HETEROCYCLES

Paper | Special issue | Vol. 82, No. 1, 2010, pp. 619-629
Received, 17th May, 2010, Accepted, 6th July, 2010, Published online, 7th July, 2010.
DOI: 10.3987/COM-10-S(E)34

■ Reactions of Heterocyclic Ketene Aminals with Acrylonitrile: An Efficient Synthesis of Dihydropyridine-Fused 1,3-Diazaheterocycles

Hui Zhao, Ai-Qun Zeng, Wei-Lin Liao, Yue-Mei Jia, Li-Ben Wang, Zhi-Tang Huang,* and Chu-Yi Yu*

Institute of Chemistry, Chinese Academy of Sciences, No. 2, 1st North Street, Zhongguancun, Beijing 100190, China

Abstract

A simple and efficient method for the synthesis of dihydropyridine-fused 1,3-diazaheterocycles has been developed via reactions of heterocyclic ketene aminals (HKAs) with acrylonitrile in good to excellent yields.

INTRODUCTION
Heterocyclic ketene aminals (HKAs) 1 or 2, also referred to as cyclic 1,1-enediamines or cyclic ketene N,N-acetals, are an unique class of polyfunctionalized heterocyclic compounds which can serve as versatile intermediates for the syntheses of a wide variety of heterocycles and fused heterocycles that are difficult to obtain by other approaches.1 The double bond of the enamine function is highly polarized and the electron density at the α-carbon increases considerably compared with normal olefins due to the extensive conjugation between electron-donating amino groups and electron-withdrawing substituents at α-carbon in HKAs.2 As a result, both the α-carbon and the secondary amino group in the HKAs can be employed as nucleophiles in the reactions with various electrophiles. Therefore, HKAs have been used as bisnucleophiles to react with biselectrophiles for the construction of a number of structurally complex aza-heterocycles3,4 and/or fused-ring heterocycles with potential therapeutic applications5 by nucleophilic addition or substitution6 with a variety of electrophiles including 1,3-diploles such as azides,7 nitrile oxides,8 and nitrile imines.9 Furthermore, a number of HKAs and their derivatives have been found as pesticides,10 antibacterial agents,11 anti-anxiety agents,12 antileishmanial agents13 and anti-cancer agents.14
In the context of our efforts in developing efficient methods for the diversity-oriented rapid generation of novel heterocycles with potential biological activities based on the chemistry of HKAs, we have reported the reaction of HKAs with a number of α,β-unsaturated compounds for the synthesis of compound libraries of dihydro- or tetrahydropyridine fused 1,3-diazaheterocycles since these compounds might be valuable in drug discovery and in agrochemical development.3,4 Herein, we report the reactions of HKAs with a simple biselectrophilic reagent, acrylonitrile. Because the –CN group can be converted into a variety of other functional groups, such as –COOH, =NH, –NHCOR etc., it can be envisaged that heterocyclic compounds containing an –CN group might be valuable intermediates for the diversity-oriented synthesis of heterocycles via reactions of the –CN group. It was expected that reactions of HKAs 1 or 2 with acrylonitrile would afford C-adducts 4 or 5, and N-adducts 8 or 9, under different neutral or strong basic reaction conditions, respectively. Subsequent intramolecular cyclization of compound 4 and 5 could form the polyfunctionalized dihydropyridine-fused 1,3-diazaheterocycles 6 or 7 (Scheme 1).

RESULTS AND DISCUSSION
HKAs 1 refluxed in acrylonitrile give products 4 while HKAs 2 refluxed in acetonitrile with just equivalent acrylonitrile (Scheme 1) afford compound 5. The difference of the reactivities between HKAs 1 and HKAs 2 was ascribed to a better delocalization of the secondary amino groups into the carbon-carbon double bond of the six-membered HKAs 2 than that of the five-membered HKAs 1. Due to the increased electron density of the double bond caused by electron-donating group, the HKAs 1 or 2 with electron-donating group on aroyl ring (Table 1, entries 2, 3, 6 and 7) gave a slightly better yield than that with electron-withdrawing group (Table 1, entries 4 and 8). The structure of the products 4 and 5 were determined by IR, 1H NMR, and 13C NMR and MS spectrometry and elemental analysis. The disappearance of the signal of H-6 in 1H NMR indicated that the products are compound 4 and 5 instead of 8 and 9. Take 4a for example, the signal of H-1, H-4 and H-6 of compound 1a appeared at δ 9.20 (br, s), 7.32 (br, s), 5.20 (s) ppm respectively,15 in product 4a the singlet signal of H-6 was disappeared while the signal of H-1 (10.13ppm, br) and H-4 (5.35ppm, br) still existed, which identified the structure of compound 4a.

Although the compound 4 and 5 was obtained smoothly with high yield, the attempts to prepare pyridine-fused 1,3-diazaheterocycles 6 and 7 from compound 4 and 5 in situ were failed. Except compound 7c, which was made directly from the reaction of 2c with equilibrium acrylonitrile in refluxing acetonitrile catalyzed by TsOH, pyridine-fused 1, 3-diazaheterocycles 6 or 7 can not be obtained either by the extension of reaction time or by addition of acid (Lewis or proton acid) and/or organic base such as Et3N, DBU. To our delight, pyridine-fused 1, 3-diazaheterocycles 6 and 7 were made from the isolated 4 and 5 in DMF under strong basic condition (NaH) in ice-water bath (Table 1, entry 9-12) or in refluxing xylene (Table 1, entry 13,15). A plausible mechanism of the reaction was depicted in Scheme 2. Firstly, the ene-component HKAs 1 or 2 and the enophile acrylonitrile 3 underwent an aza-ene reaction to give the compound 4 or 5, which successively underwent imine-enamine tautomerization under strong basic condition, followed by nucleophilic addition of the secondary amino group to the cyano group, resulting in the formation of dihydropyridine-fused 1,3-diazaheterocycles 6 or 7.

It is worth noting that the imine group of compounds 7 was easy to undergo hydrolysis under acidic conditions to give the pyridone derivatives (for example 7e,3 Figure 1), which made compound 7 difficult to purify by column chromatography.

When HKAs 1 reacted with acrylonitrile in DMF under strong basic condition (NaH) at 0 °C Michael addition products 8a–8d were obtained in excellent yields. However, the attempts to get dihydropyridine-fused 1,3-diazaheterocycles by intramolecular cyclization of 8a–8d failed. The hydrogen bond existed in compound 8 make the secondary amino group difficult to be attacked by the base to give cyclization products (Figure 2). In 1H NMR of HKAs 1, 2 and 8, compared with the signal of H-4 (7.32 ppm), the downfield shift of the H-1 signal (9.20ppm) identified the existing of the intramolecular hydrogen bond between secondary amino group and the carbonyl group of benzoyl. All the structures of the products 8a–8d were determined by the IR, 1H NMR, 13C NMR and MS. Similarly, in 1H NMR the disappearance of the signal of H-4 (7.32 ppm, brs) and the existing of the signal of H-6 (5.22 ppm, singlet) indicated that the reaction was occurred at the secondary amino group. The attempts to make compound 9 from six-membered HKAs 2 failed, i.e., no reaction occurred between 2 and 3 under the same reaction conditions.

In conclusion, a simple method for synthesis of dihydropyridine-fused 1,3-diazaheterocycles has been developed via the reaction of HKAs with acrylonitrile. Further work upon the reactions of compounds 6,7 and 8 is undergoing.

EXPERIMENTAL
General procedure for the reactions of HKAs 1 with acrylonitrile (3): A stirred solution of heterocyclic ketene aminals 1 (1.0 mmol) in acrylonitrile 3 (5 mL) was refluxed for 12 h. The reactions were monitored by TLC. When TLC indicated the disappearance of the starting materials, solvents were removed by distillation under vacuum and the resulting residue was purified by recrystallization (EtOAc) or column chromatography on silica gel (EtOAc : MeOH = 100 : 1) to afford the products. Compound 4a: white solid. mp 161–163 °C. IR (KBr): 3104, 2241, 1597, 1534 cm–1. 1H-NMR (300 MHz, CDCl3): δ = 10.13 (br s, 1H, N–H), 7.38–7.28 (m, 5H, Ph–H), 5.53 (br s, 1H, N–H), 3.73 (s, 2H, CH2), 3.45 (s, 2H, CH2), 2.50 (t, J = 8.0 Hz, 2H, CH2), 2.21 (t, J = 7.2 Hz, 2H, CH2); 13C-NMR (75 MHz, CDCl3): δ = 190.6, 165.5, 142.9, 128.3, 128.1, 125.9, 120.0, 85.4, 44.0, 42.5, 24.7, 18.4. ESI-MS: m/z 242.26 [M+H]+. Anal. Calcd (%) for C14H15N3O: C, 69.69; H, 6.27; N, 17.41. Found: C 69.51, H 6.22, N 17.11. Compound 4b: white solid. mp: 198–201 °C. IR (KBr): 3147, 2246, 1596, 1534cm–1. 1H-NMR (300 MHz, CDCl3): δ = 10.1 (s, 1H, N–H), 7.16 (s, 4H, Ph–H), 3.50 (s, 1H, N–H), 3.72 (s, 2H, CH2), 3.42 (s, 2H, CH2), 2.52 (t, J = 8.0 Hz, 2H, CH2), 2.20 (t, J = 7.0 Hz. 2H, CH2), 2.4 (s, 3H, CH3). 13C-NMR (75 MHz, CDCl3): δ = 190.2, 165.5, 140.1, 137.9, 128.9, 125.9, 120.1, 85.6, 44.0, 42.5, 24.8, 21.2, 18.3. ESI-MS: m/z 256.33 [M+H]+. Anal. Calcd (%) for C15H17N3O: C, 70.56; H, 6.71; N, 16.46. Found: C, 70.80; H, 6.67; N, 16.69. Compound 4c: white solid. mp 168–170 °C. IR (KBr): 3147, 2246, 1599, 1531cm–1. 1H-NMR (300 MHz,CDCl3): δ = 10.1 (s, 1H, N–H), 7.23–7.27 (d, J = 10.0 Hz, 2H, Ph–H), 6.87–6.93 (d, J = 10.0 Hz, 2H, Ph–H), 5.30 (s, 1H, =N–H), 3.82 (s, 3H, CH3), 3.74 (t, J = 8.5 Hz, 2H, CH2), 3.48 (t, J = 8.5 Hz, 2H, CH2), 2.56 (t, J = 8.0 Hz, 2H, CH2), 2.21 (d, J = 7.0 Hz, 2H, CH2). 13C-NMR (75 MHz, CDCl3): δ = 190.0, 185.5, 159.6, 135.5, 127.7, 120.2, 113.7, 85.6, 55.3, 44.0, 42.7, 24.9, 18.3. ESI–MS: m/z 272.33 [M+H]+. Anal. Calcd (%) for C15H17N3O2: C, 66.40; H, 6.32; N, 15.49. Found: C, 66.69; H, 6.40; N, 15.34. Compound 4d: white solid. mp 168–171 °C. IR (KBr): 3157, 2241, 1592, 1532cm–1. 1H NMR (300 MHz, CDCl3): δ = 9.99 (s, 1H, N–H), 7.20–7.38 (m, 4H, Ph–H), 6.35 (s, 1H, N–H), 3.69 (s, 2H, CH2), 3.32 (s, 2H, CH2), 2.46 (t, J = 8.0 Hz, 2H, CH2), 2.18 (t, J = 7.5 Hz, 2H, CH2). 13C NMR (75 MHz, CDCl3): δ = 188.3, 167.3, 142.8, 134.9, 129.4, 129.3, 129.1, 120.6, 87.5, 44.2, 25.0, 18.5. ESI–MS: m/z 276.28 [M+H]+. Anal. Calcd (%) C14H16ClN3O: C, 60.98; H, 5.12; N, 15.24. Found: C, 61.25; H, 5.07; N, 15.06.
General procedure for the reactions of HKAs 2 with acrylonitrile (3) in neutral condition: A stirred solution of of heterocyclic ketene aminals 2 (1.0 mmol) and acrylonitrile 3 (1.0 mmol) in MeCN (5 mL) was refluxed for 6 h. The reactions were monitored by TLC. When TLC indicated the disappearance of the starting materials, solvents were removed by distillation under vacuum and the resulting residue was purified by recrystallization (EtOAc) or column chromatography on silica gel (EtOAc : MeOH = 5 : 1) to afford the products. Compound 5a: white solid. mp 184–186 °C. IR (KBr): 3225, 2241, 1622, 1575 cm–1. 1H-NMR (300 MHz, CDCl3): δ = 12.34 (br s, 1H , N–H), 7.38–7.22 (m, 5H, Ph–H), 5.45 (br s, 1H, N–H), 3.35 (s, 4H, 2CH2), 2.46–2.41 (m, 2H, CH2), 2.21–2.16 (m, 2H, CH2), 1.96–1.89 (m, 2H, CH2). 13C-NMR (75 MHz, CDCl3): δ = 187.3, 159.2, 143.5, 128.2, 127.6, 125.9, 119.1, 86.7, 38.5, 38.5, 23.7, 20.1, 18.2. ESI–MS: m/z 256.31 [M+H]+. Anal. Calcd (%) for C15H17N3O: C, 70.56; H, 6.71; N, 16.46. Found: C, 70.62; H, 6.65; N, 16.62. Compound 5b: white solid. mp 170–172 °C. IR (KBr): 3269, 2241, 1602, 1509 cm–1. 1H-NMR (300 MHz, CDCl3): δ = 12.3 (s, 1H, N–H), 7.10–7.13 (m, 4H, Ph–H), 5.3 (s, 1H, N–H), 3.3 (s, 4H, CH2), 2.41–2.44 (m, 2H, CH2), 2.15–2.20 (m, 2H, CH2), 2.35 (s, 3H, CH3), 1.82–1.89 (m, 2H, CH2). 13C-NMR (75 MHz, CDCl3): δ = 187.1, 159.2, 140.7, 137.2, 128.8, 125.9, 120.0, 87.1, 38.4, 38.4, 23.8, 21.1, 20.0, 18.0. ESI-MS: m/z 270.31 [M+H]+. Anal. Calcd (%) for C16H19N3O: C, 71.35; H, 7.11; N, 15.60. Found: C, 71.47; H, 7.20; N, 15.57. Compound 5c: white solid. mp 158–160 °C. IR (KBr): 3263, 2241, 1603, 1513 cm–1. 1H-NMR (300 MHz, CDCl3): δ = 12.10 (s, 1H, N–H), 7.17–7.21 (d, J = 10.0 Hz, 2H, Ph–H), 6.89–6.90 (d, J = 9.0 Hz, 2H, Ph–H), 5.29 (s, 1H, N–H), 3.82 (s, 3H, CH3)3.70 (s, 2H, CH2), 3.46 (s, 2H, CH2), 2.47–2.50 (m, 2H, CH2), 2.15–2.19 (m, 2H, CH2). 13C-NMR (75 MHz, CDCl3): δ = 186.7, 159.2, 159.1 136.2, 131.3, 127.5, 120.0, 113.6, 87.1, 55.2, 38.4, 23.8, 20.0, 18.1. ESI–MS: m/z 286.32 [M+H]+. Anal. Calcd (%) for C16H19N3O2: C, 67.35; H, 6.71; N, 14.73. Found: C, 67.19; H, 6.75; N, 14.67. Compound 5d: yellow solid. mp 110–112 °C. IR (KBr): = 3157, 2242, 1593 cm–1. 1H-NMR (300 MHz, CDCl3): δ = 12.84 (br s, 1H, NH), 7.32–7.28 (m, 4H, Ph–H), 5.29 (br s, 1H, NH), 3.91 (s, 4H, 2CH2), 3.43–3.45 (m, 2H, CH2), 2.53–2.48 (m, 2H, CH2), 2.43–2.39 (m, 2H, CH2), 2.07–2.01 (m, 2H, CH2). 13C-NMR(75 MHz, CDCl3): δ = 185.6, 159.2, 141.8, 133.4, 128.5, 127.5, 119.7, 86.9, 38.5, 23.6, 20.0, 18.2. ESI–MS: m/z 290.21 [M+H]+. Anal. Calcd (%) for C15H16ClN3O: C, 62.18; H, 5.57; N, 14.50. Found: C, 62.06; H, 5.78; N, 15.94.
The procedure for the pyridine-fused 1, 3-diazaheterocycles products 6 and 7a: To an anhydrous solution of 4 or 5a (0.4mmol) in DMF (5 mL) at 0 °C was added NaH (0.7 mmol). The reactions were monitored by TLC. When TLC indicated the disappearance of the starting materials, transfer the solution into 10 mL water, then extracted with CH2Cl2 (3×3mL). The combined organic phase was washed with water, dried (anhydrous Na2SO4). After removing of the solvent under reduced pressure, the residue was purified by recrystallization (anhydrous EtOAc). Compound 6a: yellow crystals. mp 171–173 °C. IR (KBr): 3269, 1675, 1636 cm–1. 1H-NMR (300 MHz, CDCl3): δ = 9.55 (s, 1H, N–H), 7.35–7.46 (m, 5H, Ph–H; s, 1H, =N–H), 3.98–4.04 (m, 2H, CH2), 3.81 (m, 2H, CH2), 2.59–2.63 (m, 2H, CH2), 2.50–258 (m, 2H, CH2). 13C-NMR (75 MHz, CDCl3): δ = 189.9, 161.3, 158.1, 141.7, 129.0, 128.0, 126.9, 84.6, 43.3, 42.5, 33.0, 22.5. ESI–FAB: m/z 242.26 [M+H]+. HRMS-FAB: m/z for C14H15N3O [M+H]+: 242.1304; found: 242.1293. Compound 6b: yellow crystals. mp 175–177 °C. IR (KBr): 3295, 1633, 1620cm–1. 1H-NMR (300 MHz, CDCl3): δ = 9.53 (br s, 1H, NH), 7.36–7.33 (d, J = 5.3 Hz, 2H, CH2), 7.18–7.16 (d, J = 8.0 Hz, 2H, CH2), 6.90 (br s,1H, =NH), 3.96–4.02 (m, 2H, CH2), 3.79–3.85 (m, 2H, CH2), 2.59–2.95 (m, 2H, CH2), 2.49–2.54 (m, 2H, CH2), 2.36 (s, 3H, CH3). 13C-NMR (75 MHz, CDCl3): δ = 190.0, 161.3, 158.0, 139.0, 138.8, 128.5, 127.0, 84.6, 43.3, 42.5, 33.0, 22.7, 21.2. ESI–MS: m/z 256.28 [M+H]+. HRMS-FAB: m/z for C15H17N3O [M+H]+: 256.1450; found: 256.1441. Compound 6c: yellow crystals. mp 144–146 °C. IR (KBr): 3246, 1647, 1618 cm–1. 1H-NMR (300 MHz, CDCl3): δ = 9.54 (s, 1H, N–H), 7.32–7.40 (m, 4H, Ph–H; s, 1H, =N–H), 3.94–4.04 (m, 2H, CH2), 3.82–3.88 (m, 2H, CH2), 2.50–2.68 (m, 4H, –CH2–CH2–). 13C-NMR (75 MHz, CDCl3): δ = 188.3, 161.2, 158.4, 140.0, 134.9, 128.5, 128.2, 84.5, 43.4, 42.6, 33.0, 22.6. ESI-MS: m/z 276.25 [M+H]+. HRMS-FAB: m/z for C14H14N3OCl [M+H]+: 276.0900; found: 276.0904. Compound 7a: yellow solid. mp 134–136 °C. IR (KBr): 3300, 1635, 1605cm–1. 1H-NMR (300 MHz, CDCl3): δ = 12.90 (s, 1H, N–H), 7.31–7.41 (m, 5H, Ph–H), 7.27 (s, 1H, =N–H), 3.92 (t, J = 5.5Hz, 2H, CH2), 3.45–3.47 (d, J = 5.5Hz, 2H, CH2), 2.42–2.52 (m, 4H, –CH2–CH2–), 2.03–2.08 (m, 2H, CH2). 13C-NMR (75 MHz, CDCl3): δ = 187.3, 163.6, 157.2, 142.5, 128.3, 127.9, 126.8, 87.1, 40.8, 38.3, 34.3, 22.5, 20.9. ESI-MS: m/z 256.31 [M+H]+. Anal. Calcd (%) for C15H17N3O: C, 70.56; H, 6.71; N, 16.46. Found: C, 70.62; H, 6.65; N, 16.62.
The procedure for the pyridine-fused 1,3-diazaheterocycles products 7c and 7e: A stirred solution of 5c (1.0mmol) and TsOH (10mg) in anhydrous MeCN (5 mL) was refluxed for 5 h. the reactions were monitored by TLC. When TLC indicated the disappearance of the starting materials, stop the reaction, and washed the solution with water (3×3 mL). Then solvent was removed by distillation under vacuum and the resulting residue was purified by recrystallization to give 7c, or by column chromatography on silica gel (EtOAc : MeOH = 5 : 1) to give 7e. Compound 7c: yellow solid. mp 171–172 °C. IR (KBr): 3290, 1642, 1601 cm–1. 1H-NMR (300 MHz, CDCl3): δ = 12.92 (s, 1H, –N–H) , 7.33–7.38 (dd, J1 = 8.5 Hz, J2 = 2.5 Hz, 2H, Ph–H), 6.85–6.90 (dd, J1 = 8.5 Hz, J2 = 3.0 Hz, 2H, Ph–H), 7.16 (s, 1H, =N–H), 3.86–3.93 (d, 2H, CH2, J = 10.0Hz), 3.82 (s, 3H, CH3), 3.42–3.46 (m, 2H, CH2), 2.50–2.52 (d, 4H, –CH2–CH2–, J = 3.0Hz), 2.00–2.07 (m, 2H, CH2). 13C-NMR (75 MHz, CDCl3): δ = 186.9, 163.6, 159.8, 157.1, 135.1, 128.6, 113.2, 87.1, 55.2, 40.8, 38.3, 34.4, 22.8, 20.9. ESI-MS: m/z = 286.28 [M+H]+. HRMS-FAB: m/z for C14H14N3OCl [M+H]+: 286.1556; found: 286.1547. Compound 7e: white solid. mp 167–169 °C. IR (KBr): 2961, 1697, 1604 cm–1. 1H-NMR (300 MHz, CDCl3): δ = 12.76 (s, 1H, N–H), 6.86–6.91, 7.34–7.40 (m, 4H, Ph–H), 3.82 (s, 3H, CH3), 3.43–3.48 (m, 4H, CH2), 2.57–2.63 (m, 2H, CH2), 2.49–2.53 (m, 2H, CH2), 2.01–2.04 (m, 2H, CH2). 13C-NMR (75 MHz, CDCl3): δ = 188.6, 170.6, 160.1, 156.5, 134.6, 128.6, 113.2, 87.4, 55.3, 39.1, 38.6, 32.8, 21.9, 20.7. ESI-MS: m/z = 287.29 [M+H]+ (litr,3 mp 173–175 °C. IR (KBr): 1685, 1610 cm–1. 1H-NMR (60 MHz, CDCl3): δ = 12.73 (s, 1H), 7.40 (d, 2H), 6.91 (d, 2H), 3.83 (t, 2H), 3.81 (s, 3H), 3.43 (dt, 2H), 2.53 (t, 4H), 2.00 (quin, 4H). 13C-NMR (15 MHz, CDCl3): δ = 188.5, 170.9, 160.2, 156.8, 134.7, 128.9, 113.4, 87.6, 55.5, 39.4, 38.8, 33.0, 22.2, 20.9. ESI-MS: m/z = 287.29 [M+H]+. Anal. Calcd (%) for C16H18N2O3: C, 67.11; H, 6.34; N, 9.79. Found: C, 69.95; H, 6.41; N, 10.05).
The procedure for the pyridine–fused 1,3–diazaheterocycles products 7b and 7d: A stirred solution of 5b or 5d (1 mmol) in anhydrous xylene (5 mL) was refluxed for 13.5 or 8 h. The reaction was monitored by TLC. When TLC indicated the disappearance of the starting materials, solvents were removed by distillation under vacuum and the resulting residue was products 7b and 7d. Compound 7b: yellow semi–solid. IR (KBr): 3293, 1599, 1636cm–1. 1H-NMR (300 MHz, CDCl3): δ = 12.91 (s, 1H, N–H), 7.26–7.29 (d, J = 8.0 Hz, 2H, CH2), 7.14–7.17 (d, J = 8.0 Hz, 2H, Ph–H; s, 1H, =N–H), 3.92 (t, J = 6.0 Hz, 2H, CH2), 3.44–3.47 (t, J = 6.0 Hz, 2H, CH2), 2.49 (s, 4H, –CH2–CH2–), 2.36 (s, 3H, CH3), 2.01–2.17 (m, 2H, CH2). 13C-NMR (75 MHz, CDCl3): δ = 187.4, 163.7, 157.1 139.7, 138.2, 128.5, 126.9, 87.2, 40.8, 38.3, 34.4, 22.6, 21.3, 20.9. ESI–MS: m/z = 270.31 [M+H]+. HRMS-FAB: m/z for C16H19N3O [M+H]+: 270.1599; found: 270.1606. Compound 7d: yellow semi–solid. IR (KBr): 3293, 1638, 1601 cm–1. 1H-NMR (300 MHz, CDCl3): δ = 12.85 (s, 1H, N–H), 7.28–7.35 (m, 4H, Ph–H; s, 1H, =N–H), 3.93 (t, J = 6.0 Hz, 2H, CH2), 3.44–3.49 (m, 2H, CH2), 2.42–2.46 (m, 2H, CH2), 2.04–2.09 (m, 2H, CH2). 13C-NMR (75 MHz, CDCl3): δ = 185.6, 163.4, 157.4, 140.8, 134.2, 128.7, 128.3, 128.1, 87.1, 40.8, 38.3, 34.3, 22.5, 20.7. ESI–MS: m/z 290.24 [M+H]+.
General procedure for the reactions of HKAs 2 with acrylonitrile (3) in basic condition. To an anhydrous solution of heterocyclic ketene aminals 1 (0.4mmol) and acrylonitrile (0.26 mL) in DMF (5 mL) at 0 °C was added NaH (0.7 mmol). The reactions were monitored by TLC. When TLC indicated the disappearance of the starting materials, transfer the solution into 10 mL water, then extracted them with CH2Cl2 (3×3mL) followed by washed with water. After drying and filtering, the residue was purified by recrystallization (EtOAc). Compound 8a: yellow solid. mp 101–103 °C. IR (KBr): 3254, 2249, 1601cm–1. 1H-NMR (300 MHz, CDCl3): δ = 9.68 (s, 1H, N–H), 7.80–7.84 (m, 2H, Ph–H), 7.36–7.41 (m, 3H, Ph–H), 5.22 (s, 1H, =C–H), 3.68–3.73 (m, 2H, CH2), 3.60–3.67 (m, 2H, CH2), 3.52–3.59 (m, 2H, CH2), 2.64 (t, J = 6.5 Hz, 2H, CH2). 13C-NMR (75 MHz, CDCl3): δ = 186.2, 163.6, 141.2, 130.0, 128.0, 126.7, 117.5, 72.4, 48.2, 42.5, 41.8, 16.6. ESI–MS: m/z 242.31 [M+H]+. Anal. Calcd (%) for C14H15N3O: C, 69.69; H, 6.27; N, 17.41. Found: C, 69.78; H, 6.93; N, 17.67. Compound 8b: yellow solid. mp 100–103 °C. IR (KBr): = 3318, 2246, 1598 cm–1. 1H-NMR (300 MHz, CDCl3): δ = 9.65 (s, 1H, N–H), 7.71–7.74 (d, J = 8.0 Hz, 2H, Ph–H), 7.18–7.20 (d, J = 8.0 Hz, 2H, Ph–H), 5.21 (s, 1H, =C–H), 3.62–3.70 (m, 2H, CH2), 3.57–3.63 (m, 2H, CH2), 3.52–3.56 (m, 2H, CH2), 2.61–2.67 (m, 2H, CH2), 2.37 (s, 3H, CH3). 13C-NMR (75 MHz, CDCl3): δ = 186.2, 163.5, 140.2, 138.4, 128.7, 126.7, 117.5, 72.2, 48.2, 42.2, 41.9, 21.3, 16.5. ESI–MS: m/z 256.32 [M+H]+. Anal. Calcd (%) for C15H17N3O: C, 70.56; H, 6.71; N, 16.46. Found: C, 70.34; H, 6.70; N, 16.39. Compound 8c: yellow solid. mp 72–74 °C. IR (KBr): 3177, 2245 1598 cm–1. 1H-NMR (300 MHz, CDCl3): δ = 9.62 (s, 1H, N–H), 7.79–7.83 (d, J = 9.0Hz, 2H, Ph–H) , 6.88–6.91 (d, J = 9.0Hz, 2H, Ph–H) 5.19 (s, 1H, =C–H), 3.83 (s, 3H, CH3), 3.66–3.73 (m, 2H, CH2), 3.57–3.63 (m, 2H, CH2), 3.53–3.57 (m, 2H, CH2), 2.65 (t, J = 6.5 Hz, 2H, CH2). 13C-NMR (75 MHz, CDCl3): δ = 185.5, 163.4, 161.3, 133.7, 128.4, 117.6, 113.3, 71.8, 55.3, 48.2, 42.2, 41.9, 16.5; ESI–MS: m/z 272.33 [M+H]+. HRMS–FAB: m/z for C15H17N3O2 [M+H]+: 272.1400; found: 272.1399. Compound 8d: yellow solid. mp 143–145 °C. IR (KBr): 3303, 2249, 1535 cm–1. 1H-NMR (300 MHz, CDCl3): δ = 9.66 (s, 1H, N–H), 7.74–7.78 (d, J = 9.5 Hz, 2H, Ph–H), 7.33–7.37 (d, J = 8.5 Hz, 2H, Ph–H), 5.177 (s, 1H, =C–H), 3.69–3.74 (m, 2H, CH2), 3.61–3.66 (m, 2H, CH2), 3.54–3.59 (m, 2H, CH2), 2.66 (t, J = 6.5 Hz, 2H, CH2). 13C-NMR (75 MHz, CDCl3): δ = 184.7, 163.7, 139.5, 136.0, 128.2, 128.1, 117.4, 72.2, 48.2, 42.2, 41.8, 16.6; ESI-MS: m/z: 276.29 [M+H]+. Anal. Calcd (%) for C14H14ClN3O: C, 60.98; H, 5.12; N, 15.24. Found: C, 60.87; H, 5.31; N, 14.96.

ACKNOWLEDGEMENTS
This work is supported by The Ministry of Science and Technology and the Ministry of Health of the P.R. China (No. 2009ZX09501-006), and The Chinese Academy of Sciences.

References

1. Z.-T. Huang and H. Wamhoff, Chem. Ber., 1984, 117, 622; CrossRef A. Basheer and Z. Rappoport, J. Org. Chem., 2006, 71, 9743; CrossRef For reviews, see: Z.-T. Huang and M.-X. Wang, Heterocycles, 1994, 37, 1233; CrossRef M.-X. Wang and Z.-T. Huang, Prog. Nat. Sci., 2002, 12, 249.
2. R. Destro, U. Cosentino, G. Moro, E. Ortoleva, and T. Pilati, J. Mol. Struct., 1989, 212, 97; CrossRef M. W. Anderson, M. J. Begley, and R. C. F. Jones, J. Chem. Soc., Perkin Trans. 1, 1984, 2599; CrossRef R. C. F. Jones, P. Patel, S. C. Hirst, and I. Turner, Tetrahedron, 1997, 53, 11781; CrossRef R. C. F. Jones, P. Patel, S. C. Hirst, and M. J. Smallridge, Tetrahedron, 1998, 54, 6191. CrossRef
3. Z.-T. Huang and Z.-R. Liu, Synth. Commu., 1989, 19, 1801. CrossRef
4. C.-Y. Yu , P.-H. Yang, M.-X. Zhao, and Z.-T. Huang, Synlett, 2006, 1835; CrossRef J.-P. Liao, T. Zhang, C.-Y. Yu, and Z.-T. Huang, Synlett, 2007, 761; CrossRef M. Yaqub, C.-Y. Yu, Y.-M. Jia, and Z.-T. Huang, Synlett, 2008, 1357; CrossRef S.-J. Yan, C. Huang, C.-X. Sun, Y.-F. Ni, and J. Lin, J. Comb. Chem., 2010, 12, 91; CrossRef R. Pratap, A. Sharon, P. R. Maulik, and V. J. Ram, Tetrahedron Lett., 2005, 46, 85. CrossRef
5. H. Kondo, M. Taguchi, Y. Inoue, F. Sakamoto, and G. Tsukamoto, J. Med. Chem., 1990, 33, 2012; CrossRef H. Wamhoff and L. Lambers, Synthesis, 1993, 111; CrossRef B. E. Maryanoff, W. Ho, D. F. McComsey, A. B. Reitz, P. P. Grous, S. O. Nortey, R. P. Shank, B. Dubinsky, R. J. Jr. Taylor, and J. F. Gardocki, J. Med. Chem., 1995, 38, 16; CrossRef B. E. Maryanoff, S. O. Nortey, J. J. McNally, P. J. Sanfilippo, D. F. McComsey, B. Dubinsky, R. P. Shank, and A. B. Reitz, Biomed. Chem. Lett., 1999, 9, 1547; CrossRef V. J. Ram, A. Goel, S. Sarkhel, and P. R. Maulik, Bioorg. Med. Chem., 2002, 10, 1275; CrossRef A. D. Jordan, A. H.Vaidya, D. I. Rosenthal, B. Dubinsky, C. P. Kordik, P. J. Sanfilippo, W.-N. Wu, and A. B. Reitz, Biomed. Chem. Lett., 2002, 12, 2381; CrossRef M. M. Abdelhalim, M. M. T. El-Saidib, S. T. Rabie, and G. A. Elmegeeda, Steroids, 2007, 72, 459; CrossRef S. N. Suryawanshi, S. Pandey, Rashmirathi, B. A. Bhatt, and S. Gupta, Eur. J. Med. Chem., 2007, 42, 511. CrossRef
6. M.-X. Wang, J.-M. Liang, and Z.-T. Huang, J. Chem. Res., Synop., 1994, 166 ; J. Chem. Res., Miniprint, 1994, 1001.
7. Z.-T. Huang and M.-X. Wang, J. Org. Chem., 1992, 57, 184 and references cited therein. CrossRef
8. Z.-T. Huang and M.-X. Wang, Synth. Commun., 1991, 21, 1167; CrossRef Z.-T. Huang and M.-X. Wang, Synth. Commun., 1991, 21, 1909. CrossRef
9. B. Liu, M.-X. Wang, and Z.-T. Huang, Tetrahedron lett., 1999, 40, 7399. CrossRef
10. X.-S. Shao, H. Fu, X.-Y. Xu, X.-L. Xu, Z.-W. Liu, Z. Li, and X.-H. Qian, J. Agric. Food Chem., 2010, 58, 2696. CrossRef
11. M. M. Abdelhalim, M. M. T. El-Saidib, S. T. Rabie, and G. A. Elmegeeda, Steroids, 2007, 72, 459. CrossRef
12. A. D. Jordan, A. H. Vaidya, D. I. Rosenthal, B. Dubinsky, C. P. Kordik, P. J. Sanfilippo, W. N. Wu, and A. B. Reitz, Bioorg. Med. Chem. Lett., 2002, 12, 2381. CrossRef
13. S. N. Suryawanshi, S. Pandey, Rashmirathi, B. A. Bhatt, and S. Gupta, Eur. J. Med. Chem., 2007, 42, 511. CrossRef
14. S.-J. Yan, C. Huang, X.-H. Zeng, R. Huang, and J. Lin, Bioorg. Med. Chem. Lett., 2010, 20, 48. CrossRef
15. Z.-T. Huang and Z.-R. Liu, Synthesis, 1987, 357 CrossRef