N2 three times. Distilled dichlorome-
thane (5 mL) was added to the reaction tube. The reaction mixture
was stirred at room temperature overnight. The reaction crude was
filtered through a plug of Celite and rinsed with dichloromethane.
The filtrate was then evaporated to dryness under reduced pres-
sure. The residue was washed with hexanes (5 mLꢂ3), diethyl
ether (5 mLꢂ3), and a small amount of EtOAc (~1 mL). The result-
ed residue was dried in vacuo to afford complex 6. To obtain
a single-crystal for X-ray crystallographic study, complex 6 was dis-
solved in a minimum amount of dichloromethane and then layered
with hexanes for 1 day.
Acknowledgements
We thank The Hong Kong Research Grants Council
(PolyU503811P) for financial support.
[6] For other transition-metal-catalyzed arene C(sp2)ÀH aminations, Ru:
a) V. S. Thirunavukkarasu, K. Raghuvanshi, L. Ackermann, Org. Lett. 2013,
15, 3286; b) M. R. Yadav, R. K. Rit, A. K. Sahoo, Org. Lett. 2013, 15, 1638;
c) M. Bhanuchandra, M. R. Yadav, R. K. Rit, M. R. Kuram, A. K. Sahoo,
Chem. Commun. 2013, 49, 5225; d) J. Kim, J. Kim, S. Chang, Chem. Eur. J.
2013, 19, 7328; e) Q.-Z. Zheng, Y.-F. Liang, C. Qin, N. Jiao, Chem.
Commun. 2013, 49, 5654; f) for Cu: L. D. Tran, J. Roane, O. Daugulis,
Angew. Chem. 2013, 125, 6159; Angew. Chem. Int. Ed. 2013, 52, 6043;
g) Y. Miki, K. Hirano, T. Satoh, M. Miura, Org. Lett. 2013, 15, 172; h) C.
Tang, N. Jiao, J. Am. Chem. Soc. 2012, 134, 18924; i) For [Ir]: J. Ryu, J.
Kwak, K. Shin, D. Lee, S. Chang, J. Am. Chem. Soc. 2013, 135, 12861.
[7] For stoichiometric cyclorhodation, see a) Y. Boutadla, D. L. Davies, R. C.
Jones, K. Singh, Chem. Eur. J. 2011, 17, 3438; b) L. Li, W. W. Brennessel,
W. D. Jones, Organometallics 2009, 28, 3492; c) J. M. Kisenyi, G. J. Sunley,
J. A. Cabeza, A. J. Smith, H. Adams, N. J. Salt, P. M. Maitlis, J. Chem. Soc.
Dalton Trans. 1987, 2459.
[8] For reviews of transition-metal-catalyzed CÀH bond functionalization
assisted by weak directing groups: a) V. S. Thirunavukkarasu, S. I. Koz-
hushkov, L. Ackermann, Chem. Commun. 2014, 50, 29; b) K. M. Engle, T.-
S Mei, M. Wasa, J.-Q. Yu, Acc. Chem. Res. 2012, 45, 788; c) T. Satoh, M.
Miura, Chem. Eur. J. 2010, 16, 11212; d) for selected examples by using
Pd: T.-S. Mei, D.-H. Wang, J.-Q. Yu, Org. Lett. 2010, 12, 3140; e) T.-S. Mei,
R. Giri, N. Maugel, J.-Q. Yu, Angew. Chem. 2008, 120, 5293; Angew.
Chem. Int. Ed. 2008, 47, 5215; f) R. Giri, J.-Q. Yu, J. Am. Chem. Soc. 2008,
Keywords: amination · catalysis · CÀH bond activation · cross-
coupling · rhodium
[1] Selected reviews on CÀH aminations: a) G. Song, F. Wang, X. Li, Chem.
Soc. Rev. 2012, 41, 3651; b) S. H. Cho, J. Y. Kim, J. Kwak, S. Chang, Chem.
Soc. Rev. 2011, 40, 5068; c) B. J. Stokes, T. G. Driver, Eur. J. Org. Chem.
2011, 4071; d) A. Armstrong, J. C. Collins, Angew. Chem. 2010, 122,
2332; Angew. Chem. Int. Ed. 2010, 49, 2282; e) F. Collet, R. H. Dodd, P.
Dauban, Chem. Commun. 2009, 5061.
[2] Selected reviews on CÀH bond activations: a) J. Wencel-Delord, F. Glo-
rius, Nat. Chem. 2013, 5, 369; b) N. Kuhl, M. N. Hopkinson, J. Wencel-
Delord, F. Glorius, Angew. Chem. 2012, 124, 10382; Angew. Chem. Int. Ed.
2012, 51, 10236; c) S. R. Neufeldt, M. S. Sanford, Acc. Chem. Res. 2012,
45, 936; d) J. Yamaguchi, A. D. Yamaguchi, K. Itami, Angew. Chem. 2012,
124, 9092; Angew. Chem. Int. Ed. 2012, 51, 8960; e) L. Ackermann, Chem.
Rev. 2011, 111, 1315; J. Wencel-Delord, T. Drçge, F. Liu, F. Glorius, Chem.
Soc. Rev. 2011, 40, 4740; f) T. W. Lyons, M. S. Sanford, Chem. Rev. 2010,
110, 1147; g) R. Giri, B.-F. Shi, K. M. Engle, N. Maugel, J.-Q. Yu, Chem. Soc.
Rev. 2009, 38, 3242.
[3] Examples of Pd-catalyzed intermolecular CÀH amidations/aminations
with various reagents: phthalimide and PhI(OAc)2: a) R. Shrestha, P. Mu-
kherjee, Y. Tan, Z. C. Litman, J. F. Hartwig, J. Am. Chem. Soc. 2013, 135,
Chem. Eur. J. 2014, 20, 4474 – 4480
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Full Paper
130, 14082; g) R. Giri, N. Maugel, J.-J. Li, D.-H. Wang, S. P. Breazzano, L. B.
Saunder, J.-Q. Yu, J. Am. Chem. Soc. 2007, 129, 3510; h) [Ru]: W. Liu, L.
Ackermann, Org. Lett. 2013, 15, 3484; i) K. Graczyk, W. Ma, L. Ackermann,
Org. Lett. 2012, 14, 4110; j) V. S. Thirunavukkarasu, L. Ackermann, Org.
Lett. 2012, 14, 6206; k) L. Ackermann, J. Pospech, Org. Lett. 2011, 13,
4153; l) Rh: Y. Unoh, K. Hirano, T. Satoh, M. Miura, Tetrahedron 2013, 69,
4454; m) T. Litsuka, P. Schaal, K. Hirano, T. Satoh, C. Bolm, M. Miura, J.
Org. Chem. 2013, 78, 7216; n) W.-W. Chan, S.-F. Lo, Z. Zhou, W.-Y. Yu, J.
Am. Chem. Soc. 2012, 134, 13565; o) K. Morimoto, K. Hirano, T. Satoh, M.
Miura, J. Org. Chem. 2011, 76, 9548.
[12] T. W. Greene, P. G. M. Wuts in Protective Groups in Organic Synthesis, 3rd
ed., John Wiley & Sons, Inc., US, 1999, pp. 503–550.
[13] A. Krantz, R. W. Spencer, T. F. Tam, T. J. Liak, L. J. Copp, E. M. Thomas,
S. P. Rafferty, J. Med. Chem. 1990, 33, 464.
[14] a) D. S. Surry, S. L. Buchwald, Chem. Sci. 2011, 2, 27; b) J. Hartwig, Acc.
Chem. Res. 2008, 41, 1534.
[15] For preparation of silver salt of 2a, see: D. Saika, D. Swern, J. Org.
Chem. 1968, 33, 4548; for a review on N-haloamines, see: a) P. Kovacic,
M. K. Lowery, K. W. Field, Chem. Rev. 1970, 70, 639; for recent examples
using N-chloroamines as reagents, see: b) T. Hatakeyama, Y. Yoshimoto,
S. K. Ghorai, M. Nakamura, Org. Lett. 2010, 12, 1516;c) T. J. Barker, E. R.
Jarvo, J. Am. Chem. Soc. 2009, 131, 15598.
[9] a) M. S. Dunstan, J. Barnes, M. Humphries, R. C. Whitehead, R. A. Bryce,
D. Leys, L. J. Stratford, K. A. Nolan, J. Med. Chem. 2011, 54, 6597; b) A.
[16] Representative amido–rhodium complexes, see: a) M. E. Tauchert, C. D.
Incarvito, A. L. Rheingold, R. G. Bergman, J. A. Ellman, J. Am. Chem. Soc.
2012, 134, 1482; b) M. P. Doyle, W. R. Winchester, J. A. A. Hoorn, V.
Lynch, S. H. Simonsen, R. Ghosh, J. Am. Chem. Soc. 1993, 115, 9968;
c) S.-T. Mak, V. W.-W. Yam, C.-M. Che, J. Chem. Soc. Dalton Trans. 1990,
2555.
[17] [Rh(Cp*)(OAc)2] has been synthesized and characterized by X-ray crys-
tallography, see: P. M. Boyer, C. P. Roy, J. M. Bielski, J. S. Merola, Inorg.
Chim. Acta 1996, 245, 7.
[18] Intermolecular primary kinetic isoptopic effect (KIE) of value 2.0–3.0 was
observed in previous RhIII-catalyzed CÀH functionalizations, see re-
f. [5c,5i,5j,8n].
[19] Similar irreversible cyclorhodation was reported by others: D. R. Stuart,
P. Alsabeh, M. Kuhn, K. Fagnou, J. Am. Chem. Soc. 2010, 132, 18326; see
also ref. [5b,c,j].
´
Stankiewicz-Drogon, B. Dçrner, T. Erker, A. M. Boguszewska-Chachulska,
J. Med. Chem. 2010, 53, 3117; c) P. Wiklund, J. Bergman, Curr. Org. Synth.
2006, 3, 379.
[10] For our previous studies in CÀH bond functionalizations by s-aryl–
metal intermediates: a) benzoxylations: W.-N. Sit, C.-W. Chan, W.-Y. Yu,
Molecules 2013, 18, 4403; b) acylations: C.-W. Chan, Z. Zhou, W.-Y. Yu,
Adv. Synth. Catal. 2011, 353, 2999; c) C.-W. Chan, Z. Zhou, A. S. C. Chan,
W.-Y. Yu, Org. Lett. 2010, 12, 3926; d) W.-Y. Yu, W.-N. Sit, K.-M. Lai, Z.
Zhou, A. C. S. Chan, J. Am. Chem. Soc. 2008, 130, 3304; e) arylations: W.-
Y. Yu, W.-N. Sit, Z. Zhou, A. C. S. Chan, Org. Lett. 2009, 11, 3174; f) carbe-
noid insertions: Y.-T. Tsoi, Z. Zhou, W.-Y. Yu, Org. Lett. 2011, 13, 5370;
g) Y.-T. Tsoi, Z. Zhou, A. S. C. Chan, W.-Y. Yu, Org. Lett. 2010, 12, 4506;
h) W.-Y. Yu, W.-T. Tsoi, Z. Zhou, A. S. C. Chan, Org. Lett. 2009, 11, 469;
i) see also ref. [8n], alkylations: W.-W. Chan, Z. Zhou, W.-Y. Yu, Chem.
Commun. 2013, 49, 8214; for amination: refer to refs. [3e,3f,3g,5a,5c].
[11] For examples of nitrene insertion to benzylic CÀH bonds, see: a) C.
Liang, F. Collet, F. R. Peillard, P. Muller, R. H. Dodd, P. Dauban, J. Am.
Chem. Soc. 2008, 130, 343; b) J.-L. Liang, S.-X. Yuan, J.-S. Huang, W.-Y.
Yu, C.-M. Che, Angew. Chem. 2002, 114, 3615; Angew. Chem. Int. Ed.
2002, 41, 3465; c) X.-G. Zhou, X.-Q. Yu, J.-S. Huang, C.-M. Che, Chem.
Commun. 1999, 2377.
[20] For computational elucidation of a formation of RhV nitrene intermedi-
ate: L. Xu, Q. Zhu, G. Huang, B. Cheng, Y. Xia, J. Org. Chem. 2012, 77,
3017.
Received: December 12, 2013
Published online on March 5, 2014
Chem. Eur. J. 2014, 20, 4474 – 4480
www.chemeurj.org
4480
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim