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

Abstract

We report herein the synthesis of 4-amino-2,8-dichloropyrido[3,2-d]pyrimidine derivatives 2 and their regioselective diversification through S(N)Ar and metal-catalyzed cross-coupling reactions. While amination of 2 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)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-d]pyrimidine derivatives, with various substituents.

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

“…At this point, Liebeskind–Srogl cross-coupling reaction was investigated as an option . As previously reported, S N Ar reactions on 1c is highly regioselective at C-4. , Taking advantage of it, sulfur nucleophilic addition was performed regioselectively at C-4 to lead to 6 . Sodium methylthiolate was added to a solution of derivative 1 in THF at −10 °C.…”

“…Given the vastness of the chemical space, the challenge for medicinal chemists is to identify cores that are more likely to lead to drug candidates. , In our continued effort to design lead-like arrays of compounds to be included in our corporate screening collection, we were particularly interested in the accessibility of heterocyclic scaffolds bearing several reactive sites, which could be functionalized regioselectively for straightforward synthesis of analogues. In this context, we have recently reported the synthesis of 4-amino-2,8-dichloropyrido­[3,2- d ]­pyrimidine-6-carboxylic acid methyl ester derivative 1c and its regioselective diversification through S N Ar and metal-catalyzed cross-coupling reactions (Scheme ) . We report herein an extension of our studies on pyrido­[3,2- d ]­pyrimidines with a general synthesis of 2,4,8-trichloropyrido­[3,2- d ]­pyrimidines 1 having methyl, phenyl, and ester groups at C-6 and the successive and selective displacement of the different chlorides.…”

Regiocontroled SNAr and Palladium Cross‐Coupling Reactions of 2,4,7‐Trichloropyrido[3,2‐d]pyrimidine

“…Selective chlorination of heterocycles in the position β to a nitrogen atom has been observed with [1,10]phenanthroline,14 quinoline,15 1,6‐naphthyridine,16 and 7‐bromo‐2 H ‐isoquinolin‐1‐one;17 but to the best of our knowledge, the direct trichlorination of pyrido[3,2‐ d ]pyrimidine in a single step has not yet been described. The sole reported trichlorinated [3,2‐ d ]pyridopyrimidine is methyl 2,4,8‐trichloropyrido[3,2‐ d ]pyrimidine‐6‐carboxylate, which was used recently by Quattropani et al18…”

Recent advances in the chemistry and biology of pyridopyrimidines

“…The C-2 chlorine atom present in compound 83 was also reacted with n-butylamine, benzylamine or diethyl amine, affording the corresponding C-2,C-4 diamino C-8 methylthio derivatives 87 in 71e74% yield (Scheme 25) [29].…”