Copper-catalyzed arene amination in pure aqueous ammonia

Article abstract of DOI:10.1039/c8ob02708k

A simple protocol for copper-catalyzed arene amination using aqueous ammonia without any additional ligands and organic coordinating solvents has been developed. The reaction pathway via a Cu(i)/Cu(iii) mechanism is proposed based on the results of control experiments as well as DFT calculations.

Full text of DOI:10.1039/c8ob02708k

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Copper-catalyzed arene amination in pure
aqueous ammonia†
Cite this: DOI: 10.1039/c8ob02708k
Mio Takagi,‡ Ayako Watanabe,‡ Shigeo Murata and Ryo Takita
*
Received 31st October 2018,
Accepted 16th November 2018
DOI: 10.1039/c8ob02708k
rsc.li/obc
A simple protocol for copper-catalyzed arene amination using supporting ligands and the employment of coordinating sol-
aqueous ammonia without any additional ligands and organic vents were important for the catalytic reactivity, since the stabi-
coordinating solvents has been developed. The reaction pathway lization of the copper center in the active species was crucial.
via a Cu(I)/Cu(III) mechanism is proposed based on the results of For example, while high catalyst loadings were generally
control experiments as well as DFT calculations.
required in the copper system, Ma et al. reported that an opti-
mized oxalamide ligand facilitates aryl amination with a low
Ammonia is among the most abundant nitrogen sources,
based on the established Haber–Bosch process. However, the
direct use of ammonia in arene amination or Buchwald–
Hartwig amination to afford primary arylamines has been
6a
catalyst loading (0.01–0.5 mol% of Cu O). The ligand-free
2
conditions were also reported using a coordinating solvent
6l,m
(
NMP) or a bimetallic system (Scheme 1c).
Herein, we
describe arene amination using a catalytic amount of Cu O or
2
1
,2
rather limited. This is mostly because the coordination of
ammonia to transition-metals often forms inactive complexes
due to the strong Lewis basicity. Its small size enables multiple
coordination by filling the vacant sites. The strong N–H bonds
CuI in “pure” aqueous ammonium solution without any
3
of ammonia make the “N–H activation” difficult. Moreover,
the resultant monoarylamine is more reactive than ammonia
to evoke unselective di- or triarylamine formation. Recently,
Pd- or Ni-catalyzed amination reactions with ammonia or
1
,4
ammonium salts have been reported (Scheme 1a). The key is
the employment of customized ligands such as bulky phos-
phines and NHCs under anhydrous conditions.
Aqueous ammonia solution is a cost-effective reagent and
easy to handle in the laboratory, even compared with
ammonia gas, anhydrous ammonia solution, or its surrogates.
While its use as a nitrogen source would make the process
economical and user-friendly, the requirement of anhydrous
and inert conditions in many transition-metal catalyses would
not be suitable. In contrast, several Cu-catalyzed amination
reactions of aryl halides using aqueous ammonia have been
1
,5–7
developed very recently (Scheme 1b).
The optimization of
One-stop Sharing Facility Center for Future Drug Discoveries, Graduate School of
Pharmaceutical Sciences, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo, Japan.
E-mail: takita@mol.f.u-tokyo.ac.jp
1
†
Electronic supplementary information (ESI) available: Experimental details,
H
NMR spectra of known compounds, and computational details. See DOI:
10.1039/c8ob02708k
Scheme 1 Metal-catalyzed arene amination using ammonia as a nitro-
‡
These authors contributed equally to this work.
gen source.
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additional ligands and co-solvents (Scheme 1d). A variety of (entries 10–12); PPh
3
and 1,10-phenanthroline did not show
6
b
arylamines and heteroarylamines can be efficiently prepared positive effects, and the use of L1 gave similar reactivity. The
using aqueous ammonia as a nitrogen source and K CO as a chemical yield of 2a was decreased under air (entry 13), and the
base by a robust and simple protocol. The obtained mechanis- reaction was retarded in the absence of K CO (entry 14) and
tic insights and results of DFT calculations are also presented. did not proceed at room temperature (entry 15). Using either
2
3
2
3
In an aqueous ammonia solution, the multiple coordi- copper(I) iodide or copper(I) oxide as a catalyst without any
8
nation of ammonia to the copper center could be potentially additional ligands, the reaction of 1a was completed within
beneficial at least in terms of stabilization, increased electron 3 hours to afford the desired monoarylamine 2a in an excellent
density for oxidative addition, and structural requirements of yield (entries 16 and 17). The side reactions to afford the
the amide complex for reductive elimination, even without corresponding di- or triarylamine were not observed under
supporting ligands and strongly coordinating organic solvents. these conditions.
Thus, we commenced our studies with the reaction of 4-iodo-
With the optimized conditions in hand, the substrate scope
anisole (1a) using metal sources as a catalyst (2 mol% on a of this reaction was investigated, as summarized in Table 2. 2a
metal), K CO as a base in aqueous ammonia solution (ca. was isolated in 89% yield. While copper catalysis is generally
2
3
9
2
2
8%) after purging with N (Table 1). Using copper(I) iodide ineffective for sterically-hindered structures, meta- and ortho-
or copper(I) oxide as the copper source, the desired 4-methoxy- substituted anisole derivatives 1b and 1c showed good reactiv-
aniline (2a) was obtained in 81 or 84% NMR yield (entries 1 ity. Not only electron-rich but also electron-deficient iodo-
and 2). While the use of copper(I) acetate gave similar results arenes (1e and 1f) were aminated well in good yield (>80%). The
(
77%, entry 3), the yield was drastically diminished (11%) use of phenol and benzyl alcohol derivatives (1g and 1h), both
when copper(II) acetate was used (entry 4). Other metal sources of which have free OH groups, was not a problem to give the
including Pd(OAc) , CoCl , NiCl , and Mn(OAc) were ineffec- desired anilines in 80 and 85% yields, respectively. The allyloxy
2
2
2
3
tive (entries 5–8). The absence of a metal catalyst did not group was tolerated, which may not be used in Pd-catalysis,
afford product 2a (entry 9). Some ligand effects were examined and 2i was obtained in 93% in 1 hour. Further, heteroaromatic
Table 2 Copper-catalyzed arene amination in pure aqueous ammonia
as a nitrogen source
Table 1 Metal-catalyzed arene amination using aqueous ammonia as a
nitrogen source
a
Entry
Metal source
CuI
Ligand
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
—
—
—
—
—
—
—
—
1
1
1
1
1
1
1
1
1
1
1
1
1
1
23
3
81
84
77
11
0
0
0
0
0
68
54
84
45
14
0
2
Cu O
CuOAc
Cu(OAc)
2
Pd(OAc)
CoCl
NiCl
2
2
2
Mn(OAc)
3
—
—
PPh
b
10
11
12
13
14
15
16
17
Cu
2
Cu
2
Cu
2
Cu
2
Cu
2
Cu
2
O
O
O
O
O
O
3
b
1,10-Phen
b
L1
c
—
—
—
—
—
d
e
CuI
Cu
Quant.
96
2
O
3
a 1
H NMR yields using dimethylsulfone as an internal standard were
b
noted. 4 mol% of ligand was used. The structure of L1 is shown.
c
d
The reaction was performed under air. The reaction was performed
e
in the absence of K
erature.
2 3
CO .
The reaction was performed at room temp-
a 1
H NMR yields using dimethylsulfone as an internal standard were
noted. These compounds are volatile.
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substrates can also be utilized, and mono-pyridyl and -pyrazi-
nyl amines (2j, 2k, and 2l) were efficiently produced under
identical conditions. Unprotected iodocarbazole with a free
NH group was directly converted to the corresponding aniline
2
9
m in 72% yield. 6-Aminoquinoline (2n) was also obtained in
4% yield.
Regarding the side reactions, while the formation of di- or
triarylamine was not observed, tiny amounts of corresponding
phenol derivatives were generated, in particular with electron-
deficient substrates. Thus, we examined the reaction of 1-iodo-
4
-nitrobenzene (1o) (eqn (1)), a highly electron-deficient sub-
Scheme 2 Radical-clock and radical scavenger experiments of Cu-
catalyzed amination in aqueous ammonia.
strate. Under the reaction conditions, the corresponding
phenol 3o was formed in 34% NMR yield, concomitant with
the aniline 2o in 56%. Given the substrate dependency, the
decreased aniline formation using 1o implied that the nucleo-
5
b,11
tive elimination mechanism via a Cu(I)/Cu(III) cycle
can be
N
philic aromatic substitution (S Ar) mechanism should not be
reasonably proposed.
operative in the present copper-catalyzed amination reaction.
Then, we carried out preliminary DFT calculations on the
reaction pathway at the ωB97X-D/SDD (for Cu and I) and
ð1Þ 6-31+G* (for other atoms) levels of theory (Fig. 1). INT
was
1
used as the model starting complex for the oxidative addition
based on the above-mentioned findings. The rather high acti-
‡
−1
Further mechanistic insights were obtained through control vation energy for TS
(ΔG = +36.2 kcal mol ) is observed for
1
experiments. Given the results in Table 1, copper(I) species, the first oxidative addition, consistent with the requirement of
rather than copper(II) complexes, should be involved in the a high reaction temperature (entry 15, Table 1). The stabilized
catalysis. The involvement of a radical mechanism is unlikely, amide complex INT
was obtained after the deprotonation by
. The reductive elimination to form a C–N bond under
experiments shown in Scheme 2. The cyclized product (i.e. 4) the present copper catalysis proceeded very efficiently via TS
4
1
0
7
based on the radical-clock and radical scavenger (TEMPO)
2 3
K CO
2
6
b
‡
−1
was not observed in the reaction of 1p, and the corres- (ΔG = +2.0 kcal mol ) to afford the aniline product in INT
ponding monoarylamine 2p was generated in 89% NMR yield In addition, the reductive elimination directly from the
Scheme 2a). The presence of a catalytic or stoichiometric ammonia complex INT can also be postulated. The transition
amount of TEMPO did not affect the reaction outcome state TS2b is located at a very high energy (+45.3 kcal mol
Scheme 2b). From these results, the oxidative addition/reduc- from INT ), suggesting that the reaction should be retarded in
.
5
(
2
−
1
(
1
Fig. 1 DFT calculations for a model reaction with a Cu(I) complex. Energy changes and bond lengths at the ωB97X-D/SDD (for Cu and I) and
-31+G* (for other atoms) levels of theory are shown in kcal mol−1 and Å, respectively. The green line represents a model reaction in the absence
6
of a base.
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the absence of the base (entry 14, Table 1). While other possi-
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5
b,12
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and numbers of
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represent the experimental results described above.
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catalyzed amination reaction of aryl iodides using aqueous
ammonia as a nitrogen source without any additional ligands
and organic solvents. This catalytic system is composed of in-
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ammonia), and applicable for various aromatic and hetero-
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and the tube was closed after roughly purging with an N
2
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