Radical Rearrangement of Aryl/Alkylidene Malononitriles via Aza Michael Addition/Decynoformylation/Addition Sequence: An Access to α-Aminonitriles and α-Aminoamides

Article abstract of DOI:10.1021/acs.joc.0c01358

An efficient, safe, and environmentally friendly tertiary butyl hydrogen peroxide (TBHP)-mediated rearrangement of aryl/alkylidene malononitrile with anilines has been developed with in situ generation of HCN as the cyanide source for the synthesis of sub

Full text of DOI:10.1021/acs.joc.0c01358

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Article
Radical Rearrangement of Aryl/Alkylidene Malononitriles via Aza
Michael Addition/Decynoformylation/Addition Sequence: An Access
to α‑Aminonitriles and α‑Aminoamides
Shubhangi P. Bhoite,§ Ajay H. Bansode,§ and Gurunath Suryavanshi*
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ABSTRACT: An efficient, safe, and environmentally friendly tertiary butyl hydrogen peroxide (TBHP)-mediated rearrangement of
aryl/alkylidene malononitrile with anilines has been developed with in situ generation of HCN as the cyanide source for the synthesis
of substituted α-aminonitriles and α-aminoamide. A diverse set of α-aminonitriles and α-aminoamides was efficiently synthesized in
good to excellent yields. This method features a broad substrate scope and good functional group tolerance, and the in situ-generated
HCN bypasses the use of an external cyanide source.
modifications have been reported using different cyanide
sources such as TMSCN,7a Et2AlCN,7b ethyl cyanoformate,7c
acetone cyanohydrin,7d and Bu3SnCN7e under various reaction
conditions. Additionally, various catalysts such as La(O-iPr)3,8a
InCl3,8b BiCl3,8c NiCl2,8d RuCl3,8e Cu(OTf)2,8f sulfonium
salts,8g indium MOF,8h MCM-41 mesoporous silica,8i chitosan-
(biopolymer catalyst),8j organocatalysts,9 Lewis bases such as
INTRODUCTION
■
α-Aminonitriles are important precursors for the synthesis of
natural and unnatural amino acids,1a,b biologically active drug
molecules such as saframycin A1c and phthalascidin,1d nitrogen-
containing heterocycles,2 amino alcoholss,3 and pharmaceutical
intermediates.4 The α-amino amide and their analogues have
gained attention because of their importance in pharmaceutical
compounds (e.g., ampicillin, cefachlor, and teneligliptin) and
utility in natural product synthesis such as vancomycin and
related glycopeptides (Figure 1).5 In 1850, Adolph Strecker, for
the first time, described the synthesis of α-aminonitriles in his
popular three-component reaction of aldehydes, amines, and
hydrogen cyanide.6 Over the succeeding decades, significant
7a
Et3N,8f and even montmorillonite KSF6 and iodine10 were
successfully used for the synthesis of α-aminonitriles (Scheme
1). Recently, the catalytic enantioselective Strecker reaction
(cyanation of imines) has been established for the asymmetric
synthesis of α-aminonitriles.11 In previous decades, few methods
were reported for the synthesis of α-aminoamides through
tantalum−imine complexes with isocyanates,12a from disulfo-
nyloxiranes,12b with arylboronic acid via imino amides.12c
However, most of these transformations over-relied on the
use of different cyanide sources and metal catalysts. These
traditional methods require toxic reagents and unavoidable
generation of toxic byproducts. In contrast, environmentally
Received: June 8, 2020
Figure 1. Natural products having α-aminonitriles and α-aminoamides.
https://dx.doi.org/10.1021/acs.joc.0c01358
© XXXX American Chemical Society
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A

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Scheme 1. Strategies for the Synthesis of α-Aminonitriles
a
benign, safe, efficient, and metal-free methods using simple and
safe reagents are desirable and need to be developed.
Table 1. Optimization of the Reaction Conditions
In our previous report, we have shown the efficient synthesis13
of aryl/alkylidene malononitrile and its further use as a diene for
cycloaddition reaction14 and for the synthesis of 2-cyanoacry-
lamides and 3-substituted azetidine-2,4-diones.15 These findings
prompted us to investigate the further applicability of the aryl/
alkylidene malononitrile to the synthesis of substituted α-
aminonitriles. Continuing with our efforts toward the develop-
ment of metal-free methodologies,16 herein, we have developed
TBHP-mediated rearrangement of aryl/alkylidene malononi-
trile for the synthesis of α-aminonitriles and α-aminoamide.
b
entry oxidant (equiv)
solvent
DMF
toluene
time (h) temp. (°C) yield (%)
1
2
2
3
4
5
6
7
8
9
10
11
TBHP (2.0)
TBHP (2.0)
TBHP (2.0)
TBHP (2.0)
TBHP (3.0)
TBHP (4.0)
TBHP (3.0)
TBHP (3.0)
TBHP (3.0)
DTBP (3.0)
H2O2 (3.0)
TBHP (3.0)
12
12
12
12
12
12
24
12
12
12
12
12
100
100
70
70
70
70
70
70
70
70
70
70
trace
32
toluene
41
68
86
83
1,4-dioxane
1,4-dioxane
1 4-dioxane
1,4-dioxane
THF
RESULTS AND DISCUSSION
■
58
We began with optimization using 2-benzylidene malononitrile
1a, tertiary butyl hydrogen peroxide (TBHP, 5−6 M in decane),
and anilines as a nucleophile. When 2-benzylidene malononitrile
(1a, 1 equiv) as the substrate, aniline (2a), TBHP (2 equiv), and
DMF as a solvent were heated for 12 h at 100 °C, however, the
product 3a was obtained only in a trace amount (Table 1, entry
1). An expected product was obtained in 32 and 41% yield with
the change in solvent and temperature (Table 1, entries 2, 3).
Significant improvement up to 68% yield of α-aminonitriles was
observed when the toluene was replaced with 1,4-dioxane and
TBHP (2 equiv) and heated at 70 °C for 12 h. The yield of a
product further improved to 86% with 3 equivalents of TBHP in
1,4-dioxane at 70 °C for 12 h (Table 1, entry 4). However, the α-
aminonitriles were obtained up to 86% yield, even after an
intensive screening of reaction conditions such as variation in
equivalents of the oxidant, time, and different polar solvents such
as acetonitrile, DMF, and THF (Table 1, entries 5−10).
Surprisingly, when the reaction was carried out between 1 equiv
arylidene malononitrile (1) and 2 equivalents of aniline (2)
under the optimized reaction conditions for α-aminonitriles, we
observed the formation of α-aminonitriles (3) in a trace amount
and α-aminoamide (4) as a major product (Table 1, entry 11).
NR
NR
NR
NR
trace
MeCN
1,4-dioxane
1,4-dioxane
1,4-dioxane
c
d
a
Reaction condition: 1a (1 equiv), 2a (1 equiv), and TBHP (3 equiv)
in 1,4-dioxane at 70 °C in an oil bath for 12 h. Isolated yields, NR:
No reaction. 2 equiv of aniline (1). α-aminoamide (4) major
b
c
d
product.
Having optimized the reaction conditions in hand, scope and
limitation of aryl/alkylidene malononitriles and aniline were
investigated, as shown in Scheme 2. Generally, electron-
donating and -withdrawing group substitutions on aryl/
alkylidene malononitriles moieties effect reaction efficiency.
Similarly, the reaction was sensitive for electronic properties of
the substitution on anilines. The substrates having donating
substitution on aryl/alkylidene malononitriles offered α-amino-
nitriles (3f−g, 3i−j, and 3l, 76−84%) in good to excellent yield
and withdrawing substitution on arylidene malononitriles
offered α-aminonitriles (3h, and 3k, 69−73%) in moderate to
B
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a
Scheme 2. Substrate Scope for α-Aminonitriles
a
Reaction condition: 1a (1 equiv), 2a (1 equiv), and TBHP (3 equiv, 5−6 M in decane) in 1,4-dioxane at 70 °C in an oil bath for 12 h.
good yield. Notably, the α-aminonitriles (3b, 89%) were
obtained in excellent yield, when electron-rich anilines were
used. As substrates bearing both electron-donating groups (3c,
3m, and 3p, 85−87%) and electron-withdrawing groups (3d−e
and 3n, 64−75%), without substitution on arylidene malononi-
triles and aniline, gave desired product 3a in 86% yield in
millimolar scale and 1.2 gm, 80% yield in gram-scale synthesis. It
is noteworthy to mention that sterically hindered substrates with
the substitution at ortho position underwent radical rearrange-
ment very smoothly and gave the desired product α-amino-
nitriles in good yields (3c, 3m−n, and 3p−q). The nitro-
substituted aniline with substituted arylidene malononitriles was
unable to give the desired product (3o, 0%) under the optimized
reaction condition. After successful screening of arylidene
malononitriles, for the scope of the reaction to be developed,
various heterocyclic arylidene malononitriles were also inves-
tigated for synthesis of heterocyclic α-aminonitriles, and the
results are summarized in Scheme 2. To our delight, the
optimized reaction condition works well with heterocyclic and
alkylidene malononitriles and furnished heterocyclic (3r−s) and
aliphatic α-aminonitriles (3t) in good to excellent yield of the
product. Fortunately, some arylidene malononitriles also
favored the optimized reaction condition (Table 1, entry 10)
and afforded the corresponding α-aminoamide products in good
yields (4a−e, Scheme 3). The nitro-substituted arylidene
malononitrile with p-toluidine (2 equiv) was unable to give
the desired product (4f, Scheme 3) under the optimized
reaction condition.
Based on the previously reported reactions,17 a plausible
reaction mechanism was proposed for synthesis of α-amino-
nitriles (3) (Scheme 4). First, the reaction was initiated with 1,4-
addition of aniline on arylidene malononitrile to form
intermediate I. Under heating conditions, homolytic cleavage
of TBHP generates the tertiary butoxide radical. Tertiary
butoxide radical species then abstract a hydrogen from the α-
position of dicyanide to generate radical intermediates II, which
preferentially react with the tertiary butyl peroxide radical
(formed from 2 mol of TBHP), leading to the intermediate
III.17a The tertiary butyl peroxide intermediate III was reduced
to cyanohydrin intermediate IV. Subsequently, the elimination
of hydrogen cyanide from cyanohydrin intermediate IV formed
aryl amino acetyl-cyanide intermediate V. As reported,
elimination of formyl cyanide from intermediate V generated
imine intermediate VI (confirmed by NMR). Finally, the
addition of HCN across imine gave the desired product α-
aminonitriles (3). Possibly, α-aminoamide (4) could be formed
from reaction of excess aniline (1) with the nitrile group of α-
aminonitriles (3) through intermediate VIII. The homolytic
cleavage of 3 mol of TBHP will generate 2 mol of hydroxy
radicals. Subsequently, these hydroxy radicals quenched with
1,4-dioxane (used as a solvent) formed intermediates S1 and
S2.17c
C
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a
Scheme 3. Substrate Scope for α-Aminoamide
a
Reaction condition: 1 (1 equiv), 2 (2 equiv), and TBHP (3 equiv, 5−6 M in decane) in 1,4-dioxane at 70 °C in an oil bath for 12 h.
Scheme 4. Plausible Reaction Mechanism
value of products, makes this protocol useful for organic
synthesis and medicinal chemistry as well.
CONCLUSIONS
■
We have developed a safe, efficient, metal-free, and external
cyanide source-free method for synthesis of substituted α-
aminonitriles (3) and α-aminoamide (4) in good to excellent
yields from the simple starting material. The simple starting
material, without the use of any cyanide source, inexpensive
reagents, high yields, good functional group tolerance, and the
EXPERIMENTAL SECTION
■
1
General Procedure. The H and 13C{1H} NMR spectra were
recorded on a Bruker advance 500 (1H:500 MHz, 13C:125 MHz) or
Bruker advance 400 (1H:400 MHz, 13C:100 MHz) or Bruker advance
200 (1H:200 MHz, 13C:50 MHz) unless otherwise mentioned.
Spectrometers used CDCl3 with the residual undeuterated solvent
D
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(CDCl3, 7s.26/77.00) as an internal standard. Deuterated solvent
CDCl3 + CCl4 (70:30) was also used as an internal standard, and the
singlet at 96.1 ppm in 13C{1H} NMR corresponds to carbon of CCl4.
The following abbreviations were used to explain the multiplicities: s =
singlet, d = doublet, t = triplet, q = quartet, m = multiple, and br = broad.
Chemical shifts are reported in ppm and referenced to the residual
solvent peak or TMS. Coupling constants are reported in Hertz. High-
resolution mass spectra (HRMS) for all compounds were recorded
using an ESI+ method and Orbitrap mass analyzer (Thermo Scientific
Q-Exactive, Accela 1250 pump).
General Procedure for Synthesis of Aryl/Alkylidene Malo-
nonitrile (1). To a solution of benzaldehyde (1 equiv) and
malononitrile (1.5 equiv) in CH2Cl2 (15 mL) was added K2CO3 (0.5
equiv). The reaction mixture was stirred at room temperature for 12 h.
After completion of reaction (monitored by TLC), the solvent was
evaporated under reduced pressure. The crude was quenched with ice
cold water and extracted with EtOAc (10 mL* 3). The combined
organic layer was washed with brine and dried over Na2SO4. The
solvent was removed under reduced pressure, the residue was purified
by column chromatography using 100−200 mesh silica gel, and 10%
ethyl acetate in petroleum ether as an eluting solvent offered
cyanoacrylates.
3H), 6.69−6.80 (m, 2H), 5.34 (d, J = 8.2 Hz, 1H), 3.90−4.01 (1H, m),
3.83 (3H, s); 13C{1H} NMR (50 MHz, CDCl3 + CCl4): δ 160.5, 144.8,
133.4, 129.6, 128.6, 126.1, 120.3, 114.7, 114.2, 55.3, 49.7; HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C15H15ON2, 239.1179; found,
239.1180.
2-(2-Methoxyphenyl)-2-((2-methoxyphenyl)amino) Acetonitrile
1
(3c). Yield: 73 mg, 85%; yellow solid; mp 94−96 °C; H NMR (200
MHz, CDCl3 + CCl4): δ 7.55 (dd, J = 7.5, 1.6 Hz, 1H), 7.40 (td, J = 7.9,
1.6 Hz, 1H), 7.02−7.09 (m, 1H), 6.88−7.01 (m, 2H), 6.76−6.86 (m,
3H), 5.62 (d, J = 5.9 Hz, 1H), 4.82 (d, J = 8.4 Hz, 1H) 3.93 (s, 3H), 3.86
(s, 3H); 13C{1H} NMR (50 MHz, CDCl3 + CCl4): δ 156.8, 147.6,
134.9, 130.8, 128.7, 122.8, 121.3, 121.2, 119.3, 118.5, 111.8, 111.3,
110.0, 55.7, 55.5, 45.0; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C16H17O2N2 269.1285; found, 269.1284.
2-((4-Chlorophenyl)amino)-2-(4-fluorophenyl) Acetonitrile
(3d).7a Yield: 25 mg, 72%; yellow solid; mp 95−97 °C; H NMR
1
(200 MHz, CDCl3): δ 7.59 (dd, J = 8.8, 5.0 Hz, 2H), 7.21−7.28 (m,
2H), 7.14−7.19 (m, 2H), 6.69−6.73 (m, 2H), 5.39 (d, J = 7.6 Hz, 1H),
4.08 (d, J = 8.4 Hz, 1H); 13C{1H} NMR (50 MHz, CDCl3): δ 164.6,
162.2, 143.1, 129.6, 129.4, 129.4, 129.3, 129.2, 125.5, 117.8, 116.7,
116.4, 115.6, 49.7; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C14H11N2ClF, 261.0589; found, 261.0589.
General Procedure for Synthesis of α-Amino Nitrile (3). The
substituted aryl/alkylidene malononitrile (1 equiv), substituted aniline
(1 equiv), and tertiary butyl hydrogen peroxide (3 equiv, 5−6 M in
decane) were added in 1,4-dioxane as a solvent (1 mL). The reaction
mixture was stirred to heat and reflux at 70 °C in an oil bath for 12 h.
After completion of reaction (monitored by TLC), crude was quenched
with ice cold water and extracted with EtOAc (10 mL* 3). The
combined organic layer was washed with brine and dried over Na2SO4.
The solvent was removed under reduced pressure, the residue was
purified by column chromatography using 100−200 mesh silica gel, and
5% ethyl acetate in petroleum ether as an eluting solvent offered α-
amino nitrile.
General Procedure for Synthesis of α-Amino Acetamide (4).
The substituted aryl/alkylidene malononitrile (1 equiv), substituted
aniline (2 equiv), and tertiary butyl hydrogen peroxide (3 equiv, 5−6 M
in decane) were added in 1,4-dioxane as a solvent (1 mL). The reaction
mixture was stirred to heat and reflux at 70 °C in an oil bath for 12 h.
After completion of reaction (monitored by TLC), the crude was
quenched with ice cold water and extracted with EtOAc (10 mL* 3).
The combined organic layer was washed with brine and dried over
Na2SO4. The solvent was removed under reduced pressure, the residue
was purified by column chromatography using 100−200 mesh silica gel,
and 5% ethyl acetate in petroleum ether as an eluting solvent offered α-
aminoamide.
2-(4-Fluorophenyl)-2-((4-fluorophenyl) Amino) Acetonitrile
(3e).18d Yield: 51 mg, 75%; white solid; mp 116−118 °C; H NMR
1
(200 MHz, CDCl3): δ 7.51−7.66 (m, 2H), 7.17 (t, J = 8.4 Hz, 2H),
6.92−7.04 (m, 2H), 6.71−6.78 (m, 2H), 5.36 (d, J = 8.4 Hz, 1H), 3.94
(d, J = 8.4 Hz, 1H); 13C{1H} NMR (50 MHz, CDCl3): δ 164.2, 161.7,
158.4, 156.0, 140.4, 129.3, 128.8, 117.6, 116.2, 116.0, 116.0, 115.8,
115.6, 115.5, 50.1; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C14H11N2F2, 245.0885; found, 245.0885.
2-(2-Methoxyphenyl)-2-(phenylamino) Acetonitrile (3f).18b Yield:
74 mg, 81%; yellow gummy oil; 1H NMR (200 MHz, CDCl3 + CCl4): δ
7.49 (dd, J = 1.6, 7.6 Hz, 1H), 7.44−7.32 (m, 1H), 7.29−7.19 (m, 2H),
7.07−7.00 (m, 1H), 7.00−6.93 (m, 1H), 6.91−6.80 (m, 1H), 6.79−
6.72 (m, 2H), 5.55 (br s, 1H), 4.35−4.17 (m, 1H), 3.91 (s, 3H);
13C{1H} NMR (50 MHz, CDCl3 + CCl4): δ 156.7, 145.0, 130.9, 129.4,
128.8, 122.6, 121.2, 120.0, 118.4, 114.3, 111.4, 55.7, 45.7; HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C15H15ON2, 239.1179; found,
239.1177.
2-(Phenylamino)-2-(o-tolyl) Acetonitrile (3g).18f Yield: 34 mg,
1
76%; yellow solid; mp 107−109 °C; H NMR (200 MHz, CDCl3 +
CCl4): δ 7.73 (d, J = 7.2 Hz, 1H), 7.40−7.33 (m, 2H), 7.33−7.27 (m,
3H), 6.92 (t, J = 7.2 Hz, 1H), 6.81 (d, J = 8.0 Hz, 2H), 5.49 (d, J = 8.0
Hz, 1H), 3.86 (d, J = 8.0 Hz, 1H), 2.41 (s, 3H); 13C{1H} NMR (50
MHz, CDCl3 + CCl4): δ 144.8, 136.4, 132.2, 131.3, 129.7, 129.6, 127.6,
127.0, 120.2, 118.2, 113.9, 48.1, 18.7; HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C15H15N2, 223.1230; found, 223.1230.
Procedure for Gram-Scale Synthesis of 2-Phenyl-2-(phenyl-
amino) Acetonitrile (3a). 2-Benzylidenemalononitrile (1.11 gm, 7.2
mmol), aniline (0.67 gm, 7.2 mmol), and TBHP (4.3 mL, 21.6 mmol,
5−6 M in decane) were added in 1,4-dioxane (10 mL) as a solvent. The
reaction mixture was stirred to heat and reflux at 70 °C in an oil bath for
12 h. After completion of reaction (monitored by TLC), crude was
quenched with ice cold water and extracted with EtOAc (30 mL* 3).
The combined organic layer was washed with brine and dried over
Na2SO4. The solvent was removed under reduced pressure, the residue
was purified by column chromatography using 100−200 mesh silica gel,
and 5% ethyl acetate in petroleum ether as an eluting solvent offered 2-
phenyl-2-(phenylamino) acetonitrile (3a) (1.2 gm, 80% yield) as a
yellow solid.
2-(2-Chlorophenyl)-2-(phenylamino)acetonitrile (3h).18b Yield:
57 mg, 69%; yellow solid; mp 67−70 °C; 1H NMR (400 MHz,
CDCl3): δ 7.70−7.80 (m, 1H), 7.45−7.55 (m, 1H), 7.36−7.45 (m,
2H), 7.24−7.36 (m, 2H), 6.93 (t, J = 7.2 Hz, 1H), 6.81 (d, J = 7.6 Hz,
2H), 5.75 (d, J = 8.4 Hz, 1H), 4.09 (d, J = 7.6 Hz, 1H); 13C{1H} NMR
(101 MHz, CDCl3): δ 144.5, 133.5, 131.7, 131.0, 130.4, 129.5, 129.0,
127.8, 120.4, 117.7, 114.2, 48.0; HRMS (ESI-TOF) m/z: [M + H]+
calcd for C14H12N2Cl, 243.0684; found, 243.0686.
2-(4-Methoxyphenyl)-2-(phenylamino)acetonitrile (3i).18a Yield:
45 mg, 84%; yellow Solid: 94−95 °C; 1H NMR (200 MHz, CDCl3 +
CCl4): δ 7.52 (d, J = 8.5 Hz, 2H), 7.33−7.28 (m, 2H), 6.98 (d, J = 8.5
Hz, 2H), 6.95−6.87 (m, 1H), 6.79 (d, J = 7.9 Hz, 2H), 5.38 (d, J = 7.9
Hz, 1H), 3.97 (d, J = 7.3 Hz, 1H), 3.85 (s, 3H); 13C{1H} NMR (50
MHz, CDCl3 + CCl4): δ 160.5, 144.8, 133.4, 129.6, 128.6, 126.1, 120.3,
118.3, 115.2, 114.7, 114.2, 55.3, 49.7; HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C15H15N2O, 239.1179; found, 239.1181.
2-Phenyl-2-(phenylamino)acetonitrile (3a).18a Yield: 110 mg, 86%
1
and 1.2 g, 80%; yellow solid; mp 80−82 °C; H NMR (200 MHz,
CDCl3 + CCl4): δ 7.77−7.62 (m, 2H), 7.61−7.47 (m, 3H), 7.43−7.29
(m, 2H), 7.05−6.93 (m, 1H), 6.85 (d, J = 7.7 Hz, 2H), 5.51 (d, J = 8.0
Hz, 1H), 4.09 (d, J = 7.7 Hz, 1H); 13C{1H} NMR (50 MHz, CDCl3 +
CCl4): δ 144.7, 134.1, 129.6, 129.6, 129.4, 127.3, 120.4, 118.0, 114.2,
50.3; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C14H13N2, 209.1073;
found, 209.1075.
2-(4-(Methylthio)phenyl)-2-(phenylamino) Acetonitrile (3j). Yield:
1
84 mg, 82%; yellow solid; mp 104−105 °C; H NMR (500 MHz,
CDCl3): δ 7.48 (d, J = 8.2 Hz, 2H), 7.28−7.31 (m, 1H), 7.28 (s, 1H),
7.22−7.26 (m, 2H), 6.86−6.92 (m, 1H), 6.75 (dd, J = 8.7, 0.9 Hz, 2H),
5.37 (d, J = 8.2 Hz, 1H), 3.99 (d, J = 8.2 Hz, 1H), 2.49 (s, 3H); 13C{1H}
NMR (101 MHz, CDCl3): δ 144.6, 140.8, 130.3, 129.6, 127.6, 126.7,
2-((4-Methoxyphenyl) amino)-2-phenylacetonitrile (3b).18a Yield:
92 mg, 89%; yellow solid; mp 63−65 °C; 1H NMR (200 MHz, CDCl3 +
CCl4): δ 7.43−7.55 (m, 2H), 7.30 (s, 1H), 7.22 (s, 1H), 6.87−6.99 (m,
E
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120.3, 118.1, 114.2, 49.8, 15.4; HRMS (ESI-TOF) m/z: [M + H]+ calcd
for C15H15N2S, 255.0950; found, 255.0950.
(ESI-TOF) m/z: [M + H]+ calcd for C10H13N2 161.1073; found,
161.1072.
2-(4-Fluorophenyl)-2-(phenylamino) Acetonitrile (3k).18a Yield:
2-(4-Fluorophenyl)-N-(p-tolyl)-2-(p-tolylamino) Acetamide (4a).
1
1
Yield: 55 mg, 68%; gummy liquid; H NMR (200 MHz, CDCl3 +
50 mg, 73%; yellow solid; mp 108−110 °C; H NMR (200 MHz,
CCl4): δ 8.8 (s, 1H), 7.4−7.5 (m, 4H), 7.0−7.1 (m, 6H), 6.6 (d, J = 8.3
Hz 2H), 4.8 (s, 1H), 4.3 (br s, 1H), 2.3 (s, 3H), 2.3 (s, 3H); 13C{1H}
NMR (50 MHz, CDCl3 + CCl4): δ 169.2, 144.0, 135.3, 134.7, 134.2,
130.0, 129.6, 129.5, 129.4, 129.3, 129.1, 120.4, 120.0, 116.4, 116.0,
115.5, 114.2, 64.9, 20.9, 20.5; HRMS (ESI-TOF) m/z: [M + H]+ calcd
for C22H22ON2F, 349.1711; found, 349.1714.
2-(4-Methoxyphenyl)-N-(p-tolyl)-2-(p-tolylamino) Acetamide
(4b). Yield: 64 mg, 77%; gummy liquid; 1H NMR (200 MHz, CDCl3
+ CCl4): δ 8.8 (s, 1H), 7.4−7.5 (m, 4H), 7.0−7.2 (m, 4H), 6.9−7.0 (m,
2H), 6.6 (d, J = 8.1 Hz, 2H), 4.7 (s, 1H), 4.3 (br s, 1H), 3.8 (s, 3H), 2.3
(s, 3H), 2.3 (s, 3H); 13C{1H} NMR (50 MHz, CDCl3 + CCl4): δ 169.2,
159.1, 143.6, 134.2, 133.5, 130.1, 129.3, 128.8, 128.4, 128.0, 119.3,
113.9, 113.5, 64.4, 54.6, 20.2, 19.7; HRMS (ESI-TOF) m/z: [M + H]+
calcd for C23H25O2N2, 361.1911; found, 361.1922.
CDCl3 + CCl4): δ 7.68−7.57 (m, 2H), 7.48 (d, J = 1.9 Hz, 1H), 7.46 (d,
J = 2.1 Hz, 1H), 7.34−7.28 (m, 1H), 7.26−7.18 (m, 1H), 6.97−6.85
(m, 1H), 6.78 (d, J = 7.6 Hz, 2H), 5.44 (d, J = 8.3 Hz, 1H), 4.01 (d, J =
8.0 Hz, 1H); 13C{1H} NMR (50 MHz, CDCl3 + CCl4): δ 160.6, 144.7,
134.1, 129.6, 129.4, 127.3, 120.4, 114.2, 50.3; HRMS (ESI-TOF) m/z:
[M + H]+ calcd for C14H12N2F, 227.0979; found, 227.0978.
2-(3-Methoxyphenyl)-2-(phenylamino)acetonitrile (3l).18e Yield:
55 mg, 77%; yellow solid; mp 95−96 °C; 1H NMR (200 MHz, CDCl3):
δ 7.33−7.39 (m, 1H), 7.22−7.30 (m, 2H), 7.07−7.21 (m, 2H), 6.85−
7.01 (m, 2H), 6.77 (d, J = 9.2 Hz, 2H), 5.39 (d, J = 8.4 Hz, 1H), 4.08 (d,
J = 8.4 Hz, 1H), 3.82 (s, 3H); 13C{1H} NMR (50 MHz, CDCl3): δ
159.9, 144.3, 135.0, 130.0, 129.2, 120.0, 119.0, 117.8, 113.7, 114.7,
112.4, 55.1, 49.7; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C15H15ON2, 239.1179; found, 239.1178.
2-(3-Methoxyphenyl)-N-(4-methoxyphenyl)-2-((4-methoxyphen-
2-((4-Methoxyphenyl)amino)-2-(o-tolyl) Acetonitrile (3m). Yield:
1
1
yl) Amino) Acetamide (4c). Yield: 150 mg, 72%; dark brown oil; H
74 mg, 85%; yellow solid; mp 102−105 °C; H NMR (200 MHz,
NMR (200 MHz, CDCl3 + CCl4): δ 7.3−7.5 (m, 2H), 7.1−7.2 (m,
2H), 6.9−7.0 (m, 2H), 6.8−6.9 (m, 2H), 6.7−6.8 (m, 3H), 6.6−6.7 (m,
1H), 5.3 (br s, 1H), 3.9 (d, J = 3.1 Hz, 1H), 3.8 (s, 3H), 3.8 (s, 3H), 3.7
(s, 3H); 13C{1H} NMR (50 MHz, CDCl3 + CCl4): δ 160.2, 154.1,
152.8, 139.8, 138.5, 135.5, 130.3, 119.3, 116.5, 116.3, 116.2, 115.1,
115.0, 114.8, 112.7, 55.7, 55.6, 55.4, 51.5. HRMS (ESI-TOF) m/z: [M
+ H]+ calcd for C23H25O4N2, 393.1809; found, 393.1802.
CDCl3 + CCl4): δ 7.66−7.74 (m, 1H), 7.30−7.37 (m, 2H), 7.27 (d, J =
4.9 Hz, 2H), 6.82−6.92 (m, 2H), 6.73−6.82 (m, 2H), 5.40 (br s, 1H),
3.79 (s, 3H), 2.43 (s, 3H); 13C{1H} NMR (50 MHz, CDCl3 + CCl4): δ
154.2, 138.8, 136.5, 132.4, 131.3, 129.7, 127.6, 126.9, 116.0, 115.1, 55.6,
49.5, 18.7; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C16H17ON2,
253.1335; found, 253.1335.
2-(2-Chlorophenyl)-2-((4-fluorophenyl) amino) Acetonitrile
(3n).18g Yield: 50 mg, 64%; yellow solid; mp 97−98 °C; H NMR
1
N,2-Di-p-tolyl-2-(p-tolylamino) Acetamide (4d). Yield: 63 mg,
1
69%; gummy liquid; H NMR (200 MHz, CDCl3 + CCl4): δ 8.7 (s,
(200 MHz, CDCl3): δ 7.71−7.76 (m, 1H), 7.47−7.52 (m, 1H), 7.39−
7.44 (m, 2H), 7.22−7.27 (m, 1H), 7.11 (t, J = 8.8 Hz, 1H), 6.97−7.01
(m, 1H), 6.76−6.79 (m, 1H), 5.66 (d, J = 8.4 Hz, 1H), 3.95 (d, J = 8.4
Hz, 1H); 13C{1H} NMR (50 MHz, CDCl3): δ 156.7, 140.8, 133.5,
131.5, 131.1, 130.5, 129.0, 127.8, 116.3, 116.0, 116.0, 49.0; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C14H11N2ClF, 261.0589; found,
261.0587.
1H), 7.4 (t, J = 8.0 Hz, 4H), 7.0−7.2 (m, 2H), 6.6 (d, J = 8.2 Hz, 2H),
4.7 (s, 1H), 4.3 (br s, 1H), 2.4 (s, 3H), 2.3 (s, 3H), 2.3 (s, 3H); 13C{1H}
NMR (50 MHz, CDCl3 + CCl4): δ 169.5, 144.3, 138.4, 135.8, 134.9,
134.0, 130.0, 129.4, 129.0, 127.3, 127.1, 120.2, 119.9, 114.2, 65.4, 21.2,
20.9, 20.5. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C23H25ON2,
345.1961; found, 345.1965.
2-(Naphthalen-1-yl)-N-(p-tolyl)-2-(p-tolylamino)acetamide (4e).
Yield: 26 mg, 75%; faint brown oil; 1H NMR (200 MHz, CDCl3): δ 9.1
(s, 1H), 7.9−8.0 (m, 3H), 7.5−7.6 (m, 6H), 7.1−7.2 (m, 4H), 6.7 (d, J
= 8.3 Hz, 2H), 5.6 (s, 1H), 4.3 (br s, 1H), 2.3 (s, 3H), 2.3 (s, 3H);
13C{1H} NMR (50 MHz, CDCl3): δ 169.5, 143.9, 133.9, 129.5, 128.9,
128.8, 128.5, 126.5, 125.5, 124.9, 124.5, 119.3, 113.5, 61.7, 20.2, 19.8;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C26H25ON2, 381.1961;
found, 381.1969.
2-(4-Methoxyphenyl)-2-((2-methoxyphenyl) amino) Acetonitrile
1
(3p). Yield: 34 mg, 87%; yellow oil; H NMR (200 MHz, CDCl3 +
CCl4): δ 7.55 (dd, J = 7.6, 1.4 Hz, 1H), 7.35−7.47 (m, 1H), 7.03−7.11
(m, 1H), 6.89−7.03 (m, 2H), 6.76−6.87 (m, 3H), 5.63 (d, J = 6.4 Hz,
1H), 4.82 (br s, 1H), 3.93 (s, 3H), 3.86 (s, 3H); 13C{1H} NMR (50
MHz, CDCl3 + CCl4): δ 156.8, 147.9, 134.9, 130.8, 128.7, 122.8, 121.3,
121.2, 119.3, 118.5, 111.8, 111.3, 110.0, 55.8, 55.5, 45.0; HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C16H17N2O2, 269.1285; found,
269.1285.
1
Imine Intermediate (VI). Yield: 8 mg, White solid; H NMR (200
2-(Naphthalen-1-yl)-2-(phenylamino)acetonitrile (3q).18c Yield:
24 mg, 76%; gummy oil; 1H NMR (200 MHz, CDCl3): δ 7.98 (d, J = 7.4
Hz, 4H), 7.46−7.74 (m, 4H), 7.35 (t, J = 7.8 Hz, 2H), 6.77−7.11 (m,
3H), 6.05 (d, J = 7.7 Hz, 1H), 4.09 (d, J = 7.8 Hz, 1H); 13C{1H} NMR
(101 MHz, CDCl3): δ 144.8, 134.0, 130.7, 129.7, 129.1, 127.5, 126.6,
126.3, 125.3, 122.8, 120.2, 113.7 48.4; HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C18H15N2, 259.1230; found, 259.1229.
MHz, CDCl3): δ 8.47 (s, 1H), 7.90−7.94 (m, 2H), 7.50 (d, J = 2.0 Hz,
2H), 7.49 (d, J = 1.8 Hz, 1H), 7.38−7.44 (m, 2H), 7.20−7.26 (m, 3H);
13C{1H} NMR (50 MHz, CDCl3): δ 160.5, 152.0, 136.2, 131.4, 129.1,
128.8, 128.8, 125.9, 120.9.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c01358.
■
sı
2-(3-Methylthiophen-2-yl)-2-(phenylamino)acetonitrile (3r).
Yield: 80 mg, 64%; brown solid; mp 96−98 °C; 1H NMR (200 MHz,
CDCl3): δ 7.21−7.30 (m, 3H), 6.92 (d, J = 7.4 Hz, 1H), 6.88 (d, J = 5.3
Hz, 1H), 6.79 (s, 1H), 6.75 (s, 1H), 5.52 (d, J = 7.5 Hz, 1H), 4.06 (d, J =
7.2 Hz, 1H), 2.31 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3): δ 144.4,
136.8, 130.9, 129.6, 125.0, 120.4, 115.1, 114.2, 44.2, 13.9; HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C13H13N2S, 229.0794; found, 229.0795.
2-(5-Bromothiophen-2-yl)-2-(phenylamino)acetonitrile (3s).
Yield: 65 mg, 67%; brown oil; 1H NMR (200 MHz, CDCl3): δ
7.27−7.34 (m, 2H), 7.15 (d, J = 3.1 Hz, 1H), 7.02 (d, J = 3.8 Hz, 1H),
6.80 (d, J = 7.6 Hz, 2H), 5.58 (d, J = 7.5 Hz, 1H), 4.22 (d, J = 9.2 Hz,
1H); 13C{1H} NMR (101 MHz, CDCl3): δ 152.0, 143.8, 138.2, 129.9,
129.6, 129.1, 127.3, 121.2, 114.8, 46.4; HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C12H10N2BrS, 292.9743; found, 292.9740.
1H and 13C spectra of all compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Gurunath Suryavanshi − Chemical Engineering & Process
Development Division, CSIR-National Chemical Laboratory,
Pune 411008, India; Academy of Scientific and Innovative
Research (AcSIR), New Delhi 110 025, India; orcid.org/
0000-0002-6299-0914; Phone: 020-2590-2547;
Email: gm.suryavanshi@ncl.res.in; Fax: 020-2590-2676
2-(Phenylamino) Butane Nitrile (3t).18a Yield: 65 mg, 76%; brown
liquid; 1H NMR (200 MHz, CDCl3): δ 7.2−7.3 (m, 2H), 6.9 (tt, J = 7.4,
1.1 Hz, 1H), 6.7−6.7 (m, 2H), 4.1−4.2 (m, 1H), 3.8 (d, J = 8.9 Hz, 1H),
1.9−2.0 (m, 2H), 1.2 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (101 MHz,
CDCl3): δ 144.9, 129.5, 119.9, 119.4, 114.0, 47.3, 26.9, 10.1; HRMS
Authors
Shubhangi P. Bhoite − Chemical Engineering & Process
Development Division, CSIR-National Chemical Laboratory,
F
https://dx.doi.org/10.1021/acs.joc.0c01358
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Aldehydes, Amines, and Hydrogen Cyanide Using a Chiral Zirconium
Catalyst. J. Am. Chem. Soc. 2000, 122, 762−766.
Pune 411008, India; Academy of Scientific and Innovative
Research (AcSIR), New Delhi 110 025, India
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Ajay H. Bansode − Chemical Engineering & Process Development
Division, CSIR-National Chemical Laboratory, Pune 411008,
India; Academy of Scientific and Innovative Research (AcSIR),
New Delhi 110 025, India
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c01358
Author Contributions
§S.P.B. and A.H.B. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
S.P.B. is thankful to CSIR, and A.H.B. is thankful to UGC, New
Delhi, India, for the award of research fellowship.
́
́
M.; Iglesias, M.; Snejko, N.; Gutierrez-Puebla, E.; Monge, M. A.;
́
Gandara, F. A Mesoporous Indium Metal-Organic Framework:
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