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.     

Comparaison de la reactivite du bromure d'ethylmagnesium et du diethylmagnesium vis-a-vis des cetones α,β-ethyleniques dans divers solvants

The reactivity of diethylmagnesium and ethylmagnesium bromide towards 2-cyclohexenone in various solvents is studied. The 1,2 addition is always predominant, but diethylmagnesium adds almost exclusively in 1,2 manner to this ketone while ethylmagnesium bromide gives both 1,2 and 1,4 addition products with a ratio dependent of the solvent basicity. Thus, in hydrocarbons (hexane, benzene), the magnesium reagents behave similary; and with more basic solvents, for EtMgBr the yield of the 1,4 addition product increases and that of the 1,2 addition product decreases.With another α,β-ethylenic ketone, trans-3-penten-2-one, 1,4 addition occurs predominantly with both magnesium reagents, diethylmagnesium and ethylmagnesium bromide, but diethylmagnesium gives again much more 1,2 addition product than ethylmagnesium bromide.     

Synthesis of N,N‐Dimethylamines via Barbier–Grignard‐Type Electrophilic Amination

Aryl Grignard reagents react with N,N‐dimethyl O‐(mesitylenesulfonyl)hydroxylamine in THF under Barbier conditions at room temperature and give N,N‐dimethylanilines with high yields in a 2‐h reaction. The amination yield of in situ Grignard reagents were not lower than those of preformed aryl Grignard reagents. In situ cycloalkyl‐, allyl‐, and benzylmagnesium bromides did not react with N,N‐dimethyl O‐(mesitylenesulfonyl)hydroxylamine, except that amination of in situ n‐hexylmagnesium bromide resulted in a medium yield. Grignard–Barbier‐type amination of aryl bromides with N,N‐dimethyl O‐(mesitylenesulfonyl)hydroxylamine provides a new alternative route for the synthesis of N,N‐dimethylanilines.     

Dichotomy within 1,4-addition of organolithium and Grignard reagents to α,β-unsaturated Fischer alkoxycarbenes: A new synthesis of Fischer carbenes

The reaction of organolithium and Grignard reagents with pentacarbonyl[(ethoxy)(2-phenylethenyl)carbene]chromium(0) gave, after the quenching of the initially formed product of the 1,4-addition, different products depending on the organometallic and quenching reagents used. The addition of organolithiums, followed by a work-up with acid (AcOH or HCl), afforded the corresponding carbene complexes. In contrast, quenching the reaction mixture with ethanol led to the stereoselective formation of (Z)-enol ethers. The usage of Grignard reagents led to the formation of the carbene complexes regardless of which quenching reagent was used.     

Reactions of 1,2-dialkyl-3-pyrazolidinones

The condensation of 1,2-dialkyl-3-pyrazoIidinones (1) with a series of aldehydes, ketones and esters in the presence of sodium hydride is described. Alkylation of I with several alkyl bromides gave 4-alkyl substitution products in modest yield and reaction of 1,2,4-trimethyl-3-pyrazolidinone with n-butyl bromide gave a 4,4-dialkylation product. Compound 1 reacted with aryl Grignard reagents to form 3-aryl-3-pyrazoIines whereas the corresponding products were not realized in the case of alkyl Grignards. The reduction of a single example of 1 as well as the reduction of two 3-pyrazolines to pyrazolidines is also reported.     

New,recoverable and highly effective sulfinyl chiral auxiliary

A facile synthesis of a bicyclic 8-menthylsulfinate is described. The reaction of this sultine with organometallic compounds leads to γ-hydroxysulfoxides, while the reaction with lithium amide affords 8-menthylsulfinamide. The chiral efficiency of the 8-menthylsulfinyl auxiliary was tested in the reaction of sulfinimines with Grignard reagents. A highly stereoselective addition of ethylmagnesium bromide to 8-menthylsulfinimine was observed (98% de).     

Diastereoselectivite induite lors de l'addition des organomagnesiens sur les diacyl-1,1′ferrocenes

The reaction of Grignard reagents with 1,1′-diacylferrocenes proceeds with a pronounced stereoselectivity. This is demonstrated by experiments in which the nature of the reagent and the acyl groups are varied. In general, additions of ethyl, phenyl, cyclohexyl and benzylmagnesium halides to diacetylferrocene (I) afford preferentially the erythro-diols (III) whereas the threo-diastoreomers (IV) can be obtained by treatment of the corresponding ketones (IIa—IId) with methylmagnesium bromide. This stereoselectivity results from a preferential direction of attack by the Grignard reagent relative to the intermediate hydroxyketone. The same ratio of isomers is obtained if the reaction is performed on the corresponding hydroxyketone.     

Rapid, highly diastereoselective addition of dialkylzinc reagents to atropisomeric 2-formyl arylamides

We have observed that dialkylzinc reagents add to atropisomeric 2-formyl arylamides many times faster than they react with other substituted benzaldehyde derivatives. Additionally, with diethylzinc the products were formed with very high diastereoselectivity, affording the syn product (d.r. greater than 95:5), except in one case where epimerization of the product is rapid. In contrast, Grignard and trialkylaluminum reagents afforded the anti diastereomers, with diminished stereoselectivity and formation of reduction products.     

Preparation and addition--elimination reactions of benzyl alpha,beta,beta-trifluoroacrylate. A new stereoselective approach to (Z)-beta-substituted alpha,beta-difluoroacrylates

Benzyl alpha,beta,beta-trifluoroacrylate (1) was prepared in good yield via the reductive Br-F elimination of benzyl 2-bromo-2,3,3,3-tetrafluoropropanoate or the palladium-catalyzed cross-coupling reaction of 1,2,2-trifluorovinylstannane with benzyl chloroformate. On treating 1 with various Grignard reagents or dialkylzinc reagents in the presence of copper(I) salt, the corresponding beta-substituted alpha,beta-difluoroacrylates were obtained in high yields with high Z-selectivity. Additionally, trialkylaluminum reagents were also found to be good nucleophiles, the corresponding addition-elimination products being afforded in good yields but with low stereoselectivity.     

Cobalt- and rhodium-catalyzed cross-coupling reaction of allylic ethers and halides with organometallic reagents

Reactions of 2-alkenyl methyl ether with phenyl, trimethylsilylmethyl, and allyl Grignard reagents in the presence of cobalt(II) complexes are discussed. The success of the reactions heavily depends on the combination of the substrate, ligand, and Grignard reagent. In the reaction of cinnamyl methyl ether, the formation of the linear coupling products predominates over that of the relevant branched products. In the cobalt-catalyzed allylation of allylic ethers, addition of a diphosphine ligand can change the regioselectivity, mainly providing the corresponding branched products. Rhodium complexes catalyze the reactions of allylic ethers and halides with allylmagnesium chloride and allylzinc bromide, respectively, in which the branched coupling product is the major product.     

Reaction of 6-phenyl-2-(p-toluenesulfonyl)-3(2H)pyridazinone with grignard reagents

6-Phenyl-2-(p-toluenesulfonyl)-3(2H)pyridazinone (I) reacted with Grignard reagents to give 5-substituted 4,5-dihydro-3(2H)pyridazinones II and two types of dihydropyridazines, III and IV. The ratio of II, III, and IV was sensitively dependent on the reaction conditions. Further, by quenching the reaction mixture with alcohol, the ring-opened product VII was mainly isolated.     

Synthesis of epothilones molecule fragment (15<Emphasis Type="Italic">R</Emphasis>)-C<Superscript><Emphasis Type="Italic">13</Emphasis></Superscript>-C<Superscript><Emphasis Type="Italic">21</Emphasis></Superscript> from D-mannitol

Efficient synthesis of an epothilone molecules fragment (15R)-C¹³-C²¹ was carried out from D-mannitol through its conversion into methyl 2,3-O-cyclohexylidene-D-glycerate followed by the cyclopropanation of the ester group with ethylmagnesium bromide in the presence of titanium(IV) isopropoxide and the transformation of the obtained cyclopropanol into the corresponding 2-substituted allyl bromide. The coupling of the latter catalyzed by copper with 2-methylthiazolyl-4-magnesium bromide, the shift of a double carbon-carbon bond in the product obtained into the position, conjugated with the thiazole ring, and the common transformation of the protected 1,2-diol function afforded the target compound in 15% yield.     

Ultrasonic irradiation in one-pot synthesis of triethylaluminum etherate and its conversion into other organometallic compounds

A mixture of ethyl bromide, aluminum and magnesium powders was irradiated with ultrasound and ethylaluminum sesquibromide(I) formed at room temperature. As soon as diethyl ether was introduced into the reaction medium, ethylmagnesium bromide (II) was formed in situ and subsequently treated with I to give the etherate of triethylaluminum (III, TEA · OEt₂) in satisfactory yield (82%) and purity (98%). III, thus obtained, could react with triethyl borate or zinc chloride to give triethylborane (90%) and diethylzinc (82%) respectively.     

A novel stereoselective synthesis of (−)-β-conhydrine from (R)-2,3-O-cyclohexylidine glyceraldehyde

A novel stereoselective synthesis of (−)-β-conhydrine is achieved. Stereoselective Grignard reaction of (R)-2,3-O-cyclohexylidine glyceraldehyde with ethyl magnesium bromide, chelation controlled stereoselective Grignard reaction of allyl imine derivative with allyl magnesium bromide, and ring-closing metathesis (RCM) of the diallyl product provides (−)-β-conhydrine in high yield.     

Silver-catalyzed cross-coupling reactions of alkyl bromides with alkyl or aryl Grignard reagents

Treatment of secondary or tertiary alkyl bromides with alkyl Grignard reagents in the presence of catalytic amounts of silver bromide and potassium fluoride in CH₂Cl₂ afforded the corresponding cross-coupling products in reasonable yields. Moreover, silver showed catalytic activity for the cross-coupling reactions of alkyl bromides with aryl Grignard reagents.     

Hydride as a leaving group in the reaction of pinacolborane with halides under ambient Grignard and Barbier conditions. One-pot synthesis of alkyl, aryl, heteroaryl, vinyl, and allyl pinacolboronic esters

Grignard reagents (aliphatic, aromatic, heteroaromatic, vinyl, or allylic) react with 1 equiv of 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (pinacolborane, PinBH) at ambient temperature in tetrahydrofuran (THF) to afford the corresponding pinacolboronates. The initially formed dialkoxy alkylborohydride intermediate quickly eliminates hydridomagnesium bromide (HMgBr) and affords the product boronic ester in very good yield. Hydridomagnesium bromide (HMgBr) in turn disproportionates to a 1:1 mixture of magnesium hydride (MgH(2)) and magnesium bromide (MgBr(2)) on addition of pentane to the reaction mixture. DFT calculations (Gaussian09) at the B3LYP/6-31G(d) level of theory show that disproportionation of HMgBr to MgH(2) and MgBr(2) is viable in the coordinating ethereal solvents. This reaction also can be carried out under Barbier conditions, where the neat PinBH is added to the flask prior to the in situ formation of Grignard reagent from the corresponding organic halide and magnesium metal. Pinacolboronic ester synthesis under Barbier conditions does not give Wurtz coupling side products from reactive halides, such as benzylic and allylic halides. The reaction between PinBH and various Grignard reagents is an efficient, mild, and general method for the synthesis of pinacolboronates.     

Reductive ethylation of homoallyl alcohols with a disubstituted double bond with ethylmagnesium bromide in the presence of titanium(IV) isopropoxide

Homoallyl and bishomoallyl alcohols with a disubstituted double bond treated with ethylmagnesium bromide in the presence of titanium(IV) isopropoxide are converted into the products of a reductive ethylation of the olefin fragment. Under similar conditions esters of β,γ-unsaturated carboxylic acids undergo a successive cyclopropanation of the ester group and reductive ethylation of the double carbon-carbon bond and yield 1-(3-ethylalkyl)cyclopropanols. The features of the observed reactions are explained in the framework of the carbometallation mechanism of the double carbon-carbon bond by the action of dialkoxytitanacyclopropane reagents.     

Zirconocene catalysis in the synthesis of 1,4-dimagnesium reagents: using competitive inhibition to suppress β-hydrogen abstraction

Substituted 1,4-dimagnesium reagents were synthesized by the zirconocene-catalyzed reaction of alkenes with ethylmagnesium reagents in the presence of a methylmagnesium containing additive. Improved selectivity for formation of dimagnesium reagents over monomagnesium reagents was obtained in the presence of the methylmagnesium containing additive. The ratio of mono- to dimagnesiated products was extrapolated from the ratio of alkene to diene in the products formed when the reaction was quenched with allyl bromide. The extent of the increase in the alkene/diene ratio was dependent on the type of organomagnesium halide, with greatest increases (59%) for the alkylmagnesium chlorides. A mechanism for improved selectivity by suppression of β-hydrogen abstraction in the catalytic cycle is presented. Quenching the 1,4-dimagnesium reagents with allyl bromide yielded decadienes.     

Sequential One‐Pot Addition of Excess Aryl‐Grignard Reagents and Electrophiles to O‐Alkyl Thioformates

The sequential addition of aromatic Grignard reagents to O‐alkyl thioformates proceeded to completion within 30 s to give aryl benzylic sulfanes in good yields. This reaction may begin with the nucleophilic attack of the Grignard reagent onto the carbon atom of the O‐alkyl thioformates, followed by the elimination of ROMgBr to generate aromatic thioaldehydes, which then react with a second molecule of the Grignard reagent at the sulfur atom to form arylsulfanyl benzylic Grignard reagents. To confirm the generation of aromatic thioaldehydes, the reaction between O‐alkyl thioformates and phenyl Grignard reagent was carried out in the presence of cyclopentadiene. As a result, hetero‐Diels–Alder adducts of the thioaldehyde and the diene were formed. The treatment of a mixture of the thioformate and phenyl Grignard reagent with iodine gave 1,2‐bis(phenylsulfanyl)‐1,2‐diphenyl ethane as a product, which indicated the formation of arylsulfanyl benzylic Grignard reagents in the reaction mixture. When electrophiles were added to the Grignard reagents that were generated in situ, four‐component coupling products, that is, O‐alkyl thioformates, two molecules of Grignard reagents, and electrophiles, were obtained in moderate‐to‐good yields. The use of silyl chloride or allylic bromides gave the adducts within 5 min, whereas the reaction with benzylic halides required more than 30 min. The addition to carbonyl compounds was complete within 1 min and the use of lithium bromide as an additive enhanced the yields of the four‐component coupling products. Finally, oxiranes and imines also participated in the coupling reaction.     

Asymmetric grignard cross-coupling by means of polymer-supported optically active β-dimethylaminoalkylphosphine-nickel catalysts

New polymer ligands containing β-dimethylaminoalkylphosphines were prepared using chloromethylated polystyrene, and the ligands were used for nickel-catalyzed asymmetric cross-coupling of sec-alkyl Grignard reagents with vinyl bromide to yield coupling products of ～50% ee.