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. 2022 Nov 16;27(22):7943.
doi: 10.3390/molecules27227943.

Continuous-Flow Synthesis of Arylthio-Cyclopropyl Carbonyl Compounds

Davide Moi  1 , Maria Chiara Cabua  1 , Viktoria Velichko  1 , Andrea Cocco  1 , Annalisa Chiappone  1 , Rita Mocci  1 , Stefania Porcu  2 , Monica Piras  3 , Stefano Bianco  4 , Fabio Pesciaioli  5 , Francesco Secci  1
Affiliations

Continuous-Flow Synthesis of Arylthio-Cyclopropyl Carbonyl Compounds

Davide Moi et al. Molecules. .

Abstract

The straightforward, continuous-flow synthesis of cyclopropyl carbaldehydes and ketones has been developed starting from 2-hydroxycyclobutanones and aryl thiols. This acid-catalyzed mediated procedure allows access to the multigram and easily scalable synthesis of cyclopropyl adducts under mild conditions, using reusable Amberlyst-35 as a catalyst. The resins, suitably ground and used for filling steel columns, have been characterized via TGA, ATR, SEM and BET analyses to describe the physical-chemical properties of the packed bed and the continuous-flow system in detail. To highlight the synthetic versatility of the arylthiocyclopropyl carbonyl compounds, a series of selective oxidation reactions have been performed to access sulfoxide and sulfone carbaldehyde cyclopropanes, oxiranes and carboxylic acid derivatives.

Keywords: Amberlyst; cyclopropanes; flow chemistry; green chemistry; organocatalysis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
(a) Selected synthetic approaches based on the use of arylthiocyclopropyl carbaldehydes and cyclopropyl ketones for the preparation of complex molecules, phenylthiocyclobutanones and heterocyclic compounds. (b) Proposed synthetic procedures for the preparation of arylthiol cyclopropyl carbonyl compounds.
Figure 2
Figure 2
(a). TGA analysis of commercial AR-35 (red) and AR-35 after grinding process (black). (b) ATR-FTIR analysis of neat AR-35 (red) and ground AR-35 (black). (c) BET surface analysis of ground AR-35. (d) A 51× microstructure overview of sample AR-35. To better analyze the structures of the sample, the AsB backscatter method was used. (e) An 1800× image of ground AR-35. (f) A 23,000× image of ground AR-35.
Figure 3
Figure 3
(a) Representative diagram of the continuous-flow system used for the synthesis of cyclopropyl carbaldehydes starting from 1a and benzene thiol 2a; (b) 5 cm stainless steel column packed with AR-35; (c) 2, 10 and 15 cm AR-35 packed columns; (d) column components.
Scheme 1
Scheme 1
Substrate scope exploration. Reactions were performed in THF or 2Me-THF using 1a (or 1b and 1c) (0.01 mol in 20 mL of solvent), thiols 2a–h (0.01 mol in 20 mL solvent, 1.0 equiv.). Yields were calculated after purification.
Scheme 2
Scheme 2
AR-35 acid promoted continuous synthesis of 3a using 1,2-bis-TMSOCB as a starting material. Cyclobutanone 1a is formed in situ through the intermediacy of the acid resin.
Scheme 3
Scheme 3
Rationalization of the AR-35-catalyzed transformation of HCBs 1 (R = H or alkyl) into cyclopropyl derivatives 3 via the intermediacy of the cyclobutylthionium carbocation II.
Figure 4
Figure 4
(a) Evaluation of the catalytic activity of the AR-35 packed column in the reaction between 1b and 2a over six cycles. (b) Evaluation of the catalytic activity of the AR-35 packed column in the reaction between 1b and 2a over ten hours. (c) Raman acquisitions during the continuous-flow synthesis of 3j.
Scheme 4
Scheme 4
(a–e) Chemoselective transformation of compound 3a, leading to derivatives 4–8.
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