Regioselective alkylation reactions of 2,4-diphenyl-3H-1-benzazepine give either 3-alkyl-3H-1-benzazepines or 1-alkyl-1H-1-benzazepines

2,4-Diphenyl-3H-1-benzazepine is deprotonated with either LDA or KHMDS. The resulting anion is alkylated with alkyl halides or MeOTs, giving either products of alkylation at C3, or at N, or a mixture of both. The regioselectivity depends on the base, presence of the complexing agent HMPA, and the leaving group of the alkylating agent. Using MeI as alkylating agent gives exclusively the C3-methylated product, while using MeOTs gives exclusively the N-methylated product. The N-alkylated products show evidence of stereodynamic behavior in their NMR spectra.     

Synthesis and regioselective N- and O-alkylation of 3-alkyl-5-phenyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-ones and 2-phenyl-9-propyl-9H-purin-6(1H)-one with evaluation of antiviral and antitumor activities

3-Alkyl-5-phenyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-ones were prepared by nitrosative cyclization of the appropriate 5,6-diamino-2-phenylpyrimidin-4(3H)-ones with nitrous acid and were subjected to regioselective alkylation with several alkylating agents in aprotic solvent at different temperature. Simultaneous 6-N- and 7-O-alkylation were observed and the regioselectivity varied remarkably with size and shape of the alkylating agents as well as with the reaction temperature. Similarly, N- and O-alkylation as well as selectivity was also observed in the case of 2-phenyl-9-propyl-9H-purin-6(1H)-one. Some of the synthesized compounds showed moderate antiviral and antitumor activities.     

Reductive lithiation of alkoxy-substituted benzyl methyl ethers and connection with cross-coupling reactions

2-and 4-Ethoxymethoxybenzyl methyl ethers were employied as useful starting materials for the synthesis of 1,2- or 1,4-dicarbo-substituted benzenes. The proposed reaction sequence involves connection between the reductive lithiation of benzyl alkyl ethers and the metal-catalyzed cross-coupling reaction of aromatic triflates.     

Synthesis and regioselective substitution of C-6 alkoxy derivatives of (S)-nicotine

Enantiopure (S)-6-alkoxynicotine derivatives have been synthesized in two steps from (S)-nicotine via (S)-6-iodonicotine. Deprotonation and substitution at the C-5 position of the pyridine ring of (S)-6-methoxynicotine were achieved using mesityllithium as the base at 0 °C. Conditions for the C-4 lithiation/substitution of (S)-6-isopropoxynicotine and (S)-5-chloro-6-methoxynicotine were also developed.     

Regioselective synthesis of 3,4,6,7-tetrahydro-3,3-dimethyl-9-phenyl-2H-xanthene-1,8(5H,9H)-diones through ascorbic acid catalyzed three-component domino reaction

An efficient, three-component domino reaction of dimedone 1, aromatic aldehydes (2a–o), and 1,3-cyclohexanedione 1a in the regio-selective synthesis of 3,3-dimethyl-9-phenyl-2H-xanthene-1,8(5H,9H)-diones (3a–o) is reported. The desired product, 3 is efficiently promoted by ascorbic acid as an organo catalyst.     

The application of Stille cross-coupling reactions with multiple nitrogen containing heterocycles

Substituted imidazoles and purine bioisosteres have been widely studied in the literature. We endeavored to combine these heterocyclic core structures into precursors, especially 7-azaindoles, of previously unknown pharmacologically relevant lead structures. A highly flexible synthetic procedure was developed, derived from investigations of the influence of the substrates, solvents, ligand systems, and side reactions.     

Regioselective synthesis of flavone derivatives via DMAP-catalyzed cyclization of o-alkynoylphenols

A catalytic amount of DMAP promoted cyclization of o-alkynoylphenols via a 6-endo cyclization mode leading to flavone derivatives in high yields without forming 5-exo cyclized aurone derivatives. Utilizing this method, methoxy substituted flavone and alkyl substituted γ-benzopyranone derivatives were synthesized.     

Sonogashira cross-coupling reactions with heteroaryl halides in the presence of a tetraphosphine-palladium catalyst

Heteroaryl halides undergoes cross-couplings with alkynes in good yields in the presence of [PdCl(C₃H₅)]₂/cis,cis,cis-1,2,3,4-tetrakis(diphenylphosphinomethyl)cyclopentane as catalyst. A variety of heteroaryl halides such as pyridines, quinolines, a pyrimidine, an indole, a thiophene, or a thiazole have been used successfully. The reaction also tolerates several alkynes such as phenylacetylene and a range of alk-1-ynols. Furthermore, this catalyst can be used at low loading with some substrates.     

Sonogashira cross-coupling reactions of aryl chlorides with alkynes catalysed by a tetraphosphine-palladium catalyst

A range of aryl chlorides undergoes cross-couplings with alkynes in good yields in the presence of [PdCl(C₃H₅)]₂/cis,cis,cis-1,2,3,4-tetrakis(diphenylphosphinomethyl)cyclopentane as catalyst. A variety of aryl chlorides such as chloroacetophenone, chlorobenzonitrile, chloronitrobenzene, chloroanisole or chlorotoluene have been used successfully. The reaction also tolerates several alkynes such as phenylacetylene, dec-1-yne, ethynylcyclohexene or alk-1-ynols. Furthermore, this catalyst can be used at low loading with some substrates.     

Regioselective synthesis of 4-chlorophenols, 10-chloro-7-hydroxy-6H-benzo[c]chromen-6-ones, and 4-chloro-1-hydroxy-9H-fluoren-9-ones based on [3+3] cyclizations of 1,3-bis(silyloxy)-1,3-dienes with 2-chloro-3-silyloxy-2-en-1-ones

A variety of 4-chlorophenols, 10-chloro-7-hydroxy-6H-benzo[c]chromen-6-ones, and 4-chloro-1-hydroxy-9H-fluoren-9-ones were prepared by formal [3+3] cyclizations of 1,3-bis(silyloxy)-1,3-dienes with 2-chloro-3-(silyloxy)alk-2-en-1-ones.     

Synthesis of 4-unsubstituted 2H-1,2,3-benzothiadiazine 1,1-dioxides via ortho lithiation of protected benzaldehyde derivatives

Variously substituted 2-phenyl-1,3-dioxolanes and 2-(2-bromophenyl)-1,3-dioxolanes, prepared from the corresponding benzaldehydes, were lithiated ortho to the acetal group. Reaction of the lithio derivatives with sulfur dioxide led to the lithium sulfinate salts, which gave, upon oxidative chlorination with sulfuryl chloride, the corresponding benzenesulfonyl chlorides. Then, depending on the aromatic substitution pattern of the molecule, several protocols were elaborated for the functional group transformations leading to the target compounds. Ring closure was performed with hydrazine hydrate or acetylhydrazine, in the latter case with one-pot removal of the acetyl group. The 4-unsubstituted 2H-1,2,3-benzothiadiazine 1,1-dioxides thus obtained are potential drug candidates based on their structural similarity to biologically active phthalazinones.     

An efficient synthesis of cytostatic mono and bis-alkynylpyrimidine derivatives by the Sonogashira cross-coupling reactions of 2,4-diamino-6-iodopyrimidine and 2-amino-4,6-dichloropyrimidine

A series of 6-alkynyl-2,4-diaminopyrimidine derivatives bearing various substituents at alkynyl moiety was prepared by the Sonogashira cross-coupling reaction of 2,4-diamino-6-iodopyrimidine using Pd(PPh₃)₂Cl₂ as catalyst. The same reaction was applied to 2-amino-4,6-dichloropyrimidine. This compound on reaction with 1 equiv. of alkyne gave 6-alkynyl-2-amino-4-chloropyrimidine derivatives as main products, while reaction with three equivalents of alkyne afforded predominantly 4,6-bis-alkynyl-2-aminopyrimidines. Some of the resulting alkynyl pyrimidines showed considerable cytostatic activity.     

Synthesis of arylated chalcone derivatives via palladium cross-coupling reactions

A useful protocol for arylation of the olefin double bond of chalcones to afford tri- and tetra-substituted chalcone derivatives is reported. The protocol begins with the Heck reaction between chalcones and aryl iodides providing β-arylchalcones. This reaction tolerates various functional groups on both rings, as well as deactivated aryl iodides. The products are obtained in moderate to excellent yields and the (E)-β-arylchalcones (E:Z?>?96:4) can be isolated via precipitation. Competitive Heck reactions pointed to a significant effect of ring one substituents on the reaction rate, while substituents on ring two have a much smaller effect. To access α,β-diarylchalcones, a sequential bromination-Suzuki cross coupling strategy was applied to the β-arylated compounds which afforded double arylated chalcone derivatives in 60–99% yield over two steps.     

N-heterocyclic carbene ligands in cobalt-catalyzed sequential cyclization/cross-coupling reactions of 6-halo-1-hexene derivatives with Grignard reagents

[reaction: see text] N-Heterocyclic carbene/cobalt systems effectively catalyze sequential cyclization/cross-coupling reactions of 6-halo-1-hexene derivatives with trialkylsilylmethyl and 1-alkynyl Grignard reagents, which phosphine and amine ligands did not promote.     

Regioselective rapid analog synthesis of 1,3-(or 1,5-)diphenyl-4-aryl/heteroaryl-5-(or 3-)(methylthio)pyrazoles via Suzuki cross-coupling

Regioselective routes for the synthesis of 1,3-(or 1,5-)diphenyl-4-aryl/heteroaryl-5-(or 3-)(methylthio)pyrazoles via Suzuki cross-coupling of 4-bromo (or 4-iodo)-1,3-(or 1,5-)diphenyl-5-(or 3-)(methylthio)pyrazoles have been reported.     

Regioselective reactions of sulfur, selenium and tellurium chlorides with allyl trimethyl silane

Electrophilic addition of SCl₂, SeCl₂ and SeCl₄ to 2 equivalents of allyl trimethyl silane proceeds regioselectively to give bis[2-chloro-3-(trimethylsilyl)propyl] sulfide, selenide and selenium dichloride, respectively. The reaction with TeCl₄ affords only diallyl tellurium dichloride. The structures of the compounds were confirmed by ¹H, ¹³C, ⁷⁷Se and ¹²⁵Te NMR techniques.     

Synthesis and characterization of 9-methyl-2-morpholin-4-yl-8-substituted phenyl-1H-purine derivatives using polyphosphoric acid (PPA) as an efficient catalyst

We demonstrate the synthesis of various purine derivatives through the coupling of N⁴-methyl-2-morpholin-4-yl-pyrimidine-4,5-diamine with various aldehydes by using polyphosphoric acid (PPA) as an efficient catalyst in DMF at reflux temperature. The PPA catalyst gave better yields (70-85%) in short reaction times (45-60 min). This commercially available cheap catalyst is more active than many reported expensive catalysts. Many aldehydes underwent the above conversion to form a series of 9-methyl-2-morpholin-4-yl-8-phenyl-9H-purines.     

A regioselective three-component reaction for synthesis of novel 1′H-spiro[isoindoline-1,2′-quinazoline]-3,4′(3′H)-dione derivatives

A ring opening and regioselective three-component reaction of isatoic anhydride, isatins, and aromatic or aliphatic primary amines in the presence of catalytic amount of KAl(SO₄)₂·12H₂O (alum) to yield a novel series of 1′H-spiro[isoindoline-1,2′-quinazoline]-3,4′(3′H)-dione is described.     

Regioselective solvent-sensitive reactions of 6-(trifluoromethyl)comanic acid and its derivatives with phenylhydrazine

6-(Trifluoromethyl)comanic acid reacts regioselectively with phenylhydrazine in water to give 5-[3,3,3-trifluoro-2-(phenylhydrazono)propyl]-1-phenyl-1H-pyrazole-3-carboxylic acid. Similar reaction in dioxane leads to 3-[3,3,3-trifluoro-2-(phenylhydrazono)propyl]-1-phenyl-1H-pyrazole-5-carboxylic acid. A strong solvent influence on the reaction route was also found for 6-(trifluoromethyl)comanic acid derivatives.