An Efficient Protocol for the Synthesis of Pyrazolo[1,5-c]quinazolines by a Staudinger–Aza-Wittig–Dehydroaromatization Sequence

Abstract

The one-pot synthesis of azide-substituted dihydropyrazoles in isopropanol was performed by using chalcones, hydrazine hydrate, and an acyl chloride at 0 ℃. Subsequent Staudinger–aza-Wittig–dehydroaromatization reactions of the products with methyl(diphenyl)phosphine were also investigated for further application in the construction of pyrazolo[1,5-c]quinazolines.

Key words

azidodihydropyrazoles - aza-Wittig reaction - Staudinger reaction - cascade reaction - dehydroaromatization - pyrazoloquinazolines

Publication History

Received: 14 July 2021

Accepted after revision: 05 August 2021

Accepted Manuscript online:
05 August 2021

Article published online:
18 August 2021

• References and Notes

• 1 Garg M, Chauhan M, Singh PK, Alex JM, Kumar R. Eur. J. Med. Chem. 2015; 97: 444
• 2a Traquandi G, Ciomei M, Ballinari D, Casale E, Colombo N, Croci V, Fiorentini F, Isacchi A, Longo A, Mercurio C, Panzeri A, Pastori W, Pevarello P, Volpi D, Roussel P, Vulpetti A, Brasca MG. J. Med. Chem. 2010; 53: 2171
• 2b Brasca MG, Amboldi N, Ballinari D, Cameron A, Casale E, Cervi G, Colombo M, Colotta F, Croci V, D’Alessio R, Fiorentini F, Isacchi A, Mercurio C, Moretti W, Panzeri A, Pastori W, Pevarello P, Quartieri F, Roletto F, Traquandi G, Vianello P, Vulpetti A, Ciomei M. J. Med. Chem. 2009; 52: 5152
• 2c Beria I, Ballinari D, Bertrand JA, Borghi D, Bossi RT, Brasca MG, Cappella P, Caruso M, Ceccarelli W, Ciavolella A, Cristiani C, Croci V, De Ponti A, Fachin G, Ferguson RD, Lansen J, Moll JK, Pesenti E, Posteri H, Perego R, Rocchetti M, Storici P, Volpi D, Valsasina B. J. Med. Chem. 2010; 53: 3532
• 2d Colquhoun A, Lawrance GM, Shamovsky IL, Riopelle RJ, Ross GM. J. Pharmacol. Exp. Ther. 2004; 310: 505
• 2e Orvieto F, Branca D, Giomini C, Jones P, Koch U, Ontoria JM, Palumbi MC, Rowley M, Toniatti C, Muraglia E. Bioorg. Med. Chem. Lett. 2009; 19: 4196
• 2f Nagarajan S, Skoufias DA, Kozielski F, Pae AN. J. Med. Chem. 2012; 55: 2561
• 2g Kumar D, Kaur G, Negi A, Kumar S, Singh S, Kumar R. Bioorg. Chem. 2014; 57: 57

For recent reviews, see:
• 3a Li M, Zhao B.-X. Eur. J. Med. Chem. 2014; 85: 311
• 3b Jiang X, Wei X, Lin F, Zhang Z, Yao G, Yang S, Zhao W, Zhao C, Xu H. Eur. J. Org. Chem. 2020; 2020: 3997
• 3c Metwally NH, Mohamed MS. Synth. Commun. 2018; 48: 721
• 4 Beaulieu F, Ouellet C, Ruediger EH, Belema M, Qiu Y, Yang X, Banville J, Burke JR, Gregor KR, MacMaster JF, Martel A, McIntyre KW, Pattoli MA, Zusi FC, Vyas D. Bioorg. Med. Chem. Lett. 2007; 17: 1233
• 5 Varano F, Catarzi D, Colotta V, Lenzi O, Filacchioni G, Galli A, Costagli C. Bioorg. Med. Chem. 2008; 16: 2617
• 6 Varano F, Catarzi D, Colotta V, Filacchioni G, Galli A, Costagli C, Carlà V. J. Med. Chem. 2002; 45: 1035
• 7 Colotta V, Catarzi D, Varano F, Filacchioni G, Cecchi L, Galli A, Costagli C. J. Med. Chem. 1996; 39: 2915
• 8 Asproni B, Murineddu G, Pau A, Pinna GA, Langgård M, Christoffersen CT, Nielsen J, Kehler J. Bioorg. Med. Chem. 2011; 19: 642
• 9 Sawant DM, Sharma S, Pathare RS, Joshi G, Kalra S, Sukanya S, Maurya AK, Metre RK, Agnihotri VK, Khan S, Kumar R, Pardasani RT. Chem. Commun. 2018; 54: 11530
• 10 Catarzi D, Colotta V, Varano F, Poli D, Squarcialupi L, Filacchioni G, Varani K, Vincenzi F, Borea PA, Dal Ben D, Lambertucci C, Cristalli G. Bioorg. Med. Chem. 2013; 21: 283
• 11a Augusti R, Kascheres C. J. Org. Chem. 1993; 58: 7079
• 11b Varano F, Catarzi D, Colotta V, Calabri FR, Lenzi O, Filacchioni G, Galli A, Costagli C, Deflorian F, Moro S. Bioorg. Med. Chem. 2005; 13: 5536
• 11c Gupta AK, Ahamad S, Gupta E, Kant R, Mohanan K. Org. Biomol. Chem. 2015; 13: 9783
• 11d Tang H.-T, Xiong K, Li R.-H, Ding Z.-C, Zhan Z.-P. Org. Lett. 2015; 17: 326
• 11e Liu L, Li L, Mao S, Wang X, Zhou M.-D, Zhao Y.-l, Wang H. Chem. Commun. 2020; 56: 7665
• 11f Chen Q, Li K, Lu T, Zhou Q. RSC Adv. 2016; 6: 24792
• 11g Ramu G, Tangella Y, Ambala S, Nagendra Babu B. J. Org. Chem. 2020; 85: 5370
• 12a Kumar D, Kumar R. Tetrahedron Lett. 2014; 55: 2679
• 12b McQuaid LA, Smith EC. R, South KK, Mitch CH, Schoepp DD, True RA, Calligaro DO, O’Malley PJ, Lodge D, Ornstein PL. J. Med. Chem. 1992; 35: 3319
• 13a Yang X, Jin Y, Liu H, Jiang Y, Fu H. RSC Adv. 2012; 2: 11061
• 13b Guo S, Wang J, Fan X, Zhang X, Guo D. J. Org. Chem. 2013; 78: 3262
• 13c Liu Q, Yang H, Jiang Y, Zhao Y, Fu H. RSC Adv. 2013; 3: 15636
• 14a Wang T, Shao A, Feng H, Yang S, Gao M, Tian J, Lei A. Tetrahedron 2015; 71: 4473
• 14b Feng H, Wang T, Chen S, Huang Y, Yu W, Huang Y, Xiong F. RSC Adv. 2016; 6: 95774
• 14c Fetter J, Lempert K, Møller J. Tetrahedron 1975; 31: 2559
• 15a Yu Y.-F, Zhang C, Huang Y.-Y, Zhang S, Zhou Q, Li X, Lai Z, Li Z, Gao Y, Wu Y, Guo L, Wu D, Luo H.-B. ACS Chem. Neurosci. 2020; 11: 1058
• 15b Wu Y, Tian Y.-J, Le M.-L, Zhang S.-R, Zhang C, Huang M.-X, Jiang M.-Y, Zhang B, Luo H.-B. J. Med. Chem. 2020; 63: 7867
• 16a Mathuber M, Schueffl H, Dömötör O, Karnthaler C, Enyedy ÉA, Heffeter P, Keppler BK, Kowol CR. Inorg. Chem. 2020; 59: 17794
• 16b Parveen S, Alnoman RB, Hagar M, Ahmed HA, Knight JG. ChemistrySelect 2020; 5: 13163
• 16c Jang J, To C, De Clercq DJ. H, Park E, Ponthier CM, Shin BH, Mushajiang M, Nowak RP, Fischer ES, Eck MJ, Jänne PA, Gray NS. Angew. Chem. Int. Ed. 2020; 59: 14481
• 16d Lin C, Ren Z, Yang X, Yang R, Chen Y, Liu Z, Dai Z, Zhang Y, He Y, Zhang C, Wang X, Cao W, Ji T. Cancer Lett. 2020; 472: 81
• 16e Fernandes Neto JM, Nadal E, Bosdriesz E, Ooft SN, Farre L, McLean C, Klarenbeek S, Jurgens A, Hagen H, Wang L, Felip E, Martinez-Marti A, Vidal A, Voest E, Wessels LF. A, van Tellingen O, Villanueva A, Bernards R. Nat. Commun. 2020; 11: 3157
• 17a Liu Y, Jiao Y, Luo H, Huang N, Lai M, Zou K, Yao H. ACS Catal. 2021; 5287
• 17b Wang Y, Yao H, Hua M, Jiao Y, He H, Liu M, Huang N, Zou K. J. Org. Chem. 2020; 85: 7485
• 17c You C, Zhang Z, Tu Y, Tang H, Wang Y, Long D, Zhao J. J. Org. Chem. 2020; 85: 3902
• 17d Wang K, Jiang C, Zhang Z, Han C, Wang X, Li Y, Chen K, Zhao J. Chem. Commun. 2020; 56: 12817
• 17e Ren Z.-L, Cai S, Liu Y.-Y, Xie Y.-Q, Yuan D, Lei M, He P, Wang L. J. Org. Chem. 2020; 85: 11014
• 18a Palacios F, Alonso C, Aparicio D, Rubiales G, de los Santos JM. Tetrahedron 2007; 63: 523
• 18b Ren Z.-L, Lu W.-T, Cai S, Xiao M.-M, Yuan Y.-F, He P, Ding M.-W. J. Org. Chem. 2019; 84: 14911
• 18c Cai L, Zhang K, Chen S, Lepage RJ, Houk KN, Krenske EH, Kwon O. J. Am. Chem. Soc. 2019; 141: 9537
• 18d Zhang X, Ma X, Qiu W, Evans J, Zhang W. Green Chem. 2019; 21: 349
• 18e Sun M, Yu Y.-L, Zhao L, Ding M.-W. Tetrahedron 2021; 80: 131868
• 18f Sun M, Zhao L, Yu Y.-L, Ding M.-W. Synthesis 2021; 53: 1365
• 18g Pedrood K, Nazari Montazer M, Larijani B, Mahdavi M. Synthesis 2021; 53: 2342
• 18h Jayaram V, Sridhar T, Sharma GV. M, Berrée F, Carboni B. J. Org. Chem. 2018; 83: 843
• 19a Zou F, Pei F, Wang L, Ren Z, Cheng X, Sun Y, Wu J, He P. Synlett 2019; 30: 717
• 19b Wei J, Nie B.-J, Peng R, Cheng X.-H, Wang S, He P. Synlett 2016; 27: 626
• 19c He P, Nie Y.-B, Wu J, Ding M.-W. Org. Biomol. Chem. 2011; 9: 1429
• 19d Qu F, Hu R.-F, Gao L, Wu J, Cheng X.-H, Wang S, He P. Synthesis 2015; 47: 3701
• 20a Kaplancikli ZA, Turan-Zitouni G, Özdemir A, Can ÖD, Chevallet P. Eur. J. Med. Chem. 2009; 44: 2606
• 20b Zhang Y.-L, Li B.-Y, Yang R, Xia L.-Y, Fan A-L, Chu Y.-C, Wang L.-J, Wang Z.-C, Jiang A.-Q, Zhu H.-L. Eur. J. Med. Chem. 2019; 163: 896
• 21a Yang Y.-S, Li Q.-S, Sun S, Zhang Y.-B, Wang X.-L, Zhang F, Tang J.-F, Zhu H.-L. Bioorg. Med. Chem. 2012; 20: 6048
• 21b Raghav N, Singh M. Bioorg. Med. Chem. 2014; 22: 4233
• 22 For proposed intermediates condensed from hydrazine and chalcones, see: Dhakshinamoorthy A, Alvaro M, Garcia H. Adv. Synth. Catal. 2009; 351: 2271
• 23 1-Acyl-5-(2-azidophenyl)-4,5-dihydropyrazoles 4a–p: General Procedure Hydrazine hydrate (2; 3 mmol) was added to a stirred solution of the appropriate azidochalcone 1 (3 mmol) in i-PrOH (10 mL) at 0 °C, and the mixture was vigorously stirred until the reaction was complete (TLC). Acyl chloride 3 (3.3 mmol) was then added dropwise and the mixture was allowed to warm to r.t. The precipitated solid was collected, washed with EtOH, and crystallized from CH₂Cl₂–PE. 5-(2-Azidophenyl)-1-(4-chlorobenzoyl)-3-phenyl-4,5-dihydro-1H-pyrazole (4a) White crystals; yield: 1095 mg (91%); mp 164–165 ℃. IR (KBr): 3387, 2927, 2858, 2129, 1639, 1597, 1489, 1423, 1284, 1087, 748 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.03 (d, J = 8.4 Hz, 2 H, Ar-H), 7.70–7.68 (m, 2 H, Ar-H), 7.44–7.39 (m, 5 H, Ar-H), 7.34–7.30 (m, 1 H, Ar-H), 7.22–7.17 (m, 2 H, Ar-H), 7.11–7.07 (m, 1 H, Ar-H), 5.98 (q, J = 5.6 Hz, 1 H, Ar-CH), 3.79 (dd, J₁ = 11.6, J₂ = 17.6 Hz, 1 H, CH), 3.08 (dd, J₁ = 5.6, J₂ = 17.6 Hz, 1 H, CH). ¹³C NMR (100 MHz, CDCl₃): δ = 165.1, 155.4, 137.2, 136.7, 132.5, 132.0, 131.7, 131.1, 130.5, 128.9, 128.7, 127.9, 126.7, 126.2, 125.2, 118.6, 57.2, 40.8. LC-MS: m/z = 401. Anal. Calcd for C₂₂H₁₆ClN₅O: C, 65.76; H, 4.01; N, 17.43. Found: C, 65.79; H, 4.05; N, 17.40.
• 24a Alajarín M, Molina P, Vidal Á, Tovar F. Synlett 1998; 1288
• 24b Kumagai N, Matsunaga S, Shibasaki M. Angew. Chem. Int. Ed. 2004; 43: 478
• 24c Zhong Y, Wang L, Ding M.-W. Tetrahedron 2011; 67: 3714
• 25 Pyrazolo[1,5-c]quinazolines 8; General Procedure A solution of methyl(diphenyl)phosphine (0.20 g, 1 mmol) in toluene (5 mL) was added dropwise to a stirred solution of the appropriate 1-acyl-5-(2-azidophenyl)-4,5-dihydropyrazole 4 (1 mmol) in toluene (5 mL) at r.t. The mixture was stirred at r.t. for 2 h and then refluxed for 1–6 h until the reaction was complete (TLC). The solvent was then removed under reduced pressure, and the residue was crystallized from CH₂Cl₂–PE. 2-(4-Chlorophenyl)-5-phenylpyrazolo[1,5-c]quinazoline (8a) White crystals; yield: 305 mg (86%); mp 171–172 ℃. IR (KBr): 3431, 1618, 1610, 1490, 1436, 1402, 1367, 1282, 1180, 1091, 943, 825, 746, 682, 597, 557 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.56–8.54 (m, 2 H, Ar-H), 8.10–7.99 (m, 4 H, Ar-H), 7.70–7.41 (m, 7 H, Ar-H), 7.36 (s, 1 H, Ar-H). ¹³C NMR (100 MHz, CDCl₃): δ = 154.8, 146.3, 141.9, 139.9, 137.1, 132.3, 132.1, 131.2, 129.9, 129.2, 128.8, 128.7, 128.4, 127.8, 126.8, 123.0, 119.5, 95.3. LC-MS: m/z = 355. Anal. Calcd for C₂₂H₁₄ClN₃: C, 74.26; H, 3.97; N, 11.81. Found: C, 74.29; H, 3.91; N, 11.88.