Direct Synthesis of Amides by Acceptorless Dehydrogenative Coupling of Benzyl Alcohols and Ammonia Catalyzed by a Manganese Pincer Complex: Unexpected Crucial Role of Base

Article abstract of DOI:10.1021/jacs.9b05261

Amide synthesis is one of the most important transformations in chemistry and biology. The direct use of ammonia for the incorporation of nitrogen functionalities in organic molecules is an attractive and environmentally benign method. We present here a new synthesis of amides by acceptorless dehydrogenative coupling of benzyl alcohols and ammonia. The reaction is catalyzed by a pincer complex of earth-abundant manganese in the presence of a stoichiometric base, making the overall process economical, efficient, and sustainable. Interesting mechanistic insights based on detailed experimental observations, indicating the crucial role of the base, are provided.

Full text of DOI:10.1021/jacs.9b05261

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Communication
Direct Synthesis of Amides by Acceptorless Dehydrogenative
Coupling of Benzyl Alcohols and Ammonia Catalyzed by a
Manganese Pincer Complex: Unexpected Crucial Role of Base
Prosenjit Daw, Amit Kumar, Noel Angel Espinosa-Jalapa, Yehoshoa Ben-David, and David Milstein
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b05261 • Publication Date (Web): 15 Jul 2019
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Direct Synthesis of Amides by Acceptorless Dehydrogenative
Coupling of Benzyl Alcohols and Ammonia Catalyzed by a
Manganese Pincer Complex: Unexpected Crucial Role of Base
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Prosenjit Daw, Amit Kumar, Noel Angel Espinosa-Jalapa§, Yehoshoa Ben-David, and David Milstein*
Department of Organic Chemistry, Weizmann Institute of Science, Rehovot, 76100, Israel
Supporting Information Placeholder
alcohols and ammonia as the only nitrogen source, avoiding the use of
preformed amines. Such a process would be more step economic,
efficient, and effective compared to other amide synthesis pathways. It
should be noted that acceptorless dehydrogenative coupling reactions
of alcohols are generally driven by efficient H2 removal, making such
reactions using ammonia in a closed system quite challenging.6 To the
best of our knowledge, formation of amides by coupling of alcohols and
ammonia with the extrusion of H2 and water, using any catalyst, has not
been reported. Herein, we present the synthesis of secondary amides
by manganese catalyzed coupling of benzyl alcohols and gaseous am-
monia.
ABSTRACT:
Amide synthesis is one of the most important transfor-
mations in chemistry and biology. The direct use of ammonia for the
incorporation of nitrogen functionalities in organic molecules is an
attractive and environmentally benign method. We present here a new
synthesis of amides by acceptorless dehydrogenative coupling of benzyl
alcohols and ammonia. The reaction is catalyzed by a pincer complex
of earth-abundant manganese in the presence of stoichiometric base,
making the overall process economical, efficient and sustainable. Inter-
esting mechanistic insights based on detailed experimental observa-
tions, indicating the crucial role of the base, are provided.
Scheme 1. Transition Metal Catalyzed Dehydrogenative Cou-
pling of Alcohols and Amines or Ammonia
The synthesis of amides is among the most significant transfor-
mations in organic synthesis, as they are widely used as precursors for
the synthesis of polymers, biologically-active compounds, and pharma-
ceuticals.1 Conventional methods for the preparation of amides include
coupling of amines with carboxylic acid derivatives, nitrile hydrolysis,
and rearrangement of ketoximes, generating copious waste in most of
the cases. In 2007 our group reported the synthesis of amides by dehy-
drogenative coupling of alcohols and amines, generating hydrogen gas
as the only byproduct, catalyzed by a PNN-Ru-pincer complex.2 This
dehydrogenative coupling method opened up a new era for the atom
economic and environmental benign synthesis of amides, and was
followed by several groups employing various catalysts for this reac-
tion.3
The direct incorporation of a nitrogen atom in organic molecules by
use of ammonia is an attractive and step-efficient process. The selective
synthesis of primary amines by coupling of primary alcohols and am-
monia homogeneously catalyzed by an acridine-based PNP-Ru pincer
complex was reported by our group in 2008.4 Subsequently several
other groups reported on the selective formation of primary, secondary
and tertiary amine by use of alcohols and ammonia catalyzed by noble
metal complexes.5 We recently published the direct synthesis of N-
heteroaromatics from diols and ammonia (Scheme 1).6
Due to the high abundance and lower cost, development of base-
metal catalysts is desirable. Manganese is earth’s third most abundant
transition metal, and considerable progress has been made by several
groups7 including our’s8 in employing manganese complexes in various
(de)hydrogenation reactions. Direct synthesis of amides by dehydro-
genative coupling of primary amines with alcohols or esters catalyzed
by a manganese complex was recently reported by our group.8d We also
reported the dehydrogenative coupling of diols and amines to form
cyclic imides using a manganese complex.8g
Reaction of benzyl alcohol (0.5 mmol) with ammonia (7 bar) in the
presence of complex 28k (2 mol%) and KH (3 mol%) at 150°C in to-
luene resulted after 24
benzylidenebenzylamine (A, Table 1) in 25% yield and N-
benzylbenzamide (B) in 13% yield (Table 1, entry 1). Complex (see
SI) as catalyst afforded N-benzylidenebenzylamine in 26% yield as the
only product under similar conditions (Table 1, entry 2). Increasing
the base loading to 25 mol%, using under the same reaction conditi-
1
h
in the formation of N-
1
Intrigued by these recent developments in the synthesis of amides,
we explored the possibility of acceptorless dehydrogenative coupling of
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Page 2 of 6
ons resulted 32% yield of (A) and 12% of N-benzylbenzamide (B),
whereas using an equivalent amount of KH (with respect to the al-
cohol) resulted in the formation of 48% of N-benzylidenebenzylamine
and 38% of N-benzylbenzamide, the overall conversion being 90%
(Table 1, entries 3 and 4 respectively). Quite remarkably, using com-
diate, required for its dehydrogenation, as opposed to the non-
t
1
2
3
4
5
6
7
8
coordinating nonpolar toluene. Using an equivalent amount of BuOK
resulted in a similar yield and selectivity of the amide (entry 9) whereas
using KHMDS as base, lower conversion (65%) and also selectivity
(35%) to the amide was observed and some unidentified products were
formed (entry 10). Under similar conditions, using stoichiometric KH
and no catalyst, no conversion of benzyl alcohol was observed (entry
11). Analysis of the gas phase by gas chromatography indicated the
formation of H2 (see Figure S1).
plex
2
and a stoichiometric amount of KH (relative to the alcohol)
under 7 bar ammonia at 150°C for 24 h resulted in 92% conversion
with 100% selectivity to N-benzylbenzamide (Table 1, entry 5). Thus,
the amount of base used in the catalysis has a crucial effect on the selec-
tivity towards amide formation.
Using the optimized reaction conditions, in the presence of a stoi-
chiometric amount of KH with respect to the alcohol (toluene, 150°C,
2
2 mol% ), the scope of this new dehydrogenative coupling reaction
9
Table 1. Optimization of the reaction conditions for the ami-
dation of benzyl alcohol with ammoniaa
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was explored. Electron-rich benzyl alcohols showed very good reactivi-
ty, forming the corresponding N-substituted amides as the major
products (Table 1). Benzyl alcohol and its derivatives 4-methyl, 3-
methyl, 4-ethyl, 4-isopropyl, 4-tert-butyl benzyl alcohols afforded good
yields of the corresponding amides with high selectivity (Table 1, entry
A-F). 2-menthyl benzyl alcohol also showed good conversion with 47%
of the amide product and 45% of the 2,4,5-trisubstituted imidazole as
the side product (Entry G, and also see later for details). The sterically
hindered 2,4,6-trimethylbenzyl alcohol was completely inactive under
the optimized reaction conditions and unreacted alcohol was recovered
(See SI, Table S2). 4-Methoxy benzyl alcohol and 3-(N,N-dimethyl
amine)benzyl alcohol also afforded the corresponding amides in good
yields and high selectivity (Table 1, entries H, I). Employing benzyl
alcohols bearing electron withdrawing substituents such as 4-
trifluoromethyl benzyl alcohol resulted in poor yield of the secondary
amide and moderate yield of the primary amide, in addition to the
unreacted alcohol (see SI, Table S2). In case of 1-hexanol, N-
hexylhexan-1-imine was obtained as the major product along with
other unidentified condensation products (due to the enolizeable ali-
phatic aldehyde intermediate) and no amide product was detected.
The electron rich aliphatic alcohol lacking enolizeable protons, neo-
pentyl alcohol, formed 2,4,5-tri(tert-butyl)-imidazole as the major
product (see SI Table S2). Formation of imidazole derivatives was
reported in case of the ruthenium catalyzed reductive amination of
carbonyl compounds with ammonia in under hydrogen.9
Entry
Catalyst
Base(Y mol%)
Yieldb
A(%)
Conv.
(%)
(2 mol%)
B(%)
13
0
1
2
2
1
1
1
2
2
2
2
2
2
-
KH (3)
KH (3)
40
28
48
90
92
90
99
99
90
65 f
5
25
26
32
48
0
3
KH (25)
12
38
90
88
90
28
89
35
0
4
KH (100)
KH (100)
KH (100)
KH (100)
KH (100)
tBuOK (100)
KHMDS (100)
KH (100)
KH (100)
5
6c
7d
8e
9
0
0
70
0
10
11g
12h
05
0
3
99
04
92
Substrate Scope:i
To gain mechanistic insight into this unprecedented amidation reac-
tion, some control experiments were performed. Reaction of an
equimolar amount of benzyl alcohol with either benzyl amine or 1-
hexylamine in the presence of catalyst
2
(2 mol%) and a catalytic
amount of KH (3 mol%) at 150°C for 24 h in a closed system resulted
in quantitative formation of the corresponding imine as the only prod-
uct and no corresponding amide was observed (Scheme 2a). However,
when the same reaction was performed using benzyl alcohol and benzyl
amine, but in presence of a stoichiometric amount of KH, N-
benzylbenzamide was observed as the major product (Scheme 2b).
Although dehydrogenative coupling of alcohols and amines to form
amides using a manganese catalyst was reported by us, the substrate
scope for this reaction was limited to aliphatic alcohols and benzyl
amines.8d Thus, this is the first example of amide formation by dehy-
drogenative coupling of benzyl alcohols and benzyl amines catalyzed
by an earth-abundant metal complex.
aReaction conditions: Catalyst (2 mol%), benzyl alcohol (0.5 mmol),
KH (specified amounts), NH3 (7 bar), 150°C, 24h, toluene, the reac-
b
tion quenched with methanol. GC yield with mesitylene as internal
standard. In presence of 300 eq. of Hg. dSolvent 1,4-dioxane. Sol-
c
e
f
g
vent THF. Other unidentified products formed. Without any cata-
lyst, a small amount benzaldehyde was formed. hCatalyst
(2 mol%).
iOptimized reaction conditions: catalyst
(2 mol%), primary alcohol
(0.5mmol), KH (0.5 mmol), NH3 (7 bar), 150°C, 24h, toluene (2
ml).
3
2
One possible mechanism for amide formation could involve addi-
tion of water to an intermediate imine10. To explore this possibility, we
performed a reaction of N-benzylidenebenzylamine (0.05 mmol) with
Significantly, addition of 300 equivalents of Hg to the reaction solu-
tion showed no decrease in the product formation or selectivity (Table
1, entry 6), suggestive of a homogeneous catalytic pathway. Changing
catalyst (2 mol%) in the presence of KH (catalytic or stoichiometric
2
amount with respect to substrate) in a 1,4-dioxane-water mixture (1:1)
at 150°C for 24h. However, no amide product was observed and the
unreacted imine was isolated with some aldehyde and amine as hydrol-
ysis products at the end of reaction. Based on this, we exclude the pos-
sibility of formation of amide by the addition of water to an imine in-
termediate (Scheme 2c).
the solvent to 1,4-dioxane using catalyst under the optimized condi-
2
tions resulted in a similar yield of the amide product (entry 7) whereas
low yield of the amide was observed when THF was used (28 %) (en-
try 8). A possible reason for the observed different selectivity of the
product with 1,4-dioxane and THF as solvents is their coordination
ability, which competes with coordination of the hemiaminal interme-
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Journal of the American Chemical Society
with the alcohol generates the corresponding alkoxide salt (I), which
Scheme 2. Using catalyst 2, effect of amount of base on amide
formation from benzyl alcohol and benzyl amine (a, b), and lack
of reaction of imine upon heating in dioxane/water (c).
1
2
3
4
5
6
7
8
could be in some equilibrium with the large excess of ammonia at the
high reaction temperature to regenerate some alcohol and form potas-
sium amide. Reaction of the alcohol with the Mn complex forms the
corresponding aldehyde, through β-hydride elimination.8k This is fol-
lowed by the attack of ammonia (or formed potassium amide), on the
aldehyde to form a hemiaminal that undergoes deprotonation by the
base to form an 1-aminoalkoxide (II). We believe that the 1-
aminoalkoxide is an important intermediate for the second dehydro-
genation, likely via the amido intermediate (III), leading to the selec-
tive formation of the amide by retarding the water elimination and
disfavoring the imine formation. The second dehydrogenation step
leads to the corresponding primary amide salt (IV or V, Scheme 4). N-
alkylation of the formed amide with the primary alcohol via dehydro-
genative coupling and borrowing hydrogenation affords the final amide
salt product (VI).
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Another possibility is that benzyl alcohol reacts with ammonia to
form benzyl amine,4 followed by reaction of the latter with benzyl alco-
hol to form an amide via dehydrogenation of a hemiaminal intermedi-
ate. To explore this possibility, a control experiment was carried out
(Scheme 3). Reaction of equimolar amounts of 4-methylbenzyl alcohol
and benzyl amine with a stoichiometric amount of KH (with respect to
the alcohol) under the optimized conditions afforded a minor amount
of 4-methyl-N-(4-methylbenzyl)benzamide as the only amide product,
along with a major amount of a mixture of imine products (Scheme 3,
A; see SI for details). This suggests that under these catalytic condi-
tions, benzyl alcohol and the amine do not couple to form an amide.
Furthermore, treatment of equivalent amounts of benzyl alcohol and 4-
methyl benzyl alcohol with ammonia (7 bar), in the presence of two
Scheme 4. Proposed mechanism for the formation of secondary
equivalents of KH (with respect to both alcohols) and complex under
2
similar conditions afforded a mixture of all four possible amides as the
major products (Scheme 3, B). This suggests that the reaction pro-
ceeds via the formation of a 1-aminoalkoxide intermediate followed by
its dehydrogenation to the primary amide, and finally its N-alkylation
by the alcohol (see details in the mechanistic description). To establish
the initial alkoxide formation, an independently prepared potassium
salt of benzyl alcohol was treated with ammonia under similar condi-
tions. Analysis of the reaction mixture at the end of the reaction
showed the formation of N-benzylbenzamide with a similar yield
(80%) (Scheme 3, C). Additionally, N-benzylbenzamide was formed
quantitatively by treatment of benzamide with benzyl alcohol in the
amides from benzyl alcohols and ammonia
In order to gain evidence about the ionic nature of the product and
intermediate, the precipitate from the reaction mixture of benzyl alco-
2
hol with an equivalent of KH and catalyst with ammonia (7 bar) was
presence of catalyst
2
(2 mol%) using a catalytic amount of KH (3
isolated. HRMS showed a mass peak at 210 (M/Z) corresponding to
the amido anion (VI) in the negative scanning mode whereas a mass
peak at 250 (M/Z) corresponding to the K salt of N-benzylbenzamide
was detected in the positive scanning mode (See SI). Recently we re-
mol%) (Scheme 3, D), supporting that the reaction proceeds via the N-
alkylation of the amide. To our knowledge, this is the first report of
manganese catalyzed N-alkylation of an amide.11
ported that the bridged BH3 moiety of complex
by its reaction with gaseous ammonia or any primary amine.8k When
the ammonia bound complex was synthesized and used as catalyst of
2
is easily eliminated
Scheme 3. Control catalytic experiments
3
the reaction of benzyl alcohol with ammonia, 92% (Table 1, entry 12)
yield of N-benzylbenzamide was formed under the optimized reaction
conditions, which is comparable to the catalytic activity of complex
indicating that ammonia bound complex is likely an active organome-
tallic intermediate during the reaction (See SI).
2
,
3
In conclusion, for the first time, the synthesis of amides via dehydro-
genative coupling of an alcohol and ammonia is reported, ammonia
serving as the nitrogen source. The reaction is catalyzed by a complex
of the first row, earth-abundant transition metal manganese. An unusu-
al, plausible mechanism is proposed in which the role of stoichiometric
base is to form a 1-aminoalkoxide hemiaminal intermediate (II,
Scheme 4), which leads to selective amide formation by retarding water
elimination from the hemiaminal intermediate. Further investigation
regarding the mechanism of this reaction is underway. We believe that
this reaction provides an attractive new pathway to the synthesis of
secondary amides from benzyl alcohols and ammonia using a base-
metal catalyst.
ASSOCIATED CONTENT
Based on the aforementioned observations, a plausible mechanism is
proposed in Scheme 4. Reaction of an equivalent amount of base (KH)
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ic Acceptorless Dehydrogenations: Ru-Macho Catalyzed Construction of Am-
ides and Imines. Tetrahedron 2014, 70, 4213–4218.
Experimental procedure, and control experiments were describe in the
SI “This material is available free of charge via the Internet at
http://pubs.acs.org.”
1
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(4) Gunanathan, C.; Milstein, D. Selective Synthesis of Primary Amines Direct-
ly from Alcohols and Ammonia. Angew. Chem., Int. Ed. 2008, 47, 8661.
(5) (a) Baumann, W.; Spannenberg, A.; Pfeffer, J.; Haas, T.; Kçckritz, A.; Mar-
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um-Catalyzed Amination of Alcohols. Chem. Eur. J. 2013, 19, 17702 – 17706.
(b) Bähn, S.; Imm, S.; Neubert, L.; Zhang, M.; Neumann, H.; Beller, M. Synthe-
sis of Primary Amines from Secondary and Tertiary Amines: Rutheni-
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4708. (c) Nakagawa, N.; Derrah, E. J.; Schelwies, M.; Rominger, F.; Trapp, O.;
Schaub, T. Triphos Derivatives and Diphosphines as Ligands in the Ruthenium
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AUTHOR INFORMATION
Corresponding Author
*E-mail: david.milstein@weizmann.ac.il.
Present Address: §Noel Angel Espinosa-Jalapa, Institut für
Anoganische Chemie, Universität Regensburg, D-93053, Regensurg,
Germany.
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(d) Wöckel, S.; Plessow, P.; Schelwies, M.; Brinks, M. K.; Rominger, F.; Hof-
mann, P.; Limbach, M. Alcohol Amination with Aminoacidato Cp*Ir(III)-
Complexes as Catalysts: Dissociation of the Chelating Ligand During Initiation.
ACS Catal. 2014, 4, 152−161. (e) Gallardo-Donaire, J.; Ernst, M.; Trapp, O.;
Schauba, T. Direct Synthesis of Primary Amines via Ruthenium-Catalysed
Notes
The authors declare no competing financial interest.
Amination of Ketones with Ammonia and Hydrogen. Adv. Synth. Catal. 2016
,
ACKNOWLEDGMENT
358, 358 – 363. (f) Imm, S.; Bähn, S.; Neubert, L.; Neumann, H.; Beller, M. An
Efficient and General Synthesis of Primary Amines by Ruthenium-Catalyzed
This research was supported by the European Research Council (ERC
AdG 692775). D.M. holds the Israel Matz Professorial Chair of Organ-
ic Chemistry. P.D. and A.K. thank the Planning and Budgeting Com-
mittee (PBC) for a postdoctoral fellowship. PD also thanks Weizmann
Institute of Science for senior postdoctoral fellowship. N. A. E.-J.
thanks Mr. Armando Jinich for a postdoctoral fellowship.
Amination of Secondary Alcohols with Ammonia. Angew. Chem. Int. Ed. 2010
,
49, 8126 –8129. (g) Imm, S.; Bähn, S.; Zhang, M.; Neubert, L.; Neumann, H.;
Klasovsky, F.; Pfeffer, J.; Haas, T.; Beller, M. Improved Ruthenium-Catalyzed
Amination of Alcohols with Ammonia: Synthesis of Diamines and Amino Es-
ters. Angew. Chem. Int. Ed. 2011, 50, 7599 –7603. (h) Kawahara, R.; Fujita, K.;
Yamaguchi, R. Multialkylation of Aqueous Ammonia with Alcohols Catalyzed
by Water-Soluble Cp*Ir−Ammine Complexes. J. Am. Chem. Soc. 2010, 132,
15108–15111. (i) Ye, X.; Plessow, P. N.; Brinks, M. K.; Schelwies, M.; Schaub,
T.; Rominger, F.; Paciello, R.; Limbach, M.; Hofmann, P. Alcohol Amination
with Ammonia Catalyzed by an Acridine-Based Ruthenium Pincer Complex: A
Mechanistic Study. J. Am. Chem. Soc. 2014, 136, 5923−5929. (j) Pingen, D.;
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