A General Method for Aminoquinoline-Directed, Copper-Catalyzed sp2 C-H Bond Amination

Article abstract of DOI:10.1021/jacs.6b01117

An operationally simple and general method for copper-catalyzed, aminoquinoline-assisted amination of β-C(sp²)-H bonds of benzoic acid derivatives is reported. The reaction employs Cu(OAc)₂ or (CuOH)₂CO₃ catalysts, an amine coupling partner, and oxygen from air as a terminal oxidant. Exceptionally high generality with respect to amine coupling partners is observed. Specifically, primary and secondary aliphatic and aromatic amines, heterocycles, such as indoles, pyrazole, and carbazole, sulfonamides, as well as electron-deficient aromatic and heteroaromatic amines are competent coupling components.

Full text of DOI:10.1021/jacs.6b01117

Article
pubs.acs.org/JACS
A General Method for Aminoquinoline-Directed, Copper-Catalyzed
sp2 C−H Bond Amination
James Roane and Olafs Daugulis*
Department of Chemistry, University of Houston, Houston, Texas 77204-5003, United States
S
* Supporting Information
ABSTRACT: An operationally simple and general method for copper-catalyzed, aminoquinoline-assisted amination of
β-C(sp2)-H bonds of benzoic acid derivatives is reported. The reaction employs Cu(OAc)2 or (CuOH)2CO3 catalysts, an amine
coupling partner, and oxygen from air as a terminal oxidant. Exceptionally high generality with respect to amine coupling partners
is observed. Specifically, primary and secondary aliphatic and aromatic amines, heterocycles, such as indoles, pyrazole, and
carbazole, sulfonamides, as well as electron-deficient aromatic and heteroaromatic amines are competent coupling components.
aminoquinoline directing group to couple arenes with
secondary chloroamines under iron catalysis, and Miura has
disclosed copper-catalyzed reactions of heterocycles with
chloroamines.4f,g Nitrosobenzenes, azodicarboxylates, and
hydroxysuccinimide derivatives have been used as electrophilic
nitrogen sources.4h−k Ackermann has reported that azides can
be coupled with arenes under ruthenium catalysis.4l Hydroxyl-
amine derivatives have been used as sp2 C−H bond aminating
reagents by a number of groups.4m−o
Potentially, the most general and efficient method for amine
synthesis is represented by pathway D, where the arene C−H
bond is coupled with an amine N−H bond.5 Both the arene and
amine coupling components are readily available, allowing for
rapid synthesis of structurally diverse arylamines. Optimally,
amine synthesis by pathway D should meet the following
conditions: First, the scope of the reactants (amines and arenes)
that can be used in the coupling reaction has to be general.
Second, the reaction should be catalyzed by an abundant
first-row transition metal. Third, the oxidant in this reaction has
to be cheap and readily available; preferably, oxygen from air
should be employed. Fourth, the reaction has to be
regioselective. Although significant advances have been made
in recent years, limitations of C−H amination methodology are
apparent. In most cases, either second- or third-row transition
metal catalysis is employed. The use of first-row transition metal
catalysis is relatively rare. Furthermore, reactions usually employ
expensive oxidants such as silver or iodonium salts, are limited to
1. INTRODUCTION
Aryl amine functionality can be found in biologically important
substances and functional materials.1 As a consequence, their
synthesis has attracted substantial attention. Methods for aryl
amine synthesis by intermolecular formation of an aryl-nitrogen
bond are summarized in Scheme 1. Electrophilic amination
reactions can be performed under very mild conditions, but they
require the presence of two functionalized coupling components:
arylmetal and an oxidized nitrogen source (Scheme 1, pathway
A).2 Currently, the most general method for aryl amine synthesis
involves palladium- and copper-catalyzed aryl halide amination
that originates in the Goldberg reaction (Scheme 1, pathway B).3
This process typically delivers one product regioisomer, a feature
that is advantageous compared to most nondirected C−H bond
aminations that afford product mixtures. A very large number of
both coupling components are available commercially, making
this reaction a backbone of many pharmaceutically important
amine syntheses. However, the presence of a functionalized aryl
halide is required. In pathway C, an arene C−H bond is
functionalized by an electrophilic amination reagent, which may
be either a nitrene source or an amine possessing a leaving
group.4 Although C−H bond coupling components are widely
available, only a very limited number of electrophilic nitrogen
sources are commercially accessible. Currently, most examples
of C−H bond aminations feature reactivity by pathway C.
Iridium, rhodium, and cobalt catalysts have been used in the
amination of directing-group-containing arenes with azides,
acetoxycarbamates, and dioxazolones.4a−d Ellman has shown
that aryl azides can be reacted with imines under rhodium
catalysis to afford acridines.4e Nakamura has used an
Received: January 30, 2016
© XXXX American Chemical Society
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Scheme 1. Arylamine Syntheses via Cross-Coupling
a
Scheme 2. Copper-Catalyzed Arene Amination
Table 1. Optimization of Reaction Conditions
entry
x
oxidant
solvent
time, h
yield, %
b
1
20
20
20
20
20
20
30
30
NMO
NMO
NMO
air
DMF
20
20
16
18
6
33
38
b
2
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
3
4
5
6
7
68
53
air
56
air
6
87
air
6
92
c
8
air
6
quant
a
Amide (0.1 mmol), copper(II) acetate (x mol % relative to amide),
solvent (entries 1−5, 1 mL; entries 6−8, 0.2 mL), NMO (2 equiv) or
air (∼3.5 mL). Yield determined by GC analysis of reaction mixtures
b
with 2,6-diisopropyl-naphthalene as the internal standard. One equiv
c
of K2CO3 was added. Q = 8-quinolinyl. Three equiv of amine was used.
of a copper catalyst under oxygen atmosphere.5i Subsequently,
amination of acidic polyfluoroarenes was demonstrated.5j
In 2013, we reported a method for copper-catalyzed, direct,
aminoquinoline- and picolinamide-assisted6 amination of β-sp2
C−H bonds of benzoic acid derivatives and γ-sp2 C−H bonds of
benzylamine derivatives (Scheme 2C).6d The reaction employed
a Cu(OAc)2 catalyst in conjunction with a Ag2CO3 cocatalyst,
amine coupling partner, NMP or DMSO solvent, and NMO
oxidant. Although the reaction showed high generality and
functional group tolerance, several limitations were apparent.
First, only primary and secondary aliphatic amines were reactive
under the reported conditions. Second, the reaction required a
silver cocatalyst. Third, N-methylmorpholine oxide was used as a
terminal oxidant. We report here a method for copper-catalyzed
or -promoted amination of sp2 C−H bonds of aminoquinoline
benzamides that employs oxygen from air as a terminal oxidant
and allows the use of an exceptionally wide range of amine
coupling partners. Specifically, primary and secondary aliphatic
and aromatic amines, sulfonamides, heterocycles, and guanidines
are reactive.
cyclic secondary amine coupling components, and lack general-
ity. Notably, the first copper-promoted directed amination of
arene C−H bonds was reported by Yu in 2006 (Scheme 2A).5a
Several other groups have later shown similar reactivity of
2-phenylpyridine derivatives.5b,c Yu has subsequently employed
copper salts in bidentate auxiliary-directed amination of diverse
aromatic compounds with tosylamides, aromatic amides, and
electron-poor anilines (Scheme 2B).5d
Chen, Zhang, and Liu have reported efficient picolinamide-
and aminoquinoline-directed, copper- and nickel-catalyzed
amination of sp2 C−H bonds by simple amines.5e,f These
reactions appear to be limited to secondary amines; the best
results are obtained with cyclic amines, and they require either
PhI(OAc)2 oxidant or excess second-row transition metal
(silver) additive. Several papers report amination of simple
arenes by amines in the presence of iodine-based oxidants.5g,h
Specifically, Suna has developed an outstanding method
for regioselective amination of electron-rich arenes with struc-
turally diverse amines. The reaction uses a copper catalyst and
employs a stoichiometric iodine(III) oxidant.5g Mori discovered
that azoles can be coupled with secondary amines in the presence
2. Method Development Considerations. We have
previously observed that amination of 8-aminoquinoline
benzamide with morpholine gave reasonable conversion to
product if oxygen was used as the terminal oxidant.6d Thus, it
should be possible to use air or oxygen instead of the somewhat
B
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a
Table 2. Reaction with Morpholine
a
Amide (1.0 mmol), Cu(OAc)2 (0.3 mmol), pyridine (2.0 mL), morpholine (3.0 mmol), 5−36 h, 80−110 °C. Yields are isolated yields. Please see
b
c
Supporting Information for details. Reaction scale of 5 mmol. Approximately 1:1 ratio of isomers formed.
expensive NMO oxidant. Reaction optimization studies are
presented in Table 1.
the reaction yield (entry 6). The use of 30 mol % Cu(OAc)2 gave
92% yield (entry 7). Finally, if the amount of morpholine was
increased from 2 to 3 equiv, quantitative conversion to 2 was
observed (entry 8). Thus, optimal reaction conditions for
employing secondary amine aminating reagents include 0.3 equiv
of Cu(OAc)2 catalyst, air oxidant, and pyridine solvent at
elevated temperature.
The reaction performed in DMF using the NMO oxidant and
20 mol % Cu(OAc)2 gave 33% conversion to product (entry 1).
Slightly higher conversion was obtained by employing pyridine
solvent (entry 2). Omission of base was fruitful, and 68%
conversion was observed (entry 3). Replacing the NMO oxidant
with air slightly decreased the yield of the product; however,
a respectable 53% conversion was obtained in 16 h (entry 4).
Decreasing the reaction time to 6 h slightly increased the yield,
showing that some product decomposition occurs (entry 5).
Decreasing the amount of solvent to 0.2 mL from 1 mL increased
3. RESULTS
3.1. Reaction Scope with Respect to Aminoquinoline
Benzamides. Aminoquinoline benzamide amination with
morpholine is presented in Table 2. Both electron-rich
C
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(entries 2, 8, 9, 14) and electron-poor substrates (entries 3−7,
10−12) afforded products in good to excellent yields. In contrast
to other copper-catalyzed, aminoquinoline-directed C−H bond
functionalizations, the amination selectively afforded mono-
substitution products at the less sterically hindered position
(entries 2, 7, 8). Only trace amounts of diamination products
were observed in crude reaction mixtures. Reactions showed
excellent functional group tolerance. Chloro (entry 3), cyano
(entry 4), trifluoromethoxy (entry 5), trifluoromethylthio
(entry 6), nitro (entry 8), vinyl (entry 9), pyrazole (entry 13),
and sulfonamide functionalities (entry 10) were all compatible
with the reaction conditions. Importantly, heterocycles such as
pyridine (entries 11 and 12) and thiophene (entry 14) afforded
amination products in good yields. Probenecid7 amide was
reacted with morpholine to give the amination product in 76%
yield (entry 10), which shows the relevance of the methodology
to the functionalization of drug-like molecules. Aminoquinoline
3-fluorobenzamide reacted to give an approximate 1:1 mixture
of separable isomeric products (entry 15). The reactions could
be run on a 5 mmol scale without loss of yield (entry 10). The
generality of amination should allow for a rapid parallel synthesis
of drug analogues.
Table 3. Amination with Secondary Amines
3.2. Reaction Scope with Respect to Secondary
Amines. The reaction conditions optimized for coupling with
morpholine are applicable for amination with other aliphatic
secondary amines (Table 3). All reactions were carried out by
using probenecid amide as the C−H bond coupling component.
Six- (entries 1−4) and five-membered rings (entry 5) as well as
acyclic amines (entries 6 and 7) gave products in acceptable
to excellent yields. Tertiary amine (entries 1 and 3), amide
(entries 2 and 4), and heterocycle (entries 2 and 5) functionali-
ties were compatible with the reaction conditions. The amide
N−H bond was not reactive under these conditions (entry 4).
Interestingly, we were able to couple nornicotine with probenecid
amide in acceptable yield (entry 5).
3.3. Reaction Scope with Respect to Primary Aliphatic
Amines and Anilines. Copper-catalyzed amination of aromatic
C−H bonds with secondary amines has been demonstrated in
several systems.5a−f,6d We have previously shown that hindered
primary amines could be coupled with aminoquinoline
benzamides to give amination products in modest yields.6d For
nonhindered primary aliphatic amines, low coupling yields were
obtained, and aromatic amines were unreactive. Yu recently
disclosed copper-promoted, bidentate ligand-directed amination
with electron-poor anilines and sulfonamides.5d However, no
examples of electron-rich aniline use were demonstrated. We
were pleased to discover that, with slight modifications, our
amination reaction could be used to couple primary amines with
sp2 C−H bonds (Table 4). In this case, pyridine/DMSO solvent
mixture afforded the best results. One equiv of copper(II) acetate
is required, presumably because the amination product forms
a strong chelate with copper, preventing the dissociation needed
for achieving catalytic turnover. Hindered aliphatic amines
possessing secondary and tertiary substituents were reactive,
affording products in acceptable to good yields (entries 1−4).
Benzylic primary amines were compatible with the amination
conditions (entry 4). n-Dodecylamine could be coupled in 44%
yield (entry 5). Simple aniline (entry 6) as well as electron-rich,
hindered trimethylaniline (entry 7) gave products in 46−48%
yields.
a
Amide (1.0 mmol), Cu(OAc)2 (0.3 mmol), pyridine (2.0 mL), amine
(3.0 mmol), 5−36 h, 110 °C. Yields are isolated yields. Please see
Supporting Information for details. PMB = p-methoxybenzyl.
was due to low nucleophilicity of heterocycles. If an equilibrium
concentration of the heterocycle anion could be formed, perhaps
assisted by copper coordination, then amination would
be successful. The acidities of pyrazole, carbazole, and indole
(pKa = ∼20 in DMSO solvent)8 were sufficient for successful
cross-coupling reactions (Scheme 3). Thus, thiophenecarboxylic
amide 3 could be coupled with pyrazole and substituted indoles
to afford amination products 4−6 in good yields in the presence
of tetramethylguanidine base. Furthermore, electron-rich and
-poor aminoquinoline benzamides were competent coupling
partners, giving products 9 and 11 in the reaction with pyrazole.
By using excess pyrazole, double amination product 11 was
formed in good yield, which is in contrast to reactions described
earlier where only monoamination was observed. The reactions
proceeded best if copper basic carbonate (malachite) catalyst
was employed. The reaction scale can be increased from 1 to
15 mmol without loss of yield as shown in the preparation of 9.
3.5. Amination with Sulfonamides and Electron-Poor
Anilines. Following logic used in aminations with acidic hetero-
3.4. Amination with Heterocycles. Amination attempts
using heterocycles under the conditions of Tables 2−4 gave low
conversions to products. We speculated that the lack of reactivity
D
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a
Table 4. Amination with Primary Amines
Scheme 3. Amination with Heterocycles
with aminoquinoline amide occurred. After optimization of the
reactions conditions, 12 was isolated in 62% yield (eq 1).
a
Amide (1.0 mmol), Cu(OAc)2 (1.0 mmol), pyridine/DMSO
(1:1, 2.0 mL), amine (3.0 mmol), Bu4NI (1.0 mmol), 5−36 h,
110 °C. Yields are isolated yields. Please see Supporting Information
for details.
cycles, we speculated that the addition of tetramethylguanidine
base should allow for amination with sulfonamides and acidic
aniline derivatives. Gratifyingly, this reasoning was successful as
shown in Table 5. Tosylamide (entry 1), thiophenesulfonamide
(entry 2), and 4-nitrobenzenesulfonamide (entry 3) were
successfully coupled with aminoquinoline trifluoromethylbenza-
mide to give products in excellent yields. Electron-deficient
anilines were reactive as well. 2-Nitro-4-trifluoromethyl-aniline
(entry 4), perfluoro-p-toluidine (entry 5), and 2-amino-5-
chloropyridine (entry 6) reacted to afford coupling products in
moderate to good yields.
3.7. Competition Experiments. Several competition
experiments were performed to probe the reactivity of substrates
(Scheme 4). First, the influence of amide electronics was
investigated. Competitive morpholination of 3-methylbenzoic
amide and 3-trifluoromethylbenzamide derivatives afforded a
3.8:1 ratio of the products favoring the electron-deficient amide
(Scheme 4A). Second, a competition experiment in coupling
of morpholine and piperidine with aminoquinoline benzamide
showed that coupling with more nucleophilic amine was
favored (Scheme 4B). Third, thiophenecarboxylic acid amino-
quinoline amide was reacted with morpholine and carbazole
under the conditions of Scheme 3. Carbazole was coupled
selectively, and only a trace amount of coupling with
morpholine was observed (Scheme 4C). Fourth, the same
3.6. Amination with Tetramethylguanidine. In some of
the reactions using tetramethylguanidine base, a minor amount
of a side product was formed. Isolation and spectroscopic charac-
terization showed that cross-coupling of tetramethylguanidine
E
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Table 5. Amination with Electron-Poor Substances
Scheme 4. Competition Experiments
4. SUMMARY
We have developed an operationally simple and general method
for copper-catalyzed, aminoquinoline-assisted amination of
β-C(sp2)-H bonds of benzoic acid derivatives. The reaction
employs Cu(OAc)2 or (CuOH)2CO3 catalysts, an amine coupling
partner, pyridine or pyridine/DMSO solvent, and oxygen from air
as a terminal oxidant. Significant differences from earlier methods
for C-H/N-H couplings include utilization of an inexpensive first-
row transition metal catalyst in conjunction with air oxidant and
high generality with respect to amine coupling partners. Specifi-
cally, primary and secondary aliphatic and aromatic amines, hetero-
cycles, such as indoles, pyrazole, and carbazole, sulfonamides, and
electron-deficient aromatic and heteroaromatic amines as well as
guanidines are competent coupling components. Furthermore, the
reaction possesses high functional group tolerance.
5. EXPERIMENTAL SECTION
General Procedure for Coupling of Aminoquinoline Amides
with Secondary Amines. Aminoquinoline amide (1.0 mmol) and
copper acetate (0.3 mmol) were dissolved in pyridine (2 mL) in a 100 mL
heavy wall pressure vessel equipped with a magnetic stir bar. To this
mixture was added secondary amine (3.0 mmol). The closed vessel was
placed in a preheated oil bath set to 80−110 °C. After the reaction reached
completion, it was cooled to room temperature; EDTA (0.3 mmol) was
added, and the mixture was stirred for an additional 30 min. Subsequently,
the reaction was diluted with dichloromethane (50 mL), combined with
SiO2 (15 mL), and evaporated to give a free-flowing solid. After column
chromatography on silica gel in an appropriate solvent, the fractions
containing the product were combined and concentrated. The residue was
dried under reduced pressure to yield the pure product.
a
Benzamide (1.0 mmol), (CuOH)2CO3 (0.5 mmol), pyridine
(2.0 mL), amine (1.5 mmol), tetramethylguanidine (1.2 mmol)
5−8 h, 130 °C. Yields are isolated yields. Please see Supporting
Information for details.
coupling was performed under the conditions of Table 2.
In this case, selective coupling of morpholine was observed
(Scheme 4D).
3.8. Directing Group Cleavage. The aminoquinoline
directing group can be cleaved by base hydrolysis (eq 2). An
ortho-aminated probenecid derivative was isolated in nearly
quantitative yield.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.6b01117.
F
DOI: 10.1021/jacs.6b01117
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2010, 132, 3965. (c) Daugulis, O.; Roane, J.; Tran, L. D. Acc. Chem. Res.
2015, 48, 1053. (d) Tran, L. D.; Roane, J.; Daugulis, O. Angew. Chem.,
Int. Ed. 2013, 52, 6043. (e) Rouquet, G.; Chatani, N. Angew. Chem., Int.
Ed. 2013, 52, 11726.
(7) Robbins, N.; Koch, S. E.; Tranter, M.; Rubinstein, J. Cardiovasc.
Toxicol. 2012, 12, 1.
Detailed experimental procedures and characterization
data for new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
*olafs@uh.edu
■
(8) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the Welch Foundation (Chair E-0044) and NIGMS
(Grant No. R01GM077635) for supporting this research.
■
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