A convenient approach to the multigram synthesis of functionalized 1,2‐disubstituted cyclopropyltrifluoroborates was developed, based on Pd(II)‐ or Cu(I)‐catalyzed reaction of vinyltrifluoroborate and diazo compounds. Optimized protocols allowed for the preparation of the target products as pure diastereomers on multigram scale. It was shown that the title compounds were good coupling partners for the Suzuki‐Miyaura and Chan‐Lam reactions, which provide medicinally relevant (het)arylcyclopropanes with high diastereoselectivity.magnified image
A gram-scale synthesis, physico-chemical characterization, and lead-likeness assessment of 4-di/trifluoromethyl-2-heterabicyclo [2.1.1]hexanes as fluorinated bicyclic proline analogues and phenyl isosteres are disclosed. The key step of the synthesis included iodocyclization of fluorinated 3-hydroxy-/3aminomethyl methylenecyclobutanes; with the amino derivatives, the reaction was accompanied with carboxylation and further cyclization. Apart from the corresponding 4-di/ trifluoromethyl-2,4-methanoprolines, a series of fluorinated oxabicyclo[2.1.1]hexane-derived building blocks relevant to medicinal chemistry (i. e. primary iodides, carboxylic acids, alcohols, azides, primary amines, sulfonyl chlorides, and alkynes) were prepared. For representative derivatives of the resulting fluorinated 2-oxabicyclo[2.1.1]hexanes, pK a and logP values were measured to clarify their potential as the possible phenyl isosteres. Apart from the somewhat increased acidity, finetuned lipophilicity intermediate between that of non-fluorinated or aromatic counterparts was observed. Finally, the potential of the title building blocks was demonstrated by generation of virtual compound libraries using the LLAMA software. The resulting libraries fitted perfectly the lead-like chemical space, had higher three-dimensionality, and showed lower mean lead-likeness penalty as compared to those obtained from either non-fluorinated or aromatic derivatives.
An approach to all isomeric 3‐pyridylcyclobutane‐derived building blocks, i.e. ketones, alcohols and amines, is described. Synthesis of the title compounds relied on the five‐step reaction sequence including alkylation of isomeric pyridyl acetonitriles with 1,3‐dibromo‐2,2‐dimethoxypropane. Hydrolysis, decarboxylation and removal of the ketal moiety led to the key 3‐pyridylcyclobutanones (obtained on up to 120 g scale in a single run), which were transformed into the corresponding alcohols and amines with high diastereoselectivity. The title cyclobutanone derivatives were used to synthesize three isomeric nicotine analogues, as well as for parallel synthesis of a small lead‐like compound library via reductive amination.
o-Bromoarylsulfonylated amidines prepared either by acylation of amidine with o-bromoarylsulfonyl chloride or through the reaction of o-bromoarylsulfoamide with lactime ether underwent Cu(I)-catalyzed intramolecular cyclization to give 4H-1,2,4-benzothiadiazine-1,1-dioxides in good yield. By varying substituents on arylsulfonyl moieties, amidines, and lactime ethers, a small library of structurally diverse 4H-1,2,4-benzothiadiazine-1,1-dioxide derivatives was prepared.
A set of synthetic procedures was developed to yield functionalized pyrido‐, pyrimido‐, and thiazo‐annulated thiadiazine‐1,1‐dioxides on a preparative scale. In all cases the thiadiazine‐1,1‐dioxide ring closure was carried out through a reaction of hetaryl‐sulfonyl chlorides with amidines under mild noncatalytic conditions. In the case of 2‐chloropyridine‐3‐sulfonyl chloride derivatives and 2,4‐dichlorothiazole‐5‐sulfonyl chloride open‐chain sulfonylated amidine intermediates were isolated and then subjected to the cyclization step. The reaction with 2,4‐dichloropyrimidine‐5‐sulfonyl chloride gave rise to the corresponding thiadiazine‐1,1‐dioxides in one‐pot. Similarly, a reaction of 2‐chloropyridine‐3‐sulfonamide with lactime ethers proceeded in one‐pot readily giving the corresponding thiadiazine‐1,1‐dioxides. Remaining chlorine atoms on the prepared hetaryl‐annulated benzothiadiazine‐1,1‐dioxides readily undergo aromatic nucleophilic displacement reactions serving thus as additional variation points for the design of biologically potent compounds.
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