Catalyst-free synthesis of amines from cyclic ketones and formamides in superheated water

Article abstract of DOI:10.1080/00397911.2016.1152374

A novel and environmentally benign protocol for the synthesis of amines from cyclic ketones and formamides is demonstrated. The reaction proceeds under catalyst-free and superheated water conditions and yields range from poor to excellent.

Full text of DOI:10.1080/00397911.2016.1152374

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Catalyst-Free Synthesis of Amines from Cyclic
Ketones and Formamides in Superheated Water
Macharla Arun Kumar, Kodumuri Srujana, Peraka Swamy, Mameda Naresh,
Chevella Durgaiah, Banothu Rammurthy & Nama Narender
To cite this article: Macharla Arun Kumar, Kodumuri Srujana, Peraka Swamy, Mameda
Naresh, Chevella Durgaiah, Banothu Rammurthy & Nama Narender (2016): Catalyst-Free
Synthesis of Amines from Cyclic Ketones and Formamides in Superheated Water, Synthetic
Communications, DOI: 10.1080/00397911.2016.1152374
To link to this article: http://dx.doi.org/10.1080/00397911.2016.1152374
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Date: 18 March 2016, At: 19:46

Catalyst-Free Synthesis of Amines from Cyclic Ketones and Formamides in
Superheated Water
1
1
1,2
1,2
Macharla Arun Kumar , Kodumuri Srujana , Peraka Swamy , Mameda Naresh ,
1
1,2
1,2
Chevella Durgaiah , Banothu Rammurthy , Nama Narender
1
I&PC Division, CSIR-Indian Institute of Chemical Technology, Hyderabad,
2
Telangana, India, Academy of Scientific and Innovative Research, CSIR-Indian
Institute of Chemical Technology, Hyderabad, Telangana, India
Corresponding Author: Nama Narender, Email: narendern33@yahoo.co.in;
nama@iict.res.in.
Abstract
A novel and environmentally benign protocol for the synthesis of amines from cyclic
ketones and formamides is demonstrated. The reaction proceeds under catalyst-free and
superheated water conditions and yields range from low to excellent.
Graphical Abstract:
KEYWORDS: Amine; catalyst-free; formamides; superheated water
1

INTRODUCTION
The research of alternative, environmentally more acceptable processes for the
[
1]
manufacture of chemicals is of fundamental importance. In recent years, the impact of
chemicals on the environment and human health become a concern. Consequently, there
is a considerable current research activities in the development of sustainable chemical
[
2]
processes and products by using the principles of green chemistry. However, the
application of green chemistry in industry is perhaps the main challenge for researchers,
who are often limited to academic developments.
Water exhibits special properties as compared to commonly employed organic solvents.
Reactions using this solvent have attracted great attention from a synthetic point of view
because water is environmentally friendly and safe, and the problems of pollution that
[
3]
arise with organic solvents can be avoided. This purpose renewed a long time interest
for water as a reaction medium for organic synthesis.
Over the past decade the use of superheated water has emerged as an efficient, clean and
[
4-6]
economic media for organic synthesis because of its unique properties.
Depending on
the conditions of temperature and pressure, SHW supports either free radical or polar and
ionic reactions. This means that SHW is an adjustable solvent, reactant and catalyst for
[7,8]
[9]
various organic transformation such as hydrolysis,
condensations,
[
10]
[11]
[12,13]
[14]
rearrangements, alkylations, reductions
and Heck coupling reactions.
[15]
[16]
[17]
Materials such as zeolites, metal organic frameworks and mesoporous oxides are
often synthesized under SHW conditions.
2

The C-N bond formation reaction is an important transformation in modern synthetic
[
18]
chemistry. Amines are ubiquitous functionalities in current drugs, pharmaceutical
[
19]
intermediates and agrochemicals. The reductive amination of carbonyl compounds
with ammonia is one of the most efficient and direct route for the preparation of
[
20]
amines. Catalytic hydrogenation and metal hydride reduction are the two most
commonly used direct reductive amination methods. The first method is catalytic
[
21]
hydrogenation with platinum, palladium, or nickel catalysts. Catalytic hydrogenation
has limited use with compounds containing carbon-carbon multiple bonds and in the
presence of reducible functional groups such as nitro, cyano and furfuryl groups. The
catalysts are expensive and may be inhibited by compounds containing divalent sulfur.
The second method utilizes hydride reducing agents, particularly sodium
[
22]
cyanoborohydride (NaBH CN) for reduction. NaBH CN is highly toxic and produces
3
3
toxic by-products, such as HCN and NaCN upon workup.
Owing to the limitations of the above-mentioned approaches and the widespread interest
in amine compounds, still there is a need for the development of a simple, efficient and
green protocol for the synthesis of amines. From the green chemistry point of view, a
non-catalytic process is very significant and alternative for synthetic organic chemistry.
Herein, we describe a novel and environmentally benign approach for the synthesis of
higher amines by reductive amination of ketones using in situ generated amines by
thermal decomposition of formamides in superheated water without any catalyst (Scheme
1
).
3

RESULTS AND DISCUSSION
Initially, we investigated the suitable reaction conditions for the reductive amination of
cyclohexanone (1a) with formamide (2a) to the corresponding dicyclohexylamine (3a).
As shown in Table 1, a variety of parameters such as effect of amount of water (solvent),
molar ratio of reactants, reaction temperature and time were investigated to achieve
optimal conditions. The results revealed that a 1:1.5 mole ratio of cyclohexanone and
o
formamide in 300 mL of water at 225 C in 3 h was found to be optimum to achieve
highest yield of dicyclohexylamine (3a) (Table 1, entry 7).
After optimizing the reaction conditions, we explored the scope of this superheated water
system with a variety of N-substituted formamides and ketones and the results are
summarized in Table 2. The N-substituted formamides including N,N-
dimethylformamide, N-methyl-N- phenylformamide, N-formylpiperidine and 4-
formylmorpholine reacted with cyclohexanone smoothly to give the corresponding
tertiary amines 3b, 3c, 3d and 3e in 45%, 49%, 71% and 81% yields, respectively (Table
2
, entries 1-5). The reductive amination was widely used for the synthesis of secondary
amines in which various types of homogeneous and heterogeneous catalysts have been
employed. However, only few reports are available for the synthesis of tertiary amines
[23]
through reductive amination.
Next, we investigated the efficiency of this method by reacting a variety of ketones with
formamide under similar reaction conditions (Table 2, entries 6-10). Cyclic ketones such
as cyclopentanone and cycloheptanone provided the corresponding secondary amines 3f
4

and 3g in 59% and 34% yields, respectively (Table 2, entries 6-7). In the case of aromatic
ketones, acetophenone furnished the corresponding olefin in 38% yield, along with
alcohol (24% yield) (Table 2, entry 8), while tetralone afforded the respective olefin in
3
0% yield (Table 2, entry 9). This is possibly due to the reduction of ketones to alcohols
followed by dehydration (to give olefins) instead of reductive amination. However, the
reaction of aliphatic ketone i.e., 2-nonanone with formamide was not quite successful and
only starting material was recovered (Table 2, entry 10).
A plausible reaction mechanism for the formation of amines is depicted in Scheme 2. It is
assumed that, hydrolysis of formamide in presence of water to provide the formic acid
and ammonia. Formic acid plays multiple roles in this reaction (as a reducing agent and
acid catalyst). The in situ generated ammonia reacts with ketone in presence of formic
acid to give the imine, which subsequently reduced by formic acid to afford the
corresponding amine. The resulting amine reacts with another ketone in presence of
formic acid to give the corresponding imine and then it undergoes reduction by formic
acid to form the corresponding secondary amine (Path A). In the case of N-substituted
formamides, amides hydrolyzed to form formic acid and corresponding amine. Then,
amine reacts with ketone in presence of formic acid to provide corresponding iminium
ion. Finally, formic acid promotes the reduction of iminium ion to the corresponding
amine product (Path B).
5

CONCLUSIONS
An efficient and green method has been developed for the synthesis of amines
from cyclic ketones and formamides without any catalyst under superheated water
conditions. Notable advantages offered by this strategy are catalyst-free and
superheated water conditions, high atom economy (only H O, CO and H are by-
2
2
2
products), environmentally benign and simple work-up procedure, which make it
an attractive and useful alternative to the existing methods.
EXPERIMENTAL
All chemicals used were reagent grade and used as received without further purification.
1
13
H NMR spectra were recorded at 300, 400 and 500 MHz and C NMR spectra 75 MHz
in CDCl or DMSO-D . The chemical shifts (δ) are reported in ppm units relative to TMS
3
6
1
3
1
as an internal standard for H NMR and CDCl for C NMR spectra. Coupling constants
3
(J) are reported in hertz (Hz) and multiplicities are indicated as follows: s (singlet), bs
(broad singlet), d (doublet), dd (doublet of doublet), t (triplet), m (multiplet). Column
chromatography was carried out using silica gel (100-200 mesh).
General Procedure For The Synthesis Of Amines From Cyclic Ketones
The reactions were carried out in Parr autoclave (600 ml capacity, 20 cm height and 6.3
o
cm inner diameter) at 225 C temperature and 30 bar autogenous pressure under constant
stirring (50–60 revolutions per minute). The reactants cyclic ketone (0.1 mole),
formamide (0.15 mole) and water (300 ml) were loaded in an autoclave at room
temperature. Then, the autoclave was sealed and the temperature was increased to 225 C
6

under stirring. Agitation was maintained for required time (3-6 h). After completion of
the reaction, the autoclave was cooled to room temperature slowly. When the
atmospheric pressure was reached, the autoclave was opened and the reaction mixture
was extracted with DCM. Finally, the combined organic layer was washed with water,
dried over anhydrous Na SO and the solvent was evaporated under reduced pressure.
2
4
The crude was further purified by column chromatography using silica gel (100-200
mesh) afforded the pure products. All the products were identified on the basis of NMR
data and quantified by GC using EB-5 column.
ACKNOWLEDGEMENTS
We thank the CSIR Network project CSC-0123 for financial support. M. A. K., M.
N. and C.D. acknowledge the financial support from CSIR, India in the form of
fellowships. K. S., P.S. and B. R. acknowledge the financial support from UGC,
India in the form of fellowship.
SUPPLEMENTARY MATERIAL
1
13
Experimental details and H and C NMR spectral data for this article can be
accessed on the publisher’s website.
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5
1
0

Scheme 1. Synthesis of amines from cyclic ketones and formamides.
1
1

Scheme 2. Plausible reaction mechanism.
1
2

Table 1. Optimization of reaction conditions
o
a
Entry H O (ml) Molar ratio (1a:2a) Time (h) Temperature ( C) Yield (%)
2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
220
250
300
350
300
300
300
300
300
300
300
300
300
300
300
1:1
3
3
3
3
3
3
3
3
3
3
3
3
1
2
4
225
225
225
225
225
225
225
225
150
175
200
250
225
225
225
62
64
70
54
05
20
88
85
-
1:1
1:1
1:1
1:0.25
1:0.5
1:1.5
1:2
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
0
1
2
3
4
5
-
20
70
57
71
80
1
6
7
300
300
1:1.5
1:1.5
5
6
225
225
76
72
1
a
The products were characterized by NMR and quantified by GC.
1
3

a
Table 2. Synthesis of amines from various ketones and formamides
b
Entry Ketone
1
Formamide Product
Yield (%)
88
2
3
45
49
4
5
71
81
c
6
7
59
c
34
1
4

d
8
9
38 (24)
30
-
1
0
-
a
o
Ketone (0.1 mole), Formamide (0.15 mole), H O (300 mL), 225 C, 30 bar (autogenous
2
pressure), 3 h.
b
The products were characterized by NMR and quantified by GC.
c
Reaction time 6 h.
d
1-Phenylethanol.
1
5