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Synthesis of 4-Methoxy-2-(thiophen-2-yl)quinazoline by Cu-Benzotriazole Catalyzed Electrophilic Intramolecular Cyclization of N-Arylimine in Methanol; 4-Methoxy-2-(thiophen-2-yl)quinazoline

SyntheticPage 940
Submitted Oct 27, 2020, published Jan 11, 2021
Satyanarayana Battula (satyamssd@gmail.com), Bhavyesh Desai (bhavyeshdesai42@gmail.com)
A contribution from Satyam's Group
Reaction Scheme: Synthesis of 4-Methoxy-2-(thiophen-2-yl)quinazoline by Cu-Benzotriazole Catalyzed Electrophilic Intramolecular Cyclization of N-Arylimine in Methanol

Chemicals Used

(1) 2-Aminobenzonitrile (Sigma Aldrich), 99%, 294098
(2) Thiophene-2-carbaldehyade (Sigma Aldrich), 98%, T32409 

(3) Copper iodide (Sigma Aldrich), 98%,  205540

(4) Benzotriazole (Sigma Aldrich), 99%, B11400 

(5) Potassium carbonate (Sigma Aldrich), 99%, 209619

(6) Molecular sieves (CDH), 054004  

(7) Anhydrous sodium sulfate (RANKEM), 99%, S0410

(8) Methanol (RANKEM), directly used without drying

(9) n-hexane (SD Fine Chemicals Ltd), directly used without drying

(10) Ethyl acetate (SD Fine Chemicals Ltd), directly used without drying

Procedure

Reaction vessel (round bottom flask-25 mL) was charged with 2-aminobenzonitrile (100 mg, 0.854 mmol) and thiophene-2-carbaldehyde (0.095 mL,1.02 mmol). The mixture was dissolved in 4 ml of MeOH and the flask fitted with a reflux condenser. To this solution CuI (19 mg, 10 mol%), benzotriazole (24 mg, 20 mol%), potassium carbonate (235 mg, 1.7 mmol) and 4Å MS powder were successively added and the reaction allowed to reflux for 15 h. The progress of the reaction was monitored by TLC. After its completion, the reaction was cooled to room temperature and excess solvent was removed under reduced pressure. The reaction mass was extracted with ethyl acetate from the aqueous solution of the reaction mixture. The ethyl acetate extract was dried over anhydrous Na2SO4 and the resultant crude mixture was purified by column chromatography on silica gel (100-200 #) using hexane and ethyl acetate (97:3) as eluent to afford the corresponding product.

Author's Comments

  • 4-Oxyquinazolines display anti-cancer (VEGFR2, EGFR and BRAF) and anti-HIV biological properties.
  • The cyclization is proceeds through intramolecular electrophilic cyclization of Schiff base of thiophene-2-carbaldehyade and 2-aminobenzonitrile in methanol.
  • Benzotriazole, an inexpensive, air & moisture stable compound and that exerts excellent ligand properties and widely being as a catalyst.

Data

1H NMR: (400 MHz, CDCl3) δ 8.08 (dd, J = 4.3, 3.3 Hz, 2H), 7.90 (d, J = 8.4 Hz, 1H), 7.79 – 7.73 (m, 1H), 7.47 (d, J = 4.9 Hz, 1H), 7.43 (d, J = 7.1 Hz, 1H), 7.17 – 7.13 (m, 1H), 4.22 (s, 3H).

 13C NMR: (126 MHz, CDCl3) δ 166.87, 156.80, 151.66, 144.15, 133.64, 129.62, 128.97, 128.10, 127.52, 126.16, 123.53, 115.16, 54.21

 IR (CHCl3) 3104, 2937, 1619, 1575, 1563, 1497, 1456, 1425, 1376 cm-1

 ESI-MS: m/z 243 (M + 1)+; HRMS: m/z 243.0590 calcd for C13H10N2OS + H+ (243.0592).

Lead Reference

S. Battula, R. A. Vishwakarma, and Q. N. Ahmed. Synthesis Of 4-Methoxy-2-(Thiophene-2yl)-quinazoline by Cu-Benzotriazole catalyzed Electrophilic intramolecular cyclization of N-arylimines; RSC Adv. 2014, 4, 38375-38378.

https://doi.org/10.1039/C4RA07377K

Other References

(1)   M. Joshi, R. Tiwari and A. K. Verma, Org. Lett., 2012, 14, 1106–1109

https://doi.org/10.1021/ol203491p

 (2)    J. Sun, D.-D. Li, J.-R. Li, F. Fang, Q.-R. Du, Y. Qian and H.-L. Zhu, Org. Biomol.     Chem., 2013, 11, 7676-7686.

https://doi.org/10.1039/C3OB41136B

 (3)   J. P. Michael, Nat. Prod. Rep., 2008, 25, 166

https://doi.org/10.1039/B612168N

Supplementary Information

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Keywords: 4-Oxyquinazoline, Anti-cancer, Cu-Benzotriazole, heterocyclic compounds, substitution