Various arenes, including benzene, p-xylene, or mesitylenes were alkylated with benzyl alcohols 4 to afford the desired 1,1-diarylalkanes 5 in high yields. Beside the tert-butyl moiety as regio-discriminating group, other useful synthetic functional groups such as nitro-, cyano- or hydroxy functionalities could effectively be used. With 10 mol% of catalyst the α- tert-butyl-substituted propargyl acetates 116 could be substituted with silyl enol ethers, allylsilane and various arenes and heteroarenes to give the desired alkylated alkynes 117 in high yields and excellent anti diastereoselectivities of up to 99 : 1 d. Certain compounds contained in compositions of the present invention may exist in particular geometric or stereoisomeric forms. In certain embodiments, the nucleophile is an aromatic heterocycle. A gold I -catalyzed hydroarylation of indoles with styrenes as well as with aliphatic and cyclic alkenes was developed by Che et al. A comparable, non-chiral version of this C—C bond forming reaction using ceric ammonium nitrate has recently been developed.
Eight contributions address general aspects and historical background, Michael Addition, addition to carbonyl compounds, nucleophilic allylic alkylation and hydroarylation of allenes, nucleophilic substitution on Csp 3 carbon atoms, unactivated alkenes, catalytic asymmetric Friedel-Crafts alkylations in total synthesis, and industrial Friedel-Crafts chemistry. Hence, improved procedures with less sensitive and cheaper catalysts as well as unprotected alcohols had to be developed. An elegant PtCl 2-catalyzed intramolecular alkylation of indoles with inactivated alkenes has been developed by Widenhoefer et al. Specific rotations were measured on a Jasco Digital Polarimeter. The terms ortho, meta and para are art-recognized and refer to 1,2-, 1,3- and 1,4-disubstituted benzenes, respectively. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Beside indoles, anilines have gained much attention as target for hydroarylation reactions.
An advantage of this invention is that enantiomerically enriched products can be synthesized from prochiral, meso, or racemic reactants. For example, reaction of benzene with optically active 2-chloro-1-phenylpropane or 1-chloro-2-phenylpropane in the presence of AlCl 3 affords good yield 60% of alkylated product with up to quantitative optical yields see Scheme 3. The methods of this invention can also be carried out under reaction conditions suitable for commercial use, and typically proceed at reaction rates suitable for large scale operations. These results provide the first demonstration of a highly enantioselective catalytic Friedel-Crafts reaction with a simple aldehyde. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds. Here isopropanol can be used as a simple reducing reagent to afford the desired 1,1-diarylalkanes 34 in high yields after 12 h with just 1 mol% of the Ir-complex 33.
In certain embodiments, the methods of the invention are relatively insensitive to concentration, temperature, air and moisture. This may be a result of п-stacking interactions. Aldehyde 5a was used as ˜50% solution in toluene, which was commercially available. Within this context, Shimizu and co-workers discovered a Lewis-acid-catalyzed substitution of arenes with olefins, such as styrene, α- and β-methylstyrene or cyclohexenes 35. It may also be adapted for kinetic resolutions, dynamic kinetic resolutions, and regioselective reactions which may be catalyzed according to the present invention. In other embodiments, the electrophilic substrate will be a chiral compound. Hydride may also be a suitable nucleophile when reduction of the substrate is desired.
Preferred enantioselective reactions yield a product with an ee greater than about 20%, more preferably greater than about 50%, even more preferably greater than about 70%, and most preferably greater than about 80%. Examples of nucleophiles include uncharged compounds such as water, amines, mercaptans and alcohols, and charged moieties such as alkoxides, thiolates, carbanions, and a variety of organic and inorganic anions. In addition, the volatile catalyst is easily removed. While the catalysts described above gave primarily linear allylation products, procedures that would give branched allylated arenes would be even more desirable. As mentioned above, the choice of catalyst substituents can also effect the electronic properties of the catalyst. With the need for more environmentally and economically benign processes, the Friedel—Crafts-type synthesis of 1,1-diarylalkanes using catalytic amounts of a metal or acid catalyst and more environmental friendly benzylation reagents are highly desirable. The desired tetrahydronaphthalenes 81 were obtained in high yields under ambient reaction conditions.
As used herein, a catalytic amount means from 0. An enantioselective reaction yields a product with an ee greater than zero. In certain embodiments, it may be preferred to perform the catalyzed reactions in the solid phase. Notable examples are arene tricarbonylmolybdenum, i. In addition, polymers of the present invention may also be optically active.
Achille Umani-Ronchi graduated in chemistry in 1960 from the University of Rome, Italy, and has been a Full Professor at the Faculty of Sciences of the University of Bologna since 1980. For example, trifluoromethyl and pentafluoroethyl are examples of perfluoroalkyl groups. Also, the reaction steps can be combined by the joint addition of the starting materials to the optically active metal-ligand complex catalyst. Thus efficient routes to this important core structure are constantly needed. Although, the Murai reaction, the Ru-catalyzed ortho-alkylation of acetophenones with alkenes has been known since 1993 , the direct substitution of arenes with styrenes is a development that has emerged in the last decade. The materials of construction employed should be inert to the starting materials during the reaction and the fabrication of the equipment should be able to withstand the reaction temperatures and pressures. The electron-rich nature of the indole ring renders enantioselective Friedel-Crafts reactions of indoles with readily available prochiral electrophilic starting materials a strategically important approach to access enantiomerically enriched indole derivatives.
The definition of each expression, e. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein said aromatic compound is In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 70 mol % relative to said prochiral aldehyde or prochiral ketone. In addition, they successfully used benzyl acetates, 1-phenylethanol and β-hydroxy-substituted benzyl alcohols as alkylating reagents. While nitro-, cyano- and methyl ester derivatives gave remarkable anti-selectivity, the corresponding α-phosphonate showed high syn-selectivity. In this process, the equivalence of gold-complexed 2,4-dien-1-als with cyclopentenyl dications with loss of oxo O 2- has been established. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 10 mol % relative to said prochiral aldehyde or prochiral ketone.
Additionally, high selectivity towards the linear allylated indoles was observed. In certain embodiments, the methods yield products with an enantiomeric excess or diastereomeric excess of greater than about 50%, greater than about 70%, greater than about 90%, or greater than about 95%. The alkene unit was converted to a carbocation that reacted with the proximal benzene ring by an intramolecular Friedel-Crafts alkylation to give an 83% yield of 210. All such isomers, as well as mixtures thereof, are intended to be included in this invention. Surya Prakash, in , 1991 1. This strongly indicates a carbocation as reaction intermediate and rules out an S N1-type reaction mechanism. Moreover, Friedel—Crafts alkylations of arenes bearing free amines or nitrogen-containing heterocycles will be a great advance in this area.
A chapter on the application of zinc catalysts in total synthesis is also included. Likewise, the two natural occurring benzhydryl compounds mimosifoliol 99 and O-methyldetrol 100 were obtained from readily available arenes and propargyl alcohols. The systematic, logical and consistent organization of the synthetic methods for each functional group enables users to quickly find out which methods are useful for a particular synthesis and which are not. They also noted that when less ethyl bromide was employed, the product, surprisingly, was hexaethylbenzene. In certain embodiments, the electrophile is an α-ketoester or aldehyde. The reaction steps may be effected by the incremental addition of one of the starting materials to the other. Upon further heating of the secondary amine 48 in the presence of TiCl 4 the ortho-arylated aniline 49 was formed quantitatively.