Regioselective Synthesis of 2,8-Disubstituted 4-Aminopyrido[3,2-<i>d</i>]pyrimidine-6-carboxylic Acid Methyl Ester Compounds

We report herein the synthesis of 4-amino-2,8-dichloropyrido­[3,2-<i>d</i>]­pyrimidine derivatives <b>2</b> and their regioselective diversification through S_NAr and metal-catalyzed cross-coupling reactions. While amination of <b>2</b> took place selectively at C-2, the regioselectivity of thiol or thiolate addition depended on the reaction conditions. Selective C-8 addition was obtained in DMF with Hünig’s base and C-2 addition in ^<i>i</i>PrOH. These C-2 or C-8 regioselective thiolations provided an opportunistic way to selectively activate either of the two positions toward the metal-catalyzed cross-coupling reaction. The chloride could be efficiently substituted by Suzuki–Miyaura reaction and the sulfanyl group by Liebeskind–Srogl cross-coupling reaction, demonstrating the orthogonality of both reactive centers. The development of regioselective conditions for these different transformations yielded the synthesis of 4-amino-2,6,8-trisubstituted pyrido­[3,2-<i>d</i>]­pyrimidine derivatives, with various substituents

Regioselective Synthesis of 2,8-Disubstituted 4-Aminopyrido[3,2-<i>d</i>]pyrimidine-6-carboxylic Acid Methyl Ester Compounds

We report herein the synthesis of 4-amino-2,8-dichloropyrido­[3,2-<i>d</i>]­pyrimidine derivatives <b>2</b> and their regioselective diversification through S_NAr and metal-catalyzed cross-coupling reactions. While amination of <b>2</b> took place selectively at C-2, the regioselectivity of thiol or thiolate addition depended on the reaction conditions. Selective C-8 addition was obtained in DMF with Hünig’s base and C-2 addition in ^<i>i</i>PrOH. These C-2 or C-8 regioselective thiolations provided an opportunistic way to selectively activate either of the two positions toward the metal-catalyzed cross-coupling reaction. The chloride could be efficiently substituted by Suzuki–Miyaura reaction and the sulfanyl group by Liebeskind–Srogl cross-coupling reaction, demonstrating the orthogonality of both reactive centers. The development of regioselective conditions for these different transformations yielded the synthesis of 4-amino-2,6,8-trisubstituted pyrido­[3,2-<i>d</i>]­pyrimidine derivatives, with various substituents

Access and Regioselective Transformations of 6-Substituted 4-Aryl-2,8-dichloropyrido[3,2-<i>d</i>]pyrimidine Compounds

We report herein an efficient route for the synthesis of 2,4,8-trichloropyrido­[3,2-<i>d</i>]­pyrimidines <b>1</b> with R¹ substituents at C-6. The potential of such scaffolds was demonstrated by the possibility to displace regioselectively each aromatic chloride to introduce diversity. Sequential sulfur nucleophilic addition followed by Liebeskind–Srogl cross-coupling reaction yielded unprecedented aryl introduction at C-4 on a trichloropyrido­[3,2-<i>d</i>]­pyrimidine derivative. The reactivity difference of the remaining two chlorides toward S_NAr reactions was investigated. Amination yielded high C-2 regioselectivity, while thiolation was influenced by C-6 substituents, resulting in medium to high C-2 versus C-8 regioselectivity. The last chloride was efficiently displaced by S_NAr, Suzuki–Miyaura cross-coupling reaction, or reduction. C-2 arylation as a final step was also possible by Liebeskind–Srogl cross-coupling reaction on the previously introduced C-2 thioether. A concise and highly divergent synthetic use of <b>1</b> was developed, thereby providing an efficient approach to explore the structure–activity relationship of pyrido­[3,2-<i>d</i>]­pyrimidine derivatives such as <b>9</b>, <b>10</b>, <b>15</b>, and <b>16</b>

Access and Regioselective Transformations of 6-Substituted 4-Aryl-2,8-dichloropyrido[3,2-<i>d</i>]pyrimidine Compounds

We report herein an efficient route for the synthesis of 2,4,8-trichloropyrido­[3,2-<i>d</i>]­pyrimidines <b>1</b> with R¹ substituents at C-6. The potential of such scaffolds was demonstrated by the possibility to displace regioselectively each aromatic chloride to introduce diversity. Sequential sulfur nucleophilic addition followed by Liebeskind–Srogl cross-coupling reaction yielded unprecedented aryl introduction at C-4 on a trichloropyrido­[3,2-<i>d</i>]­pyrimidine derivative. The reactivity difference of the remaining two chlorides toward S_NAr reactions was investigated. Amination yielded high C-2 regioselectivity, while thiolation was influenced by C-6 substituents, resulting in medium to high C-2 versus C-8 regioselectivity. The last chloride was efficiently displaced by S_NAr, Suzuki–Miyaura cross-coupling reaction, or reduction. C-2 arylation as a final step was also possible by Liebeskind–Srogl cross-coupling reaction on the previously introduced C-2 thioether. A concise and highly divergent synthetic use of <b>1</b> was developed, thereby providing an efficient approach to explore the structure–activity relationship of pyrido­[3,2-<i>d</i>]­pyrimidine derivatives such as <b>9</b>, <b>10</b>, <b>15</b>, and <b>16</b>

Regioselective Synthesis of 2,8-Disubstituted 4-Aminopyrido[3,2-<i>d</i>]pyrimidine-6-carboxylic Acid Methyl Ester Compounds

We report herein the synthesis of 4-amino-2,8-dichloropyrido­[3,2-<i>d</i>]­pyrimidine derivatives <b>2</b> and their regioselective diversification through S_NAr and metal-catalyzed cross-coupling reactions. While amination of <b>2</b> took place selectively at C-2, the regioselectivity of thiol or thiolate addition depended on the reaction conditions. Selective C-8 addition was obtained in DMF with Hünig’s base and C-2 addition in ^<i>i</i>PrOH. These C-2 or C-8 regioselective thiolations provided an opportunistic way to selectively activate either of the two positions toward the metal-catalyzed cross-coupling reaction. The chloride could be efficiently substituted by Suzuki–Miyaura reaction and the sulfanyl group by Liebeskind–Srogl cross-coupling reaction, demonstrating the orthogonality of both reactive centers. The development of regioselective conditions for these different transformations yielded the synthesis of 4-amino-2,6,8-trisubstituted pyrido­[3,2-<i>d</i>]­pyrimidine derivatives, with various substituents