Synthesis of Sulfonamide Derived from New Tetrahydroquinazoline Derivatives via Intramolecular cyclization

Introduction

Heterocyclic compounds are one of the most important classes of organic compounds that have a wide range of biological activities: antibacterial, antifungal, and several other biological activities. Amongst these are sulfur and nitrogen containing heterocycles, are especially important. Consequently, the development of new methodologies useful for the synthesis of new heterocycle templates has gained much attention in both the academic and the industrial communities. Thus there is a growing need for new scaffolds which can act better, compared to the previous known drugs.

Quinazoline is one such heterocycles which may contain a versatile pharmacophore responsible for many biological activities. It possesses a wide spectrum of bioactivities as antimicrobial, bronchodilator, antihistaminic, anti-inflammatory, angiotensin(II) receptor antagonist, antiherpes, anti-tubercular, anti-insecticidal and cardiovascular agent etc.

Among the different bioactive molecules, sulfonamide group containing heterocycles are present at large. Owing to its wide application as antibiotics, anti-carbonic anhydrase, diuretic, hypoglycemic, anti thyroid and anticancer agent. Researchers across the world are also interested in synthesizing new sulfonamide derived heterocyclic scaffolds. However the rapid emergence of sulfonamide resistant organisms restricted its clinical application. It constantly needs new molecules to replace the old one with new scaffolds and new pathway of mechanism of action in each case.

Moreover, sometimes it becomes necessary to treat an infection with potentially toxic drugs against those organisms which are resistant to all approved antibiotics. Consequently, there is an ever-growing demand for more effective antibacterial agents against antibiotic resistant bacteria pathogens. Therefore, research efforts are focused to make new antibiotics, those which can kill the bacteria by a new pathway. Considering the potential of quinazoline and sulfonamide moiety separately, we were interested in the synthesis of new hybrid heterocyclic scaffold containing both the quinazoline and sulfonamide moiety.

Scheme1: Synthetic Route to the “N1-acyl-N2-sulfono Quinazoline

The following scheme depicts the general synthetic route for the synthesis of aryl sulfonyl group substituted tetrahydroquinazoline (Scheme: 1). To our knowledge, this is the first example of sulfonyl and acyl group substituted tetrahydroquinazoline (“N1-acyl-N2-sulfono Quinazoline”) scaffold. Owing to its importance, we have planned to synthesize a small library of these molecules using the above methodology. It is believed that this methodology will open up new easy access to this class of molecules.

Result and Discussion

The synthesis of N1-acyl-N2-sulfono Quinazoline scaffold library started by condensing an aromatic sulfonyl chloride (1) and a 2-aminobenzyl amine (2). The free amine present in the generated sulfonamide (3) undergoes Schiff base (5) formation with the aldehydes (4) in the next step. The Schiff base was then converted to the N-acylinium ion (6) by treating them with acetyl chloride, which in situ undergoes intramolecular cyclization under basic condition as shown in scheme 2, to produce the highly substituted tetrahydroquinazoline in moderate to good yield. It is worthy to mention here that we are able to confirm the structure of the N1-acyl-N2-sulfono Quinazoline derivatives unambiguously by the single X-ray crystal structure of compound 9a and 9j (Fig: 2). The crystal structure also corroborates the mechanistic pathway as proposed in scheme 2. Based on this methodology we have successfully synthesized a small library of 10 different quinazoline molecules in good to moderate yields. The rate of cyclization reaction, as is observed, has tremendous effect on the electronic nature of the R-groups of aldehydes and the substituents effect on the aromatic rings of the sulfonamide part.

For aromatic schiff’s base, +R effect of aldehydic aromatic ring decreases the electrophilicity of the carbocation and exerts detrimental effect on the final cyclization (Table 1, 9h, 9i), whereas +I effect (which is less stronger than +R), of the aliphatic group of aldehydes showed no such effect towards the rate of cyclization (Table 1, 9a-f, 9j).

Apart from the stability of iminium carbocation, nucleophilicity of the sulfonamide moiety also influences the outcome of the cyclization significantly. In case of product 9a, cyclization is facilitated by the electron donating —OMe group in the aryl ring of the sulfonamide part which stabilizes the iminium carbocation and gave 85% yield of the desired cyclic product, whereas the yield drops to 62% for product 9e due to the absences of —OMe group. Similar trend was observed for compound 9b and 9f. Again for product 9j, due to the presence of deactivating —F group, 50% yield was obtained. Hence, this reaction is substituent tolerable and can be applicable to a wide variety of substrates.

Conclusion

We have successfully synthesized 10 N1-acyl-N2-sulfono Quinazoline derivatives via N-acylinium intermediate and also achieved the cyclization with electron deficient sulfonamide as nucleophile. So, this general strategy for pursuing highly active electrophiles to facilitate the intramolecular nucleophilic attack becomes a basis for synthesizing biologically active more functionalized quinazoline derivatives. Higher yield of the cyclized product was observed in case of activated aromatic ring. Since these N1-acyl-N2-sulfono Quinazolines obtained as racemic mixture, the streoselective version of this cyclization is our next target. The library of these new heterocyclic scaffold and the compounds therefore may act as good inhibitors of different enzymes or proteins. Biological studies of these molecules are going on in the present time in our laboratory, and the results will be published in the future.

Experimental Section

General Procedure for the Final Cyclization

To a stirred solution of schiff base (5) (1 mmole) dissolved in THF or diethylether (as per requirement) at 00 C, 2,6-leutidine (1 mmole) was added followed by acetyl chloride (1mmole) addition under nitrogen atmosphere (scheme 2). The reaction was continued for 24hrs. The solvent was evaporated to concentrate the reaction mass and the residue obtained was purified by column chromatography (hexane/ethyl acetate) to afford pure cyclized product.

1-(2-Cyclopentyl-3-(4-methoxy-benzenesulfonyl)-3,4-dihydro-2H-quinazolin-1-yl)-ethanone (9a): White solid, Rf   0.40 (petroleum ether, ethyl acetate 3:2), Melting point 155⁰ C, ¹H NMR (600 MHz, CDCl₃): δ (in ppm) 1.327-1.490 (4H, m), 1.641-1.710 (4H, m), 1.833 (3H, s), 1.918 (1H, m), 3.807 (3H, s), 4.525 (1H, d, J = 17.4), 4.780 (1H, d, J = 18), 6.325 (1H, d, J = 10.2), 6.873-6.912 (3H, m), 7.146-7.207 (3H, m), 7.727 (2H, d, J = 7.2); ¹³C NMR (150 MHz, CDCl₃): δ (in ppm) 22.61, 25.08, 25.19, 27.83, 28.84, 41.30, 43.49, 55.55, 66.46, 114.07, 114.54, 124.45, 125.18, 125.50, 126.43, 127.18, 129.33, 129.88, 130.53, 135.18, 162.89, 169.01; HRMS (EI+): m/z Calcd for C₂₂H₂₆N₂O₄S (M)+ 414.1613, Found: m/z 414.16132. IR (in cm^-1) 565, 615.56, 671.30, 748.91, 804.99, 835.42, 962.61, 1020.74, 1091.86, 1160.93, 1264.53, 1322.65, 1339.75, 1378.73, 1499.43, 1596.53, 1654.66, 2867.10, 2962.84, 3008.32, 3445.52.

1-(2-Cyclohexyl-3-(4-methoxy-benzenesulfonyl)-3,4-dihydro-2H-quinazolin-1-yl)-ethanone (9b): White solid, Rf   0.50 (petroleum ether, ethylacetate 3:2), Melting point 120⁰ C, ¹H NMR (600 MHz, CDCl3): δ (in ppm) 0.86-0.94 (1H, m), 1.05-1.17 (3H, m), 1.38-1.41 (1H, m), 1.55 (1H, d, J = 9.2), 1.65 (3H, s), 1.77 (1H, d, J = 18), 1.84 (3H, s), 1.93-1.94 (1H, m), 3.80 (3H, s), 4.46 (1H, d, J = 18), 4.76 (1H, d, J = 18), 6.27-6.28 (1H, m), 6.86-6.90 (3H, m) 7.14-7.20 (3H, m), 7.71 (2H, d, J = 6); ¹³C NMR (150 MHz, CDCl³): δ (in ppm) 22.62, 25.46, 25.91, 27.99, 28.88, 29.67, 37.96, 43.29, 55.55, 66.89, 114.08, 114.39, 124.43, 125.05, 125.52, 126.48, 127.16, 129.35, 129.84, 130.63, 134.93, 162.88, 169.27; HRMS (EI+): m/z Calcd for C₂₃H₂₈N₂O₄S (M)+ 428.17698, Found: m/z 428.17697. IR (in cm^-1) 561.54, 617.27, 671.30, 746.86, 804.99, 833.02, 964.66, 1020.74, 1039.89, 1147.93, 1165.03, 1264.18, 1322.65, 1378.39, 1462.50, 1447.45, 1499.43, 1585.59, 1596.19, 1654.66, 2848.75, 2923.52, 3435.03.

1-[3-(4-methoxy-benzenesulfonyl)-2-propyl-3,4-dihydro-2H-quinazolin-1-yl)-ethanone (9c): White solid, Rf 0.50 (petroleum ether, ethyl acetate 3:2), Melting point 130⁰ C, ¹H NMR (600 MHz, CDCl₃): δ (in ppm) 0.86-0.89 (3H, m), 1.39-1.44 (2H, m), 1.59 (3H, s), 1.87-1.88 (2H, m), 3.81 (3H, s), 4.49 (1H, d, J = 12), 4.63 (1H, d, J = 18), 6.63-6.66 (1H, m), 6.89 (2H, d, J = 6), 6.93-6.94 (1H, m), 7.15-7.16 (2H, m), 7.21 (1H, t, J = 6), 7.74 (2H, d, J = 12); 13C NMR (150 MHz, CDCl₃): δ (in ppm) 13.42, 18.18, 22.66, 34.78, 43.40, 55.56, 62.68, 113.51, 114.16, 124.65, 125.42, 125.67, 126.36, 126.58, 127.33, 129.45, 129.79, 130.27, 162.99, 168.91; HRMS (EI+): m/z Calcd for C₂₀H₂₄N₂O₄S (M)+ 388.14568, Found: m/z 388.14554. IR (in cm^-1) 557.10, 615.22, 632.66, 673.35, 722.93, 753.36, 759.85, 802.94, 835.08, 928.08, 958.17, 1027.23, 1037.83, 1089.46, 1113.40, 1147.93, 1158.53, 1262.13, 1309.66, 1328.81, 1372.23, 1460.45, 1497.03, 1585.59, 1596.19, 1652.26, 1663.20, 2866.08, 2923.52, 2975.49, 3435.03.

1-(3-benzenesulfonyl-2-cyclopentyl-3,4-dihydro-2H-quinazolin-1-yl)-ethanone (9e): White solid, Rf  0.50 (petroleum ether, ethyl acetate 3:2), Melting point 1100 C, ¹H NMR (600 MHz,CDCl₃): δ (in ppm) 1.21-1.26 (1H, m), 1.32-1.38 (2H, m), 1.42-1.45 (1H, m), 1.61-1.62 (1H, m), 1.65-1.66 (3H, m), 1.70 (3H, s), 1.86-1.87 (1H, m), 4.46 (1H, d, J = 18), 4.75 (1H, d, J = 18), 6.28 (1H, d, J = 6), 6.82 (1H, d, J = 12), 7.08-7.13 (3H, m), 7.33-7.36 (2H, m), 7.41-7.44 (1H, m), 7.72 (2H, d, J = 6); ¹³C NMR (150 MHz, CDCl₃): δ (in ppm) 22.66, 25.09, 25. 19, 27.82, 28.82, 41.21, 43.61, 66.48, 124.44, 124.92, 125.54, 126.41, 127.22, 127.69, 129.00, 132.59, 138.97, 169.06; HRMS (EI+): m/z Calcd for C₂₁H₂₄N₂O₃S(M)+ 384.15076, Found: m/z 384.1505. IR (in cm^-1) 559.15, 578.64, 632.66, 690.79, 722.93, 748.91, 951.67, 1044.33, 1055.27, 1091.86, 1162.98, 1262.13, 1367.79, 1313.76, 1445.40, 1494.98, 1583.54, 1661.15, 2928.99, 2854.22, 3440.50.

1-(3-benzenesulfonyl-2-cyclohexyl-3,4-dihydro-2H-quinazolin-1-yl)-ethanone (9f): White solid, Rf   0.50 (petroleum ether, ethyl acetate 3:2), Melting point 120⁰ C, ¹H NMR (600 MHz, CDCl₃): δ (in ppm) 0.98-1.10 (4H, m), 1.33-1.35 (2H, m), 1.47-1.50 (2H, m), 1.57-1.61 (2H, m), 1.70 (3H, s), 1.85-1.87 (1H, m), 4.43 (1H, d, J = 18), 4.73 (1H, d, J = 18), 6.24 (1H, d, J = 6), 6.82 (1H, d, J = 6), 7.08-7.12 (3H, m), 7.33-7.36 (2H, m), 7.42 (1H, t, J = 6), 7.72 (2H, d, J = 12); 13C NMR (150 MHz, CDCl₃): δ (in ppm) 22.43, 25.44, 25.88, 27.95, 28.85, 29.66, 37.85, 43.42, 66.92, 125.58, 126.47, 127.21, 127.62, 129.01, 132.58, 134.79, 139.05, 169.34; HRMS (EI+): m/z Calcd for C₂₂H₂₆N₂O₃S (M)+ 398.1664, Found: m/z 398.16632. IR (in cm^-1) 567.70, 578.64, 621.72, 647.70, 690.79, 718.82, 744.81, 930.13, 964.66, 1042.28, 1091.86, 1152.04, 1169.47, 1175.97, 1260.08, 1324.70, 1352.74, 1378.39, 1447.45, 1456, 1499.43, 1585.59, 1658.76, 2854.22, 2928.99, 3435.

1-(2-Cyclopentyl-3-(4-fluoro-benzenesulfonyl)-3,4-dihydro-2H-quinazolin-1-yl)-ethanone (9j): White solid, Rf    0.40 (petroleum ether, ethyl acetate 3:2), Melting point 150⁰ C, ¹H NMR (600 MHz, CDCl₃): δ (in ppm) 1.32-1.38 (2H, m), 1.42-1.44 (1H, m), 1.51 (3H, s), 1.62-1.67 (3H, m), 1.77 (2H, b s), 1.85-1.87 (1H, m), 4.48 (1H, d, J = 18), 4.68 (1H, d, J = 18), 6.28 (1H, d, J = 12), 6.85 (1H, d, J = 6), 7.01-7.04 (2H, m), 7.08-7.16 (3H, m), 7.76-7.79 (2H, m); ¹³C NMR (150 MHz, CDCl3): δ (in ppm) 22.49, 25.06, 25.18, 27.81, 28.84, 41.29, 43.61, 66.44, 116.06, 116.21, 124.53, 124.91, 125.71, 126.48, 127.38, 130.50, 130.56, 135.03, 164.24, 165.94, 168.98; HRMS (EI+): m/z Calcd for C₂₁H₂₄N₂O₃S (M)+ 402.1413, Found: m/z 402.1415. IR (in cm^-1) 568.96, 621.035, 680.82, 742.54, 808.11, 887.19, 925.76, 977.84, 1033.77, 1099.34, 1132.13, 1157.20, 1242.07, 1311.5, 1394.43, 1450.36, 1587.3, 1654.81, 2354.92, 2856.37, 2918.09, 2950.88, 3550.70, 3770.57.

Acknowledgment

Moumita Chatterjee wishes to thank UGC, Suvankar Bera wishes to thank CSIR, Mohd Usman Mohd Siddique wishes to thank NIPER-KOLKATA for their respective fellowships. We would also like to thank the CSIR ‘ORIGIN’ CSC-0108 project for providing financial assistance towards this work. The authors would also like to thank the central instrumentation facilities of CSIR-IICB for recording the spectra.

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