Steric Effects of <i>N</i>-Alkyl Group on the Base-Induced Nitrogen to Carbon Rearrangement of Orthogonally Protected <i>N</i>-Alkyl Arylsulphonamides
The rearrangement of a total of 56 members of 22 series of orthogonally protected <i>N</i>-alkyl arylsulphonamides of general structure 4-XC<sub>6</sub>H<sub>4</sub>SO<sub>2</sub>NR<sup>1</sup>CO<sub>2</sub>R<sup>2</sup...
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| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-04-01
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| Series: | Molecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1420-3049/30/8/1823 |
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| Summary: | The rearrangement of a total of 56 members of 22 series of orthogonally protected <i>N</i>-alkyl arylsulphonamides of general structure 4-XC<sub>6</sub>H<sub>4</sub>SO<sub>2</sub>NR<sup>1</sup>CO<sub>2</sub>R<sup>2</sup> [X = H, CH<sub>3</sub>, F, Cl, Br, CH<sub>3</sub>O, CN, CF<sub>3</sub> or C(CH<sub>3</sub>)<sub>3</sub>; R<sup>1</sup> = CH<sub>3</sub>, CH<sub>2</sub>CH<sub>3</sub>, CH<sub>2</sub>CH<sub>2</sub>CH<sub>3</sub>, CH(CH<sub>3</sub>)<sub>2</sub> or CH<sub>2</sub>CH(CH<sub>3</sub>)<sub>2</sub>; R<sup>2</sup> = CH<sub>3</sub>, C<sub>2</sub>H<sub>5</sub> or C(CH<sub>3</sub>)<sub>3</sub>] when treated with lithium di-isopropylamide in tetrahydrofuran at −78 °C has been studied. The competition between directed ortho metalated rearrangement, to form 4-X-2-(R<sup>2</sup>O<sub>2</sub>C)C<sub>6</sub>H<sub>3</sub>SO<sub>2</sub>NHR<sup>1</sup> and the production of a substituted saccharin, is strongly influenced by the size of R<sup>1</sup> and R<sup>2</sup>, especially in the series with X = CH<sub>3</sub>. When R<sup>1</sup> = CH<sub>3</sub> or to a lesser degree, C<sub>2</sub>H<sub>5</sub>, formation of the saccharin competes to a significant extent, especially when the migrating group is CO<sub>2</sub>CH<sub>3</sub> or CO<sub>2</sub>C<sub>2</sub>H<sub>5</sub>. In contrast, when R<sup>1</sup> is a larger alkyl group, particularly if it is branched at either the α- or β-carbon atom [CH(CH<sub>3</sub>)<sub>2</sub> or CH<sub>2</sub>CH(CH<sub>3</sub>)<sub>2</sub>], the increased steric hindrance essentially prevents cyclisation, thus facilitating rearrangement to 4-X-2-(R<sup>2</sup>O<sub>2</sub>C)C<sub>6</sub>H<sub>3</sub>SO<sub>2</sub>NHR<sup>1</sup> in high yield. The size of the migrating CO<sub>2</sub>R<sup>2</sup> group also exerts an effect on the competition between the reactions: when R<sup>2</sup> = C(CH<sub>3</sub>)<sub>3</sub>, clean rearrangement is possible even when R<sup>1</sup> = CH<sub>3</sub> in each series of X. These results have implications for further elaboration and rearrangement of 4-X-2-(R<sup>2</sup>O<sub>2</sub>C)C<sub>6</sub>H<sub>3</sub>SO<sub>2</sub>NHR<sup>1</sup> in order to prepare substituted saccharins containing a 6-CO<sub>2</sub>R<sup>3</sup> group. |
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| ISSN: | 1420-3049 |