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>

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>

A Synthetic and Mechanistic Investigation of the Chromium Tricarbonyl-Mediated Masamune–Bergman Cyclization. Direct Observation of a Ground-State Triplet <i>p</i>-Benzyne Biradical

A new room-temperature chromium tricarbonyl-mediated cycloaromatization of enediynes is reported. The reaction occurs with both cyclic and acyclic enediynes in the presence of [Cr­(CO)₃(η⁶-naphthalene)] and both a coordinating solvent and a hydrogen atom source, providing chromium–arene complexes in reasonable yield and good diastereocontrol. The mechanism of the reaction has been probed through DFT computational and spectroscopic methods. These studies suggest that direct C1–C6 bond formation from an η⁶-enediyne complex is the lowest-energy path, forming a metal-bound <i>p</i>-benzyne biradical. NMR spectroscopy suggests that enediyne alkene coordination occurs in preference to alkyne coordination, forming a THF-stabilized olefin intermediate; subsequent alkyne coordination leads to cyclization. While biradical quenching occurs rapidly and primarily via the singlet biradical, the triplet state biradical is detectable by EPR spectroscopy, suggesting intersystem crossing to a triplet ground state

A Synthetic and Mechanistic Investigation of the Chromium Tricarbonyl-Mediated Masamune–Bergman Cyclization. Direct Observation of a Ground-State Triplet <i>p</i>-Benzyne Biradical

A new room-temperature chromium tricarbonyl-mediated cycloaromatization of enediynes is reported. The reaction occurs with both cyclic and acyclic enediynes in the presence of [Cr­(CO)₃(η⁶-naphthalene)] and both a coordinating solvent and a hydrogen atom source, providing chromium–arene complexes in reasonable yield and good diastereocontrol. The mechanism of the reaction has been probed through DFT computational and spectroscopic methods. These studies suggest that direct C1–C6 bond formation from an η⁶-enediyne complex is the lowest-energy path, forming a metal-bound <i>p</i>-benzyne biradical. NMR spectroscopy suggests that enediyne alkene coordination occurs in preference to alkyne coordination, forming a THF-stabilized olefin intermediate; subsequent alkyne coordination leads to cyclization. While biradical quenching occurs rapidly and primarily via the singlet biradical, the triplet state biradical is detectable by EPR spectroscopy, suggesting intersystem crossing to a triplet ground state