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. 2022 May 3;58(36):5490-5493.
doi: 10.1039/d2cc01518h.

Generation of formaldehyde and formaldehyde-d2 for hydroxymethylations and hydroxydeuteromethylations of difluoroenolates and difluorobenzyl carbanions

Hari R Khatri  1 , Changho Han  2 , Reem A Alkhodier  1 , Amna T Adam  1 , Baharul Islam  1 , David A Colby  1
Affiliations

Generation of formaldehyde and formaldehyde-d2 for hydroxymethylations and hydroxydeuteromethylations of difluoroenolates and difluorobenzyl carbanions

Hari R Khatri et al. Chem Commun (Camb). .

Abstract

A method for the in situ production of formaldehyde from dimethylsulfoxide, bromine, and cesium carbonate is reported for reactions with difluoroenolates and difluorobenzyl carbanions. This process also generates formaldehyde-d2 for the production of 2,2-difluoro-1,1-deuteroethanols. Mechanistic and computational studies further characterize the production of hydroxymethylated and hydroxydeuteromethylated difluorinated organic molecules.

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Conflict of interest statement

Conflicts of interest

D.A.C. serves as a scientific advisor for GnuPharma, and some of the studies in this manuscript were conducted with unrestricted support from GnuPharma. The authors declare no other competing financial interests.

Figures

Figure 1
Figure 1
Typical sources of formaldehyde.
Figure 2
Figure 2
The generation of difluorocarbanions from the release of trifluoroacetate and the preparation of 2,2-difluoroethanols from the generation of formaldehyde in the presence of these reactive intermediates.
Figure 3
Figure 3
Proposed mechanism for the generation of formaldehyde from K2CO3, Br2, and DMSO starting from the methyl(methylene)sulfonium cation. The changes in free energy and enthalpy for the fragmentation step are shown (in kcal/mol at 298.15 K). 1H NMR data was obtained in acetone-d6 at 400 MHz at rt.
Figure 4
Figure 4
Conversion of 1,1,1,3,3-pentafluoro-3-(4-nitrophenyl)propane-2,2-diol into 1-(difluoromethyl)-4-nitrobenzene 19 and 1-(deuterodifluoromethyl)-4-nitrobenzene 20 with K2CO3 in DMSO at 65 °C.
Scheme 1
Scheme 1
Synthesis of difluoroethanols 1–6 by hydroxymethylation from the in situ generation of formaldehyde and difluoroenolates, and synthesis of difluorodideuteroethanols 7–9 by hydroxydeuteromethylation (percent deuterium incorporation is listed in brackets). aStirred at rt. bStirred at 40 °C.
Scheme 2
Scheme 2
Synthesis of difluoroethanols 10–15 by hydroxymethylation from the in situ generation of formaldehyde and difluorobenzyl carbanions, and synthesis of difluorodideuteroethanols 16–18 by hydroxydeuteromethylation (percent deuterium incorporation is listed in brackets).
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