Six-membered Heteroaromatic Compounds Research Articles

Regioselective C-H Trifluoromethylation and Its Related Reactions of (Hetero)aromatic Compounds.

Fluorinated functional groups, including trifluoromethyl group, play important roles in the development of drugs, agrochemicals, and organic functional materials. Therefore, the development of highly effective and practical reactions to introduce fluorinated functional groups into (hetero)aromatic compounds is highly desirable. We have achieved several regioselective C-H trifluoromethylation and related reactions by electrophilic and nucleophilic activation of six-membered heteroaromatic compounds and steric protection of aromatic compounds. These reactions proceed in good to excellent yields, even on a gram scale, with high functional group tolerance, and are applicable to the regioselective trifluoromethylation of drug molecules. In this personal account, the background of the introduction reactions of fluorinated functional groups, our reaction designs to achieve regioselective C-H trifluoromethylation and the related reactions of (hetero)aromatic compounds are explained.

Regioselective C-H Trifluoromethylation of Heteroaromatic Compounds

Abstract Strategies for regioselective C-H trifluoromethylation of heteroaromatic compounds are summarized herein. This review article consists of four sections: (1) Introduction; (2) C-H trifluoromethylation of five-membered heteroaromatic compounds; (3) C-H trifluoromethylation of six-membered heteroaromatic compounds; and (4) Conclusion. Each section is categorized by the reaction sites.

Phosphite-Catalyzed C-H Allylation of Azaarenes via an Enantioselective [2,3]-Aza-Wittig Rearrangement.

A phosphite-mediated [2,3]-aza-Wittig rearrangement has been developed for the regio- and enantioselective allylic alkylation of six-membered heteroaromatic compounds (azaarenes). The nucleophilic phosphite adducts of N-allyl salts undergo a stereoselective base-mediated aza-Wittig rearrangement and dissociation of the chiral phosphite for overall C-H functionalization of azaarenes. This method provides efficient access to tertiary and quaternary chiral centers in isoquinoline, quinoline, and pyridine systems, tolerating a broad variety of substituents on both the allyl part and azaarenes. Catalysis with chiral phosphites is also demonstrated with synthetically useful yields and enantioselectivities.

2-Position-Selective Trifluoromethylthiolation of Six-Membered Heteroaromatic Compounds.

The regioselective C-H trifluoromethylthiolation of six-membered heteroaromatic compounds via nucleophilic attack of a CF3S source on the electrophilically activated six-membered heteroaromatic ring was developed. The reaction proceeds in good yield with good functional group tolerance, even on a gram-scale. The key to the successful regioselective transformation is the presence of an additive (2,4-dinitrobenzenesulfonyl chloride). The regioselective trifluoromethylthiolation of quinidine derivative is also demonstrated. Trifluoromethylthiolation, followed by S-oxidation, affords the corresponding sulfones.

Development of Novel C–H Bond Transformations and Their Application to the Synthesis of Organic Functional Molecules

This personal account summarizes our recent progress in the development of C–H transformations. We achieved ortho-selective C–H borylations and silylations by using Lewis acid–base interaction between two substrates and we achieved meta- and ortho-selective C–H borylations by using hydrogen bonding or Lewis acid–base interaction between a hydrogen donor or Lewis acid unit of a ligand and a functional group of a substrate. Regioselective C–H trifluoromethylations and related reactions of six-membered heteroaromatic compounds were realized at their 2- and 4-positions and at their benzylic positions. In addition, we developed C–H transformations directed towards the synthesis of organic functional materials, such as highly soluble polyimides or π-conjugated molecules containing either heteroatom(s) or a Lewis acid–base interaction.1 Introduction2 Regioselective C–H Transformations Controlled by Noncovalent Bond Interactions2.1 Regioselective C–H Transformations Controlled by Lewis Acid–Base Interaction between Two Substrates2.2 Regioselective C–H Transformation Controlled by Hydrogen Bonding between Ligand and Substrate2.3 Regioselective C–H Transformations Controlled by Lewis Acid–Base Interactions between Ligands and Substrates3 Trifluoromethylation and Related Transformations of Six-Membered Heteroaromatic Compounds3.1 2-Position-Selective C–H Trifluoromethylation of Six-Membered Heteroaromatic Compounds3.2 4-Position-Selective C–H Trifluoromethylation of Six-Membered Heteroaromatic Compounds3.3 Benzyl Position-Selective C–H Trifluoromethylation of Six-Membered Heteroaromatic Compounds4 C–H Transformations Leading to the Synthesis of Organic Functional Materials4.1 Heteroatom-Containing π-Conjugated Molecules4.2 π-Conjugated Molecules Containing a Lewis Acid–Base Interaction4.3 Soluble Polyimide Derivatives5 Conclusions

ChemInform Abstract: 4‐Position‐Selective C—H Perfluoroalkylation and Perfluoroarylation of Six‐Membered Heteroaromatic Compounds.

AbstractPerfluoroalkylation of six‐membered N‐heterocycles proceeds regioselectively at the position para to the ring‐nitrogen.

4-Position-Selective C-H Perfluoroalkylation and Perfluoroarylation of Six-Membered Heteroaromatic Compounds.

The first 4-position-selective C-H perfluoroalkylation and perfluoroarylation of six-membered heteroaromatic compounds were achieved using nucleophilic perfluoroalkylation and perfluoroarylation reagents. The regioselectivity was controlled by electrophilically activating the heteroaromatic rings, while sterically hindering the 2-position, with a sterically bulky borane Lewis acid. The reaction proceeded in good yield, even in gram scale, and by a sequential reaction without isolating the intermediates. This reaction could be applied to late-stage trifluoromethylation of a bioactive compound.

Benzylic C(sp(3) )H Perfluoroalkylation of Six-Membered Heteroaromatic Compounds.

Successful benzylic C(sp(3) )-H trifluoromethylation, pentafluoroethylation, and heptafluoropropylation of six-membered heteroaromatic compounds were achieved as the first examples of a practical benzylic C(sp(3) )-H perfluoroalkylation. In these reactions, BF2 Cn F2n+1 (n=1-3) functioned as both a Lewis acid to activate the benzylic position and a Cn F2n+1 (n=1-3) source. The perfluoroalkylation proceeded at both terminal and internal positions of the alkyl chains. Perfluoroalkylated products were obtained in moderate to excellent yields, even on gram scale, and in a sequential procedure without isolation of the intermediates. By using this method, trifluoromethylation of a bioactive compound, as well as introduction of a CF3 group into a bioactive molecular skeleton, proceeded regioselectively.

Regioselective trifluoromethylation of N-heteroaromatic compounds using trifluoromethyldifluoroborane activator

Many important drugs, agrochemicals and their lead compounds contain trifluoromethyl group(s). Most processes currently used to access trifluoromethyl group-containing molecules are performed by substitution of the carboxy or trichloromethyl groups using hazardous fluorinating reagents under harsh reaction conditions. Cross-coupling reactions between organohalides or boronic acids/esters and trifluoromethylating reagents are also used. Direct C-H trifluoromethylation of organic molecules, however, is the ideal method of introducing trifluoromethyl group(s). Despite the recent advances in C-H trifluoromethylation of N-heteroaromatic compounds, regioselective C-H trifluoromethylation of six-membered heteroaromatic compounds has yet to be achieved. Herein we present a general and reliable method for the synthesis of trifluoromethyl group-containing N-heteroaromatics through highly regioselective addition of a trifluoromethyl nucleophile to pyridine, quinoline, isoquinoline and two or three heteroatom-containing N-heteroaromatic N-oxides activated by trifluoromethyldifluoroborane. The C-H trifluoromethylation proceeds under mild conditions in gram scale with high functional group tolerance. This method will be useful in both laboratory and industrial processes.

Development of quantum-chemical investigations of heterocycles at the Institute of Organic Chemistry, Russian Academy of Sciences (review)

Quantum-chemical investigations of the electronic structure and reactivity of five- and six-membered heteroaromatic compounds conducted at the N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, from the seventies of the twentieth century are reviewed and discussed.

ChemInform Abstract: A Metathesis‐Based Approach to the Synthesis of 2‐Pyridones and Pyridines.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

A Metathesis-Based Approach to the Synthesis of 2-Pyridones and Pyridines

The ring-closing metathesis reaction has been successfully employed to form a range of dihydropyridone intermediates, which are in the correct oxidation state to undergo a base-induced elimination to reveal the aromatic 2-pyridone. This mild and novel approach to six-membered heteroaromatic compounds then provides access to a wide variety of substituted pyridines in excellent overall yield.

Substituent Effects in the 13C-NMR Spectra of Six-Membered Nitrogen Heteroaromatic Compounds

It is shown that the 13C-NMR chemical shifts of carbon atoms in substituted sixmembered heteroaromatic compounds correlate with the correponding "additivity parameters" for substituted benzene derivatives. Thus, for precalculation of chemical shifts in such compounds, just one set of parameters can be used. The differences between experimental chemical shifts and those calculated from correlation with the common set may provide insights into intramolecular interactions not reported in the literature.

ChemInform Abstract: Regioselective Substitution in Aromatic Six‐Membered Nitrogen Heterocycles

Publisher Summary The reactivity of various six-membered heteroaromatic compounds has been previously reviewed through 1982. This chapter describes the nucleophilic, electrophilic, and free-radical substitution reactions on the ring carbon atoms of pyridines, pyridazines, pyrimidines, pyrazines, triazines, and tetrazines. Fused-ring derivatives of these heterocycles are not covered. Multistep substitutions involving dihydro intermediates are included. The primary chemical literature between 1982 and June 1987 is also surveyed.

ChemInform Abstract: 1‐CHLORO‐1,3‐BIS(DIMETHYLAMINO)‐2‐AZAPROPENYLIUM SALTS: INTERMEDIATES FOR THE SYNTHESIS OF 1,3,5‐TRIAZINES, PYRIMIDINES, ISOQUINOLINES, QUINAZOLINES, AND A 1,3,5‐THIADIAZINIUM SALT

AbstractDie im Titel genannten Salze (I) reagieren zu Heterocyclen (III), (V), (VI) und (X).

1-Chloro-1,3-bis(dimethylamino)-2-azapropenylium salts: intermediates for the synthesis of 1,3,5-triazines, pyrimidines, isoquinolines, quinazolines, and a 1,3,5-thiadiazinium salt

The title salts, which are formed by the action of dimethylcyanamide on the phosphorus oxychloride complexes of a variety of tertiary amides, are useful precursors of six-membered heteroaromatic compounds: they react with simple amidines to yield 1,3,5-triazines and with N,N-dimethylamidines to give pyrimidines; 3-arylmethyl-1-chloro-1,3-bis(dimethylamino)-2-azapropenylium perchlorates form isoquinolines, the related 3-arylamino-1-chloro-1-dimethylamino-2-azapropenylium salts cyclise to quinazolinium salts, and treatment of 1-chloro-1,3-bis(dimethylamino)-3-phenyl-2-azapropenylium perchlorate with potassium thiocyanate results in a rearranged 1,3,5-thiadiazinium salt.

Isotopic hydrogen exchange in methyl derivatives of five-membered aromatic heterocycles

The kinetics of isotopic exchange of the hydrogen atoms of the methyl groups in an alcohol solution of potassium ethoxide were studied for an extensive series of methyl derivatives of azoles and di-, tri-, and tetrazoles. The electronic effect of one or several heteroatoms and substituents on the rate of deuterium exchange of five-membered heterocycles is satisfactorily conveyed by the correlation relationship previously established for a series of substituted toluenes and six-membered heteroaromatic compounds (ρ 25°=7.6). The limitations that exist in a number of cases are discussed in connection with the peculiarities of the electron-density distribution in five- and six-membered heterocycles.