Access to chiral α-bromo and α-H-substituted tertiary allylic alcohols via copper(I) catalyzed 1,2-addition of Grignard reagents to enones

The catalytic asymmetric synthesis of tertiary alcohols by the addition of organometallic reagents to ketones is of central importance in organic chemistry. The resulting quaternary stereocentres are difficult to prepare selectively by other means despite their widespread occurrence in natural products and pharmaceuticals. Here we report on a new methodology which allows access to both α-bromo-substituted and α-H-substituted allylic tertiary alcohols with excellent yields, and enantioselectivities of up to 98% using the copper(I)-catalysed 1,2-addition of Grignard reagents to enones. As an example, the methodology is applied in the synthesis of a chiral dihydrofuran.     

Copper(I) catalyzed asymmetric 1,2-addition of Grignard reagents to α-methyl substituted α,β-unsaturated ketones

The first catalytic enantioselective 1,2-addition of Grignard reagents to ketones is presented. This additive-free copper(I) catalyzed 1,2-addition provides chiral allylic tertiary alcohols with an er of up to 98:2 and excellent yields due to the complete shift of overwhelming 1,4-selectivity of copper(I)-catalysts towards 1,2-selectivity in the addition reaction to enones.     

Synthesis of homoallylic chiral tertiary alcohols via chelation-controlled diastereoselective nucleophilic addition on alpha-alkoxyketones: application for the synthesis of the C(1)-C(11) subunit of 8-epi-fostriecin

[reaction: see text] Chiral beta-syn-alkoxyhomoallylic alcohols derived from alkoxyallylboration of aldehydes upon oxidation provided the corresponding chiral ketones. Chelation-controlled nucleophilic addition to these ketones occurred in a highly stereoselective manner to afford anti-homoallylic tertiary alcohols. This methodology has been applied for the synthesis of the C(1)-C(11) subunit of C(8)-epi-fostriecin.     

Addition of grignard reagents to aryl acid chlorides: an efficient synthesis of aryl ketones

[chemical reaction: see text]. Direct addition of Grignard reagents to acid chlorides in the presence of bis[2-(N,N-dimethylamino)ethyl] ether proceeds selectively to provide aryl ketones in high yields. A possible tridentate interaction between Grignard reagents and bis[2-(N,N-dimethylamino)ethyl] ether moderates the reactivity of Grignard reagents, preventing the newly formed ketones from nucleophilic addition by Grignard reagents.     

Catalytic asymmetric vinylation and dienylation of ketones

A solution to the long-standing problem of catalytic asymmetric vinylation of ketones is reported. Vinylzinc reagents are generated via hydrozirconation of terminal alkynes followed by transmetalation to zinc. In the presence of our catalyst, which is formed in situ from a bis(sulfonamide) diol ligand (1) and titanium tetraisopropoxide, the vinylzinc reagent undergoes 1,2-addition to a variety of ketones and enones with enantioselectivities (typically >90%) and high yields. This method is tolerant of functional groups, including alkyl, aryl and vinyl halides, esters, silyl protected alcohols, sulfides, and alkenes. Thus, enantioenriched tertiary allylic alcohols bearing a variety of functional groups can be prepared. It has also been found that 2,2-disubstituted vinylzinc reagents, substitution patterns not accessible through hydrozirconation, can be added to ketones with high enantioselectivities to generate trisubstituted allylic alcohols. Furthermore, we have developed an asymmetric addition of dienyl groups to ketones in the presence of our catalyst. This method enables the synthesis of dienols in high yields with enantioselectivities as high as 94%.     

trans-1-Sulfonylamino-2-isoborneolsulfonylaminocyclohexane derivatives: excellent chiral ligands for the catalytic enantioselective addition of organozinc reagents to ketones

The catalytic enantioselective addition of different organozinc reagents (such as alkyl and aryl derivatives or in situ generated aryl, allyl alkenyl, and alkynyl derivatives obtained through different transmetallation processes) to simple ketones has been accomplished by using titanium tetraisopropoxide and chiral ligands derived from substituted trans-1-sulfonylamino-2-isoborneolsulfonylaminocyclohexane, producing the corresponding tertiary alcohols with enantiomeric excesses (ee) up to >99 %. A simple and efficient procedure for the synthesis of the chiral ligands used in these reactions is described.     

Generation of allyl Grignard reagents via titanocene-catalyzed activation of allyl halides

A protocol for the generation of allyl Grignard reagents via the catalytic activation of allyl halides is described herein. Subsequent nucleophilic addition to carbonyl derivatives provided the desired homo allylic alcohols in excellent yields (84-99%). Evidence suggests that titanocene dichloride catalyzes the formation of an allyl Grignard species which reacts solely with the carbonyl electrophile as evidenced by the complete absence of Würtz coupling. This methodology will have wide-ranging applicability in the generation of highly reactive organometallic reagents.     

Formation of Contiguous Quaternary and Tertiary Stereocenters by Sequential Asymmetric Conjugate Addition of Grignard Reagents to 2‐Substituted Enones and Mg–Enolate Trapping

Herein a comprehensive study is provided on the asymmetric conjugate addition (ACA) of Grignard reagents to α‐substituted cyclic enones. After the elucidation of the optimal experimental conditions, the scope of Grignard reagents and Michael acceptors was examined. Whereas secondary Grignards gave better enantioselectivities with 2‐cyclopentenones, both linear and branched Grignard reagents were tolerated for the ACA to 2‐methylcyclohexenone. The sequential ACA–enolate trapping, which leads to quaternary stereocenters, was then studied. Thus, many electrophiles have been tested, thereby giving rise to highly functionalized cyclic ketones with contiguous α‐quaternary and β‐tertiary centers. The present technique is believed to bring a new approach to versatile terpenoid‐like skeletons of bioactive natural products. Straightforward derivatizations of enantioenriched saturated cyclic ketones further support the potential of the present methodology in synthesis.     

Reaction of Grignard reagents with carbonyl compounds under continuous flow conditions

This contribution details how a continuous flow reactor was used to react carbonyl compounds with Grignard reagents at room temperature in an efficient and safe manner. Flow rate, residence time and temperature were optimized for the preparation of a small collection of secondary and tertiary alcohols. Excellent yields and general applicability were observed using the set-up protocol. The procedure was also applied for the preparation of Tramadol, an analgesic drug belonging to the opioid group. The developed conditions allowed the selective addition of Grignard reagents to aldehydes and ketones in the presence of a nitrile function.     

Efficient catalytic transition-metal-free conditions for nucleophilic addition of arylacetylenes to aromatic ketones

A mild, efficient, and transition-metal-free method for nucleophilic addition of arylacetylenes to diverse aromatic ketones, using catalytic amount of tetrabutylammonium chloride as a promoter and solid KOH as a base in THF, was developed to afford aromatic tertiary propargylic alcohols with high and excellent yields. Aliphatic ketones also gave satisfactory results.     

Selective synthesis of functionalized, tertiary silanes by diastereoselective rearrangement-addition

[reaction: see text] Treatment of hydroxy-substituted silyl epoxides with Grignard reagents induces a 1,2-carbon shift to reveal alpha-silyl aldehydes, which are trapped by highly diastereoselective addition reactions of the Grignard reagent. The starting epoxides are readily accessible from propargylic alcohols by regio- and diastereoselective hydrosilylation and epoxidation reactions. In addition to providing functionalized tertiary silane products, the method is shown to offer a tertiary olefin synthesis through chemo- and diastereoselective Peterson elimination of the product tertiary silane diols.     

Alkylation des carbenoides par des nucleophiles. : II. Substitution nucleophile de l'halogene de carbenoides α phosphonates catalysee par le cuivre(I)

The addition of a catalytic amount (12%) of a copper(I) salt to a mixture of an α-lithio-α-chloroalkylphosphonate and an alkyllithium RLi or a Grignard reagent RMgX leads to the formation of a new organometallic reagent in which the R group has replaced the chlorine atom of the carbenoid. This nucleophilic alkylation of carbenoids can be performed with secondary-alkyl Grignard reagents, and with aryllithium, alkenyllithium and alkynyllithium reagents in good yields (60–80%).     

Influence of catalytic system composition on formation of adamantane containing ketones

The preparation of non-symmetrical ketones by the reaction of acyl chlorides and the corresponding Grignard reagents in the presence of catalytic amounts of metal halides is described. The composition of catalyst has a great influence on the yield of the required ketone as well as on side product formation. For each catalytic system, the yield of ketone and the number of side products changes with the time of addition of the Grignard reagent. We examined the influence of both factors in our model reaction of adamantane-1-carbonyl chloride with ethylmagnesium bromide and discussed the possible mechanisms from this point of view. We have found ZnCl₂, MnCl₂, AlCl₃ and CuCl to be active catalytic components and developed very efficient, cheap and fast methods for the preparation of alkyl adamantyl ketones. The procedure was also tested for the synthesis of other alkyl aryl ketones.     

Chiral tertiary alcohols from a trans-1-arenesulfonyl-amino-2-isoborneolsulfonylaminocyclohexane-catalyzed addition of organozincs to ketones

The catalytic enantioselective addition of different organozinc reagents, such as alkyl, or in situ generated aryl, allyl, alkenyl and alkynyl derivatives to simple aryl ketones, was accomplished using titanium tetraisopropoxide and chiral ligands derived from 1-arenesulfonylamino-2-isoborneolsulfonylamidocyclohexane, giving the corresponding tertiary alcohols with enantioselectivities up to >99%. A simple and efficient procedure for the synthesis of the disulfonamide ligands used is described.     

Reactifs de Grignard vinyliques γ fonctionnels : III. Addition a quelques derives carbonyles

Δt^α,β-Butenolides can be obtained by carbonation of γ-functionally substituted vinylic Grignard reagents, prepared by addition of organomagnesium compounds to α-acetylenic or α-allenic alcohols. By addition to aldehydes and ketones, these vinylic Grignard reagents yield diols, which give unsaturated ethers by cyclization reactions.     

Cyclic vinylogous triflate hemiacetals as new surrogates for alkynyl aldehydes

Cyclic vinylogous triflate hemiacetals can serve as ‘synthetic equivalents’ for alkynyl aldehydes: treatment of a vinylogous triflate hemiacetal with excess amounts of Grignard reagents produces acyclic alkynyl alcohols in good to high yields. This transformation likely involves the Grob-type C-C bond cleaving fragmentation to form the alkynyl aldehyde in situ. Subsequent nucleophilic attack of the Grignard reagent furnishes secondary alkynols. Vinylogous triflate hemiacetals are easily prepared by DIBALH reduction of vinylogous acyl triflates, which are derived from cyclic 1,3-diketones.     

A practical catalytic asymmetric addition of alkyl groups to ketones

Many catalysts will promote the asymmetric addition of alkylzinc reagents to aldehydes. In contrast, there are no reports of additions to ketones that are both general and highly enantioselective. We describe herein a practical catalytic asymmetric addition of ethyl groups to ketones. The catalyst is derived from reaction of camphor sulfonyl chloride and trans-1,2-diaminocyclohexane. The resulting diketone is reduced with NaBH4 to give the C2-symmetric exo diastereomer. Use of this ligand with titanium tetraisopropoxide and dialkylzinc at room temperature results in enantioselective addition of the alkyl group to the ketone. The resulting tertiary alcohols are isolated with high enantiomeric excess (all cases give greater than 87% ee, except one). The reaction has been run with 37 mmol (5 g) 3-methylacetophenone and 2 mol % catalyst to afford 73% yield of the resulting tertiary alcohol with 99% ee.     

Polymer supported trans-1-phenylsulfonylamino-2-isoborneolsulfonylaminocyclohexane ligand for the titanium catalyzed organozinc addition to ketones

The catalytic enantioselective addition of different organozinc reagents, such as diethylzinc, or in situ generated phenylzinc derivatives to simple ketones was accomplished using titanium tetraisopropoxide and supported chiral ligands derived from trans-1-phenylsulfonylamino-2-isoborneolsulfonylamidocyclohexane, to give the corresponding tertiary alcohols with enantioselectivities up to >99%. A simple and efficient procedure for the synthesis of the disulfonamide monomeric ligand and the corresponding polymerization is described.     

CuI-catalyzed tandem carbomagnesiation/carbonyl addition of Grignard reagents with acetylenic ketones: Convenient access to tetrasubstituted allylic alcohols

Highly functionalized tetrasubstituted allylic alcohols were prepared conveniently by CuI-catalyzed tandem carbomagnesiation/carbonyl addition of Grignard reagents with acetylenic ketones. The obtained allylic alcohols can be further transformed to polysubstituted indenes by intramolecular cyclization.     

Benzotriazole-Mediated [2,3]-Wittig Rearrangement. General and Stereocontrolled Syntheses of Homoallyl Alcohols and beta,gamma-Unsaturated Ketones

Readily accessible allyl 1-(benzotriazol-1-yl)alkyl ethers (13 and 19), upon treatment with 2.5 equiv of nucleophilic lithium reagents, give secondary and tertiary homoallyl alcohols (16 and 21), respectively, exclusively in the E configuration in excellent yields. This is achieved by deprotonation followed by [2,3]-Wittig rearrangement, departure of the benzotriazolyl group, and then nucleophilic addition to the resulting carbonyl compound. Following a similar protocol, primary E-homoallyl alcohols 18 are prepared in good yield by the reaction of ethers 13 with LDA in the presence of NaBH(4). Our approach complements the stereochemical Z-selective syntheses of primary homoallyl alcohols of Still and of Bruckner. Wittig rearrangement of the anions of 19 generated with LDA analogously furnishes E-beta,gamma-unsaturated ketones 20 in excellent yields.