Manganese-Catalyzed Environmentally Benign Dehydrogenative Coupling of Alcohols and Amines to Form Aldimines and H2: A Catalytic and Mechanistic Study

Article abstract of DOI:10.1021/jacs.5b13519

The catalytic dehydrogenative coupling of alcohols and amines to form aldimines represents an environmentally benign methodology in organic chemistry. This has been accomplished in recent years mainly with precious-metal-based catalysts. We present the dehydrogenative coupling of alcohols and amines to form imines and H₂ that is catalyzed, for the first time, by a complex of the earth-abundant Mn. Detailed mechanistic study was carried out with the aid of NMR spectroscopy, intermediate isolation, and X-ray analysis.

Full text of DOI:10.1021/jacs.5b13519

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Communication
Unprecedented Manganese Catalyzed Environmentally
Benign De-hydrogenative Coupling of Alcohols and Amines
to Form Imines and H2: A Catalytic and Mechanistic Study
Arup Mukherjee, Alexander Nerush, Gregory Leitus, Linda J. W. Shimon,
Yehoshoa Ben-David, Noel-Angel Espinosa-Jalapa, and David Milstein
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b13519 • Publication Date (Web): 29 Feb 2016
Downloaded from http://pubs.acs.org on February 29, 2016
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Manganese Catalyzed Environmentally Benign Dehydrogena-
tive Coupling of Alcohols and Amines to Form Aldimines and
H2: A Catalytic and Mechanistic Study
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Arup Mukherjee,†, ‡ Alexander Nerush,†, ‡ Gregory Leitus, § Linda J. W. Shimon,§ Yehoshoa Ben
David,† Noel Angel Espinosa Jalapa†, and David Milstein†,*
Departments of †Organic Chemistry, and §Chemical Research Support, Weizmann Institute of Science, Rehovot 76100, Israel
Supporting Information Placeholder
Feringa, Barta as well as Kempe separately reported the alkylation
of amines with alcohols by the ‘borrowing hydrogen’
ABSTRACT: The catalytic dehydrogenative coupling of alcohols
and amines to form aldimines represents an environmentally
benign methodology in organic chemistry. This has been
accomplished in recent years mainly with precious-metal-based
catalysts. Here we present the dehydrogenative coupling of
alcohols and amines to form imines and H2 catalyzed, for the first
time, by a complex of the earth-abundant manganese. A detailed
mechanistic study was carried out with the aid of NMR
spectroscopy, intermediate isolation, and X-ray analysis.
methodology
utilizing
an
iron
catalyst
based
on
cyclopentadienone ligands, or a cobalt catalyst based on a triazine
backbone13, in which an imine intermediate is in situ hydrogena-
ted to the corresponding amine. Several iron-based catalysts for
the hydrogenation and dehydrogenation of alkynes, ketones, alde-
hydes, esters, and alcohols were developed.14 Substantial efforts
were also made towards the development of cobalt catalysts for
homogeneous hydrogenation and dehydrogenation reactions.15
Very recently, we reported the hydrogenation of nitriles and esters
catalyzed by a homogeneous pincer cobalt complex.16 In contrast
to the development of several homogenous catalysts based on iron
and cobalt, catalytic reactions based on manganese complexes are
less exploited.17 To the best of our knowledge, there are no litera-
ture reports on hydrogenation and dehydrogenation reactions cata-
lyzed by manganese complexes, although manganese is one of the
most abundant transition metals on Earth crust, third only to iron
and titanium. We now report the unprecedented dehydrogenative
coupling of alcohols and amines catalyzed by a manganese PNP
pincer complex, yielding selectively imines and H2.
Imines and their derivatives are important synthetic intermediates
because of their diverse reactivity. As a result, they have been
extensively utilized in the synthesis of dyes, fragrances,
fungicides, pharmaceuticals, and agricultural chemicals.1
Moreover, imines also serve as common ligands in coordination
chemistry. Conventionally, imines are synthesized by the
condensation reaction of aldehydes or ketones with amines in the
presence of an acid catalyst. Recently, versatile alternative
methods have been reported, such as oxidation of secondary
amines,2 self-condensation of primary amines upon oxidation,3
oxidative coupling of alcohols and amines,4 hydroamination of
alkynes with amines,5 and the partial hydrogenation of nitriles
followed by coupling with the amines6. Self-coupling of amines
involves use of O2 atmosphere as an oxidant and the products are
limited to symmetric imines.
Alternatively, the direct acceptorless dehydrogenative coupling
of alcohols and amines is one of the most promising, ‘‘green’’
synthetic pathways for the preparation of imines, since alcohols
are readily available by a variety of industrial processes and can
be obtained renewably via fermentation or catalytic conversion of
lignocellulosic biomass7. Moreover, only hydrogen and water are
produced as by-products in this pathway. In 2010, we reported the
first acceptorless dehydrogenative coupling of alcohols and
amines to selectively form imines, catalyzed by a ruthenium
pincer complex.8 Since then, this field has progressed rapidly and
several catalytic systems for such transformation have been
developed, mainly with precious metals-based catalysts. 9
There is strong current interest in the replacement of noble
metal catalysts by more economical, environmentally friendly
catalysts based on earth-abundant metals.10 However, the
tendency of first-row transition-metal complexes to react by one-
electron pathways, rather than by the prevailing two-electron
transformations of second- and third-row metals, can make it
difficult to develop catalytic reactivity similar to that of noble
metal complexes.11 Nevertheless, noteworthy progress has been
made in the area of homogeneous earth-abundant metal-based
hydrogenation and dehydrogenation catalysis.12 Recently,
Figure 1. Overview of the present work and the dearomatized
manganese pincer complex 1 used in this study.
The dehydrogenative coupling reaction of benzyl alcohol with
benzylamine to give N-benzylidene-1-phenylmethanamine was
chosen as a model system for initial studies. Thus, a dry toluene
solution containing equimolar amounts of benzyl alcohol and
benzylamine, and a catalytic amount of complex 118 (Figure 1)
was heated at 135°C (bath temperature) for the specified time
(Table 1). The products were analyzed by GC-MS and NMR
spectroscopy and identified by comparison with authentic
samples. Heating a solution of benzyl alcohol (0.5 mmol) and
benzylamine (0.5 mmol) with complex 1 (4 mol%) in a closed
system under a nitrogen atmosphere at 135 °C in toluene (2 mL)
resulted
in
76%
conversion
to
N-benzylidene-1-
phenylmethanamine after 30 h (Table 1, entry 1). Analysis of the
gas phase by GC revealed the formation of H2. No side products,
such as amides or esters, which were observed in small amounts
when a ruthenium catalyst was used,8 were observed here.
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Interestingly, no products resulting from hydrogenation of the
imine double bond, such as dibenzylamine were observed.
and a small amount of benzaldehyde. Complex 1 also catalyzed
1
2
3
4
5
6
7
8
effectively the reaction of 4-methoxybenzyl alcohol with
benzylamine, cyclohexylamine, and 4-fluorobenzylamine to
afford the corresponding imines in 93%, 78%, and 73% yields,
respectively (Table 2, entries 5-7). When hexylamine reacted with
4-methoxybenzyl alcohol only 50% of the corresponding imine
was formed under analogous reaction conditions (Table 2, entry
8). Prolonging the reaction time slightly increased the yield of the
desired imine.
Table 1. Optimization of reaction conditions for the coupling of
benzyl alcohol with benzylamine catalyzed by 1.a
Table 2. Dehydrogenative coupling of various alcohols and
amines catalyzed by 1.a
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Carrying out the reaction in benzene (2 mL) for 36 h in a closed
system resulted in 85% consumption of benzyl alcohol and 82%
yield of N-benzylidene-1-phenylmethanamine, together with a
small amount of unreacted aldehyde, generated from the alcohol
(Table 1, entry 2). Lowering the loading of complex 1 from 4
mol% to 3 mol% or 2 mol% resulted in 89% and 62% yield of N-
benzylidene-1-phenylmethanamine, respectively, after 48 h (Table
1, entries 3 and 4). However, prolonging the reaction time to 60 h
using 3 mol% of complex 1 resulted in 92% yield of the desired
imine (Table 1, entry 5). It is noteworthy that when the
dehydrogenation reaction was carried out in an open system under
an
argon
atmosphere,
94%
of
N-benzylidene-1-
phenylmethanamine was furnished, comparable to the yield obtai-
ned in the closed system (Table 1, entries 5 and 6), indicating that
the presence of hydrogen does not have a significant effect on the
reaction. Use of polar solvents has an adverse effect on the cataly-
tic reaction. Thus, when the reaction was carried out using dioxa-
ne or THF as solvents, only <5% of N-benzylidene-1-
phenylmethanamine was formed in both the cases (Table 1, ent-
ries 7 and 8), the rest being the starting compounds. The catalyst
can be generated in situ from the air stable mer-
[Mn(PNPtBu)(CO)3]Br18 and an equivalent of tBuOK (Table 1,
entry 9; see SI for details)
Under the optimized conditions (Table 1, entry 5), we explored
the substrate scope of the manganese-catalysed dehydrogenative
coupling of alcohols and amines. A variety of substituted benzyl
alcohols underwent efficient dehydrogenative coupling with
amines containing either electron-donating or -withdrawing
substituents (Table 2). Thus, heating a solution of benzyl alcohol
with cyclohexylamine or 2-phenylethylamine using catalyst 1 at
135 °C in benzene (2 mL) in a closed system resulted in the
exclusive formation of the corresponding imines in 93% and 95%
yields, respectively (Table 2, entries 1 and 2). Use of amines
bearing electron donating substituents often resulted in higher
yields than when amines with electron withdrawing substituents
were used, presumably because of higher nucleophilicity of the
former. Thus, 4-methoxybenzylamine and4-fluorobenzylamine
react with benzyl alcohol under similar reaction conditions to give
97% and 52% yields of the corresponding imines (Table 2, entries
Reaction of 3,4-dimethoxybenzyl alcohol with 2-
phenylethylamine
or
cyclohexylamine
furnished
the
corresponding imines in 99% and 78% yields, respectively (Table
2, entries 9 and 10). 4-methylbenzyl alcohol reacted with the 4-
fluorobenzylamine to yield the corresponding imine in 65% yield
and traces of aldehyde (Table 2, entry 11). Alcohols with an
electron withdrawing substituent at the para-position also
underwent the catalytic reaction. Thus, reaction of 4-fluorobenzyl
alcohol with benzylamine or cyclohexylamine using catalyst 1
produced 91% and 78% of the corresponding imines, respectively
(Table 2, entries 12 and 13). Further, the catalytic reaction of 4-
1
3 and 4). Analysis of the reaction mixture in the latter case by H
NMR and GC-MS indicated the presence of the starting materials
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chlorobenzyl alcohol with benzylamine and cyclohexylamine
dissolved in benzyl alcohol (270 equivalents), a dramatic change
in the 31P{1H} NMR spectrum was observed, with the appearance
of a broad singlet at δ 104.5 ppm, suggesting a dynamic process
(Figure 2B). This could be due to reversible formation of an
alkoxo complex with concomitant aromatization of the pincer
ligand, as we had observed previously in the case of a ruthenium
pincer system.19 In order to verify this, the alkoxo complex
[Mn(PNPtBu–OCH2Ph)(CO)2] (2) was synthesized independently
by addition of 3 equivalents of benzyl alcohol to a saturated
pentane solution of complex 1. Storing the reaction mixture at –38
℃ for 72 h resulted in formation of single crystals of complex 2.
The molecular structure of 2 was unambiguously established by a
single crystal X-ray diffraction analysis (Scheme 2 inset), which
revealed the activation of the O–H bond of the benzyl alcohol by
complex 1. Complex 2 exhibits a Mn(I) center in a distorted
octahedral geometry, with the alkoxo moiety bound in an axial
position to the manganese center (See SI for details). The IR
spectrum of 2 exhibits absorption bands at 1814 and 1891 cm–1
that are characteristic of an octahedral dicarbonyl compound in a
cis arrangement. Previously, we demonstrated similar activation
of X–H bonds (X = H, O, N) by metal-ligand cooperation (MLC)
using PNP- or PNN-based ruthenium pincer complexes under
catalytic or stoichiometric conditions.20
1
2
3
4
5
6
7
8
under analogous reaction conditions yielded 99% and 70% of the
corresponding imines, respectively (Table 2, entries 14 and 15).
However, the reaction with aliphatic amines under analogous
reaction conditions proceeded slowly and reaction of 4-
cholorobenzyl alcohol with hexylamine produced the imine in
45% yield (Table 2, entry 16). The lower yield of hexylamine
compared to that of cyclohexylamine can be attributed to the
higher nucleophilicity of the latter.
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Figure 2. A selected part of 31P{1H} NMR spectra of 1 with
benzyl alcohol at room temperature: A) complex 1 in C6D6; B)
complex 1 in neat benzyl alcohol; C) after 20 min of addition; D)
after 60 min of addition; E) after 120 min of addition; F)
complexes 4 and 5 independently dissolved in benzyl alcohol.
In continuation of the NMR experiment, 20 minutes after the
addition of benzyl alcohol to complex 1, a new set of two sharp
AB doublets appeared in solution at δ 120.2 and 126.2 ppm (2JP-P
= 106.4 Hz, Figure 2C), which we assign to the benzaldehyde
adduct, [Mn(PNPtBu–OCHPh)(CO)2] (4, Scheme 2). Formation of
complex 4 involves the dehydrogenation of benzyl alcohol to
benzaldehyde by 1 followed by its electrophilic attack on the
dearomatized ligand. Analogous alkoxo and aldehyde-addition
complexes were observed in alcohol dehydrogenative coupling
catalyzed by a PNP-Ru complex (Scheme 2).19 In accordance with
our observations; we believe that the mechanism of the Mn-
catalyzed process follows a similar pathway to that of the PNP
ruthenium-catalyzed reactions. The dehydrogenation of the
R1
H
P
P
Mn
P
O
N
CO
CO
CO
CO
R1
N
Mn
OH
+
H2
P
1
2
O
H
R1
P = PtBu2
H
H
H
P
P
H
CO
CO
CO
N
Mn
N
Mn
X-ray structure of 2
CO
P
P
R1
5
3
alcohol likely proceeds through
a (presumably concerted)
P
P
O
O
N
CO
CO
bifunctional proton and hydride transfer, illustrated as transition
state 3 (Scheme 2).21 Formation of the aldehyde by direct β-H
elimination of the alkoxy ligand of the coordinatively saturated
complex 2 (reversibly formed under the reaction conditions) is
less likely. The identity of 4 was also verified by its independent
synthesis. Thus, treating a saturated THF solution of complex 1
with two equivalents of benzaldehyde, followed by exposure to
pentane vapor in a sealed 20 mL vial, yielded after 72 h at room
temperature, single crystals of 4 suitable for X-ray diffraction.
The solid state structure of complex 4, shown in Scheme 2 inset,
indicates the product of aldehyde binding to the ligand framework
in a cooperative fashion with formation of Mn–O and C–O bonds
(See SI for details)20. Complex 4 was also dissolved in neat
benzyl alcohol to verify the 31P NMR shift and was found to be in
accordance with the NMR experiment (Figure 2F). This
eliminates the other possibility of subsequent attack of alcohol on
4, making the hydroxy arm to open up as suggested earlier in case
of Ru catalysis.9a
+
N
Mn
Mn
R1
H
CO
CO
P
P
R2-NH2
1
4
HO
R2
R2
R1
N
R1
N
H
H2O
X-ray structure of 5
X-ray structure of 4
Scheme 2. Proposed mechanism for imine formation. The
molecular structures of complexes 2, 4, and 5 are shown in the
inset with thermal ellipsoids set at 50% probability. Hydrogen
atoms were omitted for clarity, except for the Mn–H in structure
5. The P(tBu)2 groups are drawn as wire frames for clarity (See SI
for details).
The synthesis of aliphatic imines is intrinsically more
challenging because of their instability. Aliphatic alcohols also
react with aliphatic amines under the reaction condition to give
the imine, albeit at a lower yield. Thus, 1-hexanol reacted with
cyclohexylamine to yield the corresponding imine in 30% yield
(Table 2, entry 17). Prolonging the reaction time did not increase
the yield of the desired amine appreciably.
Moreover, in continuation of the NMR experiment, after 60
minutes a new singlet at δ 128.7 ppm appeared (Figure 2D and
2E). This was identified as the hydride complex [Mn(PNPtBu
–
H)(CO)2] (5). Interestingly, when this reaction mixture was
pressurized with H2, an increase in intensity of the singlet at δ
128.7 ppm was observed, indicating formation of the Mn–H
complex 5. Moreover, complex 5 was separately synthesized by
treatment of 1 with H2 in C6D6. The 1H NMR spectrum of 5
shows a hydride resonance at δ –4.19 ppm. The molecular
structure of 5 is presented in Scheme 2 (inset), as obtained from a
single crystal x-ray analysis. Dissolving it in neat benzyl alcohol
Aiming at gaining insight regarding possible intermediates in
the reaction, the reaction of complex 1 with benzyl alcohol was
monitored by 31P{1H}NMR spectroscopy (Figure 2). Complex 1
exhibits a set of two sharp doublets at δ 87.15 and 101.3 ppm (2JP-
P = 68.2 Hz) in the 31P{1H} NMR spectrum (Figure 2A). When
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verified the assignment of the observed 31P NMR signal in the
NMR experiment (Figure 2F). Complex 5 then undergoes
dehydrogenation under the catalytic condition to regenerate the
active complex 1 which then enters into the second catalytic cycle
(Scheme 2). The released aldehyde reacts with an amine to yield
an unstable hemiaminal which releases a molecule of water to
form the final imine product. Although, few studies related to the
mechanistic aspects of the ruthenium catalyzed dehydrogenation
of alcohols are reported, most of them are based on computational
studies, except for few reports.9h,19 This is a rare case of isolation
and structural characterization of possible intermediates in
catalytic dehydrogenation of alcohols.
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In conclusion, an unprecedented dehydrogenative coupling of
alcohols and amines to form imines catalyzed by a complex of
earth-abundant manganese is reported. The catalytic reaction
proceeds under neutral conditions with liberation of molecular
hydrogen. A variety of alcohols and amines were employed to
furnish imines in good to excellent yields in an environmentally
friendly method.
A
mechanistic study involving NMR
spectroscopy, intermediate isolation and X-ray crystallography
sheds light on the catalytic mechanism.
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Supporting Information
Experimental details of the catalytic reactions, synthesis of the new
complexes and X-ray crystallographic details. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* david.milstein@weizmann.ac.il
Author Contributions
‡These authors contributed equally.
ACKNOWLEDGMENT
This research was supported by the Israel Science Foundation, the
MINERVA Foundation and the Kimmel Center for molecular design. D.
M. holds the Israel Matz Professorial Chair of Organic Chemistry. A.M.
thanks the Planning and Budgeting Committee (PBC) of the Council for
Higher Education in Israel for a fellowship.
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