Mandelic acid catalyzed one-pot three-component synthesis of α-aminonitriles and α-aminophosphonates under solvent-free conditions at room temperature

Article abstract of DOI:10.1080/00397911.2020.1745844

A simple, mild, straightforward, efficient and eco-friendly protocol has been developed for the synthesis of a series of α-aminonitriles via the one-pot three-component Strecker reactions between various aldehydes, amines and trimethylsilyl cyanide using a catalytic amount of mandelic acid as a naturally occurring, low-cost, efficient organo-catalyst under solvent-free conditions at room temperature. Under the same optimized conditions synthesis of α-aminophosphonates were also achieved via the one-pot three-component Kabachnik-Fields reactions of aldehydes, amines and triethyl phosphate.

Full text of DOI:10.1080/00397911.2020.1745844

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Mandelic acid catalyzed one-pot three-
component synthesis of α-aminonitriles and α-
aminophosphonates under solvent-free conditions
at room temperature
Gurpreet Kaur, Mussarat Shamim, Vaishali Bhardwaj, Vivek Kumar Gupta &
Bubun Banerjee
To cite this article: Gurpreet Kaur, Mussarat Shamim, Vaishali Bhardwaj, Vivek Kumar Gupta
& Bubun Banerjee (2020): Mandelic acid catalyzed one-pot three-component synthesis of α-
aminonitriles and α-aminophosphonates under solvent-free conditions at room temperature,
Synthetic Communications, DOI: 10.1080/00397911.2020.1745844
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https://doi.org/10.1080/00397911.2020.1745844
Mandelic acid catalyzed one-pot three-component
synthesis of a-aminonitriles and a-aminophosphonates
under solvent-free conditions at room temperature
Gurpreet Kaura, Mussarat Shamima, Vaishali Bhardwaja, Vivek Kumar Guptab, and
Bubun Banerjeea
b
aDepartment of Chemistry, Indus International University, Una, Himachal Pradesh, India; Post-Graduate
Department of Physics, University of Jammu, Jammu, India
ABSTRACT
ARTICLE HISTORY
Received 14 January 2020
A simple, mild, straightforward, efficient and eco-friendly protocol
has been developed for the synthesis of a series of a-aminonitriles
via the one-pot three-component Strecker reactions between various
KEYWORDS
aldehydes, amines and trimethylsilyl cyanide using
a catalytic
a-Aminonitriles; a-amino-
phosphonates; mandelic
acid; room temperature;
organocatalysis
amount of mandelic acid as a naturally occurring, low-cost, efficient
organo-catalyst under solvent-free conditions at room temperature.
Under the same optimized conditions synthesis of a-aminophospho-
nates were also achieved via the one-pot three-component
Kabachnik-Fields reactions of aldehydes, amines and triethyl phos-
phate.
GRAPHICAL ABSTRACT
CONTACT Bubun Banerjee
banerjeebubun@gmail.com/bubun.banerjee@iiuedu.in Department of Chemistry, Indus
International University, V.P.O Bathu, Una, Himachal Pradesh 174301, India.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2020 Taylor & Francis Group, LLC

2
G. KAUR ET AL.
Figure 1. Glimpse of bioactive scaffolds containing a-aminonitrile as a structural subunit.
Introduction
a-Aminonitriles are recognized as versatile precursors of diverse bioactive scaffolds
including porphyrins, nicotinic acids, corrins, nucleic acids etc.[1,2] In many occasions,
a-aminonitriles are found as important intermediates for the synthesis of various nitro-
gen- and sulfur-containing heterocycles that include imidazoles and thiadiazoles.[3]
Moreover, many bioactive molecules contain a-aminonitrile as an important structural
subunit (Figure 1).[4–9] On the other hand, a-aminophosphonate bearing molecules in
many occasions showed significant biological efficacies including anti-bacterial, anti-
oxidant, herbicidal, anti-viral, anti-phytoviral, anti-cancer, anti-microbial, anti-tumor etc
activities (Figure 2).[10–23] After realizing the importance of a-aminonitrile as well as
a-aminophosphonate derivatives, scientists were motivated to synthesize these important
scaffolds under various reaction conditions. As a result, number methods are available
in the literature for the synthesis of a-aminonitriles via one-pot three-component
Strecker reaction between aldehydes, amines and trimethylsilyl cyanide using various
homogeneous as well as heterogeneous catalysts (Table 1).[24–52] Similarly, syntheses of
a-aminophosphonates were also achieved via the one-pot three-component Kabachnik-
Fields reaction between aldehydes, amines and triethyl phosphite under various catalytic
conditions (Table 2).[23,53–71] Although these methods reported by others possess certain
merits, still under Green Chemistry perspective they are suffering from few drawbacks
which include in most of the cases they used either metal containing catalysts
(Bi(NO3)3, La(NO3)3ꢀ6H2O, NiCl2, ZrOCl2.8H2O, FeCl3 etc.) or expensive catalysts
(Ga(OTf)3, GdCl3ꢀ6H2O, RuCl3, Fe3O4@PVA-SO3H, Fe3O4@DHAA, RhI3.H2O,
Cu(OTf)2 etc.), some of them utilized organic solvents (MeCN, EtOH, MeOH, toluene,
THF), involvement of ionic liquids ([EtNH3]NO3, [Sipim]HSO4, [bmim]BF4/[bmim]PF6,
[bmim]ClO4, [hmim]HSO4), reflux conditions etc. In some reported methods a-amino-
nitriles were synthesized under microwave or ultrasound irradiated conditions. De[35]
synthesized a-aminonitriles using nickel(II)chloride as catalyst in acetonitrile which
took 6–18 h at room temperature. Moreover, all these reported methods focused only

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Figure 2. Glimpse of bioactive synthetic scaffolds containing a-aminophosphonates.
on the synthesis of either a-aminonitriles or a-aminophosphonates. Therefore, search
for a common, efficient, environmentally benign and high yielding route for the synthe-
sis of a-aminonitriles as well as a-aminophosphonates remains a valid exercise.
In these environmental conscious days, metal-free organo-catalyzed reactions are in
high demand.[72–74] In recent times, among many others, mandelic acid is also regarded
as an efficient organo-catalyst. The catalytic efficiency of mandelic acid was first
explored by our group.[75,76] To the best of our knowledge, this is the third report
where mandelic acid acts as an efficient catalyst in organic synthesis. On the other
hand, in many circumstances, it was noticed that the best solvent to carry out organic
transformation is ‘no solvent’.[77] Under this purview, in continuation of our strong
research interest toward organo-catalyzed reactions,[78–81] in this communication we
wish to report the synthesis of both a-aminonitriles as well as a-aminophosphonates
under solvent-free conditions at room temperature using a catalytic amount of mandelic
acid as an efficient, commercially available, low cost, environmentally benign
organo-catalyst.
Results and discussion
To optimize the protocol, we carried out a series of trial reactions between benzalde-
hyde (1 mmol), aniline (1 mmol) and trimethylsilyl cyanide (1 mmol) under various con-
ditions. Initially, we performed the above mentioned reaction without using any catalyst
in aqueous medium at room temperature which produced only 20% of 2-phenyl-2-(phe-
nylamino)acetonitrile (5a) after two hours (Table 3, entry 1). The same reaction yielded
73% of 5a after one hour in the presence of a catalytic amount of mandelic acid
(20 mol%) in water at room temperature (Table 3, entry 2). Using the same amount of

4
G. KAUR ET AL.
Table 1. Reported protocols for the synthesis of a-aminonitriles.
Entry
1
Catalyst
Pr(OTf)3
Solvent
CH3CN
Temp.
RT
Time (min)
600
Yield (%)[REF]
89[24]
2
3
4
5
6
7
8
9
H3BO3
La(NO3)3ꢀ6H2O/ GdCl3ꢀ6H2O
Bi(NO3)3
H2O
CH3CN
CH3CN
CH2Cl2
CH3CN
CH3CN
neat
neat
EtOH
EtOH
CH3CN
neat
CH3CN
neat
ClCH2CH2Cl
diethylether
CH3CN
EtOH
neat
EtOH
neat
neat
neat
neat
CH2Cl2
CH2CN
aq. AcOH
CH2CN
neat
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
10
60/180
60
180
20
60
5
20
5
15
720
2
10
3
600
5
10 h
88[25]
96/94[26]
94[27]
90[28]
74[29]
95[30]
95[31]
85[32]
96[33]
90[34]
92[35]
99[36]
97[37]
87[38]
99[39]
92[40]
84[41]
85[42]
92[43]
90[44]
86[45]
87[46]
93[47]
80[48]
95[49]
89[50]
93[51]
95[52]
93[this work]
Ga(OTf)3
RuCl3
Anhy. CeCl2
ZrOCl2.8H2O
Ph3P/DEAD
Fe3O4@PVA-SO3H
Fe3O4@DHAAa
NiCl2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
Sulfated Polyborate
RhI3.H2O
RT
NH4Cl
Na2SO4
LiClO4
MW, 90 oC
ꢁ20 oC
RT
BiCl3
RT
RT
RT
RT
RT
RT
SBPPSAb
5
c[bmim]BF4/[bmim]PF6
d[Sipim]HSO4
[bmim]ClO4
Choline chloride. ZnCl2
e[hmim]HSO4
Co/SBA-15
300
75
15
3
RT
MW, 45 oC
60 oC
RT
15
30
240
360
50
120
3
Nafion-Fe
Cu(OTf)2
nano-CuFe2O4
L-proline
mandelic acid
RT
RT
RT
aDHAA: dehydroascorbic acid; bSBPPSA: silica-bonded N-propylpiperazine sulfamic acid; [bmim]: 1-butyl-3-methylimida-
c
zolium; d[Sipim]: N-(3-silicapropyl) imidazolium; [hmim]: methyl imidazolium
e
catalyst, comparable yields (67–75%) of 5a were recorded in other organic solvents such
as ethanol, methanol, acetonitrile and chloroform (Table 3, entry 3–6). An excellent
yield (93%) of 5a was obtained within just three minutes when the same reaction car-
ried out using 20 mol% of mandelic acid as catalyst under solvent-free conditions at
room temperature (Table 3, entry 7). This may be due to the greater interaction
between the reactant molecules and catalyst in solid phase. We tried to optimize the
required catalyst amount keeping the other parameters remain same. Lesser amount of
5a (81% & 86%) was isolated using 10 mol% and 15 mol% of mandelic acid respectively
(Table 3, entry 8-9). No significant improvement was observed in the reaction rate even
by increasing the catalyst amount to 25 mol% (Table 3, entry 10). On the basis of these
above experimental outcomes, it was came out that 20 mol% of mandelic acid is an effi-
cient organo-catalyst for the synthesis of 2-phenyl-2-(phenylamino)acetonitrile (5a)
under solvent-free conditions at room temperature. To check the generality as well as

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Table 2. Reported protocols for the synthesis of a-aminophosphonates.
Entry
Catalyst
Solvent
Temp.
Time
90 min
30 min
120 min
360 min
45 min
24 h
21 h
30 min
24 h
60 min
2 min
30 min
5/8 h
90 min
1 min
240 min
2 min
90 min
5 min
0.5 h
Yield (%)[REF]
73[53]
1
2
3
4
5
6
7
8
FeCl3
THF
RT
RT
RT
Amberlyst-IRC 748
[EtNH3]NO3
BiCl3
toluene
neat
CH3CN
THF
CH3CN
THF
neat
CH2Cl2
neat
neat
neat
92[23]
95[54]
92[55]
95[56]
93[57]
79[58]
96[59]
92[60]
87[61]
90[62]
95[63]
90/84[64]
92[65]
96[66]
89[67]
98[68]
93[69]
95[70]
96[71]
reflux
RT
FeCl3
YbCl2
RT
In(OTf)3 þ MgSO4
reflux
RT
Al(OTf)3
TaCl5-SiO2
PPh3
9
RT
10
11
12
13
14
15
16
17
18
19
20
60 oC
MW
50 oC
RT
Amberlite-IR 120
NbCl5
[bmim]BF4/[bmim]PF6
neat
InCl3
THF
RT
RT
RT
RT
a[bnmim][HSO4]
Yb(OTf)3
neat
CH2Cl2
neat
neat
neat
Mg(ClO4)2
Al(H2PO4)3
100 oC
RT
ZrOCl2ꢀ8H2O
bCu(3,4-tmtppa)(MeSO4)4
mandelic acid
H2O
80oC
RT
c
[this work]
2
neat
7 min
87
a[bnmim]: 1-Benzyl-3-methyl imidazolium; bCu(3,4-tmtppa)(MeSO4)4: tetramethyl-tetra-3,4-pyridinoporphyrazinato copper
c
(II) methyl sulfate; 4-bromoaniline was used instead of aniline
Table 3. Optimization of reaction conditions for the synthesis of 2-phenyl-2-
(phenylamino)acetonitrile.
Entry
Catalyst (mol%)
Catalyst-free
Condition
Time (min)
Yield (%)a,b
1.
2
3
4
5
6
7
8
9
H2O
H2O
EtOH
MeOH
MeCN
CHCl3
120
60
60
60
60
60
3
10
5
3
20
73
70
67
72
75
93
81
86
94
Mandelic acid (20)
Mandelic acid (20)
Mandelic acid (20)
Mandelic acid (20)
Mandelic acid (20)
Mandelic acid (20)
Mandelic acid (10)
Mandelic acid (15)
Mandelic acid (25)
solvent-free
solvent-free
solvent-free
solvent-free
10
aReaction conditions: benzaldehyde (1; 1 mmol), aniline (2; 1 mmol) and TMSCN (3; 1 mmol) in the absence or presence
of a catalytic amount of naturally occurring mandelic acid in neat/4 mL of water/ethanol/methanol/aqueous ethanol
at 20–25 ꢂC. bIsolated yields.

6
G. KAUR ET AL.
Table 4. Synthesis of 2-aryl-2-(arylamino)acetonitrile (5a–5j) and diethyl (aryl(arylamino) methyl)-
phosphonate (6a–6c) using mandelic acid as catalyst under solvent-free conditions.
Sl No.
R
R1
Product
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
H
4-Cl
4-F
H
H
H
5a
5b
5c
5d
5e
5f
5g
5h
5i
3
3
3
3
3
3
3
5
5
5
7
8
8
93
94
91
89
84
86
88
90
94
92
87
86
89
H
4-Br
4-Br
4-Me
4-Br
3-Me
4-F
3-Cl
4-Br
4-Br
4-Me
4-OMe
4-OMe
4-Me
3,4-OCH2-
3,4-OCH2-
3,4-OCH2-
H
9
10
11
12
13
5j
6a
6b
6c
4-OMe
4-OMe
aReaction conditions: aldehydes (1; 1 mmol), amines (2; 1 mmol) and TMSCN (3; 1 mmol) or triethyl phosphite (4;
1 mmol) in the presence of mandelic acid (20 mol%) as catalyst under solvent-free conditions at 28–32 ꢂC.
bIsolated yields.
Figure 3. ORTEP view of the molecule 5c with displacement ellipsoids drawn at 50%
(CCDC 1975998).

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Figure 4. Packing view of molecules down b-axis within the unit cell of compound 5c.
effectiveness of this optimized reaction conditions, we were then motivated to synthesize
some other derivatives of 2-aryl-2-(arylamino)acetonitrile via one-pot three-component
Strecker reaction. Therefore, we carried out the reactions between various benzaldehyde
derivatives (1; 1 mmol) substituted anilines (2; 1 mmol) and TMSCN (3; 1 mmol) in the
presence of 20 mol% mandelic acid as catalyst under solvent-free conditions at room
temperature which afforded excellent yields (84–94%) of the desired 2-aryl-2-(arylami-
no)acetonitriles (5b–5j) (Table 4; entry 2–10). As expected, aldehydes with electron
donating substituent like methoxy produced lower yields of the desired products. To
extend the scope of our developed protocol, one-pot three component Kabachnik-Fields
reactions between benzaldehydes (1; 1 mmol) anilines (2; 1 mmol) and triethyl phosphite
(4; 1 mmol) were also carried out under the same optimized reaction conditions which
afforded the corresponding diethyl (aryl(arylamino)methyl)phosphonate (6a–6c) with
87–89% yields (Table 4; entry 11 & 13).
No column chromatographic purification was required as all the products were iso-
lated pure just by simple filtration and subsequent washing with aqueous ethanol.
Under the same optimized reaction conditions, gram scale production (1.83 g; 88%) of
2-phenyl-2-(phenylamino)acetonitrile (5a) was also achieved from the reactions of
10 mmol benzaldehyde, 10 mmol aniline and 11 mmol trimethylsilyl cyanide within
30 min. All the synthesized compounds were well characterized by the detail spectro-
1
scopic analyses including FT-IR, H NMR, 13C NMR and HRMS. It is also note worthy
to mention that we were able to form single crystal of two compounds i.e., compound

8
G. KAUR ET AL.
Figure 5. ORTEP view of the molecules 6c with displacement ellipsoids drawn at 40% probability
level. (CCDC 1976000).
5c and 6c. ORTEP view of compound 5c is shown in Figure 3. In this ORTEP small
spheres of arbitrary radii represent H atoms. Figure 4 shows the packing view of mole-
cules down b-axis within the unit cell of compound 5c. ORTEP diagram of compound
6c is shown in Figure 5 which indicates that the structure contains two crystallographic-
ally independent molecules, A and B, in the asymmetric unit. In this ORTEP, H-atoms
have been excluded for better clarity. Figure 6 represents the packing view of molecules
6c down a-axis within the unit cell.
Experimental section
General
Melting points were recorded on a Digital Melting Point Apparatus (Model No. MT-
934) and are uncorrected. TLC was performed on silica gel 60 F254 (Merck) plates.
Infrared spectra were recorded on Agilent (Cary 660) FT-IR spectrophotometer on KBr
1
disks. H and 13C NMR spectra were obtained at 500 MHz Jeol (JNM ECX-500) NMR

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Figure 6. Packing view of molecules down a-axis within the unit cell of compound 6c.
machines with CDCl3 as the solvent. Mass spectra (TOF-MS ESþ) were measured on a
Bruker Impact HD QTOF Micro mass spectrometer.
General procedure for the synthesis of 2-phenyl-2-(phenylamino)acetonitrile (5a)
In an oven-dried screw-cap test tube a magnetic stir bar, benzaldehyde (1; 1 mmol),
aniline (2; 1 mmol), trimethyl silylcyanide (3; 1 mmol) and a catalytic amount of man-
delic acid (20 mol%) were taken sequentially. The reaction mixture was then stirred vig-
orously at room temperature under solvent-free conditions. The reaction was monitored
by TLC. After completion of the reaction, 10 mL of water was added in the reaction ves-
sel and the mixture was allowed to stir for 5 min. 2-Phenyl-2-(phenylamino)acetonitrile
(5a) was isolated pure with 93% yield just by simple filtration and subsequent washing
with aqueous ethanol (H2O:EtOH ¼ 4:1).
General procedure for the synthesis of diethyl (((4-
bromophenyl)amino)(phenyl)methyl)phosphonate (6a)
By repeating the above mentioned procedure, diethyl (((4-bromophenyl)amino)(phe-
nyl)methyl)phosphonate (6a) was also synthesized with 87% yield from the reactions of
benzaldehydes (1; 1 mmol), 4-bromoaniline (2; 1 mmol) and triethyl phosphite (4;
1 mmol) by using 20 mol% of mandelic acid as catalyst under the same optimized

10
G. KAUR ET AL.
conditions. The structures of the synthesized compounds were determined by the detail
1
spectral analysis including FT-IR, H NMR, 13C NMR and HRMS.
Characterization data of some representative entries
2-Phenyl-2-(phenylamino)acetonitrile (5a): White solid; mp 81–83 ꢂC; IR (KBr) mmax
/
cm–1: 3335, 335, 2359, 1599, 1496, 1450, 1284, 1244, 1196, 1115, 1066, 1029, 925, 879,
1
751; H NMR (500 MHz, CDCl3) d/ppm: 7.60 (2H, dd, J ¼ 7.37 & 1.85 Hz, aromatic H),
7.47–7.44 (2H, m, aromatic H), 7.29–7.25 (2H, m, aromatic H), 6.91 (1H, t, J ¼ 7.45 &
7.00 Hz, aromatic H), 6.78 (2H, d, J ¼ 8.05 Hz, aromatic H), 5.43 (1H, d, J ¼ 8.20 Hz),
4.04 (1H, d, J ¼ 8.00 Hz); 13C NMR (125 MHz, CDCl3) d/ppm: 144.75, 134.00, 129.69
(2 C), 129.46 (2 C), 127.38 (2 C), 120.39 (2 C), 118.29, 114.23 (2 C), 50.31; HRMS (ESI-
TOF) m/z: For C14H12N2 Calcd. [M þ Na]þ 231.0898; Found [M þ Na]þ 231.0988.
Diethyl (((4-bromophenyl)amino)(phenyl)methyl)phosphonate (6a): Grayish solid; mp
99–101 ꢂC; IR (KBr) mmax/cm–1: 3286, 2980, 2904, 1591, 1514, 1488, 1449, 1391, 1292,
1233, 1199, 1071, 963, 878, 732; 1H NMR (500 MHz, CDCl3) d/ppm: 7.43 (2H, d,
J ¼ 7.60 Hz, aromatic H), 7.34 (2H, t, J ¼ 7.55 & 6.85 Hz, aromatic H), 7.29–7.26 (1H,
m, aromatic H), 7.17 (2H, d, J ¼ 8.95 Hz, aromatic H), 6.46 (2H, d, J ¼ 8.95 Hz, aromatic
H), 4.87 (1H, t, J ¼ 8.90 & 8.25 Hz), 4.69 (1H, dd, J ¼ 24.08 & 7.55 Hz), 4.16–4.06 (2H,
m), 3.64–3.89 (1H, m), 3.67–3.62 (1H, m), 1.29 (3H, t, J ¼ 6.90 & 6.85 Hz. -OCH2CH3),
1.10 (3H, t, J ¼ 7.55 & 6.85 Hz, -OCH2CH3); 13C NMR (125 MHz, CDCl3) d/ppm:
145.29, 145.18, 135.29, 131.86 (2 C), 128.66, 128.11, 127.75, 127.71, 115.42 (2 C), 110.14,
63.43 (d, JPC ¼ 7.16 Hz, OCH2CH3), 63.26 (d, JPC ¼ 7.15 Hz, OCH2CH3), 56.48 (d, JPC
¼ 150.22 Hz, CHP), 16.41 (d, JPC ¼ 5.96 Hz, OCH2CH3), 16.16 (d, JPC ¼ 5.95 Hz,
OCH2CH3); HRMS (ESI-TOF) m/z: For C17H21BrNO3P Calcd. [M þ Na]þ; 420.0340
Found [M þ Na]þ 420.0613.
Supporting information
1
General procedure, characterization data including scanned spectra of FTIR, H-NMR,
13C-NMR and HRMS for all entries are supplemented in Supporting information.
Conclusions
We have developed a simple, facile and general pathway for the synthesis of both
a-aminonitriles as well as a-aminophosphonates via one-pot three-component reactions
of aldehydes, amines and trimethylsilyl cyanide or triethyl phosphate using a catalytic
amount of mandelic acid as an efficient, low cost, easily available naturally occurring
organo-catalyst under solvent-free conditions at room temperature. Mild, general,
energy efficiency, high atom economy, one-pot three component strategy, use of cheap
and efficient organo-catalyst, column-free easy isolation procedure, solvent-free reaction
conditions are some of the salient features of this developed protocols.

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Acknowledgements
Dr. B. Banerjee is thankful to the Indus International University, Una, Himachal Pradesh, India
and the Kartha Education Society, Mumbai, India for the support. Authors are grateful to
AMRC, IIT Mandi, Himachal Pradesh, India for the spectral measurements such as FTIR, NMR,
HRMS as well as single XRD data.
Disclosure statement
The authors declare no conflict of interest.
ORCID
Bubun Banerjee
http://orcid.org/0000-0001-7119-9377
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