Directed amination of non-acidic arene C-H bonds by a copper-silver catalytic system

Article abstract of DOI:10.1002/anie.201300135

Amine meets arene: A method for direct amination of β-C(sp ²)-H bonds of benzoic acid derivatives and γ-C(sp ²)-H bonds of benzylamine derivatives has been developed. The reaction is catalyzed by Cu(OAc)₂ and a Ag₂

Full text of DOI:10.1002/anie.201300135

Angewandte
Chemie
DOI: 10.1002/anie.201300135
Direct Amination
ꢀ
Directed Amination of Non-Acidic Arene C H Bonds by a Copper–
Silver Catalytic System**
Ly Dieu Tran, James Roane, and Olafs Daugulis*
New methods for direct arylation, alkylation, and oxygen-
(Table 1). Use of Cu(OAc)2 (1 equiv) gave 39% conversion
into the product (entry 1). Higher conversion was obtained by
employing of Cu(OAc)2 (0.5 equiv) in the presence of oxygen
2
ꢀ
ation of C(sp ) H bonds in directing-group-containing ben-
zenes have resulted in efficient synthetic routes to function-
alized arenes.[1] In contrast, direct amination reactions that do
not proceed through nitrenoid intermediates[2] are relatively
rare. In most cases, palladium catalysis is used for amination-
s.[3a–p] Furthermore, the majority of publications describe
Table 1: Optimization of reaction conditions.
[3a–i]
ꢀ
intramolecular C N bond formation.
Typically, protected
amines or hydroxylamine derivatives are used to install the
nitrogen moiety; simple amine coupling partners are
employed only rarely. Several deprotonative, copper-cata-
lyzed thiazole and oxazole aminations have been report-
ed.[4b,c,e] Yu et al. have reported a method for palladium-
catalyzed benzamide amination by employing a removable
auxiliary.[3k] Herein, we disclose a method for the auxiliary-
Entry
x equiv
Oxidant
Additive
Yield [%]
1
2
3
4
1
none
O2
NMO
NMO
none
none
K2CO3
39[a]
51[a]
44[a]
74[b]
0.5
0.25
0.25
ꢀ
assisted amination of non-acidic benzamide b-C H bonds and
Ag2CO3
0.25 equiv
Ag2CO3
0.13 equiv
Ag2CO3
0.075 equiv
Ag2CO3
0.125 equiv
ꢀ
benzylamine derivative g-C H bonds, which is catalyzed by
5
6
7
0.1
0.05
0
NMO
NMO
NMO
87[b]
80[a]
<2[a]
copper(II) acetate.
Notably, the first copper-catalyzed directed amination of
ꢀ
arene C H bonds was reported by Yu et al. in 2006
[Eq. (1)].[5a] Subsequently, several other groups have shown
that 2-phenylpyridine derivatives can be ortho aminated by
employing copper salts.[5]
1
[a] Yield determined by H NMR analysis of crude reaction mixtures.
[b] Yield of isolated product. NMO=N-methylmorpholine oxide.
(entry 2). If N-methylmorpholine oxide (NMO) oxidant was
used in the presence of a catalytic amount of Ag2CO3 additive,
74% conversion into the product was observed (entry 4). It
was possible to decrease the catalyst loading to 10 mol%
(entry 5). A control experiment showed that Cu(OAc)2 is
essential for the amination reaction (entry 7).
However, the scope of these reactions is limited by the
presence of a non-removable pyridine moiety. We hypothe-
sized that 8-aminoquinoline and picolinic acid auxiliaries[3g,6]
2
ꢀ
would effect ortho-amination of C(sp ) H bonds based on the
following considerations: 1) copper promotes amination and
sulfenylation of 2-phenylpyridine derivatives,[5] and 2) sulfen-
ylation can be directed by 8-aminoquinoline and picolinic acid
moieties.[6c] The reaction of 8-aminoquinoline p-meth-
oxybenzamide and morpholine was investigated with respect
to oxidant, additives, and amount of copper(II) acetate
The reaction of morpholine with 8-aminoquinoline ben-
zamides is presented in Table 2. The amination is successful
for both electron-rich (entries 1, 3, 5, 7, 8) and electron-poor
amides (entries 2, 4, 6). In contrast with copper-promoted
sulfenylation, amination selectively delivers monofunctional-
ization products at the less sterically demanding position
(entries 5, 6, 8). Diamination products were not detected in
crude reaction mixtures. The reaction shows good functional
group tolerance. Ethers (entries 1 and 5), fluoride (entry 2),
and ester substituents (entry 4) are tolerated. Moreover, the
reaction is successful for five- and six-membered ring hetero-
cycles. Pyridine (entry 9) and furan (entry 10) derivatives are
aminated in good yields. Substrates possessing electron-
withdrawing groups require higher catalyst loading. Reac-
tions can be scaled up at least tenfold without significant loss
of yield (entry 3).
[*] L. D. Tran, J. Roane, Prof. Dr. O. Daugulis
Department of Chemistry, University of Houston
Houston, TX 77204-5003 (USA)
E-mail: olafs@uh.edu
[**] We thank the Welch Foundation (E-1571), NIGMS (R01GM077635),
Camille and Henry Dreyfus Foundation, and Norman Hackerman
Advanced Research Program for supporting this research.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201300135.
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Table 2: Copper-catalyzed reaction of morpholine with carboxylic acid derivatives.[a]
Entry
1
Ar
Product
Yield [%]
87
Entry
6
Ar
Product
Yield [%]
67
4-MeOC6H4
3-CF3C6H4
2
3
4-FC6H4
70
7
8
2-MeC6H4
2-naphthyl
70
66
81
4-tBuC6H4
80[b]
4
5
4-MeO2CC6H4
3-MeOC6H4
68
82
9
3-(2-Me-pyridyl)
3-(2-Me-furyl)
56
57
10
[a] 0.5 mmol scale, NMP (2 mL), NMO (2 equiv), morpholine (2 equiv), Cu(OAc)2 (10–25 mol%), Ag2CO3 (12–25 mol%), 1108C, 14–25 h. Yields
shown are of isolated products (please see the Supporting Information for details). [b] 5 mmol scale.
a,a-Disubstituted benzylamine picolinamides can also be
aminated, albeit in moderate yields (Scheme 1). Thus, a,a-
dimethylbenzylamine picolinamide and its p-fluoroderivative
were reacted with morpholine, and the amination products
were isolated in moderate yields. Benzylamine picolinamide
amination reactions require relatively high temperatures to
achieve reasonable conversions.
The reaction scope with respect to amines is presented in
Table 3. Simple secondary amines, such as methylbenzyl- and
methylpropylamine, are reactive and the products are
obtained in good yields (entries 1 and 2). The reaction
tolerates many functional groups on the amine coupling
component. Ethyl isonipecotate (entry 3), 4-cyanopiperidine
(entry 4), the ethylene ketal of 4-ketopiperidine (entry 5), and
Boc-protected 4-aminopiperidine (entry 6) afforded products
in good yields. Selective coupling with amine NH in the
presence of an amide NH was observed (entry 6). Reactions
with primary amines were also successful, albeit with some-
what reduced yields. Thus, coupling with cyclohexyl-
(entry 7), cyclooctyl- (entry 8), and neopentylamine
(entry 9) afforded products in moderate yields. Straight-
chain primary amines afford low yields (entry 10).
The aminoquinoline directing group can be efficiently
removed by base hydrolysis. Thus, 4 was heated with NaOH in
ethanol for 72 h to afford 4-tert-butyl-2-morpholinobenzoic
acid in high yield (Scheme 2).
The amination mechanism is unclear at this point.
II
ꢀ
However, activation of an aryl C H bond by a Cu complex
to form aryl–CuIII species has been reported in a highly
geometrically constrained system.[7] Additionally, well-
defined CuIII complexes react with N-nucleophiles to form
carbon–nitrogen bonds.[8] Furthermore, an early report by
Reinaud showed that copper(II) mediates aromatic hydrox-
ylation by trimethylamine N-oxide.[9] The reaction presum-
ably proceeds via a CuIII intermediate.
Scheme 1. Benzylamine picolinamide amination.
2
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Table 3: Copper-catalyzed amination of 8-amino-quinoline amides.[a]
Entry Amine
Product
Yield [%]
82
Entry Amine
Product
Yield [%]
83
4-BocNH-piperi-
dine
1
2
HNMeBn
6
7
HNMePr
74
69
cyclohexylamine
40
52
3
4-EtO2C-piperidine
8
9
cyclooctylamine
neopentylamine
4
5
4-NC-piperidine
71
82
32
20
ethylene ketal of 4-keto-piperidine
10[b] nC12H25NH2
[a] 0.5 mmol scale, NMP (2 mL), NMO (2 equiv), amine (2 equiv), Cu(OAc)2 (12–25 mol%), Ag2CO3 (12–25 mol%), 1108C, 12 h. Yields shown are of
isolated products (please see the Supporting Information for details). [b] Pyridine solvent. Boc=tert-butyloxycarbonyl.
functional group tolerance, as well as providing a straightfor-
ward means for the preparation of ortho-aminobenzoic acid
derivatives. Attempts to isolate and characterize reaction
intermediates are in progress.
Scheme 2. Directing group removal.
Experimental Section
N-(2-Morpholino-4-tert-butylbenzoyl)-8-aminoquinoline
entry 3): N-4-tert-butylbenzoyl-8-aminoquinoline
(Table 2,
(152 mg,
In conclusion, we have developed a method for direct,
0.5 mmol), Cu(OAc)2 (11 mg, 0.06 mmol), and Ag2CO3 (17 mg,
0.06 mmol) were added to a 1-dram vial equipped with a stir bar.
Inside a glove box, NMO (117 mg, 1.0 mmol) was added to the vial.
Outside the glove box, NMP (2 mL) and morpholine (0.09 mL,
1.03 mmol) were added to the resulting mixture. The vial was
wrapped with aluminum foil and stirred at 1108C for 11 h and 15 min.
After completion, the reaction mixture was cooled down to room
temperature and dry absorbed on silica gel. Purification by column
chromatography in hexanes/ethyl acetate (4:1) gave 158 mg (81%) of
product as a tan solid. Rf = 0.40 (SiO2, hexanes/EtOAc, 3:1), mp 142–
1448C (from hexanes/EtOAc). 1H NMR (400 MHz, CDCl3): d =
2
ꢀ
auxiliary-assisted amination of b-C(sp ) H bonds of benzoic
2
ꢀ
acid derivatives and g-C(sp ) H bonds of benzylamine
derivatives. The reaction employs Cu(OAc)2 as catalyst in
conjunction with a Ag2CO3 cocatalyst, an amine coupling
partner, NMP or dimethylsulfoxide solvent, and NMO as an
oxidant. The utilization of an inexpensive copper acetate
catalyst and removable directing group are advantages that
allow for a favorable comparison with previous direct
amination reactions. The reaction shows high generality and
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12.75–12.67 (s, 1H) 9.13 (dd, J = 7.8 Hz, J = 1.4 Hz, 1H) 8.87 (dd, J =
4.1 Hz, J = 1.8 Hz, 1H) 8.19 (dd, J = 8.2 Hz, J = 1.4 Hz, 1H) 8.13 (d,
J = 8.2 Hz, 1H) 7.63–7.51 (m, 2H) 7.48 (dd, J = 8.2 Hz, J = 4.1 Hz,
1H) 7.31–7.26 (m, 2H) 4.03–3.93 (m, 4H) 3.21–3.15 (m, 4H) 1.37 ppm
(s, 9H). 13C NMR (100 MHz, CDCl3): d = 166.0, 156.3, 151.2, 148.4,
139.2, 136.7, 136.1, 132.3, 128.7, 127.9, 126.3, 121.9, 121.8, 118.0, 116.4,
66.5, 54.3, 35.6, 31.3 ppm. The signal for one carbon could not be
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ꢀ
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Received: January 8, 2013
Published online: && &&, &&&&
ꢀ
Keywords: amination · arenes · C H activation · copper
.
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4
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Direct Amination
L. D. Tran, J. Roane,
O. Daugulis*
&&&& — &&&&
Directed Amination of Non-Acidic Arene
ꢀ
C H Bonds by a Copper–Silver Catalytic
System
Amine meets arene: A method for direct
and shows high generality and functional-
2
ꢀ
amination of b-C(sp ) H bonds of ben-
group tolerance, as well as providing
a straightforward means for the prepara-
tion of ortho-aminobenzoic acid deriva-
tives.
2
ꢀ
zoic acid derivatives and g-C(sp ) H
bonds of benzylamine derivatives has
been developed. The reaction is catalyzed
by Cu(OAc)2 and a Ag2CO3 cocatalyst,
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
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