HETEROCYCLES

Paper | Special issue | Vol. 84, No. 2, 2012, pp. 893-911
Received, 30th June, 2011, Accepted, 10th August, 2011, Published online, 17th August, 2011.
DOI: 10.3987/COM-11-S(P)70

■ Expedient Synthesis of 3,4-Dihydroquinazolines via Tandem Addition — Conjugate Addition Cyclization of Carbodiimides Bearing a Michael Acceptor

Takao Saito,* Hayato Nakano, Hidenori Terada, Noriki Kutsumura, and Takashi Otani

Department of Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka 1-3, Shinjuku-ku, Tokyo 162-8601, Japan

Abstract

Michael acceptor-possessing N-phenylcarbodiimides, which were prepared by an aza-Wittig reaction of the corresponding functionalized iminophosphoranes with aromatic and aliphatic isocyanates, reacted with enolate carbon-nucleophiles of active methylene compounds via the tandem cumulene addition—hetero (NH) Michael addition cyclization, to provide 2,3,4-trisubstituted 3,4-dihydroquinazolines. It was also found that 2-aminoquinolines and 2-amino-3,4-dihydroquinolines were competitively formed in some cases. Based on these observations, possible mechanistic pathways leading to these heterocycles are proposed.

INTRODUCTION
Quinazolines and quinazolinones are important classes of nitrogen-containing heterocycles, and their derivatives occur widely in natural products and synthetic drugs.1 They are known to exhibit a diverse range of biological and pharmacological properties2 such as central nervous system depressant and stimulant activities,2 as well as antiparkinsonian,2 anticancer,3 antidiabetic,4 antiinflammatory,5 antimicrobial,6 anticonvulsant,7 antibacterial,8 antimalarial,9 antiallergy,10 and analgesic properties.11 Because quinazoline and quinazolinone derivatives display such biologically and pharmacologically rich properties, a number of synthetic methods to generate these compounds have been developed.1,12,13 However, further advances in terms of new, efficient, and more general methods for the synthesis of these heterocyclic compounds are always desired.13
The present method is based on our own, previously developed protocol involving a carbodiimide-mediated tandem nucleophilic addition—conjugate addition cyclization methodology (A)14 and its intramolecular–intramolecular version (B)15 involving the tandem reaction for the synthesis of 2,3,4-tri- or 2,3-disubstituted 3,4-dihydroquinazoline and 1,2,3,6-tetrahydro-4H-pyrimido[2,1-b]- quinazolin-4-one derivatives (Scheme 1). The first step of the reaction involves the addition of a hetero nucleophile such as an alcohol, thiol, or amine to one of the carbodiimide cumulene bonds, followed by an intramolecular hetero-conjugate addition by the newly formed NH moiety to form a dihydroquinazoline ring.14 In the present study, we extended this tandem method to the reaction involving a carbon nucleophile, anticipating this to be a new route to synthesize 3,4-dihydroquinazolines having carbon substituents at the 2-, 3-, and 4-positions.16 This is a valid investigation because of the important biological and pharmacological properties of these compounds.1-11,16,17 Here we report our results on the above tandem methodology (A) involving the addition of a carbon nucleophile, particularly an enolate anion of an active methylene compound, to produce 3,4-dihydroquinazolines. We also observed the formation of quinoline compounds as alternative heterocyclic products in some cases. An entire pathway to produce these heterocycles will also be discussed.

RESULTS AND DISCUSSION
In the previous work, 14,16,18 3,4-dihydroquinazolines were synthesized essentially from three components, i.e., ortho-nitrocinnamic acid, isocyanate, and a nucleophile, via the key carbodiimide intermediates (via 1. reduction, 2. esterification, 3. azidation, 4. Staudinger reaction, 5. aza-Wittig reaction, and 6. nucleophilic addition).14,18 In the present work, we took advantage of a more convergent synthesis of 2-R3, 3-R2, 4-R1CH2-trisubstituted 3,4-dihydroquinazolines from four components via the reactions indicated in Figure 1. The Heck coupling of 2-iodoaniline (1) with acrylonitrile (R1 = CN) and methyl acrylate (R1 = CO2Me) afforded compounds 2 in good yields (Scheme 2, (a)). The Kirsanov reaction of 2 with triphenylphosphine yielded iminophosphoranes 3 quantitatively (Scheme 2, (b)). The aza-Wittig reaction of iminophosphoranes 3 with a variety of isocyanates 4 gave the functionalized carbodiimides 5 in good-to-excellent yields (Table 1).

When carbodiimides 5Aa–e bearing an acrylonitrile moiety (R1 = CN) were allowed to react with enolate generated from diethyl malonate (6a), dihydroquinazolines 7a–e were obtained as exclusive products, as expected (Table 2a). In contrast, in the reaction of 5Ah (R2 = tBu) with 6a, 2-(t-butylamino)quinoline-3-carboxylic ethyl ester (8h) was formed as the sole product instead of the expected product 7h. The same tendency was observed in the reactions of 5Aa–h with cyanoacetate (6b) (Table 2b). Namely, dihydroquinazolines 9a–g were preferentially formed when the substituent R2 was relatively less bulky, whereas the predominant formation of 2-(t-butylamino)quinoline-3-carbonitrile (10h) was observed in the reaction of 5Ah involving the bulky tBu group. The fact that formation of dihydroquinazolines 7h/9h was not observed can be ascribed to the steric hindrance caused by the bulky tBu group on the nitrogen encountered in the aza-Michael addition cyclization step (Scheme 3). Unsurprisingly, all the dihydroquinazolines 7 and 9 obtained exist exclusively in the enol forms rather than the keto forms, which were indicated by spectroscopic data (IR, 1H- and 13C-NMR).16a

In a similar way, the reaction of carbodiimides 5B with cyanoacetate 6b afforded dihydroquinazolines 13a,c–g,i almost exclusively and the reaction of 5Bh (R2 = tBu) with 6b predominantly yielded quinoline-3-carbonitrile 10h (Table 3b). In contrast, the reaction of carbodiimides 5B with malonate 6a showed similar but somewhat different product distributions (Table 3a). The reactions of entries a, c–e and i produced corresponding dihydroquinazolines 11a,c–e,i and quinolines 8a,c–i, while the formation of quinolines 8f–h and dihydroquinolines 12f–h in place of 11f–h was observed when the substituent R2 was relatively bulky (iPr, cHex, or tBu) (Scheme 3).

MECHANICTIC CONSIDERATION
As shown in Scheme 4, the formation of dihydroquinazoline B and dihydroquinoline C can readily be understood. The enolate anion attacks the carbodiimide cumulene carbon of 5 to give the intermediate A via proton migration from A’, which undergoes N- and C-Michael addition to give, after tautomerization, dihydroquinazoline B and dihydroquinoline C, respectively. However, the formation of 2-aminoquinoline D is rather unusual. It is known that carbodiimide 5 readily undergoes 6π-electrocyclization on heating to give, after re-aromatization by proton shift, 2-aminoquinoline E18 in which the R1 group (CO2Me or CN) undoubtedly originates from the carbodiimide 5. In the present case, however, the obtained 2-aminoquinoline D possesses an R4 group (CO2Et or CN), which must have originated from the added

nucleophile. This raises the question of how 2-aminoquinoline D was formed.
In the reaction between carbodiimide 5A (R1 = CN) and cyanoacetate (6b) (R4 = CN), the quinolines E and D are the same (R1 = R4 = CN) and the electrocyclization route for the formation of D can not be excluded. To confirm that the R4 group in D originates from the R4 group in the nucleophile, we performed the reactions illustrated in Scheme 5, wherein we selected the carbodiimide 5Ch (R2 = tBu) with an acetyl group in R1 since predominant formation of D (8, 10) was observed only when the R2-substituent was a bulky group such as the tBu group (see Tables 2 and 3). As a result, the reactions of 5Ch with the enolate anions of 6a, 6b, and 6c all produced the corresponding quinolines (8h, 10h, 14h) in good yields. This clearly shows that the ethyl acetate, acetonitrile, and acetone moieties (R4C) in the quinolines originate from those in the enolates 6a–c (R4CH2), respectively, with concurrent removal of the ethoxy carbonyl group from 6 and the acetonyl group (R1C) from the substrate 5Ch, as observed above. On the basis of these observations, we propose Scheme 6, which illustrates the entire pathway for the formation of these heterocycles.

The reaction is initiated by nucleophilic attack at the two possible electrophilic centers, giving the intermediate A via path a or the intermediate F via path b. As described above in Scheme 4, the intramolecular N-Michael addition from A affords the dihydroquinazoline B (7, 9, 11, 13). In contrast, the dihydroquinazoline B was scarcely formed when the substituent R2 was a bulky tBu group or even an iPr or a cHex group in the reaction of 5B (R1 = CO2Me, bulkier than CN) with diethyl malonate (6a). This is consistent with the observation that cyclization by R2N-attack on A to give dihydroquinazoline B is less favored for steric reasons. Instead, in these cases only C-Michael addition/cyclization occurred to give the dihydroquinoline C (12f–h). The alternative pathway to produce the dihydroquinoline C from the intermediate F is also possible. The formation of the 2-aminoquinoline D (8, 10, 14) is proved by the existence of the intermediate F formed and vice versa. When the substituent R2 is bulky and even R4 is relatively bulky (CO2Et), the intermediate A scarcely cyclizes to give B and C, and the equilibrated F in basic conditions undergoes retro-Michael reaction and electrocyclization to give H via G. Work-up of the reaction mixture predominantly furnishes the 2-aminoquinoline D after decarboxylation.

In conclusion, we have developed a functionalized carbodiimide-mediated tandem carbon-nucleophilic addition—conjugate addition cyclization methodology, for the synthesis of 3,4-dihydroquinazolines having carbon substituents at the 2-, 3-, and 4-positions. Furthermore, we have elucidated the mechanism by which these nitrogen heterocycles are formed.

EXPERIMENTAL
Preparation of methyl 2-aminocinnamate (2B) via the Mizoroki–Heck cross coupling: Triethylamine (4.4 mL, d 0.73, 32 mmol) and methyl acrylate (9.0 mL, d 0.96, 0.11 mol) were added to a mixture of 2-iodoaniline (4.99 g, 22.8 mmol), palladium acetate (256 mg, 1.14 mmol, 5 mol%), and triphenylphosphine (598 mg, 2.28 mmol) in acetonitrile (35 mL) at 0 °C with stirring. The reaction mixture was heated at 80 °C for 9 h. After being cooled to room temperature, the reaction mixture was filtered and water was added to the filtrate. The mixture was extracted with AcOEt, washed with saturated aqueous NaCl, dried over MgSO4 and concentrated under reduced pressure. Column chromatography of the residue on silica gel (AcOEt/hexane = 1/4) gave 2B (3.73 g, 94%) as yellow crystals.
Preparation of methyl 3-[2-(triphenylphosphoranylidene)amino]phenylpropenoate (3B):
Triphenylphosphine (3.61 g, 13.7 mmol) and hexachloroethane (3.25 g, 13.7 mmol) were added to a solution of 2B (2.03 g, 11.4 mmol) in dichloromethane (30 mL) with stirring. After the mixture being cooled to 0 °C, triethylamine (3.8 mL, d 0.73, 27 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. Removal of the solvent and column chromatography of the residue on silica gel (AcOEt/hexane = 1/4) gave 3B (4.62 g, 92%) as yellow crystals.
Preparation of (E)-N-[2-(2-methoxycarbonylethenyl)phenyl]-N’-phenylcarbodiimide (5Ba)16a: Phenyl isocyanate (0.270 mL, d 1.10, 2.50 mmol) was added to a solution of iminophosphorane 3B (1.10 g, 2.51 mmol) in dichloromethane (30 mL) at room temperature with stirring. After being stirred for 1 h, the solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (AcOEt/hexane = 1/4) gave 5Ba (0.670 g, 96%) as a colorless viscous oil (lit.16a mp 54 °C). 1H-NMR (270.0 MHz, CDCl3) δ 3.80 (s, 3H), 6.51 (d, J = 16.2 Hz, 1H), 7.14–7.59 (m, 9H), 8.14 (d, J = 16.2 Hz, 1H); IR, neat/NaCl (cm-1) 2144 (NCN), 1718 (CO), 1622.
Typical procedure for the reaction of carbodiimides 5 with enolate carbon-nucleophiles: Ethyl cyanoacetate (6b) (0.040 mL, d 1.06, 0.375 mmol) was added to a suspension of NaH (40%, 22.5 mg, 0.375 mmol) in THF (1 mL) with stirring at -78 °C under an atmosphere of argon. After 0.5 h, a solution of carbodiimide 5Be (74.0 mg, 0.303 mmol) in THF (3 mL) was added at -78 °C. The reaction mixture was warmed to room temperature with stirring for 17 h and quenched with saturated aqueous NH4Cl, extracted with AcOEt three times. The organic layer was washed with water and brine, dried over MgSO4 and concentrated under reduced pressure. Column chromatography of the residue on silica gel (AcOEt/hexane = 1/2) gave 13e (0.106 g, 98%) as colorless crystals.
2,3,4-Trisubstituted 3,4-dihydroquinazolines (7, 9, 11, and 13)
Diethyl 2-[4-(cyanomethyl)-3-phenyl-3,4-dihydroquinazolin-2-yl]propanedioate (7a): Colorless solid; mp 68–70 °C; 1H-NMR (500.0 MHz, CDCl3) δ 1.16 (t, J = 7.1 Hz, 6H), 2.84 (dd, J = 8.5, 16.9 Hz, 1H), 3.08 (dd, J = 6.3, 16.9 Hz, 1H), 3.75–3.99 (m, 4H), 4.99 (dd, J = 6.3, 8.5 Hz, 1H), 7.08–7.18 (m, 4H), 7.22–7.33 (m, 4H), 7.38 (dd, J = 7.7, 7.7 Hz, 1H), 12.2 (s, 1H); 13C-NMR (125.65 MHz, CDCl3) δ 14.1 (CH3 x2), 23.4 (CH2), 59.7 (CH), 60.0 (CH2 x2), 83.9 (C), 116.2 (CH), 116.6 (C), 121.6 (C), 124.0 (CH), 124.3 (CH x2), 125.9 (CH x2), 129.1 (CH x2), 130.0 (CH), 133.1 (C), 144.1 (C), 155.5 (C), 168.1 (C x2); IR, KBr (cm-1) 3494, 2985, 2245, 1697, 1620, 1566; HRMS-ESI (m/z) [M + Na]+ Calcd for C23H23N3O4Na: 428.1581, Found: 428.1586.
Diethyl 2-[4-(cyanomethyl)-3-(4-tolyl)-3,4-dihydroquinazolin-2-yl]propanedioate (7b): Colorless solid; mp 85–87 °C; 1H-NMR (500.0 MHz, CDCl3) δ 1.08 (t, J = 7.1 Hz, 6H), 2.21 (s, 3H), 2.73 (dd, J = 8.2, 16.9 Hz, 1H), 2.97 (dd, J = 6.4, 16.9 Hz, 1H), 3.67–3.92 (m, 4H), 4.89 (dd, J = 6.4, 8.2 Hz, 1H), 6.89–7.09 (m, 7H), 7.28 (dd, J = 7.7, 7.7 Hz, 1H), 12.13 (s, 1H); 13C-NMR (125.65 MHz, CDCl3) δ 14.0 (CH3 x2), 20.7 (CH3), 23.3 (CH2), 59.77 (CH), 59.82 (CH2 x2), 83.4 (C), 116.0 (CH), 116.6 (C), 121.5 (C), 123.9 (CH), 124.3 (CH x2), 125.8 (CH), 129.5 (CH x2), 129.8 (CH), 133.1 (C), 135.9 (C), 141.6 (C), 155.6 (C), 168.1 (C x2); IR, KBr (cm-1) 3541, 3502, 3055, 2985, 2908, 2252, 1682, 1620, 1574; HRMS-ESI (m/z) [M + Na]+ Calcd for C24H25N3O4Na: 442.1737, Found: 442.1738.
Diethyl 2-[4-(cyanomethyl)-3-(4-methoxyphenyl)-3,4-dihydroquinazolin-2-yl]propanedioate (7c): Colorless solid; mp 52–56 °C; 1H-NMR (500.0 MHz, CDCl3) δ 1.17 (t, J = 7.1 Hz, 6H), 2.80 (dd, J = 8.1, 16.9 Hz, 1H), 3.04 (dd, J = 6.5, 16.9 Hz, 1H), 3.77 (s, 3H), 3.80–3.99 (m, 4H), 4.90 (dd, J = 6.5, 8.1 Hz, 1H), 6.82 (d, J = 8.9 Hz, 2H), 7.09–7.16 (m, 3H), 7.18 (d, J = 8.9 Hz, 2H), 7.37 (dd, J = 7.6, 7.6 Hz, 1H), 12.18 (s, 1H); 13C-NMR (125.65 MHz, CDCl3) δ 14.1 (CH3 x2), 23.5 (CH2), 55.4 (CH3), 59.9 (CH2 x2), 60.2 (CH), 83.2 (C), 114.2 (CH x2), 116.1 (CH), 116.7 (C), 121.5 (C), 124.0 (CH), 125.8 (CH), 126.3 (CH x2), 129.9 (CH), 133.2 (C), 137.2 (C), 155.8 (C), 157.7 (C), 168.2 (C x2); IR, KBr (cm-1) 3525, 3062, 2978, 2252, 1704, 1620, 1574, 756; HRMS-ESI (m/z) [M + Na]+ Calcd for C24H25N3O5Na: 458.1686, Found: 458.1687.
Diethyl 2-[4-(cyanomethyl)-3-benzyl-3,4-dihydroquinazolin-2-yl]propanedioate (7d): Colorless powder; mp 39–41 °C; 1H-NMR (500.0 MHz, CDCl3) δ 1.36 (t, J = 7.1 Hz, 6H), 2.60 (dd, J = 7.9, 16.7 Hz, 1H), 2.83 (dd, J = 6.3, 16.7 Hz, 1H), 4.25–4.32 (m, 4H), 4.35 (d, J = 14.6 Hz, 1H), 4.53 (dd, J = 6.3, 7.9 Hz, 1H), 4.83 (d, J = 14.6 Hz, 1H), 6.79 (d, J = 7.5 Hz, 1H), 7.04 (dd, J = 7.5, 7.5 Hz, 1H), 7.07 (d, J = 7.9 Hz, 1H), 7.09–7.13 (m, 2H), 7.24–7.30 (m, 3H), 7.32 (dd, J = 7.9, 7.9 Hz, 1H), 11.8(s, 1H); 13C-NMR (125.65 MHz, CDCl3) δ 14.6 (CH3 x2), 21.4 (CH2), 53.2 (CH), 56.0 (CH2), 60.1 (CH2 x2), 78.3 (C), 116.0 (CH), 116.7 (C), 120.9 (C), 124.6 (CH), 125.3 (CH), 128.3 (CH x2), 128.6 (CH), 129.0 (CH x2), 129.8 (CH), 133.2 (C), 134.9 (C), 159.7 (C), 168.9 (C x2); IR, KBr (cm-1) 3386, 3201, 3132, 3047, 2985, 2939, 2252, 1720, 1697, 1550, 1450, 1389, 1335, 1065; HRMS-ESI (m/z) [M + Na]+ Calcd for C24H25N3O4Na: 442.1737, Found: 442.1738.
Diethyl 2-[4-(cyanomethyl)-3-propyl-3,4-dihydroquinazolin-2-yl]propanedioate (7e): Colorless crystals; mp 85–87 °C; 1H-NMR (600.1 MHz, CDCl3) δ 0.73 (t, J = 7.3 Hz, 3H), 1.35 (t, J = 7.1 Hz, 6H), 1.50–1.70 (m, 2H), 2.64 (dd, J = 8.2, 16.8 Hz, 1H), 2.80 (dd, J = 6.0, 16.8 Hz, 1H), 3.30 (ddd, J = 4.2, 8.1, 14.1 Hz, 1H), 3.49 (ddd, J = 6.7, 8.1, 14.1 Hz, 1H), 4.20–4.30 (m, 4H), 4.73 (dd, J = 6.0, 8.2 Hz, 1H), 7.07 (d, J = 7.8 Hz, 1H), 7.18 (dd, J = 7.5, 7.5 Hz, 1H), 7.23 (d, J = 7.5 Hz, 1H), 7.37 (dd, J = 7.8, 7.8 Hz, 1H), 11.82 (s, 1H); 13C-NMR (150.9 MHz, CDCl3) δ 10.6 (CH3), 14.6 (CH3 x2), 21.7 (CH2), 21.9 (CH2), 54.4 (CH), 54.6 (CH2), 60.0 (CH2 x2), 78.0 (C), 116.1 (CH), 116.7 (C), 120.9 (C), 124.7 (CH), 125.5 (CH), 130.0 (CH), 133.3 (C), 159.4 (C), 168.9 (C x2); IR, KBr (cm-1) 3456, 3078, 2978, 2931, 2252, 1705, 1558, 1065, 771; HRMS-ESI (m/z) [M + Na]+ Calcd for C20H25N3O4Na: 394.1737, Found: 394.1737.
Ethyl 2-cyano-2-[4-(cyanomethyl)-3-phenyl-3,4-dihydroquinazolin-2-yl]ethanoate (9a): Colorless solid; mp 198.5–200.6 °C; 1H-NMR (500.0 MHz, CDCl3) δ 1.31 (t, J = 7.1 Hz, 3H), 2.87 (dd, J = 8.6, 16.6 Hz, 1H), 3.03 (dd, J = 5.8, 16.6 Hz, 1H), 4.18–4.28 (m, 2H), 4.97 (dd, J = 5.8, 8.6 Hz, 1H), 7.14 (d, J = 7.9 Hz, 1H), 7.18–7.23 (m, 2H), 7.29–7.38 (m, 3H), 7.40–7.47 (m, 3H), 12.20 (s, 1H); 13C-NMR (125.65 MHz) δ 14.3 (CH3), 24.7 (CH2), 60.3 (CH), 60.9 (CH2), 62.8 (C), 115.9 (C), 116.3 (CH), 116.4 (C), 120.6 (C), 125.1 (CH), 125.6 (CH x2), 126.3 (CH), 128.0 (CH), 130.1 (CH x2), 130.3 (CH), 132.2 (C), 143.3 (C), 157.8 (C), 170.3 (C); IR, KBr (cm-1) 3471, 3062, 2978, 2939, 2360, 2198, 1658, 1574, 1296, 1134, 756; HRMS-ESI (m/z) [M + Na]+ Calcd for C21H18N4O2Na: 381.1322, Found: 381.1323.
Ethyl 2-cyano-2-[4-(cyanomethyl)-3-(4-tolyl)-3,4-dihydroquinazolin-2-yl]ethanoate (9b): Colorless solid; mp 209.4–210.8 °C; 1H-NMR (500.0 MHz, CDCl3) δ 1.30 (t, J = 7.1 Hz, 3H), 2.36 (s, 3H), 2.85 (dd, J = 8.5, 16.8 Hz, 1H), 3.01 (dd, J = 5.8, 16.8 Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 4.92 (dd, J = 5.8, 8.5 Hz, 1H), 7.13 (d, J = 8.0 Hz, 1H), 7.16–7.25 (m, 6H), 7.42 (dd, J = 7.4, 7.4 Hz, 1H), 12.18 (s, 1H); 13C-NMR (125.65 MHz) δ 14.3 (CH3), 21.1 (CH3), 24.6 (CH2), 60.4 (CH), 60.8 (CH2), 62.4 (C), 115.9 (C), 116.2 (CH), 116.5 (C), 120.5 (C), 125.0 (CH), 125.5 (CH x2), 126.2 (CH), 130.2 (CH), 130.6 (CH x2), 132.2 (C), 138.1 (C), 140.8 (C), 157.8 (C), 170.4 (C); IR, KBr (cm-1) 3479, 3093, 3039, 2985, 2954, 2931, 2198, 1736, 1658, 1612, 1574, 1288, 1273, 1134, 1041; HRMS-ESI (m/z) [M + Na]+ Calcd for C22H20N4O2Na: 395.1478, Found: 395.1478.
Ethyl 2-cyano-2-[4-(cyanomethyl)-3-(4-methoxyphenyl)-3,4-dihydroquinazolin-2-yl]ethanoate (9c): Colorless crystals; mp 197.6–199.1 °C; 1H-NMR (500.0 MHz, CDCl3) δ 1.29 (t, J = 7.1 Hz, 3H), 2.84 (dd, J = 8.2, 16.7 Hz, 1H), 2.99 (dd, J = 6.0, 16.7 Hz, 1H), 3.80 (s, 3H), 4.21 (q, J = 7.1 Hz, 2H), 4.89 (dd, J = 6.0, 8.2 Hz, 1H), 6.92 (d, J = 9.0 Hz, 2H), 7.13 (d, J = 8.0 Hz, 1H), 7.16–7.21 (m, 2H), 7.24 (d, J = 9.0 Hz, 2H), 7.41 (dd, J = 8.0, 8.0 Hz, 1H), 12.19 (s, 1H); 13C-NMR (125.65 MHz, CDCl3) δ 14.3 (CH3), 24.5 (CH2), 55.4 (CH3), 60.5 (CH), 60.7 (CH2), 61.9 (C), 115.0 (CH x 2), 116.0 (C), 116.1 (CH), 116.5 (C), 120.4 (C), 124.9 (CH), 126.1 (CH), 127.4 (CH x2), 130.2 (CH), 132.2 (C), 136.0 (C), 157.9 (C), 159.1 (C), 170.4 (C); IR, KBr (cm-1) 3494, 3055, 2978, 2934, 2915, 2206, 1658, 1619, 1773, 1295, 1126; HRMS-ESI (m/z) [M + Na]+ Calcd for C22H20N4O3Na: 411.1428, Found: 411.1429.
Ethyl 2-cyano-2-[4-(cyanomethyl)-3-benzyl-3,4-dihydroquinazolin-2-yl]ethanoate (9d): Colorless solid; mp 50.6–52.9 °C; 1H-NMR (500.0 MHz, CDCl3) δ 1.35 (t, J = 7.0 Hz, 3H), 2.59 (dd, J = 7.8, 16.6 Hz, 1H), 2.70 (dd, J = 6.5, 16.6 Hz, 1H), 4.22–4.30 (m, 2H), 4.59 (dd, J = 6.5, 7.8 Hz, 1H), 4.79 (d, J = 15.1 Hz, 1H), 5.42 (d, J = 15.1 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H), 7.02–7.12 (m, 2 H), 7.15–7.21 (m, 2H), 7.25–7.37 (m, 4H), 11.95 (s, 1H); 13C-NMR (125.65 MHz) δ 14.3 (CH3), 22.8 (CH2), 54.3 (CH), 56.7 (CH2), 59.2 (C), 60.7 (CH2), 115.8 (CH), 115.9 (C), 118.9 (C), 120.3 (C), 125.0 (CH), 125.5 (CH), 128.1 (CH x2), 128.6 (CH), 128.9 (CH x2), 130.0 (CH), 132.2 (C), 134.4 (C), 159.1 (C), 170.3 (C); IR, KBr (cm-1) 3487, 3062, 3039, 2978, 2931, 2252, 2198, 1736, 1658, 1574, 1273, 1134, 756; HRMS-ESI (m/z) [M + Na]+ Calcd for C22H20N4O2Na: 395.1478, Found: 395.1478.
Ethyl 2-cyano-2-[4-(cyanomethyl)-3-propyl-3,4-dihydroquinazolin-2-yl]ethanoate (9e): Colorless needles; mp 140.2–141.0 °C; 1H-NMR (500.0 MHz, CDCl3) δ 0.89 (t, J = 7.3 Hz, 3H), 1.35 (t, J = 7.1 Hz, 3H), 1.65–1.91 (m, 2H), 2.64 (dd, J = 8.5, 16.6 Hz, 1H), 2.72 (dd, J = 5.9, 16.6 Hz, 1H), 3.60 (ddd, J = 5.1, 9.8, 14.8 Hz, 1H), 4.07 (ddd, J = 6.2, 9.5, 14.8 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 4.68 (dd, J = 5.9, 8.3 Hz, 1H), 7.05 (d, J = 7.6 Hz, 1H), 7.20 (ddd, J = 0.9, 7.5, 7.5 Hz, 1H), 7.25 (d, J = 7.5 Hz, 1H), 7.39 (ddd, J = 1.5, 7.6, 7.6 Hz, 1H), 11.97 (s, 1H); 13C-NMR (125.65 MHz, CDCl3) δ 10.6 (CH3), 14.4 (CH3), 22.4 (CH2), 23.6 (CH2), 55.5 (CH2), 56.7 (CH), 58.8 (C), 60.7 (CH2), 115.8 (C), 115.9 (CH), 118.9 (C), 120.2 (C), 124.9 (CH), 125.7 (CH), 130.1 (CH), 132.5 (C), 158.7 (C), 170.5 (C); IR, KBr (cm-1) 3240, 3201, 3062, 2978, 2931, 2191, 1658, 1620, 1574, 1273, 764; HRMS-ESI (m/z) [M + Na]+ Calcd for C18H20N4O2Na: 347.1478, Found: 347.1478.
Ethyl 2-cyano-2-[4-(cyanomethyl)-3-isopropyl-3,4-dihydroquinazolin-2-yl]ethanoate (9f): Colorless solid; mp 70–71 °C; 1H-NMR (500.0 MHz, CDCl3) δ 1.12 (d, J = 6.6 Hz, 3H), 1.35 (t, J = 7.1 Hz, 3H), 1.55 (d, J = 6.6 Hz, 3H), 2.59 (dd, J = 5.7, 16.6 Hz, 1H), 2.65 (dd, J = 9.1, 16.6 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 4.69 (sept, J = 6.6 Hz, 1H), 4.79 (dd, J = 5.7, 9.1 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 7.22 (dd, J = 7.6, 7.6 Hz, 1H), 7.29 (d, J = 7.6 Hz, 1H), 7.39 (dd, J = 7.6, 7.6 Hz, 1H), 11.88 (s, 1H); 13C-NMR (125.65 MHz, CDCl3) δ 14.4 (CH3), 21.0 (CH3), 22.1 (CH3), 23.7 (CH2), 49.0 (CH), 54.4 (CH), 59.6 (C), 60.6 (CH2), 115.9 (C), 116.0 (CH), 118.8 (C), 121.4 (C), 125.2 (CH), 125.5 (CH), 130.0 (CH), 132.6 (C), 160.0 (C), 170.3 (C); IR, KBr (cm-1) 3479, 3240, 2985, 2191, 1666, 1612, 1566, 1288; HRMS-ESI (m/z) [M + Na]+ Calcd for C18H20N4O2Na: 347.1478, Found: 347.1482.
Ethyl 2-cyano-2-[4-(cyanomethyl)-3-cyclohexyl-3,4-dihydroquinazolin-2-yl]ethanoate (9g): Colorless solid; mp 103–106 °C; 1H-NMR (500.0 MHz, CDCl3) δ 1.06–1.21 (m, 1H), 1.36 (t, J = 7.1 Hz, 3H), 1.28–1.62 (m, 5H), 1.66–1.80 (m, 2H), 1.89–1.99 (m, 1H), 2.34–2.47 (m, 1H), 2.57 (dd, J = 5.5, 16.6 Hz, 1H), 2.64 (dd, J = 9.2, 16.6 Hz, 1H), 4.18–4.33 (m, 3H), 4.81 (dd, J = 5.5, 9.2 Hz, 1H), 7.05 (d, J = 7.6 Hz, 1H), 7.21 (dd, J = 7.6, 7.6 Hz, 1H), 7.29 (d, J = 7.6 Hz, 1H), 7.34 (dd, J = 7.6, 7.6 Hz, 1H), 11.87 (s, 1H); 13C-NMR (125.65 MHz, CDCl3) δ 14.4 (CH3), 23.8 (CH2), 24.9 (CH2), 25.5 (CH2), 25.6 (CH2), 31.7 (CH2), 32.6 (CH2), 50.0 (CH), 59.5 (C), 60.6 (CH2), 62.3 (CH), 115.9 (C), 116.0 (CH), 118.6 (C), 121.4 (C), 125.1 (CH), 125.5 (CH), 130.0 (CH), 132.6 (C), 160.0 (C), 170.4 (C); IR, KBr (cm-1) 3487, 2931, 2854, 2198, 1650, 1620, 1574, 1288; HRMS-ESI (m/z) [M + Na]+ Calcd for C21H24N4O2Na: 387.1791, Found: 388.1791.
Diethyl 2-[4-(methoxycarbonylmethyl)-3-phenyl-3,4-dihydroquinazolin-2-yl]propanedioate (11a):
Colorless crystals; mp 40–42 °C; 1H-NMR (600.1 MHz, CDCl3) δ 1.16 (t, J = 7.1 Hz, 6H), 2.90 (dd, J = 9.8, 16.2 Hz, 1H), 3.13 (dd, J = 4.7, 16.2 Hz, 1H), 3.69 (s, 3H), 3.74–3.95 (m, 4H), 5.25 (dd, J = 4.7, 9.8 Hz, 1H), 7.04 (dd, J = 7.7, 7.7 Hz, 1H), 7.08–7.13 (m, 3H), 7.22–7.33 (m, 5H), 12.18 (s, 1H); 13C-NMR (150.90 MHz, CDCl3) δ 14.2 (CH3 x2), 39.2 (CH2), 52.0 (CH3), 59.2 (CH), 59.8 (CH2 x2), 82.9 (C), 116.0 (CH), 123.7 (CH), 123.9 (CH x2), 124.0 (C), 125.3 (CH), 125.8 (CH), 128.9 (CH x2), 129.1 (CH), 133.1 (C), 144.5 (C), 156.6 (C), 168.4 (C x2), 170.7 (C); IR, neat/NaCl (cm-1) 3348, 2985, 1743, 1658, 1481, 1250, 1057, 756; HRMS-ESI (m/z) [M + H]+ Calcd for C24H27N2O6: 439.1869, Found: 439.1864.
Diethyl 2-[4-(methoxycarbonylmethyl)-3-(4-methoxyphenyl)-3,4-dihydroquinazolin-2-yl]propane- dioate (11c): Colorless crystals; mp 40–43 ºC; 1H-NMR (500.0 MHz, CDCl3) δ 1.16 (t, J = 7.1 Hz, 6H), 2.87 (dd, J = 9.8, 16.1 Hz, 1H), 3.09 (dd, J = 4.9, 16.1 Hz, 1H), 3.68 (s, 3H), 3.76 (s, 3H), 3.78–3.96 (m, 4H), 5.13 (dd, J = 4.9, 9.8 Hz, 1H), 6.79 (d, J = 9.0 Hz, 2H), 7.04 (dd, J = 7.6, 7.6 Hz, 1H), 7.09 (d, J = 7.6 Hz, 2H), 7.15 (d, J = 9.0 Hz, 2H), 7.30 (dd, J = 7.6, 7.6 Hz, 1H), 12.11 (s, 1H); 13C-NMR (125.65 MHz, CDCl3) δ 14.2 (CH3 x2), 39.4 (CH2), 51.9 (CH3), 55.4 (CH3), 59.6 (CH), 59.7 (CH2 x2), 82.3 (C), 114.0 (CH x2), 115.9 (CH), 123.6 (CH), 123.8 (C), 125.7 (CH), 125.8 (CH x2), 129.0 (CH), 133.2 (C), 137.7 (C), 156.9 (C), 157.3 (C), 168.5 (C x2), 170.7 (C); IR, KBr (cm-1) 3456, 3062, 2978, 2908, 1736, 1620, 1574, 1250, 1072, 756; HRMS-ESI (m/z) [M + Na]+ Calcd for C25H28N2O7Na: 491.1789, Found: 491.1789.
Diethyl 2-[3-benzyl-4-(methoxycarbonylmethyl)-3,4-dihydroquinazolin-2-yl]propanedioate (11d): Colorless solid; mp 126.6–129.2 °C; 1H-NMR (500.0 MHz, CDCl3) δ 1.34 (t, J = 7.0 Hz, 6H), 2.51 (dd, J = 6.4, 16.5 Hz, 1H), 2.95 (dd, J = 7.6, 16.5 Hz, 1H), 3.70 (s, 3H), 4.20–4.29 (m, 4H), 4.32 (d, J = 14.3 Hz, 1H), 4.76 (dd, J = 6.6, 7.6 Hz, 1H), 4.79 (d, J = 14.3 Hz, 1H), 6.67 (d, J = 7.0 Hz, 1H), 6.92–6.98 (m, 1H), 7.03 (d, J = 7.6 Hz, 1H), 7.08–7.14 (m, 2H), 7.18–7.30 (m, 4H), 11.67 (s, 1H); 13C-NMR (125.65 MHz, CDCl3) δ 14.5 (CH3 x2), 37.5 (CH2), 51.8 (CH3), 52.9 (CH), 55.9 (CH2), 59.6 (CH2 x2), 77.2 (C), 115.7 (CH), 123.3 (C), 124.3 (CH), 124.7 (CH), 128.1 (CH), 128.4 (CH x2), 128.5 (CH x2), 128.7 (CH), 133.5 (C), 135.7 (C), 160.4 (C), 168.9 (C x2), 171.0 (C); IR, KBr (cm-1) 3209, 3062, 2954, 2924, 1736, 1674, 1466, 1296; HRMS-ESI (m/z) [M + Na]+ Calcd for C25H28N2O6Na: 475.1840, Found: 475.1840.
Diethyl 2-[4-(methoxycarbonylmethyl)-3-propyl-3,4-dihydroquinazolin-2-yl]propanedioate (11e): Colorless solid; mp 54.4–56.6 °C; 1H-NMR (500.0 MHz, CDCl3) δ 0.69 (t, J = 7.3 Hz, 3H), 1.31 (t, J = 7.1 Hz, 6H), 1.49–1.70 (m, 2H), 2.59 (dd, J = 7.6, 16.5 Hz, 1H), 2.87 (dd, J = 6.6, 16.5 Hz, 1H), 3.30 (ddd, J = 4.3, 8.3, 13.9 Hz, 1H), 3.43 (ddd, J = 7.9, 8.9, 13.9 Hz, 1H), 3.68 (s, 3H), 4.15–4.26 (m, 4H), 4.95 (dd, J = 6.6, 7.5 Hz, 1H), 7.03 (d, J = 7.9 Hz, 1H), 7.09 (dd, J = 7.4, 7.4 Hz, 1H), 7.13 (d, J = 7.4 Hz, 1H), 7.28 (dd, J = 7.9, 7.9 Hz, 1H), 11.59 (s, 1H); 13C-NMR (125.65 MHz, CDCl3) δ 10.7 (CH3), 14.6 (CH3 x2), 21.8 (CH2), 37.9 (CH2), 51.9 (CH3), 53.8 (CH), 54.4 (CH2), 59.7 (CH2 x2), 77,2 (C), 115.8 (CH), 123.3 (C), 124.3 (CH), 125.0 (CH), 128.9 (CH), 133.6 (C), 160.2 (C), 169.0 (C x2), 171.0 (C); IR, KBr (cm-1); 3456, 3248, 3209, 2970, 2939, 1712, 1311, 1072, 767; HRMS-ESI (m/z) [M + Na]+ Calcd for C21H28N2O6Na: 427.1840, Found: 427.1840.
Diethyl 2-[4-(methoxycarbonylmethyl)-3-(prop-2-enyl)-3,4-dihydroquinazolin-2-yl]propanedioate (11i): Colorless crystals; mp 81.0–83.0 °C; 1H-NMR (500.0 MHz, CDCl3) δ 1.32 (t, J = 7.1 Hz, 6H), 2.56 (dd, J = 7.3, 16.5 Hz, 1H), 2.86 (dd, J = 6.8, 16.5 Hz, 1H), 3.68 (s, 3H), 3.86 (dd, J = 8.6, 14.7 Hz, 1H), 4.08–4.14 (m, 1H), 4.17–4.27 (m, 4H), 5.01 (dd, J = 6.8, 7.3 Hz, 1H), 5.28 (d, J = 10.1 Hz, 1H), 5.35 (d, J = 17.0 Hz, 1H), 5.54–5.68 (m, 1H), 7,03 (d, J = 7.8 Hz, 1H), 7.07–7.10 (m, 2H), 7.25–7.31 (m, 1H), 11.62 (s, 1H); 13C-NMR (125.65 MHz, CDCl3) δ 14.5 (CH3 x2), 37.7 (CH2), 51.8 (CH), 52.7 (CH3), 54.9 (C), 55.3 (CH2), 59.8 (CH2 x2), 115.8 (CH), 120.5 (CH2), 123.2 (C), 124.4 (CH), 125.1 (CH), 128.9 (CH), 132.8 (CH), 133.7 (C), 160.1 (C), 168.9 (C x2), 170.9 (C); IR, KBr (cm-1) 3440, 2985, 1736, 1604, 1550, 1304, 1157, 1080, 763; HRMS-ESI (m/z) [M + Na]+ Calcd for C21H26N2O6Na: 425.1689, Found: 425.1677.
Ethyl 2-cyano-2-[4-(methoxycarbonylmethyl)-3-phenyl-3,4-dihydroquinazolin-2-yl]ethanoate (13a): Colorless crystals; mp 178–179 °C (lit.16a 179 °C); 1H-NMR (500.0 MHz, CDCl3) δ 1.31 (t, J = 7.1 Hz, 3H), 2.80 (dd, J = 8.4, 15.0 Hz, 1H), 3.01 (dd, J = 6.5, 15.0 Hz, 1H), 3.72 (s, 3H), 4.23 (q, J = 7.1 Hz, 2H), 5.18 (dd, J = 6.5, 8.4 Hz, 1H), 7.09–7.14 (m, 3H), 7.23–7.30 (m, 3H), 7.32–7.42 (m, 3H), 12.07 (s, 1H); 13C-NMR (125.65 MHz, CDCl3) δ 14.4 (CH3), 40.3 (CH2), 52.3 (CH3), 60.3 (CH), 60.6 (CH2), 62.7 (C), 116.1 (CH), 116.9 (C), 123.2 (C), 124.7 (CH), 125.0 (CH x2), 125.9 (CH), 127.2 (CH), 129.4 (CH), 129.7 (CH x2), 132.2 (C), 143.7 (C), 158.5 (C), 170.2 (C), 170.4 (C).
Ethyl 2-cyano-2-[4-(methoxycarbonylmethyl)-3-(4-methoxyphenyl)-3,4-dihydroquinazolin-2-yl]- ethanoate (13c): Colorless crystals; mp 116.6–120.2 °C; 1H-NMR (500.0 MHz, CDCl3) δ 1.31 (t, J = 7.1 Hz, 3H), 2.78 (dd, J = 8.5, 15.1 Hz, 1H), 2.98 (dd, J = 6.4, 15.1 Hz, 1H), 3.71 (s, 3H), 3.79 (s, 3H), 4.22 (q, J = 7.1 Hz, 2H), 5.09 (dd, J = 6.4, 8.5 Hz, 1H), 6.89 (d, J = 9.0 Hz, 2H), 7.08–7.12 (m, 3H), 7.16 (d, J = 9.0 Hz, 2H), 7.30–7.37 (m, 1H), 12.05 (s, 1H); 13C-NMR (125.65 MHz, CDCl3) δ 14.4 (CH3), 40.2 (CH2), 52.2 (CH3), 55.4 (CH3), 60.3 (C), 60.5 (CH), 60.7 (CH2), 114.8 (CH x2), 116.0 (CH), 117.1 (C), 123.0 (C), 124.6 (CH), 125.8 (CH), 126.8 (CH x2), 129.3 (CH), 132.3 (C), 136.6 (C), 158.57 (C), 158.59 (C), 170.2 (C), 170.6 (C); IR, KBr (cm-1) 3464, 2978, 2954, 2206, 1736, 1574; HRMS-ESI (m/z) [M + Na]+ Calcd for C23H23N3O5Na: 444.1535, Found: 444.1530.
Ethyl 2-cyano-2-[3-benzyl-4-(methoxycarbonylmethyl)-3,4-dihydroquinazolin-2-yl]ethanoate (13d):
Colorless crystals; mp 123.2–124.7 °C; 1H-NMR (500.0 MHz, CDCl3) δ 1.35 (t, J = 7.1 Hz, 3H), 2.45 (dd, J = 5.8, 15.5 Hz, 1H), 2.77 (dd, J = 9.0, 15.5 Hz, 1H), 3.75 (s, 3H), 4.22–4.32 (m, 2H), 4.59 (d, J = 14.9 Hz, 1H), 4.76 (dd, J = 5.8, 9.0 Hz, 1H), 5.39 (d, J = 14.9 Hz, 1H), 6.76 (d, J = 7.7 Hz, 1H), 6.99–7.04 (m, 2H), 7.09–7.17 (m, 2H), 7.20–7.30 (m, 4H), 11.75 (s, 1H); 13C-NMR (125.65 MHz, CDCl3) δ 14.5 (CH3), 38.8 (CH2), 52.3 (CH), 54.5 (CH3), 57.1 (CH2), 58.9 (C), 60.5 (CH2), 115.7 (CH), 119.4 (C), 122.9 (C), 124.81 (CH), 124.83 (CH), 128.21 (CH x2), 128.24 (CH), 128.7 (CH x2), 129.1 (CH), 132.5 (C), 135.2 (C), 159.8 (C), 170.4 (C), 170.6 (C); IR, KBr (cm-1) 3448, 2985, 2946, 2198, 1735; HRMS-ESI (m/z) [M + Na]+ Calcd for C23H23N3O4Na: 428.1581, Found: 428.1577.
Ethyl 2-cyano-2-[4-(methoxycarbonylmethyl)-3-propyl-3,4-dihydroquinazolin-2-yl]ethanoate (13e):
Colorless solid; mp 108.4–110.4 °C; 1H-NMR (500.0 MHz, CDCl3) δ 0.82 (t, J = 7.3 Hz, 3H), 1.35 (t, J = 7.2 Hz, 3H), 1.60–1.81 (m, 2H), 2.56 (dd, J = 7.3, 15.3 Hz, 1H), 2.72 (dd, J = 7.4, 15.3 Hz, 1H), 3.48–3.56 (m, 1H), 3.71 (s, 3H), 4.00–4.16 (m, 1H), 4.25 (q, J = 7.2 Hz, 2H), 4.86 (dd, J = 7.3, 7.4 Hz, 1H), 7.01 (d, J = 7.8 Hz, 1H), 7.10–7.25 (m, 2H), 7.31 (dd, J = 7.8, 7.8 Hz, 1H), 11.80 (s, 1H); 13C-NMR (125.65 MHz, CDCl3) δ 10.7 (CH3), 14.4 (CH3), 22.3 (CH2), 39.4 (CH2), 52.2 (CH3), 55.5 (CH2), 56.7 (CH), 58.4 (C), 60.4 (CH2), 115.7 (CH), 119.3 (C), 122.7 (C), 124.7 (CH), 125.2 (CH), 129.2 (CH), 132.7 (C), 159.3 (C), 170.3 (C), 170.7 (C); IR, KBr (cm-1) 3456, 2970, 2198, 1736, 1574, 1373, 1273, 764; HRMS-ESI (m/z) [M + Na]+ Calcd for C19H23N3O4Na: 380.1581, Found: 380.1581.
Ethyl 2-cyano-2-[3-isopropyl-4-(methoxycarbonylmethyl)-3,4-dihydroquinazolin-2-yl]ethanoate (13f): Colorless oil; 1H-NMR (300.0 MHz, CDCl3) δ 1.12 (d, J = 6.6 Hz, 3H), 1.35 (t, J = 7.1 Hz, 3H), 1.48 (d, J = 6.6 Hz, 3H), 2.55 (dd, J = 5.8, 15.2 Hz, 1H), 2.64 (dd, J = 9.0, 15.2 Hz, 1H), 3.65 (s, 3H), 4.21–4.35 (m, 2H), 4.64 (sept, J = 6.6 Hz, 1H), 4.96 (dd, J = 5.7, 9.0 Hz, 1H), 7.01 (d, J = 7.9 Hz, 1H), 7.12 (dd, J = 7.5, 7.5 Hz, 1H), 7.21 (d, J = 7.5 Hz, 1H), 7.30 (dd, J = 7.9, 7.9 Hz, 1H), 11.73 (s, 1H); 13C-NMR (75.45 MHz, CDCl3) δ 14.5 (CH3), 20.8 (CH3), 22.2 (CH3), 39.6 (CH2), 49.0 (CH), 52.0 (CH3), 54.2 (CH), 58.9 (C), 60.4 (CH2), 115.7 (CH), 119.4 (C), 123.8 (C), 124.8 (CH), 125.2 (CH), 129.1 (CH), 132.8 (C), 160.6 (C), 170.1 (C), 170.6 (C); IR, neat/NaCl (cm-1) 3448, 3109, 2978, 2900, 2198, 1728, 1658, 1574, 1288, 1103; HRMS-ESI (m/z) [M + Na]+ Calcd for C19H23N3O4Na: 380.1581, Found: 380.1587.
Ethyl 2-cyano-2-[3-cyclohexyl-4-(methoxycarbonylmethyl)-3,4-dihydroquinazolin-2-yl]ethanoate (13g): Colorless crystals; mp 102.1–105.2 °C; 1H-NMR (500.0 MHz, CDCl3) δ 1.06–1.21 (m, 1H), 1.24–1.42 (m, 2H), 1.36 (t, J = 7.1 Hz, 3H), 1.47–1.76 (m, 5H), 1.83–1.96 (m, 1H), 2.21–2.30 (m, 1H), 2.55 (dd, J = 5.7, 15.2 Hz, 1H), 2.61 (dd, J = 9.1, 15.2 Hz, 1H), 3.65 (s, 3H), 4.16 (tt, J = 3.6, 11.6 Hz, 1H), 4.21–4.32 (m, 2H), 4.99 (dd, J = 5.7, 9.1 Hz, 1H), 7.00 (d, J = 7.8 Hz, 1H), 7.11 (dd, J = 7.6, 7.6 Hz, 1H), 7.19 (d, J = 7.6 Hz, 1H), 7.29 (dd, J = 7.8, 7.8 Hz, 1H), 11.72 (s, 1H); 13C-NMR (125.65 MHz, CDCl3) δ 14.5 (CH3), 24.9 (CH2), 25.6 (CH2), 25.7 (CH2), 31.3 (CH2), 32.7 (CH2), 39.7 (CH2), 50.0 (CH), 52.0 (CH3), 59.0 (C), 60.4 (CH2), 62.3 (CH), 115.8 (CH), 119.2 (C), 123.9 (C), 124.7 (CH), 125.2 (CH), 129.1 (CH), 132.9 (C), 160.7 (C), 170.2 (C), 170.6 (C); IR, KBr (cm-1) 2931, 2198, 1743, 1574, 1489, 1450, 1373, 1288, 1103, 764; HRMS-ESI (m/z) [M + Na]+ Calcd for C22H27N3O4Na: 420.1899, Found: 420.1894.
Ethyl 2-cyano-2-[4-(methoxycarbonylmethyl)-3-(prop-2enyl)-3,4-dihydroquinazolin-2-yl]ethanoate (13i): Colorless crystals; mp 147.8–149.8 °C; 1H-NMR (500.0 MHz, CDCl3) δ 1.35 (t, J = 7.12, 3H), 2.53 (dd, J = 7.4, 15.3 Hz, 1H), 2.70 (dd, J = 7.4, 15.3 Hz, 1H), 3.70 (s, 3H), 4.22–4.29 (m, 1H), 4.26 (q, J = 7.2 Hz, 2H), 4.52 (dd, J = 6.1, 15.5 Hz, 1H), 4.91 (dd, J = 7.4, 7.4 Hz, 1H), 5.30 (dd, J = 1.0, 10.1 Hz, 1H), 5.36 (dd, J = 1.0, 17.0 Hz, 1H), 5.74–5.84 (m, 1 H), 7.00–7.34 (m, 4H), 11.73 (s, 1H); 13C-NMR (125.65 MHz, CDCl3) δ 14.5 (CH3), 39.2 (CH2), 52.2 (CH3), 54.8 (CH), 56.5 (CH2), 58.5 (C), 60.5 (CH2), 115.8 (CH), 119.5 (C), 120.7 (CH2), 122.7 (C), 124.8 (CH), 125.4 (CH), 129.2 (CH), 132.4 (CH), 132.7 (C), 159.6 (C), 170.2 (C), 170.6 (C); IR, KBr (cm-1) 2985, 2198, 1728, 1620, 1581, 1496, 1434, 1373, 1273, 1103, 1034, 764; HRMS-ESI (m/z) [M + Na]+ Calcd for C19H21N3O4Na: 378.1430, Found: 378.1425.
Dihydroquinolines (12)
Diethyl 2-(isopropylamino)-4-(methoxycarbonylmethyl)quinoline-3,3(4H)-dicarboxylate (12f): Colorless oil; 1H-NMR (500.0 MHz, CDCl3) δ 1.02 (t, J = 7.1 Hz, 3H), 1.27 (d, J = 6.3 Hz, 3H), 1.28 (d, J = 6.3 Hz, 3H), 1.31 (t, J = 7.1 Hz, 3H), 2.41 (dd, J = 9.8 , 15.8 Hz, 1H), 2.58 (dd, J = 3.9, 15.8 Hz, 1H), 3.60 (s, 3H), 3.96–4.06 (m, 2H), 4.11 (dd, J = 3.9, 9.8 Hz, 1H), 4.24–4.35 (m, 2H), 4.36–4.43 (m, 1H), 6.42 (d, J = 6.9 Hz, 1H), 6.87 (dd, J = 7.4, 7.4 Hz, 1H), 7.03 (d, J = 7.8 Hz, 1H), 7.09–7.17 (m, 2H); 13C-NMR (125.65 MHz, CDCl3) δ 13.6 (CH3), 13.8 (CH3), 22.1 (CH3), 22.6 (CH3), 35.7 (CH2), 39.3 (CH), 42.6 (CH), 51.6 (CH3), 60.3 (C), 62.3 (CH2), 62.8 (CH2), 122.3 (CH), 123.6 (CH), 126.6 (C), 127.2 (CH), 128.2 (CH), 143.8 (C), 150.6 (C), 165.7 (C), 168.6 (C), 171.8 (C); IR, neat/NaCl (cm-1) 3394, 3062, 2978, 2877, 1736, 1581, 1242, 1165; HRMS-ESI (m/z) [M + H]+ Calcd for C21H29N2O6: 405.2020, Found: 405.2022.
Diethyl 2-(cyclohexylamino)-4-(methoxycarbonylmethyl)quinoline-3,3(4H)-dicarboxylate (12g): Colorless oil; 1H-NMR (500.0 MHz, CDCl3) δ 1.02 (t, J = 7.1 Hz, 3H), 1.24–1.35 (m, 3H), 1.32 (t, J = 7.2 Hz, 3H), 1.40–1.51 (m, 2H), 1.57–1.66 (m, 1H), 1.68–1.78 (m, 2H), 2.00–2.15 (m, 2H), 2.41 (dd, J = 9.9, 15.7 Hz, 1H), 2.57 (dd, J = 3.9, 15.7 Hz, 1H), 3.59 (s, 3H), 3.95–4.06 (m, 2H), 4.11 (dd, J = 3.9, 9.9 Hz, 1H), 4.12–4.18 (m, 1H), 4.23–4.35 (m, 2H), 6.55 (d, J = 7.2 Hz, 1H), 6.86 (dd, J = 7.4, 7.4 Hz, 1H), 7.02 (d, J = 7.8 Hz, 1H), 7.08–7.16 (m, 2H); 13C-NMR (125.65 MHz, CDCl3) δ 13.6 (CH3), 13.8 (CH3), 24.5 (CH2 x2), 25.9 (CH2), 32.1 (CH2), 32.7 (CH2), 35.7 (CH2), 39.3 (CH), 49.0 (CH), 51.6 (CH3), 60.3 (C), 62.3 (CH2), 62.8 (CH2), 122.3 (CH), 123.6 (CH), 126.6 (C), 127.2 (CH), 128.2 (CH), 143.9 (C), 150.6 (C), 165.7 (C), 168.6 (C), 171.8 (C); IR, neat/NaCl (cm-1) 3386, 3062, 2978, 2931, 2854, 1743, 1612, 1581, 1234; HRMS-ESI (m/z) [M + H]+ Calcd for C24H33N2O6: 445.2333, Found: 445.2336.
Diethyl 2-(tert-butylamino)-4-(methoxycarbonylmethyl)quinoline-3,3(4H)-dicarboxylate (12h): Colorless oil; 1H-NMR (500.0 MHz, CDCl3) δ 1.02 (t, J = 7.1 Hz, 3H), 1.31 (t, J = 7.2 Hz, 3H), 1.51 (s, 9H), 2.41 (dd, J = 10.0 Hz, 15.9 Hz, 1H), 2.63 (dd, J = 3.7, 15.9 Hz, 1H), 3.61 (s, 3H), 3.96–4.12 (m, 2H), 4.07 (dd, J = 3.7, 10.0 Hz, 1H), 4.22–4.34 (m, 2H), 6.34 (s, 1H), 6.85 (dd, J = 7.4, 7.4 Hz, 1H), 7.02 (d, J = 7.7 Hz, 1H), 7.09 (d, J = 7.4 Hz, 1H), 7.13 (dd, J = 7.7, 7.7 Hz, 1H); 13C-NMR (125.65 MHz, CDCl3) δ 13.6 (CH3), 13.8 (CH3), 28.6 (CH3 x3), 35.8 (CH2), 39.3 (CH), 51.6 (CH3), 52.2 (C), 60.4 (C), 62.2 (CH2), 62.7 (CH2), 122.2 (CH), 123.8 (CH), 126.4 (C), 127.1 (CH), 128.1 (CH), 143.9 (C), 149.6 (C), 166.0 (C), 168.7 (C), 171.9 (C); IR, neat/NaCl (cm-1) 3386, 3062, 2970, 1743, 1581, 1219, 1111; HRMS-ESI (m/z) [M + Na]+ Calcd for C22H30N2O6Na: 441.1996, Found: 441.1994.
2-Aminoquinolines (8, 10, and 14)
Ethyl 2-(phenylamino)quinoline-3-carboxylate (8a): Yellow needles; mp 124–125 °C; 1H-NMR (500.0 MHz, CDCl3) δ 1.42 (t, J = 6.9 Hz, 3H), 4.38 (q, J = 6.9 Hz, 2H), 7.06 (dd, J = 7.4, 7.4 Hz, 1H), 7.29 (dd, J = 7.4, 7.4 Hz, 1H), 7.38 (dd, J = 7.8, 7.8 Hz, 2H), 7.66 (dd, J = 7.8, 7.8 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.98 (d, J = 7.8 Hz, 2H), 8.65 (s, 1H), 10.29 (s, 1H, NH); 13C-NMR (125.65 MHz, CDCl3) δ 14.2 (CH3), 61.6 (OCH2), 110.5 (C), 119.9 (CH x2), 122.3 (CH), 122.3 (C), 123.2 (CH), 126.8 (CH), 128.7 (CH x2), 128.7 (C), 132.3 (C), 140.2 (C), 142.3 (CH), 149.6 (C), 152.5 (C), 167.1 (CO); IR, KBr (cm-1) 3316, 3276, 2978, 1698; MS-EI (m/z) 292 [M+, 91%], 291 [M+ -H, 100%].
Ethyl 2-(4-methoxyphenylamino)quinoline-3-carboxylate (8c): Yellow crystals; mp 79.7–80.5 °C; 1H-NMR (500.0 MHz, CDCl3) δ 1.47 (t, J = 7.1 Hz, 3H), 3.83 (s, 3H), 4.45 (q, J = 7.1 Hz, 2H), 6.93 (d, J = 9.0 Hz, 2H), 7.25 (dd, J = 7.9, 7.9 Hz, 1H), 7.63 (dd, J = 7.8, 7.8 Hz, 1H), 7.67 (d, J = 7.9 Hz, 1H), 7.74 (d, J = 7.9 Hz, 1H), 7.85 (d, J = 9.0 Hz, 2H), 8.75 (s, 1H), 10.13 (s, 1H, NH); 13C-NMR (125.65 MHz, CDCl3) δ 14.3 (CH3), 55.6 (CH3), 61.6 (CH2), 110.4 (C), 114.0 (CH x2), 121.8 (CH x2), 122.2 (C), 123.0 (CH), 126.7 (CH), 128.8 (CH), 132.4 (CH), 133.4 (C), 142.4 (CH), 149.9 (C), 152.8 (C), 155.2 (C), 167.2 (C); IR, KBr (cm-1) 3309, 3271, 2978, 2931, 2839, 1689, 1604, 1211; HRMS-ESI (m/z) [M + H]+ Calcd for C19H19N2O3: 322.1396, Found: 323.1392.
Ethyl 2-(benzylamino)quinoline-3-carboxylate (8d): Yellow oil; 1H-NMR (500.0 MHz, CDCl3) δ 1.42 (t, J = 7.1 Hz, 3H), 4.38 (q, J = 7.1 Hz, 2H), 4.87 (d, J = 5.2 Hz, 2H), 7.20 (dd, J = 7.3, 7.3 Hz, 1H), 7.24–7.28 (m, 1H), 7.34 (dd, J = 7.5, 7.5 Hz, 2H), 7.45 (d, J = 7.5 Hz, 2H), 7.58–7.70 (m, 3H), 8.29 (t, J = 5.2 Hz, 1H, NH), 8.67 (s, 1H); 13C-NMR (125.65 MHz, CDCl3) δ 14.3 (CH3), 45.0 (CH2), 61.2 (CH2), 110.2 (C), 121.7 (C), 122.2 (CH), 126.3 (CH), 127.0 (CH), 127.9 (CH x2), 128.5 (CH x2), 129.0 (CH), 132.3 (CH), 139.7 (C), 142.3 (CH), 150.5 (C), 155.3 (C), 167.1 (C); IR, neat/NaCl (cm-1) 3371, 3062, 3032, 2978, 2931, 2862, 1697, 1612, 1527, 1288; HRMS-ESI (m/z) [M + H]+ Calcd for C19H19N2O2: 307.1441, Found: 307.1440.
Ethyl 2-(propylamino)quinoline-3-carboxylate (8e)19: 1H-NMR (500.0 MHz, CDCl3) δ 1.05 (t, J = 7.4 Hz, 3H), 1.44 (t, J = 7.1 Hz, 3H), 1.74 (qt, J = 7.4, 7.4 Hz, 2H), 3.57–3.63 (m, 2H), 4.40 (q, J = 7.1 Hz, 2H), 7.17 (dd, J = 7.9, 7.9 Hz, 1H), 7.58 (dd, J = 7.9, 7.9 Hz, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.64 (d, J = 7.9 Hz, 1H), 7.97 (brs, 1H, NH), 8.64 (s, 1H); IR, neat/NaCl (cm-1) 3386, 3055, 2924, 1743, 1604, 1458; HRMS-ESI (m/z) [M + H]+ Calcd for C15H19N2O2: 259.1441, Found: 259.1440.
Ethyl 2-(isopropylamino)quinoline-3-carboxylate (8f): Yellow oil; 1H-NMR (500.0 MHz, CDCl3) δ 1.32 (d, J = 6.4 Hz, 6H), 1.44 (t, J = 7.1 Hz, 3H), 4.39 (q, J = 7.1 Hz, 2H), 4.53 (septd, J = 6.3, 6.4 Hz, 1H), 7.16 (dd, J = 7.9, 7.9 Hz, 1H), 7.57 (dd, J = 7.9, 7.9 Hz, 1H), 7.60 (d, J = 7.9 Hz, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.83 (d, J = 6.3 Hz, 1H, NH), 8.62 (s, 1H); 13C-NMR (125.65 MHz, CDCl3) δ 14.3 (CH3), 22.8 (CH3 x2), 41.9 (CH), 61.1 (CH2), 110.0 (C), 121.3 (C), 121.8 (CH), 126.2 (CH), 129.0 (CH), 132.2 (CH), 142.2 (CH), 150.8 (C), 154.9 (C), 167.2 (C); IR, neat/NaCl (cm-1) 3371, 3055, 2970, 2931, 1697, 1527, 1288, 1203; HRMS-ESI (m/z) [M + H]+ Calcd for C15H19N2O2: 259.1441, Found: 259.1439.
Ethyl 2-(cyclohexylamino)quinoline-3-carboxylate (8g): Yellow oil; 1H-NMR (500.0 MHz, CDCl3) δ 1.21–1.84 (m, 8H), 1.44 (t, J = 7.2 Hz, 3H), 2.04–2.18 (m, 2H), 4.23–4.33 (m, 1H), 4.39 (q, J = 7.2 Hz, 2H), 7.14 (dd, J = 7.6, 7.6 Hz, 1H), 7.56 (dd, J = 7.6, 7.6 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.94 (d, J = 7.4 Hz, 1H, NH), 8.62 (s, 1H); 13C-NMR (125.65 MHz, CDCl3) δ 14.3 (CH3), 24.8 (CH2 x2), 26.0 (CH2), 32.9 (CH2 x2), 48.5 (CH), 61.1 (CH2), 110.0 (C), 121.3 (C), 121.7 (CH), 126.1 (CH), 128.9 (CH), 132.2 (CH), 142.2 (CH), 150.8 (C), 154.9 (C), 167.2 (C); IR, neat/NaCl (cm-1) 3371, 2931, 1697, 1527, 1458, 1288, 1203, 1072, 748; HRMS-ESI (m/z) [M + H]+ Calcd for C18H23N2O2: 299.1760, Found: 299.1760.
Ethyl 2-(tert-butylamino)quinoline-3-carboxylate (8h): Yellow oil; 1H-NMR (500.0 MHz, CDCl3) δ 1.43 (t, J = 7.1 Hz, 3H), 1.58 (s, 9H), 4.38 (q, J = 7.1 Hz, 2 H), 7.15 (dd, J = 8.0, 8.0 Hz, 1H), 7.56 (dd, J = 8.0, 8.0 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.98 (s, 1H, NH), 8.61 (s, 1H); 13C-NMR (125.65 MHz, CDCl3) δ 14.3 (CH3), 29.0 (CH3 x3), 51.4 (C), 61.1 (CH2), 110.3 (C), 121.0 (C), 121.7 (CH), 126.4 (CH), 128.9 (CH), 132.0 (CH), 141.9 (CH), 150.3 (C), 155.0 (C), 167.4 (C); IR, neat/NaCl (cm-1) 3363, 2962, 1697, 1535, 1403, 1365, 1288, 1203, 1080; HRMS-ESI (m/z) [M + H]+ Calcd for C16H21N2O2: 273.1598, Found: 273.1597.
Ethyl 2-(prop-2-enylamino)quinoline-3-carboxylate (8i): Yellow oil; 1H-NMR (300.0 MHz, CDCl3) δ 1.44 (t, J = 7.1, 3H), 4.31 (dddd, J = 1.5, 1.7, 3.8, 5.4 Hz, 2H), 4.40 (q, J = 7.1 Hz, 2H), 5.17 (ddt, J = 1.5, 3.3, 10.2 Hz, 1H), 5.32 (ddt, J = 1.7, 3.3, 17.2 Hz, 1H), 6.08 (ddt, J = 5.4, 10.2, 17.2 Hz, 1H), 7.15–7.21 (m, 1H), 7.55–7.67 (m, 3H), 8.05 (t, J = 3.8 Hz, 1H), 8.65 (s, 1H); 13C-NMR (75.45 MHz, CDCl3 ) δ 14.3 (CH3), 43.3 (CH2), 61.2 (CH2), 110.2 (C), 115.6 (CH2), 121,6 (C), 122.2 (CH), 126.2 (CH), 129.0 (CH), 132.3 (CH), 135.3 (CH), 142.2 (CH), 150.5 (C), 155.3 (C), 167.1 (C); IR, neat/NaCl (cm-1) 3379, 2924, 2854, 1728, 1697, 1535, 1458, 1288, 1088, 1026, 802; HRMS-ESI (m/z) [M + H]+ Calcd for C15H17N2O2: 257.1290, Found: 257.1285.
2-(Isopropylamino)quinoline-3-carbonitrile (10e): Yellow oil; 1H-NMR (300.0 MHz, CDCl3) δ 1.32 (d, J = 6.5 Hz, 6H), 4.51 (sept, J = 6.5 Hz, 1H), 5.05 (s, 1H, NH), 7.16 (dd, J = 7.9, 7.9 Hz, 1H), 7.51–7.71 (m, 3H), 8.21 (s, 1H); 13C-NMR (150.9 MHz, CDCl3) δ 22.7 (CH3 x2), 42.9 (CH), 95.8 (C), 116.6 (C), 121.0 (C), 123.2 (CH), 126.9 (CH), 128.1 (CH), 132.8 (CH), 143.8 (CH), 149.6 (C), 153.2 (C); IR, neat/NaCl (cm-1) 3425, 3055, 2970, 2222, 1620, 1527, 1203, 756; HRMS-ESI (m/z) [M + H]+ Calcd for C13H14N3: 212.1182, Found: 212.1179.
2-(tert-Butylamino)quinoline-3-carbonitrile (10h): Yellow crystals; mp 124.9–125.3 °C; 1H-NMR (500.0 MHz, CDCl3) δ 1.58 (s, 9H), 5.12 (s, 1H, NH), 7.24 (dd, J = 8.0, 8.0 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.61 (dd, J = 8.0, 8.0 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 8.16 (s, 1H); 13C-NMR (125.65 MHz, CDCl3) δ 28.9 (CH3 x3), 52.6 (C), 96.3 (C), 116.7 (C), 120.6 (C), 123.1 (CH), 127.2 (CH), 127.9 (CH), 132.5 (CH), 143.4 (CH), 149.1 (C), 153.2 (C); IR, KBr (cm-1) 3416, 2912, 2200, 1602, 1512, 1408, 1354, 1198, 750; HRMS-EI (m/z) Calcd for C14H15N3: 225.1266, Found: 225.1259.
3-Acetyl-2-(tert-butylamino)quinoline (14h): Yellow crystals; mp 128.3–129.1 °C; 1H-NMR (270.0 MHz, CDCl3) δ 1.58 (s, 9H), 2.67 (s, 3H), 7.11–7.16 (m, 1H), 7.53–7.62 (m, 3H), 8.41 (s, 1H), 8.63 (s, 1H); 13C-NMR (67.80 MHz, CDCl3) δ 27.7 (CH3), 29.0 (CH3 x3), 51.4 (C), 116.8 (C), 120.7 (C), 121.8 (CH), 126.4 (CH), 129.0 (CH), 132.5 (CH), 143.0 (CH), 150.5 (C), 154.7 (C), 200.2 (C); IR, KBr (cm-1) 3264, 3052, 2948, 1652, 1572, 1536, 1446, 1378, 1346, 1270, 1190, 1138, 908, 728; HRMS-EI (m/z) Calcd for C15H18N2O: 242.1419, Found: 242.1420; Anal. Calcd for C15H18N2O: C, 74.35; H, 7.49; N, 11.56. Found: C, 73.99; H, 7.60; N, 11.28.

References

1. (a) S. B. Mhaske and N. P. Argade, Tetrahedron, 2006, 62, 9787; CrossRef (b) C. Wattanapiromsakul, P. I. Forster, and P. G. Waterman, Phytochemistry, 2003, 64, 609, and references cited therein. CrossRef
2. S. Sinha and M. Srivastava, Prog. Drug Res., 1994, 43, 143.
3. (a) A. Lüth and W. Löwe, Eur. J. Med. Chem., 2008, 43, 1478; CrossRef (b) J. B. Jiang, D. P. Hesson, B. A. Dusak, D. L. Dexter, G. J. Kang, and E. Hamel, J. Med. Chem., 1990, 33, 1721; CrossRef (c) S.-L. Cao, Y.-P. Feng, Y.-Y. Jiang, S.-Y. Liu, G.-Y. Ding, and R.-T. Li, Bioorg. Med. Chem. Lett., 2005, 15, 1915. CrossRef
4. M. S. Malamas and J. Millen, J. Med. Chem., 1991, 34, 1492. CrossRef
5. J. A. Lowe, R. L. Archer, D. S. Chapin, J. B. Cheng, D. Helweg, J. L. Johnson, B. K. Koe, L. A. Lebel, P. F. Moore, J. A. Nielsen, L. L. Russo, and J. T. Shirley, J. Med. Chem., 1991, 34, 624. CrossRef
6. O. M. Habib, E. B. Moawad, M. M. Girges, and A. M. El-Shafei, Boll. Chim. Farm., 1995, 134, 503.
7. (a) A. Mannscherck, H. Koller, G. Stuhler, M. A. Davis, and J. Traber, Eur. J. Med. Chem., 1984, 19, 381; (b) M. Hori, R. Iemura, H. Hara, A. Ozaki, T. Sukamoto, and H. Ohtaka, Chem. Pharm. Bull., 1990, 1286.
8. (a) P.-P. Kung, M. D. Casper, K. L. Cook, L. Wilson-Lingard, L. M. Risen, T. A. Vickers, R. Ranken, L. B. Blyn, J. R. Wyatt, P. D. Cook, and D. J. Ecker, J. Med. Chem., 1999, 42, 4705; CrossRef (b) P. M. S. Bedi, V. Kumar, and M. P. Mahajan, Bioorg. Med. Chem. Lett., 2004, 14, 5211. CrossRef
9. (a) S. Kobayashi, M. Ueno, R. Suzuki, and H. Ishitani, Tetrahedron Lett., 1999, 40, 2175; CrossRef (b) C. S. Jang, F. Y. Fu, C. Y. Wang, K. C. Huang, G. Lu, and T. C. Thou, Science, 1946, 103, 59; CrossRef (c) T.-Q. Chou, F. Y. Fu, and Y. S. Kao, J. Am. Chem. Soc., 1948, 70, 1765. CrossRef
10. R. A. LeMahieu, M. Carson, W. C. Nason, D. R. Parrish, A. F. Welton, H. W. Baruth, and B. Yaremko, J. Med. Chem., 1983, 26, 420. CrossRef
11. L. Fišnerová, B. Brunová, Z. Kocfeldová, J. Tíkalová, E. Maturová, and J. Grimová, Collect. Czech. Chem. Commun., 1991, 56, 2373.
12. D. J. Connolly, D. Cusak, T. P. O’Sullivan, and P. J. Guiry, Tetrahedron, 2005, 61, 10153, and references cited therein. CrossRef
13. For review, combinatorial synthesis: (a) D. A. Horton, G. T. Bourne, and M. L. Smythe, Chem. Rev., 2003, 103, 893; CrossRef For selected recent literature : (b) T. Saito, T. Ote, M. Shiotani, H. Kataoka, T. Otani, and N. Kutsumura, Heterocycles, 2010, 82, 305; CrossRef (c) W. Xu, Y. Jin, H. Liu, Y. Jiang, and H. Fu, Org. Lett., 2011, 13, 1274; CrossRef (d) F. Portela-Cubillo, J. S. Scott, and J. C. Walton, J. Org. Chem., 2009, 74, 4934; CrossRef (e) J. A. Bleda, P. M. Fresneda, R. Orenes, and P. Molina, Eur. J. Org. Chem., 2009, 2490; CrossRef (f) Z. Zheng and H. Alper, Org. Lett., 2008, 10, 829; CrossRef (g) M.-W. Ding, Y.-F. Chen, and N.-Y. Huang, Eur. J. Org. Chem., 2004, 3872; CrossRef (h) P. Langer and A. Bodtke, Tetrahedron Lett., 2003, 44, 5965; CrossRef (i) C. Larksarp and H. Alper, J. Org. Chem., 2000, 65, 2773. CrossRef
14. T. Saito, K. Tsuda, and Y. Saito, Tetrahedron Lett., 1996, 37, 209. CrossRef
15. T. Saito and K. Tsuda, Tetrahedron Lett., 1996, 37, 9071. CrossRef
16. The carbodiimide–mediated tandem carbon nucleophile (e.g., Grignard and lithium reagents, enolates) addition–conjugate addition methodology and its application to the synthesis of bioactive 3,4-dihydroquinazoline derivatives (T-type calcium channel blocker) have been reported: (a) B. H. Lee, J. Y. Lee, B. Y. Chung, and Y. S. Lee, Heterocycles, 2004, 63, 95; CrossRef (b) J. A. Jeong, H. Cho, S. Y. Jung, H. B. Kang, J. Y. Park, J. Kim, D. J. Choo, and J. Y. Lee, Bioorg. Med. Chem. Lett., 2010, 20, 38, and references cited therein. CrossRef
17. PCT Int. Appl. (2005), WO 2005047278 A2 20050526; Ger. Patent (2004), DE 10251914 A1 20040519; Eur. Pat. Appl. (2005), EP 1568695 A1 20050831.
18. (a) T. Saito, H. Ohmori, E. Furuno, and S. Motoki, J. Chem. Soc., Chem. Commun., 1992, 22; CrossRef (b) T. Saito, H. Ohmori, T. Ohkubo, and S. Motoki, J. Chem. Soc., Chem. Commun., 1993, 1802; CrossRef (c) P. Molina, M. Alajarin, A. Vidal, and P. Sanchez-Andrada, J. Org. Chem., 1992, 57, 929. CrossRef
19. Jpn. Kokai Tokkyo Koho (1995), JP 07089957 A 19950404; Can. Pat. Appl. (1994), CA. 2106135 A119940315; Eur. Pat. Appl. (1994), EP 588299 A2 19940323; PCT Int. Appl. (1993), WO 9317682 A1 19930916.