Site-Selective and Stereoselective C(sp³)–H Borylation of Alkyl Side Chains of 1,3-Azoles with a Silica-Supported Monophosphine-Iridium Catalyst

Abstract

Site-selective and stereoselective C(sp³)–H borylation of alkyl side chains of 1,3-azoles with bis(pinacolato)diboron was effectively catalyzed by a silica-supported monophosphine-iridium catalyst. The borylation occurred under relatively mild conditions (2 mol% Ir, 50–90 °C), affording the corresponding primary and secondary alkylboronates. This system was applicable to a variety of 1,3-(benzo)azoles such as thiazoles, oxazoles, and imidazoles.

Key words

1,3-azole - C–H activation - borylation - iridium - hetero­geneous catalyst

• References and Notes

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Heteroatom-directed C(sp³)–H borylation:
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See also ref 10. An example of C(sp³)–H borylation of aliphatic substrates without strong directing groups:
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Borylation of C(sp³)–H bonds located α or β to heteroatoms:
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C(sp³)–H borylation of cyclopropanes, see:
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Borylation of benzylic C(sp³)–H bonds:
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Borylation of allylic C(sp³)–H bonds:
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• 11 Typical Procedure for the C(sp³)–H Borylation of Alkyl Side Chains on 1,3-Azoles with a Silica-SMAP-Ir Catalyst System (Table 1, Entry 1)In a glove box, Silica-SMAP (0.07 mmol/g, 57.1 mg, 0.0040 mmol, 2 mol%), bis(pinacolato)diboron (2, 50.8 mg, 0.20 mmol), and anhydrous, degassed THF (0.3 mL) were placed in a 10 mL glass tube containing a magnetic stirring bar. A solution of [Ir(OMe)(cod)]₂ (1.3 mg, 0.0020 mmol, 1 mol%) in THF (0.7 mL) and 2-ethylbenzo[d]thiazole (1a, 97.9 mg, 0.60 mmol) were added successively. The tube was sealed with a screw cap and removed from the glove box. The reaction mixture was stirred at 60 °C for 15 h, and filtered through a glass pipette equipped with a cotton filter. The solvent was removed under reduced pressure. An internal standard (1,1,2,2-tetrachloroethane) was added to the residue. The yields of the products 3a and 4a were determined by ¹H NMR spectroscopy (82% and 32% yields, respectively). The crude material was then purified by Kugelrohr distillation (1 mmHg, 145 °C), to give the corresponding product 3a (43.1 mg, 0.15 mmol, 75% yield) contaminated with the diborylation product 4a (<1%) and traces of impurities, as estimated by ¹H NMR spectroscopy. Total yield over 100% based on 2 indicates that HBpin formed during catalytic turnover also served as a borylating reagent (theoretical maximum yield is 200%). ¹H NMR (400 MHz, CDCl₃): δ = 1.24 (s, 12 H), 1.38 (t, J = 7.6 Hz, 2 H), 3.24 (t, J = 7.6 Hz, 2 H), 7.32 (td, J = 8.4, 1.2 Hz, 1 H), 7.42 (td, J = 7.6, 0.8 Hz, 1 H), 7.82 (d, J = 8.0 Hz, 1 H), 7.94 (d, J = 8.4 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 11.10 (br), 24.75 (4 C), 28.85, 83.36 (2 C), 121.42, 122.41, 124.42, 125.67, 135.19, 153.19, 173.81. ¹¹B NMR (128 MHz, CDCl₃): δ = 32.6. IR (ATR): 2976, 2931, 1519, 1436, 1370, 1313, 1142, 1082, 967, 845, 758 cm^–1. ESI-HRMS: m/z [M + H]⁺ calcd for C₁₅H₂₁O₂N¹⁰BS: 289.14169; found: 289.14170.
• 12 The Silica-SMAP-Ir catalyst was easily separated from the reaction mixture by filtration. However, attempts to reuse the catalyst were unsuccessful.
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• 15 In some cases, the formation of C=N reduction products of starting materials 1 was indicative by ¹H NMR analyses of the crude products. Similar C=N reduction was observed in the C(sp³)–H boylation of small-ring carbocycles bearing 1,3-azoles with the Silica-SMAP-Ir catalyst system (ref. 7b). The desired products 3 or 5 could be isolated by bulb-to-bulb distillation or silica gel column chromatography.

Cyclooctene would act as a scavenger of H₂ or HBpin. The use of alkene derivatives as a H₂ or HBpin scavenger in an Ir-catalyzed aromatic C–H borylation of aldimines was also reported:
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• 17 Methyl groups on the thiazole ring in 1g were necessary for the C(sp³)–H borylation. In fact, the reaction of 2-ethylthiazole with 2 in the presence of the Silica-SMAP-Ir catalyst (2 mol%, 60 °C, 15 h) gave the corresponding arylboronates exclusively via the C(sp²)–H borylation.
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• 21 Isolated product 7 was contaminated with 4,4′-dimethoxy-1,1′-biphenyl (2%), probably generated through homocoupling of 4-chloroanisole.
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