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Synlett 2023; 34(01): 86-92
DOI: 10.1055/a-1929-0085
letter

Visible-Light-Driven α-Hydroxymethylation of Ketones in a Continuous-Flow Microreactor

Huinan Sun 
a   Department State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, P. R. of China
,
Jianing Li
a   Department State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, P. R. of China
,
Lei Yun
b   University of Leicester, Leicester, LE1 7RH, UK
,
Cunfei Ma
a   Department State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, P. R. of China
,
Zongyi Yu
a   Department State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, P. R. of China
,
Hongfei Zhu
a   Department State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, P. R. of China
,
Qingwei Meng∗
a   Department State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, P. R. of China
c   Ningbo Institute of Dalian University of Technology, Dalian University of Technology, Ningbo 315000, P. R. of China
,
Jingnan Zhao∗
a   Department State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, P. R. of China
› Author AffiliationsWe are grateful for financial support from the National Natural ­Science Foundation of China (U20A20143), Liaoning Province ‘Xingliao Talent Program’ Project (XLYC1902086), and the Dalian Science and Technology Innovation Fund (2019J11CY006). We thank the State Key Laboratory of Fine Chemicals and Advanced Science Center of ­Intelligent Materials and Chemical Engineering for their support.
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Abstract

A visible-light-driven α-hydroxymethylation of ketones to generate the corresponding alcohols was achieved under continuous-flow conditions. MeOH was used as a green and renewable C1 source and solvent to enable the α-C(sp3)–H functionalization of ketones under irradiation by white LEDs. A flow microreactor operated under optimized conditions permitted this oxidation to proceed with a higher efficiency and a shortened reaction time of 215 minutes, which was improved ten times compared with the batch parallel reaction (36 h). Mechanism studies indicate the reaction proceeds by a radical pathway.

Key words

continuous flow - hydroxymethylation - photocatalysis - methanol - radical reactions - ketones

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/a-1929-0085.
  • Supporting Information


Publication History

Received: 18 July 2022

Accepted after revision: 22 August 2022

Accepted Manuscript online:
22 August 2022

Article published online:
19 October 2022

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  • 19 Batch Photocatalytic α-Hydroxymethylation of Priopiophenone (1a) Propiophenone (1a; 40.3 mg, 0.3 mmol), rose bengal (15.3 mg, 5 mol%), K2CO3 (41.5 mg, 1.0 equiv), MeOH (1 mL), and H2O (0.3 mL) were added to a 10 mL quartz tube. The mixture was stirred at rt and irradiated by a 7 W white LED under ambient air for 36 h. When the reaction was complete (TLC), the solution was concentrated under reduced pressure, and the mixture was purified by column chromatography [silica gel, PE–EtOAc (5:1)] to afford pure product 2a.
  • 20 Photocatalytic α-Hydroxymethylation of Priopiophenone (1a) in a Microreactor A solution of propiophenone (1a; 0.1342 g, 1 mmol), rose bengal (0.3053 g, 30 mol%), and K2CO3 (0.1382 g, 1.0 equiv) in MeOH (10 mL) and H2O (3 mL) was delivered by an HPLC pump at 2 mL min–1 and the air flow was set to 12 mL min–1 with the mass-flow controller. Both fluids were conveyed to the continuous-flow photoreactor through per(fluoroalkoxyalkane) tubing (ID = 1.5 mm). Mixing and irradiation (6000 K white LED, 45 W) occurred along the entire reactor channel (10 mL internal volume) under 3 barg of pressure. After completion of the reaction (TLC), the solution was concentrated under reduced pressure and the residue was purified by column chromatography [silica gel, PE–EtOAc (5:1)] to afford pure product 2a. 1-(3-Hydroxy-2-methylphenyl)propan-1-one (2a) Colorless oil; yield: 0.103 g (63%). 1H NMR (600 MHz, CDCl3): δ = 7.96 (d, J = 7.2 Hz, 2 H), 7.57 (t, J = 7.2 Hz, 1 H), 7.47 (t, J = 7.2 Hz, 2 H), 3.93 (dd, J = 10.8, 7.2 Hz, 1 H), 3.80 (dd, J = 10.8, 4.2 Hz, 1 H), 3.70–3.62 (m, 1 H), 2.22 (s, 1 H), 1.23 (d, J = 7.2 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 204.4, 136.1, 133.3, 128.7, 128.4, 64.5, 42.9, 14.6.