The first regioselective metalation and functionalization of unprotected 4-halobenzoic acids

[reaction: see text] By treatment with s-BuLi, s-BuLi/TMEDA, or t-BuLi at approximately -78 degrees C, 4-fluoro- and 4-chlorobenzoic acids (1a,b) are metalated preferentially in the position adjacent to the carboxylate. A complete reversal in regioselectivity is observed for 1a when treated with LTMP; a sequential process involving a rapid intraaggregate lithiation through a quasi dianion complex "QUADAC" is postulated to explain the unusual reactivity of Me(2)S(2) and I(2).     

Ring-selective functionalization of N,N'-diarylureas by regioselective N-alkylation and directed ortho metalation

[reaction: see text]. Unsymmetrical N,N'-diarylureas may be alkylated regioselectively at the more sterically congested nitrogen atom. The resulting mono-N-alkylated ureas undergo directed metalation (ortholithiation) with sec-BuLi to yield, on electrophilic quench, products functionalized regioselectively at the ring bearing the alkylated nitrogen atom.     

Highly regioselective synthesis of 2,3,4-trisubstituted 1H-pyrroles: a formal total synthesis of lukianol A

A combined use of alpha-lithiation and nucleophilic substitutions of N,N-dimethyl 3,4-bis(trimethylsilyl)-1H-pyrrole-1-sulfonamide 8c led to several 2-substituted 3, 4-bis(trimethylsilyl)-1H-pyrrole-1-sulfonamides. Utilizing the beta-effect of a trimethylsilyl group, a highly regioselective synthesis of 2,3,4-trisubstituted 1H-pyrroles 23 and 34 was accomplished. The marine natural product lukianol A (3) was prepared utilizing this strategy.     

Directed metalation and regioselective functionalization of 3-bromofuran and related heterocycles with NaHMDS

A mild and regioselective functionalization protocol for 3-bromofuran and analogs has been developed. Selective metalation and functionalization of C2 can be achieved as a result of the directing effect of the adjacent electron-withdrawing bromo group. In addition, the C5 position can also be selectively functionalized by blocking the C2 position via silylation or by simply controlling the reaction temperature. These functionalized compounds bearing a C3 bromo substituent may be further elaborated by utilizing a Suzuki–Miyaura cross-coupling procedure.     

A new regioselective synthesis and ambient light photochemistry of quinazolin-1-oxides

Quinazolin-1-oxides were prepared by the oxidation of tetrahydroquinazolines with H₂O₂-tungstate and their ambient light photochemistry was investigated. Substituent effects on their photochemical cyclization and the reactions of the products 1aH-[1,2]oxazireno[2,3-a]quinazolines under photochemical and thermal conditions are reported. The cyclization of quinazolin-1-oxides and the reactions of 1aH-[1,2]oxazireno[2,3-a]quinazolines show pronounced solvent isotope and solvent effects.     

Solution and solid-supported synthesis of 3,4,5-trisubstituted 1,2,4-triazole-based peptidomimetics

[reaction: see text] 3,4,5-Trisubstituted 1,2,4-triazoles were synthesized in solution from various thioamides and hydrazides in smooth experimental conditions leading to peptidomimetic scaffolds. This strategy was found to be compatible with the usual peptide synthesis protecting groups. This methodology was then applied on solid support by anchoring alpha-amino acids through their amino function to an activated carbonate resin.     

Palladium(0)-catalyzed regioselective and multicomponent synthesis of 1,2,3-trisubstituted 1H-indenes

A multicomponent synthesis of biologically important indenes bearing three substituent groups at the 1-, 2-, and 3-positions from available o-ethynylbenzaldehyde derivatives and organoboron reagents under palladium(0) catalysis is described. A two-component coupling reaction in methanol provides 1H-indenols, whereas a three-component reaction involving secondary aliphatic amines as the third component in DMF affords 1H-indenamines. This method allows combinatorial preparation of unsymmetrically substituted 1H-indenes that cannot be prepared via previous synthetic routes.     

Reaction of N-monosubstituted hydrazones with nitroolefins: a novel regioselective pyrazole synthesis

A novel regioselective synthesis of substituted pyrazoles from N-monosubstituted hydrazones and nitroolefins is described. The reaction is performed in a one-pot manner and the yields range from moderate to excellent. A key nitropyrazolidine intermediate is characterized and a plausible mechanism is proposed.     

Synthesis of 3,4,5-trisubstituted indoles via iterative directed lithiation of 1-(triisopropylsilyl)gramines

Directed lithiation of 1-(triisopropylsilyl)gramines 1 with tert-butyllithium followed by reaction with trimethylsilylmethyl azide produced 4-amino-1-(triisopropylsilyl)gramines 7. The N-tert-butoxycarbonyl derivatives 8 were lithiated selectively at C-5 with tert-butyllithium and the lithiated species were reacted with a variety of electrophiles to give 5-functionalized compounds, 9 and 10. A facile method to produce 3,4,5-trisubstituted indoles from readily available gramine derivatives is thereby established.     

Highly stereo- and regioselective synthesis of (Z)-trisubstituted alkenes via 1-bromo-1-alkyne hydroboration-migratory insertion-Zn-promoted iodinolysis and Pd-catalyzed organozinc cross-coupling

Hydroboration of 1-bromo-1-alkynes with dibromoborane followed by addition of 3 or 4 equiv of Me2Zn provides an efficient and selective route to (Z)-2-alkenyldimethylboranes (3) or (Z)-2-alkenylmethylzincs (4), respectively, which have been successfully applied to one-pot Suzuki (B-I) or Negishi (Zn-I) coupling in some less demanding cases. However, in more demanding cross-coupling reactions, only the use of either (Z)-2-alkenyliodides (5) or the alkenylzincs prepared from lithiation and then zincation of 5 proves to be highly satisfactory (Zn-II or Zn-III protocol). On the contrary, the corresponding organoboron coupling under B-II or B-III protocol appears to be less satisfactory. Preliminary studies indicate that certain substituents proximal to trisubstituted alkenes seriously affect the course of the desired alkenylboron cross-coupling.     

Divergent and regioselective synthesis of 1,2,4- and 1,2,5-trisubstituted imidazoles

A divergent and regioselective synthesis of 1,2,4- and 1,2,5-trisubstituted imidazoles from a readily available (two steps) common intermediate has been developed. This methodology is based on the regiocontrolled N-alkylation of 1-(N,N-dimethylsulfamoyl)-5-iodo-2-phenylthio-1H-imidazole (10). When this intermediate is engaged in reaction with methyl triflate, selective formation of the corresponding 1,2,5-trisubsituted 1H-imidazole is observed. NMR studies have revealed that this regioselectivity can be accounted for by in situ rapid isomerization of 10 into its 1,2,4-isomer (13) followed by regiospecific N-alkylation of the latter. Conversely, when key intermediate 10 is slowly added to Meerwein's salt, isomerization can be constrained and regiospecific N-alkylation of 10 leads to 1,2,4-trisubstituted 1H-imidazole with a high selectivity. The general character of this methodology has been illustrated by showing that iodine in position 4 or 5 could be easily substituted by an aryl group by Suzuki coupling, whereas the phenylthio group at position 2 could, after oxidation into sulfone, be displaced by nucleophilic substitution.     

A simple, modular method for the synthesis of 3,4,5-trisubstituted pyrazoles

A modular approach for the regiocontrolled preparation of pyrazoles bearing substituents on all three carbon atoms is described. Central to this method is the use of a switchable metal-directing group (MDG) to enable sequential direct lithiation of the 3- and 5-positions of the pyrazole ring. Pyrazole boronic esters obtained from these lithiated intermediates can undergo efficient Suzuki cross-coupling under the developed nonaqueous conditions, which minimize undesirable protolytic deboronation. Halogenation of the 4-position provides the means for substitution at the remaining carbon atom.     

Stereoselective synthesis of chiral 3,4,5-trisubstituted 1,5-dihydropyrrol-2-ones from azadienes

A new access to enantiopure 3-phthalimido-4-amino-5-(1-hydroxyalkyl) 1,5-dihydropyrrol-2-ones has been developed from 1,3-azadienes. Stereoselective Lewis acid catalyzed addition of a cyano group to an azadiene, followed by intramolecular ring closure, in a four-step one-pot synthesis, results in the formation of γ-lactams in satisfactory yields.     

Recent advances in the synthesis and functionalization of 1,2,5-oxadiazole 2-oxides

Among the variety of nitrogen heterocycles, the furoxan (1,2,5-oxadiazole 2-oxide) scaffold has attracted considerable attention owing to its ability to release NO under physiological conditions. Therefore, significant efforts of organic chemists have been directed toward the construction of new drug candidates containing the NO-donor furoxan subunit connected to a known pharmaceutical or a potential pharmacophore by CC/CN bonds or through an appropriate linker. This digest summarizes the recent information concerning both new synthetic approaches for the furoxan ring construction and various methods for the functionalized furoxan synthesis with particular focus on the last three years. Methods for the furoxan ring formation including cyclodimerization of nitrile oxides, nitrosation of unsaturated compounds, and acylation of dinitromethane sodium salt are reviewed. The functionalization of furoxan ring is represented by nucleophilic substitution of nitro and arylsulfonyl groups as well as by different condensations of cyano-, carbonyl- and carboxyfuroxan derivatives. Synthesis of hybrid structures combining NO-donor furoxan ring and some pharmacophoric moiety is also considered.     

Enantioselective syntheses of 3,4,5-trisubstituted γ-lactones: formal synthesis of (−)-blastmycinolactol

A kinetic resolution process of Rh-catalyzed intramolecular Alder-ene reaction is described along with the studies of the substrate scope and stereochemistry of this remarkably efficient process. 3,4,5-Trisubstituted γ-lactones were synthesized in high enantioselectivity (>99% ee) and efficiency. The formal asymmetric syntheses of (−)-blastmycinolactol and (+)-blastmycinone, degradation products of the macrocyclic dilactone (+)-antimycin, were reported to address the applications of this methodology.     

Highly regioselective synthesis of aryl chalcogenides through C-H functionalization of arenes

We report here the regioselective synthesis of aryl chalcogenides through the iridium-catalyzed meta C-H borylation followed by copper-catalyzed C-S coupling reaction with chalcogenide sources in one pot, giving the 3,5-disubstituted aryl chalcogenides with high regioselectivity and good yields.     

Studies on pyrazines. 29 . High regioselective synthesis of chloropyrazines from 3-substituted pyrazine 1-oxides

Reaction of 3-methoxy- or 3-chloropyrazine 1-oxides with refluxing phosphoryl chloride in the presence of amine led to a high regioselective formation of 3-substituted 2-chloropyrazines. In contrast, the use of chloroacetyl chloride instead of phosphoryl chloride enabled different regioselectivity to yield 6-substituted 2-chloropyrazines, particularly 3-methoxycarbonylpyrazine 1-oxide was almost exclusively converted into methyl 6-chloropyrazinecarboxylate under the conditions without the amine.