QUINAZOLINE-10-CARBOXYLIC ACIDS - Springer Link

Chemistry of Heterocyclic Compounds, Vol. 47, No. 12, March, 2012 (Russian Original Vol. 47, No. 12, December, 2011)

FIRST REPRESENTATIVE OF 6b,9-EPOXYISOINDOLO[2,1-a]QUINAZOLINE-10-CARBOXYLIC ACIDS V. P. Zaytsev1*, F. I. Zubkov1, E. L. Motorygina1, M. G. Gorbacheva1, E. V. Nikitina1, and A. V. Varlamov1 Keywords: 2-furylquinazolin-4-ones, furfurylamines, isoindolo[2,1-a]quinazolines, Diels-Alder reaction, intramolecular [4+2] cycloaddition. We have developed a synthetic route for the preparation of epoxyisoindolones condensed with various heterocycles based on the cycloaddition of unsaturated acid derivatives to -furyl-substituted hydrogenated azaheterocycles [1]. To explore the synthetic scope of this method we have prepared the 3-alkyl-2-furylquinazolines 1 by the method reported in [2] and studied their reaction with maleic anhydride for the first time. Acylation of the quinazolin-4-ones 1a-c by refluxing with maleic anhydride in toluene is accompanied by a spontaneous exo-[4+2] cycloaddition of an N-maleinamide fragment to the 2-furyl substituent [3, 4]. The epoxyisoindoloquinazoline carboxylic acids 3a-c are formed as a single diastereomer with yields from moderate to quantitative. O

O O N H

H

+

O

O

O

RCH2NH2 EtOH, H+ , 4 h

5

4

6

N 2

7

N1 H

8

R O

1a–c O

O

O

O 4

PhMe, 

O

5

N

3

6a

2

N

1

N

R

H

[4+2]

7

6b

8

O

O

10

HO2C

N

R O

O

9

HO2C

3a–c

2a–c a R = Me; b R = 2-furyl; c R = Ph

_______ *To whom correspondence should be addressed, e-mail: [email protected]. 1

Peoples' Friendship University of Russia, 6 Miklukho-Maklaya St., Moscow 117198, Russia. __________________________________________________________________________________________

Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp, 1909-1913, December 2011. Original article submitted September 20, 2011. 0009-3122/12/4712-1603©2012 Springer Science+Business Media, Inc.

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Refluxing compound 3b in methanol with a catalytic amount of concentrated sulfuric acid gave methyl (6aR*,6bS*,9R*,10S*,10aR*)-5,11-dioxo-6-(2-furylmethyl)-6,6a,9,10,10a,11-hexahydro-5H-6b,9-epoxyisoindolo[2,1-a]quinazoline-10-carboxylate 4 whose steric structure was proved by X-ray structural analysis. The crystallographic data has been placed in the Cambridge Crystallographic Data Center (CCDC 844755). Hence in this work, we propose an efficient, two-stage method for the synthesis of the epoxyisoindolo[2,1-a]quinazoline skeleton based on an available starting material. The steric structure of the [4+2] cycloaddition adducts of maleic anhydride to 2-furylquinazolines has been established. IR spectra were recorded on an Infralum FT-801 Fourier spectrometer using KBr pellets. 1H NMR spectra were recorded on a Bruker WH-400 instrument (400 MHz) and on a JEOL JNM-ECA600 instrument (600 MHz) for ~ 3% solutions in CDCl3 or DMSO-d6 with the residual solvent signals as internal standard ( 7.26 ppm for CDCl3 and 2.49 ppm for DMSO). 13C NMR spectra were recorded on Bruker Avance 600 (150 MHz) or WH-400 (100 MHz) instruments using the central signal of the DMSO-d6 multiplet at 40.0 ppm or the triplet of CDCl3 at 77.4 ppm as internal standards. Mass spectra for the compounds prepared were recorded on a Thermo Trace DSQ mass spectrometer (70 eV electron ionization, source temperature 200ºC, direct introduction of the sample into the ion source). Melting points for the synthesized samples were measured on an SMP 30 instrument and are not corrected. TLC was performed on Sorbfil plates and revealed using iodine vapor and column chromatography was performed on activated neutral 50-200 mesh alumina with EtOAc–hexane (1:5) as eluent. Reagents were used from the Acros Organics company without additional purification and solvents were freshly distilled before use. 2-(2-Furyl)-2,3-dihydroquinazolin-4(1H)-ones 1 (General Method). TsOH·H2O (4.30 g, 0.025 mol) was added to a solution of isatoic anhydride (8.15 g, 0.050 mol), furfural (4.14 ml, 0.050 mol), and the corresponding amine (0.060 mol) in ethanol (100 ml) and refluxed for 4 h with TLC monitoring. The reaction mixture was poured into water (200 ml), basified with aqueous NaHCO3 solution, and extracted with chloroform (3×50 ml). The extract was dried with anhydrous MgSO4. The residue after distillation of chloroform was purified by column chromatography to give the quinazolines 1 as colorless needles. 3-Ethyl-2-(2-furyl)-2,3-dihydroquinazolin-4(1H)-one (1a). Yield 4.84 g (40%); mp 120-121ºC (EtOAc–hexane). IR spectrum, , cm-1: 1613 (N–C=O); 3261 (NH). 1H NMR spectrum (600 MHz, CDCl3), , ppm (J, Hz): 1.21 (3H, t, J = 7.2, CH3); 3.09 (1H, dq, J = 7.2, J = 14.4) and 4.05 (1H, dq, J = 7.2, J = 14.4, NCH2); 4.79 (1H, br. s, NH); 5.72 (1H, d, J = 2.4, H-2); 6.19 (1H, br. d, J = 3.4, H-3 Fur); 6.23 (1H, dd, J = 1.7, J = 3.4, H-4 Fur); 6.60 (1H, br. d, J = 7.9, H-8); 6.84 (1H, dt, J = 1.0, J = 7.9, H-6); 7.25 (1H, dt, J = 1.7, J = 7.9, H-7); 7.31 (1H, dd, J = 0.7, J = 1.7, H-5 Fur); 7.91 (1H, dd, J = 1.7, J = 7.9, H-5). 13C NMR spectrum (100 MHz, CDCl3), , ppm: 13.4 (CH3); 40.2 (NCH2); 65.3 (C-2); 108.2 (С-3 Fur); 110.4 (C-8); 114.8 (C-6); 116.7 (C-4a); 119.5 (С-4 Fur); 128.4 (C-5); 133.3 (C-7); 142.9 (С-5 Fur); 145.2 (C-8a); 152.7 (С-2 Fur); 162.8 (NCO). Mass spectrum, m/z (Irel, %): 242 [М]+ (100), 211 (31), 197 (14), 170 (33), 147 (22), 130 (16), 119 (25), 92 (28), 76 (17), 64 (28), 39 (14). Found, %: C 69.79; H 6.01; N 11.14. C14H14N2O2. Calculated, %: C 69.41; H 5.82; N 11.56. 2-(2-Furyl)-3-(2-furylmethyl)-2,3-dihydroquinazolin-4(1H)-one (1b). Yield 9.25 g (63%); mp 125-127ºC (EtOAc–hexane). IR spectrum, , cm-1: 1628 (N–C=O); 3254 (NH). 1H NMR spectrum (400 MHz, CDCl3), , ppm (J, Hz): 4.10 (1H, d, J = 15.6) and 5.41 (1H, d, J = 15.6, NCH2); 4.82 (1H, br. s, NH); 5.78 (1H, br. d, J = 2.5, H-3 Fur); 6.14 (1H, br. d, J = 3.1, H-3 Fur); 6.21 (1H, dd, J = 1.9, J = 3.1, H-4 Fur); 6.31 (2H, m, H-2, H-4 Fur); 6.60 (1H, d, J = 8.1, H-8); 6.84 (1H, t, J = 8.1, H-6); 7.24 (1H, d, J = 8.1, H-7); 7.29 (1H, br. s, H-5 Fur); 7.31 (1H, d, J = 1.9, H-5 Fur); 7.94 (1H, d, J = 8.1, H-5). 13C NMR spectrum (150 MHz, CDCl3), , ppm: 40.6 (NCH2); 64.8 (C-2); 108.2 (С-3 Fur); 109.0 (С-3 Fur); 110.4 (C-8); 110.6 (С-4 Fur); 115.0 (C-6); 116.0 (C-4a); 119.3 (С-4 Fur); 128.6 (C-5); 133.7 (C-7); 142.7 (С-5 Fur); 143.0 (С-5 Fur); 145.5 (C-8a); 150.3 (С-2 Fur); 152.2 (С-2 Fur); 163.0 (NCO). Mass spectrum, m/z (Irel, %): 294 [М]+ (7), 170 (19), 143 (8), 115 (17), 96 (37), 81 (100), 69 (14), 53 (86), 39 (45). Found, %: C 69.13; H 4.44; N 9.89. C17H14N2O3. Calculated, %: C 69.38; H 4.79; N 9.52. 1604

3-Benzyl-2-(2-furyl)-2,3-dihydroquinazolin-4(1H)-one (1c). Yield 6.54 g (43%); mp 175-176ºC (hexane–EtOAc). IR spectrum, , cm-1: 1628 (N–C=O), 3245 (NH). 1H NMR spectrum (400 MHz, CDCl3), , ppm (J, Hz): 3.87 (1H, d, J = 15.6) and 5.66 (1H, d, J = 15.6, NCH2); 4.73 (1H, br. s, NH); 5.58 (1H, s, H-2); 6.16 (1H, dd, J = 0.9, J = 3.2, Н-3 Fur); 6.21 (1H, dd, J = 1.8, J = 3.2, Н-4 Fur); 6.58 (1Н, d, J = 7.8, H-8); 6.84 (1Н, t, J = 7.8, H-6); 7.28 (7Н, m, H-7, Н-5 Fur, Н Ph); 7.96 (1Н, d, J = 7.8, H-5). 13C NMR spectrum (100 MHz, CDCl3), , ppm: 47.4 (NCH2); 64.4 (C-2); 108.2 (С-3 Fur); 110.4 (C-8); 114.8 (C-6); 116.4 (C-4a); 119.8 (С-4 Fur); 127.7; 128.1; 128.7 (C Ph); 128.8 (C-5); 133.6 (C-7); 136.8 (С Ph); 143.1 (С-5 Fur); 145.1 (C-8a); 152.1 (С-2 Fur); 163.1 (NCO). Mass spectrum, m/z (Irel, %): 304 [М]+ (100), 273 (67), 196 (29), 169 (9), 140 (8), 91 (36), 65 (21). Found, %: C 75.23; H 5.48; N 9.45. C19H16N2O2. Calculated, %: C 74.98; H 5.30; N 9.20. 6b,9-Epoxyisoindolo[2,1-a]quinazoline-10-carboxylic Acids (3) (General Method). A mixture of quinazoline 1 (1.5 mmol) and maleic anhydride (0.15 g, 1.5 mmol) in toluene (15 ml) was refluxed for 4 h and left overnight at room temperature. The crystalline precipitate was filtered off, washed with ether, and dried in air to give the Diels-Alder adducts 3 as colorless powders. (6aR*,6bS*,9R*,10S*,10aR*)-5,11-Dioxo-6-ethyl-6,6a,9,10,10a,11-hexahydro-5H-6b,9-epoxyisoindolo[2,1-a]quinazoline-10-carboxylic Acid (3a). Yield 0.49 g (96%); mp 204-205ºC (decomp.) (2-PrOH–DMF). IR spectrum, , cm-1: 1618, 1717 (N–C=O); 1723 (O–C=O). 1H NMR spectrum (400 MHz, DMSO-d6), , ppm (J, Hz): 1.12 (3H, t, J = 7.2, CH3); 2.63 (1H, d, J = 8.9, H-10); 3.22 (1H, d, J = 8.9, H-10a); 3.24 (1H, dq, J = 7.2, J = 14.4) and 3.75 (1H, dq, J = 7.2, J = 14.4, NCH2); 5.17 (1H, d, J = 1.7, H-9); 6.23 (1H, s, H-6a); 6.54 (1H, dd, J = 1.7, J = 5.6, H-8); 6.82 (1H, d, J = 5.6, H-7); 7.24 (1H, dt, J = 1.4, J = 7.6, H-3); 7.56 (1H, ddd, J = 1.7, J = 7.6, J = 7.9, H-2); 7.91 (1H, dd, J = 1.4, J = 7.9, H-1); 8.18 (1H, br. d, J = 7.6, H-4). 13C NMR spectrum (100 MHz, DMSO-d6), , ppm: 12.5 (CH3); 38.1 (NCH2); 45.8 (С-10); 51.2 (С-10а); 68.9 (С-6а); 82.1 (С-9); 89.3 (С-6b); 118.6 (С-1); 119.3 (С-4а); 124.8 (С-3); 128.6 (C-4); 133.8 (C-7); 134.7 (C-2); 137.4 (C-8,12a); 162.2; 169.6 (NCO); 173.1 (OCO). Mass spectrum, m/z (Irel, %): 340 [М]+ (4), 241 (100), 213 (23), 175 (17), 146 (42), 120 (18), 108 (21), 94 (32), 80 (32), 54 (38), 43 (32). Found, %: C 63.89; H 5.00; N 8.14. C18H16N2O5. Calculated, %: C 63.53; H 4.74; N 8.23. (6aR*,6bS*,9R*,10S*,10aR*)-6-(2-Furylmethyl)-5,11-dioxo-6,6a,9,10,10a,11-hexahydro-5H-6b,9-epoxyisoindolo[2,1-a]quinazoline-10-carboxylic Acid (3b). Yield 0.39 g (66%); mp 195-196ºC (2-PrOH–DMF). IR spectrum, , cm-1: 1667, 1695 (N–C=O); 1734 (O–C=O). 1H NMR spectrum (400 MHz, DMSO-d6), , ppm (J, Hz): 2.68 (1H, d, J = 9.0, H-10); 3.26 (1H, d, J = 9.0, H-10a); 4.20 (1H, d, J = 16.2) and 5.29 (1H, d, J = 16.2, NCH2); 5.23 (1H, d, J = 1.8, H-9); 6.17 (1H, s, H-6a); 6.36 (1H, dd, J = 0.7, J = 3.2, H-3 Fur); 6.43 (1H, dd, J = 1.8, J = 3.2, H-4 Fur); 6.57 (1H, dd, J = 1.8, J = 5.6, H-8); 6.62 (1H, d, J = 5.6, H-7); 7.28 (1H, t, J = 7.5, H-3); 7.60 (1H, dd, J = 0.7, J = 1.8, H-5 Fur); 7.61 (1H, ddd, J = 1.2, J = 7.5, J = 8.1, H-2); 7.95 (1H, dd, J = 1.2, J = 7.5, H-4); 8.19 (1H, br. d, J = 8.1, H-1). 13C NMR spectrum (100 MHz, DMSO-d6), , ppm: 38.5 (NCH2); 45.3 (C-10); 50.6 (С-10а); 68.6 (С-6а); 81.6 (С-9); 88.5 (С-6b); 108.4 (С-3 Fur); 110.5 (С-4 Fur); 118.2 (С-1); 118.3 (С-4а); 124.4 (С-3); 128.3 (C-4); 133.5 (C-7); 134.3 (C-2); 136.5 (C-8); 136.9 (C-12a); 142.6 (С-5 Fur); 149.8 (С-2 Fur); 161.7; 168.9 (NCO); 172.4 (OCO). Mass spectrum, m/z (Irel, %): 392 [М]+ (5), 294 (74), 252 (11), 198 (69), 170 (51), 143 (32), 119 (26), 96 (100), 80 (98), 65 (14), 53 (53), 43 (55). Found, %: C 64.01; H 4.42; N 7.45. C21H16N2O6. Calculated, %: C 64.28; H 4.11; N 7.14. (6aR*,6bS*,9R*,10S*,10aR*)-6-Benzyl-5,11-dioxo-6,6a,9,10,10a,11-hexahydro-5H-6b,9-epoxyisoindolo[2,1-a]quinazoline-10-carboxylic Acid (3c). Yield 0.50 g (83%); mp 202-203ºC (2-PrOH-DMF). IR spectrum, , cm-1: 1665, 1702 (N–C=O), 1744 (O–C=O). 1H NMR spectrum (400 MHz, DMSO-d6), , ppm (J, Hz): 2.63 (1H, d, J = 9.3, H-10); 3.18 (1H, d, J = 9.3, H-10a); 4.30 (1Н, d, J = 16.2) and 5.38 (1Н, d, J = 16.2, NCH2); 5.21 (1Н, d, J = 1.4, H-9); 6.21 (1Н, s, H-6a); 6.27 (1Н, d, J = 5.6, H-7); 6.53 (1Н, dd, J = 1.4, J = 5.6, H-8); 7.22–7.38 (6Н, m, H-3, H Ph); 7.64 (1Н, t, J = 8.1, H-2); 8.03 (1Н, dd, J = 1.2, J = 8.1, H-4); 8.23 (1Н, d, J = 8.1, H-1). 13C NMR spectrum (150 MHz, DMSO-d6), , ppm: 45.9 (NCH2); 46.0 (С-10); 51.2 (С-10а); 69.0 (С-6а); 82.3 (С-9); 89.2 (С-6b); 118.9 (С-4а); 119.0 (С-1); 125.0 (С-3); 127.7 (С-3',4',5'); 129.0 (C-4); 129.1 (C-2',6'); 134.1 (C-7); 134.5 (C-2); 136.5 (C-8); 137.1 (C-1'); 137.5 (C-12a); 162.6; 169.6 (NCO); 173.1 (OCO). Mass spectrum, m/z (Irel, %): 402 [М]+ (8), 304 (51), 237 (17), 213 (100), 198 (42), 186 (12), 170 (75), 143 (34), 1605

130 (14), 119 (55), 106 (78), 92 (72), 76 (37), 54 (66), 43 (53). Found, %: C 68.78; H 4.40; N 7.13. C23H18N2O5. Calculated, %: C 68.65; H 4.51; N 6.96. Methyl (6aR*,6bS*,9R*,10S*,10aR*)-6-(2-Furylmethyl)-5,11-dioxo-6,6a,9,10,10a,11-hexahydro5H-6b,9-epoxyisoindolo[2,1-a]quinazoline-10-carboxylate (4). Yield 0.29 g (72%), colorless needles; mp 235-237ºC (EtOAc–EtOH). IR spectrum, , cm-1: 1661 (N–C=O), 1726 (O–C=O). 1H NMR spectrum (400 MHz, CDCl3), , ppm (J, Hz): 2.84 (1H, d, J = 8.7, H-10); 3.06 (1H, d, J = 8.7, H-10a); 3.76 (3H, s, CH3); 4.25 (1H, d, J = 16.2) and 5.49 (1H, d, J = 16.2, NCH2); 5.35 (1H, d, J = 1.2, H-9); 6.05 (1H, s, H-6a); 6.33 (2H, br. s, H-3,4 Fur); 6.51 (1H, dd, J = 1.2, J = 5.6, H-8); 6.76 (1H, d, J = 5.6, H-7); 7.20 (1H, t, J = 7.5, H-3); 7.33 (1H, br. s, H-5 Fur); 7.48 (1H, ddd, J = 1.2, J = 7.5, J = 8.1, H-2); 8.07 (1H, dd, J = 1.2, J = 7.5, H-4); 8.18 (1H, br. d, J = 8.1, H-1). 13C NMR spectrum (100 MHz, CDCl3), , ppm: 38.8 (NCH2); 45.8 (C-10); 51.4 (C-10a); 52.6 (OCH3); 69.4 (С-6а); 81.8 (С-9); 88.9 (С-6b); 109.2 (С-3 Fur); 110.8 (С-4 Fur); 118.9 (С-1); 119.0 (С-4а); 125.0 (С-3); 129.2 (C-4); 133.7 (C-7); 135.1 (C-2); 136.3 (C-8); 136.6 (C-12a); 142.2 (С-5 Fur); 150.6 (С-2 Fur); 162.5; 168.3 (NCO); 171.6 (OCO). Mass spectrum, m/z (Irel, %): 406 [М]+ (42), 293 (58), 252 (33), 232 (10), 198 (100), 175 (23), 146 (19), 113 (63), 80 (98), 53 (37), 43 (37). Found, %: C 65.11; H 4.55; N 7.01. C22H18N2O6. Calculated, %: C 65.02; H 4.46; N 6.89. This work was carried out with the financial support of the Russian Foundation for Fundamental Investigations, grant 10-03-00177a. The authors thank colleagues in the Central Laboratory for Precision Analytical Instrumentation "PRIMA" of the Collective Use Center of the Peoples' Friendship University of Russia for carrying out the spectroscopic studies.

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F. I. Zubkov, I. K. Airiyan, A. A. Dzyubenko, N. I. Yudina, V. P. Zaytsev, E. V. Nikitina, A. V. Varlamov, V. N. Khrustalev, and D. G. Grudinin, J. Heterocycl. Chem., 47, 400 (2010). M. Baghbanzadeh, P. Salehi, M. Dabiri, and G. Kozehgary, Synthesis, 344 (2006). F. I. Zubkov, J. D. Ershova, A. A. Orlova, V. P. Zaytsev, E. V. Nikitina, A. S. Peregudov, A. V. Gurbanov, R. S. Borisov, V. N. Khrustalev, A. M. Maharramov, and A. V. Varlamov, Tetrahedron, 65, 3789 (2009). F. I. Zubkov, I. K. Airiyan, K. F. Turchin, V. P. Zaytsev, A. V. Gurbanov, A. M. Maharramov, V. N. Khrustalev, A. S. Peregudov, E. V. Nikitina, and A. V. Varlamov, Synthesis, 4235 (2009).