Stereoselective synthesis of isoindolinones and tert-butyl sulfoxides

A reaction of Grignard reagents with an optically pure N-sulfinylimine derived from methyl 2-formylbenzoate yields enantioenriched isoindolinones and tert-butyl sulfoxides. The products are formed by the addition of the nucleophile to N-sulfinylimine followed by cyclization to form N-tert-butylsulfinylisoindolinone, which readily undergoes substitution with a second equivalent of Grignard reagent. The reaction can be carried out in dichloromethane at room temperature or at elevated temperatures without any loss of stereoselectivity. The use of nucleophiles other than Grignard reagents has also been investigated.     

Nickel catalyzed cross-coupling of modified alkyl and alkenyl Grignard reagents with aryl- and heteroaryl nitriles: activation of the CCN bond

The nickel catalyzed cross-coupling of alkyl and alkenyl Grignard reagents with aryl nitrile derivatives affords good yields of the corresponding aryl alkanes or aryl alkenes via activation of the CCN bond. To prevent direct addition of the nucleophile to the nitrile group, the reactivity of the Grignard reagent was modulated by reaction with either LiOt-Bu or PhSLi prior to cross-coupling. The optimum catalyst was determined to be NiCl₂(PMe₃)₂, which is a convenient air stable commercially available complex.     

Reaction of mixed carboxylic anhydrides with grignard reagents : Application to the preparation of keto esters; scope and limitations

The low-temperature Grignard reaction of mixed carboxylic anhydrides derived from acid chlorides and o-anisic acid to the general synthesis of keto esters is demonstrated for compounds 1–6, although, some limitations on substrate and Grignard reagent species are also encountered; attempts in the oxa series 2 are unsuccessful, and reaction with ω-phenylpropyl Grignard species for 1 and 4 shows a drastic decrease in yields of the keto esters for m-methoxy analogues. Anomalous behaviour may be associated with an alternative type of specific metal-coordination complex which includes the ether oxygen atom properly situated in the substrate or the reagent     

The synthesis of (1S,8aS)-1-hydroxyindolizidine using a stereoselective Grignard addition to an N-benzyl-3-deoxy sugar imine derived from D-Glucose

A highly stereoselective approach to 1-hydroxyindolizidine is described using a Grignard reaction on N-benzyl imine derived from 3-deoxy-1,2-O-isopropylidine-α-d-xylo-pentodialdofuranose and reductive cyclization as key steps.     

An efficient stereoselective synthesis of (2S,3S)-3-hydroxy-2-phenylpiperidine

A concise enantioselective synthesis of N-Boc-(2S,3S)-3-hydroxy-2-phenylpiperidine 1 is described starting from l-phenyl-glycine and using a Grignard reaction as a key step.     

Hydroxylated terphenylphosphine ligands for palladium-catalyzed ortho-selective cross-coupling of dibromophenols, dibromoanilines, and their congeners with Grignard reagents

p-Terphenylphosphines bearing one or two hydroxy groups were used as ligands to palladium in the cross-coupling of dibromophenols, dibromoanilines, and their congeners with Grignard reagents. High ortho-selectivity that cannot be achieved using other phosphine ligands was observed. ortho-Preference was also observed in competitive cross-coupling reactions of two substrates. A significant effect of the concentration of the Grignard reagent on the ortho-selectivity was observed, when the hydroxylated terphenylphosphines were used. Kinetic studies on this effect showed that high concentrations of the Grignard reagent retard the cross-coupling reaction only at the para-position, but not at the ortho-position.     

Amidation through carbamates

N-Alkyl carbamates of primary amines are easily converted into amides under treatment with Grignard reagents. Consequently, primary amines can be converted into amides in a one-pot reaction through carbamate protection and Grignard addition.     

A convenient preparation of furo[2,3-b]indoles by conjugated addition of organomagnesium reagents to 2-hydroxyindolylidenemalonates

The chelate-controlled conjugated addition of Grignard reagents to 2-hydroxyindolylidenemalonates was studied as a means of preparing 3a-alkyl-3-methoxycarbonyl-2-oxofuro[2,3-b]indoles in one or two steps. In addition to the alkylorganometallic group variation, the effects of substitution at the aromatic ring on the reaction outcome were established. The indolylidenemalonates were found to be less reactive than the analogous indolylidenecyanoacetates.     

Stereoselective approach to pentenocins using RCM: synthesis of 6-epi-pentenocin B

The stereoselective synthesis of 6-epi-pentenocin B 3 is described using a stereoselective Grignard reaction and ring-closing metathesis (RCM) as the key steps.     

The retro Grignard addition reaction revisited: the reversible addition of benzyl reagents to ketones

The Grignard addition reaction is known to be a reversible process with allylic reagents, but so far the reversibility has not been demonstrated with other alkylmagnesium halides. By using crossover experiments it has been established that the benzyl addition reaction is also a reversible transformation. The retro benzyl reaction was shown by the addition of benzylmagnesium chloride to di-tert-butyl ketone followed by exchange of both the benzyl and the ketone moiety with another substrate. Similar experiments were performed with phenylmagnesium bromide and tert-butylmagnesium chloride, but in these two cases the Grignard addition reaction did not show any sign of a reverse transformation.     

Mechanism of the Grignard reaction in terms of the cluster model of reaction center. A quantum-chemical study

Most probable paths of the classical Grignard reaction between ethyl bromide and Mg₃₁ cluster simulating the reaction center on the surface of metallic magnesium were analyzed in terms of the density functional theory [B3PW91/6-31G(d)]. Principal thermodynamic parameters of the radical reaction path, including the energy of adsorption of oxidant molecules on the cluster, the energy of formation of ethyl radicals, and the energy of their subsequent interaction with the surface, were calculated. The structure corresponding to the true transition state of the Grignard reaction was identified. The low energy of activation of the reaction occurring at the phase boundary (5.1 kcal/mol) indicated that the surface reaction of radical formation cannot be rate-determining.     

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.     

Highly stereoselective synthesis of 6-perfluoroalkyl-6-fluoroalka-2,3,5-(Z)-trienols through carbometallation-elimination of 5-perfluoroalkyl-substituted 4(E)-alken-2-ynols with Grignard reagents

A highly regio- and stereoselective sequential carbometallation and Z-selective β-elimination reaction of 5-perfluoroalkyl-4(E)-en-2-ynols with Grignard reagents in Et₂O has been developed to afford various 6-perfluoroalkyl-6-fluoroalka-2,3,5(Z)-trienols in good to excellent yields. Primary or secondary alkyl or aryl Grignard reagents may be used to introduce the R² group to the 2-position of the starting materials referring to the hydroxyl group. A mechanism for this transformation has been proposed.     

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.     

Probing the reactivity of nebularine N1-oxide. A novel approach to C-6 C-substituted purine nucleosides

A novel approach to the synthesis of purine nucleoside analogues, featuring the reaction of the C6-N1-O⁻ aldonitrone moiety of 9-ribosyl-purine (nebularine) N1-oxide with some representative dipolarophiles, as well as Grignard reagents, is reported. Addition of Grignard reagents to the electrophilic C-6 carbon of the substrate allows a facile access to C-6 C-substituted purine nucleosides without using metal catalysts. 1,3-Dipolar cycloaddition processes lead to novel nucleoside analogues via opening, degradation or ring-enlargement of the pyrimidine ring of the base system of the first-formed isoxazoline or isoxazolidine cycloadduct.     

Synthesis of cross-conjugated dienic alcohols

Cross-conjugated dienols 3 were satisfactorily obtained via the palladium-catalyzed coupling reaction of 2-iodo-2-alken-1-ol 6 with vinyl Grignard reagents.     

Stereoselective total synthesis of (+)-cardiobutanolide and (+)-3-epi-cardiobutanolide from diacetone d-glucose

A chiron approach starting with 3-O-benzyl-1,2-O-isopropylidene-α-d-xylo-pentodialdo-1,4-furanose utilizing a Grignard reaction, Mitsunobu stereoinversion, ethyl diazoacetate addition, and selective reduction of the ketone is employed as a key step for the total synthesis of (+)-cardiobutanolide described; a similar strategy is also reported for the first total synthesis of (+)-3-epi-cardiobutanolide.     

A short and common stereoselective approach to 5/6, 6/6, 6/7 bicyclic aza sugars

An efficient and highly stereoselective approach to bicyclic aza sugars is described using Grignard reaction on an N-benzyl imine derived from 3-O-benzyl-1,2-O-isopropylidine-α-d-xylo-pentodialdofuranose, ring closing metathesis, and reductive cyclization as key steps.     

Reaction of (bromodifluoromethyl)phenyldimethylsilane with organometallic reagents

A new fluorine-containing organosilicon compound, (bromodifluoromethyl)-phenyldimethylsilane (II), was synthesized by the N-bromosuccinimide (NBS) bromination of difluoromethyl)phenyldimethylsilane (I), which was prepared from phenyldimethylsilyllithium and chlorodifluoromethane. Compound II reacted with dimethyl sulfoxide to give dimethyl sulfide and phenyldimethylfluorosilane in quantitative yield. The reaction of II with nucleophiles, such as sodium ethoxide, Grignard or lithium reagents, afforded products arising from cleavage of the carbonsilicon bond. In contrast, the reaction of II with Grignard reagents in the presence of appropriate catalysts (Group VIII transition metal salts or complexes) afforded the homo-coupling product of II, 1,2-bis-(phenyldimethylsilyl)-1,1,2,2-tetrafluoroethane (IV), in excellent yield. The silver(I) salt-catalyzed reaction of II with ethylmagnesium bromide gave the cross-coupling product, (1,1-difluoropropyl)phenyldimethylsilane (V) as well as III and IV. When cuprous bromide was employed as catalyst, the reaction of II with ethylmagnesium bromide afforded 1-phenyldimethylsilyl-1-propene (VI) and 3-phenyldimethylsilyl-2-pentene (VII) as main products.     

5,6-Trimethylenethiapyrylium and 5,6,7,8-tetrahydrothiochromylium salts

5,6-Trimethylenethiapyrylium salts have been obtained for the first time. 5,6-Trimethyleneγ-thiopyrans (or 5,6,7,8-tetrahydro-γ-thiochromenes), which belong to a previously unknown series of two-ring sulfides, are formed by reaction of the 5,6-trimethylenethiapyrylium salts (or 5,6,7,8-tetrahydrothiochromylium salts) with Grignard reagents and lithium aluminum hydride.