Regioselective Reactions of Organozinc Reagents with 2,4-Dichloroquinoline and 5,7-Dichloropyrazolo[1,5-a]pyrimidine

Abstract

Strategies for controlling the regioselective reactions between 2,4-dichloroquinoline and organozinc reagents are described. 2,4-Dichloroquinoline has been found to react with benzylic zinc and phenylzinc reagents in the presence of catalytic amounts of palladium complexes to exclusively give R-substituted products. Several metal salts were examined as an additive for γ-selective coupling reactions. The most effective additive for selective coupling reaction at the γ-position has been found to be LiCl. These conditions for Ror γ-selective coupling reactions were applied to the reaction between 5,7-dichloropyrazolo[1,5-a]pyrimidine and a biphenylmethylzinc reagent in the synthesis of the angiotensin II receptor antagonists. This regioselectivity should be generally applicable to other R,γ-dichloroazine systems.

Theoretical Bond Dissociation Energies of Halo-Heterocycles: Trends and Relationships to Regioselectivity in Palladium-Catalyzed Cross-Coupling Reactions

“…The fused phenyl ring has C-Cl BDEs that are similar to that of chlorobenzene (97.6 kcal/mol19) and approximately 4 kcal/mol higher than the 2-position. A Negishi cross-coupling of 2,4-dichloroquinoline with phenylzinc chloride gives the product arising from substitution at the 2-position in 80% yield 33. This substitution pattern can also be seen with a Suzuki or a Stille reaction 1…”

Palladium-Catalyzed Coupling Reactions of Aryl Chlorides

“…(3)] 12, 13. Subsequently, other chloro‐substituted nitrogen heterocycles have been shown to undergo Suzuki coupling in the presence of traditional palladium catalysts including pyridines,13a–13c, 14 pyridine N ‐oxides,14h pyrazines,12d, 13b–13d, 15 pyridazines,12d, 16 triazines,13e, 13g, 17 quinolines,13c, 18 isoquinolines,13a, 19 quinazolines,20 cinnolines,20b phthalazines,21 β‐carbolines,22 phenanthrolines,23 imidazo[1,2‐ b ]pyridazines,24 pyrazolo[1,5‐ a ]pyrimidines,18b pyrazolopyrimidines,13e triazolopyrimidines,13e pyrrolopyrimidines,13e and purines 25 …”

“…As with Suzuki and Stille couplings, there are quite a few examples of heteroaryl chlorides, mainly nitrogen‐containing species, which participate in the Negishi reaction. Thus, chloropyridines,141 pyrazines,15a, 142 pyrimidines,143 and triazines144 are suitable substrates, as are fused heterocycles such as chloroquinolines,18b, 110d, 145 quinazolines,113 and purines 25d, 116b…”

Six‐Membered Heterocycles: Quinoline and Isoquinoline

“…Strategies for controlling the regiochemistry of the addition reaction between organozinc reagents and 2,4-dichloroquinoline have been developed [181]. Similarly, the palladium-catalyzed carbonylation of quinolyl bromides and triflates has been described [182].…”