An umpolung reaction of α-iminonitriles and its application to the synthesis of aminomalononitriles

Article abstract of DOI:10.1039/c9nj05114g

An umpolung N-alkylation reaction of α-iminonitriles with Grignard reagents affords the corresponding N-alkylated α-aminonitriles in good yields. Subsequent oxidation and cyanation of the N-alkylated products proceeds effectively to give aminomalononitriles in good yields, and the presence of dichlorodimethylsilane as an additive is crucial for obtaining the optimum yield. Furthermore, an electrophilic addition reaction of the intermediate halomagnesium vinylideneamide is shown to give the alkylated and acylated products in good yields.

Full text of DOI:10.1039/c9nj05114g

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An umpolung reaction of a-iminonitriles
and its application to the synthesis of
aminomalononitriles†
Cite this: New J. Chem., 2020,
44, 152
ab
a
Makoto Shimizu,
*
Yuki Furukawa,b Isao Mizotab and Yusong Zhu
An umpolung N-alkylation reaction of a-iminonitriles with Grignard reagents affords the corresponding
N-alkylated a-aminonitriles in good yields. Subsequent oxidation and cyanation of the N-alkylated
products proceeds effectively to give aminomalononitriles in good yields, and the presence of
dichlorodimethylsilane as an additive is crucial for obtaining the optimum yield. Furthermore, an
electrophilic addition reaction of the intermediate halomagnesium vinylideneamide is shown to give the
alkylated and acylated products in good yields.
Received 11th October 2019,
Accepted 20th November 2019
DOI: 10.1039/c9nj05114g
rsc.li/njc
including the ethylation reagent, solvent, time, and tempera-
ture were examined. Table 1 summarizes the results.
1 Introduction
The intriguing reactivity of a-iminoesters has broadened the
One of the side reactions associated with the use of
utility of imino compounds as amination reagents and precursors a-iminonitrile 1 as the electrophile is the replacement of
to a-aminoesters via an addition to the imino carbon.1–3 Three the cyano group with a nucleophile, since the cyano group is
reactive positions are available for the addition of nucleophiles to known to be a relatively good leaving group in many organic
a-iminoesters: the first is the imino carbon, the second is the ester transformations.10 This side reaction was the major pathway,
carbonyl group, and the third is the imino nitrogen. The reactions
involving the addition to the nitrogen atom of the imine moiety
are categorized as umpolung reactions because the reversal of the
polarity at the imine part is crucial for this type of reaction. We
have already disclosed several intriguing reactions based on the
umpolung reactivity of a-iminoesters,3 demonstrating that the
alkoxycarbonyl3a–e and dialkoxyphosphoryl4 groups are useful
as electron-withdrawing groups next to the imine moiety for
the umpolung N-alkylations. In addition to these groups, we were
interested in cyano derivatives, since the cyano moiety can be
readily transformed into several useful functional groups such as
amines, amides, and carboxylic acids.5–8 In this paper we examined
the umpolung reactions of a-iminonitriles (Scheme 1).
2 Results and discussion
The starting a-iminonitrile 1 was readily prepared according
to the procedure reported by Masson and Zhu.9 First, the
conditions for the ethylation reaction of a-iminonitrile 1a
a School of Energy Science and Engineering, Nanjing Tech University,
Nanjing 211816, Jiangsu Province, China
b Department of Chemistry for Materials, Graduate School of Engineering,
Mie University, Tsu, Mie 514-8507, Japan. E-mail: mshimizu@chem.mie-u.ac.jp
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
Scheme 1 Reaction of a-iminoesters and a-iminonitriles.
c9nj05114g
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Table 1 N-Ethylation of a-iminonitrile
Table 3 N-Alkylation with various Grignard reagents
Yielda (%)
Entry
R
Time (min)
2: yielda (%)
Nucleophile
Entry (equiv.)
Time
Temp. (1C) (min) 2b
Solv.
3
4
1
2
3
4
5
6
7
8
9
Me
Et
15
15
25
25
35
60
15
15
15
15
2a: 0
2b: 89
2c: 77
2d: 77
2e: 70
2f: 42
2g: 28
2h: 24
2i: 0
1
2
3
4
5
6
7
8
EtMgBr/Et2O (1.2) PhCH3
EtMgBr/THF (1.2) PhCH3
Et2AlCl/nhex (2.0) EtCN
À40 to rt 15
À40 to rt 15
À78 to rt 300
À78 to rt 300
76
3
—
14 77
—
—
—
—
9
—
nPr
nBu
nOct
iBu
iPr
Cy
0b
—
—
—
—
18
2
55
—
—
Et2Zn/nhex (2.0)
PhCH3
0c
EtMgBr/Et2O (1.2) PhCH3
EtMgBr/Et2O (1.2) PhCH3
EtMgBr/Et2O (1.2) CH2Cl2
EtMgBr/Et2O (1.2) Et2O
EtMgBr/Et2O (1.2) DME
EtMgBr/Et2O (1.2) nhex
À40
60
60
63
62
52
52d
0
À40 to 0
À40 to rt 15
À40 to rt 15
À40 to rt 15
À40 to rt 15
Ph
Bn
6
10
2j: 0
9
—
—
—
10
43e
74
a
Isolated yield.
11 f
EtMgBr/Et2O (1.2) PhCH3/nhex À40 to rt 15
a
b
c
Isolated yield. Recovery of the starting material (95%). Recovery of
the starting material (89%). Recovery of the starting material (16%).
Recovery of the starting material (46%). The reaction was carried out
d
Under the best N-alkylation conditions found for the sub-
strate 1a (entry 3, Table 2), a variety of Grignard reagents were
subjected to N-alkylation, and Table 3 summarizes the results.
Primary alkyl Grignard reagents were added to the nitrogen
atom in moderate to good yields (entries 2–6), whereas
their sterically bulky secondary alkyl counterparts underwent
the addition sluggishly. In the present N-addition reaction
(entries 7 and 8), methyl, phenyl, and benzyl derivatives did
not give the desired products at all (entries 1, 9, and 10).12
Other a-iminonitriles 1b to 1j were also examined for the
N-ethylation reaction, and Table 4 summarizes the results.
Almost all the substrates examined here participated in the
present N-alkylation reaction to give the desired product 2 in
moderate to good yields. Electron-withdrawing or electron-
donating groups on the aromatic carbons were tolerated and
a sterically congesting 2-bromo group did not decrease the
product yield (entries 2–4). Heteroaromatic substituents such
as 2-pyridyl, 2-furyl, and 2-thienyl were also tolerated (entries 5–7).
We next examined the subsequent oxidation/cyanation reactions,
and Table 5 summarizes the results.
e
f
in toluene : nhexane = 2 : 1 (0.67 M).
when the addition was conducted with the Grignard reagent
prepared in THF or when the reaction was carried out in DME
(entries 2 and 9). Among the ethylation reagents examined,
ethylmagnesium bromide added to the imino nitrogen,
whereas diethylaluminum chloride and diethylzinc were not
effective as the nucleophiles (entries 3 and 4). Regarding the
solvent, EtCN did not promote the present N-ethylation, while
N-ethylation proceeded in toluene, dichloromethane, ether,
and nhexane. The N-ethylation product 2b was not stable under
the purification conditions on silica gel TLC;11 however, silica
gel column chromatography using an eluent containing triethyl-
amine (10 v/v%) was found to be suitable for purification. In
terms of the clearness of the reaction medium, the best result
was obtained when the reaction was carried out in toluene–
nhexane (2: 1) (entry 11), and the product was purified as
summarized in Table 2.
Table 2 Purification conditions for N-ethylation products
Table 4 N-Ethylation of various a-iminonitriles
Entry
1: R
Temp. (1C)
Time (min)
2: yielda (%)
1
2
3
4
1a: Ph
À40 to rt
À10 to rt
À20 to rt
À40 to rt
À78
15
25
35
15
15
15
45
15
15
25
2b: 85
2k: 67
2l: 52
2m: 85
2n: 52
2o: 82
2p: 49
2q: 72
2r: 78
2s: 31
1b: 4-BrC6H4
1c: 4-MeOC6H4
1d: 2-BrC6H4
1e: 2-Pyridyl
1f: 2-Furyl
1g: 2-Thienyl
1h: 1-Naphthyl
1i: 2-Naphthyl
1j: Cy
5b
6b
7c
8b
9
Entry Sol (M)
Purification procedurea 2b: yieldb (%)
À78
1
2
3
4
PhCH3 (0.1)
SiO2 TLC
SiO2 CCc
76
85
89
87
À15
PhCH3 (0.1)
À20 to rt
À40 to rt
À40 to rt
PhCH3/nhex (2 : 1, 0.07) SiO2 CCc
PhCH3/nhex (1 : 1, 0.03) SiO2 CCc
10
a
b
c
a
b
Et3N (10 v/v%) was added to the eluent. Isolated yield. Column
Isolated yield. The reaction was carried out in toluene (0.033 M).
EtMgBr in Et2O (1.5 equiv.) was used.
c
chromatography.
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Table
5
Examination of chlorosilanes for the synthesis of a-amino
Table 7 Examination of cyanation reagents
malononitrile
Yielda (%)
R4ÀnSiCln
Entry (equiv.)
Time
Temp.
Entry
Cyanide (equiv.)
Time (h)
Yielda (%)
Temp. 1 (1C) (min) 2 (1C)
5a
6
1
2
3
4
5
6
7
8
—
—
—
—
—
—
À40
0
—
—
—
15
15
60
15
15
60
15
15
0
49
49
—
—
1
2
3
4
5
6
7
8
TMSCN (1.2)
TMSCN (1.2)
TMSCN (1.2)
Et3AlCN (1.2)
TBSCN (1.2)
nBu3SnCN (1.2)
nBu3SnCN (1.5)
nBu3SnCN (2.0)
4.5
1.5
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
61
60
63
53
64
72
65
63
53
66
65
À20
À40
44 16
44 10
40 14
46 13
46 10
45 Trace
45
55
50 16
Me3SiCl (1.2)
Me3SiCl (1.2)
Me3SiCl (1.2)
0
0
0
0
0
0
0
0
0
Me2SiCl2 (1.2) À40
Me2SiCl2 (1.2)
Me2SiCl2 (1.2)
Me2SiCl2 (0.6)
Me2SiCl2 (0.2)
0
0
0
0
9b
10c
11d
Acetone cyanohydrin (1.2)
Acetone cyanohydrin (2.0)
Acetone cyanohydrin (3.0)
9
10
11
—
5
a
a
b
c
Isolated yield.
Isolated yield. Et3N (1.2 equiv.) was used as an additive. Et3N
d
(2.0 equiv.) was used as an additive. Et3N (3.0 equiv.) was used as
an additive.
As mentioned above, since a slight excess of Grignard
reagent was needed to effectively accomplish the N-ethylation,
the formation of the diethylated product was observed in
several cases. To supress the formation of the undesired
diethylated product 6, we examined a series of additives and
oxidation reagents. Although the use of Me3SiCl did not
improve the product yield noticeably (entries 4–6), the presence
of Me2SiCl2 (0.6 equiv.) increased the yield of the desired
product 5a up to 55% (entry 10). Table 6 summarizes the
screening of the oxidation reagents. As can be seen, NBS
(1.2 equiv.), DBDMH (0.6 equiv.), NCS (1.2 equiv.), and
NIS (1.2 equiv.) in MeCN could be used, with the latter affording
the best result (entry 12). We next examined the cyanation
reagent, and Table 7 summarizes the results.
Trimethylsilyl cyanide and acetone cyanohydrin13 were
applicable; however, the best result was obtained when the
reaction was carried out with tributyltin cyanide (entry 6).14
Under the optimized conditions, various a-iminonitriles 1 were
subjected to the present N-alkylation/oxidation/cyanation reac-
tion, and Scheme 2 summarizes the results.
para-Substitution of aromatic carbon with the electron-
donating methoxy group considerably decreased the product
yield, whereas the electron-withdrawing bromo group in the
ortho or para positions did not affect the reaction outcome,
giving the desired products 5b and c in good yields. 2-Pyridyl
and 1- and 2-naphthyl derivatives also gave the corresponding
malononitriles 5e, h, and i in moderate yields, respectively. In
contrast, in the butylation or octylation/oxidation/cyanation
reactions, the reaction proceeded sluggishly, giving the desired
products 5j and k in low yields. We next examined the use of an
intermediate N-addition product for the subsequent C–C bond
formations, and Scheme 3 shows the results.
Treatment of the N-ethylation intermediate with MVK or
benzoyl chloride gave the corresponding addition products 7
or 8 in 50% or 74% yield, respectively, indicating that this
type of three-component coupling reaction is also possible
using a-iminonitriles 1. However, the addition of benzaldehyde
and methyl iodide did not proceed, giving exclusively
N-ethylation product 2b. On the basis of the above results
and our previous investigations,3 we propose the following
reaction pathways (Scheme 4). First, the Grignard reagent
attacks at the nitrogen atom to form bromomagnesium amide
9, which is oxidized with NIS to form the iminium salt 10.
Table 6 Examination of oxidation reagents
Entry
Oxidant (equiv.)
Solv.
Temp. (1C)
Yielda (%)
1
2
3
4
5
6
7
8
NBS (1.2)
NBS (1.5)
NCS (1.2)
NIS (1.2)
DBDMH (0.6)
BPO (1.2)
DMP (1.2)
DDQ (1.2)
NIS (1.2)
NIS (1.2)
NIS (1.2)
NIS (1.2)
NIS (1.2)
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
—
MeCN
CH2Cl2
DMF
0
0
0
0
0
0
0
0
0
55
51
50
61
55
13
12
35
44
37
34
58
44
9
10
11
12
13
0
0
—
MeCN
MeCN
À40
40
a
Isolated yield.
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addition of bromomagnesium amide 9 with an electrophile
such as MVK or benzoyl chloride.
3 Conclusions
In conclusion, a-iminonitriles readily underwent the N-alkylation
reaction with Grignard reagents, giving the corresponding
a-aminonitriles in good yields. Subsequent oxidation/cyanation
of the N-alkylated products was conducted with NIS/nBu3SnCN
to produce the malononitrile derivatives in moderate to good
yields. We also found that the N-alkylation intermediate could
be used for further C–C bond formations with MVK and benzoyl
chloride.15 The present umpolung reaction of a-iminonitriles
offers a new approach for the synthesis of a-aminonitriles and
aminomalononitriles.16
4 Experimental
General aspects
Melting point (mp) measurements were performed using a
YAMATO MP-21 instrument and are uncorrected. Infrared
spectra were recorded using a JASCO FT/IR-460 plus spectro-
meter. 1H NMR and 13C NMR spectra were recorded using a
JEOL ECX-400P, or a JEOL A-500 spectrometer using tetra-
methylsilane as an internal standard. Mass spectra were
recorded using a JEOL MS-700D spectrometer. Acetonitrile
(MeCN) and propionitrile (EtCN) were distilled from phos-
phorus pentaoxide and then from calcium hydride, and stored
over molecular sieves 4 Å. Diethylether (Et2O) was purified
using a Glass Contour Organic Solvent Purification System
from Nikko Hansen & Co., Ltd. Toluene, nhexane, dichloro-
methane (CH2Cl2), and dimethyl formamide (DMF) were dis-
tilled from calcium hydride and stored over molecular sieves
4 Å. Dimethoxyethane (DME) was distilled from calcium hydride
and then from copper(I) chloride, and stored over sodium.
Purification of products was performed by column chromato-
graphy on silica gel (Kanto Silica Gel 60N) and/or preparative
TLC on silica gel (Merck Kiesel Gel GF254 or Wako Gel B-5F).
Scheme 2 N-Ethylation/oxidation/C-cyanation of various a-iminonitriles.
Scheme 3 N-Ethylation/C-alkylation or acylation of a-iminonitrile.
Synthesis of (Z)-N-(4-methoxyphenyl)benzimidoylcyanide:
general procedure for the synthesis of a-iminonitrile 1a
In a 100 mL two-necked round-bottomed flask equipped with
a magnetic stirring bar was placed a solution of p-anisidine
(1.82 g, 14.8 mmol) in MeCN (15.0 mL) under an argon atmo-
sphere. To it were added benzaldehyde (1.50 mL, 14.8 mmol)
and TMSCN (2.04 mL, 16.3 mmol). After the reaction mixture
was stirred at room temperature for 1 h, IBX (4.57 g, 16.3 mmol)
and nBu4NBr (5.25 g, 16.3 mmol) were added successively at
0 1C. After being stirred at 0 1C for 20 h, the mixture was filtered
through a pad of Celite with the aid of nhexane. The solvent was
evaporated, and the residue was purified by silica gel column
chromatography (nhexane : ethyl acetate = 10 : 1) to give the title
compound 1a.
Scheme 4 Proposed reaction pathways.
This iminium salt 10 is attacked by nBu3SnCN to give
Yield 70% (2.45 g); m.p. 77–78 1C; yellow solid; Rf = 0.20
a-aminomalononitrile 5. Products 7 or 8 are formed via the (nhexane : ethyl acetate = 10 : 1); 1H NMR (400 MHz, CDCl3)
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d 3.85 (s, 3H), 6.97–7.03 (m, 2H), 7.25–7.36 (m, 2H), 7.49–7.58 (Z)-N-(4-Methoxyphenyl)thiophen-2-carbimidoylcyanide 1g
(m, 3H), 8.12–8.15 (m, 2H); 13C NMR (100 MHz, CDCl3) d 55.5,
Yield 29% (1.08 g); m.p. 95–96 1C; orange solid; Rf = 0.44
(toluene); H NMR (400 MHz, CDCl3) d 3.86 (s, 3H), 6.96–7.01
111.6, 114.4, 123.0, 127.9, 128.9, 132.3, 134.1, 136.8, 141.7,
159.5; IR (KBr) 2963, 2837, 2217, 1607, 1503, 1275, 1245,
1107, 826, 685 cmÀ1. These spectra were identical to the
reported data.9
1
(m, 2H), 7.16–7.21 (m, 1H), 7.32–7.37 (m, 2H), 7.56–7.58
(m, 1H), 7.76–7.77 (m, 1H); 13C NMR (100 MHz, CDCl3) d
55.5, 111.2, 114.4, 123.4, 128.2, 130.4, 131.9, 132.4, 141.0,
141.5, 159.6; IR (KBr) 2967, 2947, 2213, 1607, 1501, 1249,
1106, 927, 838, 634 cmÀ1; HRMS (EI) calcd for C13H10N2OS
(M)+ 242.0514, found 242.0505.
(Z)-4-Bromo-N-(4-methoxyphenyl)benzimidoylcyanide 1b
Yield 7% (326.0 mg); m.p. 103–106 1C; yellow solid; Rf = 0.70
(nhexane : ethyl acetate = 4 : 1); 1H NMR (400 MHz, CDCl3) d 3.86
(s, 3H), 6.97–7.01 (m, 2H), 7.34–7.38 (m, 2H), 7.63–7.67 (m, 2H),
7.97–8.00 (m, 2H); 13C NMR (100 MHz, CDCl3) d 55.5, 111.5,
114.5, 123.3, 127.2, 129.2, 132.2, 133.1, 135.2, 141.3, 159.8;
IR (KBr) 2957, 2930, 2214, 1611, 1505, 1262, 1163, 825, 712,
695 cmÀ1; HRMS (EI) calcd for C15H11BrN2O (M)+ 314.0055,
found 314.0045.
(Z)-N-(4-Methoxyphenyl)-1-naphthimidoylcyanide 1h
Yield 43% (1.97 g); m.p. 130–133 1C; orange solid; Rf = 0.58
1
(toluene); H NMR (400 MHz, CDCl3) d 3.87 (s, 3H), 7.00–7.05
(m, 2H), 7.36–7.40 (m, 2H), 7.56–7.66 (m, 3H), 7.92–7.94 (m,
1H), 8.01–8.03 (m, 1H), 8.20–8.21 (m, 1H), 9.11–9.26 (m, 1H);
13C NMR (100 MHz, CDCl3) d 55.5, 111.0, 112.3, 114.5, 117.4,
122.7, 124.8, 125.4, 126.8, 128.3, 128.9, 131.2, 133.1, 134.1,
159.4; IR (KBr) 2982, 2942, 2221, 1604, 1509, 1256, 1166, 841,
753, 633 cmÀ1; HRMS (EI) calcd for C19H14N2O (M)+ 286.1106,
found 286.1115.
(Z)-4-Methoxy-N-(4-methoxyphenyl)benzimidoylcyanide 1c
Yield 42% (1.76 g); m.p. 59–60 1C; yellow solid; Rf = 0.56
(nhexane : ethyl acetate = 4 : 1); 1H NMR (400 MHz, CDCl3) d
3.85 (s, 3H), 3.89 (s, 3H), 6.96–7.02 (m, 4H), 7.24–7.28 (m, 2H),
8.05–8.09 (m, 2H); 13C NMR (100 MHz, CDCl3) d 55.5, 55.5,
111.7, 114.3, 114.4, 122.7, 127.0, 129.8, 136.6, 142.1, 159.0,
163.1; IR (KBr) 2962, 2934, 2219, 1605, 1503, 1249, 1109, 840,
707, 666 cmÀ1; HRMS (EI) calcd for C16H14N2O2 (M)+ 266.1055,
found 266.1054.
(Z)-N-(4-Methoxyphenyl)-2-naphthimidoylcyanide 1i
Yield 67% (2.65 g); m.p. 100–101 1C; yellow solid; Rf = 0.47
1
(toluene); H NMR (400 MHz, CDCl3) d 3.85 (s, 3H), 6.99–7.02
(m, 2H), 7.36–7.39 (m, 2H), 7.54–7.61 (m, 2H), 7.87–7.98
(m, 3H), 8.21–8.26 (m, 1H), 8.54–8.57 (m, 1H); 13C NMR
(100 MHz, CDCl3) d 55.5, 111.8, 114.4, 122.8, 123.1, 127.1,
127.8, 128.4, 128.8, 129.2, 130.4, 131.8, 132.7, 135.1, 136.7,
141.8, 159.5; IR (KBr) 3000, 2968, 2215, 1606, 1505, 1255,
1169, 837, 763, 619 cmÀ1; HRMS (EI) calcd for C19H14N2O
(M)+ 286.1106, found 286.1093.
(Z)-2-Bromo-N-(4-methoxyphenyl)benzimidoylcyanide 1d
Yield 33% (1.52 g); m.p. 59–61 1C; yellow solid; Rf = 0.58
(nhexane : ethyl acetate = 4 : 1); 1H NMR (400 MHz, CDCl3) d
3.87 (s, 3H), 7.00–7.03 (m, 2H), 7.35–7.48 (m, 4H), 7.69–7.72
(m, 2H); 13C NMR (100 MHz, CDCl3) d 55.5, 111.7, 114.5, 121.7,
123.3, 127.8, 131.2, 132.1, 134.1, 135.5, 135.8, 141.0, 160.1.;
IR (KBr) 2961, 2942, 2211, 1607, 1502, 1278, 1107, 835, 709,
676 cmÀ1; HRMS (EI) calcd for C15H11BrN2O (M)+ 314.0055,
found 314.0053.
(Z)-N-(4-Methoxyphenyl)cyclohexanecarbimidoylcyanide 1j
Yield 23% (665.2 mg); m.p. 51–52 1C; yellow solid; Rf = 0.43
(toluene); 1H NMR (400 MHz, CDCl3) d 1.21–1.59 (m, 5H), 1.72–
1.76 (m, 1H), 1.86–1.90 (m, 2H), 2.04–2.08 (m, 2H), 2.57–2.76
(m, 1H), 3.82 (s, 3H), 6.90–6.94 (m, 2H), 7.06–7.10 (m, 2H);
13C NMR (100 MHz, CDCl3) d 25.4, 25.6, 29.4, 47.0, 55.4, 111.8,
114.3, 122.0, 142.0, 146.3, 158.8; IR (KBr) 2937, 2854, 2211,
1608, 1507, 1416, 1246, 1168, 839, 634 cmÀ1; HRMS (EI) calcd
for C15H18N2O (M)+ 242.1419, found 242.1420.
(Z)-N-(4-Methoxyphenyl)picolimidoylcyanide 1e
Yield 52% (1.91 g); m.p. 73–74 1C; orange solid; Rf = 0.14
1
(toluene); H NMR (400 MHz, CDCl3) d 3.87 (s, 3H), 6.99–7.03
(m, 2H), 7.42–7.46 (m, 1H), 7.48–7.52 (m, 2H), 7.82–7.86
(m, 1H), 8.23–8.25 (m, 1H), 8.79–8.84 (m, 1H); 13C NMR
(100 MHz, CDCl3) d 55.5, 112.0, 114.4, 121.5, 124.0, 125.8,
136.5, 136.8, 140.5, 149.7, 152.5, 160.2; IR (KBr) 2982, 2946,
2218, 1613, 1508, 1248, 1176, 772, 742, 664 cmÀ1; HRMS (EI)
calcd for C14H11N3O (M)+ 237.0902, found 237.0912.
Synthesis of 2-[ethyl(4-methoxyphenyl)amino]-2-
phenylacetonitrile: general procedure for the synthesis of
a-aminonitrile 2b
In a 30 mL two-necked round-bottomed flask equipped with a
magnetic stirring bar, a rubber septum, and an argon balloon
(Z)-N-(4-Methoxyphenyl)furan-2-carbimidoylcyanide 1f
Yield 38% (1.38 g); m.p. 97–98 1C; orange solid; Rf = 0.22 was placed (Z)-N-(4-methoxyphenyl)benzimidoylcyanide (47.3 mg,
1
(toluene); H NMR (400 MHz, CDCl3) d 3.85 (s, 3H), 6.62–6.64 0.20 mmol) in toluene (2.0 mL) and nhexane (1.0 mL) at À40 1C.
(m, 1H), 6.96–7.00 (m, 2H), 7.20–7.21 (m, 1H), 7.35–7.39 To it was added EtMgBr (0.13 mL, 0.24 mmol, 1.80 M in Et2O).
(m, 2H), 7.67–7.67 (m, 1H); 13C NMR (100 MHz, CDCl3) d After the mixture was stirred for 15 min at room temperature, the
55.5, 111.0, 112.8, 114.5, 117.4, 123.5, 125.6, 141.0, 146.9, reaction was quenched with sat aq NaHCO3 (5 mL), and the whole
150.1, 159.7; IR (KBr) 2972, 2951, 2217, 1611, 1503, 1255, mixture was extracted with ethyl acetate (5 mL Â 3). The com-
1108, 1082, 912, 753 cmÀ1; HRMS (EI) calcd for C13H10N2O2 bined extracts were washed with brine (5 mL Â 2), dried over
(M)+ 226.0742, found 226.0741.
anhydrous Na2SO4, and concentrated in vacuo. The crude product
156 | New J. Chem., 2020, 44, 152--161
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was purified by silica gel column chromatography (nhexane : 718, 695 cmÀ1; HRMS (EI) calcd for C19H22N2O (M)+ 294.1732,
Et3N = 10 : 1) to give the title compound 2b.
found 294.1740.
Yield 89% (47.4 mg); m.p. 46–47 1C; yellow solid; Rf = 0.61
(nhexane : ethyl acetate = 6 : 1); 1H NMR (400 MHz, CDCl3) d 1.00
2-[Isopropyl(4-methoxyphenyl)amino]-2-phenylacetonitrile 2g
(dd, J = 6.9, 6.9 Hz, 3H), 2.99 (dq, J = 6.9, 13.3 Hz, 1H), 3.21 (dq, Yield 28% (15.7 mg); yellow oil; Rf = 0.53 (nhexane : ethyl acetate
1
J = 6.9, 13.3, 1H), 3.77 (s, 3H), 5.39 (s, 1H), 6.84–6.87 (m, 2H), = 10 : 1); H NMR (400 MHz, CDCl3) d 1.07 (d, J = 6.4 Hz, 3H),
7.05–7.07 (m, 2H), 7.38–7.40 (m, 3H), 7.54–7.56 (m, 2H); 13C 1.29 (d, J = 6.4 Hz, 3H), 3.66 (qq, J = 6.4, 6.4 Hz, 1H), 3.74 (s, 3H),
NMR (100 MHz, CDCl3) d 13.1, 43.5, 55.4, 61.2, 114.4, 117.0, 5.43 (s, 1H), 6.70–6.74 (m, 2H), 6.97–7.01 (m, 2H), 7.26–7.33
123.7, 127.5, 128.7, 128.7, 134.0, 140.4, 156.1; IR (KBr) 2983, (m, 3H), 7.38–7.41 (m, 2H); 13C NMR (100 MHz, CDCl3) d 20.7,
2831, 2228, 1880, 1615, 1512, 1448, 1254, 1225, 1035 cmÀ1
;
22.6, 51.8, 55.3, 56.3, 113.4, 118.7, 127.1, 127.9, 128.4, 128.5,
HRMS (EI) calcd for C17H18N2O (M)+ 266.1419, found 266.1423. 134.8, 138.7, 156.6; IR (neat) 2970, 2934, 2226, 1606, 1511, 1247,
1155, 880, 787, 648 cmÀ1; HRMS (EI) calcd for C18H20N2O (M)+
2-[(4-Methoxyphenyl)propylamino]-2-phenylacetonitrile 2c
280.1576, found 280.1563.
Yield 77% (43.2 mg); yellow oil; Rf = 0.60 (nhexane : ethyl acetate
= 6 : 1); H NMR (400 MHz, CDCl3) d 0.79 (dd, J = 7.3, 7.3 Hz,
2-[Cyclohexyl(4-methoxyphenyl)amino]-2-phenylacetonitrile 2h
1
Yield 24% (15.2 mg); yellow oil; Rf = 0.48 (nhexane : ethyl acetate
3H), 1.31–1.48 (m, 2H), 2.83 (dt, J = 8.3, 12.8 Hz, 1H), 3.15 (dt,
J = 8.3, 12.8 Hz, 1H), 3.78 (s, 3H), 5.37 (s, 1H), 6.83–6.87 (m, 2H),
7.06–7.10 (m, 2H), 7.35–7.38 (m, 3H), 7.40–7.56 (m, 2H);
13C NMR (100 MHz, CDCl3) d 11.4, 20.7, 50.9, 55.4, 61.8, 114.5,
117.0, 124.0, 127.7, 128.7, 128.8, 134.1, 140.8, 156.2; IR (neat)
1
= 10 : 1); H NMR (400 MHz, CDCl3) d 1.11–1.43 (m, 5H), 1.58–
1.88 (m, 4H), 2.17–2.19 (m, 1H), 3.23–3.29 (m, 1H), 3.73 (s, 3H),
5.47 (s, 1H), 6.68–6.72 (m, 2H), 6.95–6.99 (m, 2H), 7.24–7.31 (m,
3H), 7.34–7.38 (m, 2H); 13C NMR (100 MHz, CDCl3) d 25.3, 25.8,
29.7, 31.1, 32.6, 55.3, 56.0, 60.0, 113.7, 118.8, 127.5, 127.9,
128.3, 128.4, 134.8, 138.7, 156.7; IR (neat) 2931, 2855, 2227,
1606, 1511, 1452, 1291, 1181, 1037, 696 cmÀ1; HRMS (EI) calcd
for C21H24N2O (M)+ 320.1889, found 320.1879.
2962, 2934, 2836, 2228, 1509, 1451, 1246, 1181, 1037, 825 cmÀ1
;
HRMS (EI) calcd for C18H20N2O (M)+ 280.1576, found 280.1574.
2-[Butyl(4-methoxyphenyl)amino]-2-phenylacetonitrile 2d
Yield 77% (45.1 mg); yellow oil; Rf = 0.10 (nhexane : ethyl acetate =
50 : 1); 1H NMR (400 MHz, CDCl3) d 0.76 (t, J = 7.3 Hz, 3H),
1.16–1.40 (m, 4H), 2.88 (dt, J = 7.3, 13.2 Hz, 1H), 3.16 (dt, J = 7.3,
13.2 Hz, 1H), 3.78 (s, 3H), 5.36 (s, 1H), 6.83–6.87 (m, 2H),
7.05–7.10 (m, 2H), 7.35–7.42 (m, 3H), 7.53–7.56 (m, 2H); 13C NMR
(100 MHz, CDCl3) d 13.7, 20.0, 29.6, 48.8, 55.4, 61.9, 114.4, 116.9,
124.0, 127.7, 128.7, 128.8, 134.0, 140.8, 156.2; IR (neat) 2957, 2933,
2868, 2228, 1510, 1451, 1246, 1039, 825, 696 cmÀ1; HRMS (EI) calcd
for C19H22N2O (M)+ 294.1732, found 294.1726.
2-(4-Bromophenyl)-2-[ethyl(4-methoxyphenyl)amino]acetonitrile 2k
Yield 67% (46.0 mg); yellow oil; Rf = 0.64 (toluene); 1H NMR
(400 MHz, CDCl3) d 1.00 (dd, J = 6.9, 6.9 Hz, 3H), 2.95 (dq, J =
6.9, 10.4 Hz, 1H), 3.20 (dq, J = 6.9, 10.4 Hz, 1H), 3.78 (s, 3H),
5.30 (s, 1H), 6.83–6.87 (m, 2H), 7.03–7.07 (m, 2H), 7.41–7.43 (m,
2H), 7.51–7.54 (m, 2H); 13C NMR (100 MHz, CDCl3) d 13.2, 43.9,
55.4, 60.9, 114.5, 116.6, 122.9, 124.2, 129.2, 131.9, 133.2, 140.0,
156.4; IR (neat) 2990, 2954, 2223, 1612, 1516, 1253, 1186, 847,
787, 629 cmÀ1; HRMS (EI) calcd for C17H17BrN2O (M)+
344.0524, found 344.0534.
2-[(4-Methoxyphenyl)octylamino]-2-phenylacetonitrile 2e
2-[Ethyl(4-methoxyphenyl)amino]-2-(4-methoxyphenyl)aceto-
nitrile 2l
Yield 70% (48.9 mg); yellow oil; Rf = 0.48 (nhexane : ethyl acetate
= 5 : 1); 1H NMR (400 MHz, CDCl3) d 0.85 (t, J = 7.3 Hz, 3H),
1.11–1.41 (m, 12H), 2.86 (dt, J = 8.2, 13.3 Hz, 1H), 3.15 (dt, J =
8.2, 13.3, 1H), 3.78 (s, 3H), 5.37 (s, 1H), 6.83–6.87 (m, 2H), 7.05–
7.09 (m, 2H), 7.35–7.43 (m, 3H), 7.54–7.56 (m, 2H); 13C NMR
(100 MHz, CDCl3) d 14.1, 22.6, 26.8, 27.4, 29.1, 29.2, 31.7, 49.0,
55.4, 61.8, 114.4, 116.9, 124.0, 127.7, 128.7, 128.8, 134.1, 140.8,
156.2; IR (neat) 2927, 2854, 2229, 1510, 1455, 1244, 1182, 1037,
825, 695 cmÀ1; HRMS (EI) calcd for C23H30N2O (M)+ 350.2358,
found 350.2344.
Yield 52% (30.7 mg); yellow oil; Rf = 0.32 (toluene); 1H NMR
(400 MHz, CDCl3) d 0.99 (dd, J = 6.9, 6.9 Hz, 3H), 3.00 (dq, J =
7.4, 11.9 Hz, 1H), 3.18 (dq, J = 7.4, 11.9 Hz, 1H), 3.78 (s, 3H),
3.82 (s, 3H), 5.33 (s, 1H), 6.83–6.92 (m, 4H), 7.03–7.07 (m, 2H),
7.42–7.45 (m, 2H); 13C NMR (100 MHz, CDCl3) d 13.2, 43.4, 55.3,
55.4, 60.7, 114.0, 114.4, 117.3, 123.9, 126.0, 128.9, 140.4, 156.1,
160.0; IR (neat) 2966, 2938, 2226, 1613, 1514, 1253, 1176, 851,
738, 628 cmÀ1; HRMS (EI) calcd for C18H20N2O2 (M)+ 296.1525,
found 296.1520.
2-[Isobutyl(4-methoxyphenyl)amino]-2-phenylacetonitrile 2f
2-(2-Bromophenyl)-2-[ethyl(4-methoxyphenyl)amino]acetonitrile 2m
Yield 42% (24.9 mg); yellow oil; Rf = 0.30 (nhexane : ethyl acetate
= 15 : 1); H NMR (400 MHz, CDCl3) d 0.76 (d, J = 6.9 Hz, 3H), Yield 85% (59.0 mg); yellow oil; Rf = 0.62 (toluene); 1H NMR
0.82 (d, J = 6.9 Hz, 3H), 1.56–1.66 (m, 1H), 2.48 (dd, J = 9.2, 12.4 (400 MHz, CDCl3) d 0.99 (dd, J = 6.9, 6.9 Hz, 3H), 3.18 (dq, J =
Hz, 1H), 3.05 (dd, J = 9.2, 12.4 Hz, 1H), 3.78 (s, 3H), 5.32 (s, 1H), 8.2, 11.0 Hz, 2H), 3.77 (s, 3H), 5.57 (s, 3H), 6.78–6.82 (m, 2H),
6.79–6.87 (m, 2H), 7.10–7.14 (m, 2H), 7.35–7.42 (m, 3H), 7.54– 7.01–7.06 (m, 2H), 7.21–7.29 (m, 2H), 7.39–7.41 (m, 1H), 7.62–
7.56 (m, 2H); 13C NMR (100 MHz, CDCl3) d 20.2, 20.5, 25.9, 55.4, 7.64 (m, 1H); 13C NMR (100 MHz, CDCl3) d 13.2, 45.2, 55.3, 60.4,
57.0, 62.9, 114.4, 116.8, 125.0, 127.9, 128.6, 128.8, 134.0, 141.0, 114.1, 117.0, 124.5, 125.1, 127.3, 130.5, 130.8, 133.2, 133.6,
156.6; IR (neat) 2956, 2870, 2229, 1510, 1465, 1248, 1180, 1038, 139.5, 156.6; IR (neat) 2974, 2934, 2228, 1606, 1510, 1247,
1
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1181, 839, 759, 626 cmÀ1; HRMS (EI) calcd for C17H17BrN2O 133.0, 133.3, 140.6, 156.2; IR (neat) 2984, 2973, 2229, 1510,
(M)+ 344.0524, found 344.0528.
1249, 1178, 1105, 864, 728, 643 cmÀ1; HRMS (EI) calcd for
21H20N2O (M)+ 316.1576, found 316.1579.
C
2-[Ethyl(4-methoxyphenyl)amino]-2-(pyridin-2-yl)acetonitrile 2n
Yield 54% (28.7 mg); yellow oil; Rf = 0.08 (toluene); 1H NMR
2-Cyclohexyl-2-[ethyl(4-methoxyphenyl)amino]acetonitrile 2s
(400 MHz, CDCl3) d 1.06 (dd, J = 6.7, 6.7 Hz, 3H), 3.11 (dq, J = Yield 31% (16.9 mg); yellow oil; Rf = 0.31 (toluene); 1H NMR
6.7, 10.0 Hz, 1H), 3.33 (dq, J = 6.7, 10.0 Hz, 1H), 3.77 (s, 3H), (500 MHz, CDCl3) d 0.89–1.02 (m, 2H), 1.05 (dd, J = 7.3, 7.3 Hz,
5.50 (s, 1H), 6.82–6.85 (m, 2H), 7.04–7.08 (m, 2H), 7.28–7.30 (m, 3H), 1.12–1.36 (m, 3H), 1.69–1.80 (m, 4H), 2.02–2.04 (m, 1H),
1H), 7.52–7.54 (m, 1H), 7.69–7.74 (m, 1H), 8.65–8.66 (m, 1H); 2.15–2.17 (m, 1H), 3.09 (dq, J = 7.3, 11.0 Hz, 1H), 3.19 (dq, J =
13C NMR (100 MHz, CDCl3) d 13.2, 44.9, 55.4, 63.2, 114.5, 116.7, 7.3, 11.0 Hz, 1H), 3.68 (d, J = 10.4 Hz, 1H), 3.79 (s, 3H), 6.84–
122.1, 123.5, 123.5, 137.0, 140.2, 149.6, 154.0, 156.1; IR (neat) 6.87 (m, 2H), 7.04–7.07 (m, 2H); 13C NMR (125 MHz, CDCl3) d
2973, 2935, 2229, 1608, 1512, 1247, 1180, 750, 735, 642 cmÀ1
;
13.4, 25.4, 25.6, 26.3, 30.2, 30.4, 38.7, 44.2, 55.5, 63.1, 114.4,
HRMS (EI) calcd for C16H17N3O (M)+ 267.1372, found 267.1366. 118.2, 123.8, 141.4, 155.9; IR (neat) 2931, 2853, 2224, 1511,
1245, 1140, 894, 737, 626, 543 cmÀ1; HRMS (EI) calcd for
C
17H24N2O (M)+ 272.1889, found 272.1885.
2-[Ethyl(4-methoxyphenyl)amino]-2-(furan-2-yl)acetonitrile 2o
Yield 82% (41.9 mg); yellow oil; Rf = 0.24 (toluene); 1H NMR
(400 MHz, CDCl3) d 1.01 (dd, J = 6.9, 6.9 Hz, 3H), 3.16 (dq, J =
6.9, 10.4 Hz, 2H), 3.78 (s, 3H), 5.34 (s, 1H), 6.34–6.37 (m, 1H),
6.45–6.46 (m, 1H), 6.82–6.86 (m, 2H), 7.01–7.05 (m, 2H), 7.45–
Synthesis of 2-[ethyl(4-methoxyphenyl)amino]-2-phenylmalono-
nitrile: general procedure for the synthesis of a-aminomalono-
nitrile 5a
7.45 (m, 1H); 13C NMR (100 MHz, CDCl3) d 13.2, 44.3, 55.1, 55.4, In a 30 mL two-necked round-bottomed flask equipped with a
110.5, 110.6, 114.3, 115.6, 124.1, 139.7, 143.6, 146.8, 156.4; IR magnetic stirring bar, a rubber septum, and an argon balloon
(neat) 2975, 2936, 2234, 1608, 1511, 1248, 1089, 1181, 901, 744 was placed (Z)-N-(4-methoxyphenyl)benzimidoylcyanide (0.25 mL,
cmÀ1; HRMS (EI) calcd for C15H16N2O2 (M)+ 256.1212, found 0.24 mmol, 0.95 M in Et2O) in toluene (2.0 mL) at À40 1C. To it
256.1224.
was added EtMgBr (0.20 mL, 0.23 mmol, 0.99 M THF). After the
mixture was stirred for 15 min at room temperature,Me2SiCl2
(0.01 mL, 0.12 mmol) was added at 0 1C, and the mixture was
2-[Ethyl(4-methoxyphenyl)amino]-2-(thiphen-2-yl)acetonitrile 2p
Yield 57% (30.8 mg); yellow oil; Rf = 0.42 (toluene); 1H NMR stirred at 0 1C for another 15 min. A solution of NIS (40.0 mg,
(500 MHz, CDCl3) d 1.01 (dd, J = 6.7, 6.7 Hz, 3H), 3.05 (dq, J = 0.23 mmol) in MeCN (1.5 mL) was added, and the reaction
7.3, 10.8 Hz, 1H), 3.22 (dq, J = 7.3, 10.8 Hz, 1H), 3.79 (s, 3H), mixture was stirred for 1 min at room temperature. Then,
5.45 (s, 1H), 6.85–6.92 (m, 2H), 6.97–6.99 (m, 1H), 7.12–7.15 nBu3SnCN (75.9 mg, 0.24 mmol) was added and the mixture
(m, 2H), 7.22–7.23 (m, 1H), 7.34–7.35 (m, 1H); 13C NMR was stirred at room temperature for 3 hr. The reaction was
(125 MHz, CDCl3) d 13.1, 43.4, 55.4, 57.9, 114.5, 116.4, 124.5, quenched with sat aq NaHCO3 (5.0 mL), and the whole mixture
126.7, 126.9, 138.7, 140.1, 156.7; IR (neat) 2975, 2935, 2231, was extracted with ethyl acetate (5 mL Â 3). The combined extracts
1609, 1510, 1246, 1105, 917, 839, 710 cmÀ1; HRMS (EI) calcd for were washed with brine (5 mL Â 2), dried over anhydrous Na2SO4,
C
15H16N2OS (M)+ 272.0983, found 272.0976.
and concentrated in vacuo. The crude product was purified by
silica gel column chromatography (ethyl acetate : nhexane =
15 : 1 + 5% Et3N) to give the title compound 5a.
2-[Ethyl(4-methoxyphenyl)amino]-2-(naphthalen-1-yl)acetonitrile 2q
Yield 72% (45.4 mg); yellow oil; Rf = 0.43 (toluene); 1H NMR
Yield 72% (41.9 mg); yellow oil; Rf = 0.46 (nhexane : ethyl
1
(500 MHz, CDCl3) d 0.94 (dd, J = 6.7, 6.7 Hz, 3H), 3.20 (m, 2H), acetate = 6 : 1); H NMR (400 MHz, CDCl3) d 0.90 (t, J = 7.3 Hz,
3.77 (s, 3H), 6.01 (s, 1H), 6.81–6.84 (m, 2H), 6.91–7.03 (m, 2H), 3H), 3.12 (q, J = 7.3 Hz, 2H), 3.77 (s, 3H), 6.79–6.83 (m, 2H),
7.39–7.45 (m, 1H), 7.52–7.57 (m, 2H), 7.70–7.71 (m, 1H), 7.86– 7.23–7.26 (m, 2H), 7.41–7.44 (m, 3H), 7.66–7.71 (m, 2H); 13C
7.90 (m, 2H), 8.09–8.10 (m, 1H); 13C NMR (125 MHz, CDCl3) d NMR (100 MHz, CDCl3) d 13.3, 45.5, 55.3, 64.7, 113.7, 114.3,
13.1, 44.6, 55.4, 58.0, 114.4, 117.6, 123.3, 123.5, 124.9, 126.2, 127.4, 129.2, 129.3, 130.6, 132.5, 135.8, 159.0; IR (neat) 2976,
126.9, 127.3, 128.8, 129.1, 130.1, 130.9, 133.8, 140.0, 156.0; 2935, 2362, 2251, 1581, 1507, 1253, 1253, 1171, 1038, 696 cmÀ1
;
IR (neat) 2969, 2931, 2229, 1597, 1514, 1250, 1180, 837, 738, HRMS (EI) calcd for C18H17N3O (M)+ 291.1372, found 291.1374.
630 cmÀ1; HRMS (EI) calcd for C21H20N2O (M)+ 316.1576, found
2-(4-Bromophenyl)-2-[ethyl(4-methoxyphenyl)amino]malono-
316.1571.
nitrile 5b
Yield 59% (43.8 mg); yellow oil; Rf = 0.76 (toluene); 1H NMR
2-[Ethyl(4-methoxyphenyl)amino]-2-(naphthalen-2-yl)acetonitrile 2r
Yield 78% (49.6 mg); yellow oil; Rf = 0.31 (toluene); 1H NMR (400 MHz, CDCl3) d 0.90 (t, J = 6.9 Hz, 3H), 3.13 (q, J = 6.9 Hz,
(500 MHz, CDCl3) d 1.00 (dd, J = 7.3, 7.3 Hz, 3H), 3.02 (dq, J = 2H), 3.78 (s, 3H), 6.80–6.84 (m, 2H), 7.19–7.23 (m, 2H), 7.52–
7.3, 11.0 Hz, 1H), 3.24 (dq, J = 7.3, 11.0 Hz, 1H), 3.78 (s, 3H), 7.58 (m, 4H); 13C NMR (100 MHz, CDCl3) d 13.3, 45.7, 55.3, 64.1,
5.54 (s, 1H), 6.84–6.88 (m, 2H), 7.10–7.14 (m, 2H), 7.51–7.55 113.3, 114.4, 125.2, 129.0, 129.2, 131.6, 132.5, 135.4, 159.0;
(m, 2H), 7.63–7.65 (m, 1H), 7.85–7.88 (m, 3H), 8.03 (m, 1H); IR (neat) 2979, 2936, 2231, 1607, 1510, 1251, 1181, 832, 739,
13C NMR (125 MHz, CDCl3) d 13.2, 43.5, 55.4, 61.4, 114.5, 117.1, 628 cmÀ1; HRMS (EI) calcd for C18H16BrN3O (M)+ 369.0477,
123.7, 125.0, 126.7, 126.8, 126.9, 127.7, 128.2, 128.7, 131.5, found 369.0465.
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2-[Ethyl(4-methoxyphenyl)amino]-2-(4-methoxyphenyl)malono- 3.73 (s, 3H), 6.72–6.74 (m, 2H), 7.22–7.26 (m, 2H), 7.34–7.42
nitrile 5d
(m, 1H), 7.60–7.65 (m, 1H), 7.70–7.73 (m, 1H), 7.84–7.92 (m,
3H), 8.94–8.95 (m, 1H); 13C NMR (125 MHz, CDCl3) d 13.5, 45.9,
55.3, 65.5, 113.5, 114.2, 124.6, 124.8, 126.2, 126.8, 127.1, 128.0,
128.8, 129.2, 129.4, 132.2, 134.5, 135.6, 158.8; IR (neat) 2977, 2934,
2228, 1606, 1510, 1251, 1111, 843, 758, 652 cmÀ1; HRMS (EI) calcd
for C22H19N3O (M)+ 341.1528, found 341.1525.
Yield 27% (17.5 mg); yellow oil; Rf = 0.46 (toluene); 1H NMR
(400 MHz, CDCl3) d 0.89 (t, J = 7.3 Hz, 3H), 3.12 (q, J = 7.3 Hz, 2H),
3.79 (s, 3H), 6.80–6.84 (m, 2H), 6.89–6.93 (m, 2H), 7.20–7.24 (m, 2H),
7.56–7.60 (m, 2H); 13C NMR (100 MHz, CDCl3) d 13.4, 45.4, 55.3, 55.5,
64.2, 113.9, 114.3, 114.5, 124.3, 128.9, 129.3, 135.9, 158.9, 161.1; IR
(neat) 2981, 2940, 2247, 1605, 1512, 1285, 1118, 974, 758, 633 cmÀ1
;
2-[Ethyl(4-methoxyphenyl)amino]-2-(maphthalen-2-yl)malono-
nitrile 5i
HRMS (EI) calcd for C19H19N3O2 (M)+ 321.1477, found 326.1468.
Yield 52% (35.2 mg); yellow oil; Rf = 0.47 (toluene); 1H NMR
(500 MHz, CDCl3) d 0.92 (t, J = 7.3 Hz, 3H), 3.12 (q, 6.7 Hz, 2H),
3.75 (s, 3H), 6.81–6.84 (m, 2H), 7.27–7.35 (m, 2H), 7.55–7.59
(m, 2H), 7.80–7.97 (m, 4H), 8.15–8.15 (m, 1H); 13C NMR
(125 MHz, CDCl3) d 13.3, 45.3, 55.3, 64.9, 113.7, 114.4, 123.4,
127.2, 127.6, 127.7, 127.9, 128.6, 129.3, 129.7, 129.7, 132.6,
133.9, 136.0, 159.0; IR (neat) 2979, 2936, 2231, 1606, 1582,
1251, 1034, 811, 758, 656 cmÀ1; HRMS (EI) calcd for C22H19N3O
(M)+ 341.1528, found 341.1538.
2-(2-Bromophenyl)-2-[ethyl(4-methoxyphenyl)amino]malono-
nitrile 5c
Yield 61% (45.1 mg); m.p. = 68–71 1C; yellow solid; Rf = 0.57 (toluene);
1H NMR (500 MHz, CDCl3) d 0.94 (t, J = 6.7 Hz, 3H), 3.15 (q,
J = 7.3 Hz, 2H), 3.77 (s, 3H), 6.79–6.82 (m, 2H), 7.29–7.39 (m, 4H),
7.67–7.75 (m, 2H); 13C NMR (125 MHz, CDCl3) d 13.2, 45.5, 55.3, 65.7,
112.5, 114.2, 122.4, 127.9, 128.9, 129.7, 130.8, 131.9, 135.7, 136.2,
158.9; IR (KBr) 2978, 2933, 2227, 1606, 1510, 1252, 1109, 844, 752,
629 cmÀ1; HRMS (EI) calcd for C18H16BrN3O (M)+ 369.0477, found
369.0494.
2-[Butyl(4-methoxyphenyl)amino]-2-phenylmalononitrile 5j
Yield 32% (20.6 mg); yellow oil; Rf = 0.59 (toluene); 1H NMR
(500 MHz, CDCl3) d 0.75 (t, J = 7.3 Hz, 3H), 1.20–1.26 (m, 4H),
3.06 (t, J = 6.1 Hz, 2H), 3.78 (s, 3H), 6.80–6.83 (m, 2H), 7.22–7.26
(m, 2H), 7.40–7.44 (m, 3H), 7.66–7.70 (m, 2H); 13C NMR
(125 MHz, CDCl3) d 13.6, 19.7, 29.6, 50.5, 55.3, 64.9, 113.7,
114.3, 127.5, 129.2, 130.6, 132.5, 136.1, 158.9; IR (neat) 2959,
2933, 2230, 1607, 1510, 1250, 1181, 823, 747, 633 cmÀ1; HRMS
(EI) calcd for C20H21N3O (M)+ 319.1685, found 319.1687.
2-[Ethyl(4-methoxyphenyl)amino]-2-(pyridine-2-yl)malononitrile 5e
Yield 45% (26.5 mg); yellow oil; Rf = 0.11 (toluene); 1H NMR
(400 MHz, CDCl3) d 0.94 (t, J = 6.9 Hz, 3H), 3.20 (q, J = 6.9 Hz, 2H),
3.77 (s, 3H), 6.79–6.82 (m, 2H), 7.22–7.27 (m, 2H), 7.35–7.39
(m, 1H), 7.72–7.74 (m, 1H), 7.78–7.82 (m, 1H), 8.63–8.65 (m, 1H);
13C NMR (100 MHz, CDCl3) d 13.3, 46.2, 55.3, 67.0, 113.2, 114.3,
122.3, 125.1, 129.2, 135.6, 137.9, 149.6, 151.7, 158.9; IR (neat) 2973,
2938, 2250, 1610, 1509, 1232, 1157, 965, 850, 634 cmÀ1; HRMS (EI)
calcd for C17H16N4O (M)+ 292.1324, found 292.1319.
2-[4-Methoxyphenyl(octyl)amino]-2-phenylmalononitrile 5k
Yield 23% (17.5 mg); yellow oil; Rf = 0.62 (toluene); 1H NMR
(500 MHz, CDCl3) d 0.85 (t, J = 7.3 Hz, 3H), 1.10–1.22 (m, 12H),
3.05 (t, J = 6.1 Hz, 2H), 6.80–6.82 (m, 2H), 7.23–7.24 (m, 2H),
7.43–7.44 (m, 3H), 7.67–7.69 (m, 2H); 13C NMR (125 MHz,
CDCl3) d 14.0, 22.6, 26.5, 27.5, 29.0, 29.1, 31.7, 50.8, 55.3,
113.7, 114.3, 127.5, 129.2, 130.6, 132.5, 136.2, 158.9; IR (neat)
2-[Ethyl(4-methoxyphenyl)amino]-2-(furan-2-yl)malononitrile 5f
Yield 8% (4.3 mg); yellow oil; Rf = 0.50 (toluene); 1H NMR
(500 MHz, CDCl3) d 0.96 (t, J = 7.3 Hz, 3H), 3.24 (q, J = 6.7 Hz,
2H), 3.78 (s, 3H), 6.35–6.36 (m, 1H), 6.56–6.57 (m, 1H), 6.80–
6.83 (m, 2H), 7.16–7.19 (m, 2H), 7.50–7.50 (m, 1H); 13C NMR
(125 MHz, CDCl3) d 13.3, 45.8, 55.3, 59.0, 111.2, 111.8, 113.2,
114.3, 128.9, 135.2, 142.6, 145.2, 159.0; IR (neat) 2979, 2932,
2202, 1509, 1246, 1168, 975, 758, 650, 593 cmÀ1; HRMS (EI)
calcd for C16H15N3O2 (M)+ 281.1164, found 281.1170.
2954, 2855, 2282, 1607, 1510, 1250, 1035, 841, 747, 663 cmÀ1
;
HRMS (EI) calcd for C24H29N3O (M)+ 375.2311, found 375.2322.
2-[Ethyl(4-methoxyphenyl)amino]-5-oxo-2-phenylhexanenitrile 7
In a 30 mL two-necked round-bottomed flask equipped with a
magnetic stirring bar, a rubber septum, and an argon balloon
was placed a solution of (Z)-N-(4-methoxyphenyl)benzimidoylcyanide
(47.3 mg, 0.20 mmol) in toluene (2.0 mL) at À40 1C. To it was added
EtMgBr (0.12 mL, 0.24 mmol, 2.02 M in Et2O). After the mixture was
stirred for 15 min at room temperature, it was cooled to À40 1C. To
the mixture MVK (0.020 mL, 0.24 mmol) was added, and it was
stirred at À40 1C for 4 h. The reaction was quenched with sat aq
NaHCO3 (5 mL), and the whole mixture was extracted with ethyl
acetate (5 mL Â 3). The combined extracts were washed with brine
(5 mL Â 2), dried over anhydrous Na2SO4, and concentrated in
vacuo. The crude product was purified by alumina column chroma-
tography (nhexane : EtOAc = 5 : 1) to give the title compound 7.
2-[Ethyl(4-methoxyphenyl)amino]-2-(thiophen-2-yl)malononitrile 5g
Yield 29% (17.4 mg); yellow oil; Rf = 0.47 (toluene); 1H NMR
(500 MHz, CDCl3) d 0.93 (t, J = 7.3 Hz, 3H), 3.12 (q, J = 7.3 Hz,
2H), 3.81 (s, 3H), 6.88–6.89 (m, 2H), 6.99–7.00 (m, 1H), 7.34–
7.36 (m, 2H), 7.39–7.40 (m, 1H), 7.47–7.48 (m, 1H); 13C NMR
(125 MHz, CDCl3) d 13.2, 45.4, 55.4, 60.6, 113.0, 114.5, 126.9,
129.2, 129.4, 129.6, 136.1, 136.5, 159.3; IR (neat) 2978, 2936,
2231, 1607, 1510, 1242, 1033, 844, 715, 761 cmÀ1; HRMS (EI)
calcd for C16H15N3OS (M)+ 297.0936, found 297.0929.
2-[Ethyl(4-methoxyphenyl)amino]-2-(maphthalen-1-yl)malono-
nitrile 5h
Yield 39% (26.9 mg); yellow oil; Rf = 0.50 (toluene); 1H NMR
Yield 50% (33.7 mg); yellow oil; Rf = 0.46 (nhexane : ethyl
1
(500 MHz, CDCl3) d 0.91 (t, J = 7.3 Hz, 3H), 3.28 (q, J = 7.3 Hz, 2H), acetate = 5 : 1); H NMR (500 MHz, CDCl3) d 0.73 (dd, J = 6.7,
New J. Chem., 2020, 44, 152--161 | 159
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Paper
´
(d) A. Cordova, W. Notz, G. Zhong, J. M. Betancort and C. F.
Barbas, J. Am. Chem. Soc., 2002, 124, 1842–1843; (e) K. P.
Chiev, S. Roland and P. Mangeney, Tetrahedron: Asymmetry,
2002, 13, 2205–2209; ( f ) P. Wipf and C. R. J. Stephenson,
Org. Lett., 2003, 5, 2449–2452; (g) M. Mitani, Y. Tanaka,
A. Sawada, A. Misu and Y. Matsumoto, Eur. J. Org. Chem.,
2008, 1383–1391; (h) P. Fu, M. L. Snapper and A. H.
Hoveyda, J. Am. Chem. Soc., 2008, 130, 5530–5541; (i) S. Fustero,
6.7 Hz, 3H), 1.84–1.91 [(m, 5H) including a singlet of C(O)CH3 at
d = 1.89], 1.97 (dt, J = 6.7, 11.0 Hz, 1H), 2.36 (dt, J = 6.7, 11.0 Hz,
1H), 2.64 (dq, J = 6.7, 11.0 Hz, 1H), 2.98 (dq, J = 6.7, 11.0 Hz,
1H), 3.82 (s, 3H), 6.87–6.92 (m, 2H), 7.36–7.44 (m, 5H), 7.67–
7.70 (m, 2H); 13C NMR (125 MHz, CDCl3) d 13.6, 29.9, 35.4, 38.9,
46.2, 55.3, 69.9, 114.3, 119.6, 126.5, 128.7, 128.8, 129.9, 137.8,
139.0, 158.4, 206.2; IR (neat) 2973, 2934, 2221, 1718, 1608, 1511,
1244, 1168, 1034, 702 cmÀ1; HRMS (EI) calcd for C21H24N2O2
(M)+ 336.1838, found 336.1846.
˜
N. Mateu, L. Albert and J. L. Acena, J. Org. Chem., 2009, 74,
4429–4432; ( j) K. Yeung, F. Talbot, G. P. Howell, A. P. Pulis and
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2-[Ethyl(4-methoxyphenyl)amino]-3-oxo-2,3-diphenylpropane-
nitrile 8
2 For N-alkylation to a-iminoesters, see: (a) J.-C. Fiaud and
H. B. Kagan, Tetrahedron Lett., 1971, 12, 1019–1022;
(b) Y. Yamamoto and W. Ito, Tetrahedron, 1988, 44, 5415–5423;
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see: (a) Y. Niwa, K. Takayama and M. Shimizu, Bull. Chem.
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In a 30 mL two-necked round-bottomed flask equipped with a
magnetic stirring bar, a rubber septum, and an argon balloon was
placed a solution of (Z)-N-(4-methoxyphenyl)benzimidoylcyanide
(47.3 mg, 0.20 mmol) in toluene (2.0 mL) and nhexane (1.0 mL) at
À40 1C. To it was added EtMgBr (0.12 mL, 0.24 mmol, 2.02 M in
Et2O). After the mixture was stirred for 15 min at room tempera-
ture, it was cooled to À40 1C. To the mixture was added benzoyl
chloride (0.070 mL, 0.60 mmol), and it was stirred at À40 1C for
35 min. The reaction was quenched with sat aq NaHCO3 (5 mL),
and the whole mixture was extracted with ethyl acetate (5 mL Â 3).
The combined extracts were washed with brine (5 mL Â 2), dried
over anhydrous Na2SO4, and concentrated in vacuo. The crude
product was purified by silica gel column chromatography
(nhexane: EtOAc = 10 :1 + 5% Et3N) to give the title compound 8.
Yield 74% (54.6 mg); yellow oil; Rf = 0.22 (nhexane : ethyl
1
acetate = 6 : 1); H NMR (400 MHz, CDCl3) d 1.05 (dd, J = 6.9,
6.9 Hz, 3H), 3.08 (dq, J = 6.9, 12.3 Hz, 1H), 3.27 (dq, J = 6.9,
12.3 Hz, 1H), 3.70 (s, 3H), 6.64–6.66 (m, 2H), 7.18–7.45 (m, 8H),
7.62–7.64 (m, 2H), 7.81–7.83 (m, 2H); 13C NMR (100 MHz,
CDCl3) d 13.5, 48.5, 55.2, 79.6, 113.6, 118.2, 128.1, 128.2,
128.7, 129.0, 129.3, 129.7, 133.1, 133.6, 134.6, 138.0, 157.6,
190.9; IR (neat) 2977, 2222, 1681, 1511, 1245, 1181, 1035, 915,
700, 639 cmÀ1; HRMS (EI) calcd for C24H22N2O2 (M)+ 370.1681,
found 370.1672.
4 M. Shimizu, M. Tateishi and I. Mizota, Chem. Lett., 2014, 43,
1752–1754.
Conflicts of interest
5 Hydrolysis: V. Yu, K. Armando and J. L. Pombeiro, Inorg.
Chim. Acta, 2005, 358, 1–21, and refernces cited therein.
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37, 137–153.
7 Addition: A. L. Smith and P. Tan, J. Chem. Educ., 2006, 83,
1654–1657.
8 Reductive decyanation: (a) C. E. Berkoff, D. E. Rivard,
D. Kirkpatrick and J. L. Ives, Synth. Commun., 1980, 10,
939–945; (b) J.-M. Mattalia, C. Marchi-Delapierre, H. Hazimeh
and M. Chanon, ARKIVOC, 2006, 90–118.
There are no conflicts to declare.
Acknowledgements
This work was supported by Grants-in-Aid for Scientific
Research (B) and Innovative Areas ‘‘Organic Synthesis Based
on Reaction Integration. Development of New Methods and
Creation of New Substances’’ from JSPS and MEXT.
9 P. Fontaine, A. Chiaroni, G. Masson and J. Zhu, Org. Lett.,
2008, 10, 1509–1512.
Notes and references
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a-iminonitriles.
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Y. Kita, E. Remond and N. Chatani, J. Am. Chem. Soc., 2012, 16 Aminomalononitriles are useful units for further construc-
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