Facile Approach to Geminal Heterodihalogenation. One-Pot Synthesis of α-Bromo-α-Chloro Ketones

Abstract

An efficient and practical protocol for the geminal heterodihalogenation of methyl ketones by using readily available dimethyl sulfoxide and a combination of HCl and HBr is reported. Control experiments suggested that the acidity of the solution, as well as the oxidizing ability and nucleophilicity of the dimethyl sulfoxide might work cooperatively in ensuring the success of the tandem substitution. Its operational simplicity, easy accessibility, and mild oxidative conditions suggest that the present strategy might be useful for the assembly of bromochloromethyl functional groups in drug discovery.

Key words

heterodihalogenation - dimethyl sulfoxide - bromochloromethyl ketones - tandem reaction

• References and Notes


For recent reviews, see:
• 1a Vaillancourt FH, Yeh E, Vosburg DA, Garneau-Tsodikova S, Walsh CT. Chem. Rev. 2006; 106: 3364
• 1b Butler A, Sandy M. Nature 2009; 460: 848
• 1c Latham J, Brandenburger E, Shepherd SA, Menon BR. K, Micklefield J. Chem. Rev. 2018; 118: 232
• 2 Landry ML, Burns NZ. Acc. Chem. Res. 2018; 51: 1260
• 3a Qin L, Tian Y, Yu Z, Shi D, Wang J, Zhang C, Peng R, Chen X, Liu C, Chen Y, Huang W, Deng W. Oncotarget 2016; 7: 1395
• 3b Xu B, Yu Z, Xiang S, Li Y, Zhang S.-L, He Y. Eur. J. Med. Chem. 2018; 155: 275
• 4 Halpern DF. In Organofluorine Chemistry: Principles and Commercial Applications . Banks RE, Smart BE, Tatlow JC. Plenum Press; New York: 1994. Chap. 25 543

For a recent review, see:
• 5a Vekariya RH, Patel HD. Tetrahedron 2014; 70: 3949

For a recent application, see:
• 5b Nishii Y, Ikeda M, Hayashi Y, Kawauchi S, Miura M. J. Am. Chem. Soc. 2020; 142: 1621

For a review, see:
• 6a Podgoršek A, Zupan M, Iskra J. Angew. Chem. Int. Ed. 2009; 48: 8424

For selected oxidative brominations, see:
• 6b Zhang G, Liu R, Xu Q, Ma X, Liang X. Adv. Synth. Catal. 2006; 348: 862
• 6c Podgoršek A, Stavber S, Zupan M, Iskra J. Green Chem. 2007; 9: 1212
• 6d Adimurthy S, Ghosh S, Patoliya PU, Ramachandraiah G, Agrawal M, Gandhi MR, Upadhyay SC, Ghosh PK, Ranu BC. Green Chem. 2008; 10: 232
• 6e Yang L, Lu Z, Stahl SS. Chem. Commun. 2009; 6460
• 6f Podgoršek A, Eissen M, Fleckenstein J, Stavber S, Zupan M, Iskra J. Green Chem. 2009; 11: 120
• 6g Pandit P, Gayen KS, Khamarui S, Chatterjee N, Maiti DK. Chem. Commun. 2011; 47: 6933
• 6h Yonehara K, Kamata K, Yamaguchi K, Mizuno N. Chem. Commun. 2011; 47: 1692
• 6i Wang G.-W, Gao J. Green Chem. 2012; 14: 1125
• 6j Gu L, Lu T, Zhang M, Tou L, Zhang Y. Adv. Synth. Catal. 2013; 355: 1077
• 6k Yu T.-Y, Wang Y, Hu X.-Q, Xu P.-F. Chem. Commun. 2014; 50: 7817
• 6l Prebil R, Stavber S. Adv. Synth. Catal. 2014; 356: 1266
• 7a Hering T, Mühldorf B, Wolf R, König B. Angew. Chem. Int. Ed. 2016; 55: 5342
• 7b Hering T, Meyer AU, König B. J. Org. Chem. 2016; 81: 6927
• 7c Yuan Y, Yao A, Zheng Y, Gao M, Zhou Z, Qiao J, Hu J, Ye B, Zhao J, Wen H, Lei A. iScience 2019; 12: 293
• 7d Li YM, Mou T, Liu LL, Jiang XF. Chem. Commun. 2019; 55: 14299

For selected geminal heterodihalogenations, see:
• 8a Pfab J. Tetrahedron Lett. 1976; 17: 943
• 8b Barluenga J, Fernández-Simón J, Concellón JM, Yus M. J. Chem. Soc., Perkin Trans 1 1989; 691
• 8c Hashem A, Khan MA. E. J. Bangladesh Chem. Soc. 2007; 20: 1
• 8d Kazutaka S, Akira N, Yoshinori S, Tsubasa M, Seiji I. Org. Lett. 2011; 13: 2944
• 8e Shariff N, Mathi S, Rameshkumar C, Emmanuvel L. Tetrahedron Lett. 2015; 56: 934
• 8f Gallo RD. C, Ahmad A, Metzker G, Burtoloso AC. B. Chem. Eur. J. 2017; 23: 16980
• 8g Mazenauer M, Manov S, Galati V, Kappeler P, Stohner J. RSC Adv. 2017; 7: 55434
• 8h Naruse A, Kitahara K, Iwasa S, Shibatomi K. Asian J. Org. Chem. 2019; 8: 691
• 8i Kitahara K, Mizutani H, Iwasa S, Shibatomi K. Synthesis 2019; 51: 4385
• 9 Martin D, Weise A, Niclas HJ. Angew. Chem. Int. Ed. Engl. 1967; 6: 318

For selected reviews, see:
• 10a Epstein W, Sweat F. Chem. Rev. 1967; 67: 247
• 10b Tidwell TT. Synthesis 1990; 857
• 11a Kornblum N, Powers JW, Anderson GJ, Jones WJ, Larson HO, Levand O, Weaver WM. J. Am. Chem. Soc. 1957; 79: 6562
• 11b Tomita R, Yasu Y, Koike T, Akita M. Angew. Chem. Int. Ed. 2014; 53: 7144
• 11c Mupparapu N, Khan S, Battula S, Kushwaha M, Gupta AP, Ahmed QN, Vishwakarma RA. Org. Lett. 2014; 16: 1152
• 11d Wu X, Gao Q, Liu S, Wu A. Org. Lett. 2014; 16: 2888
• 11e Gao Q, Wu X, Liu S, Wu A. Org. Lett. 2014; 16: 1732
• 11f Ashikari Y, Nokami T, Yoshida J.-i. J. Am. Chem. Soc. 2011; 133: 11840
• 11g Ashikari Y, Nokami T, Yoshida J.-i. Org. Lett. 2012; 14: 938
• 11h Xu R, Wan J.-P, Mao H, Pan Y. J. Am. Chem. Soc. 2010; 132: 15531 ; corrigendum: J. Am. Chem. Soc. 2011, 133: 387
• 11i Ashikari Y, Nokami T, Yoshida J.-i. Org. Biomol. Chem. 2013; 11: 3322
• 11j Mori S, Takubo M, Yanase T, Maegawa T, Monguchi Y, Sajiki H. Adv. Synth. Catal. 2010; 352: 1630
• 12a Floyd MB, Du MT, Fabio PF, Jacob LA, Johnson BD. J. Org. Chem. 1985; 50: 5022
• 12b Liang Y.-F, Wu K, Song S, Li X, Huang X, Jiao N. Org. Lett. 2015; 17: 876
• 12c Li H.-L, An X.-L, Ge L.-S, Luo X, Deng W.-P. Tetrahedron 2015; 71: 3247

For I₂-mediated reactions, see:
• 12d Kale A, Bingi C, Ragi NC, Sripadi P, Tadikamalla PR, Atmakur K. Synlett 2017; 1603
• 12e Wu X, Gao Q, Lian M, Liu S, Wu A. RSC Adv. 2014; 4: 51180
• 12f Yin G, Zhou B, Meng X, Wu A, Pan Y. Org. Lett. 2006; 8: 2245 ; see also Refs. 11 (d) and 11 (e)
• 13a Song S, Huang XQ, Liang Y.-F, Tang CH, Li XW, Jiao N. Green Chem. 2015; 17: 2727
• 13b Song S, Li X, Sun X, Yuana Y, Jiao N. Green Chem. 2015; 17: 3285
• 13c Song S, Sun X, Li XW, Yuan YZ, Jiao N. Org. Lett. 2015; 17: 2886
• 14a Majetich G, Hicks R, Reister S. J. Org. Chem. 1997; 62: 4321

For selected recent applications, see:
• 14b Taylor CA, Zhang YA, Snyder SA. Chem. Sci. 2020; 11: 3036
• 14c Zhang Y.-A, Yaw N, Snyder SA. J. Am. Chem. Soc. 2019; 141: 7776
• 14d Shen M, Kretschmer M, Brill ZG, Snyder SA. Org. Lett. 2016; 18: 5018
• 14e Ke Z, Tan CK, Chen F, Yeung Y.-Y. J. Am. Chem. Soc. 2014; 136: 5627
• 14f Ashikari Y, Shimizu A, Nokami T, Yoshida J.-i. J. Am. Chem. Soc. 2013; 135: 16070
• 14g Bonney KJ, Braddock DC. J. Org. Chem. 2012; 77: 9574
• 14h Stefan E, Taylor RE. Org. Lett. 2012; 14: 3490
• 14i Synder SA, Treitler DS, Brucks AP, Sattler W. J. Am. Chem. Soc. 2011; 133: 15898
• 14j Synder SA, Treitler DS. Org. Synth. 2011; 88: 54
• 14k Snyder SA, Treitler DS, Brucks AP. J. Am. Chem. Soc. 2010; 132: 14303
• 14l Synder SA, Gollner A, Chiriac MI. Nature 2011; 474: 461
• 14m Synder SA, Treitler DS. Angew. Chem. Int. Ed. 2009; 48: 7899
• 15a Sorabad GS, Maddani MR. Asian J. Org. Chem. 2019; 8: 1336
• 15b Demertzidou VP, Pappa S, Sarli V, Zografos A. J. Org. Chem. 2017; 82: 8710
• 16 2-Bromo-2-chloro-1-phenylethanone (2a); Typical Procedure Acetophenone (1a; 1.0 mmol), DMSO (234.4 mg, 3.0 mmol), 38% aq HCl (145.8 mg, 4.0 mmol), and 40% aq HBr (202.3 mg, 1.0 mmol) were combined in EtOAc (3.0 mL) under air, and the mixture was stirred for 15 h at 30 °C while the reaction was monitored by TLC. The mixture was then dried (MgSO₄) and concentrated in vacuum, and the residue was purified by flash column chromatography (silica gel, PE–EtOAc) to give a white solid; yield: 163.1 mg (70%); mp 37-40 °C; R_f = 0.55 (PE–EtOAc, 30:2). ¹H NMR (500 MHz, CDCl₃): δ = 8.08 (d, J = 7.4 Hz, 2 H), 7.65 (t, J = 7.8 Hz, 1 H), 7.52 (t, J = 7.8 Hz, 2 H), 6.77 (s, 1 H). ¹³C NMR (125 MHz, CDCl₃) δ = 186.01, 134.55, 131.18, 129.65, 128.96, 54.18. HRMS(EI): m/z [M + Na]⁺ calcd for C₈H₆BrClNaO: 256.9162; found: 256.9158.
• 17 Inagaki M, Matsumoto S, Tsuri T. J. Org. Chem. 2003; 68: 1128
• 18 Cao Z, Shi D, Qu Y, Tao C, Liu W, Yao G. Molecules 2013; 18: 15717
• 19a Bauer DP, Macomber RS. J. Org. Chem. 1975; 40: 1990
• 19b Kornblum N, Jones WJ, Anderson GJ. J. Am. Chem. Soc. 1959; 81: 4113