Manganese-Catalyzed Direct Conversion of Ester to Amide with Liberation of H2

Article abstract of DOI:10.1021/acs.orglett.8b01305

A simple and efficient Mn-catalyzed acylation of amines is achieved using both acyl and alkoxy functions of unactivated esters with the liberation of molecular hydrogen as a sole byproduct. The present protocol provides an atom-economical and sustainable route for the synthesis of amides from esters by employing an earth-abundant manganese salt and inexpensive phosphine-free tridentate ligand.

Full text of DOI:10.1021/acs.orglett.8b01305

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Manganese-Catalyzed Direct Conversion of Ester to Amide with
Liberation of H2
Akash Mondal, Murugan Subaramanian, Avanashiappan Nandakumar, and Ekambaram Balaraman*
Organic Chemistry Division, CSIR-National Chemical Laboratory (CSIR-NCL), Dr. Homi Bhabha Road, Pune-411008, India
S
* Supporting Information
ABSTRACT: A simple and efficient Mn-catalyzed acylation of
amines is achieved using both acyl and alkoxy functions of
unactivated esters with the liberation of molecular hydrogen as
a sole byproduct. The present protocol provides an atom-
economical and sustainable route for the synthesis of amides
from esters by employing an earth-abundant manganese salt
and inexpensive phosphine-free tridentate ligand.
mides are common in nature and have found widespread
for the synthesis of amides since both the acyl part and the
alkoxy part of the ester are incorporated into the product
amide.7 Though unprecedented progress has been achieved on
catalytic aminolysis of esters using the ADC strategy with
expensive, less abundant, toxic noble metals, the use of a
catalytic system derived from and earth-abundant, economical,
and biorelevant system is highly desirable in contemporary
science.8,9 In this regard, we report a facile protocol for the
direct conversion of esters to amides with the liberation of
molecular hydrogen using a base metal (manganese) as a
catalyst featuring an inexpensive phosphine-free tridentate
ligand.10 The present protocol was successfully applied for
various unactivated esters and amines (Scheme 1).
1
Aapplications in the pharmaceutical industry.
Amide
linkages (or peptide bonds) are omnipresent in biomolecules,
fine chemicals, and drug candidates. For instance, approx-
imately 25% of drug molecules contain an amide moiety in
their structural composition.2 The classical approach to prepare
amides involves coupling of carboxylic acids with amines at
elevated temperature or aminolysis of activated carboxylic acid
derivatives such as halides, anhydrides, and azides.3 However,
such protocols are limited by a narrow substrate scope, poor
atom economy, need of reactive substrates, and cumulative
waste generation. In this regard, catalytic aminolysis of esters is
one of the elegant methods for the construction of amides, as
this protocol involves the direct conversion of ubiquitous esters
into biologically significant amides.4 Indeed, aminolysis of
esters results in alcohols as undesired byproducts, limiting the
scope of the process. An efficient and newer strategy for amide
synthesis that avoids byproduct formation and utilizes earth-
abundant resources is highly demanding and challenging in
chemical production.
Scheme 1. Strategies for Amide Bond Formation
In 2007, the pioneering work on highly atom-economical and
direct synthesis of amides from alcohols and amines was
reported by the research group of Milstein.5 This reaction is
catalyzed by a dearomatized PNN−Ru pincer complex and
operates via the acceptorless dehydrogenative coupling (ADC)
pathway with the liberation of molecular hydrogen as the sole
byproduct. Subsequently, several interesting reports on ADC
for the preparation of amides were developed using expensive
and less-abundant noble-metal-based catalytic systems.6 In
continuation of earlier work, Milstein and co-workers reported
the direct synthesis of amides by dehydrogenative coupling of
esters and amines with the liberation of hydrogen gas using the
same PNN−Ru(II) catalytic system.7a However, the ester
substrates had to be purified prior to the reaction in order to
eliminate carboxylic acid impurities that were responsible for
catalyst deactivation even in the presence of the amine partner.
In contrast to conventional approaches, the dehydrogenative
coupling of esters with amines provides a sustainable protocol
Received: April 25, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01305
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Inspired by Mn-catalyzed acceptorless dehydrogenation of
alcohols,9 we started by using simple, commercially available
MnBr(CO)5 as the catalyst along with the tridentate ligand
3,3′-iminobis(N,N-dimethylpropylamine) (Ln) for the dehy-
drogenative coupling of esters with amines. The unactivated
ester ethyl acetate (1a) and 4-methoxybenzylamine (1b) as the
amine coupling partner were selected as benchmark substrates
for the optimization process. Thus, the initial reaction was
carried out in the presence of MnBr(CO)5 (5 mol %), Ln (10
mol %), and t-BuOK (1 mmol) in toluene at 90 °C. After 16 h,
quantitative conversion of 1b was observed, and amide 1c was
obtained in 87% isolated yield (Table 1, entry 1). Gratifyingly,
absence of the Mn catalyst and the ligand (Ln) significantly
affected the aminolysis process, which gave a trace amount of
1c under standard conditions (Table 1, entries 7 and 8).
Notably, the quantity (mol %) and nature of the base have a
significant effect on the present Mn-catalyzed direct amidation
of esters, and also, the potassium salt of ligand Ln showed an
unsatisfactory yield of amide 1c (Table 1, entries 9−12). These
results revealed that the presence of the catalyst, ligand, and
base are necessary for the effective formation of the desired
amide via ADC. Among various ligand systems employed for
the amidation reaction (Table 1, entries 13−21, and Figure 1),
the phosphine-free tridentate ligand Ln was found to be
optimal.
Table 1. Optimization of the Conditions for Ester
a
Amidation
temp
time
(h)
conv of amine
yield
b
b
entry
(°C)
ligand
solvent
toluene
(%)
(%)
c
1
2
90
90
90
90
130
90
90
110
90
90
90
90
90
90
90
90
90
90
90
90
90
16
16
16
16
22
16
22
16
16
16
16
16
22
22
22
22
22
22
22
22
22
Ln
Ln
Ln
Ln
Ln
Ln
Ln
−
Ln
Ln
Ln
Ln
L1
L2
L3
L4
L5
L6
L7
L8
L9
99
87
c
decane
41
32
c
3
1,4-dioxane
CH3CN
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
53
34
Figure 1. Ligands used for the optimization.
c
4
50
39
c
5
71
47
d
6
NQ
NQ
NQ
NQ
NQ
NQ
NQ
33
trace
With the optimized reaction conditions in hand, the scope
with respect to alkyl and aryl esters and amines were
investigated. As shown in Table 2, a diverse range of
unactivated alkyl esters such as ethyl acetate, pentyl pentanoate,
and hexyl hexanoate as well as activated esters (e.g., benzyl
benzoate) were smoothly converted into the corresponding
amides in excellent yields (up to 87%) using the optimized
conditions. The present catalytic system was compatible with a
range of 1° and 2° aliphatic amines and afforded the
corresponding amides in varying yields of 35−81% (Table 2).
Several benzylamines underwent the catalytic aminolysis with
esters to afford the corresponding amides in good to excellent
yields (Table 2, products 1c in 87%, 2c in 82%, 9c in 60%, 22c
in 61%, and 23c in 73% isolated yield). In particular, biomass-
derived heretocyclic furfurylamine was well-tolerated under our
catalytic conditions and gave the expected product 10c in 85%
yield.
e
7
18
8
26
fj
9
15 ,
gj
,
10
11
12
13
14
15
16
17
18
19
20
21
20
40
hj
,
ij
63 ,
14
18
17
9
49
26
21
c
73
41
57
33
40
NQ
21
44
c
55
39
a
Reaction conditions: ethyl acetate (1.5 mmol), 4-methoxybenzyl-
amine (2.6 mmol), t-BuOK (1 mmol), MnBr(CO)5 (5 mol %), ligand
Notably, cyclic secondary amines such as morpholine,
pyrrolidine, piperidine, and N-methylpiperazine showed good
reactivity with various esters and yielded the corresponding
amides 11c−19c in moderate yields (up to 57%). The reaction
of anilines containing both electron-donating and -withdrawing
substituents afforded the corresponding amides 21c (51%), 29c
(51%), 31c (43%), and 32c (35%). Regrettably, aniline
containing an electron-withdrawing group (−CN at the para
position or −NO2 at the meta position) failed to give the
corresponding amides under the optimized reaction conditions.
However, the reaction of 2-(aminomethyl)aniline with ethyl
acetate under the standard conditions led to the bisacylated
product N-(2-acetamidobenzyl)acetamide (26c) in 36% yield
with the liberation of hydrogen gas. Interestingly, the scope of
this protocol was explored with 1,4- and 1,2-amino alcohols
(e.g., 4-aminobutan-1-ol and (S)-2-amino-3-phenylpropan-1-
ol) under mild catalytic conditions. Interestingly, 4-amino-
butan-1-ol underwent the acylation of both the amine and
alcohol functional groups to afford 27c under Mn-catalyzed
(10 mol %), and solvent (2 mL) in an open argon atmosphere.
Conversions of amine and (unless noted otherwise) yields of amide
b
1c were determined by GC using m-xylene as an internal standard. NQ
c
d
e
= not quantified. Isolated yield. In the absence of base. In the
f
g
absence of Mn catalyst. 10 mol % t-BuOK was used. The potassium
h
i
salt of Ln was used. KH (1 mmol) was used. t-BuONa (1 mmol) was
j
used. NMR yield.
the generation of molecular hydrogen was qualitatively analyzed
by gas chromatography. Indeed, the possibility of competing
imine formation (self-dehydrogenative coupling of benzyl-
amine) was not observed. The screening of other solvents such
as decane, 1,4-dioxane, and acetonitrile under the same reaction
conditions provided poor yields of 1c (Table 1, entries 2−4).
When the reaction temperature was increased to 130 °C, a
lower yield of 1c (47%) was obtained (Table 1, entry 5). The
control experiment illustrated that there was no formation of 1c
in the absence of the base (Table 1, entry 6). Similarly, the
B
DOI: 10.1021/acs.orglett.8b01305
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 2. Substrate Scope for Ester Aminolysis
Scheme 2. Control Experiments
catalysis led to the amide 1-morpholinoethan-1-one in 38%
isolated yield and ethyl acetate (8%). Next, the intermolecular
competitive reaction of an ester and alcohol with an amine
partner was performed under standard catalytic conditions. The
results revealed that the present catalytic system is more
suitable for aminolyis of the ester (62%) than the alcohol
(10%).
As shown in Scheme 3, the present Mn-catalyzed direct
conversion of esters to amides proceeds via Mn-catalyzed
Scheme 3. Proposed Mechanisms for Direct Conversion of
Esters to Amides
a
Reaction conditions: ester (1.5 mmol), amine (2.6 mmol), t-BuOK
(1 mmol), MnBr(CO)5 (5 mol %), Ln (10 mol %), and toluene (2
b
mL) heated at 90 °C under an argon atmosphere. Isolated yields.
activation of the ester for nucleophilic addition of the amine to
give the amide and alcohol, followed by dehydrogenative
coupling of the alkoxy part of the ester moiety with an amine,
thus resulting in dihydrogen as the greener waste. Indeed,
acceptorless self-dehydrogenative coupling of the alcohol to the
ester is also operative.
In summary, a facile protocol for the direct conversion of
esters to amides with the liberation of molecular hydrogen
using a base metal (manganese) as a catalyst and an inexpensive
phosphine-free tridentate ligand is reported. Interestingly, the
activated symmetric esters were selectively transformed into the
corresponding N-acylated amines as a result of incorporation of
both the acyl and alkoxy functions of ubiquitous esters into the
product amides. This reaction operates via catalytic ester
activation for the amine addition, followed by dehydrogenative
coupling of the alkoxy part of the ester with the amine.
c
The yield was calculated with respect to the amine.
reaction conditions. It is worth mentioning that the chiral
molecule (S)-2-amino-3-phenylpropan-1-ol was tolerated in the
present Mn-catalyzed acylation process, providing N- and O-
acylated product 28c with retention of configuration.
A series of experiments were carried out (Scheme 2) to gain
insight into the mechanisms of ester aminolysis. A mercury
poisoning study revealed that the active catalytic system in the
amidation of esters is homogeneous in nature. The benchmark
reaction of 1a and 1b in the presence of a radical scavenger
(TEMPO) showed the formation of amide 1c in 72% yield with
the liberation of molecular hydrogen, which completely
eliminates a radical mechanism. Upon treatment of n-hexanol
under the Mn-catalyzed reaction conditions (5 mol % [Mn], 10
mol % Ln, and 1 equiv of t-BuOK in toluene at 110 °C), the
formation of hexyl hexanoate (36%) with the liberation of
molecular hydrogen was observed. This result clearly indicates
that the present Mn catalytic system follows the dehydrogen-
ative coupling pathway. Heating equimolar amounts of the
alcohol and amine partners in the presence of manganese
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01305.
C
DOI: 10.1021/acs.orglett.8b01305
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
56, 1663−1666. (d) Kallmeier, F.; Dudziec, B.; Irrgang, T.; Kempe, R.
Angew. Chem., Int. Ed. 2017, 56, 7261−7265. (e) Chakraborty, S.;
Gellrich, U.; Diskin-Posner, Y.; Leitus, G.; Avram, L.; Milstein, D.
Angew. Chem., Int. Ed. 2017, 56, 4229−4233.
Experimental section, mechanistic investigation, charac-
terization data, 1H and 13C NMR spectra, HRMS spectra,
and GC analyses (PDF)
(10) During the preparation of our manuscript, a similar work was
reported by Milstein and co-workers using an electron-rich phosphine-
based ligand system. See: Kumar, A.; Espinosa-Jalapa, N. A.; Leitus, G.;
Diskin-Posner, Y.; Avram, L.; Milstein, D. Angew. Chem., Int. Ed. 2017,
56, 14992−14996.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: eb.raman@ncl.res.in; balaramane2002@yahoo.com.
ORCID
Ekambaram Balaraman: 0000-0001-9248-2809
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the SERB under the Green
Chemistry Programme (EMR/2015/30) and CSIR-IN-
PROTICS Pharma & Agro (HCP0011A). A.M. and M.S.
thank the UGC for research fellowships.
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DOI: 10.1021/acs.orglett.8b01305
Org. Lett. XXXX, XXX, XXX−XXX