Intramolecular Cyclization of Vinyldiazoacetates as a Versatile Route to Substituted Pyrazoles

In memory of Prof. Dr. Ludwig Knorr, professor at Friedrich-Schiller-University Jena (1889–1921)

Abstract

Vinyldiazo compounds undergo a thermal electrocyclization to form pyrazoles in yields of up to 95%. The reactions are operationally simple, use readily available starting materials, require no intervention of a catalyst, and enable the synthesis of mono-, di- and tri-substituted pyrazoles. With the ability to produce highly substituted pyrazoles and the flexibility in installing various types of substituents, this method constitutes a new entry to this valuable heterocyclic scaffold and may be of interest to all branches of the chemical industry.

Key words

pyrazoles - vinyldiazoacetates - vinyldiazo compounds - cyclization - electrocyclization

• References and Notes

• 1 Knorr L. Ber. Dtsch. Chem. Ges. 1883; 16: 2597
• 2a Liu J.-J, Zhao M.-y, Zhang X, Zhao X, Zhu H.-L. Mini-Rev. Med. Chem. 2013; 13: 1957
• 2b Czarnomysy R, Surażyński A, Muszynska A, Gornowicz A, Bielawska A, Bielawski K. J. Enzyme Inhib. Med. Chem. 2018; 33: 1006
• 2c Hura N, Naaz A, Prassanawar SS, Guchhait KS, Panda D. ACS Omega 2018; 3: 1955
• 2d Karrouchi K, Radi S, Ramli Y, Taoufik J, Mabkhot YN, Al-aizari FA, Ansar M. Molecules 2018; 23: 134
• 3a Kidwai M, Jain A, Poddar R. J. Organomet. Chem. 2011; 696: 1939
• 3b Vaddula RB, Varma SR, Leazer J. Tetrahedron Lett. 2013; 54: 1538
• 3c Venkateswarlu V, Kour J, Kumar KA. A, Verma KP, Reddy LG, Hussain Y, Tabassum A, Balgotra S, Gupta S, Hudwekar DA, Vishwakarma AR, Sawant DS. RSC Adv. 2018; 8: 26523
• 3d Wang H, Sun X, Zhang S, Liu G, Wang C, Zhu L, Zhang H. Synlett 2018; 29: 2689
• 3e Yang G.-P, He X, Yu B, Hu C.-W. Appl. Organomet. Chem. 2018; 32: e4532
• 4a Kumar V, Kaur K, Gupta KG, Sharma KA. Eur. J. Med. Chem. 2013; 69: 735
• 4b Pizzuti L, Barschak GA, Stefanello MF, Farias DM, Lencina C, Roesch-Ely M, Cunico W, Moura S, Pereira CM. P. Curr. Org. Chem. 2014; 18: 115
• 4c Ansari A, Ali A, Asif M. Shamsuzzaman, New J. Chem. 2017; 41: 16
• 5a Chen B, Zhu C, Tang Y, Ma S. Chem. Commun. 2014; 50: 7677
• 5b Pires SC, de Oliveira DH, Pontel MR. B, Kazmierczak CJ, Cargnelutti R, Alves D, Jacob GR, Schumacher FR. Beilstein J. Org. Chem. 2018; 14: 2789
• 5c Preeti, Singh NK. Org. Biomol. Chem. 2018; 16: 9084
• 5d Mamaghani M, Nia RH. Polycyclic Aromat. Compd. 2019; 1
• 6a Aggarwal KV, de Vicente J, Bonnert VR. J. Org. Chem. 2003; 68: 5381
• 6b Vuluga D, Legros J, Crousse B, Bonnet-Delpon D. Green Chem. 2009; 11: 156
• 6c Pramanik MM. D, Kant R, Rastogi N. Tetrahedron 2014; 70: 5214
• 7a Chandanshive ZJ, Bonini FB, Gentili D, Fochi M, Bernardi L, Franchini CM. Eur. J. Org. Chem. 2010; 6440
• 7b Voronin VV, Ledovskaya SM, Gordeev GE, Rodygin SK, Ananikov PV. J. Org. Chem. 2018; 83: 3819
• 7c Yavari I, Taheri Z, Naeimabadi M, Bahemmat S, Halvagar RM. Synlett 2018; 29: 918
• 8a Nájera C, Sansano MJ, Yus M. Org. Biomol. Chem. 2015; 13: 8596
• 8b Bakthadoss M, Agarwal V. ChemistrySelect 2018; 3: 6960
• 9a Brewbaker LJ, Hart H. J. Am. Chem. Soc. 1969; 91: 711
• 9b Padwa A, Kulkarni SY, Zhang Z. J. Org. Chem. 1990; 55: 4144
• 9c Supurgibekov BM, Cantillo D, Kappe OC, Surya Prakash GK, Nikolaev AV. Org. Biomol. Chem. 2014; 12: 682
• 9d O’Connor NR, Bolgar P, Stoltz MB. Tetrahedron Lett. 2016; 57: 849
• 9e Bien J, Davulcu A, DelMonte AJ, Fraunhoffer JK, Gao Z, Hang C, Hsiao Y, Hu W, Katipally K, Littke A, Pedro A, Qiu Y, Sandoval M, Schild R, Soltani M, Tedesco A, Vanyo D, Vemishetti P, Waltermire ER. Org. Process Res. Dev. 2018; 22: 1393
• 10a Ito K, Maruyama J. Heterocycles 1984; 22: 1057
• 10b Ito K, Maruyama J. J. Heterocycl. Chem. 1988; 25: 1681
• 10c Davies HM. L, Hougland WP, Cantrell WR. Jr. Synth. Commun. 1992; 22: 971
• 10d Antos MJ, Francis BM. J. Am. Chem. Soc. 2004; 126: 10256
• 10e Qian Y, Xu X, Wang X, Zavalij JP, Hu W, Doyle PM. Angew. Chem. Int. Ed. 2012; 51: 1
• 10f Cui S, Zhang Y, Wang D, Wu Q. Chem. Sci. 2013; 4: 3912
• 10g Supurgibekov BM, Prakash GK. S, Nikolaev AV. Synthesis 2013; 45: 1215
• 10h Guo H, Zhang D, Zhu C, Li J, Xu G, Sun J. Org. Lett. 2014; 16: 3110
• 10i Deng Y, Jing C, Doyle PM. Chem. Commun. 2015; 51: 12924
• 10j Xu G, Zhu C, Gu W, Li J, Sun J. Angew. Chem. Int. Ed. 2015; 54: 883
• 10k Martin CS, Vohidov F, Wang H, Knudsen ES, Marzec AA, Ball TZ. Bioconjugate Chem. 2017; 28: 659
• 10l Roizen LJ, Jones CA, Smith CR, Virgil CS, Stoltz MB. J. Org. Chem. 2017; 82: 13051
• 10m Zhao M.-N, Zhang M.-N, Ren Z.-H, Wang Y.-Y, Guan Z.-H. Sci. Bull. 2017; 62: 493
• 10n Craig AR, Smith CR, Roizen LJ, Jones CA, Virgil CS, Stoltz MB. J. Org. Chem. 2018; 83: 3467
• 10o Zhang X, Zheng Y, Qiu L, Xu X. Org. Biomol. Chem. 2018; 16: 70
• 11 Drikermann D, Mößel SR, Al-Jammal WK, Vilotijevic I. Org. Lett. 2020; 22: 1091
• 12a Miyamoto T, Matsumoto J. Chem. Pharm. Bull. 1988; 36: 1321
• 12b Miyamoto T, Matsumoto J. Chem. Pharm. Bull. 1990; 38: 3211
• 12c Nikolaev AV, Zakharova MV, Hennig L, Sieler J. J. Fluorine Chem. 2007; 128: 507
• 12d Supurgibekov BM, Zakharova MV, Sieler J, Nikolaev AV. Tetrahedron Lett. 2011; 52: 341
• 12e Bel Abed H, Mammoliti O, Bande O, Van Lommen G, Herdewijn P. J. Org. Chem. 2013; 78: 7845
• 12f Nikolaev AV, Cantillo D, Kappe OC, Medvedev JJ, Prakash GK. S, Supurgibekov BM. Chem. Eur. J. 2016; 22: 174
• 12g Moslin R, Zhang Y, Wrobleski TS, Lin S, Mertzman M, Spergel S, Tokarski SJ, Strnad J, Gillooly K, McIntyre KW, Zupa-Fernandez A, Cheng L, Sun H, Chaudhry C, Huang C, D’Arienzo C, Heimrich E, Yang X, Muckelbauer KJ, Chang C, Tredup J, Mulligan D, Xie D, Aranibar N, Chiney M, Burke RJ, Lombardo L, Carter HP, Weinstein SD. J. Med. Chem. 2019; 62: 8953
• 13 Pavlyuk O, Teller H, McMills MC. Tetrahedron Lett. 2009; 50: 2716
• 14 Ye F, Qu S, Zhou L, Peng C, Wang C, Cheng J, Hossain LM, Liu Y, Zhang Y, Wang Z.-X, Wang J. J. Am. Chem. Soc. 2015; 137: 4435
• 15 Green PS, Wheelhouse MK, Payne DA, Hallett PJ, Miller WP, Bull AJ. Org. Process Res. Dev. 2020; 24: 67
• 16 Methyl 5-Phenyl-1H-pyrazole-3-carboxylate (2a); Typical Procedure A mixture of cinnamic alcohol (3.35 g, 25.0 mmol, 1.00 equiv), formic acid (2.83 mL, 75.0 mmol, 3.00 equiv), acetic anhydride (7.09 mL, 75.0 mmol, 3.00 equiv), tris(dibenzylideneacetone)dipalladium(0) (114 mg, 0.5 mol%) and Xantphos (289 mg, 2.0 mol%) was suspended in toluene (15 mL) and heated to 80 °C for 12 h.¹⁷ The mixture was filtered through a short pad of silica and washed with ethyl acetate. The volatiles were removed under reduced pressure to give a crude product. The product could be purified by column chromatography (dry loading, 10–20% v/v ethyl acetate/petroleum ether) and isolated as a yellow solid (3.45 g, 85% yield). A suspension of the crude carboxylic acid from the previous step (3.00 g, 18.5 mmol, 1.00 equiv), Cs₂CO₃ (3.01 g, 9.25 mmol, 0.50 equiv) and MeI (2.30 mL, 37.0 mmol, 2.00 equiv) in acetone (150 mL) was heated at 80 °C for 3 h.^[18] Silica gel was added and the solvent was evaporated. After column chromatography purification (dry loading, 5–20% v/v ethyl acetate/petroleum ether), methyl (E)-4-phenylbut-3-enoate (3a) was isolated as a yellow oil (2.29 g, 70% yield). To a solution of p-ABSA (4.09 g, 17.0 mmol, 1.50 equiv) and ester 3a (2.00 g, 11.3 mmol, 1.00 equiv) in dry acetonitrile (0.10 M) at 0 °C under a N₂ atmosphere was slowly added DBU (3.37 mL, 22.6 mmol, 2.00 equiv) over a period of 30 min. After the addition was complete, the mixture was allowed to warm to RT overnight and then quenched by addition of sat. NH₄Cl solution. The aqueous layer was extracted with ethyl acetate (3 × 150 mL), and the combined organic phase was dried over MgSO₄, concentrated and the crude residue purified by column chromatography (5–20% v/v ethyl acetate/petroleum ether) to give methyl (E)-2-diazo-4-phenylbut-3-enoate (1a) as a dark red oil (2.29 g, 72% yield).^[13] A solution of vinyldiazo compound 1a (101 mg, 0.50 mmol, 1.00 equiv) in benzotrifluoride (0.42 mL, 1.20 M) was heated to reflux until complete consumption of the vinyldiazo compound was observed (<10 min). Silica gel was then added and the solvent was evaporated. The product was purified by column chromatography (dry loading, 50–70% v/v ethyl acetate/petroleum ether) and pyrazole 2a was isolated as an off-white solid (95.2 mg, 94%). The analytical data matched with the literature.^{[10d] 1}H NMR (250 MHz, CDCl₃): δ = 7.89–7.76 (m, 2 H), 7.51–7.37 (m, 3 H), 7.14 (s, 1 H), 3.97 (s, 3 H).
• 17 Fu M.-C, Shang R, Cheng W.-M, Fu Y. Chem. Eur. J. 2017; 23: 8818
• 18 Eissler S, Nahrwold M, Neumann B, Stammler H.-G, Sewald N. Org. Lett. 2007; 9: 817