Cobalt-Catalyzed Alkylation of Aromatic Amines by Alcohols

Article abstract of DOI:10.1002/anie.201507955

The implementation of inexpensive, Earth-abundant metals in typical noble-metal-mediated chemistry is a major goal in homogeneous catalysis. A sustainable or green reaction that has received a lot of attention in recent years and is preferentially catalyzed by Ir or Ru complexes is the alkylation of amines by alcohols. It is based on the borrowing hydrogen or hydrogen autotransfer concept. Herein, we report on the Co-catalyzed alkylation of aromatic amines by alcohols. The reaction proceeds under mild conditions, and selectively generates monoalkylated amines. The observed selectivity allows the synthesis of unsymmetrically substituted diamines. A novel Co complex stabilized by a PN₅P ligand catalyzes the reactions most efficiently. Sustainable C-N bond formation: An easily accessible Co complex efficiently catalyzes the alkylation of aromatic amines by alcohols. The mild reaction conditions permit the use of sensitive functional groups (I, Br) and the observed selective monoalkylation allows the synthesis of unsymmetrically alkylated diamines.

Full text of DOI:10.1002/anie.201507955

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Angewandte
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International Edition: DOI: 10.1002/anie.201507955
German Edition: DOI: 10.1002/ange.201507955
Amine Alkylation
Cobalt-Catalyzed Alkylation of Aromatic Amines by
Alcohols
Sina Rçsler, Michael Ertl, Torsten Irrgang, and Rhett Kempe*
Angewandte
Chemie
1
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Abstract: The implementation of inexpensive, Earth-abundant
metals in typical noble-metal-mediated chemistry is a major
goal in homogeneous catalysis. A sustainable or green reaction
that has received a lot of attention in recent years and is
preferentially catalyzed by Ir or Ru complexes is the alkylation
of amines by alcohols. It is based on the borrowing hydrogen
or hydrogen autotransfer concept. Herein, we report on the Co-
catalyzed alkylation of aromatic amines by alcohols. The
reaction proceeds under mild conditions, and selectively
generates monoalkylated amines. The observed selectivity
allows the synthesis of unsymmetrically substituted diamines.
Herein we describe the efficient alkylation of aromatic
amines by alcohols catalyzed by a cobalt complex stabilized
by a PN P ligand. The catalyst operates under mild conditions
5
and selective monoalkylation is observed. On the basis of this
selectivity, the synthesis of unsymmetrically alkylated dia-
mines becomes feasible.
We recently introduced PN3–5P-Ir complexes as highly
efficient homogeneous catalysts for the sustainable synthesis
[
12]
of N-heteroarenes, such as pyrroles and pyridines.
Very
recently, we showed that Co complexes stabilized by a PN P
5
ligand (triazine backbone) are highly active and selective
catalysts for the hydrogenation of C=O bonds.[ The Co
7a]
A novel Co complex stabilized by a PN P ligand catalyzes the
5
reactions most efficiently.
complexes are easy to synthesize and simple to activate. They
can be synthesized quantitatively on a multigram scale and
are air-stable as crystalline materials for a few months. The
T
he borrowing hydrogen or hydrogen autotransfer (BH/
HA) concept (Scheme 1) is an elegant method for the “green”
or sustainable formation of CÀC and CÀN bonds. In this
PN P ligand system (pyridine backbone) was introduced by
3
[
1]
[13]
Haupt and co-workers,
and the Kirchner group demon-
[
14]
concept, an alcohol is first oxidized by a transition-metal
strated the broad applicability of the ligand class. Reports
[7a,15]
on Co complexes are rare.
The reaction of aniline with benzyl alcohol was inves-
tigated to identify an efficient Co-based catalyst for the
alkylation of amines. To our delight, 5.0 mol% complex 1c
(which was the most active precatalyst in the hydrogenation
of C=O bonds) already afforded N-benzylaniline (3a) in 84%
yield under relatively mild reaction conditions (808C). A
catalyst screening with 2.5 mol% of the complexes 1a–
e (Figure 1, Table 1) was next carried out. In addition to
Scheme 1. Mechanism of BH/HA reactions. X=CH, N; [M]=transi-
tion-metal catalyst.
catalyst to the corresponding carbonyl compound. It can then
undergo condensation reactions followed by a reduction step
using the hydrogen equivalents obtained from the alcohol
[1,2]
oxidation. The first examples of the N-alkylation of amines
[
3]
by alcohols were reported by the groups of Watanabe and
[4]
Grigg. In the last 10 years, this type of reaction has received
a lot of attention, and elegant synthesis concepts have been
[1]
developed. Typically, noble transition metals such as
ruthenium and iridium catalyze the alkylation of amines
Figure 1. Synthesized Co complexes 1a–f and molecular structure
determined by X-ray crystal-structure analysis of 1d with 50% proba-
bility of thermal ellipsoids. Hydrogen atoms (except NH) are omitted
for clarity. Selected bond lengths [Š] and angles [8]: P1-Co1 2.202(1),
P2-Co1 2.196(1), Co1-Cl1 2.464(1), Co1-Cl2 2.220(1), Co1-N1 1.926(2),
C2-N2 1.318(3); P1-Co1-P2 164.36(3), N1-Co1-Cl1 90.34(7), N1-Co1-
Cl2 162.43(7), N4-P1-Co1 99.18(8), N5-P2-Co1 99.97(8).
[
1]
efficiently. Our group has contributed to the development of
[5]
such Ir catalysts.
A key challenge in transition-metal-mediated catalysis is
the substitution of expensive noble metals by Earth-abun-
dant, inexpensive base metals. Homogeneous cobalt catalysts
have been reported in reactions related to the key steps of
[
6]
[7]
BH/HA such as in hydrogenation (olefins, ketones,
[
8]
[9]
[10]
[11]
[7a]
nitriles, esters, and CO2 ) as well as dehydrogenations.
these already published Co complexes (1a–c), three new
However, the use of homogeneous cobalt catalysts in amine
alkylation reactions by alcohols has not been reported to the
best of our knowledge.
CoCl complexes stabilized by a PN P ligand (1d–f) were
synthesized, characterized, and applied (Figure 1, Table 1; see
Table S2 in the Supporting Information). The cobalt precur-
2
5
sor, CoCl , was also investigated, but afforded only 3% of the
2
alkylated aniline (Table 1, entry 6). Complex 1d was found to
be the most active precatalyst in the test reaction. The
molecular structure of 1d was determined by X-ray crystal-
structure analysis. The N2ÀC2 and the N3ÀC1 bonds (1.318-
[
*] S. Rçsler, M. Ertl, Dr. T. Irrgang, Prof. Dr. R. Kempe
Anorganische Chemie II—Katalysatordesign
Universität Bayreuth
(
3) Š) of 1d are shorter than the corresponding NÀC bonds in
9
5440 Bayreuth (Germany)
E-mail: kempe@uni-bayreuth.de
1a–c (average 1.331 Š). This indicates a partial double-bond
character for these NÀC bonds in 1d and, consequently,
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201507955.
a more positively charged alkyl amine (N6) and a more
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[a]
Table 1: Screening of cobalt complexes in the alkylation of aniline with
benzyl alcohol.
Table 3: Alkylation of various aniline derivatives with benzyl alcohol.
[
a]
[b]
Entry
Amine
Product
Yield [%]
[b]
Entry
Precatalyst
Yield [%]
1
2
3
4
5
6
R=4-F
R=4-Cl
R=4-Br
R=4-I
R=4-Et
R=4-iPr
4a
4b
4c
4d
4e
4 f
86
69
72
51
76
76
1
2
3
4
5
6
1a
1b
1c
1d
1e
CoCl2
42
17
35
62
35
3
[
1
a] Reaction conditions: 1.0 mmol aniline, 1.1 mmol benzyl alcohol,
.0 mmol KOtBu, 5 mL toluene, 808C, 20 h. [b] Determined by GC with
7
8
R=3-Br
4g
4h
57
86
dodecane as internal standard.
negatively charged coordinating N atom (N1). Interestingly,
the Co complexes stabilized by a PN P ligand (pyridine
3
backbone) resulted in significantly lower reaction rates than
their PN P (triazine backbone) counterparts (see Table S2).
5
The catalyst based on 1d was used for the final optimizations
of the reaction conditions. The use of a precatalyst at a loading
of 2.0 mol% led to the formation of 93% N-benzylaniline
9
4i
63
(
Table S7). An amine/alcohol ratio of 1.4:1 is beneficial.
With these optimized conditions in hand, aniline was
[
a] Reaction conditions: 1.4 mmol aniline, 1.0 mmol alcohol, 2.0 mol%
alkylated with various alcohol derivatives (Table 2, 3a–l).
Substituted benzyl alcohols (3a–h) with several functional
groups (halides, alkyl, thioether, methoxy) are applicable as
well as aliphatic alcohols (3i–l). The resulting N-alkylated
anilines were isolated in good to excellent yields, except for
precatalyst 1d, 1.2 mmol KOtBu, 3 mL toluene, 808C, 24 h. [b] Yield of
isolated product.
Cl, Br, and I) substituted N-benzylanilines (4a–d, 4g) as well
as 3,5-substituted N-benzylanilines (4h,i) were isolated in
good to excellent yields, except for 4d and 4g, where partially
dehalogenation again takes place. In addition, 3-aminopyr-
idine was successfully alkylated with benzyl and aliphatic
alcohols (Table 4).
3
d where debromination lowered the yield.
Next, substituted anilines were alkylated with benzyl
alcohol to show the aniline variability (Table 3). Again,
a notable functional group tolerance was observed. Halide (F,
[
a]
Finally, we were interested in the preferential selective
alkylation of diamines with two different alcohols (Table 5).
First, a monoalkylated diamine (6a) was synthesized in 91%
yield. In a second step, 6a was alkylated with benzylic and
aliphatic alcohols to afford the corresponding unsymmetri-
cally alkylated diamines (7b–e).
Table 2: Alkylation of aniline with various primary alcohols.
[b]
Entry Alcohol
Product
Yield [%]
1
2
3
4
5
6
7
8
R=C H
R=4-F(C H )
R=4-Cl(C H )
R=4-Br(C H )
R=4-Me(C H )
R=4-OMe(C H )
R=4-SMe(C H )
R=4-tert-butyl(C H ) 3h
3a
3b
3c
3d
3e
3 f
90
84
72
53
94
88
71
93
6
5
[a]
6
4
Table 4: Alkylation of 3-aminopyridine with various alcohols.
6
4
6
4
6
4
6
4
3g
[b]
6
4
Entry
Alcohol
Product
Yield [%]
6
4
1
2
3
4
R=C H
R=4-OMe(C
R=4-SMe(C H )
R=4-Me(C H )
5a
5b
5c
5d
89
61
76
94
6
5
6 4
H )
9
1
1
1-butanol
1-hexanol
C H OH
3i
3j
3k
90
82
86
0
1
6
4
6
5
2
2
45
5
6
C H OH
1-butanol
5e
5 f
69
76
2
2
45
1
2
(À)-Nopol
3l
96
[
a] Reaction conditions: 1.4 mmol aniline, 1.0 mmol alcohol, 2.0 mol%
[a] Reaction conditions: 1.4 mmol aminopyridine, 1.0 mmol alcohol,
2.0 mol% precatalyst 1d, 1.2 mmol KOtBu, 3 mL toluene, 808C, 24 h.
[b] Yield of isolated product.
precatalyst 1d, 1.2 mmol KOtBu, 3 mL toluene, 808C, 24 h. [b] Yield of
isolated product.
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Table 5: Alkylation of diamines.
1
2
[d]
Entry
1
Alcohol R
Alcohol R
Product
Yield [%]
1
[a]
[b]
[c]
R =4-OMe(C H )
–
6a
91
73
71
57
6
4
1
2
2
3
4
R =C H
R =C H
7a
6
5
6
5
5
1
2
R =4-OMe(C H )
R =C H
7b
6
4
6
1
2
[c]
R =4-OMe(C H )
R =4-F-(C H )
7c
6
4
6
4
1
2
[c]
[c]
5
6
R =4-OMe(C H )
R =propyl
7d
7e
76
79
6
4
1
2
R =4-OMe(C H )
R =pentyl
6
4
[
a] 3.0 mmol benzenediamine, 1.0 mmol alcohol, 2.0 mol% precatalyst 1d, 1.2 mmol KOtBu, 3 mL toluene, 808C, 24 h. [b] 1.0 mmol benzenediamine,
2
1
.0 mmol alcohol, 4.0 mol% precatalyst 1d, 2.4 mmol KOtBu, 3 mL toluene, 808C, 24 h. [c] 1.0 mmol 6a, 1.0 mmol alcohol, 2.0 mol% precatalyst 1d,
.2 mmol KOtBu, 3 mL toluene, 808C, 24 h. [d] Yield of isolated product.
In conclusion, we have reported on the first example of an
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alkylation of amines by alcohols catalyzed by a cobalt
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carried out under mild conditions (808C) with a relatively low
catalyst loading (2 mol%). The precatalyst is easily prepared
from commercially available reagents in a two-step procedure
and in almost quantitative yields. The mild reaction con-
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and the synthesis of unsymmetrically alkylated diamines.
[
[
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Keywords: alcohols · amine alkylation · base metals ·
hydrogen-transfer catalysis · cobalt
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Published online: October 16, 2015
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