Alkyl Coupling Research Articles

Facile and Selective Cross‐Coupling of Phenols Using Selenium Dioxide

Nonsymmetric biphenols are important structural motifs in organic chemistry. Therefore, an easy and versatile protocol for oxidative cross‐coupling is essential to generate these so‐called “privileged ligands”. We developed an efficient and selective oxidative pathway to synthesize 2,2′‐biphenols as well as 2,4′‐ and 4,4′‐biphenols. The use of selenium dioxide, a stable, powerful, and commercially available oxidizer, in 1,1,1,3,3,3‐hexafluoroisopropanol allowed the oxidative coupling of alkyl‐, alkoxy‐, and halogen‐substituted phenols.

Solid-Phase Synthesis of 1,3,4-Thiadiazole Derivatives via Desulfurative Cyclization of Thiosemicarbazide Intermediate Resin.

A 1,3,4-thiadiazole library was constructed by solid-phase organic synthesis. The key step of this solid-phase synthesis involves the preparation of polymer-bound 2-amido-5-amino-1,3,4-thiadiazole resin by the cyclization of thiosemicarbazide resin using p-TsCl as the desulfurative agent, followed by the functionalization of the resin by alkylation, acylation, alkylation/acylation, and Suzuki coupling reactions. Both the alkylation and acylation reactions chemoselectively occurred at the 2-amide position of 2-amido-5-amino-1,3,4-thiadiazole resin and the 5-amine position of 2-amido-5-amino-1,3,4-thiadiazole resin, respectively. Finally, these functionalized 1,3,4-thiadiazole resins were treated with trifluoroacetic acid in dichloromethane, affording diverse 1,3,4-thiadiazole analogs in high yields and purities. The 1,3,4-thiadiazole analogs show a different distribution of physicochemical and biological properties compared with our previously constructed 1,3,4-oxadiazole and 1,3,4-thiadiazole libraries in a range of orally available drug properties.

Recent developments for the photoinduced Ar–X bond dissociation reaction

Recent developments in the photochemical carbon–carbon and carbon–heteroatom bond formation via photoinduced Ar–X bond dissociation are summarized. The transformations through the Ar–X bond dissociation enabled by photoenergy include nucleophilic substitution, arylation, alkylation, aminocarbonylation, aminosulfonylation and decarboxylative coupling reactions. Usually, the reactions undergo one-electron-transfer couplings and aryl radicals or cations are involved as the key intermediates. Under ultraviolet irradiation or visible light, the reactions of aryl halides with reactive partners proceed smoothly under mild conditions. In some cases, the transformations can proceed without any metals or photo-redox catalysts. Moreover, the broad reaction scope is demonstrated with good functional group tolerance.

ChemInform Abstract: Rhodium(I)‐Catalyzed Sequential C(sp)—C(sp3) and C(sp3)—C(sp3) Bond Formation Through Migratory Carbene Insertion.

AbstractThe Rh(I)‐catalyzed three‐component reaction of tert‐propargyl alcohol, various diazo ester, and alkyl halides can be considered as a carbene‐involving sequential alkyl and alkynyl coupling, in which C(sp)—C(sp3) and C(sp3)—C(sp3) bonds are formed successively on the carbenic carbon atom via Rh(I)‐carbene migratory insertion of an alkynyl moiety and subsequent alkylation.

Low-Valent Iron Mono-Diazadiene Compounds: Electronic Structure and Catalytic Application

A series of monodiazadiene diolefin iron compounds, [Fe(trop2dad)(L)] (4; L = neutral ligand), has been prepared by one-electron oxidation of the FeI species [NaFe(trop2dad)(thf)3] (dad = diazadiene; trop = 5H-dibenzo[a,d]cyclohepten-5-yl). The electronic structures of compounds 4 were investigated by NMR and Mossbauer spectroscopy, single-crystal X-ray diffraction, solid- and liquid-phase magnetic susceptibility measurements, and DFT calculations. Compounds of type 4 with labile ligands L were found to be active (pre)catalysts for the dehydrogenative coupling of (alkyl)amine–boranes. Remarkably high activities were observed, especially for the homogeneous dehydrogenative polymerization of methylamine–borane.

Rhodium(I)-Catalyzed Sequential C(sp)-C(sp(3)) and C(sp(3))-C(sp(3)) Bond Formation through Migratory Carbene Insertion.

A Rh(I)-catalyzed three-component reaction of tert-propargyl alcohol, diazoester, and alkyl halide has been developed. This reaction can be considered as a carbene-involving sequential alkyl and alkynyl coupling, in which C(sp)-C(sp(3)) and C(sp(3))-C(sp(3)) bonds are built successively on the carbenic carbon atom. The Rh(I)-carbene migratory insertion of an alkynyl moiety and subsequent alkylation are proposed to account for the two separate C-C bond formations. This reaction provides an efficient and tunable method for the construction of all-carbon quaternary center.

Rhodium(I)‐Catalyzed Sequential C(sp)C(sp3) and C(sp3)C(sp3) Bond Formation through Migratory Carbene Insertion

AbstractA RhI‐catalyzed three‐component reaction of tert‐propargyl alcohol, diazoester, and alkyl halide has been developed. This reaction can be considered as a carbene‐involving sequential alkyl and alkynyl coupling, in which C(sp)C(sp3) and C(sp3)C(sp3) bonds are built successively on the carbenic carbon atom. The RhI‐carbene migratory insertion of an alkynyl moiety and subsequent alkylation are proposed to account for the two separate CC bond formations. This reaction provides an efficient and tunable method for the construction of all‐carbon quaternary center.

Iron Fluoride/N-Heterocyclic Carbene Catalyzed Cross Coupling­ between Deactivated Aryl Chlorides and Alkyl Grignard Reagents with or without β-Hydrogens

High-yielding cross-coupling reactions of various combinations of aryl chlorides and alkyl Grignard reagents have been developed by using an iron(III) fluoride/1,3-bis(2,6-diisopropylphenyl)imidazolin-2-ylidene (SIPr) catalyst composite. The iron(III) fluoride/SIPr-catalyzed aryl–alkyl coupling demonstrates unprecedented scope for both aryl chlorides and alkyl Grignard reagents, thus enabling the first efficient coupling of electron-rich (deactivated) aryl chlorides with alkyl Grignard­ reagents without β-hydrogens. The present reaction is also effective for diverse alkyl Grignard reagents such as (trimethylsilyl)methyl, primary, and secondary alkyl Grignard reagents.

Addition reactions of organometallic reagents to nitrogen trifluoride and enhanced alkyl–alkyl coupling by NF3

Abstract A survey of the reaction of nitrogen trifluoride (NF 3 ) with various organometallic reagents finds that organomagnesium (Grignard) reagents are the most useful for producing N , N -difluoroaminoalkanes. Alkyl–alkyl coupling is a persistant side reaction. Organolithiums are marginally effective. Organocopper, organozinc reagents undergo primarily alkyl–alkyl coupling catalyzed by the presence of NF 3 . Organocalcium and organoaluminum reagents are unreactive.

Alkyl-aryl ketone synthesis via nickel-catalyzed reductive coupling of alkyl halides with aryl acids and anhydrides.

The present work disclosed a considerably improved method for the construction of alkyl-aryl ketones by the direct coupling of unactivated alkyl bromides with 1.5 equiv. of acids. In addition, the synthesis of aroyl C-glycosides was first achieved by the reductive coupling of 1-glycosyl bromides with acid derivatives, which may otherwise require multi-step synthesis.

ChemInform Abstract: Expedient Iron‐Catalyzed Coupling of Alkyl, Benzyl and Allyl Halides with Arylboronic Esters.

ChemInform Abstract: Expedient Iron‐Catalyzed Coupling of Alkyl, Benzyl and Allyl Halides with Arylboronic Esters.

ChemInform Abstract: A “Green” Variation of the Hirao Reaction: The P—C Coupling of Diethyl Phosphite, Alkyl Phenyl‐H‐phosphinates and Secondary Phosphine Oxides with Bromoarenes Using a P‐Ligand‐Free Pd(OAc)2 Catalyst under Microwave and Solvent‐Free Conditions.

The P–C coupling of diethyl phosphite, alkyl phenyl-H-phosphinates, diphenylphosphine oxide and dialkylphosphine oxides with bromoarenes may be performed in the presence of a P-ligand-free Pd(OAc)2 catalyst and triethylamine under microwave-assisted (MW) and, in almost all cases, solvent-free conditions to afford diethyl arylphosphonates, alkyl diphenylphosphinates, aryldiphenylphosphine oxides and dialkylphenylphosphine oxides, respectively. This is the “greenest” accomplishment of the well-known Hirao reaction that has now been found to have general application for a broad spectrum of >P(O)H species with different reactivity and a great variety of substituted bromobenzenes. The alkyl phenyl-H-phosphinates were prepared by the MW-promoted alkylation of phenyl-H-phosphinic acid in the absence of any solvent.

ChemInform Abstract: Development of (Trimethylsilyl)ethyl Ester Protected Enolates and Applications in Palladium‐Catalyzed Enantioselective Allylic Alkylation: Intermolecular Cross‐Coupling of Functionalized Electrophiles.

The development of (trimethylsilyl)ethyl ester protected enolates is reported. The application of this class of compounds in palladium-catalyzed asymmetric allylic alkylation is explored, yielding a variety of α-quaternary six- and seven-membered ketones and lactams. Independent coupling partner synthesis engenders enhanced allyl substrate scope relative to traditional β-ketoester substrates; highly functionalized α-quaternary ketones generated by the union of (trimethylsilyl)ethyl β-ketoesters and sensitive allylic alkylation coupling partners serve to demonstrate the utility of this method for complex fragment coupling.

Cross Alkyl–Aryl versus Homo Aryl–Aryl Coupling in Palladium-Catalyzed Coupling of Alkyl–Gold(I) and Aryl–Halide

Experiments on palladium-catalyzed cross-coupling of [AuMe(PPh3)] with aryl iodides show that Ar–Ar homocoupling products are the main product or an abundant byproduct of the reaction. The percentage of cross-coupling product is higher for aryls with a larger σp Hammet parameter. The scrambling of organic groups via bimetallic intermediates explains the formation of these products. This scrambling can be observed and the activation energies partially quantified in some cases using as aryl C6Cl2F3, which is relatively reluctant to coupling.

Development of (trimethylsilyl)ethyl ester protected enolates and applications in palladium-catalyzed enantioselective allylic alkylation: intermolecular cross-coupling of functionalized electrophiles.

The development of (trimethylsilyl)ethyl ester protected enolates is reported. The application of this class of compounds in palladium-catalyzed asymmetric allylic alkylation is explored, yielding a variety of α-quaternary six- and seven-membered ketones and lactams. Independent coupling partner synthesis engenders enhanced allyl substrate scope relative to traditional β-ketoester substrates; highly functionalized α-quaternary ketones generated by the union of (trimethylsilyl)ethyl β-ketoesters and sensitive allylic alkylation coupling partners serve to demonstrate the utility of this method for complex fragment coupling.

Expedient Iron‐Catalyzed Coupling of Alkyl, Benzyl and Allyl Halides with Arylboronic Esters

While attractive, the iron-catalyzed coupling of arylboron reagents with alkyl halides typically requires expensive or synthetically challenging diphosphine ligands. Herein, we show that primary and secondary alkyl bromides and chlorides, as well as benzyl and allyl halides, can be coupled with arylboronic esters, activated with alkyllithium reagents, by using very simple iron-based catalysts. The catalysts used were either adducts of inexpensive and widely available diphosphines or, in a large number of cases, simply [Fe(acac)3] with no added co-ligands. In the former case, preliminary mechanistic studies highlight the likely involvement of iron(I)-phosphine intermediates.

Highly Efficient Preparation of Selectively Isotope Cluster-Labeled Long Chain Fatty Acids via Two Consecutive Csp3–Csp3 Cross-Coupling Reactions

An efficient synthesis involving two copper-catalyzed alkyl-alkyl coupling reactions has been designed to easily access doubly isotope-labeled fatty acids. Such NMR- and IR-active compounds were obtained in excellent overall yields and will be further used for determining the conformation of an alkyl chain of lipidic biomolecules upon interaction with proteins.

Reactivities of mixed organozinc and mixed organocopper reagents: 9. Solvent dependence of group transfer selectivity in sp3C coupling and acylation of mixed diorganocuprates and diorganozincs

The selectivity and/or reactivity of organyl group transfer of mixed diorganocuprates in their alkyl coupling in THF depends on N- or O-donor solvents as cosolvents. Selective n-Bu group transfer is observed in room temperature alkylation of Grignard reagent derived stoichiometric n-BuPhCuMgBr reagent in THF:cosolvent and solvation effects do not change the group transfer ability. However, in the alkylation of catalytic mixed cuprates derived from CuI catalyzed n-BuPh2ZnMgBr and n-Bu2PhZnMgBr, group transfer ability depends on the solvation effect and it can be controlled by using N- or O-donor solvents. In alkylation of CuI catalyzed mixed zincate n-BuPh2ZnMgBr and also n-Bu2PhZnMgBr in THF at reflux temperature Ph group transfer takes place (n-Bu/Ph transfer ratio is 1:9 and 4:6, respectively) whereas n-Bu transfer increases in THF:NMP (1:1) resulting n-Bu/Ph transfer ratio of 4:6 and 8:2, respectively. Group transfer ability in allylation of n-BuPhZn seems not to be solvent dependent. The solvent effect on the group transfer ability has been found to be dependent also on the R1 and R2 partnership in room temperature benzoylation of catalytic mixed cuprates, R1R2CuZnI, derived from CuI catalyzed R1R2Zn. These results are briefly discussed in terms of solvation of mixed diorganocuprate and diorganozinc reagents and provide useful information in their atom-economic alkyl, allyl and acyl coupling reactions.

ChemInform Abstract: Nickel‐Catalyzed Ring‐Opening Alkylative Coupling of Enone with Methylenecyclopropane in the Presence of Triethylborane.

AbstractNickel‐catalyzed alkylative coupling of an enone or enal with methylenecyclopropanes in the presence of triethylborane is achieved via stereospecific proximal C—C bond cleavage.

DIPYRROLO[1,2- a ;2',1'- c ]PYRAZINES. 5. AZO COUPLING OF DIPYRROLO[1,2- a ;2',1'- c ]PYRAZINES AND 5,6-DIHYDRODIPYRROLO[1,2- a ;2',1'- c ]PYRAZINES

We have synthesized a series of previously unreported azo dyes via the azo coupling of alkyl substituted dipyrrolopyrazines with aryldiazonium chloride. For this type of substrate where one or both α-positions of the pyrrole rings of the molecules are not occupied by substituents, electrophilic attack was found to occur initially at carbon atom C(3). Authors: V. I. Terenin, A. V. Borisov, E. L. Ruchkina, and A. P. Pleshkova. English Translation in Chemistry of Heterocyclic Compounds , 1999, 35 (2), pp 211-215 http://link.springer.com/article/10.1007/BF02251713