Iron(III) Chloride Catalyzed Nucleophilic Substitution of Tertiary Propargylic Alcohols and Synthesis of Iodo-3H-Pyrazoles

Abstract

A straightforward and concise method was developed for the efficient and rapid synthesis of iodo-3H-pyrazoles by the FeCl₃/I₂-mediated propargylic substitution of tertiary propargylic alcohols with p-toluenesulfonyl hydrazide and subsequent cyclization under mild conditions. The method constitutes a novel approach to the synthesis of various iodo-3H-pyrazoles with a wide substrate scope and in high yields.

Key words

propargylic alcohols - tosyl hydrazide - iodopyrazoles - cyclization - iodination

• References and Notes

• 1a Hao L, Zhan Z.-P. Curr. Org. Chem. 2011; 15: 1625
• 1b Ding C.-H, Hou X.-L. Chem. Rev. 2011; 111: 1914
• 1c Ljungdahl N, Kann N. Angew. Chem. Int. Ed. 2009; 48: 642
• 1d Detz R, Hiemstra H, van Maarseveen JH. Eur. J. Org. Chem. 2009; 6263
• 2a Guillena G, Ramón D, Yus M. Chem. Rev. 2010; 110: 1611
• 2b Debleds O, Gayon E, Ostaszuk E, Vrancken E, Campagne J.-M. Chem. Eur. J. 2010; 16: 12207
• 2c Kabelka GW, Yao M.-L. Curr. Org. Synth. 2008; 5: 28
• 2d Bandini M, Tragni M. Org. Biomol. Chem. 2009; 7: 1501
• 2e Wang X, Li S.-y, Pan Y.-m, Wang H.-s, Liang H, Chen Z.-f, Qin X.-h. Org. Lett. 2014; 16: 580
• 2f Zhu Y, Yin G, Hong D, Lu P, Wang Y. Org. Lett. 2011; 13: 1024
• 2g Bauer EI. Synthesis 2012; 44: 1131
• 2h Yin G, Zhu Y, Zhang L, Lu P, Wang Y. Org. Lett. 2011; 13: 940
• 2i Chatterjee P, Roy S. J. Org. Chem. 2010; 75: 4413
• 2j Yan W, Wang Q, Chen Y, Petersen J, Shi X. Org. Lett. 2010; 12: 3308
• 2k Fang Z, Liu J, Liu Q, Bi X. Angew. Chem. Int. Ed. 2014; 53: 7209
• 2l Yoshimatsu M, Watanabe H, Koketsu E. Org. Lett. 2010; 12: 4192
• 2m Fang C, Pang Y, Forsyth C. Org. Lett. 2010; 12: 4528
• 2n Sanz R, Miguel D, Martínez A, Álvarez-Gutiérrez JM, Rodríguez F. Org. Lett. 2007; 9: 727
• 2o Zhan Z.-p, Yang W.-z, Yang R.-f, Yu J.-l, Li J.-p, Liu H.-j. Chem. Commun. 2006; 3352

For selected examples of the use of secondary propargyl alcohols and hydrazines as nucleophiles, see:
• 3a Xu S.-X, Hao L, Wang T, Ding Z.-C, Zhan Z.-P. Org. Biomol. Chem. 2013; 11: 294
• 3b Reddy C, Vijaykumar J, Grée R. Synthesis 2013; 45: 830
• 4a Elguero J, Goya P, Jagerovic N, Silva AM. S In Targets in Heterocyclic Systems: Chemistry and Properties . Vol. 6. Attanasi OA, Spinelli D. RSC; Cambridge: 2002: 52
• 4b Kiyokawa K, Ito Y, Kakehi R, Ogawa T, Goto Y, Yoshimatsu M. Eur. J. Org. Chem. 2016; 4998
• 5 Yoshimatsu M, Ohta K, Takahashi N. Chem. Eur. J. 2012; 18: 15602
• 6a Wen J.-J, Zhu Y, Zhan Z.-P. Asian J. Org. Chem. 2012; 1: 108
• 6b Wang T, Chen X.-l, Chen L, Zhan Z.-p. Org. Lett. 2011; 13: 3324
• 6c Liu X.-t, Huang L, Zheng F.-j, Zhan Z.-p. Adv. Synth. Catal. 2008; 350: 2778
• 6d Pan Y.-m, Zheng F.-j, Lin H.-x, Zhan Z.-p. J. Org. Chem. 2009; 74: 3148
• 6e Gao X, Pan Y.-m, Lin M, Chen L, Zhan Z.-p. Org. Biomol. Chem. 2010; 8: 3259
• 6f Hao L, Pan Y, Wang T, Lin M, Chen L, Zhan Z.-p. Adv. Synth. Catal. 2010; 352: 3215
• 6g Zhan Z.-p, Yu J.-l, Liu H.-j, Cui Y.-y, Yang R.-f, Yang W-z, Li J.-p. J. Org. Chem. 2006; 71: 8298
• 7 Hao L, Wu F, Ding Z.-C, Xu S.-X, Ma Y.-L, Chen L, Zhan Z.-p. Chem. Eur. J. 2012; 18: 6453
• 8 Hao L, Hong J.-J, Zhu J, Zhan Z.-p. Chem. Eur. J. 2013; 19: 5715
• 9 Liu W, Wang H, Zhao H, Li B, Chen S. Synlett 2015; 26: 2170
• 10a Closs GL, Boll WA. J. Am. Chem. Soc. 1963; 85: 3904
• 10b Hamdi N, Dixneuf PH, Arfaoui Y, Haloui E. J. Chem. Res. 2005; 289
• 10c Hamdi N, Lachheb J, Msaddek M. J. Soc. Alger. Chim. 2007; 17: 37
• 10d Anet R, Anet FA. L. J. Am. Chem. Soc. 1964; 86: 525
• 10e Padwa A, Wannamaker MW, Dyszlewski AD. J. Org. Chem. 1987; 52: 4760
• 10f Mataka S, Ohshima T, Tashiro M. J. Org. Chem. 1981; 46: 3960
• 10g Jefferson EA, Warkentin J. J. Org. Chem. 1994; 59: 455
• 10h Franck-Neumann M. Angew. Chem. Int. Ed. 1967; 6: 79
• 10i Rigby JH, Kierkus PC. J. Am. Chem. Soc. 1989; 111: 4125
• 10j Merchant RR, Allwood DM, Blakemore DC, Ley SV. J. Org. Chem. 2014; 79: 8800
• 11a Moritani I, Hosokawa T, Obata N. J. Org. Chem. 1969; 34: 670
• 11b Wenkert E, McPherson CA. J. Am. Chem. Soc. 1972; 94: 8084
• 11c Pyron RS, Jones WM. J. Org. Chem. 1967; 32: 4048
• 11d Zimmerman HE, Hovey MC. J. Org. Chem. 1979; 44: 2331
• 12 N′-(1,1-Dimethyl-3-phenylprop-2-yn-1-yl)-4-toluenesulfonohydrazide (3a); Typical Procedure TsNHNH₂ (2; 129.5mg, 0.75 mmol), propargylic alcohol 1a (80 mg, 0.5 mmol), and FeCl₃ (8.1 mg, 0.05 mmol) were added to a 10 mL round-bottomed flask. MeNO₂ (5 mL) was added, and the mixture was stirred in air at r.t. until the reaction was complete (TLC). The solvent was removed under vacuum, and the crude residue was purified by column chromatography on silica gel to give a white solid; yield: 156 mg (95%); mp 117–119 °C. IR (film): 3461, 3130, 2180, 1598, 1499 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.29 (s, 6 H), 2.41 (s, 3 H), 3.67 (s, 1 H), 6.15 (s, 1 H), 7.26–7.38 (m, 7 H), 7.82 (d, J = 8.0 Hz, 2 H). ¹³C NMR (100 MHz, CDCl3): δ = 21.5, 27.0, 53.2, 83.3, 91.7, 122.4, 128.2, 128.3, 128.3, 129.3, 131.7, 135.3, 143.8. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₈H₂₁N₂O₂S: 329.1318; found: 329.1320. 4-Iodo-3,3-dimethyl-5-phenyl-3H-pyrazole (4a) Propargyl hydrazide 3a (164 mg, 0.5 mmol), I₂ (381 mg, 1.5 mmol), and NaHCO₃ (126 mg, 1.5 mmol) were added to a 10 mL round-bottomed flask. MeCN (5 mL) was added, and the mixture was stirred at r.t. in air until the reaction was complete (TLC). Sat. aq Na₂S₂O₃ was added to quench the reaction, and the mixture was diluted with H₂O (10 mL). The aqueous phase was extracted with EtOAc (3 × 10 mL). The combined organic layers were dried (Na₂SO₄), the solvent was removed under vacuum, and the crude residue was purified by column chromatography (silica gel) to give a yellow solid; yield: 140 mg (94%); mp 138–140 °C. IR (film): 3102, 1597, 1489 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.47 (s, 6 H), 7.47–7.53 (m, 3 H), 8.26–8.28 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 21.3, 97.5, 111.3, 128.2, 128.5, 129.5, 130.6, 154.0. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₁H₁₂IN₂: 299.0040; found: 299.0042.