Catalyst- and Metal-Free Rapid Functionalizations of Alkynes Using TsNBr₂

Abstract

A very rapid (3–12 min) and efficient method has been developed for a one-pot synthesis of α,α-dibromoalkanones and β-bromoenol alkanoates directly from alkynes using N,N-dibromo-p-toluenesulfonamide (TsNBr₂). The protocol is embellished with features like ambient temperature, high regioselectivity, operational simplicity, and metal- and catalyst-free conditions.

Key words

alkynes - TsNBr₂ - α,α-dibromoalkanones - β-bromoenol alkanoates - catalyst-free conditions

• References and Notes


For recent selected examples of difunctionalization of terminal alkyne, see:
• 1a Goossen LJ, Rodriguez N, Goossen K. Angew. Chem. Int. Ed. 2009; 48: 9592
• 1b Mizuno A, Kusama H, Iwasawa N. Angew. Chem. Int. Ed. 2009; 48: 8318
• 1c Sha F, Huang X. Angew. Chem. Int. Ed. 2009; 48: 3458
• 1d Ye L, Cui L, Zhang G, Zhang L. J. Am. Chem. Soc. 2010; 132: 3258
• 1e Dutta B, Gilboa N, Marek I. J. Am. Chem. Soc. 2010; 132: 5588
• 1f Zhang C, Jiao N. J. Am. Chem. Soc. 2010; 132: 28
• 1g Kuang J, Ma S. J. Am. Chem. Soc. 2010; 132: 1786
• 2a Garrett CE, Prasad K. Adv. Synth. Catal. 2004; 346: 889
• 2b Welch CJ, Albaneze-Walker J, Leonard WR, Biba M, DaSilva J, Henderson D, Laing B, Mathre DJ, Spencer S, Bu X, Wang T. Org. Process Res. Dev. 2005; 9: 198
• 2c Qiu F, Norwood DL. J. Liq. Chromatogr. Relat. Technol. 2007; 30: 877
• 3 Palisse A, Kirsch SF. Org. Biomol. Chem. 2012; 10: 8041
• 4a Ahluwalia VK, Mehta B, Kumar R. Synth. Commun. 1989; 19: 619
• 4b Prakash R, Kumar A, Aggarwal R, Prakash O, Singh SP. Synth. Commun. 2007; 37: 2501
• 4c Duggan PJ, Liepa AJ, O’Dea LK, Tranberg CE. Org. Biomol. Chem. 2007; 5: 472

For selected examples, see:
• 5a Bruneau C, Dixneuf PH. Chem. Commun. 1997; 507
• 5b Goossen LJ, Paetzold J. Angew. Chem. Int. Ed. 2004; 43: 1095
• 5c Zhang D, Ready JM. Org. Lett. 2005; 7: 5681
• 5d DeBergh JR, Spivey KM, Ready JM. J. Am. Chem. Soc. 2008; 130: 7828
• 5e Tang W, Liu D, Zhang X. Org. Lett. 2003; 5: 205

Haloenol acetates are known to be effective precursors of α-keto dianions, see:
• 6a Kowalski CJ, Haque MS. J. Org. Chem. 1985; 50: 5140
• 6b Kowalski CJ, O’Dowd ML, Burke MC, Fields KW. J. Am. Chem. Soc. 1980; 102: 5411
• 6c Kowalski CJ, Haque MS, Fields KW. J. Am. Chem. Soc. 1985; 107: 1429

For recent selected examples, see:
• 7a Corbet J.-P, Mignani G. Chem. Rev. 2006; 106: 2651
• 7b Cahiez G, Moyeux A. Chem. Rev. 2010; 110: 1435
• 7c Amatore C, Jutand A. Acc. Chem. Res. 2000; 33: 314
• 7d Bettinger HF, Filthaus M. J. Org. Chem. 2007; 72: 9750
• 7e Uchiyama M, Furuyama T, Kobayashi M, Matsumoto Y, Tanaka K. J. Am. Chem. Soc. 2006; 128: 8404
• 7f Boukouvalas J, Loach RP. J. Org. Chem. 2008; 73: 8109
• 8 Kajigaeshi S, Kakinami T, Okamoto T, Fujisaki S. Bull. Chem. Soc. Jpn. 1987; 60: 1159
• 9 Paul S, Gupta V, Gupta R, Loupy A. Tetrahedron Lett. 2003; 44: 439
• 10 Ye C, Shreeve JM. J. Org. Chem. 2004; 69: 8561
• 11 Pandit P, Gayen KS, Khamarui S, Chatterjee N, Maiti DK. Chem. Commun. 2011; 47: 6933
• 12 Schmidt R, Stolle A, Ondruschka B. Green Chem. 2012; 14: 1673
• 13a Barluenga J, Rodriguez MA, Campos PJ. J. Org. Chem. 1990; 55: 3104
• 13b Chen Z, Li J, Jiang H, Zhu S, Li Y, Qi C. Org. Lett. 2010; 12: 3262
• 13c Chen X, Chen D, Lu Z, Kong L, Zhu G. J. Org. Chem. 2011; 76: 6338
• 14 Kharasch MS, Priestley HN. J. Am. Chem. Soc. 1939; 61: 3425
• 15a Daniher FA, Butler PE. J. Org. Chem. 1968; 33: 4336
• 15b Terauchi H, Kowata K, Minematsu T, Takemura S. Chem. Pharm. Bull. 1977; 25: 556
• 15c Hegedus LS, McKearin JM. J. Am. Chem. Soc. 1982; 104: 2444
• 15d Li G, Wei H.-X, Kim SH, Neighbors M. Org. Lett. 1999; 1: 395
• 15e Li G, Wei H.-X, Kim SH. Org. Lett. 2000; 2: 2249
• 15f Wei H.-X, Kim SH, Li G. Tetrahedron 2001; 57: 3869
• 15g Wei H.-X, Kim SH, Li G. Tetrahedron 2001; 57: 8407
• 15h Xu X, Kotti SR. S. S, Liu J, Cannon JF, Headley AD, Li G. Org. Lett. 2004; 6: 4881
• 16a Phukan P, Chakraborty P, Kataki D. J. Org. Chem. 2006; 71: 7533
• 16b Saikia I, Phukan P. Tetrahedron Lett. 2009; 50: 5083
• 16c Saikia I, Chakraborty P, Phukan P. ARKIVOC 2009; (xiii): 281
• 16d Saikia I, Kashyap B, Phukan P. Synth. Commun. 2010; 40: 2647
• 16e Saikia I, Kashyap B, Phukan P. Chem. Commun. 2011; 47: 2967
• 16f Saikia I, Rajbonshi KK, Phukan P. Tetrahedron Lett. 2012; 53: 758
• 16g Borah AJ, Phukan P. Chem. Commun. 2012; 48: 5491
• 17 Shen R, Huang X. Org. Lett. 2009; 11: 5698
• 18a Singh AK, Chawla R, Rai A, Yadav LD. S. Chem. Commun. 2012; 48: 3766
• 18b Chawla R, Kapoor R, Singh AK, Yadav LD. S. Green Chem. 2012; 14: 1308
• 18c Singh AK, Yadav LD. S. Synthesis 2012; 44: 591
• 18d Chawla R, Singh AK, Yadav LD. S. Tetrahedron Lett. 2012; 53: 3382
• 18e Singh AK, Chawla R, Yadav LD. S. Synthesis 2012; 44: 2353
• 18f Chawla R, Singh AK, Yadav LD. S. Tetrahedron 2013; 69: 1720
• 19 Schmid GH, Modro A, Yates K. J. Org. Chem. 1980; 45: 665
• 20 General Procedure for the Synthesis of α,α-Dibromoalkanones 3 A mixture of alkyne 1 (1.0 mmol) and TsNBr₂ (2, 2.0 mmol) in MeCN (2 mL) with H₂O (0.2 mL) was stirred at r.t. for 3–10 min (Table 2). After completion of the reaction (monitored by TLC), H₂O was added and the mixture was extracted with EtOAc (3 × 5 mL). The combined organic phases were dried over anhyd Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography using a mixture of EtOAc–n-hexane (1:99) as eluent to afford an analytically pure sample of α,α-dibromoalkanones 3 (Table 2). Characterization Data of Representative Compounds Compound 3a: viscous liquid; yield 87%. IR (neat): ν_max = 3448, 2926, 1600, 1475, 1092 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 6.71 (s, 1 H), 7.49–7.57 (m, 2 H), 7.63–7.67 (m, 1 H), 8.08–8.10 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 39.7, 128.9, 129.8, 130.3, 134.7, 185.7. MS (EI): m/z = 276 [M⁺], 278 [M⁺ + 2]. Anal. Calcd for C₈H₆Br₂O: C, 34.57; H, 2.18. Found: C, 34.33; H, 2.26. Compound 3h: viscous liquid; yield 78%. IR (neat): ν_max = 2960, 2938, 2871, 1720, 1461, 1380, 1243, 1147, 1105, 627 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 0.99 (m, 6 H), 1.70 (m, 4 H), 2.43 (m, 2 H), 3.09 (t, J = 7.2 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 13.1, 13.6, 18.6, 20.7, 38.3, 46.8, 71.5, 198.0. MS (EI): m/z = 284 [M⁺], 286 [M⁺ + 2]. Anal. Calcd for C₈H₁₄Br₂O: C, 33.60; H, 4.93. Found: C, 33.52; H, 5.02.
• 21 General Procedure for the Synthesis of Bromoenol Alkanoates 5 and 6 A mixture of alkyne 1 (2.0 mmol) and TsNBr₂ (2, 1.0 mmol) in carboxylic acid 4 (2 mL) was stirred at r.t. for 3–12 min (Table 3). After completion of the reaction (monitored by TLC), H₂O was added, and the mixture was extracted with EtOAc (3 × 5 mL). The combined organic phases were dried over anhyd Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting crude product was purified by preparative chromatography using a mixture of EtOAc–n-hexane (1:99) as eluent to afford an analytically pure sample of bromoenol alkanoates 5 and 6 (Table 3). Characterization Data of Representative Compounds Compound 5a: yellow oil; yield 60%. IR (KBr): ν_max = 3095, 2928, 2852, 1765, 1625, 1436, 1370, 1180, 1036, 740, 694, 627, 569, 488 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 2.34 (s, 3 H), 6.55 (s, 1 H), 7.33–7.35 (m, 3 H), 7.37–7.41 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 20.5, 96.6, 124.3, 126.1, 128.5, 133.0, 150.2, 166.6. MS (EI): m/z = 240 [M⁺], 242 [M⁺ + 2]. Anal. Calcd for C₁₀H₉BrO₂: C, 49.82; H, 3.76. Found: C, 49.46; H, 3.82. Compound 6a: yellow oil; yield 24%. IR (KBr): ν_max = 3096, 2929, 2855, 1762, 1624, 1438, 1370, 1185, 1036, 740, 690, 625, 567, 489 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 2.17 (s, 3 H), 6.31 (s, 1 H), 7.34–7.43 (m, 4 H), 7.61–7.64 (m, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 20.3, 94.6, 124.8, 128.5, 129.3, 133.2, 148.7, 167.3. MS (EI): m/z = 240 [M⁺], 242 [M⁺ + 2]. Anal. Calcd for C₁₀H₉BrO₂: C, 49.82; H, 3.76. Found: C, 49.55; H, 3.78. Compound 5d: yellow oil; yield 54%. IR (KBr): ν_max = 3094, 2938, 1765, 1609, 1510, 1458, 1370, 1035, 896, 835, 770, 658, 597, 512 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 2.31 (s, 3 H), 3.76 (s, 3 H), 6.37 (s, 1 H), 6.85 (d, J = 8.8 Hz, 2 H), 7.33 (d, J = 8.8 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 20.8, 55.2, 96.4, 113.5, 125.3, 126.3, 150.2, 160.1, 167.3. MS (EI): m/z = 270 [M⁺], 272 [M⁺ + 2]. Anal. Calcd for C₁₁H₁₁BrO₃: C, 48.73; H, 4.09. Found: C, 48.44; H, 4.12. Compound 6d: yellow oil; yield 20%. IR (KBr): ν_max = 3092, 2940, 1763, 1606, 1514, 1457, 1370, 1035, 898, 835, 770, 657, 595, 511 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 2.13 (s, 3 H), 3.80 (s, 3 H), 6.22 (s, 1 H), 6.87 (d, J = 9.2 Hz, 2 H), 7.56 (d, J = 8.0 Hz, 2 H).¹³C NMR (100 MHz, CDCl₃): δ = 20.5, 55.3, 94.4, 114.1, 125.8, 129.7, 148.5, 160.4, 168.6. MS (EI): m/z = 270 [M⁺], 272 [M⁺ + 2]. Anal. Calcd for C₁₁H₁₁BrO₃: C, 48.73; H, 4.09. Found: C, 48.40; H, 4.19.