Expeditious and efficient synthesis of Strecker's α-aminonitriles catalyzed by sulfated polyborate

Article abstract of DOI:10.1016/j.tetlet.2017.04.058

A straightforward, mild, efficient, and environmentally benign protocol for a three-component Strecker reaction of aldehydes or ketones, amines, and trimethylsilyl cyanide catalyzed by sulfated polyborate has been described to afford α-aminonitriles under solvent-free reaction conditions. The major advantages of the present method are excellent yields, shorter reaction time, simple experimental procedure, easy workup procedure, recyclability of the catalyst, solvent-free reaction conditions and ability to tolerate a variety of functional groups which gives economical as well as ecological rewards.

Full text of DOI:10.1016/j.tetlet.2017.04.058

Accepted Manuscript
Expeditious and efficient synthesis of Strecker’s α-aminonitriles catalyzed by
sulfated polyborate
Krishna S. Indalkar, Chetan K. Khatri, Ganesh U. Chaturbhuj
PII:
S0040-4039(17)30496-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.04.058
TETL 48850
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
25 March 2017
17 April 2017
18 April 2017
Please cite this article as: Indalkar, K.S., Khatri, C.K., Chaturbhuj, G.U., Expeditious and efficient synthesis of
Strecker’s α-aminonitriles catalyzed by sulfated polyborate, Tetrahedron Letters (2017), doi: http://dx.doi.org/
10.1016/j.tetlet.2017.04.058
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Graphical Abstract
Expeditious and efficient synthesis of Strecker’s
α-aminonitriles catalyzed by sulfated polyborate
Krishna S. Indalkar, Chetan K. Khatri, and Ganesh U. Chaturbhuj*

1
Tetrahedron Letters
journal homepage: www.els evier.com
Expeditious and efficient synthesis of Strecker’s α-aminonitriles catalyzed by sulfated
polyborate
Krishna S. Indalkar, Chetan K. Khatri, and Ganesh U. Chaturbhuj∗
Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Mumbai- 400019 India.
ARTICLE INFO
ABSTRACT
Article history:
Received
A straightforward, mild, efficient, and environmentally benign protocol for a three-component
Strecker reaction of aldehydes or ketones, amines, and trimethylsilyl cyanide catalyzed by
sulfated polyborate has been described to afford α-aminonitriles under solvent-free reaction
conditions. The major advantages of the present method are excellent yields, shorter reaction
time, simple experimental procedure, easy workup procedure, recyclability of the catalyst,
solvent-free reaction conditions and ability to tolerate a variety of functional groups which gives
economical as well as ecological rewards.
Received in revised form
Accepted
Available online
Keywords:
Sulfated polyborate
Strecker reaction
Aminonitriles
2016 Elsevier Ltd. All rights reserved.
Trimethylsilyl cyanide
Solvent free
The Strecker reaction one of the most important
multicomponent reactions in organic chemistry and find wide
applications in the fields of chemistry and biology.1 Its reliability,
the usefulness of the resulting products and easy accessibility of
the starting materials are reasons behind its use in the large-scale
synthesis of amino acids, chelating agents, and herbicides.2 α-
Aminonitriles constitute a major class of naturally occurring
compounds with remarkable biological activities3 such as
antibacterial, anticancer, antifungal, antiviral and antibiotic also
serve as efficient precursors and valuable intermediates for the
synthesis of natural and unnatural α-amino acids.4-5 Further, they
are widely used as essential building blocks in peptide and
protein synthesis,1 and various types of structurally diverse
nitrogen and sulfur-containing heterocycles such as imidazoles,
thiadiazoles.6-7 α-Aminonitriles are scaffolds in biologically
important molecules like saframycin-A an antitumor,8
clopidogrel, prasugrel, manzacidin A and short-acting opioid
analgesics.9 Their synthetic utility has valuable, considered as a
versatile synthon for the formation of amides, diamines, and
pharmaceutical intermediates.1
Scheme 1. Schematic representation of sulfated polyborate catalyzed
Strecker reaction
easy of handling and safe in use makes it the best cyanation
source.18
Protocols based on TMSCN often require variety of Lewis or
Bronsted acid catalyst such as Pr(OTf)3,19 Yb(OTf),20 Cu(OTf)2,2
LiClO4,21 NiCl2,22 BiCl3,23 RuCl3,24 CeCl3,25 InI3,26 InCl3,27
31
RhI3,28 GaCl3,29 I2,30 FeCl3, p-TSA,32 Montmorillonite KSF,33
34
polymer-supported Sc(OTf)3,
silica-supported heteropoly
acids,35 cellulose sulfuric acid,36 alumina supported tungstosilicic
acid,37 SBA-15 supported sulfonic acid,38 sulfamic acid
functionalized magnetic Fe3O4 nanoparticles,39 H2SO4/Silica
gel,40 silica-bonded S-sulfonic acid,41 sulphated tungstate,42
MCM-41 anchored sulfonic acid,43
zirconia,44 sulfamic acid,45 and xanthan sulfuric acid.46
Traditionally, Strecker reaction involves the nucleophilic
addition of the cyanide ion to the imine.10 The common cyanide
sources used during the course of this reaction such as HCN,1
nano magnetic sulfated
KCN,11
Et2AlCN,12
BuSnCN,13
(EtO)2POCN,14
(CH3)2C(OH)CN,15 EtOCOCN,16 and K4[Fe(CN)6].17 The
majority of cyanide sources are hazardous, toxic, involve harsh
reaction conditions and require special handling and precaution is
required during use. However, trimethylsilyl cyanide (TMSCN)
is the best alternative, due to its properties like effectiveness,
However, many of these methods suffer from several
shortcomings such as low reactivity, unsatisfactory yields,
moisture sensitive nature, longer reaction time, harsh reaction
conditions, tedious workup, generation of toxic byproducts, use
of expensive, metal-based, corrosive/toxic catalysts or reagent.
Therefore, the development of environmentally benign, a safe,
———
∗ Corresponding author. Tel.: +91-223-361-2212; fax: +91-222-414-5614; e-mail: gu.chaturbhuj@gmail.com

2
Table 3
Substrate scope of aldehyde variant for the Strecker reaction
Scheme 2. Strecker reaction of benzaldehyde, aniline, and TMSCN.
Table 1
Entry
Results of optimization studies
Aldehyde/ketone
Product
Time
(min)
2
Yielda
(%)
Entry
Catalyst
(wt %)
0
Solvent
Time (min)
Yielda (%)
(R1)
(R2)
H
1.
C6H5
99
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
solvent free
solvent free
solvent free
solvent free
solvent free
EtOH
360
30
10
2
NRb
89
1
2.5
5
95
99
2.
2-Cl-C6H4
4-Cl-C6H4
H
H
H
5
2
7
95
7.5
5
2
99
30
10
30
30
30
85
5
ACN
95
5
CHCl3
88
3.
4.
98
91
5
Water
Traces
60
5
Toluene
Reaction conditions: benzaldehyde (1.0 mmol), aniline (1.0 mmol),
trimethylsilyl cyanide (1.0 mmol), at room temperature.
a Isolated yields, b No reaction.
4-O2N-
C6H4
mild, efficient, and high yielding rapid reaction procedure using
cost effective and recyclable catalyst would be valuable.
In the perpetuation of the development of eco-friendly,
convenient and practical catalytic methods for the current interest
in organic synthesis and commercial process; recently we have
synthesized and characterized sulfated polyborate and proved its
efficiency for various useful organic transformations.47-52 Its easy
preparation, mild acidity, eco-friendliness, and reusability have
5.
6.
7.
2-CH3O-
C6H4
H
H
H
7
5
5
95
97
96
4-CH3O-
C6H4
encouraged us to investigate its potential to catalyze many other
useful organic transformations. Therefore, inspired by our
previous finding, herein we report a rapid, efficient and green
method for synthesis of α-aminonitriles via Strecker reaction
using aldehyde, amine, and TMSCN in the presence of a sulfated
polyborate as a recyclable catalyst under solvent-free conditions.
(Scheme 1).
4-Br-C6H4
8.
9.
4-CH3-
C6H4
H
H
5
5
96
95
Literature revealed that boric acid catalyzes many important
organic transformations at temperature above 100 °C.53 Boric
Table 2
2-HO-
C6H4
Efficiency of sulfated polyborate in comparison with literature reported
catalysts for the Strecker reaction
Entry
Catalyst
Condition
Time
(min)
2
Yielda Ref.
(%)
1.
Sulfated polyborate
Sulfated tungstate
solvent
free/ rt
solvent
free/ rt
water/ rt
99b
97
This
work
42
10.
4-HO-
C6H4
H
3
97
2.
10
10
3.
Sulfamic acid-
magnetic Fe3O4
nanoparticles
Polyboric acid
97
39
11.
12.
2-Thienyl
H
H
7
7
94
95
98b
95
This
work
41
2-Methyl-
furyl
CN
4.
5.
solvent
free/ 90°C
EtOH/rt
15
30
N
Silica-bonded S-
sulfonic acid
H
O
13.
14.
15.
2-Pyridyl
H
H
7
95
95
91
6.
Sulfated zirconia
EtOH/rt
30
95
44
7.
8.
H2SO4/Silica gel
Xanthan sulfuric
acid
MeCN/rt
MeCN/rt
60
65
93
97
40
46
c-C6H11
3
9.
MCM-41 anchored
sulfonic acid
Montmorillonite
KSF
EtOH/rt
DCM/rt
MeCN/rt
70
97
90
90
43
33
45
–(CH2)5–
30
10.
210
240
11.
Sulfonic acid
a Isolated yield. bcatalyst loading of 5 w %.

3
Table 4
Substrate scope of amine variant for the Strecker reaction56
Entry
16.
Aldehydes/ketone
Product
Time
(min)
30
Yielda
(%)
(R1)
CH3
(R2)
CH3
87
a Isolated yield.
acid dehydrates above 100 °C and converts to its polymeric
forms, which presumably is the active species catalyzing the
reaction.54-55 Dehydrative polymerization of boric acid liberates
water molecules which may hamper the progress of the reactions.
This inspired us to develop a polymeric boric acid catalyst
with mild Bronsted acidity. To accomplish this boric acid was
dehydrated at 200 °C to convert it into its polymeric Lewis acid
form and then sulfonated to introduce a mild Bronsted acid
character. Boron is an electron deficient element and electron
withdrawing effect of adjacent sulfate enhances its Lewis acidity,
hence it has both Lewis as well as Bronsted acid characters
(Scheme 1).
Entry
Amines
Product
Time
(min)
5
Yielda
R3
R4
H
(%)
96
1.
4-Cl-C6H4
2.
4-CH3O-
C6H4
H
5
97
3.
4.
4-O2N-C6H4
4-CH3-C6H4
H
H
7
5
88
97
For initial screening, the study was designed for the synthesis
of α-aminonitriles via Strecker reaction to investigate the
suitability of sulfated polyborate as a catalyst at different reaction
conditions. In the initial experiment, equimolar mixture
benzaldehyde; a representative substrate, aniline, and TMSCN
were used (Scheme 2). The results are summarized in Table 1
To understand the effect of the catalyst loading on time and
yields of the product. (Table 1, entries 1-5). A control experiment
was performed in the absence of a catalyst at rt, the reaction did
not occur (Table 1, entry 1). Further experiments were conducted
to optimize the amount of sulfated polyborate catalyst and an
increase in the catalyst loading increased the product yield with
significate reduction in the reaction time was observed (Table 1,
entries 2-5). The catalyst loading beyond 5 wt % was not
advantageous (Table 1, entries 4 and 5). Hence, 5 wt % catalyst
loading was chosen for further study.
The effect of various solvents on time and yield of the
reaction was ascertained (Table 1, entries 6-10). None of the
solvents has the advantage of time and yield over solvent free
condition. Hence, the solvent free condition was regarded as best
for the cost and environmental benefits. There are various
catalysts reported in the literature for the synthesis of α-
aminonitriles via Strecker reaction. Herein, the other acid
catalysts are compared with the present study which indicates
that sulfated polyborate catalyst showed an advantage in many
cases with respect to reaction conditions, workup procedure,
yields and time (Table 2, entry 1-11).
CN
N
H
5.
6.
C6H5CH2
H
H
5
7
97
92
c-C6H11
7.
8.
9.
-(CH2)2-O-(CH2)2-
3
5
5
95
97
95
-(CH2)5-
-(CH2)4-
a Isolated yield.
Furthermore, substrate scope was extended to various
substituted aromatic, aliphatic amines, alicyclic secondary
amines viz. morpholine, piperidine, and pyrrolidine which also
resulted in higher yields of products in shorter reaction time.
Various electron donating or electron withdrawing substituents at
the para position of aromatic amines have been examined (Table
4, entries 1-4). The protocol was also extended to benzylamine
and cyclohexylamine led to good yields in shorter reaction time.
(Table 4, entries 5-6). As expected, alicyclic secondary amines
reacted smoothly and gave high yields (Table 4, entries 7-9). The
nature of substitutions on aromatic amines has no significant
effect on the reaction yields and time (Table 4, entries 1-4),
except 4-nitroaniline. This protocol tolerated a variety of
substituents on aromatic aldehydes and amines, whereas, an
attempt with straight chain aliphatic aldehydes viz.
butyraldehyde, valeraldehyde and butylamine was unsuccessful.
The reusability of the catalyst in the model reaction of
benzaldehyde, aniline, and TMSCN under solvent-free conditions
at room temperature was evaluated. After completion of each
reaction cycle, water was added and the product was filtered off.
The filtrate was evaporated in vacuum rotary evaporator to
recover the catalyst quantitatively. The recovered catalyst was
recycled for four times without any considerable loss in a
catalytic activity (Fig. 1).
To study the synthetic utility and scope, optimized reaction
conditions56 were applied to various aldehydes and ketones. All
the substituted aromatic, heterocyclic, alicyclic aldehydes, as
well as aliphatic and alicyclic ketones, reacted well to afford
higher yields of the corresponding α-aminonitriles in shorter
reaction time with good yields (Table 3, entry 1-16 and Table 4,
entry 1-9). Benzaldehyde and substituted benzaldehydes
containing
electron-donating
or
electron-withdrawing
functionalities have been examined and giving very good to
excellent yields. (Table 3, entries 1–10), Reaction proceeded
equally smooth with heterocyclic aldehydes and cyclohexane
carbaldehyde (Table 3, entry 11-14), including an acid-sensitive
5-methyl furfural (Table 3, entry 12).
The optimized protocol was also applied to the reaction of
aromatic and aliphatic ketones. The reaction gives lower yield
with longer reaction time as compared to aldehydes (Table 3,
entries 15, 16). Only a few extents of research on the Strecker
reaction with ketones has been reported. Due to their steric
hindrance, ketones hardly react with an amine, In the present
method, the catalyst was effective with ketones.50

4
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5
Highlights:
•
Solvent free, efficient, rapid and
environmentally benign Strecker reaction.
•
Key advantages are high yields, short
reaction time and simple work-up
procedure.
•
•
Recyclable catalyst with no significant loss
in activity.
Method tolerates various functional groups
and extendable to multiple substrates.