DOI 10.1007/s11030-011-9350-1 F U L L - L E N G T H PA P E R
Ionic liquid-supported synthesis of dihydroquinazolines
and tetrahydroquinazolines under microwave irradiation
Hai-Yuan Hsu · Chih-Chun Tseng · Banrali Matii ·Chung-Ming Sun
Received: 23 September 2011 / Accepted: 3 December 2011 / Published online: 17 December 2011 © Springer Science+Business Media B.V. 2011
Abstract An efficient microwave-assisted and water-solu-ble ionic liquid (IL)-supported synthesis of medicinally important dihydro- and tetrahydroquinazolines has been developed. The protocol involves the SN2 substitution reac-tion of IL-bound 4-bromomethyl-3-nitrobenzoic acid with various primary amines to provide IL-bound 4-((alkylamino) methyl)-3-nitrobenzoate under microwave irradiation. Further elaboration followed by sequential cyclization with various isothiocyanates and aldehydes furnished IL-bound target compounds. Cleavage of the IL support by methan-olysis gave dihydro- and tetrahydroquinazolines with high purity and excellent yields. The new protocol has the advan-tages of shorter reaction time, easy workup process, excellent yields, reduced environmental impact, wide substrate scope, and convenient procedure.
Keywords Tetrahydroquinazolines· Ionic liquid support · Microwave-assisted synthesis· Green chemistry
Introduction
Quinazoline-based heterocycles have a significant impact on the drug discovery process due to their essential roles in all levels of biology such as cell growth, signaling, prolifera-tion, and sensing, and such frameworks are pervasive in both pharmaceutical industry and academic research [1,2]. Dihy-dro- and tetrahydroquinazolines, congeners of quinazoline, Electronic supplementary material The online version of this article (doi:10.1007/s11030-011-9350-1) contains supplementary material, which is available to authorized users.
H.-Y. Hsu· C.-C. Tseng · B. Matii · C.-M. Sun (
B
)Department of Applied Chemistry, National Chiao Tung University, Hsinchu 300-10, Taiwan
e-mail: [email protected]
serve as an essential core structure for a wide range for nat-ural products and are important pharmacophore of synthetic drugs demonstrating anti-inflammatory, antiviral, anticancer agents, anticonvulsants, antimalarial, antibacterial analgesic, and anti-Alzheimer properties [3–5]. Moreover, they have been employed as potent inhibitors against tyrosine kinases and cellular phosphorylation [6–8]. Recently, it has been found that 3,4-dihydroquinazoline derivatives such as I and II act as potent T-type Ca2+channel blockers (Fig.1), par-ticularly against two isoforms of T-type Ca2+ channel [9– 12]. Moreover, the quinazoline skeleton in the natural prod-uct-like vasicine and deoxypeganine III shows broncho-dialatory, thrombopoietic, and antihistamine activity [13]. Commercialized drug compounds Gefitinib (IV) and Erloti-nib (V) both feature a quinazoline framework that is active toward epidermal growth factor receptor for the treatment of lung cancer [14,15].
Access to these bioactive heterocycles with desired com-plexity by an efficient synthetic sequence remains a chal-lenge in synthetic chemistry. A phase-tagged strategy aiming for the rapid construction of pharmacologically promising compounds to meet the demand of high-throughput screen-ing has been developed. However, polymer-supported solid-phase synthesis suffers from serious drawbacks, such as heterogeneous reaction conditions, nonlinear kinetics, excess reagents as well as inability to characterize intermedi-ates without the use of destructive compound cleavage meth-ods for their analysis [16].
In contrast to biphasic reaction media raising from solid-phase chemistry, soluble polymer support technologies such as polyethylene glycol (PEG) was developed as an alternative carrier to provide homogeneous reaction media and facil-itate the characterization of intermediates by conventional analytical methods. However, low loading support capacity and recovery rate of product limit their implementation for
Fig. 1 Representative examples of biologically active quinazoline derivatives
molecular library construction [17–20]. The use of “fluorous phase” in organic synthesis has gained acceptance due to its broad application potential. Fluorous phase technology has been successfully applied in the synthesis of oligopeptides, oligosaccharide, and small molecules [21–24].
The development of cleaner, safer, and more economi-cal synthetic methods is a central goal for chemists. Ionic liquids (IL) featuring zero vapor pressure, high thermal and superb chemical stability, recyclability, and nonflammability were originally used as reaction media to replace conven-tional organic solvents in organic synthesis [25]. In general, IL-tagged molecules are purified by simply washing the reac-tion mixture with a solvent in which the IL-anchored product is immiscible [26–32]. These features dramatically reduced the usage of organic solvents during synthetic exercises.
Microwave-assisted organic synthesis (MAOS) has had a great impact in the area of synthetic organic chemistry with the introduction of precision controlled microwave reactors [33–43]. Just as other well-documented phase tag protocols, IL-supported technology is compatible with microwave-assisted conditions so that reaction times and efficiency can be dramatically enhanced in comparison with conventional reflux conditions.
In line with our efforts to establish more facile approaches to synthesize structurally diverse small molecules, IL-sup-ported technology has been introduced as a platform to explore a novel protocol to access desired heterocycles. Herein, we report the IL-supported synthesis of quinazoline-based heterocycles using microwave-assisted conditions.
Results and discussion
Commercially available 4-bromomethyl-3-nitrobenzoic acid was employed as a pilot precursor in order to plot the scope of the IL-supported synthesis, while the tagged conjugate serves as the key intermediate to be further elaborated into the desired dihydro- and tetrahydroquinazoline derivatives. Condensation of 4-bromomethyl-3-nitrobenzoic acid with IL via N,N-dicyclohexylcarbodiimide (DCC) coupling reac-tion [44–47] generates the IL conjugate 1 (Scheme1). After reaction completion, the insoluble dicyclohexyl urea (DCU) was filtered off and the IL conjugate 1 was purified by precip-itating out the product from the reaction mixture with excess of cold ether. IL conjugate 1 was then derivatized by react-ing it with primary amines via nucleophilic substitution in acetonitrile under microwave irradiation for 5 min to give IL-tagged nitroamines 2 with satisfactory yields.
Then, IL-tagged nitroamines 2 were successfully reduced using Pd/C and ammonium formate under microwave irradi-ation conditions for 5 min followed by precipitirradi-ation giving the master intermediates 3 (Scheme1).
To construct the quinazoline framework with extended molecular diversity, the elaboration of the master intermedi-ates 3 to the desired heterocyclic skeleton requires a one-carbon electrophile. Therefore, a divergent synthetic design involving isothiocyanates or aldehydes serving as the one-carbon synthon to rapidly access toward the desired tar-get dihydro- and tetrahydroquinazolines has been delineated (Scheme2).
Treatment of IL conjugates 3 with isothiocyanates in the presence of DCC as an activating agent in anhydrous aceto-nitrile under microwave irradiation at 80◦C furnished dihy-droquinazoline IL conjugates 4, whereas condensation of IL conjugates 3 with aldehydes resulted in tetrahydroquinazo-line IL conjugates 5. Cleavage of the IL tag from conjugates 4 and 5 under basic methanolysis conditions liberated hetero-cycles 6 and 7 with diverse molecular complexity (Table1).
Scheme 2 Rapid diversification of master IL conjugates 3 toward the target heterocyclic frameworks 6 and 7
Most of the chemical manipulations in our research were complete with short reaction times (ca. 10–15 min) under microwave irradiation versus the required 2 h (or longer) when using conventional heating/refluxing conditions.
The formation of the IL-conjugated dihydroquinazolines 6 involves the nucleophilic addition of the secondary amine group of IL conjugates 3 into isothiocyanates forming intermediate “a”. The use of a coupling agent further activates the thiocarbonyl moiety of intermediate “a” which after an intramolecular cyclization followed by a rearrange-ment generates the target compounds 6 as anticipated (Scheme3).
It is worth mentioning that the main advantage of the IL support is that a reaction can be monitored by thin-layer chro-matography (TLC), MS, and/or1H NMR analysis. The final product obtained post IL-tag cleavage is highly pure.
Figure2 shows a clear1H NMR comparison of IL spe-cies indicating how convenient IL-based synthesis can be monitored avoiding the use of sample-destructive analytical methods.
Conclusion
In conclusion, an efficient IL-supported microwave irradi-ation synthesis strategy for dihydro- and tetrahydroquinaz-oline derivatives has been developed. Room temperature IL (RTIL)-supported synthesis offers the advantages of uniform
Table 1 IL-supported synthesis of quinazoline derivatives under micro-wave irradiation
Entry R1 R2/R3 product Yield (%)a
1 6a 70 2 6b 71 3 6c 85 4 6d 82 5 6e 70 6 iBuNH2 6f 80 7 iBuNH2 6g 84 8 iBuNH2 6h 70 9 iPrNH 2 6i 85 10 iPrNH 2 7a 82 11 iBuNH2 7b 74 12 7c 78 13 7d 91 14 7e 81 15 7f 81
aIsolated overall yields
reaction conditions, easier monitoring of reaction progress in contrast to other phase-supported chemistry. This method provides minimum chromatographic purification exercises in general, with a better loading capacity than that of using sol-uble PEG or resins as carriers in organic synthesis. Currently, more IL-tagging strategies to access more diverse heterocy-clic frameworks are under investigation and will be reported in due course.
Experimental section General directions
Acetonitrile was distilled from calcium hydride before use. All reactions were performed under inert atmosphere with unpurified reagents and dry solvents. Analytical TLC was performed using 0.25-mm silica gel-coated 60-F plates with
Scheme 3 Proposed mechanism for the formation of dihydroquinazo-lines
a fluorescent indicator. Flash chromatography was performed using the indicated solvent and silica gel 60 (230–400 mesh). All the microwave heating experiments were conducted under optimized reaction conditions of power and temper-ature in a closed vessel in a Biotage initiator model no: Ini-tiator US, 355286, 10429-22T, using IR sensor as internal probe for temperature control and compressed air system for cooling.1H NMR and13C NMR spectra were recorded on a Bruker Avance 300 MHz NMR spectrometer. Chemical shifts are reported in parts per million (ppm) on theδ scale from an internal standard. Low-resolution and high-resolu-tion mass spectra were recorded on either a VG platform II or VG AutoSpec spectrometers with only molecular ions (M+, MH+or MNH+4) were quoted. High-resolution mass spectra (HRMS) were recorded using positive mode elec-tron spray ionization (ESI) and measurements are valid to ±5ppm. Analytical HPLC analyses were performed using an Agilent 1100 Series HPLC system with UV detection at
λ = 254 nm (column: Sphereclone 5μ Si (250 × 4.6 mm).
General procedure for the synthesis of IL-bound 4-bromomethyl-3-nitrobenzene carboxylate 1
4-Bromomethyl-3-nitrobenzoic acid (0.63 g, 2.43 mmol), 1-methyl-3-ethyl imidazolium tetrafluoroborate (IL) (0.40 g, 1.87 mmol), and N,N-dimethylamino pyridine (DMAP) (0.005 g) are placed in a dry, nitrogen-purged, pressure-sus-taining microwave reaction vessel charged with dry CH3CN (15 mL). DCC (0.54 g, 2.62 mmol) dissolved in dry CH2Cl2(5 mL) was added dropwise to the reaction mixture for a period
of 5 min. The reaction mixture was stirred for another 15 min at room temperature. Then, this vessel was exposed to micro-wave radiation to 75◦C for 12 min. After reaction com-pletion, the reaction mixture was allowed to settle, and the insoluble DCU was filtered off and washed with CH3CN (50 mL× 3). The solvent was evaporated, and the residue was crystallized in cold ether, filtered through a fritted funnel, and dried under vacuo to give IL conjugate 1 as pale white solid.
General procedure for the preparation IL-bound 4-((substituted amino) methyl)-3-nitrobenzene carboxylates 2
IL-bound 4-bromomethyl-3-nitrobenzene carboxylate 1 (1.0 g, 2.19 mmol) in acetonitrile (15 mL) was treated with various primary amines (1.5 equiv). The reaction mixtures were irradiated with microwaves at 80◦C, 1 bar for 5 min to complete the reactions followed by evaporation of the sol-vent and washing the residue with cold ether (75 mL), dried over oven (50◦C) to obtain the ionic IL conjugates 2 as pale red solids.
General procedure for the preparation IL-bound 3-amino-4-((substituted amino) methyl) benzene carboxylates 3
To a suspension solution of IL conjugate 2 in acetonitrile (15 mL), 10% Pd/C (5 equiv) and ammonium formate (7 equiv) were added. The crude mixture was irradiated with micro-waves at 65◦C for 12 min to completely reduce the nitro group. The reaction mixture was filtered through a Celite plug to obtain the master intermediate IL conjugate 3. General procedure for the preparation IL-bound dihydro-(4) and tetrahydroquinazoline derivatives 5
To a stirred solution of 3 in dry CH3CN (20 mL), DCC (2.0 equiv) and isothiocyanates (2.0 equiv) were added. The reac-tion mixture was sealed and exposed to microwave irradiareac-tion at 80◦C, 1 bar for 10 min. Upon completion of the irradia-tion time, the insoluble DCU was allowed to settle, and the reaction mixture was filtered and washed with CH3CN (50 mL× 3). The crude product was purified by precipitation with cold ether and dried in an oven (50◦C) to obtain the IL conjugates 4 in high purity.
In the case of tetrahydroquinazoline derivatives, various aldehydes (3 equiv) were added to the stirred solution of IL conjugates 5 in dry CH3CN (20 mL). The reaction mixture was irradiated with microwaves at 80◦C, 1 bar for 10 min. Upon completion of the irradiation time, the crude product
Fig. 2 Representative1H NMR spectra of IL-tagged intermediates 10 9 8 7 6 5 4 3 2 1 ppm 10 9 8 7 6 5 4 3 2 1 ppm 10 9 8 7 6 5 4 3 2 1 ppm
was purified by precipitation with cold ether and dried to obtain the IL conjugates 5 in high purity.
General procedure for the cleavage of IL-bound substituted leading dihydro- (6) and tetrahydroquinazoline
derivatives 7
To a solution of conjugates 4 and 5 in methanol (20 mL), NaOMe (100 mg) was added. The reaction mixture was exposed to microwave radiation at 80◦C for 8 min. After reaction completion, the crude product was precipitated with excess of cold ether (100 mL), the IL was filtered off from the organic mixture. The filtration liquid was dried over MgSO4. The organic liquid was dried under vacuo, and subjected to crude HPLC analysis with UV detection at 254 nm (column:
Sphereclone 5μ Si (250 × 4.6mm); gradient: 35% ethyl ace-tate in hexane; flow rate: 1 mL/min). The residue was dis-solved in dichloromethane (5 mL) and the solvent was again removed using a rotavapor. The slurry obtained was loaded on a silica gel column and eluted with a mixture of ethyl acetate and hexane (1:4) to get title compounds 6 and 7 in good yields. Methyl 3-[2-(cyclohex-1-en-1-yl)ethyl]-2-(phenylamino)-3, 4-dihydroquinazoline-7-carboxylate (6a) 1H NMR (300 MHz, CDCl3): δ 7.44 (s, 1H), 7.37 (dd, J = 6.1, 1.7 Hz, 1H), 7.35–7.32 (m, 3H), 7.31 (d, J = 1.7 Hz, 1H), 7.23 (m, 1H), 7.14 (d, J = 6.1 Hz, 1H), 5.48 (m, 1H), 4.62 (brs, 1H), 3.89 (s, 3H), 3.57 (t, J = 7.4 Hz, 2H), 2.18 (t,
J = 7.4 Hz, 2H), 1.98–1.88 (m, 4H), 1.88–1.80 (m, 2H), 1.62–1.48 (m, 4H);13C NMR (75 MHz, CDCl3): δ 181.9, 167.6, 146.6, 140.0, 134.8, 131.5, 131.3, 129.2, 126.5, 126.4, 125.0, 124.5, 118.9, 116.8, 53.9, 52.5, 48.2, 35.5, 29.0, 25.6, 23.1, 22.5; MS (ESI): m/z 390 (MH+); HRMS (ESI) calcd for C24H28N3O2: m/z 390.2181, found 390.2184; IR (KBr): 3322, 2925, 1707, 1600, 1533, 1448 cm−1. Methyl 3-[2-(cyclohex-1-en-1-yl)ethyl]-2-[(2-methylpropyl) amino]-3,4-dihydroquinazoline-7-carboxylate (6b) 1H NMR (300 MHz, CDCl3): δ 7.34–7.28 (m, 2H), 7.09 (d, J = 7.7 Hz, 1H), 5.67 (t, J = 4.8 Hz, 1H), 5.41 (brs, 1H), 3.88 (s, 3H), 3.52 (t, J = 6.3 Hz, 2H), 3.38 (t, J = 7.7 Hz, 2H), 2.04 (t, J = 7.7 Hz, 2H), 1.97–1.88 (m, 3H), 1.89–1.83(m, 3H), 1.63–1.49 (m, 5H), 0.95 (d, J = 6.3 Hz, 6H);13C NMR (75 MHz, CDCl3): δ 181.4, 167.6, 146.6, 134.7, 131.4, 131.3, 124.9, 124.6, 118.7, 116.6, 54.3, 54.0, 52.5, 47.3, 35.3, 28.9, 28.6, 25.6, 23.1, 22.4, 20.7; MS (ESI):
m/z 370 (MH+). HRMS (ESI) calcd for C22H32N3O2: m/z
370.2494, found 370.2496; IR (KBr): 3324, 2925, 1710, 1631, 1529, 1438 cm−1. Methyl 3-cyclopentyl-2-[(furan-2-ylmethyl)amino]-3, 4-dihydroquinazoline-7-carboxylate (6c) 1H NMR (300 MHz, CDCl3): δ 7.39 (dd, J = 7.9, 1.4 Hz, 1H), 7.35 (d, J = 1.4 Hz, 1H), 7.27 (m, 1H), 7.04 (d, J = 7.9 Hz, 1H), 6.27 (dd, J = 3.1, 1.8 Hz, 1H), 6.17 (d, J = 3.1 Hz, 1H), 5.74 (t, J = 4.4 Hz, 1H), 5.29 (t, J = 8.5 Hz, 1H), 4.83 (d, J = 4.8 Hz, 2H), 4.62 (s, 2H), 3.95(brs, 1H), 3.88 (s, 3H), 1.99–1.93 (m, 2H), 1.69–1.55 (m, 4H), 1.48–1.41 (m, 4H);13C NMR (75 MHz, CDCl3): δ 182.7, 167.4, 151.3, 144.1, 142.5, 130.7, 127.7, 125.8, 120.4, 117.5, 110.8, 108.0, 61.7, 52.5, 47.2, 43.6, 29.3, 24.2; MS (ESI) m/z 354 (MH+); HRMS (ESI) calcd for C20H24N3O3: m/z 354.1818, found 354.1815; IR (KBr): 3365, 2952, 1708, 1631, 1529, 1436 cm−1. Methyl 3-cyclopentyl-2-(prop-2-en-1-ylamino)-3, 4-dihydroquinazoline-7-carboxylate (6d) 1H NMR (300 MHz, CDCl3): δ 7.45 (dd, J = 7.9, 1.4Hz 1H), 7.41 (d, J = 1.4 Hz, 1H), 7.10 (d, J = 7.9 Hz, 1H), 5.84 (m, 1H), 5.44 (t, J= 5.3 Hz, 2H), 5.38 (m, 1H), 5.10– 5.02 (m, 2H), 4.61 (s, 2H), 4.30 (t, J = 5.3 Hz, 2H), 3.89 (s, 3H), 2.03–1.95 (m, 2H), 1.69–1.55 (m, 3H), 1.48–1.41 (m, 2H);13C NMR (75 MHz, CDCl3): δ 182.9, 167.4, 144.0, 134.2, 130.8, 127.6, 125.7, 120.4, 117.5, 117.0, 61.8, 52.6, 49.0, 47.0, 29.3, 24.2; MS (ESI) m/z 314 (MH+); HRMS (ESI) calcd for C18H24N3O2: m/z 314.1868, found 314.1866; IR (KBr): 3370, 2954, 1710, 1631, 1577, 1444 cm−1. Methyl3-(2-methoxyethyl)-2-[(2-methylpropyl)amino] -3, 4-dihydroquinazoline-7-carboxylate (6e) 1H NMR (300 MHz, CDCl3): δ 7.50 (t, J = 8.1, Hz 1H), 7.32–7.28 (m, 1H), 7.05 (d, J = 8.1 Hz, 1H), 3.89 (s, 3H), 3.80 (s, 2H), 3.52 (t, J = 8.4 Hz, 2H), 3.45 (t, J = 5.7 Hz, 2H), 3.30 (t+s, 5H), 1.97–1.88 (m, 2H), 0.87 (d, J = 8.4 Hz, 6H); 13C NMR (75 MHz, CDCl3): δ 184.2, 167.6, 146.8, 131.6, 131.4, 125.1, 118.6, 116.5, 72.1, 59.6, 54.9, 54.5, 52.5, 49.7, 28.4, 20.7; MS (ESI) m/z 320 (MH+); HRMS (ESI) calcd for C17H26N3O3: m/z 320.1974, found 320.1977. IR (KBr): 3338, 2952, 1728, 1629, 1579, 1240 cm−1. Methyl 3-(2-methylpropyl)-2-[(2-methylpropyl)amino]-3,4-dihydroquinazoline-7-carboxylate (6f) 1H NMR (300 MHz, CDCl3): δ 7.32 (dd, J = 7.8, 1.5 Hz 1H), 7.29 (d, J = 1.5 Hz, 1H), 7.04 (d, J = 7.8 Hz, 1H), 5.70 (m, 2H), 4.80–4.55 (brs, 1H), 3.87 (s, 3H), 3.51 (t, J = 6.8 Hz, 2H), 3.16 (d, J = 7.6 Hz, 2H), 2.06 (m, 1H), 1.93 (m, 1H), 0.91 (t, 6.8 Hz, 12H);13C NMR (75 MHz, CDCl3): δ 182.1, 167.5, 146.5, 131.3, 131.2, 124.9, 118.9, 116.8, 55.1, 54.4, 54.3, 52.5, 28.5, 27.6, 20.9, 20.7; MS (ESI) m/z 318
(MH+); HRMS (ESI) calcd for C18H28N3O2: m/z 318.2181,
found 318.2179; IR (KBr): 3370, 2954, 1710, 1631, 1577, 1444 cm−1. Methyl 2-[(furan-2-ylmethyl)amino]-3-(2-methylpropyl) -3, 4-dihydroquinazoline-7-carboxylate (6g) 1H NMR (300 MHz, CDCl3): δ 7.35–7.28 (m, 3H), 7.04 (d, J = 7.8 Hz, 1H), 6.32 (dd, J = 3.2, 2.0 Hz, 1H), 6.27 (d, J = 3.2, 1H), 5.94 (t, J = 4.6 Hz, 2H), 4.88 (d, J = 4.6 Hz, 2H), 3.90 (s, 3H), 3.15 (d, J = 7.6 Hz, 2H), 2.05– 1.99 (m, 1H) 0.86 (d, J = 6.7 Hz, 6H);13C NMR (75 MHz, CDCl3): δ 181.9, 167.6, 151.2, 146.4, 142.6, 131.3, 131.2, 124.8, 118.9, 116.8, 110.9, 108.3, 55.0, 54.5, 52.5, 43.8, 27.5, 20.8; MS (ESI) m/z 342 (MH+); HRMS (ESI) calcd for C19H24N3O3: m/z 342.1818, found 342.1817; IR (KBr): 3446, 2927, 1704, 1531, 1438 cm−1. Methyl 3-(2-methylpropyl)-2-(prop-2-en-1-ylamino)-3, 4-dihydroquinazoline-7-carboxylate (6h) 1H NMR (300 MHz, CDCl3): δ 7.31 (dd, J = 7.7, 1.6 Hz 1H), 7.28 (d, J = 1.6 Hz, 1H), 7.03 (d, J = 7.7 Hz, 1H), 5.90 (m, 1H), 5.73 (t, J = 5.1 Hz, 1H), 5.19 (s, 2H), 5.15– 5.11 (m, 1H), 4.34–4.30 (m, 2H), 3.85 (s, 3H), 3.16 (d, J = 7.7 Hz, 2H), 2.06 (m, 1H), 0.83 (d, J = 7.7 Hz, 6H); 13C NMR (75 MHz, CDCl3): δ 182.1, 167.6, 146.4, 134.3, 131.2, 130.8, 124.9, 118.9, 117.3, 116.8, 55.0, 54.4, 52.5, 49.2, 27.5, 20.8; MS (ESI) m/z 302 (MH+); HRMS (ESI)
calcd for C17H24N3O2: m/z 302.1868, found 302.1867; IR (KBr): 3370, 2954, 1710, 1631, 1577, 1444 cm−1. Methyl 3-(propan-2-yl)-2-(prop-2-en-1-ylamino)-3, 4-dihydroquinazoline-7-carboxylate (6i) 1H NMR (300 MHz, CDCl3): δ 7.45 (d, J = 8.3, 1.4 Hz, 1H), 7.42 (d, J = 3.3 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 5.80 (m, 1H), 5.46–5.37 (m, 2H), 5.07–4.99 (m, 2H), 4.60 (s, 2H), 4.31–4.26 (m, 2H), 3.89 (s, 3H), 1.21 (s, 6H);13C NMR (75 MHz, CDCl3): δ 182.1,166.9, 143.7, 133.8, 130.5, 127.5, 125.1, 119.9, 117.1, 116.5, 52.1, 51.5, 48.5, 45.3, 19.9; MS (ESI) m/z 288 (MH+); HRMS (ESI) calcd for C16H22N3O2: m/z 288.1712, found 288.1710; IR (KBr): 3376, 2954, 1712, 1629, 1577, 1444 cm−1. Methyl 3-(propan-2-yl)-2-(pyridin-3-yl)-1,2,3,4-tetrahydroquinazoline-7-carboxylate (7a) 1H NMR (300 MHz, CDCl3): δ 8.70 (s, 1H), 8.51 (dd, J = 4.8 Hz, 1H), 7.76 (dt, J = 6.8, 1.5 Hz, 1H), 7.34–7.22 (m, 3H), 6.93 (d, J= 7.6 Hz, 1H), 5.38 (s, 1H), 4.64 (brs, NH), 3.88 (s, 3H), 3.78 (d, J = 16.8 Hz, 1H), 3.65 (d, J = 16.8 Hz, 1H), 2.97–2.87 (m, 1H), 1.18 (d, J = 6.2 Hz, 3H), 1.08 (d, J = 6.2 Hz, 3H);13C NMR (75 MHz, CDCl3): δ 167.3, 149.2, 149.0, 142.2, 138.3, 135.0, 129.2, 127.0, 125.3, 123.7, 119.0, 114.9, 68.6, 52.4, 49.9, 44.3, 22.2, 20.4. MS (ESI) m/z 311 (M+) HRMS (EI) calcd for C18H21N3O2: m/z 311.1634, found 311.1639; IR (KBr): 3394, 1706, 1297 cm−1. Methyl 3-isobutyl-2-phenyl-1,2,3,4-tetrahydro-7-quinazolinecarboxylate (7b) 1H NMR (300 MHz, CDCl3): δ 7.65–7.43 (m, 2H), 7.38– 7.28 (m, 5H), 6.94 (d, J = 7.8 Hz, 1H), 5.10 (s, 1H), 4.52 (brs, 1H), 3.91 (s, 3H), 3.76 (d, J = 16.7 Hz, 1H), 3.56 (d, J = 16.7 Hz, 1H), 2.41 (dd, J = 16.7, 7.8 Hz, 1H), 2.24 (dd, J = 16.7, 7.8 Hz, 1H), 1.84 (m, 1H), 0.93 (m, 6H);13C NMR (75 MHz, CDCl3): δ 167.4, 142.7, 129.1, 128.9, 128.5, 127.8, 127.7, 127.2, 126.9, 125.2, 118.3, 114.2, 72.5, 60.0, 52.0, 49.9, 26.0, 19.0; MS (EI): m/z 324 (M+); HRMS (ESI) calcd for C19H24N2O2: m/z 324.1838, found: 324.1833; IR (KBr): 3386, 1706, 1502, 1295 cm−1. Methyl 2-phenyl-3-(thiophen-2-ylmethyl)-1,2,3, 4-tetrahydroquinazoline-7-carboxylate (7c) 1H NMR (300 MHz, CDCl3): δ 7.53–7.50 (m, 2H), 7.38– 7.26 (m, 6H), 6.98–6.92 (m, 3H), 5.21 (s, 1H), 4.55 (brs, 1H), 4.02 (d, J = 16.8 Hz, 1H), 3.89 (s, 3H), 3.85-3.80 (m, 2H), 3.65 (d, J = 16.8 Hz, 1H);13C NMR (75 MHz, CDCl3): δ167.8, 143.3, 142.4, 142.3, 129.8, 128.9, 128.3, 128.1, 127.4, 126.9, 126.2, 125.7, 124.0, 119.0, 115.0, 71.2, 52.4, 51.7, 48.8; M S(E I ): m/z 364 (M+1). HRMS (ESI) calcd for C21H20N2O2S: m/z 364.1245, found 364.1243; IR (KBr): 3380, 1705, 1616, 1505 cm−1. Methyl 2-(4-nitrophenyl)-3-(thiophen-2-ylmethyl)- 1,2,3, 4-tetrahydroquinazoline-7-carboxylate(7d) 1H NMR (300 MHz, CDCl3): δ 8.17 (dd, J = 6.9, 2.1 Hz, 1H), 7.69(d, J = 8.7 Hz, 2H), 7.43 (d, J = 1.5 Hz, 1H), 7.39 (d, J = 1.5 Hz, 1H), 7.30 (dd, J = 7.5, 1.5 Hz, 1H), 6.98–6.91 (m, 4H), 5.23 (s, 1H) 4.63 (brs, 1H), 4.06 (d, J = 16.4 Hz, 1H), 3.91 (s, 3H), 3.80–3.70 (m, 2H), 3.58 (d, J = 16.5 Hz, 1H);13C NMR (75 MHz, CDCl3): δ 167.2, 147.6, 140.8, 130.5, 129.8, 128.1, 127.8, 126.7, 126.4, 125.7, 124.3, 124.1, 123.7, 119.3, 115.0, 70.5, 69.3, 52.1, 51.7; MS (ESI)
m/z 410 (MH+1); HRMS (ESI) calcd for C21H20N3O4S:
m/z 410.1174, found 410.1176; IR (KBr): 2931, 1708, 1600, 1505 cm−1.
Methyl 2-(phenyl)-3-[2-(pyridin-2-yl)ethyl]-1,2,3, 4-tetrahydroquinazoline- 7-carboxylate (7e)
1H NMR (300 MHz, CDCl3): δ 8.49 (d, J = 4.8 Hz, 1H), 8.09 (dd, J = 9.3, 1.8 Hz, 1H), 7.60 (td, J = 7.5, 1.8 Hz, 1H), 7.35–7.31 (m, 3H), 7.18–7.11 (m, 4H), 6.91 (d, J = 7.5 Hz, 1H), 5.27 (s, 1H), 4.78 (brs, 1H), 3.87 (s, 3H), 3.65 (s, 2H), 3.15-3.00 (m, 2H), 2.95–2.89 (m, 2H);13C NMR (75 MHz, CDCl3): δ 167.2, 159.6, 149.6, 148.5, 147.4, 141.2, 137.0, 129.6, 128.1, 127.7, 123.7, 123.6, 121.6, 119.1, 115.2, 71.3, 52.3, 52.0, 48.1, 36.7; MS (ESI) m/z 419 (MH+1); HRMS (ESI) calcd for C23H23N4O2: m/z 419.1719, found 419.1717; IR (KBr): 2925, 1712, 1294 cm−1. Methyl 2-(2-fluorophenyl)-3-[2-(pyridin-2-yl)ethyl]-1,2,3, 4-tetrahydroquinazoline-7-carboxylate (7f) 1H NMR (300 MHz, CDCl3): δ 8.45 (dd, J = 4.2, 0.9 Hz, 1H), 7.56 (td, J = 4.2, 1.8 Hz, 1H), 7.35–7.17 (m, 4H), 7.16 (d, J = 8.4 Hz, 1H), 7.06–6.95 (m, 4H), 5.58 (s, 1H), 4.54 (brs, 1H), 3.90 (s, 3H), 3.76 (d, J = 16.7 Hz, 1H), 3.56 (d, J = 16.7 Hz, 1H), 3.15–3.00 (m, 2H), 2.95–2.89 (m, 2H); 13C NMR (75 MHz, CDCl3): δ 167.3, 159.9, 149.0, 142.3, 136.4, 129.7, 129.1, 128.4, 128.3, 127.4, 123.7, 123.4, 121.2, 118.6, 115.8, 115.5, 114.4, 66.7, 53.4, 52.0, 49.0, 36.9; MS (ESI) m/z 392 (MH+); HRMS (ESI) calcd for C23H23N3O2: m/z 392.1774, found 392.1772; IR (KBr): 2933, 2854, 1706, 1228 cm−1.
Acknowledgments The authors thank the National Science Council of Taiwan for the financial assistance and the authorities of the National Chiao Tung University for providing the laboratory facilities. This arti-cle is particularly supported by “Aim for the Top University Plan” of
the National Chiao Tung University and Ministry of Education, Taiwan, R.O.C.
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