C−H Bond Arylation of Pyrazoles at the β-Position: General Conditions and Computational Elucidation for a High Regioselectivity

Direct arylation of most five-membered ring heterocycles are generally easily accessible and strongly favored at the α-position using classical palladium-catalysis. Conversely, regioselective functionalization of such heterocycles at the concurrent β-position remains currently very challenging. Herein, we report general conditions for regioselective direct arylation at the β-position of pyrazoles, while C−H α-position is free. By using aryl bromides as the aryl source and a judicious choice of solvent, the arylation reaction of variously N-substituted pyrazoles simply proceeds via β-C−H bond functionalization. The β-regioselectivity is promoted by a ligand-free palladium catalyst and a simple base without oxidant or further additive, and tolerates a variety of substituents on the bromoarene. DFT calculations revealed that a protic solvent such as 2-ethoxyethan-1-ol significantly enhances the acidity of the proton at β-position of the pyrazoles and thus favors this direct β-C−H bond arylation. This selective pyrazoles β-C−H bond arylation was successfully applied for the straightforward building of π-extended poly(hetero)aromatic structures via further Pd-catalyzed combined α-C−H intermolecular and intramolecular C−H bond arylation in an overall highly atom-economical process.     

Expedient synthesis of 3-substituted cycloalkanones via a Pd-catalyzed decarboxylative protonation protocol

We developed an efficient method for the introduction of -CH₂EWG moiety at the β-position of 2-cycloalken-1-ones via a Pd-catalyzed decarboxylative protonation protocol.     

A facile and efficient one-pot synthesis of thiirans by the reaction of benzoxazolyl β-ketosulfides with NaBH4/NaOH

Convenient and efficient procedures for thiirans have been developed via a one-pot reaction of benzoxazolyl β-ketosulfides with NaBH₄ and NaOH in MeOH and THF. The reaction is considered to proceed via the spiro intermediate by the ipso-addition of β-hydroxygroup, which is formed by the NaBH₄ reduction of β-keto group, to 2-position of benzoxazole group.     

Low band gap thiophene-perylene diimide systems with tunable charge transport properties

Perylenediimide-pentathiophene systems with varied architecture of thiophene units were synthesized. The photophysical, electrochemical, and charge transport behavior of the synthesized compounds were studied. Both molecules showed a low band gap of ～1.4 eV. Surprisingly, the molecule with pentathiophene attached via β-position to the PDI unit upon annealing showed a predominant hole mobility of 1 × 10(-4) cm(2) V(-1) s(-1) whereas the compound with branched pentathiophene attached via β-position showed an electron mobility of 9.8 × 10(-7) cm(2) V(-1) s(-1). This suggests that charge transport properties can be tuned by simply varying the architecture of pentathiophene units.     

Lithium n-benzyltrimethylsilylamide (LSA): a new reagent for conjugate addition - enolate trapping reactions

Lithium N-benzyltrimethylsilyl amide (LSA) adds to crotonates in a 1,4-manner, though the reaction of ordinary lithium amides with α,β-unsaturated carbonyl compounds is accompanied with a 1,2-addition and hydrogen abstraction at the γ-position. The conjugate addition via LSA followed by enolate trapping with electrophiles produces the corresponding α-substituted β-amino esters, which are, in turn, converted into β-lactams and α-substituted α, β-unsaturated esters.     

Synthesis and reactivity of 2-(porphyrin-2-yl)-1,3-dicarbonyl compounds

A simple and efficient procedure for the synthesis of porphyrins bearing 1,3-dicarbonyl moieties at the β-position is described. The new compounds were further functionalized and new derivatives containing an heterocyclic ring, an ethyl acetate residue or a 2-oxopropyl group at the β-position have been obtained.     

Computational studies on the mechanism of the gold(I)-catalysed rearrangement of cyclopropenes

Density functional theory calculations have been employed to investigate the mechanism of gold(I)-catalysed rearrangements of cyclopropenes. Product formation is controlled by the initial ring-opening step which results in the formation of a gold-stabilised carbocation/gold carbene intermediate. With 3-phenylcyclopropene-3-methylcarboxylate, the preferred intermediate allows cyclisation via nucleophilic attack of the carbonyl group and hence butenolide formation. Further calculations on simple model systems show that substituent effects can be rationalised by the charge distribution in the ring-opening transition state and, in particular, a loss of negative charge at what becomes the β-position of the intermediate. With 1-C(3)H(3)R cyclopropenes (R = Me, vinyl, Ph), ring-opening therefore places the substituent at the β-position.     

A new synthesis of β,γ-unsaturated esters from three components, aldehydes, chloromethyl p-tolyl sulfoxide, and tert-butyl acetate, via magnesium carbenoid 1,2-CH and 1,2-CC insertion as the key reaction

Addition reaction of 1-chlorovinyl p-tolyl sulfoxides, which were derived from various aldehydes, with lithium enolate of tert-butyl acetate at −78 °C in THF gave adducts in high yields. Magnesium carbenoids were generated by treatment of these adducts with Grignard reagents via the sulfoxide-magnesium exchange reaction. When the adducts were derived from alkyl aldehydes or electron-deficient aromatic aldehydes, carbenoid 1,2-CH insertion reaction took place from the magnesium carbenoids to afford β,γ-unsaturated butyric esters having a substituent at the β-position. On the contrary, when the adducts were derived from electron-rich aromatic aldehydes, carbenoid 1,2-CC insertion reaction took place from the magnesium carbenoids to give β,γ-unsaturated butyric esters having the aromatic group at the γ-position. Highly stereospecific 1,2-CC insertion reactions were observed in the latter reactions. This procedure provides a good way for a synthesis of β,γ-unsaturated esters from aldehydes with two carbon-carbon bond-formations.     

Straightforward synthesis of alkynyl imines via 1,2-elimination of α,α-dichloroketimines

Alkylation of α,α-dichloroketimines at the α-position with benzyl bromides afforded β-arylated α,α-dichloroketimines in good yields. The latter imines could be easily transformed to the corresponding alkynyl imines, a synthetically important class of compounds, via 1,2-elimination of HCl upon treatment with 2 equiv of sodium hydride in DMSO or potassium tert-butoxide in THF.     

Synthesis of cyclobutanones and four-membered enol ethers by using a rearrangement reaction of enol triflates

A new synthetic method of cyclobutanone derivatives and four-membered enol ethers via an intramolecular cyclization of a ketone enolate was developed. The cyclization precursors, enol triflates having a silyloxy group at the β′-position, were synthesized from the corresponding β-hydroxy ketones, which were prepared via an aldol reaction of a cycloalkanone and an aldehyde. Under the influence of TBAF, the enol triflates afforded a cyclobutanone or a four-membered enol ether through rearrangement of the trifluoromethanesulfonyl group followed by an intramolecular C- or O-alkylation reaction.     

Rhenium-catalyzed insertion of terminal alkenes into a C(sp)-H bond and successive transfer hydrogenation

Treatment of aromatic aldimines with terminal alkenes in the presence of a rhenium catalyst, [HRe(CO)₄]_n, gives 2-alkenylbenzylamines in good to excellent yields. This reaction proceeds via the insertion of the alkene into a C-H bond at the ortho-position of the imino group of the aromatic aldimine followed by sequential β-hydride elimination from the formed alkyl rhenium intermediate and then by hydrogenation of the imino group of the aldimine.     

La transformation d'indolines en indoles et d'autres reactions apparentees

Phenylseleninic anhydride reacts rapidly with indolines at 0° to give, when the β-position is substituted, the corresponding indoles. When the β-position is unsubstituted β-phenylseleno- indoles are formed. These are readily reduced by nickel boride to the parent indole. Tetrahyrdroisoquinoline is dehydrogenated with comparable ease. Phenylseleninic acid is also an efficient agent for these dehydrogenations.     

Highly diastereoselective synthesis of enantiopure β-trifluoromethyl β-amino alcohols from chiral trifluoromethyl oxazolidines (Fox)

The organolithium species addition to 2-hydroxymethyl fluorinated oxazolidines (Fox) provides a highly diastereoselective and straightforward route for the synthesis of enantiopure trifluoromethyl β-amino alcohols quaternarized at the β-position.     

Synthesis of β-amino-α-trifluoromethyl-α-amino acids exhibiting intramolecular interaction of CF3 with NHβ

We prepared β-amino-α-trifluoromethyl-α-amino acids through ring-opening reaction of N-tosyl-2-trifluoromethyl-2-ethoxycarbonylaziridine with aromatic and benzylic amines, and investigated the intramolecular interaction between the trifluoromethyl (CF₃) group at the α-position and the NH group at the β-position (NH_β). NMR, UV/vis, and circular dichroism measurements indicated that the conformation of these compounds is fixed by intramolecular interaction of CF₃ with NH_β to form a six-membered ring.     

A synthesis of di- and tri-substituted β,γ-unsaturated esters from aldehydes by the magnesium carbenoid 1,2-CH and 1,2-CC insertion as the key reaction

Addition reaction of 1-chlorovinyl p-tolyl sulfoxides, which were derived from aldehydes, with lithium enolate of tert-butyl acetate at −78 °C in THF gave adducts in high yields. Treatment of these adducts with Grignard reagents resulted in the formation of magnesium carbenoids via the sulfoxide-magnesium exchange reaction. When the adducts were derived from alkyl aldehydes or electron-deficient aromatic aldehydes, carbenoid 1,2-CH insertion reaction took place from the magnesium carbenoids to afford β,γ-unsaturated butyric esters having a substituent at the β-position. On the other hand, when the adducts were derived from electron-rich aromatic aldehydes, carbenoid 1,2-CC insertion reaction took place from the magnesium carbenoids to give β,γ-unsaturated butyric esters having the aromatic group at the γ-position. Highly stereospecific 1,2-CC insertion reactions were observed in the latter reactions. When the addition reactions were quenched with iodoalkanes, the alkylated adducts were obtained in quantitative yields. Tri-substituted β,γ-unsaturated esters, or in some case γ,δ-unsaturated esters, were obtained by the treatment of the alkylated adducts with EtMgCl. These procedures provide a good way for a new synthesis of di- and tri-substituted β,γ-unsaturated esters from aldehydes with two or three carbon-carbon bond-formations.     

Lewis acid-promoted reaction of β,γ-unsaturated α,α-dimethoxy esters with silyl nucleophiles

The Lewis acid-promoted reaction of β,γ-unsaturated α,α-dimethoxy esters, which are easily prepared by the acetalization of β,γ-unsaturated α-keto esters, with silyl nucleophiles is presented. By employing trimethylsilyl enolate and allyltrimethylsilane as nucleophiles, the BF₃-promoted reactions of a series of β,γ-unsaturated α,α-dimethoxy esters bearing aromatic and aliphatic substituents proceeded at the γ-position in an SN2′ manner to furnish γ-substituted α,β-unsaturated α-methoxy esters in good yields with high regioselectivity. In contrast, the reaction using trimethylsilyl cyanide predominantly occurred at the α-position, and the reaction of silyl hydride resulted in a mixture of α- and γ-regioisomers in favor of the γ-substitution products.     

Phosphine-catalyzed [3+2] annulations of γ-functionalized butynoates and 1C,3O-bisnucleophiles: highly selective reagent-controlled pathways to polysubstituted furans

In this paper, a reagent-controlled [3+2] annulation of γ-functionalized butynoates 1 and 1C,3O-bisnucleophiles 2 is reported, which leads to three distinct furan skeletons 3-5. A PPh(3) catalyst preferentially attached the β-position of 1a, facilitating α-addition to furnish Type I annulations. With the assistance of Ag(2)O, Type II annulations were achieved via selective γ-substitution. In the absence of the PPh(3) catalyst, the reagent Cs(2)CO(3) promoted β-addition to realize Type III annulations.     

Synthesis of functionalized furopyrazines as restricted dipeptidomimetics

Herein, an efficient synthetic approach to a furopyrazine scaffold with four points of diversity, starting from 2(1H)-pyrazinones, with dipeptomimetic properties, is presented. R-groups corresponding to amino acid side chains were introduced during the 2(1H)-pyrazinone and subsequent furopyrazine formation. The furopyrazine scaffold was further functionalized with an amino- and a carboxy-terminus resulting in a conformationally restricted dipeptidomimetic scaffold. The carboxy-terminus was introduced via a chemoselective vinylation of the 7-position followed by oxidative cleavage, while the amino-terminus was obtained via Buchwald–Hartwig amidation of the 2-position of the scaffold. The versatility of the synthetic method was demonstrated by the synthesis of a small library of diversely substituted furopyrazines having various amino acid side chains on the four points of diversity. Evaluation with an X-ray structure of the scaffold and computational analysis supports the exploitation of the furopyrazine scaffold as a restricted dipeptide mimic, which can mimic the two central residues of a β-turn.     

Synthesis of heteroarylated ketones via bismuth(III) triflate-promoted regioselective 1,4- and 1,6-additions of electron-rich heteroarenes to cyclic enones and dienones

The development and optimization of bismuth(III) triflate-promoted regioselective 1,4- and 1,6-additions of electron-rich heteroarenes to cyclic, β,β-disubstituted enones and dienones is described. Additions of a range of heteroarenes, including furan, thiophene, pyrrole, and indole nucleophiles, to cyclic, β,β-disubstituted enones occur to form all-carbon quaternary centers in up to 88% yield. In addition, regioselective 1,6-additions of electron-rich heteroarenes to 3-vinyl-2-cyclohexenone occur to produce a variety of δ-heteroarylated, β,β-disubstituted enones in up to 93% yield. The high 1,6-selectivity for these reactions is attributed to the increased steric bulk at the β-position relative to the δ-position, and no competing 1,4-conjugate addition is observed.     

Cross-coupling reactions of two different activated alkenes through tetrabutylammonium fluoride (TBAF) promoted deprotonation/activation strategy: a regioselective construction of quaternary carbon centers

A novel TBAF-promoted intermolecular crossed-conjugate addition has been developed. For a range of cyclic β-halo-α,β-unsaturated carbonyl compounds, the vinylogous enolates generated by deprotonation at the γ-position preferentially reacted with Michael acceptors at the α-position to deliver cross-coupling products in good yields.