One-Pot Three-Component Synthesis of 4(3H)-Quinazolinones from Benzyl Halides, Isatoic Anhydride, and Primary Amines

Abstract

A novel, one-pot, and three-component synthesis of 4(3H)-quinazolinones is described. Benzyl halides are oxidized to aldehydes under mild Kornblum conditions then undergo a three-component reaction with isatoic anhydride and primary amines to produce 4(3H)-quinazolinones in excellent yields.

Key words

benzyl halides - Kornblum oxidation - isatoic anhydride - amines - 4(3H)-quinazolinones - multicomponent reactions

References and Notes

• 1a Multicomponent Reactions   Zhu J. Bienaymé H. Wiley-VCH; Weinheim: 2005. 
• 1b Basso A. Banfi L. Riva R. Guanti G. J. Org. Chem.  2005,  70:  575 
• 1c Ramón DJ. Yus M. Angew. Chem. Int. Ed.  2005,  44:  1602 
• 1d Nair V. Rajesh C. Vinod AU. Bindu S. Sreekanth AR. Mathen JS. Balagopal L. Acc. Chem. Res.  2003,  36:  899 
• 1e Ma C. Yang Y. Org. Lett.  2005,  7:  1343 
• 1f Cheng Y. Meth-Cohn O. Chem. Rev.  2004,  104:  2507 
• 1g Lee CF. Yang LM. Hwu TY. Feng AS. Tseng JC. Luh TY. J. Am. Chem. Soc.  2000,  122:  4992 
• 1h Nair V. Vinod AU. Chem. Commun.  2000,  1019 
• 1i Brown RCD. Angew. Chem. Int. Ed.  2005,  44:  850 
• 2a Rewcastle GW. In Comprehensive Heterocyclic Chemistry III   Vol. 8:  Katritzky AR. Ramsden CA. Scriven EFV. Taylor RJK. Elsevier Science; Oxford: 2008.  Chapt. 2. p.117-252  
• 2b Undheim K. Benneche T. In Comprehensive Heterocyclic Chemistry II   Vol. 6:  Katritzky AR. Rees CW. Scriven EVF. Pergamon Press; London: 1996.  Chapt. 2. p.93-231  
• 3 Armarego WLF. Fused Pyrimidines, Part 1: Quinazolines   Interscience; New York: 1967. 
• 4 Cao SL. Feng YP. Jiang YY. Liu SY. Ding GY. Li RT. Bioorg. Med. Chem. Lett.  2005,  15:  1915 
• 5 Kenichi O. Yoshihisa Y. Toyonari O. Toru I. Yoshio I. J. Med. Chem.  1985,  28:  568 
• 6 Wolfe JF. Rathman TL. Sleevi MC. Campbell JA. Greenwood TD. J. Med. Chem.  1990,  33:  161 
• 7 Tereshima K. Shimamura H. Kawase A. Tanaka Y. Tanimura T. Kamisaki T. Ishizuka Y. Sato M. Chem. Pharm. Bull.  1995,  43:  2021 
• 8 Kurogi Y. Inoue Y. Tsutsumi K. Nakamura S. Nagao K. Yohsitsugu H. Tsuda Y. J. Med. Chem.  1996,  39:  1433 
• 9 Kuneš J. Ba˛ant J. Pour M. Waisser K. Šlosárek M. Janota J. Farmaco  2000,  55:  725 
• 10a Jang CS. Fu FY. Wang CY. Huang KC. Lu G. Thou TC. Science  1946,  103:  59 
• 10b Koepfli JB. Mead JF. Brockman JA. J. Am. Chem. Soc.  1947,  69:  1837 
• 11 Kobayashi S. Ueno M. Suzuki R. Ishitani H. Tetrahedron Lett.  1999,  40:  2175 
• 12 Ried W. Stephan W. Chem. Ber.  1962,  95:  3042 
• 13 Connolly DJ. Guiry PJ. Synlett  2001,  1707 
• 14 Couture A. Cornet H. Grandclaudon P. Synthesis  1991,  1009 
• 15 Abdel-Jalil RJ. Voelter W. Saeed M. Tetrahedron Lett.  2004,  45:  3475 
• 16 Liu JF. Lee J. Dalton AM. Bi G. Yu L. Baldino CM. McElory E. Brown M. Tetrahedron Lett.  2005,  46:  1241 
• 17 Salehi P. Dabiri M. Zolfigol MA. Baghbanzadeh M. Tetrahedron Lett.  2005,  46:  7051 
• 18 Zhou J. Fu L. Lv M. Liu J. Pei D. Ding K. Synthesis  2008,  3974 
• 19 Zheng Z. Alper H. Org. Lett.  2008,  10:  829 
• 20 Giri R. Lam JK. Yu JQ. J. Am. Chem. Soc.  2010,  132:  686 
• 21 Snider BB. Zeng H. Heterocycles  2003,  61:  173 
• 22 Croce PD. Ferracioli R. La Rosa C. Heterocycles  1997,  45:  1309 
• 23 Paterson TMcC. Smalley RK. Suschitzky H. Synthesis  1975,  187 
• 24a Adib M. Mohamadi A. Sheikhi E. Ansari S. Bijanzadeh HR. Synlett  2010,  1606 
• 24b Adib M. Ansari S. Feizi S. Bijanzadeh HR. Synlett  2010,  921 
• 24c Adib M. Ansari S. Fatemi S. Bijanzadeh HR. Zhu LG. Tetrahedron  2010,  66:  2723 
• 24d Adib M. Ansari S. Feizi S. Asgarian Damavandi J. Mirzaei P. Synlett  2009,  3263 
• 24e Adib M. Riazati Kesheh M. Ansari S. Bijanzadeh HR. Synlett  2009,  1575 
• 24f Adib M. Sheibani E. Bijanzadeh HR. Zhu LG. Tetrahedron  2008,  64:  10681 
• 24g Adib M. Mohammadi B. Bijanzadeh HR. Synlett  2008,  177 
• 24h Adib M. Sayahi MH. Ziyadi H. Bijanzadeh HR. Zhu LG. Tetrahedron  2007,  63:  11135 
• 24i Adib M. Mahdavi M. Abbasi A. Haghighat Jahromi A. Bijanzadeh HR. Tetrahedron Lett.  2007,  48:  3217 
• 24j Adib M. Sheibani E. Mostofi M. Ghanbary K. Bijanzadeh HR. Tetrahedron  2006,  62:  3435 
• 24k Adib M. Mahdavi M. Mahmoodi N. Pirelahi H. Bijanzadeh HR. Synlett  2006,  1765 
• 25 Adib M. Ansari S. Mohammadi A. Bijanzadeh HR. Tetrahedron Lett.  2010,  51:  30 
• 26a Kornblum N. Jones WJ. Anderson GJ. J. Am. Chem. Soc.  1959,  81:  4113 
• 26b Kornblum N. Powers JW. Anderson GJ. Jones WJ. Larson HO. Levand O. Weaver WM. J. Am. Chem. Soc.  1957,  79:  6562 
• 26c Dave P. Byun HS. Engel R. Synth. Commun.  1986,  16:  1343 
• 28a Narasimhulu M. Mahesh KC. Reddy TS. Rajesh K. Venkateswarlu Y. Tetrahedron Lett.  2006,  47:  4381 
• 28b Khosropour AR. Mohammadpoor-Baltork I. Ghorbankhani H. Tetrahedron Lett.  2006,  47:  3561 
• 28c Xue S. McKenna J. Shieh WC. Repi O. J. Org. Chem.  2004,  69:  6474 
• 28d Kamal A. Reddy KS. Prasad BR. Babu AH. Ramana AV. Tetrahedron Lett.  2004,  45:  6517 
• 29 Liu JF. Lee J. Dalton AM. Bi G. Yu L. Baldino CM. McElory E. Brown M. Tetrahedron Lett.  2005,  46:  1241 
• 30 Levy PR. Stephen H. J. Chem. Soc.  1956,  985 
• 31 Kshirsagar UA. Mhaske SB. Argade NP. Tetrahedron Lett.  2007,  48:  3243 
• 32 Montazeri N. Rad-Moghadam K. Phosphorus, Sulfur Silicon Relat. Elem.  2004,  179:  2533 
• 33 Bhat BA. Sahu DP. Synth. Commun.  2004,  34:  2169 
• 34 Zheng Z. Alper H. Org. Lett.  2008,  10:  829 
• 35 Dabiri M. Salehi P. Khajavi MS. Mohammadi AA. Heterocycles  2004,  63:  1417 

27

Typical Procedure for the Preparation of Compounds 4a-m, Exemplified with 4a (Table 1, Entry 1)
A mixture of benzyl chloride (0.126 g, 1 mmol) and K₂CO₃ (1.5 mmol) in DMSO (1 mL) was stirred for 4 h at 90 ˚C. Then, isatoic anhydride (0.163 g, 1 mmol) and aniline (0.093 g, 1 mmol) were added to the reaction mixture and stirring continued at 90 ˚C for 2 h. The reaction mixture was cooled to r.t., H₂O (3 mL) was added, and stirring was continued for 1 h at ambient temperature. The white precipitate was filtered, washed with H₂O (2 × 2 mL), dried, and then recrystallized from of n-hexane-EtOAc (3:1) to give 4a as white solid.
2,3-Diphenylquinazolin-4 (3 H )-one (4a, Table 1, Entry 1)
Yield 0.286 g (96%); white solid. ^¹H NMR (500.1 MHz, CDCl₃): δ = 7.12-7.35 (m, 10 H, 10 × CH), 7.53 (d, J = 7.8 Hz, 1 H, CH), 7.80 (d, J = 7.5 Hz, 2 H, 2 × CH), 8.33 (d, J = 8.0 Hz, 1 H, CH). ^¹³C NMR (125.8 MHz, CDCl₃): δ = 121.0, 127.4, 127.8, 128.0, 128.2, 128.5, 128.7, 129.4, 129.5, 129.6, 135.0, 135.9, 138.2, 147.7, 155.2, 162.5.
3-(4-Methoxyphenyl)-2-phenylquinazolin-4 (3 H )-one (4c, Table 1, Entry 3)
Yield 0.312 g (95%); white solid. ^¹H NMR (500.1 MHz, CDCl₃): δ = 3.75 (s, 3 H, OCH₃), 6.77 (d, J = 8.2 Hz, 2 H, 2 × CH), 6.99 (d, J = 8.2 Hz, 2 H, 2 × CH), 7.15-7.23 (m, 3 H, 3 × CH), 7.35 (d, J = 7.7 Hz, 2 H, 2 × CH), 7.47 (d, J = 7.8 Hz, 1 H, CH), 7.73-7.77 (m, 2 H, 2 × CH), 8.33 (d, J = 8.0 Hz, 1 H, CH). ^¹³C NMR (125.8 MHz, CDCl₃): δ = 55.3, 114.4, 121.0, 127.1, 127.4, 128.2, 128.8, 129.2, 129.6, 130.3, 130.5, 135.2, 136.3, 147.7, 155.5, 159.8, 162.7. 3-(4-Methoxybenzyl)-2-phenylquinazolin-4 (3 H )-one (4f, Table 1, Entry 6)
Yield 0.308 g (90%); white solid. ^¹H NMR (500.1 MHz, CDCl₃): δ = 3.79 (s, 3 H, OCH₃), 5.20 (s, 2 H, CH₂), 6.75 (d, J = 8.1 Hz, 2 H, 2 × CH), 6.84 (d, J = 8.1 Hz, 2 H, 2 × CH), 7.33-7.56 (m, 6 H, 6 × CH), 7.76 (d, J = 7.7 Hz, 2 H, 2 × CH), 8.35 (d, J = 7.9 Hz, 1 H, CH). ^¹³C NMR (125.8 MHz, CDCl₃): δ = 48.7, 55.0, 113.2, 121.0, 127.0, 127.1, 127.7, 127.9, 128.4, 128.5, 128.7, 129.9, 134.0, 135.2, 147.0, 156.5, 158.8, 162.7. 2-Phenyl-3-phenylethylquinazolin-4 (3 H )-one (4g, Table 1, Entry 7)
Yield 0.300 g (92%); white solid. ^¹H NMR (500.1 MHz, CDCl₃): δ = 3.41 (t, J = 7.7 Hz, 2 H, CH₂), 4.68 (t, J = 7.7 Hz, 2 H, CH₂), 7.37-7.60 (m, 10 H, 10 × CH), 7.66 (d, J = 7.9 Hz, 1 H, CH), 7.95 (d, J = 7.6 Hz, 2 H, 2 × CH), 8.44 (d, J = 7.9 Hz, 1 H, CH). ^¹³C NMR (125.8 MHz, CDCl₃): δ = 33.9, 46.8, 120.1, 126.6, 126.7, 127.1, 127.3, 127.6, 127.9, 128.4, 128.7, 130.0, 134.1, 135.3, 138.3, 147.0, 156.5, 162.3.
2-(4-Chlorophenyl)-3-phenylquinazoline-4 (3 H )-one (4j, Table 1, Entry 10)
Yield 0.312 g (94%); white solid. ^¹H NMR (500.1 MHz, CDCl₃): δ = 7.12-7.21 (m, 4 H, 4 × CH), 7.26-7.33 (m, 5 H, 5 × CH), 7.52 (d, J = 7.9 Hz, 1 H, CH), 7.79 (d, J = 8.3 Hz, 2 H, 2 × CH), 8.34 (d, J = 8.1 Hz, 1 H, CH). ^¹³C NMR (125.8 MHz, CDCl₃): δ = 121.1, 127.1, 127.4, 127.8, 128.1, 128.7, 129.3, 129.5, 130.6, 133.7, 134.9, 135.6, 137.2, 147.1, 154.8, 162.6. 2-(4-Chlorophenyl)-3-(4-methoxybenzyl)quinazolin-4 (3 H )-one (4k, Table 1, Entry 11)
Yield 0.361 g (96%); white solid. ^¹H NMR (500.1 MHz, CDCl₃): δ = 3.79 (s, 3 H, CH₃), 5.22 (s, 2 H, CH₂), 6.77 (d, J = 8.2 Hz, 2 H, 2 × CH), 6.82 (d, J = 8.4 Hz, 2 H, 2 × CH), 7.33 (d, J = 8.2 Hz, 2 H, 2 × CH), 7.43 (d, J = 8.4 Hz, 2 H, 2 × CH), 7.49-7.53 (m, 1 H, CH), 7.70-7.81 (m, 2 H, 2 × CH), 8.33 (d, J = 7.9 Hz, 1 H, CH). ^¹³C NMR (125.8 MHz, CDCl₃): δ = 48.7, 55.1, 113.6, 121.1, 127.0, 127.2, 127.6, 128.1, 128.4, 128.8, 129.3, 133.9, 134.4, 136.2, 147.5, 155.7, 158.2, 162.5.
3-(4-Methylphenyl)-2-(4-nitrophenyl)quinazolin-4 (3 H )-one (4m, Table 1, Entry 13)
Yield 0.328 g (92%); pale yellow solid. ^¹H NMR (500.1 MHz, CDCl₃): δ = 2.29 (s, 3 H, CH₃), 7.00 (d, J = 8.3 Hz, 2 H, 2 × CH), 7.17 (d, J = 8.3 Hz, 2 H, 2 × CH), 7.51-7.62 (m, 3 H, 3 × CH), 7.90 (d, J = 8.2 Hz, 2 H, 2 × CH), 8.12 (d, J = 8.2 Hz, 2 H, 2 × CH), 8.34 (d, J = 7.9 Hz, 1 H, CH). ^¹³C NMR (125.8 MHz, CDCl₃): δ = 22.3, 121.7, 123.4, 127.2, 127.7, 127.9, 128.7, 129.9, 130.2, 134.4, 134.8, 139.3, 141.6, 147.4, 147.6, 153.2, 161.6.