5 research outputs found
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 R<sup>1</sup> 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<sub>N</sub>Ar 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<sub>N</sub>Ar, 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<sub>N</sub>Ar 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 <sup><i>i</i></sup>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 R<sup>1</sup> 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<sub>N</sub>Ar 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<sub>N</sub>Ar, 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<sub>N</sub>Ar 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 <sup><i>i</i></sup>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<sub>N</sub>Ar 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 <sup><i>i</i></sup>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