TEMPO-Catalyzed Oxidative Amidation of Alcohols via Hexa­fluoroisopropyl Esters

Abstract

Stepwise oxidative amidation of alcohols using trichloroisocyanuric acid, a catalytic amount of TEMPO in combination with pyridine and hexafluoroisopropyl (HFIP) alcohol followed by amines is described. This procedure used HFIP esters as activating esters which were found to be very efficient acylating agents for amide bond formation. This process is compatible with a number of functional groups and acid-sensitive protecting groups.

Key words

alcohols - amidation - hexafluoroisopropyl esters - tandem oxidative process - TEMPO

• References and Notes

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• 23 TEMPO-Oxidative Esterification of Alcohols with HFIP Alcohol; General Procedure: To a cooled (0 °C) solution of the alcohol (1 mmol) in CH₂Cl₂ (2 mL) were added successively TEMPO (7.8 mg, 5 mol%), TCCA (278 mg, 1.2 equiv) in portions and the suspension was stirred until the consumption of the alcohol (progress of the reaction was monitored by TLC). In the case of substrates 2g,j–n, NaHCO₃ (8 equiv) was added before the addition of TCCA. HFIP alcohol (210 μL, 2 equiv) and pyridine (320 μL, 4 equiv) were then successively added dropwise at 0 °C. After warming, the solution was stirred at r.t. until consumption of the aldehyde (for substrates 1j–n, the oxidative esterification was conducted at 0 °C). The yellow suspension was poured onto a small column of silica gel and the HFIP ester was eluted with petroleum ether or a mixture of petroleum ether–Et₂O. 1,1,1,3,3,3-Hexafluoropropan-2-yl-5-[(tert-butyldimethylsilyl)oxy]pentanoate (2j): Eluent: PE–Et₂O (97:3); yield: 79%; liquid. ¹H NMR (300 MHz, CDCl₃): δ = 5.77 (hept, J = 6.2 Hz, 1 H), 3.63 (t, J = 6.1 Hz, 2 H), 2.55 (t, J = 7.4 Hz, 2 H), 1.68–1.93 (m, 2 H), 1.56 (dq, J = 9.9, 6.2 Hz, 2 H), 0.88 (s, 9 H), 0.04 (s, 6 H). ¹³C NMR (75 MHz, CDCl₃): δ = 170.3, 120.5 (q, J = 282 Hz), 66.3 (sept, J = 35 Hz), 62.3, 33.0, 31.7, 25.8 (3 × C), 21.3, 18.3, –5.5 (2 × C).¹⁹F NMR (283 MHz): δ = –73.39 (d, J = 6.1 Hz). HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₄H₂₄F₆NaO₃Si: 405.1291; found: 405.1292.

For selected examples of the use of TCCA/TEMPO in the presence of NaHCO₃ in organic synthesis, see:
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• 26 Amide Formation from HFIP Esters; General Procedure: To a solution of HFIP ester (1 mmol) in MeCN (2 mL) was added the amine (2 equiv except for allylamine: 3 equiv) and the solution was stirred at r.t. (at reflux for entries 6 and 7 in Table 2 and entry 6 in Table 3) for the reaction time indicated in Tables 2 and 3. The solution was concentrated and the amide was separated from the excess of amine on a pad of silica gel using a mixture of petroleum ether–EtOAc as eluent. 5-[(tert-Butyldimethylsilyl)oxy]-N-phenethylpentanamide (3j): Eluent: PE–EtOAc (2:1); yield: 97%; oil. ¹H NMR (300 MHz, C₆D₆): δ = 6.92–7.32 (m, 5 H), 5.58 (br s, 1 H), 3.52 (t, J = 6.3 Hz, 2 H), 3.41–3.45 (m, 2 H), 2.65 (t, J = 7.1 Hz, 2 H), 1.93 (t, J = 7.2 Hz, 2 H), 1.64–1.78 (m, 2 H), 1.44–1.57 (m, 2 H), 0.98 (s, 9 H), 0.006 (s, 6 H). ¹³C NMR (75 MHz, C₆D₆): δ = 172.3, 139.7, 129.1 (2 × C), 128.8 (2 × C), 126.6, 63.1, 41.0, 36.3, 36.2, 32.8, 26.2 (3 × C), 22.6, 18.5, –5.1 (2 × C). HRMS (ESI): m/z [M + H]⁺ calcd for C₁₉H₃₄NO₂Si: 336.2353; found: 336.2344. For other compounds, see Supporting Information.
• 27 [α]_D ²⁰ +81.5 (c 1, CHCl₃) for compound 3m {see ref. 28 for the (S)-enantiomer [α]_D ²⁰ –80.8 (c 1, CH₂Cl₂)}.
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