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

Abstract

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.

---

1 Introduction

The intriguing reactivity of α-iminoesters has broadened the utility of imino compounds as amination reagents and precursors to α-aminoesters via an addition to the imino carbon.^1–3 Three reactive positions are available for the addition of nucleophiles to α-iminoesters: the first is the imino carbon, the second is the ester 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 α-iminoesters,³ demonstrating that the alkoxycarbonyl^3a–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 α-iminonitriles (Scheme 1).

Scheme 1 Reaction of α-iminoesters and α-iminonitriles.

2 Results and discussion

The starting α-iminonitrile 1 was readily prepared according to the procedure reported by Masson and Zhu.⁹ First, the conditions for the ethylation reaction of α-iminonitrile 1a including the ethylation reagent, solvent, time, and temperature were examined. Table 1 summarizes the results.

Table 1 N-Ethylation of α-iminonitrile

Entry	Nucleophile (equiv.)	Solv.	Temp. (°C)	Time (min)	Yield^a (%)
					2b	3	4
a Isolated yield. b Recovery of the starting material (95%). c Recovery of the starting material (89%). d Recovery of the starting material (16%). e Recovery of the starting material (46%). f The reaction was carried out in toluene : nhexane = 2 : 1 (0.67 M).
1	EtMgBr/Et2O (1.2)	PhCH3	−40 to rt	15	76	—	—
2	EtMgBr/THF (1.2)	PhCH3	−40 to rt	15	3	14	77
3	Et2AlCl/nhex (2.0)	EtCN	−78 to rt	300	0^b	—	—
4	Et2Zn/nhex (2.0)	PhCH3	−78 to rt	300	0^c	—	—
5	EtMgBr/Et2O (1.2)	PhCH3	−40	60	63	—	—
6	EtMgBr/Et2O (1.2)	PhCH3	−40 to 0	60	62	—	—
7	EtMgBr/Et2O (1.2)	CH2Cl2	−40 to rt	15	52	9	18
8	EtMgBr/Et2O (1.2)	Et2O	−40 to rt	15	52^d	6	2
9	EtMgBr/Et2O (1.2)	DME	−40 to rt	15	0	—	55
10	EtMgBr/Et2O (1.2)	nhex	−40 to rt	15	43^e	—	—
11^f	EtMgBr/Et2O (1.2)	PhCH3/nhex	−40 to rt	15	74	—	—

---

One of the side reactions associated with the use of α-iminonitrile 1 as the electrophile is the replacement of the cyano group with a nucleophile, since the cyano group is known to be a relatively good leaving group in many organic transformations.¹⁰ This side reaction was the major pathway, 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 triethylamine (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

Entry	Sol (M)	Purification procedure^a	2b: yield^b (%)
a Et3N (10 v/v%) was added to the eluent. b Isolated yield. c Column chromatography.
1	PhCH3 (0.1)	SiO2 TLC	76
2	PhCH3 (0.1)	SiO2 CC^c	85
3	PhCH3/nhex (2 : 1, 0.07)	SiO2 CC^c	89
4	PhCH3/nhex (1 : 1, 0.03)	SiO2 CC^c	87

---

Under the best N-alkylation conditions found for the substrate 1a (entry 3, Table 2), a variety of Grignard reagents were subjected to N-alkylation, and Table 3 summarizes the results.

Table 3 N-Alkylation with various Grignard reagents

Entry	R	Time (min)	2: yield^a (%)
a Isolated yield.
1	Me	15	2a: 0
2	Et	15	2b: 89
3	nPr	25	2c: 77
4	nBu	25	2d: 77
5	nOct	35	2e: 70
6	iBu	60	2f: 42
7	iPr	15	2g: 28
8	Cy	15	2h: 24
9	Ph	15	2i: 0
10	Bn	15	2j: 0

---

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 α-iminonitriles 1b to 1j were also examined for the N-ethylation reaction, and Table 4 summarizes the results.

Table 4 N-Ethylation of various α-iminonitriles

Entry	1: R	Temp. (°C)	Time (min)	2: yield^a (%)
a Isolated yield. b The reaction was carried out in toluene (0.033 M). c EtMgBr in Et2O (1.5 equiv.) was used.
1	1a: Ph	−40 to rt	15	2b: 85
2	1b: 4-BrC6H4	−10 to rt	25	2k: 67
3	1c: 4-MeOC6H4	−20 to rt	35	2l: 52
4	1d: 2-BrC6H4	−40 to rt	15	2m: 85
5^b	1e: 2-Pyridyl	−78	15	2n: 52
6^b	1f: 2-Furyl	−78	15	2o: 82
7^c	1g: 2-Thienyl	−15	45	2p: 49
8^b	1h: 1-Naphthyl	−20 to rt	15	2q: 72
9	1i: 2-Naphthyl	−40 to rt	15	2r: 78
10	1j: Cy	−40 to rt	25	2s: 31

---

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.

Table 5 Examination of chlorosilanes for the synthesis of α-amino malononitrile

Entry	R4−nSiCln (equiv.)	Temp. 1 (°C)	Time (min)	Temp. 2 (°C)	Yield^a (%)
					5a	6
a Isolated yield.
1	—	—	—	0	49	—
2	—	—	—	−20	49	—
3	—	—	—	−40	44	16
4	Me3SiCl (1.2)	−40	15	0	44	10
5	Me3SiCl (1.2)	0	15	0	40	14
6	Me3SiCl (1.2)	0	60	0	46	13
7	Me2SiCl2 (1.2)	−40	15	0	46	10
8	Me2SiCl2 (1.2)	0	15	0	45	Trace
9	Me2SiCl2 (1.2)	0	60	0	45	—
10	Me2SiCl2 (0.6)	0	15	0	55	5
11	Me2SiCl2 (0.2)	0	15	0	50	16

---

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.

Table 6 Examination of oxidation reagents

Entry	Oxidant (equiv.)	Solv.	Temp. (°C)	Yield^a (%)
a Isolated yield.
1	NBS (1.2)	MeCN	0	55
2	NBS (1.5)	MeCN	0	51
3	NCS (1.2)	MeCN	0	50
4	NIS (1.2)	MeCN	0	61
5	DBDMH (0.6)	MeCN	0	55
6	BPO (1.2)	MeCN	0	13
7	DMP (1.2)	—	0	12
8	DDQ (1.2)	MeCN	0	35
9	NIS (1.2)	CH2Cl2	0	44
10	NIS (1.2)	DMF	0	37
11	NIS (1.2)	—	0	34
12	NIS (1.2)	MeCN	−40	58
13	NIS (1.2)	MeCN	40	44

---

Table 7 Examination of cyanation reagents

Entry	Cyanide (equiv.)	Time (h)	Yield^a (%)
a Isolated yield. b Et3N (1.2 equiv.) was used as an additive. c Et3N (2.0 equiv.) was used as an additive. d Et3N (3.0 equiv.) was used as an additive.
1	TMSCN (1.2)	4.5	61
2	TMSCN (1.2)	1.5	60
3	TMSCN (1.2)	3.0	63
4	Et3AlCN (1.2)	3.0	53
5	TBSCN (1.2)	3.0	64
6	nBu3SnCN (1.2)	3.0	72
7	nBu3SnCN (1.5)	3.0	65
8	nBu3SnCN (2.0)	3.0	63
9^b	Acetone cyanohydrin (1.2)	3.0	53
10^c	Acetone cyanohydrin (2.0)	3.0	66
11^d	Acetone cyanohydrin (3.0)	3.0	65

---

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 α-iminonitriles 1 were subjected to the present N-alkylation/oxidation/cyanation reaction, and Scheme 2 summarizes the results.

Scheme 2 N-Ethylation/oxidation/C-cyanation of various α-iminonitriles.

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.

Scheme 3 N-Ethylation/C-alkylation or acylation of α-iminonitrile.

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 α-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. This iminium salt 10 is attacked by nBu₃SnCN to give α-aminomalononitrile 5. Products 7 or 8 are formed via the addition of bromomagnesium amide 9 with an electrophile such as MVK or benzoyl chloride.

Scheme 4 Proposed reaction pathways.

3 Conclusions

In conclusion, α-iminonitriles readily underwent the N-alkylation reaction with Grignard reagents, giving the corresponding α-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 α-iminonitriles offers a new approach for the synthesis of α-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 spectrometer. ¹H NMR and ¹³C NMR spectra were recorded using a JEOL ECX-400P, or a JEOL A-500 spectrometer using tetramethylsilane as an internal standard. Mass spectra were recorded using a JEOL MS-700D spectrometer. Acetonitrile (MeCN) and propionitrile (EtCN) were distilled from phosphorus 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, dichloromethane (CH₂Cl₂), and dimethyl formamide (DMF) were distilled 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 chromatography on silica gel (Kanto Silica Gel 60N) and/or preparative TLC on silica gel (Merck Kiesel Gel GF254 or Wako Gel B-5F).

Synthesis of (Z)-N-(4-methoxyphenyl)benzimidoylcyanide: general procedure for the synthesis of α-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 atmosphere. 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 °C. After being stirred at 0 °C 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.

Yield 70% (2.45 g); m.p. 77–78 °C; yellow solid; R_f = 0.20 (nhexane : ethyl acetate = 10 : 1); ¹H NMR (400 MHz, CDCl₃) δ 3.85 (s, 3H), 6.97–7.03 (m, 2H), 7.25–7.36 (m, 2H), 7.49–7.58 (m, 3H), 8.12–8.15 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 55.5, 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 cm⁻¹. These spectra were identical to the reported data.⁹

(Z)-4-Bromo-N-(4-methoxyphenyl)benzimidoylcyanide 1b

Yield 7% (326.0 mg); m.p. 103–106 °C; yellow solid; R_f = 0.70 (nhexane : ethyl acetate = 4 : 1); ¹H NMR (400 MHz, CDCl₃) δ 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) δ 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 cm⁻¹; HRMS (EI) calcd for C₁₅H₁₁BrN₂O (M)⁺ 314.0055, found 314.0045.

(Z)-4-Methoxy-N-(4-methoxyphenyl)benzimidoylcyanide 1c

Yield 42% (1.76 g); m.p. 59–60 °C; yellow solid; R_f = 0.56 (nhexane : ethyl acetate = 4 : 1); ¹H NMR (400 MHz, CDCl₃) δ 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) δ 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 cm⁻¹; HRMS (EI) calcd for C₁₆H₁₄N₂O₂ (M)⁺ 266.1055, found 266.1054.

(Z)-2-Bromo-N-(4-methoxyphenyl)benzimidoylcyanide 1d

Yield 33% (1.52 g); m.p. 59–61 °C; yellow solid; R_f = 0.58 (nhexane : ethyl acetate = 4 : 1); ¹H NMR (400 MHz, CDCl₃) δ 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) δ 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 cm⁻¹; HRMS (EI) calcd for C₁₅H₁₁BrN₂O (M)⁺ 314.0055, found 314.0053.

(Z)-N-(4-Methoxyphenyl)picolimidoylcyanide 1e

Yield 52% (1.91 g); m.p. 73–74 °C; orange solid; R_f = 0.14 (toluene); ¹H NMR (400 MHz, CDCl₃) δ 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) δ 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 cm⁻¹; HRMS (EI) calcd for C₁₄H₁₁N₃O (M)⁺ 237.0902, found 237.0912.

(Z)-N-(4-Methoxyphenyl)furan-2-carbimidoylcyanide 1f

Yield 38% (1.38 g); m.p. 97–98 °C; orange solid; R_f = 0.22 (toluene); ¹H NMR (400 MHz, CDCl₃) δ 3.85 (s, 3H), 6.62–6.64 (m, 1H), 6.96–7.00 (m, 2H), 7.20–7.21 (m, 1H), 7.35–7.39 (m, 2H), 7.67–7.67 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 55.5, 111.0, 112.8, 114.5, 117.4, 123.5, 125.6, 141.0, 146.9, 150.1, 159.7; IR (KBr) 2972, 2951, 2217, 1611, 1503, 1255, 1108, 1082, 912, 753 cm⁻¹; HRMS (EI) calcd for C₁₃H₁₀N₂O₂ (M)⁺ 226.0742, found 226.0741.

(Z)-N-(4-Methoxyphenyl)thiophen-2-carbimidoylcyanide 1g

Yield 29% (1.08 g); m.p. 95–96 °C; orange solid; R_f = 0.44 (toluene); ¹H NMR (400 MHz, CDCl₃) δ 3.86 (s, 3H), 6.96–7.01 (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) δ 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 cm⁻¹; HRMS (EI) calcd for C₁₃H₁₀N₂OS (M)⁺ 242.0514, found 242.0505.

(Z)-N-(4-Methoxyphenyl)-1-naphthimidoylcyanide 1h

Yield 43% (1.97 g); m.p. 130–133 °C; orange solid; R_f = 0.58 (toluene); ¹H NMR (400 MHz, CDCl₃) δ 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) δ 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 cm⁻¹; HRMS (EI) calcd for C₁₉H₁₄N₂O (M)⁺ 286.1106, found 286.1115.

(Z)-N-(4-Methoxyphenyl)-2-naphthimidoylcyanide 1i

Yield 67% (2.65 g); m.p. 100–101 °C; yellow solid; R_f = 0.47 (toluene); ¹H NMR (400 MHz, CDCl₃) δ 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) δ 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 cm⁻¹; HRMS (EI) calcd for C₁₉H₁₄N₂O (M)⁺ 286.1106, found 286.1093.

(Z)-N-(4-Methoxyphenyl)cyclohexanecarbimidoylcyanide 1j

Yield 23% (665.2 mg); m.p. 51–52 °C; yellow solid; R_f = 0.43 (toluene); ¹H NMR (400 MHz, CDCl₃) δ 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) δ 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 cm⁻¹; HRMS (EI) calcd for C₁₅H₁₈N₂O (M)⁺ 242.1419, found 242.1420.

Synthesis of 2-[ethyl(4-methoxyphenyl)amino]-2-phenylacetonitrile: general procedure for the synthesis of α-aminonitrile 2b

In a 30 mL two-necked round-bottomed flask equipped with a magnetic stirring bar, a rubber septum, and an argon balloon was placed (Z)-N-(4-methoxyphenyl)benzimidoylcyanide (47.3 mg, 0.20 mmol) in toluene (2.0 mL) and nhexane (1.0 mL) at −40 °C. To it was added EtMgBr (0.13 mL, 0.24 mmol, 1.80 M in Et₂O). After the mixture was stirred for 15 min at room temperature, the reaction was quenched with sat aq NaHCO₃ (5 mL), and the whole mixture was extracted with ethyl acetate (5 mL × 3). The combined extracts were washed with brine (5 mL × 2), dried over anhydrous Na₂SO₄, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (nhexane : Et₃N = 10 : 1) to give the title compound 2b.

Yield 89% (47.4 mg); m.p. 46–47 °C; yellow solid; R_f = 0.61 (nhexane : ethyl acetate = 6 : 1); ¹H NMR (400 MHz, CDCl₃) δ 1.00 (dd, J = 6.9, 6.9 Hz, 3H), 2.99 (dq, J = 6.9, 13.3 Hz, 1H), 3.21 (dq, J = 6.9, 13.3, 1H), 3.77 (s, 3H), 5.39 (s, 1H), 6.84–6.87 (m, 2H), 7.05–7.07 (m, 2H), 7.38–7.40 (m, 3H), 7.54–7.56 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 13.1, 43.5, 55.4, 61.2, 114.4, 117.0, 123.7, 127.5, 128.7, 128.7, 134.0, 140.4, 156.1; IR (KBr) 2983, 2831, 2228, 1880, 1615, 1512, 1448, 1254, 1225, 1035 cm⁻¹; HRMS (EI) calcd for C₁₇H₁₈N₂O (M)⁺ 266.1419, found 266.1423.

2-[(4-Methoxyphenyl)propylamino]-2-phenylacetonitrile 2c

Yield 77% (43.2 mg); yellow oil; R_f = 0.60 (nhexane : ethyl acetate = 6 : 1); ¹H NMR (400 MHz, CDCl₃) δ 0.79 (dd, J = 7.3, 7.3 Hz, 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) δ 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) 2962, 2934, 2836, 2228, 1509, 1451, 1246, 1181, 1037, 825 cm⁻¹; 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; R_f = 0.10 (nhexane : ethyl acetate = 50 : 1); ¹H NMR (400 MHz, CDCl₃) δ 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) δ 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 cm⁻¹; HRMS (EI) calcd for C₁₉H₂₂N₂O (M)⁺ 294.1732, found 294.1726.

2-[(4-Methoxyphenyl)octylamino]-2-phenylacetonitrile 2e

Yield 70% (48.9 mg); yellow oil; R_f = 0.48 (nhexane : ethyl acetate = 5 : 1); ¹H NMR (400 MHz, CDCl₃) δ 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) δ 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 cm⁻¹; HRMS (EI) calcd for C₂₃H₃₀N₂O (M)⁺ 350.2358, found 350.2344.

2-[Isobutyl(4-methoxyphenyl)amino]-2-phenylacetonitrile 2f

Yield 42% (24.9 mg); yellow oil; R_f = 0.30 (nhexane : ethyl acetate = 15 : 1); ¹H NMR (400 MHz, CDCl₃) δ 0.76 (d, J = 6.9 Hz, 3H), 0.82 (d, J = 6.9 Hz, 3H), 1.56–1.66 (m, 1H), 2.48 (dd, J = 9.2, 12.4 Hz, 1H), 3.05 (dd, J = 9.2, 12.4 Hz, 1H), 3.78 (s, 3H), 5.32 (s, 1H), 6.79–6.87 (m, 2H), 7.10–7.14 (m, 2H), 7.35–7.42 (m, 3H), 7.54–7.56 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 20.2, 20.5, 25.9, 55.4, 57.0, 62.9, 114.4, 116.8, 125.0, 127.9, 128.6, 128.8, 134.0, 141.0, 156.6; IR (neat) 2956, 2870, 2229, 1510, 1465, 1248, 1180, 1038, 718, 695 cm⁻¹; HRMS (EI) calcd for C₁₉H₂₂N₂O (M)⁺ 294.1732, found 294.1740.

2-[Isopropyl(4-methoxyphenyl)amino]-2-phenylacetonitrile 2g

Yield 28% (15.7 mg); yellow oil; R_f = 0.53 (nhexane : ethyl acetate = 10 : 1); ¹H NMR (400 MHz, CDCl₃) δ 1.07 (d, J = 6.4 Hz, 3H), 1.29 (d, J = 6.4 Hz, 3H), 3.66 (qq, J = 6.4, 6.4 Hz, 1H), 3.74 (s, 3H), 5.43 (s, 1H), 6.70–6.74 (m, 2H), 6.97–7.01 (m, 2H), 7.26–7.33 (m, 3H), 7.38–7.41 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 20.7, 22.6, 51.8, 55.3, 56.3, 113.4, 118.7, 127.1, 127.9, 128.4, 128.5, 134.8, 138.7, 156.6; IR (neat) 2970, 2934, 2226, 1606, 1511, 1247, 1155, 880, 787, 648 cm⁻¹; HRMS (EI) calcd for C₁₈H₂₀N₂O (M)⁺ 280.1576, found 280.1563.

2-[Cyclohexyl(4-methoxyphenyl)amino]-2-phenylacetonitrile 2h

Yield 24% (15.2 mg); yellow oil; R_f = 0.48 (nhexane : ethyl acetate = 10 : 1); ¹H NMR (400 MHz, CDCl₃) δ 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) δ 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 cm⁻¹; HRMS (EI) calcd for C₂₁H₂₄N₂O (M)⁺ 320.1889, found 320.1879.

2-(4-Bromophenyl)-2-[ethyl(4-methoxyphenyl)amino]acetonitrile 2k

Yield 67% (46.0 mg); yellow oil; R_f = 0.64 (toluene); ¹H NMR (400 MHz, CDCl₃) δ 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) δ 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 cm⁻¹; HRMS (EI) calcd for C₁₇H₁₇BrN₂O (M)⁺ 344.0524, found 344.0534.

2-[Ethyl(4-methoxyphenyl)amino]-2-(4-methoxyphenyl)acetonitrile 2l

Yield 52% (30.7 mg); yellow oil; R_f = 0.32 (toluene); ¹H NMR (400 MHz, CDCl₃) δ 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) δ 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 cm⁻¹; HRMS (EI) calcd for C₁₈H₂₀N₂O₂ (M)⁺ 296.1525, found 296.1520.

2-(2-Bromophenyl)-2-[ethyl(4-methoxyphenyl)amino]acetonitrile 2m

Yield 85% (59.0 mg); yellow oil; R_f = 0.62 (toluene); ¹H NMR (400 MHz, CDCl₃) δ 0.99 (dd, J = 6.9, 6.9 Hz, 3H), 3.18 (dq, J = 8.2, 11.0 Hz, 2H), 3.77 (s, 3H), 5.57 (s, 3H), 6.78–6.82 (m, 2H), 7.01–7.06 (m, 2H), 7.21–7.29 (m, 2H), 7.39–7.41 (m, 1H), 7.62–7.64 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 13.2, 45.2, 55.3, 60.4, 114.1, 117.0, 124.5, 125.1, 127.3, 130.5, 130.8, 133.2, 133.6, 139.5, 156.6; IR (neat) 2974, 2934, 2228, 1606, 1510, 1247, 1181, 839, 759, 626 cm⁻¹; HRMS (EI) calcd for C₁₇H₁₇BrN₂O (M)⁺ 344.0524, found 344.0528.

2-[Ethyl(4-methoxyphenyl)amino]-2-(pyridin-2-yl)acetonitrile 2n

Yield 54% (28.7 mg); yellow oil; R_f = 0.08 (toluene); ¹H NMR (400 MHz, CDCl₃) δ 1.06 (dd, J = 6.7, 6.7 Hz, 3H), 3.11 (dq, J = 6.7, 10.0 Hz, 1H), 3.33 (dq, J = 6.7, 10.0 Hz, 1H), 3.77 (s, 3H), 5.50 (s, 1H), 6.82–6.85 (m, 2H), 7.04–7.08 (m, 2H), 7.28–7.30 (m, 1H), 7.52–7.54 (m, 1H), 7.69–7.74 (m, 1H), 8.65–8.66 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 13.2, 44.9, 55.4, 63.2, 114.5, 116.7, 122.1, 123.5, 123.5, 137.0, 140.2, 149.6, 154.0, 156.1; IR (neat) 2973, 2935, 2229, 1608, 1512, 1247, 1180, 750, 735, 642 cm⁻¹; HRMS (EI) calcd for C₁₆H₁₇N₃O (M)⁺ 267.1372, found 267.1366.

2-[Ethyl(4-methoxyphenyl)amino]-2-(furan-2-yl)acetonitrile 2o

Yield 82% (41.9 mg); yellow oil; R_f = 0.24 (toluene); ¹H NMR (400 MHz, CDCl₃) δ 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), 7.45–7.45 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 13.2, 44.3, 55.1, 55.4, 110.5, 110.6, 114.3, 115.6, 124.1, 139.7, 143.6, 146.8, 156.4; IR (neat) 2975, 2936, 2234, 1608, 1511, 1248, 1089, 1181, 901, 744 cm⁻¹; HRMS (EI) calcd for C₁₅H₁₆N₂O₂ (M)⁺ 256.1212, found 256.1224.

2-[Ethyl(4-methoxyphenyl)amino]-2-(thiphen-2-yl)acetonitrile 2p

Yield 57% (30.8 mg); yellow oil; R_f = 0.42 (toluene); ¹H NMR (500 MHz, CDCl₃) δ 1.01 (dd, J = 6.7, 6.7 Hz, 3H), 3.05 (dq, J = 7.3, 10.8 Hz, 1H), 3.22 (dq, J = 7.3, 10.8 Hz, 1H), 3.79 (s, 3H), 5.45 (s, 1H), 6.85–6.92 (m, 2H), 6.97–6.99 (m, 1H), 7.12–7.15 (m, 2H), 7.22–7.23 (m, 1H), 7.34–7.35 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 13.1, 43.4, 55.4, 57.9, 114.5, 116.4, 124.5, 126.7, 126.9, 138.7, 140.1, 156.7; IR (neat) 2975, 2935, 2231, 1609, 1510, 1246, 1105, 917, 839, 710 cm⁻¹; HRMS (EI) calcd for C₁₅H₁₆N₂OS (M)⁺ 272.0983, found 272.0976.

2-[Ethyl(4-methoxyphenyl)amino]-2-(naphthalen-1-yl)acetonitrile 2q

Yield 72% (45.4 mg); yellow oil; R_f = 0.43 (toluene); ¹H NMR (500 MHz, CDCl₃) δ 0.94 (dd, J = 6.7, 6.7 Hz, 3H), 3.20 (m, 2H), 3.77 (s, 3H), 6.01 (s, 1H), 6.81–6.84 (m, 2H), 6.91–7.03 (m, 2H), 7.39–7.45 (m, 1H), 7.52–7.57 (m, 2H), 7.70–7.71 (m, 1H), 7.86–7.90 (m, 2H), 8.09–8.10 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 13.1, 44.6, 55.4, 58.0, 114.4, 117.6, 123.3, 123.5, 124.9, 126.2, 126.9, 127.3, 128.8, 129.1, 130.1, 130.9, 133.8, 140.0, 156.0; IR (neat) 2969, 2931, 2229, 1597, 1514, 1250, 1180, 837, 738, 630 cm⁻¹; HRMS (EI) calcd for C₂₁H₂₀N₂O (M)⁺ 316.1576, found 316.1571.

2-[Ethyl(4-methoxyphenyl)amino]-2-(naphthalen-2-yl)acetonitrile 2r

Yield 78% (49.6 mg); yellow oil; R_f = 0.31 (toluene); ¹H NMR (500 MHz, CDCl₃) δ 1.00 (dd, J = 7.3, 7.3 Hz, 3H), 3.02 (dq, J = 7.3, 11.0 Hz, 1H), 3.24 (dq, J = 7.3, 11.0 Hz, 1H), 3.78 (s, 3H), 5.54 (s, 1H), 6.84–6.88 (m, 2H), 7.10–7.14 (m, 2H), 7.51–7.55 (m, 2H), 7.63–7.65 (m, 1H), 7.85–7.88 (m, 3H), 8.03 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 13.2, 43.5, 55.4, 61.4, 114.5, 117.1, 123.7, 125.0, 126.7, 126.8, 126.9, 127.7, 128.2, 128.7, 131.5, 133.0, 133.3, 140.6, 156.2; IR (neat) 2984, 2973, 2229, 1510, 1249, 1178, 1105, 864, 728, 643 cm⁻¹; HRMS (EI) calcd for C₂₁H₂₀N₂O (M)⁺ 316.1576, found 316.1579.

2-Cyclohexyl-2-[ethyl(4-methoxyphenyl)amino]acetonitrile 2s

Yield 31% (16.9 mg); yellow oil; R_f = 0.31 (toluene); ¹H NMR (500 MHz, CDCl₃) δ 0.89–1.02 (m, 2H), 1.05 (dd, J = 7.3, 7.3 Hz, 3H), 1.12–1.36 (m, 3H), 1.69–1.80 (m, 4H), 2.02–2.04 (m, 1H), 2.15–2.17 (m, 1H), 3.09 (dq, J = 7.3, 11.0 Hz, 1H), 3.19 (dq, J = 7.3, 11.0 Hz, 1H), 3.68 (d, J = 10.4 Hz, 1H), 3.79 (s, 3H), 6.84–6.87 (m, 2H), 7.04–7.07 (m, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 13.4, 25.4, 25.6, 26.3, 30.2, 30.4, 38.7, 44.2, 55.5, 63.1, 114.4, 118.2, 123.8, 141.4, 155.9; IR (neat) 2931, 2853, 2224, 1511, 1245, 1140, 894, 737, 626, 543 cm⁻¹; HRMS (EI) calcd for C₁₇H₂₄N₂O (M)⁺ 272.1889, found 272.1885.

Synthesis of 2-[ethyl(4-methoxyphenyl)amino]-2-phenylmalononitrile: general procedure for the synthesis of α-aminomalononitrile 5a

In a 30 mL two-necked round-bottomed flask equipped with a magnetic stirring bar, a rubber septum, and an argon balloon was placed (Z)-N-(4-methoxyphenyl)benzimidoylcyanide (0.25 mL, 0.24 mmol, 0.95 M in Et₂O) in toluene (2.0 mL) at −40 °C. To it 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 °C, and the mixture was stirred at 0 °C for another 15 min. A solution of NIS (40.0 mg, 0.23 mmol) in MeCN (1.5 mL) was added, and the reaction mixture was stirred for 1 min at room temperature. Then, nBu₃SnCN (75.9 mg, 0.24 mmol) was added and the mixture was stirred at room temperature for 3 hr. The reaction was quenched with sat aq NaHCO₃ (5.0 mL), and the whole mixture was extracted with ethyl acetate (5 mL × 3). The combined extracts were washed with brine (5 mL × 2), dried over anhydrous Na₂SO₄, 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.

Yield 72% (41.9 mg); yellow oil; R_f = 0.46 (nhexane : ethyl acetate = 6 : 1); ¹H NMR (400 MHz, CDCl₃) δ 0.90 (t, J = 7.3 Hz, 3H), 3.12 (q, J = 7.3 Hz, 2H), 3.77 (s, 3H), 6.79–6.83 (m, 2H), 7.23–7.26 (m, 2H), 7.41–7.44 (m, 3H), 7.66–7.71 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 13.3, 45.5, 55.3, 64.7, 113.7, 114.3, 127.4, 129.2, 129.3, 130.6, 132.5, 135.8, 159.0; IR (neat) 2976, 2935, 2362, 2251, 1581, 1507, 1253, 1253, 1171, 1038, 696 cm⁻¹; HRMS (EI) calcd for C₁₈H₁₇N₃O (M)⁺ 291.1372, found 291.1374.

2-(4-Bromophenyl)-2-[ethyl(4-methoxyphenyl)amino]malononitrile 5b

Yield 59% (43.8 mg); yellow oil; R_f = 0.76 (toluene); ¹H NMR (400 MHz, CDCl₃) δ 0.90 (t, J = 6.9 Hz, 3H), 3.13 (q, J = 6.9 Hz, 2H), 3.78 (s, 3H), 6.80–6.84 (m, 2H), 7.19–7.23 (m, 2H), 7.52–7.58 (m, 4H); ¹³C NMR (100 MHz, CDCl₃) δ 13.3, 45.7, 55.3, 64.1, 113.3, 114.4, 125.2, 129.0, 129.2, 131.6, 132.5, 135.4, 159.0; IR (neat) 2979, 2936, 2231, 1607, 1510, 1251, 1181, 832, 739, 628 cm⁻¹; HRMS (EI) calcd for C₁₈H₁₆BrN₃O (M)⁺ 369.0477, found 369.0465.

2-[Ethyl(4-methoxyphenyl)amino]-2-(4-methoxyphenyl)malononitrile 5d

Yield 27% (17.5 mg); yellow oil; R_f = 0.46 (toluene); ¹H NMR (400 MHz, CDCl₃) δ 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) δ 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 cm⁻¹; HRMS (EI) calcd for C₁₉H₁₉N₃O₂ (M)⁺ 321.1477, found 326.1468.

2-(2-Bromophenyl)-2-[ethyl(4-methoxyphenyl)amino]malononitrile 5c

Yield 61% (45.1 mg); m.p. = 68–71 °C; yellow solid; R_f = 0.57 (toluene); ¹H NMR (500 MHz, CDCl₃) δ 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) δ 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 cm⁻¹; HRMS (EI) calcd for C₁₈H₁₆BrN₃O (M)⁺ 369.0477, found 369.0494.

2-[Ethyl(4-methoxyphenyl)amino]-2-(pyridine-2-yl)malononitrile 5e

Yield 45% (26.5 mg); yellow oil; R_f = 0.11 (toluene); ¹H NMR (400 MHz, CDCl₃) δ 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) δ 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 cm⁻¹; HRMS (EI) calcd for C₁₇H₁₆N₄O (M)⁺ 292.1324, found 292.1319.

2-[Ethyl(4-methoxyphenyl)amino]-2-(furan-2-yl)malononitrile 5f

Yield 8% (4.3 mg); yellow oil; R_f = 0.50 (toluene); ¹H NMR (500 MHz, CDCl₃) δ 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) δ 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 cm⁻¹; HRMS (EI) calcd for C₁₆H₁₅N₃O₂ (M)⁺ 281.1164, found 281.1170.

2-[Ethyl(4-methoxyphenyl)amino]-2-(thiophen-2-yl)malononitrile 5g

Yield 29% (17.4 mg); yellow oil; R_f = 0.47 (toluene); ¹H NMR (500 MHz, CDCl₃) δ 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) δ 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 cm⁻¹; HRMS (EI) calcd for C₁₆H₁₅N₃OS (M)⁺ 297.0936, found 297.0929.

2-[Ethyl(4-methoxyphenyl)amino]-2-(maphthalen-1-yl)malononitrile 5h

Yield 39% (26.9 mg); yellow oil; R_f = 0.50 (toluene); ¹H NMR (500 MHz, CDCl₃) δ 0.91 (t, J = 7.3 Hz, 3H), 3.28 (q, J = 7.3 Hz, 2H), 3.73 (s, 3H), 6.72–6.74 (m, 2H), 7.22–7.26 (m, 2H), 7.34–7.42 (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) δ 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 cm⁻¹; HRMS (EI) calcd for C₂₂H₁₉N₃O (M)⁺ 341.1528, found 341.1525.

2-[Ethyl(4-methoxyphenyl)amino]-2-(maphthalen-2-yl)malononitrile 5i

Yield 52% (35.2 mg); yellow oil; R_f = 0.47 (toluene); ¹H NMR (500 MHz, CDCl₃) δ 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) δ 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 cm⁻¹; HRMS (EI) calcd for C₂₂H₁₉N₃O (M)⁺ 341.1528, found 341.1538.

2-[Butyl(4-methoxyphenyl)amino]-2-phenylmalononitrile 5j

Yield 32% (20.6 mg); yellow oil; R_f = 0.59 (toluene); ¹H NMR (500 MHz, CDCl₃) δ 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) δ 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 cm⁻¹; HRMS (EI) calcd for C₂₀H₂₁N₃O (M)⁺ 319.1685, found 319.1687.

2-[4-Methoxyphenyl(octyl)amino]-2-phenylmalononitrile 5k

Yield 23% (17.5 mg); yellow oil; R_f = 0.62 (toluene); ¹H NMR (500 MHz, CDCl₃) δ 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) δ 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) 2954, 2855, 2282, 1607, 1510, 1250, 1035, 841, 747, 663 cm⁻¹; 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 −40 °C. 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 −40 °C. To the mixture MVK (0.020 mL, 0.24 mmol) was added, and it was stirred at −40 °C for 4 h. The reaction was quenched with sat aq NaHCO₃ (5 mL), and the whole mixture was extracted with ethyl acetate (5 mL × 3). The combined extracts were washed with brine (5 mL × 2), dried over anhydrous Na₂SO₄, and concentrated in vacuo. The crude product was purified by alumina column chromatography (nhexane : EtOAc = 5 : 1) to give the title compound 7.

Yield 50% (33.7 mg); yellow oil; R_f = 0.46 (nhexane : ethyl acetate = 5 : 1); ¹H NMR (500 MHz, CDCl₃) δ 0.73 (dd, J = 6.7, 6.7 Hz, 3H), 1.84–1.91 [(m, 5H) including a singlet of C(O)CH₃ at δ = 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) δ 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 cm⁻¹; HRMS (EI) calcd for C₂₁H₂₄N₂O₂ (M)⁺ 336.1838, found 336.1846.

2-[Ethyl(4-methoxyphenyl)amino]-3-oxo-2,3-diphenylpropanenitrile 8

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 −40 °C. 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 −40 °C. To the mixture was added benzoyl chloride (0.070 mL, 0.60 mmol), and it was stirred at −40 °C for 35 min. The reaction was quenched with sat aq NaHCO₃ (5 mL), and the whole mixture was extracted with ethyl acetate (5 mL × 3). The combined extracts were washed with brine (5 mL × 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; R_f = 0.22 (nhexane : ethyl acetate = 6 : 1); ¹H NMR (400 MHz, CDCl₃) δ 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) δ 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 cm⁻¹; HRMS (EI) calcd for C₂₄H₂₂N₂O₂ (M)⁺ 370.1681, found 370.1672.

Conflicts of interest

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.

Notes and references

1. For C-alkylation to α-iminoesters, see: (a) J.-C. Fiaud and H. B. Kagan, Tetrahedron Lett., 1970, 21, 1813–1816; (b) L. M. Harwood, K. J. Vines and M. G. B. Drew, Synlett, 1996, 1051–1053; (c) D. Ferraris, B. Young, T. Dudding and T. Lectka, J. Am. Chem. Soc., 1998, 120, 4548–4549; (d) A. Córdova, 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, N. Mateu, L. Albert and J. L. Aceña, J. Org. Chem., 2009, 74, 4429–4432; (j) K. Yeung, F. Talbot, G. P. Howell, A. P. Pulis and D. J. Procter, ACS Catal., 2019, 9, 1655–1661.
2. For N-alkylation to α-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; (c) K. Uneyama, F. Yan, S. Hirama and T. Katagiri, Tetrahedron Lett., 1996, 37, 2045–2048; (d) S. E. Yoo and Y. D. Gong, Heterocycles, 1997, 45, 1251–1255; (e) M. P. Bertrand, L. Feray, R. Nouguier and P. Perfetti, Synlett, 1999, 1148–1150; (f) M. Mae, H. Amii and K. Uneyama, Tetrahedron Lett., 2000, 41, 7893–7896; (g) K. P. Chiev, S. Roland and P. Mangeney, Tetrahedron: Asymmetry, 2002, 13, 2205–2209; (h) J. S. Dickstein, M. W. Fennie, A. L. Norman, B. J. Paulose and M. C. Kozlowski, J. Am. Chem. Soc., 2008, 130, 15794–15795; (i) J. S. Dickstein and M. C. Kozlowski, Chem. Soc. Rev., 2008, 37, 1166–1173; (j) J. M. Curto, J. S. Dickstein, S. Berritt and M. C. Kozlowski, Org. Lett., 2014, 16, 1948–1951.
3. For N-alkylation to α-iminoesters found in our laboratories, see: (a) Y. Niwa, K. Takayama and M. Shimizu, Bull. Chem. Soc. Jpn., 2002, 75, 1819–1825; (b) Y. Niwa and M. Shimizu, J. Am. Chem. Soc., 2003, 125, 3720–3721; (c) M. Shimizu, H. Itou and M. Miura, J. Am. Chem. Soc., 2005, 127, 3296–3297; (d) I. Mizota and M. Shimizu, Chem. Rec., 2016, 16, 688–702; (e) I. Mizota, Y. Tadano, Y. Nakamura, T. Haramiishi, M. Hotta and M. Shimizu, Org. Lett., 2019, 21, 2663–2667; (f) M. Shimizu, H. Imazato, I. Mizota and Y. Zhu, RSC Adv., 2019, 9, 17341–17346; (g) M. Shimizu, M. Mushika, I. Mizota and Y. Zhu, RSC Adv., 2019, 9, 23400–23407.
4. M. Shimizu, M. Tateishi and I. Mizota, Chem. Lett., 2014, 43, 1752–1754.
5. Hydrolysis: V. Yu, K. Armando and J. L. Pombeiro, Inorg. Chim. Acta, 2005, 358, 1–21 , and refernces cited therein.
6. Reduction: J. Barrault and Y. Pouilloux, Catal. Today, 1997, 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.
9. P. Fontaine, A. Chiaroni, G. Masson and J. Zhu, Org. Lett., 2008, 10, 1509–1512.
10. (a) N. Picci, M. Pocci, A. Gugliuzza, F. Puoci, A. De Munno, F. Iemma and V. Bertini, Heterocycles, 2001, 55, 2075–2084; (b) J. J. Garcia, N. M. Brunkan and W. D. Jones, J. Am. Chem. Soc., 2002, 124, 9547–9555; (c) J. M. Penney, Tetrahedron Lett., 2004, 45, 2667–2669; (d) J. M. Penney and J. A. Miller, Tetrahedron Lett., 2004, 45, 4989–4992; (e) Y. Nakao, S. Oda and T. Hiyama, J. Am. Chem. Soc., 2004, 126, 13904–13905; (f) Y. Nakao, A. Yada, S. Ebata and T. Hiyama, J. Am. Chem. Soc., 2007, 129, 2428–2429; (g) M. Tobisu, Y. Kita, Y. Ano and N. Chatani, J. Am. Chem. Soc., 2008, 130, 15982–15989; (h) D.-G. Yu, M. Yu, B.-T. Guan, B.-J. Li, Y. Zheng, Z.-H. Wu and Z.-J. Shi, Org. Lett., 2009, 11, 3374–3377; (i) M. Columbo, S. Vallese, I. Peretto, X. Jacq, J.-C. Rain, F. Colland and P. Guedat, Chem. Med. Chem, 2010, 5, 552–558; (j) Y. Kita, M. Tobisu and N. Chatani, Org. Lett., 2010, 12, 1864–1867; (k) K. Nakai, T. Kurahashi and S. Matsubara, J. Am. Chem. Soc., 2011, 133, 11066–11068; (l) M. Tobisu, H. Kinuta, Y. Kita, E. Rémond and N. Chatani, J. Am. Chem. Soc., 2012, 134, 115–118; (m) A. D. Thompson and M. P. Huestis, J. Org. Chem., 2013, 78, 762–769.
11. (a) T. Opatz, Synthesis, 2009, 1941–1959; (b) N. Otto and T. Opatz, Chem. – Eur. J., 2014, 20, 13064–13077; (c) C. Grundke and T. Opatz, Green Chem., 2019, 21, 2362–2366 , and references cited therein.
12. Addition of methyl-, benzyl-, and arylmetal reagents to α-iminoesters is available only for the doubly activated derivatives: (a) I. Mizota, C. Ueda, Y. Tesong, Y. Tsujimoto and M. Shimizu, Org. Lett., 2018, 20, 2291–2296 . These reactivity differences could be explained in terms of the different pK_a values and nucleophilicity of the reagents, see: ; (b) F. G. Bordwell, Acc. Chem. Res., 1988, 21, 456–463; (c) H. Mayr and A. R. Ofial, J. Phys. Org. Chem., 2008, 21, 584–595 , and references cited therein. See also, ref. 3a and g.
13. R. J. H. Gregory, Chem. Rev., 1999, 99, 3649–3682.
14. M. Tanaka, Tetrahedron Lett., 1980, 21, 2959–2962.
15. Although we have not fully examined the substituents at the starting imino nitrogen, we presume that a similar reactivity tendency to that observed for previously reported α-iminoesters would be expected for the present α-iminonitriles.
16. Aminomalononitriles are useful units for further construction of molecules. See for example: (a) J. P. Ferris, R. A. Sanchez and R. W. Mancuso, Org. Synth., 1973, 5, 32–34; (b) J. P. Ferris and R. A. Sanchez, Org. Synth., 1973, 5, 344–345; (c) M. A. Metwally and M. A. Mogieb, Synth. Commun., 2001, 31, 1901–1905; (d) D. Kikelj and U. Urleb, Thiazoles, in Science of Synthesis Houben-Weyl Methods of Organic Chemistry, ed. E. Schaumann, Thieme, Stuttgart, New York, 2002, pp. 627–833; (e) V. Arava and S. Gogireddy, Der Pharma Chem., 2013, 5, 232–239; (f) A. W. Schwartz, H. Joosten and A. B. Voet, BioSystems, 1982, 15, 191–193.

---

Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c9nj05114g

---