Synlett, Table of Contents Synlett 2024; 35(20): 2459-2464DOI: 10.1055/a-2422-1263 letter Special Issue to Celebrate the 75th Birthday of Prof. B. C. Ranu Lewis Acid Catalyzed Domino Ring-Opening Cyclization of Azetidines with Alkynes: Synthesis of Tetrahydropyridines Authors Dipti Shukla Shishir Singh Amit Kumar Sharma Bharat Singh Aditya Bhattacharyya Ranadeep Talukdar Manas K. Ghorai ∗ Recommend Article Abstract Buy Article(opens in new window) All articles of this category(opens in new window) Dedicated to Prof. B. C. Ranu on the occasion of his 75th birthday Abstract A simple strategy for the synthesis of a variety of tetrahydropyridines in good to excellent yields via a Cu(OTf)2 catalyzed quaternary ammonium salt mediated ring-opening of activated azetidines followed by cyclization with alkynes in a domino ring-opening cyclization (DROC) is described. The formation of the products has been explained by an SN2-type ring-opening of azetidines with alkynes. 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Lett. 2024; 26: 3195 7i Shukla D, Kashyap S, Singh B, Sharma AK, Bhattacharyya A, Rahman N, Ghorai MK. Synthesis 2024; in press; DOI: 10.1055/a-2415-1629 8a Baeg J.-O, Bensimon C, Alper H. J. Org. Chem. 1995; 60: 253 8b Alcaide B, Salgado NR, Sierra MA. Tetrahedron Lett. 1998; 39: 467 8c Prasad BA. B, Bisai A, Singh VK. Org. Lett. 2004; 6: 4829 8d Couty F, Evano G. Synlett 2009; 3053 8e Alcaide B, Almendros P, Aragoncillo C. Curr. Opin. Drug Discovery Dev. 2010; 13: 685 8f Barbier V, Marrot J, Couty F, David OR. P. Eur. J. Chem. 2016; 549 8g Dao Thi H, Decuyper L, Mollet K, Kenis S, De Kimpe N, Van Nguyen T, D’hooghe M. Synlett 2016; 27: 1100 8h Dao Thi H, Danneels B, Desmet T, Van Hecke K, Van Nguyen T, D’Hooghe M. Asian J. Org. Chem. 2016; 5: 1480 8i Wang X, Liu C, Zeng X, Wang X, Wang X, Hu Y. Org. Lett. 2017; 19: 3378 8j Singh A, Sharma B, Sachdeva D, Mehra V, Singh P, Kumar V. 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Synlett 2020; 708 For azetidines, see 10g Goswami G, Singh B, Wani IA, Mal A, Ghorai MK. J. Org. Chem. 2024; 89: 11576 10h Goswami G, Chauhan N, Mal A, Das S, Das M, Ghorai MK. ACS Omega 2018; 3: 17562 10i Ghorai MK, Kumar A, Das K. Org. Lett. 2007; 9: 5441 11a Ghorai MK, Shukla D, Bhattacharyya A. J. Org. Chem. 2012; 77: 3740 11b Ghorai MK, Kumar A, Tiwari DP. J. Org. Chem. 2010; 75: 137 11c Bhattacharyya A. Synlett 2012; 23: 2142 (A) General procedure for DROC of azetidine with alkynes in the presence of catalytic Cu(OTf)2 and stoichiometric TBAFP and characterization data of compounds 6a–h and 10a–13a′A solution of azetidine (1.0 equiv), TBAFP (1.0 equiv), and alkyne (3.0 equiv) in dichloromethane was added to anhydrous Cu(OTf)2 (20 mol%) at 0 °C under an argon atmosphere. The reaction mixture was stirred for the appropriate time, then quenched with saturated NaHCO3 at the same temperature. The aqueous layer was extracted with CH2Cl2 (3 × 5.0 mL) and dried over anhydrous Na2SO4. The crude compound was purified by flash column chromatography on neutral alumina (ethyl acetate/petroleum ether) to provide the corresponding cyclized product.During the temperature-dependence studies, the reaction was performed at the appropriate temperature. When the reaction was performed with BF3·OEt2 as the Lewis acid, it was added to the reaction mixture after the addition of all other reagents. These compounds were unstable, and some amount of the product was hydrolyzed during workup or column chromatographic purification or during the preparation of the analytical sample.(B) Racemization studies of (S)-2-phenyl-N-tosylazetidine 4a in the presence of Cu(OTf)2 in dichloromethane (Ref. 11a)We studied the racemization of enantiopure (S)-2-phenyl-N tosylazetidine 4a by performing the reaction with a stoichiometric amount of Cu(OTf)2 in CH2Cl2 at room temperature, as well as at 0 °C without adding nucleophile. The aliquots were taken from the reaction mixture at defined time intervals and analyzed by chiral HPLC (Chiralpak AD-H column, flow rate 1 mL/min; hexane-isopropanol, 95:5). At room temperature, the ee of (S)-4a was found to decrease with increasing time and the compound racemized completely within 5 minutes (Table 2, Figure 2)Table 1 Racemization study of (S)-4a (1.0 equiv) in the Presence of Cu(OTf)2 (1.0 equiv) at RT and 0 °C in CH2Cl2 When the reaction was carried out at 0 °C, the racemization occurred within 1.5 h (Table 2, Figure 3). Racemization of (S)-4a during the course of the reaction is responsible for the reduced ee of the product. When the racemization of (S)-2-phenyl-N-tosylazetidine 4a was studied in the presence of a catalytic amount of Cu(OTf)2 (30 mol%) and stoichiometric TBAHS (1.0 equiv) in CH2Cl2 at 0 °C without adding a nucleophile, the ee of (S)-4a did not decrease with increasing reaction time in dichloromethane. 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