Dihalooxygenation of Alkynes and Alkynols: Preparation of 2,2-Dihaloketones and gem-Dihalolactols

Abstract

A mild and convenient method for the synthesis of 2,2-dihaloketones and gem-dihalolactols has been developed. For the synthesis of 2,2-dihaloketones, alkynes were employed as substrates to react with halogenating agents, Cl₂ or ClBr, that were generated in situ from aqueous HCl and NCS or NBS, respectively. On the other hand, gem-dihalolactols could be prepared from alkynol substrates by using the same reaction conditions. This method could be applied to a broad range of substrates to give the corresponding products in low to good yields.

Key words

dihaloketones - dihalolactols - alkynes - alkynols - halogenation

Publication History

Received: 23 January 2022

Accepted after revision: 17 February 2022

Accepted Manuscript online:
17 February 2022

Article published online:
15 March 2022

• References and Notes

• 1a Sadhukhan S, Santhi J, Baire B. Chem. Eur. J. 2020; 26: 7145
• 1b Chung W.-j, Vanderwal CD. Angew. Chem. Int. Ed. 2016; 55: 4396
• 1c Ponce P, Fomina L, García P, Fomine S. Polym. Int. 2003; 52: 1454
• 1d Srivastava S, Bajpai LK, Batra S, Bhaduri AP, Maikhuri J, Gupta G, Dhar J. Bioorg. Med. Chem. 1999; 7: 2607
• 1e Srivastava S, Bajpai LK, Batra S, Bhaduri AP, Maikhuri J, Gupta G, Dhar J. Bioorg. Med. Chem. 1999; 7: 2607
• 2 Iacono CE, Stephens TC, Rajan TS, Pattison G. J. Am. Chem. Soc. 2018; 140: 2036
• 3a Vražič D, Jereb M, Laali KK, Stavber S. Molecules 2013; 18: 74
• 3b Pu X, Li Q, Lu Z, Yang X. Eur. J. Org. Chem. 2016; 2016: 5937
• 3c McDonald RN, Cousins RC. J. Org. Chem. 1980; 45: 2976
• 3d Terent’ev AO, Khodykin SV, Troitskii NA, Ogibin YN, Nikishin GI. Synthesis 2004; 2845
• 3e Pravst I, Zupan M, Stavber S. Tetrahedron 2008; 64: 5191
• 3f Zheng Z, Han B, Cheng P, Niu J, Wang A. Tetrahedron 2014; 70: 9814
• 4 Shiina I, Imai Y, Kagayama A, Mukaiyama T. Chem. Lett. 2000; 29: 190
• 5 Meng X, Zhang Y, Luo J, Wang F, Cao X, Huang S. Org. Lett. 2020; 22: 1169
• 6 Li Y, Mou T, Lu L, Jiang X. Chem. Commun. 2019; 55: 14299
• 7a Gibson SM, D’Oyley JM, Higham JI, Sanders K, Laserna V, Aliev AE, Sheppard TD. Eur. J. Org. Chem. 2018; 2018: 4018
• 7b D’Oyley JM, Aliev AE, Sheppard TD. Angew. Chem. 2014; 126: 10923
• 7c Dutta MM, Rajbongshi KK, Phukan P. Synth. Commun. 2017; 47: 2330
• 7d Catano B, Lee J, Kim C, Farrell D, Petersen JL, Xing Y. Tetrahedron Lett. 2015; 56: 4124
• 7e Liu J, Li W, Wang C, Li Y, Li Z. Tetrahedron Lett. 2011; 52: 4320
• 8a Zhang X, Wu Y, Zhang Y, Liu H, Xie Z, Fu S, Liu F. Tetrahedron 2017; 73: 4513
• 8b Stodulski M, Goetzinger A, Kohlhepp SV, Gulder T. Chem. Commun. 2014; 50: 3435
• 9 Yamamoto Y, Gridnev ID, Patil NT, Jin T. Chem. Commun. 2009; 5075
• 10a Maibunkaew T, Thongsornkleeb C, Tummatorn J, Bunrit A, Ruchirawat S. Synlett 2014; 25: 1769
• 10b Aroonkit P, Thongsornkleeb C, Tummatorn J, Krajangsri S, Mungthin M, Ruchirawat S. Eur. J. Med. Chem. 2015; 94: 56
• 10c Kaewsri W, Thongsornkleeb C, Tummatorn J, Ruchirawat S. RSC Adv. 2016; 6: 48666
• 10d Norseeda K, Chaisan N, Thongsornkleeb C, Tummatorn J, Ruchirawat S. J. Org. Chem. 2019; 84: 16222 ; corrigendum: J. Org. Chem. 2020, 85, 14271
• 10e Chaisan N, Ruengsangtongkul S, Tummatorn J, Ruchirawat S, Chainok K, Thongsornkleeb C. J. Org. Chem. 2021; 86: 4671
• 11 The results are summarized in the Supporting Information.
• 12 These were observable in their ¹H NMR spectra: 3w-Br/2w-Br = 88:12 and 3x-Br/2x-Br = 81:19; see the Supporting Information.
• 13 2,2-Dichloro-3-hydroxy-1-phenylpropan-1-one (2a-Cl); Typical Procedure NCS (193.3 mg, 1.448 mmol, 2.0 equiv) and 1 M aq HCl (0.38 mL, 0.38 mmol, 0.5 equiv) were added to a solution of alkynol 1a (95.8 mg, 0.725 mmol, 1.0 equiv) in 1,4-dioxane (3.6 mL), and the mixture was stirred at r.t. until the reaction was complete (TLC; typically 5 h). The mixture was then diluted with H₂O, and the separated aqueous phase was extracted with EtOAc (×3). The combined organic phases were washed with sat. aq NaCl then dried (Na₂SO₄), filtered, and concentrated to give a crude product. This was purified by column chromatography (silica gel, 10% EtOAc–hexane) to give a yellow oil; yield: 117.2 mg (74%). IR (neat): 2926, 1691, 1260, 688 cm^–1.¹H NMR (300 MHz, CDCl₃): δ = 8.33–8.29 (m, 2 H), 7.61 (tt, J = 7.5, 1.2 Hz, 1 H), 7.51–7.45 (m, 2 H), 4.27 (s, 2 H), 2.95(br s, 1 H). ¹³C{¹H} NMR (75 MHz, CDCl₃): δ = 189.1, 134.1, 131.1, 131.0, 128.2, 83.6, 70.4. HRMS (ESI-TOF):m/z [M]^∙/+ calcd for C₉H₉ ³⁵Cl₂O₂: 218.9974; found: 218.9972.