Cobalt-Catalyzed N-Alkylation of Amines with Alcohols

Article abstract of DOI:10.1021/acs.orglett.5b03461

A well-defined nonprecious metal cobalt(II) catalyst based on a pincer PNP ligand has been employed for the efficient N-alkylation of both aromatic and aliphatic amines with alcohols. A subtle change of reaction conditions (simply adding 4 ? molecular sieves) was observed to readily switch the resulting products (amines vs imines) with high chemoselectivity. A range of alcohols and amines including both aromatic and aliphatic substrates were efficiently converted to secondary amines in good-to-excellent yields when 2 mol % cobalt catalyst was used. Additional experiments indicate that a hydrogen-borrowing mechanism is responsible for the tandem acceptorless dehydrogenation/condensation/hydrogenation process.

Full text of DOI:10.1021/acs.orglett.5b03461

Letter
pubs.acs.org/OrgLett
Cobalt-Catalyzed N‑Alkylation of Amines with Alcohols
,
†
†,‡
‡
Guoqi Zhang,* Zhiwei Yin, and Shengping Zheng
†Department of Sciences, John Jay College and Ph.D. Program in Chemistry, The Graduate Center of the City University of New
York, New York, New York 10019, United States
‡
Department of Chemistry, Hunter College, The City University of New York, New York, New York 10065, United States
*
S Supporting Information
ABSTRACT: A well-defined nonprecious metal cobalt(II)
catalyst based on a pincer PNP ligand has been employed for
the efficient N-alkylation of both aromatic and aliphatic amines
with alcohols. A subtle change of reaction conditions (simply
adding 4 Å molecular sieves) was observed to readily switch
the resulting products (amines vs imines) with high chemo-
selectivity. A range of alcohols and amines including both
aromatic and aliphatic substrates were efficiently converted to
secondary amines in good-to-excellent yields when 2 mol %
cobalt catalyst was used. Additional experiments indicate that a
hydrogen-borrowing mechanism is responsible for the tandem
acceptorless dehydrogenation/condensation/hydrogenation
process.
1
4
recious metal (Ru, Ir, Pd, etc.) catalysis has been involved in
(potassium tert-butoxide). Therefore, the discovery of new
molecular catalysts based on nonprecious metals enabling this
type of reaction is still highly desirable.
P
most crucial organic transformations to date, including
1
some C−C and C−N bond-forming reactions. High catalytic
activity and turnover frequencies have been achieved by using
Recently, we have observed that an ionic cobalt(II) alkyl
complex [(PNHP )Co(CH
1
Cy
F
such precious metal catalysts. However, the scarcity, cost, and
2 3 4
SiMe )][BAr ] (2, Scheme 1)
toxicity of precious metals can be problematic, making them less
attractive for widespread and large-scale commercial applications
in industry. In recent decades, the replacement of precious metal
catalysts with earth-abundant element alternatives has become a
focused research theme, in consideration of “greener” and more
built on a pincer-type PNP ligand carries out hydrogenation
reactions as a precatalyst under mild conditions and at low H
2
15−18
pressure (1−4 atm).
The catalyst was found to be versatile
for the highly efficient reduction of a broad range of chemicals
15,16
including alkenes, aldehydes, ketones, and imines
and the
2
sustainable chemistry for the future. Significant progress has
transfer hydrogenation of a variety of polar double bonds,
been made in the development of homogeneous base metal (Fe,
indicating great potential of cobalt in replacing precious metal
3
,4
17
Co, Ni, etc.) catalysts, although major challenges remain as the
first-row transition metals tend to undergo one-electron changes
in oxidation state and radical reactions, which has limited their
applications as catalysts.
hydrogenation catalysts. Furthermore, it was revealed that the
same cobalt complex catalyzed the acceptorless dehydrogenation
of alcohols as well as the formation of imines from alcohols and
amines upon heating a toluene solution of both substrates in the
18
presence of in situ formed catalyst 2 (Scheme 2). The capability
of cobalt 2 in catalyzing acceptorless dehydrogenation has been
The catalytic N-alkylation of amines with alcohols provides a
green and atom-economic pathway for the synthesis of
substituted amines that have important synthetic applications
19
further established by the Jones group very recently. During the
course of cobalt-catalyzed imine formation from alcohols and
amines, we noticed that in a few cases reduced imines (amines)
were formed as byproducts in less than 10% yield. We envisaged
that a hydrogenation process of imine in the same catalytic
system should have occurred and that it might be possible to
switch the major products from imines to amines by altering the
reaction conditions. Indeed, after many attempts, we were
pleased to find that by simply adding 4 Å molecular sieves (MS)
to the same reaction system the selective formation of
monoalkylated amines occurred in high yields (Scheme 2).
5
−7
in pharmaceutical chemistry.
Precious metal Ir- and Ru-
catalyzed amine alkylation by alcohols has been previously
8
−10
reported by several groups.
In these examples, a “hydrogen-
borrowing” mechanism has been proposed that involves three
successive steps, i.e., acceptorless dehydrogenation of alcohols,
imine formation, and the hydrogenation of imines using the
hydrogen equivalents generated from the previous dehydrogen-
1
1
ation step. Despite such advances, well-defined molecular
catalysts composed of earth-abundant metals for direct amine
1
2−14
alkylation remain extremely scarce to date.
The only
II
homogeneous catalyst system involving a Co complex that
catalyzed N-alkylation of aromatic amines by alcohols was
reported very recently but required the use of a strong base
Received: December 7, 2015
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03461
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Cobalt Complexes Studied for Catalytic N-
Alkylation
Table 1. Screening of Reaction Conditions for the Selective N-
Alkylation of Aniline by Benzyl Alcohol
a
b
entry
1
catalyst
solvent
toluene
yield (%)
no
1
2
3
4
5
6
7
8
2
2
2
2
2
2
0
0
c
2
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
3
4
5
6
7
8
9
98
55
85
81
97
2
4
1
1
1
1
1
1
0
1
2
3
4
5
45
66
51
49
45
78
1,4-dioxane
fluorobenzene
toluene
toluene
toluene
d
e
f
a
Conditions: benzyl alcohol (0.5 mmol), aniline (0.6 mmol), cobalt
catalyst (2 mol %), 4 Å MS (0.5 g), and solvent (4 mL) refluxed in a
b
1
00 mL Schlenk tube, 48 h. Determined by GC with
Scheme 2. Comparison of Distinct Product Selectivities in
Cobalt-Catalyzed C−N Bond Formation
c
hexamethylbenzene as internal standard. 12% imine was observed.
d
e
f
Reaction run at 80 °C. Reaction run in a 50 mL Schlenk tube. 1 mol
%
of 2 was used.
efficacy to the cobalt(II) catalyst 2 (entry 7). Two new cobalt(II)
dihalide complexes (7 and 8, see the SI) were also examined
under the same conditions, yet no significant catalytic activity was
detected (entries 8 and 9). Other solvents including THF, 1,4-
dioxane, and fluorobenzene were tested using 2 (2 mol %) as a
catalyst, but only inferior results were obtained (entries 10−12).
Furthermore, lowering the reaction temperature drastically
decreased the yield of 9a, and reducing the volume of the
reaction vial to 50 mL also suppressed the formation of the
product (entries 13 and 14). Finally, it was found that the use of
only 1 mol % of 2 also afforded the desired product in 78% GC
yield (entry 15). Remarkably, no basic additives were required
for the highly selective formation by using the active catalyst 2, in
Therefore, we present herein the versatile cobalt complex
catalyzed direct N-alkylation of various amines with alcohols,
highlighting the importance of homogeneous earth abundant
cobalt catalysts in C−N bond coupling reactions that involve a
hydrogen-borrowing mechanism.
Several related cobalt complexes (1−6, Scheme 1) previously
reported were first screened for the reaction between benzyl
alcohol and aniline (1.2 equiv) in toluene at reflux in a 100 mL
Schlenk tube with added 4 Å MS, and the results are summarized
in Table 1. It was quite delightful to observe that when 2 (2 mol
sharp contrast to the previously reported Co(PN P) precatalyst,
5
where the presence of an excess amount of strong base,
potassium tert-butoxide, was necessary for good catalytic
14
performance.
%
based on alcohol, generated in situ by the reaction of 1 and
Having established the optimal catalytic conditions for the
effective N-alkylation of aniline with benzyl alcohol, we sought to
apply this methodology to other substrates, i.e., various alcohols
and amines. First, we tested the reactions of benzyl alcohol with
various aniline derivatives under standard reaction conditions (2
mol % of 2 and 4 Å MS in toluene at reflux), and the products
were isolated by silica gel column chromatography after workup.
The results are listed in Table 2. It was observed that electron-
donating substituents such as isopropyl and methoxy groups in
the ortho- or para-position of aniline favored the formation of sec-
amine products, and 9b−d were isolated in excellent yields
(entries 2−4, Table 2). In contrast, para-substituents on aniline
with electron-withdrawing groups led to slightly lower yields, and
in the case of 4-fluoroaniline, 4% imine as a byproduct was
observed on the basis of GC analysis (entry 5, Table 2). Next, we
investigated the reactions of substituted benzylic alcohols with
F
H[BAr ]·(Et O) ) was used as a catalyst, the desired N-
4
2
2
alkylated amine 9a was detected in 98% GC yield and the imine
byproduct was largely suppressed to only a trace amount, while
neutral complex 1 did not favor the formation of 9a (entries 2
and 3, Table 1). However, in the latter case, the formation of an
imine product in 12% yield was confirmed by GC analysis. In
contrast, a control experiment in the presence of 4 Å MS, without
the addition of a cobalt catalyst, gave no reaction at all (entry 1).
In addition, changing the substituent (phenyl group vs
cyclohexyl group) on the phosphorus atom of the PNP ligand
−
F −
(
3) or the counteranion (4, BPh4 instead of BAr 4 ) resulted in
lower yields of 9a (entries 4 and 5), and adding a methyl group
on the nitrogen atom of the ligand (5) also affected the reactivity
16
(
entry 6). Interestingly, the cobalt(III) complex 6 was found to
be an active catalyst as well, displaying comparable catalytic
B
DOI: 10.1021/acs.orglett.5b03461
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 2. Substrate Scope of the N-Alkylation Reactions of
Different Amines by Alcohols
(Scheme 3). Second, when cyclohexanol, a secondary alcohol
that was not previously utilized in the N-alkylation reaction, was
a
Scheme 3. N-Alkylation of 1,3-Diaminobenzene with Benzyl
Alcohol
b
entry
alcohol (R =)
amine (R =)
yield (%)
1
2
1
2
3
4
5
6
7
8
9
C H
C H
94 (9a)
6
5
5
5
5
5
5
6
i
5
C H
6
4- Pr(C H )
90 (9b)
6
4
C H
6
4-MeO(C H )
96 (9c)
6
4
C H
6
2-MeO(C H )
95 (9d)
6
4
C H
6
4-F(C H )
82 (9e), 4% imine
80 (9f)
6
4
C H
6
4-Cl(C H )
used to react with aniline under the optimal conditions, a mixture
of amine, imine and ketone was detected after 48 h, with the
expected N-cyclohexylaniline being the major product (48% GC
yield, Scheme 4). Despite modest selectivity and yield, this result
6
4
4-Me(C H )
C H
84 (9g), 13% imine
90 (9h)
6
4
6
5
5
5
5
5
5
5
5
4-MeO(C H )
C H
6
6
4
4-F(C H )
C H
6
80 (9i), 15% imine
74 (9j), 14% imine
91 (9k)
6
4
10
11
12
13
14
15
16
17
18
(C H )CH
6
C H
6
4
2
propyl
isopropyl
pentyl
heptyl
C H
C H
6
Scheme 4. Reaction of Cyclohexanol and Aniline Catalyzed by
2
C H
6
96 (9l)
C H
6
90 (9m)
C H
6
95 (9n)
(CH ) C H
5
82 (9o), 11% imine
93 (9p), 2% imine
75 (9q)
6
5
5
2
2
6
C H
6
2-butyl
c
c
pentyl
heptyl
4-fluorobenzyl
further indicates the exceptional catalytic activity of the CoII
complex 2, which certainly deserves further investigation in the
future. Finally, tert-butanol and phenol were tested for the
reactions with aniline and, as expected, no coupling reactions
were detected, which is consistent with a pathway involving
initial alcohol dehydrogenation and supports the hydrogen-
borrowing mechanism for the current cobalt-catalyzed N-
alkylation reaction (Scheme 5).
1-hexyl
86 (9r), 6% imine
a
Conditions: alcohol (0.5 mmol), amine (0.6 mmol), cobalt catalyst 2
2 mol %), 4 Å MS (0.5 g), and toluene (4 mL) at reflux in a 100 mL
Schlenk tube, 48 h. Isolated yields. Yields determined by GC
(
b
c
analysis.
aniline. It was noticed that strongly electron-donating 4-
methoxy-derived benzylic alcohol was an excellent substrate for
the reaction, affording the corresponding product 9h in 90%
yield (entry 8, Table 2), while electron-withdrawing substituents
on the benzylic alcohol slightly decreased the yield of the desired
sec-amine products, yet concomitant with the observation of 15%
imine byproduct (entry 9). 2-Phenylethanol was also a suitable
substrate, giving the desired sec-amine 9j in reasonable yield,
although a minor imine product was also detected (entry 10).
Interestingly, several aliphatic alcohols also underwent the N-
alkylation reactions with aniline smoothly, affording the desired
products in high yields (entries 11−14). In addition, aliphatic
amines were found to be suitable substrates for N-alkylation with
alcohols including benzylic alcohol and aliphatic alcohols
Scheme 5. Reactivity Test of tert-Butyl Alcohol or Phenol with
Aniline
In summary, we have here reported on the selective, direct N-
alkylation of both aromatic and aliphatic amines by alcohols
catalyzed by a base metal cobalt complex under base-free
conditions. The cobalt complex proved to be versatile for both
dehydrogenation and hydrogen-transfer reactions by slightly
changing the reaction conditions (adding molecular sieves). Our
efficient cobalt-catalyzed (2 mol % catalyst loading) N-alkylation
can be applied to a wide range of substrates, including even
secondary alcohols and aliphatic amines that were scarcely
addressed previously. This represents a new breakthrough in
cobalt-based catalysis in relation to sustainable chemical
synthesis and has implications for future catalyst design based
upon earth-abundant elements.
(
entries 15−18). For instance, both 2-phenylethylamine and
sec-butylamine reacted effectively with benzyl alcohol to provide
the corresponding products in 82% and 93% yield, respectively,
although minor imine byproducts were also present in the
resulting reaction mixtures. Moreover, direct N-alkylation
occurred between aliphatic alcohols and 4-fluorobenzylamine
or 1-hexylamine producing, in the latter case, a sec-amine with a
long alkyl chain in good yield. The good substrate scope
involving aliphatic amines observed here is remarkable as, to the
best of our knowledge, such substrates were only previously
employed in an iron complex catalyzed N-alkylation through the
13
hydrogen-borrowing process.
ASSOCIATED CONTENT
■
Encouraged by the above findings on a wide substrate scope
for the alkylation of amines by alcohols, we performed additional
experiments to further assess the ability of cobalt catalyst 2 to
promote the reactions of other types of substrates. First, it was
noted that m-diaminobenzene (0.5 mmol) could also be
alkylated with benzyl alcohol (2.0 equiv), and the bis-alkylation
product 9s was isolated in 87% yield under standard conditions
*
S
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b03461.
Experimental procedures and product characterization
data (PDF)
C
DOI: 10.1021/acs.orglett.5b03461
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(
15) Zhang, G.; Scott, B. L.; Hanson, S. K. Angew. Chem., Int. Ed. 2012,
AUTHOR INFORMATION
■
*
5
1, 12102−12106.
16) Zhang, G.; Vasudevan, K. V.; Scott, B. L.; Hanson, S. K. J. Am.
Chem. Soc. 2013, 135, 8668−8681.
17) Zhang, G.; Hanson, S. K. Chem. Commun. 2013, 49, 10151−
0153.
Corresponding Author
(
E-mail: guzhang@jjay.cuny.edu.
(
1
Notes
(
18) Zhang, G.; Hanson, S. K. Org. Lett. 2013, 15, 650−653.
The authors declare no competing financial interest.
(19) Xu, R.; Chakraborty, S.; Yuan, H.; Jones, W. D. ACS Catal. 2015,
5
, 6350−6354.
ACKNOWLEDGMENTS
■
We are grateful to the donors of the American Chemical Society
Petroleum Research Fund for partial support of this work (No.
54247-UNI3). We also acknowledge the support from CUNY
Collaborative Research Incentive Program, a Seed grant support
from the Office for the Advancement of Research, and the
Program for Research Initiatives for Science Majors (PRISM) at
John Jay College, CUNY.
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