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...
Saved in:
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-04-01
|
| Series: | Molecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1420-3049/30/8/1823 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849713397325627392 |
|---|---|
| author | Amie Saidykhan Jenessa Ebert Nathan W. Fenwick William H. C. Martin Richard D. Bowen |
| author_facet | Amie Saidykhan Jenessa Ebert Nathan W. Fenwick William H. C. Martin Richard D. Bowen |
| author_sort | Amie Saidykhan |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-cd5184e1d89340a891aba307df14bf39 |
| institution | DOAJ |
| issn | 1420-3049 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj-art-cd5184e1d89340a891aba307df14bf392025-08-20T03:13:58ZengMDPI AGMolecules1420-30492025-04-01308182310.3390/molecules30081823Steric Effects of <i>N</i>-Alkyl Group on the Base-Induced Nitrogen to Carbon Rearrangement of Orthogonally Protected <i>N</i>-Alkyl ArylsulphonamidesAmie Saidykhan0Jenessa Ebert1Nathan W. Fenwick2William H. C. Martin3Richard D. Bowen4School of Chemistry and Biosciences, Faculty of Life Sciences, University of Bradford, Bradford BD7 1DP, UKSchool of Chemistry and Biosciences, Faculty of Life Sciences, University of Bradford, Bradford BD7 1DP, UKSchool of Chemistry and Biosciences, Faculty of Life Sciences, University of Bradford, Bradford BD7 1DP, UKSchool of Chemistry and Biosciences, Faculty of Life Sciences, University of Bradford, Bradford BD7 1DP, UKSchool of Chemistry and Biosciences, Faculty of Life Sciences, University of Bradford, Bradford BD7 1DP, UKThe 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.https://www.mdpi.com/1420-3049/30/8/1823sulphonamidesrearrangementortho metalationsteric effectssaccharins |
| spellingShingle | Amie Saidykhan Jenessa Ebert Nathan W. Fenwick William H. C. Martin Richard D. Bowen Steric Effects of <i>N</i>-Alkyl Group on the Base-Induced Nitrogen to Carbon Rearrangement of Orthogonally Protected <i>N</i>-Alkyl Arylsulphonamides Molecules sulphonamides rearrangement ortho metalation steric effects saccharins |
| title | Steric Effects of <i>N</i>-Alkyl Group on the Base-Induced Nitrogen to Carbon Rearrangement of Orthogonally Protected <i>N</i>-Alkyl Arylsulphonamides |
| title_full | Steric Effects of <i>N</i>-Alkyl Group on the Base-Induced Nitrogen to Carbon Rearrangement of Orthogonally Protected <i>N</i>-Alkyl Arylsulphonamides |
| title_fullStr | Steric Effects of <i>N</i>-Alkyl Group on the Base-Induced Nitrogen to Carbon Rearrangement of Orthogonally Protected <i>N</i>-Alkyl Arylsulphonamides |
| title_full_unstemmed | Steric Effects of <i>N</i>-Alkyl Group on the Base-Induced Nitrogen to Carbon Rearrangement of Orthogonally Protected <i>N</i>-Alkyl Arylsulphonamides |
| title_short | Steric Effects of <i>N</i>-Alkyl Group on the Base-Induced Nitrogen to Carbon Rearrangement of Orthogonally Protected <i>N</i>-Alkyl Arylsulphonamides |
| title_sort | steric effects of i n i alkyl group on the base induced nitrogen to carbon rearrangement of orthogonally protected i n i alkyl arylsulphonamides |
| topic | sulphonamides rearrangement ortho metalation steric effects saccharins |
| url | https://www.mdpi.com/1420-3049/30/8/1823 |
| work_keys_str_mv | AT amiesaidykhan stericeffectsofinialkylgrouponthebaseinducednitrogentocarbonrearrangementoforthogonallyprotectedinialkylarylsulphonamides AT jenessaebert stericeffectsofinialkylgrouponthebaseinducednitrogentocarbonrearrangementoforthogonallyprotectedinialkylarylsulphonamides AT nathanwfenwick stericeffectsofinialkylgrouponthebaseinducednitrogentocarbonrearrangementoforthogonallyprotectedinialkylarylsulphonamides AT williamhcmartin stericeffectsofinialkylgrouponthebaseinducednitrogentocarbonrearrangementoforthogonallyprotectedinialkylarylsulphonamides AT richarddbowen stericeffectsofinialkylgrouponthebaseinducednitrogentocarbonrearrangementoforthogonallyprotectedinialkylarylsulphonamides |