A novel approach for the synthesis of α-aminonitriles using Mitsunobu's reagent under solvent-free conditions

Article abstract of DOI:10.1016/j.tetlet.2012.07.117

A highly efficient, one-pot, three-component, solvent-free protocol for the synthesis of α-aminonitriles starting from their corresponding carbonyl compounds, amines, using Mitsunobu's reagent has been developed. Diversity of α-aminonitriles has been synthesized in good to excellent yields (80-99%) using various kinds of aldehydes/ketones and a variety of amines.

Full text of DOI:10.1016/j.tetlet.2012.07.117

Tetrahedron Letters 53 (2012) 5398–5401
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A novel approach for the synthesis of
reagent under solvent-free conditions
a-aminonitriles using Mitsunobu’s
Devdutt Chaturvedi a, , Amit K. Chaturvedi b, Nisha Mishra b, Virendra Mishra b
⇑
a Laboratory of Medicinal Chemistry, Amity Institute of Pharmacy, Amity University Uttar Pradesh, Lucknow Campus, Lucknow 226010, UP, India
b Synthetic Research Laboratory, Department of Chemistry, B. S. A. P. G. College, Mathura 281004, UP, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly efficient, one-pot, three-component, solvent-free protocol for the synthesis of
a-aminonitriles
Received 7 June 2012
Revised 23 July 2012
Accepted 26 July 2012
Available online 4 August 2012
starting from their corresponding carbonyl compounds, amines, using Mitsunobu’s reagent has been
developed. Diversity of -aminonitriles has been synthesized in good to excellent yields (80–99%) using
various kinds of aldehydes/ketones and a variety of amines.
a
Ó 2012 Elsevier Ltd. All rights reserved.
Dedicated to my Doctoral mentor,
Dr. Suprabhat Ray on the occasion of his
70th Birthday
Keywords:
a-Aminonitriles
Carbonyl compounds
Amines
Strecker’s synthesis
Mitsunobu’s reagent
a
-Aminonitriles constitute a major class of naturally occurring
cyanoformate, bis(dialkyl)aminocyanoboranes, K4[Fe(CN)6] etc.7
majority of which are hazardous, toxic, and involve harsh reaction
conditions. Among the aforementioned reagents, TMSCN is rela-
tively a safer and more efficient cyanide source and has been
frequently employed during the Strecker’s synthesis. In recent
years, in order to search for novel and efficient protocols for
compounds of great interest displaying remarkable biological
activities1 such as anticancer, antibacterial, antifungal, antibiotic,
and antiviral etc. and also serve as efficient precursors for the syn-
thesis of natural and unnatural
a
-amino acids.2 They have also
been widely used as the essential building blocks of peptides and
proteins synthesis.3 Their tremendous synthetic utility has further
been explored as versatile synthon for the syntheses of amides,
diamines, and various kinds of structurally diverse nitrogen and
sulfur heterocycles4 such as imidazoles, thiadiazoles etc. Further-
more, their synthetic utility has also been explored through the
the syntheses of
a-aminonitriles, a broad spectrum of various
kinds of metal complexes, Lewis acids, solid supported acids, bases,
and organic catalysts which include NiCl2, RuCl3, RuI3.H2O, GdCl3,
InCl3, BiCl3, InI3, I2, TiCl3, H2PdCl4, Al2O3, Fe3O4, Cu(OTf)3, Sc(OTf)3,
Ga(OTf)3, Zr(HSO4)4, La(NO3)3Á6H2O, GdCl3Á6H2O, H4CoW12
O40Á3H2O, Fe(Cp)2PF6, H4SiW12O40/Al2O3, [Bmim]BF4, H2SO4/silica-
gel, vanadyltriflate, xanthansulfuric acid, amberlyst-15, montmo-
rillonite, lithium perchlorate, zinc halides, silica-supported
heteropolyacids, guanidine hydrochloride, cellulose, sulfamic acid,
nanocrystalline magnesium oxide, trimethylsilyltrifluoromethane
sulfonate etc. have been developed to promote this reaction.8,9
Although, majority of these catalytic systems were found to be
effective in carrying out this transformation, most of these systems
are associated with several drawbacks such as low reactivity,
requirement of large amount of catalysts, cost, toxic and moisture
sensitive nature, harsh reaction conditions, tedious work-up, long-
er reaction times, generation of toxic byproducts, and few of them
also involve two or more steps. The majority of these catalysts are
carbanion induced nucleophilic attack of
a-carbon atom with a
variety of electrophiles which offers many other interesting syn-
thetic transformations of importance in synthetic organic chemis-
try.5 Among the traditional methods reported for their syntheses,
Strecker reaction, the nucleophilic addition of cyanide ion to imi-
nes, is of great importance in modern organic chemistry as it offers
one of the most direct and viable method for the syntheses of
a
-aminonitriles.6 The cyanide sources used during the course of
this reaction are mainly HCN, KCN, TMSCN, (EtO)2P(O)CN, Et2AlCN,
Bu3SnCN, MeCOCN, acetone cyanohydrin, or acyl cyanides, ethyl
⇑
Corresponding author.
E-mail addresses: ddchaturvedi002@yahoo.co.in, dchaturvedi@lko.amity.edu
(D. Chaturvedi).
only efficient for the synthesis of
a-aminonitriles from active
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.117

D. Chaturvedi et al. / Tetrahedron Letters 53 (2012) 5398–5401
5399
Table 2
CN
O
Synthesis of various kinds of a-aminonitriles of general formula I
Ph3P/DEAD
solvent-free, rt
R
NH2
TMSCN
+
+
R2
R1
R2
Time
(min.)
Yield
(%)
R1
R1
Entry
R
Reference
NHR
R2
80-99%
8d
8m
8i
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-Me-
Ph
4-
MeO-
Ph
Ph
4-
MeO-
Ph
4-ClPh Ph
PhCH2
Ph
Ph
Ph
PhCH2
Ph
Ph
Ph
Ph
PhCH2
Ph
Ph
Ph
Ph
4Cl-Ph
4-NO2Ph
4-BrPh
3,4-Dichloro-Ph
4-F-Ph
4-CH3Ph
4-MeOPh
Py
C9H19
C2H5-
Ph
H
H
H
H
H
H
H
H
H
H
H
H
20
20
25
25
25
30
25
30
25
60
60
20
98
97
94
94
95
91
90
91
89
80
89
95
R1 = alkyl, cycloalkyl, phenyl / substituted phenyl,
naphthyl, anthracenyl, heteroaryl
R2 = H, Me, Et, Ph
I
9i
9i
R = alkyl, Ph, substituted aryl
9b
9a
9a
8i
Scheme 1.
8p
7f
10
11
12
-
aldehydes and are not suitable for ketone substrates. Therefore,
there is continued interest in developing new, efficient, and safer
protocols employing mild reaction conditions.
8m
8p
13
Ph
H
20
96
In recent years, Mitsunobu’s reagent (i.e. equimolar mixture of
triphenyl phosphine and diethyl azadicarboxylate) is a most popu-
lar reagent in synthetic organic chemistry and has been employed
in a variety of synthetic transformations.10 We have also reported
the synthesis of carbamates, dithiocarbamates, carbonates, xan-
thates, S-alkyl carbamates, trithiocarbonates, S,S-dialkyl carbon-
ates, carbazates, dithiocarbazates, and substituted ureas from a
variety of starting materials employing Mitsunobu’s reagent.11 In
the present Letter, we wish to report an efficient and novel proto-
9b
8n
14
15
Ph
Ph
Me
Me
25
25
98
99
8n
9b
8o
8q
8o
9b
8n
8n
9a
9b
9b
9b
9b
9b
9b
8i
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
Me
H
H
H
H
25
20
25
30
25
25
25
25
30
92
95
93
91
90
93
94
98
96
92
88
85
84
82
80
81
Ph
1-Naphthyl
9-Anthracenyl
Cyclopropyl
Ph
R1 = R2 = Cyclopentanone
R1 = R2 = Cyclohexanone
R1 = R2 = Cycloheptanone
Ph
Ph
Ph
col for the synthesis of
a-aminonitriles involving the reaction of
Me
the corresponding carbonyl compounds, amines, and TMSCN using
Mitsunobu’s reagent under solvent-free conditions.12 To the best of
our knowledge this is the first report for the synthesis of
nitriles employing Mitsunobu’s reagent.
a-amino-
CH2CH3 25
CH2CH3 25
Ph
Me
CH3
H
In order to carry out this synthetic protocol, a reaction of equimo-
lar amount of aniline with benzaldehyde, trimethysilylcyanide,
using Mitsunobu’s reagent was tried in various organic solvents
such as CH2Cl2, THF, diethylether, CH3CN, DMF, nitromethane,
30
30
40
40
30
Naph
(CH3)2CH
PhCH@CH
Ph
Ph
n-
H
methanol at room temperature and the corresponding a-aminoni-
C4H9
n-
C4H9
PhCH2
Ph
Ph
Ph
Ph
Ph
trile product was indeed obtained. The characterization of the prod-
uct was confirmed through the various spectroscopic and analytical
techniques and was further confirmed through the data of reported
authentic sample. This reaction was further optimized employing
various kinds of reaction conditions and the different molar
amounts of the Mitsunobu’s reagent wherein it was realized that
a-aminonitrile could be achieved
using at least one equivalent of the reagent along with the equimolar
amount of aldehyde, and amine without using a solvent (Scheme 1).
32
4-Me-Ph
H
30
83
33
34
35
36
37
38
Cyclohexyl
Cyclohexyl
n-C4H9
H
H
30
30
40
45
50
50
81
80
86
83
81
83
8q
8q
9b
8o
n-C4H9
Ph
CH3
Me
Naph
4-NO2Ph
3-Me-2-
thiophenyl
best yields (99%) of the desired
8n
8n
39
40
4MeO- 3-Pyridyl
Ph
4MeO- 3,4-
Me
Me
40
45
87
82
It was further realized that the desired
a-aminonitrile could be
achieved through the reaction of benzaldehyde with aniline using
TMSCN without using Mitsunobu’s reagent under solvent-free con-
ditions, wherein the reaction takes longer time (4 h) and afforded
lower yield (92%). A reaction of acetophenone, tried with aniline
using TMSCN and Mitsunobu’s reagent, afforded high-yield of the
desired a-aminonitrile under solvent-free conditions at room tem-
perature (Table 1). However, when this reaction was repeated with-
out using Mitsunobu’s reagent even for a longer time (4 h), the
Ph
Methylenedioxy-
Ph
imine was obtained, while without using Mitsunobu’s reagent the
formation of imine could not be realized. This would clearly explain
the role of Mitsunobu’s reagent in the in situ generation of corre-
sponding imine specifically from ketones.
corresponding
a-aminonitrile could not be achieved. This would
Encouraged by our above mentioned experiment, the synthetic
utility and scope of this reaction were further explored employing
various kinds of aliphatic/aromatic substituted aldehydes/ketones
bearing electron releasing and electron withdrawing functional-
ities using at least 1 equiv of Mitsunobu’s reagent and one equiva-
lent of primary aliphatic/aromatic amines having electron
releasing and electron withdrawing functional groups. Best yields
of the products were obtained when the electron releasing group
was introduced at the p-position of aryl-substituted aldehydes/ke-
tones and amines, respectively. It must be emphasized here that
only primary aliphatic/aromatic/cyclic/heterocyclic amines would
give the resultant imine which on subsequent nucleophilic attack
of cyanide ion afforded the corresponding product. Thus, various
clearly suggest that
a
-aminonitriles from ketones could not be
achieved without using Mitsunobu’s reagent and thus further
confirm that Mitsunobu’s reagent facilitates the formation of
corresponding imine. Furthermore, this reaction was tried employ-
ing Mitsunobu’s reagent without using TMSCN, the corresponding
Table 1
Effect of Mitsunobu’s reagent in the formation of
a-aminonitriles I
R
R1
R2
Time
Mitsunobu’s reagent
Yield (%)
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
H
Me
Me
20 min
4 h
25 min
4 h
Used (1 Molar)
Not used
Used (1 Molar)
Not used
98
92
98
Nil

5400
D. Chaturvedi et al. / Tetrahedron Letters 53 (2012) 5398–5401
COOEt
Ph3P
N
N
COOEt
Ph3P
EtOOC N N COOEt
+
Mitsunobu's zwiterion A
COOEt
COOEt
H
Ph3P
R1
N
N
COOEt
O
PPh3
N
N
COOEt
O
R1
N
H
R2
R2
B
R
RNH2
-Ph3PO, (NHCOOEt)2
TMSCN
R1
CN
NHR
R2
I
Scheme 2. Proposed mechanism of formation.
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kinds of
a-aminonitriles from a variety of carbonyl compounds
(aldehydes and ketones) have been synthesized employing Mits-
unobu’s reagent and their structural confirmation was correlated
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We propose that Mitsunobu’s reagent plays a crucial role in
facilitating this transformation through in situ generation of imine.
Initially, the Mitsunobu zwitterion A formed through the reaction
of triphenylphosphine with diethylazadicarboxylate, reacts with
the mixture of a keto-compound and amine generating the inter-
mediate B. The electronic rearrangement of intermediate B result-
ing in situ generated imine which on subsequent nucleophilic
attack of cyanide ion afforded the corresponding
in a one-pot reaction (Scheme 2).
a-aminonitrile I
In conclusion, we have developed a simple and efficient method
for the synthesis of -aminonitriles starting from their correspond-
a
ing carbonyl compounds, amines, and trimethylsilyl cyanide using
Mitsunobu’s reagent under solvent-free conditions. Mitsunobu’s
reagent a cheap, easy to handle, and mild reagent has been used
during the course of this reaction to generate the corresponding
imines from a variety of aldehydes and ketones, afforded the
desired a-aminonitriles in high yields (80–99%).
Acknowledgements
Author is thankful to Pro-Vice Chancellor, Amity University
Uttar Pradesh, Lucknow Campus, for his constant encouragement
and support for research.
References and notes
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mesh) with petroleum ether–EtOAc (5:1) as eluent gave the pure product.
Data of selected compounds
2-Anilino-2-phenyl acetonitrile (Entry 1):
Light yellow solid; mp = 85–86 °C; IR (CHCl3):
m = 3368, 3055, 2233, 1602,
1502 cmÀ1 1H NMR (300 MHz, CDCl3): d = 4.03 (d, 1H, J = 9 Hz), 5.41 (d, 1H,
;
J = 9 Hz), 6.76 (d, 2H, J = 9 Hz), 6.90 (t, 1H, J = 6 Hz), 7.30 (t, 2H, J = 9 Hz), 7.44
(m, 3H), 7.59 (m, 2H) ppm; 13C NMR (75 MHz, CDCl3): d = 49.8, 114.0, 118.1,
119.9, 127.0, 128.3, 129.4, 129.8, 133.6, 144.6 ppm; MS (ESI): m/z = 208.2 (M+);
Anal. Cald for C14H12N2: C, 80.74; H, 5.81; N, 13.45%. Found: C, 80.80; H, 5.76;
N, 13.47%.
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2-Anilino-2-(4-chloro phenyl) acetonitrile (Entry 2)
White solid; mp 96–98 °C; IR (CHCl3):
m ;
= 3365, 3055, 2235, 1603, 1504 cmÀ1
1H NMR (300 MHz, CDCl3): d = 4.02 (d, 1H, J = 6 Hz), 5.41 (d, 1H, J = 9 Hz), 6.75
(d, 2H, J = 9 Hz), 6.92 (t, 1H, J = 6 Hz), 7.28 (m, 2H), 7.42 (d, 2H, J = 9 Hz), 7.53 (d,
2H, J = 6 Hz) ppm; 13C NMR (75 MHz, CDCl3): d = 49.5, 114.2, 117.8, 120.4,
128.4, 129.2, 129.6, 132.8, 135.4, 144.3 ppm; MS (ESI): m/z = 242.1 (M+); Anal.
Cald for C14H11ClN2: C, 69.28; H, 4.57; N, 11.54%; Found: C, 69.19; H, 4.63; N,
11.56%.
2-Anilino-2-(4-nitro phenyl) acetonitrile (Entry 3)
Gummy; IR (CHCl3):
m ;
= 3381, 3063, 2225, 1601, 1550, 1502 cmÀ1 1H NMR
12. Typical experimental procedure: Synthesis of
a
-aminonitriles from carbonyl
(300 MHz, CDCl3): d = 4.08 (d, 1H, J = 9 Hz), 5.57 (d, 1H, J = 9 Hz), 6.68 (d, 2H,
J = 9 Hz), 6.78 (t, 1H, J = 8 Hz), 7.29 (t, 2H, J = 9 Hz), 7.8 (d, 2H, J = 9 Hz), 8.1 (d,
2H, J = 9 Hz) ppm; 13C NMR (75 MHz, CDCl3): d = 49.8, 115.3, 118.0, 127.0,
127.7, 127.8, 128.6, 129.0, 133.8, 144.1, 145.0 ppm; MS (ESI): m/z = 276.2
(M++Na); Anal. Cald for C14H11N3O2: C, 66.40; H, 4.38; N, 16.59%; Found: C,
66.46; H, 4.40; N, 16.51%.
compounds:A mixture of aldehyde (1 mmol), amine (1 mmol), Mitsunobu’s
reagent (1 mmol), and trimethylsilylcyanide (1.2 mmol) was added at room
temperature and stirring was continued until the reaction was complete
(monitored by TLC). After completion of the reaction, the reaction mixture was
extracted with ethylacetate, dried over anhydrous Na2SO4, and concentrated.