A convenient method for the synthesis of 3,4-dihydroquinazolines from iminoester hydrochlorides via microwave irradiation

Abstract

This work presents a simple and practical strategy for the synthesis of 2-substituted-3,4-dihydroquinazolines in which the ring closure reaction of 2-aminobenzylamine with corresponding iminoester hydrochlorides via microwave irradiation allows the formation of the target compounds. Also, the 3,4-quinazoline derivatives were synthesized by conventional heating procedures for comparison in terms of reaction time and yield.

Introduction

The presence of nitrogen-containing heterocycles has contributed significantly to the rapid growth of the field of medicinal chemistry for decades. Among these heterocycles, quinazoline derivatives have attracted attention due to their various pharmacological properties such as antitumor, antimicrobial, anti-inflammatory, anticonvulsant, antihypertensive, analgesic, anti-viral, and anti-urease.^1–8 Quinazoline compounds are also active ingredients of many commercially available drugs such as Prazosin, Gefitinib, Erlotinib, Alfuzosin, Trimetrexate, Bunazosin, and Vandetanib. ⁹ Among quinazoline derivatives, the structure of 3,4-dihydroquinazoline is among those of well-known alkaloids and demonstrates different and important biological activities such as antimicrobial activity, ¹⁰ antifungal activity, ¹¹ Type-T calcium channel blocking activity, ¹² anticancer activity, ¹³ inhibition of trypanothione reductase (TryR), ¹⁴ anticholinesterase activity, ¹⁵ antidepressant, ¹⁶ and anticonvulsant activities. ¹⁷

Over the last few decades, a vast number of synthetic methods have been developed for the synthesis of new, original, and functionalized quinazolines to provide more effective medicines and to design synthetic medicines. ¹⁸ Some of these methods can be listed as follows: Niementowski’s synthesis; Grimmel, Guinther, and Morgan’s synthesis; from isatoic anhydride; from 1,3,4-benoxazones (acylanthranils) and amines; from ethyl 2-acetamido-5-nitrobenzoate; Sen and Ray’s synthesis; from anthranilic acid and urea; from o-ureidobenzoic acid; from o-ethoxy carbonylaminobenzoic esters or amides; from phthalic acid derivatives; from isatins; from 2-aminobenzylamine; and from 2-azido-4-chlorobenzoic acid. ¹⁹ The majority of these methods are associated with the synthesis of quinazolinone derivatives. Besides these methods, there are certain methods of synthesis of 3,4-dihydroquinazolines in the literature: solid-phase synthesis; ²⁰ reduction or oxidation of quinazolines, tetrahydroquinazolines, or quinazolinones; ²¹ synthesis from N-acylation and cesium carbonate–mediated N-alkylation reactions; ²¹ synthesis from o-iodoxybenzoic acid by mediated tandem reactions; ²² synthesis from sequential Ugi/Staudinger/aza-Wittig reactions; ²³ and synthesis from para- and meta-substituted anilines. ²⁴ In most of these methods, 2-aminobenzylamine or N-functionalization of the aliphatic amino group of 2-aminobenzylamine is used, which reacts with the aldehydes, carboxylic acids, amidines, and orthoformates, which require long-time reactions, harsher conditions, and the use of specific reactants and catalysts. Therefore, the present study provides a more suitable and effective alternative method for the synthesis of 3,4-dihydroquinazoline compounds than those methods that are currently available.

This study describes condensation of 2-aminobenzylamine with the corresponding iminoester hydrochlorides (1a–m) under microwave irradiation that permitted the formation of the 2-substituted-3,4-dihydroquinazoline compounds (2a–m) without intermediate steps and without the need for any catalysts in a single step. The reactions are environmentally friendly and highly efficient.

Results and discussions

Our previous work has shown that nitrogen-containing heterocyclic compounds such as benzimidazoles, pyrimidines, and quinazolinones can be synthesized by condensation of compounds containing diamino groups in a suitable position with iminoester hydrochlorides by using a simple and efficient method.^25–28 From this point of view, we have synthesized some 3,4-dihydroquinazolines (2a–m) in high yields by reaction of 2-aminobenzylamine with iminoester hydrochlorides (1a–m) using microwave heating and also by conventional methods. Therefore, we have developed a very suitable and alternative protocol for the synthesis of 3,4-dihydroquinazolines, which is environmentally friendly and highly efficient (Scheme 1 and Table 1).

Scheme 1.

Synthetic route for the compounds 2a–m.

Table 1.

Comparison of conventional and microwave heating methods in terms of reaction time and yield for the synthesis of compounds 2a–2m.

Compound	Microwave irradiation		Conventional heating
	Time (min)	Yield (%)	Time (h)	Yield (%)
2a	5	76	12	78
2b	5	79	12	76
2c	5	68	12	57
2d	5	82	12	78
2e	5	84	12	84
2f	5	89	12	76
2g	5	62	12	56
2h	5	74	12	74
2i	5	78	12	72
2j	5	72	12	68
2k	5	92	12	89
2l	5	68	12	61
2m	5	85	12	79

First, the iminoester hydrochlorides (1a–m) were synthesized according to the literature. ²⁹ This literature involves the synthesis of iminoester hydrochlorides by passing hydrogen chloride gas, obtained by the reaction of ammonium chloride and sulfuric acid, into a solution of suitable nitriles in ethanol and ether.

Then, the synthesis of 3,4-dihydroquinazoline compounds (2a–m) was carried out by nucleophilic attack of the nitrogen atom of the 2-aminobenzylamine with the iminoester hydrochloride imine carbon leading to the elimination of the ammonium chloride and the ethoxy group, respectively. The spectral data of the synthesized compounds (2a–m) were found to be compatible with the assigned structures. In the ¹H NMR spectra of the synthesized compounds (2a–m), benzylic CH₂ signals were observed in the range of 3.41–4.56 ppm, and NCH₂ signals were observed in the range of 4.45–4.70 ppm as singlet peaks. The aromatic protons resonated between 6.68 and 8.16 ppm indicative of the target compounds (2a–m). Also, in the ¹³C NMR spectra of the synthesized compounds (2a–m), the carbons of the benzylic CH₂ group resonated between 35.80 and 42,74 ppm, and those of the NCH₂ function resonated between 43.62 and 55.15 ppm. The optimum reaction conditions for the synthesis of the compounds (2a–m) were determined using both microwave irradiation and the conventional heating method. The results obtained are compared in Table 1 in terms of reaction time and yield.

Conclusion

In this study, we have developed a convenient microwave-assisted method for the synthesis of 3,4-dihydroquinazoline derivatives, which provides a suitable way of synthesizing compounds of possible bioactive interest. Shorter reaction times, a simple work-up procedure, and no need for a catalyst are the most obvious advantages of this protocol.

Experimental

All the chemicals were supplied from Sigma-Aldrich, Merck, and Fluka. The progress of reactions was determined using thin-layer chromatography (TLC) plates (silica gel 60F 2.54–0.2 mm thickness). Melting points were determined in capillary tubes in the Stuart SMP30 melting point apparatus and were uncorrected. ¹H NMR and ¹³C NMR (attached proton test (APT)) spectra were performed on the Varian-Mercury 400 MHz spectrometer in dimethyl sulfoxide-d₆ (DMSO-d₆) or CDCl₃ using tetramethylsilane as internal standard and chemical shifts (δ values) are given in ppm. The microwave experiments were carried out in a monomod CEM Discover Microwave apparatus. The microwave radiation was adjusted so that the reaction mixture in the microwave process vials was kept at a constant temperature of 60 °C which was monitored by a computer. The elemental compositions were determined on a Carlo Erba 1106 CHN analyzer. The composition values were in agreement (±0.4%) with the calculated ones.

General procedure for synthesis of compounds 2a–m

Microwave method

A mixture of the iminoester hydrochlorides (1a–m) (0.01 mol) and 2-aminobenzylamine (0.01 mol) in absolute methanol (5 mL) was irradiated with the monomod microwave device for 5 min (monitored by TLC, n-hexane–ethyl acetate (1:2)) in a microwave vial (10 m) at constant 60 °C and 300 W maximum power. Then, the reaction mixture was cooled to room temperature and the crude product was observed by adding water (50 mL) to the mixture. The product was filtered, washed with water, and purified by crystallization from ethanol–water (2:1).

Conventional method

A mixture of the iminoester hydrochlorides (1a–m) (0.01 mol) and 2-aminobenzylamine (0.01 mol) in absolute methanol (15 mL) was stirred at room temperature for 12 h (monitored by TLC, n-hexane–ethyl acetate (1:2)). The crude product was precipitated by adding water (50 mL) to the mixture. Then, the product was filtered, washed with water, and purified by crystallization with ethanol–water (2:1).

2-Benzyl-3,4-dihydroquinazoline (2a): Yellow solid; m.p. 127–128 °C (lit. ³⁰ 130–131 °C); ¹H NMR (400 MHz, CDCl₃): δ 3.60 (s, 2H), 4.57 (s, 2H), 5.12 (br, 1H), 6.85 (d, J = 8.0 Hz, 1H), 6.93–7.00 (m, 2H), 7.05–7.11 (m, 2H), 7.24–7.30 (m, 4H).

2-(2-Fluorobenzyl)-3,4-dihydroquinazoline (2b): Beige solid; m.p. 142–143 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 3.48 (s, 2H), 4.45 (s, 2H), 6.70 (d, J = 8.0 Hz, 1H), 6.86 (d, J = 8.0 Hz, 2H), 7.01–7.25 (m, 3H), 7.36–7.38 (m, 2H); ¹³C NMR (100 MHz, CDCl₃): δ 35.80, 45.02, 115.52 (d, J_F = 22 Hz), 119.72, 123.08, 124.13, 124.66, 125.58, 127.93, 129.15, 131.36, 134.13, 155.78, 160.98 (d, J_F = 244 Hz). Anal. calcd for C₁₅H₁₃FN₂: C, 74.98; H, 5.45; N, 11.66; found: C, 75.02; H, 5.47; N, 11.67%.

2-(4-Fluorobenzyl)-3,4-dihydroquinazoline (2c): Beige solid; m.p. 112–113 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 3.58 (s, 2H), 4.59 (s, 2H), 6.86 (d, J = 8.0 Hz, 2H), 6.99–7.04 (m, 2H), 7.10–7.15 (m, 2H), 7.25–7.28 (m, 2H); ¹³C NMR (100 MHz, DMSO-d₆): δ 41.68, 44.84, 115.64, (d, J_CF = 21 Hz), 119.69, 124.13, 125.65, 127.98, 130.51 (d, J_CF = 8 Hz), 131.75, 140.65, 156.72, 161.97 (d, J_CF = 244 Hz). Anal. calcd for C₁₅H₁₃FN₂: C, 74.98; H, 5.45; N, 11.66; found: C, 74.95; H, 5.40; N, 11.70%.

2-(2-Chlorobenzyl)-3,4-dihydroquinazoline (2d): Beige solid; m.p. 162–163 °C; ¹H NMR (400 MHz, CDCl₃): δ 3.77 (s, 2H), 4.59 (s, 2H), 6.85–7.08 (m, 3H), 7.21–7.51 (m, 5H); ¹³C NMR (100 MHz, CDCl₃): δ 40.13, 43.62, 119.79, 124.15, 125.56, 127.40, 127.95, 128.81, 129.69, 131.28, 133.95, 134.21, 142.03, 160.72. Anal. calcd for C₁₅H₁₃ClN₂: C, 70.18; H, 5.10; N, 10.91; found: C, 70.21; H, 5.13; N, 10.88%.

2-(4-Chlorobenzyl)-3,4-dihydroquinazoline (2e): Yellowish solid; (CAS Registry Number 92434-93-0) m.p. 124–125 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 3.41 (s, 2H), 4.45 (s, 2H), 6.72 (d, J = 8.0 Hz, 1H), 6.85 (d, J = 8.0 Hz, 2H), 7.00–7.04 (m, 1H), 7.29–7.39 (m, 4H). Anal. calcd for C₁₅H₁₃ClN₂: C, 70.18; H, 5.10; N, 10.91; found: C, 70.22; H, 5.09; N, 10.93%.

2-(3,4-Dichlorobenzyl)-3,4-dihydroquinazoline (2f): Yellowish solid; m.p. 205–207 °C; ¹H NMR (400 MHz, CDCl₃): δ 3.57 (s, 2H), 4.61 (s, 2H), 6.87 (d, J = 8.0 Hz, 1H), 6.98–7.26 (m, 3H), 7.35–7.52 (m, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 41.76, 45.27, 119.53, 124.55, 125.64, 127.12, 128.10, 128.39, 130.95, 131.53, 132.88, 134.31, 135.99, 142.49, 160.92. Anal. calcd for C₁₅H₁₂Cl₂N₂: C, 61.87; H, 4.15; N, 9.62; found: C, 61.90; H, 4.18; N, 9.58%.

2-(2-Bromobenzyl)-3,4-dihydroquinazoline (2g): Beige solid; m.p. 171–172 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 3.57 (s, 2H), 4.45 (s, 2H), 6.70 (d, J = 8.0 Hz, 1H), 6.87 (d, J = 8.0 Hz, 2H), 7.14–7.23 (m, 2H), 7.56–7.61 (m, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ 41.41, 41.78, 119.84, 123.34, 124.89, 125.97, 127.82, 128.01, 128.87, 129.59, 131.50, 132.68, 134.96, 137.30, 157.64. Anal. calcd for C₁₅H₁₃BrN₂: C, 59.82; H, 4.35; N, 9.30; found: C, 59.86; H, 4.31; N, 9.28%.

2-(4-Bromobenzyl)-3,4-dihydroquinazoline (2h): Beige solid; m.p. 118–119 °C; ¹H NMR (400 MHz, CDCl₃): δ 3.58 (s, 2H), 4.00 (bs, 1H), 4.59 (s, 2H), 6.72 (d, J = 8.0 Hz, 1H), 6.85 (d, J = 8.0 Hz, 2H), 7.00–7.02 (m, 1H), 7.28 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃): δ 41.98, 45.64, 119.57, 121.32, 124.42, 125.64, 128.07, 130.80, 132.03, 134.74, 140.28, 150.39, 156.17. Anal. calcd for C₁₅H₁₃BrN₂: C, 59.82; H, 4.35; N, 9.30; found: C, 59.84; H, 4.38; N, 9.34%.

2-(2-Methylbenzyl)-3,4-dihydroquinazoline (2i): Beige solid; m.p. 114–115 °C; ¹H NMR (400 MHz, CDCl₃): δ 1.80 (s, 3H), 4.56 (s, 2H), 4.70 (s, 2H), 6.84 (d, J = 8.0 Hz, 1H),7.04–7.16 (m, 4H), 7.59 (d, J = 8.0 Hz, 1H), 7.71–7.90 (m, 2H); ¹³C NMR (100 MHz, CDCl₃): δ 17.04, 42.48, 42.37, 116.63, 117.93, 126.08, 127.13, 128.04, 128.16, 128.94, 128.98, 131.55, 138.10, 141.74, 164.56. Anal. calcd for C₁₆H₁₆N₂: C, 81.32; H, 6.82; N, 11.85; found: C, 81.29; H, 6.85; N, 11.88%.

2-(3-Methylbenzyl)-3,4-dihydroquinazoline (2j)): Yellowsolid; m.p. 110–111 °C; ¹H NMR (400 MHz, CDCl₃): δ 2.33 (s, 3H), 3.59 (s, 2H), 4.58 (s, 2H), 6.83–6.96 (m, 3H),7.09–7.30 (m, 5H); ¹³C NMR (100 MHz, CDCl₃): δ 21.36, 42.74, 46.17, 119.82, 124.08, 125.55, 126.21, 127.30, 127.96, 128.08, 128.84, 129.97, 135.65, 138.70, 142.94, 160.82. Anal. calcd for C₁₆H₁₆N₂: C, 81.32; H, 6.82; N, 11.85; found: C, 81.38; H, 6.85; N, 11.88%.

2-(4-Methylbenzyl)-3,4-dihydroquinazoline (2k): Yellowish solid; m.p. 123–124 °C; ¹H NMR (400 MHz, CDCl₃): δ 2.34 (s, 3H), 3.61 (s, 2H), 4.57 (s, 2H), 6.85 (d, J = 8.0 Hz, 2H), 6.95 (d, J = 8.0 Hz, 2H), 7.10–7.26 (m, 4H); ¹³C NMR (100 MHz, CDCl₃): δ 21.07, 42.25, 44.76, 119.75, 124.12, 127.97, 129.12, 129.66, 132.53, 137.02, 140.76, 157.04. Anal. calcd for C₁₆H₁₆N₂: C, 81.32; H, 6.82; N, 11.85; found: C, 81.35; H, 6.86; N, 11.81%.

2-(4-Methoxybenzyl)-3,4-dihydroquinazoline (2l): Beige solid; m.p. 101–102 °C; ¹H NMR (400 MHz, CDCl₃): δ 3.61 (s, 2H), 4.06 (s, 3H), 4.65 (s, 2H), 6.68–6.74 (m, 2H), 6.85–6.91 (m, 1H), 7.08–7.11 (m, 2H), 7.43–7.48 (m, 1H), 7.66–7.74 (m, 2H); ¹³C NMR (100 MHz, CDCl₃): δ 36.30, 42.21, 55.15, 114.31, 116,35, 117.75, 124.82, 126.18, 127.09, 129.02, 130.79, 131.41, 159.31, 161.41. Anal. calcd for C₁₆H₁₆N₂O: C, 76.16; H, 6.39; N, 11.10; found: C, 76.19; H, 6.36; N, 11.07%.

2-(4-Nitrobenzyl)-3,4-dihydroquinazoline (2m): Yellowsolid; m.p. 200 °C (decom.); ¹H NMR (400 MHz, CDCl₃): δ 3.68 (s, 2H), 4.62 (s, 2H), 6.87 (d, J = 8.0 Hz, 2H), 6.99–7.25 (m, 2H), 7.49 (d, J = 8.0 Hz, 2H), 8.16 (d, J = 8.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃): δ 42.56, 45.96, 119.59, 123.98, 124.59, 125.66, 128.08, 129.79, 138.11, 143.69, 147.17, 158.96. Anal. calcd for C₁₅H₁₃N₃O₂: C, 67.40; H, 4.90; N, 15.72; found: C, 67.38; H, 4.87; N, 15.75%.