Solvent- and transition metal-free amide synthesis from phenyl esters and aryl amines

Article abstract of DOI:10.1039/C8RA10040C

A general, economical, and environmentally friendly method of amide synthesis from phenyl esters and aryl amines was developed. This new method has significant advantages compared to previously reported palladium-catalyzed approaches. The reaction is performed transition metal- and solvent-free, using a cheap and environmentally benign base, NaH. This approach enabled us to obtain target amides in high yields with high atom economy.

Full text of DOI:10.1039/C8RA10040C

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Solvent- and transition metal-free amide synthesis
from phenyl esters and aryl amines†
Cite this: RSC Adv., 2019, 9, 1536
ab
a
ab
Sergey A. Rzhevskiy,
Pavel S. Gribanov,
Alexandra A. Ageshina,
Gleb A. Chesnokov,
ac
ab
ab
*
Maxim A. Topchiy,
and Andrey F. Asachenko
Mikhail S. Nechaev
ab
*
A general, economical, and environmentally friendly method of amide synthesis from phenyl esters and aryl
amines was developed. This new method has significant advantages compared to previously reported
palladium-catalyzed approaches. The reaction is performed transition metal- and solvent-free, using
a cheap and environmentally benign base, NaH. This approach enabled us to obtain target amides in
high yields with high atom economy.
Received 6th December 2018
Accepted 19th December 2018
DOI: 10.1039/c8ra10040c
rsc.li/rsc-advances
from aryl halides and amines used abundantly in industrial ne
organic synthesis.27–31
Introduction
In the past two years, efforts of groups lead by Stephen G.
Newman (Scheme 1A),32 Michal Szostak (Scheme 1B),33 and
Nilay Hazari (Scheme 1C)34 resulted in a successful transfer of
aryl halide cross-coupling techniques onto esters.35–37 Che-
moselective cleavage of the C(acyl)–O bond provided easy
access to various arylamides hardly available by traditional
methods.19,38–40 These new cross-coupling methods utilize
easily available unactivated esters, non-nucleophilic amines,
and air-stable catalytic systems. Despite the fact that the
above-mentioned methods are rather efficient, they are not
free from drawbacks, requiring toxic solvents, transition
Amides are one of the widest classes of compounds found in
natural products, as well as in pharmaceuticals. Their synthesis
has been, and continues to be, the focus of signicant attention
in synthetic chemistry.1–3 Many of the well-established methods
for amide synthesis involve reagents that are difficult to handle
and lead to generation of large quantities of waste products.
Recent publications demonstrated the increasing interest of the
pharmaceutical industry (e.g. ACS Green Chemistry Institute
Pharmaceutical Roundtable) in amide bond formation. Thus,
amide bond formation is among the most important synthetic
transformations requiring improved methods.4
Most popular approaches of amide synthesis utilize prelimi-
nary preparation of expensive activated esters or use of stoi-
chiometric quantities of peptide-coupling reagents, followed by
treatment with amines.2,5,6 Several methods of one-pot direct
synthesis of amides from carboxylic acids as well as a number of
non-conventional approaches, such as oxidative amidation of
alcohols, are reported.3,4,7–9 Transamidation route to amides is
also well-known.4,10–15 A number of reviews were published on the
methods of amide synthesis.9,16–19
Amide synthesis from amines and cheap unactivated esters
using various catalysts is rather promising.20–26 Recent publica-
tions have documented rapid transformation of Buchwald–
Hartwig cross-coupling into an efficient tool to create C–N bonds
aA.V. Topchiev Institute of Petrochemical Synthesis, Russian Academy of Sciences,
Leninsky Prospect 29, Moscow, 119991, Russia. E-mail: aasachenko@ips.ac.ru
bM.V. Lomonosov Moscow State University, Leninskie Gory 1 (3), Moscow, 119991,
Russia. E-mail: m.s.nechaev@org.chem.msu.ru
cA.N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of
Sciences, Vavilov str. 28, Moscow, 119991, Russian Federation
† Electronic supplementary information (ESI) available: Detailed experimental
procedures, 1H and 13C NMR spectra. See DOI: 10.1039/c8ra10040c
Scheme 1 Cross-coupling reactions of amines and esters.
1536 | RSC Adv., 2019, 9, 1536–1540
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metal-based catalysts, and generating a lot of waste (low atom benzoate (Table 1). Initially, we compared performance of
economy). IPrPd(allyl)Cl, proposed by Stephen G. Newman, under solvent
One of the major challenges in organic chemistry is the (Table 1, example 1),32 and solvent-free conditions (Table 1,
development of methods that are of high performance, ecologi- example 2). Yield of product under solvent-free conditions was
cally benign, and economically feasible. Application of solvents found to decrease from 98 to 90%. Performing reaction in the
as reaction media negatively affects product cost through solvent absence of both solvent and catalyst resulted in product yield
price and cost of solvent processing or utilization. Besides, usage of 32% (Table 1, example 3). In the absence of the catalyst,
of solvents can cause harm for employees and environment. solvent, and base the reaction proceeded with only 3% yield
Therefore, development of cross-coupling reaction conditions (Table 1, example 3). Temperature increase up to 150 ꢀC in the
requiring no use of solvents is rather promising since it could absence of base and catalyst have led to a considerable
lower direct and indirect expenses by means of lower amount of increase of amide yield from 3 to 32% (Table 1, example 4).
waste, increase of reaction rate, lower catalyst load, and better Utilization of K2CO3 base under these conditions resulted in
synthesis scaling up.
a small increase of the product yield compared to base-free
For the last several years our group was active in the conditions, from 32 to 39% (Table 1, example 4). Since
development of “green” chemical approaches that might be further increase of temperature seemed unreasonable, we
relevant both for academia and industry. Our target is “to screened bases available at 150 ꢀC. Replacement of K2CO3 with
eliminate organic solvents from organic chemistry” by devel- Cs2CO3, decreased the yield down to 15% (Table 1, example 6).
opment of solvent-free synthetic approaches. This motivated Utilization of a strong base t-BuOK did not lead to increase of
us to report for the rst time a new general method of amides the reaction yield (Table 1, example 7). Reaction proceeded
synthesis from phenyl esters under green solvent- and transi- with higher yield (57%) in case of K3PO4 (Table 1, example 5).
tion metal-free conditions. The implementation of this Strong organic bases, such as DBN (1,5-diazabicyclo(4.3.0)
approach promises simplicity, high efficiency, atom economy non-5-ene)41 and DABCO (1,4-diazabicyclo[2.2.2]octane)
and ecological safety, while giving opportunities to avoid showed moderate yields, whereas DBU (1,8-diazabicyclo[5.4.0]
particular disadvantages of conventional methods (Scheme 1D undec-7-ene)17,18,23 was slightly more active (Table 1, examples
vs. Scheme 1A–C).
8–10). The highest yield (80%) was obtained when NaH was
used as a base (Table 1, example 11).
Next, we studied the temperature effect on the product yield
employing NaH as the most suitable base (Table 1, examples
11–14). It turned out that practically quantitative yield was
achieved at 130 ꢀC (Table 1, example 12). Thus, heating of nearly
equimolar mixture of phenyl benzoate, ortho-toluidine and
sodium hydride in absence of solvent and palladium catalyst
produced target amide 3a in almost quantitative yield.
With optimal conditions in hand, the scope and limitations
of the elaborated conditions was examined; we screened various
aryl amines in reaction with phenyl benzoate (Table 2). For
example, aniline yielded 82% of corresponding amide (Table 2,
3d). The described conditions were found to tolerate halogen-
substituted anilines. In case of meta- and para-substituted F-,
Cl-, and Br-substituted anilines, as well as 2-uoroaniline,
amides were obtained in good to quantitative yields (Table 2, 3j,
3k, 3l, 3v, 3w, 3u).
Anilines bearing one substituent at the ortho-position affor-
ded products 3a, 3g, 3p, 3u in high yields. Good yields were
obtained for anilines with both donor (Table 2, 3h, 3i, 3o, 3p)
and acceptor functional groups (Table 2, 3c, 3t). Utilization of
acceptor heterocyclic amines resulted in some decrease in
yields (Table 2, 3q, 3r, 3s). Notably, benzylamine also gave good
product yield (Table 2, 3n).
Results and discussion
We performed optimization of solvent-free amidation of
phenyl esters using model reaction of o-toluidine and phenyl
Table 1 Optimization of the reaction conditionsa
Entry
Catalyst
Base
T (ꢀC)
Yieldb, %
c,d
1
2
3
4
5
6
7
8
3 mol% IPrPd(allyl)Cl
3 mol% IPrPd(allyl)Cl
K2CO3
K2CO3
K2CO3
K2CO3
K3PO4
Cs2CO3
t-BuOK
DBU
DBN
DABCO
NaH
NaH
NaH
110
110
110
150
150
150
150
150
150
150
150
130
120
90
98
90
c
—
—
—
—
—
—
—
—
—
—
—
—
32(3)e
39(32)e
57
15
38
75
56
9
10
11
12
13
14
61
Diminished yields were observed in case of anilines bearing
bulky substituents in ortho-positions, e.g. anilines 2e and 2f
(38% for 3e, 62% for 3f).
Next stage of our studies was screening of aryl esters in
a model reaction with aniline (Table 3).
For example, esters of aliphatic acids demonstrated lower
reactivity compared to phenyl benzoate (Table 3, examples 3df,
3di vs. 3a of Table 2). The aniline reaction with heterocyclic
80
97a
95
NaH
80
a
Reaction conditions: phenyl benzoate 1a (0.7 mmol), o-toluidine 2a
(0.735 mmol, 1.05 equiv.), base (0.735 mmol, 1.05 equiv.), T ꢀC (oil-
bath temperature), 20 h, heat. Yield determined by 1H NMR of the
b
c
crude mixture with BHT as internal standard. 1.5 equiv. of base.
d
Conditions ref. 32. e Without base.
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acids esters proceeded with good yields (Table 3, examples 3dc,
3dh, 3dj).
Table 2 Scope of anilidesa,b
Interestingly, ve-membered heterocyclic esters exhibited
higher activity than six-membered counterparts (Table 3, 3dh,
3dj vs. 3dc). The phenyl esters of para-substituted benzoic acids
produced amides in high yields (3db, 3de, Table 3 vs. 3d, Table
2). Phenyl ester of sterically hindered 2,4,6-trimethylbenzoic
acid showed lower reactivity (Table 3, 3dd).
Thus, we successfully elaborated conditions for high-yield
solvent- and transition metal based catalyst-free amide
synthesis and tested them on a wide range of substrates.
It should be noted that our method showed product yields
comparable to those in palladium-catalyzed methods of amide
synthesis (Table 4). In some cases, proposed method showed
higher efficiency compared to palladium-catalyzed methods
(Table 4, examples 3b, 3o, 3z, 3dh, 3v, 3c).
Thus, compared with previously reported transition-metal-
catalyzed methods, the elaborated method possesses several
advantages, the most important of which is exploitation of
sodium hydride, one of the simplest and most readily available
inorganic bases, whereas catalytic methods require expensive
catalysts, bases and solvents. Absence of transition metals,
solvents, toxic reagents for carboxylic group activation (e.g.
carbodiimides) makes proposed protocol a viable alternative for
green amide synthesis. At the same time several disadvantages,
such as hydrogen evolution and high reaction temperature,
Table 3 Scope of phenyl estersa,b
a
Reaction conditions: aryl ester 1 (0.7 mmol), aniline 2d (0.735 mmol),
a
Reaction conditions: phenyl benzoate 1a (0.7 mmol), amine 2 (0.735
b
NaH (0.735 mmol), 130 ꢀC (oil-bath temperature), 20 h. Yield
b
mmol), NaH (0.735 mmol), 130 ꢀC (oil-bath temperature), 20 h. Yield
determined by 1H NMR of the crude mixture with BHT as internal
standard.
determined by 1H NMR of the crude mixture with BHT as internal
standard.
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Table 4 Comparison of different methods
Entry
Product
Method Aa, %
Method Bb, %
Method Cc, %
This workd, %
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3h
3o
3p
3q
3v
98
—
55
91
—
—
61
93
85
—
—
—
68
—
75
—
—
96
90
84
—
—
—
—
—
—
75
78
96
92
—
90
—
95
—
—
—
95
87
82
—
—
97
95
85
82
38
85
72
80
72
99
72
96
90
70
9
10
11
12
13
14
3y
3z
3dh
3df
a
Reaction conditions: 1 (0.2 mmol), 2 (0.24 mmol), IPrPd(allyl)Cl (0.006 mmol), K2CO3 (0.3 mmol), H2O (2 mmol), toluene (1 mL) at 110 ꢀC for 16 h
under Ar. b Reaction conditions: 1 (1.0 equiv.), 2 (2.0 equiv.), K2CO3 (3.0 equiv.), PEPPSI-IPr (3 mol%), 1,2-DME (0.25 M), 110 ꢀC, 16 h. c Reaction
conditions: 1 (0.50 mmol), 2 (0.60 mmol), Cs2CO3 (0.75 mmol), SIPrPd(h3-1-t-Bu-indenyl)Cl (0.005 mmol), H2O (2 mL), THF (0.5 mL), 40 ꢀC, 4 h.
d
Reaction conditions: 1 (0.7 mmol), 2 (0.735 mmol), NaH (0.735 mmol), 130 ꢀC (oil-bath temperature), 20 h.
should be noted. Therefore, our method is a preparatively
useful extension of existing methodology of amide synthesis.
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There are no conicts to declare.
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