Benzylmagnesium Chloride Research Articles

Synthesis and reactions of 4-amino-3-carbethoxy-1,2-dihydrospiro(naphthalene-2,1′-cyclopentane)

Addition of benzylmagnesium chloride to cyclopentylidenecyanoacetic ester gives 1-benzyl-1-(cyanocarbethoxymethyl)cyclopentane and this can be cyclized to 4-amino-3-carbethoxy-1,2-dihydrospiro-(naphthalene-2,1′-cyclopentane). Acylation of the obtained aminoester with carboxylic acid chlorides produces the corresponding amides (which can react with an excess of benzoyl chloride). It can also react with orthoformic ester. In both cases the product can then react with hydrazine hydrate. Treatment of the same aminoester with caprolactam gives a tetrahydrospiro(benzo[h]quinazoline-5,1′-cyclopentane) derivative.

Synthesis of C2-symmetric dibenzyldiamino diols by double stereoselective grignard addition to (S,S)-tartraldehyde dinitrone

A new asymmetric two-dimensional synthesis of 1,4-diamino 2,3-diols is illustrated by double addition of benzylmagnesium chloride to the bis-nitrone derived from ( R , R )-tartraldehyde and reduction of the resulting dihydroxylamines. Via double benzylmagnesium chloride addition and reduction of the resulting bis-hydroxylamines.

Stereocontrolled synthesis of pseudo C2-symmetric 1,3-diamino-2-propanol core units of HIV protease inhibitors

The synthesis of the pseudo C 2-symmetric dibenzyldiamino alcohol (S,S)- 1 and the two meso stereoisomers 1a and 1b (R = PhCH 2) is described by stereocontrolled benzylmagnesium chloride addition to the nitrones 3 derived from chiral β-amino-α-hydroxy aldehydes 2 that in turn were obtained from phenylalanine; the overall yield of (S,S)- 1 is 23% from N-Boc l-phenylalaninal; the antipode (R,R)- 1 can be prepared in a similar way starting from the d-isomer of the same α-amino aldehyde.

(Hydrotris(3,5-dimethylpyrazolyl)borato)niobium Alkyne Complexes: Dichloro and Dialkyl Derivatives and Formation of a Butadienyl Complex with an α-Agostic Interaction

A high-yield one-pot synthesis of Tp*NbCl2(alkyne) is described [Tp* = hydrotris(3,5-dimethylpyrazolyl)borate; alkyne = PhC⋮CCH3 (1a), PhC⋮CCH2CH3 (1b), PhC⋮CCH2CH2CH3 (1c), CH3C⋮CCH3 (1d), PhC⋮CPh (1e)]. It involves treatment of NbCl3(DME) (DME = 1,2-dimethoxyethane) with first an alkyne and then with KTp*. The dimethyl derivatives Tp*Nb(CH3)2(alkyne) (alkyne = PhC⋮CCH3 (2a), PhC⋮CCH2CH3 (2b), PhC⋮CCH2CH2CH3 (2c)) and the dibenzyl complex Tp*Nb(CH2Ph)2(PhC⋮CCH3) (3a) have been obtained from the appropriate dichloro complex and 2 equiv of either methyllithium or benzylmagnesium chloride, respectively. These 16-electron niobium(III) d2 complexes, 1a-e, 2a-c, and 3a, have been characterized spectroscopically. In all cases the alkyne is shown to occupy the molecular mirror plane. The barrier to alkyne rotation is high and could be measured only in the case of 1d (68 kJ mol-1 at 358 K). On the basis of qualitative arguments, the structure of these complexes is basically governed by steric interactions. A comparison with the isoelectronic cyclopentadienyl derivatives is provided. When 1a is treated with 2 equiv of ethylmagnesium chloride, the formal dehydrogenation of an ethyl group results in the alkyne-coupled product Tp*Nb(CH2CH3)[C(Ph)C(CH3)CHCH2] (4a), which has been spectroscopically characterized. 1H and 13C NMR data suggest that an α-agostic interaction is present in the ethyl group in this complex.

Synthetic and Mechanistic Investigations of Trimethylsilyl-Substituted Triamidoamine Complexes of Tantalum That Contain Metal−Ligand Multiple Bonds

[N3N]TaPPh ([N3N]3- = [(Me3SiNCH2CH2)3N]3-) reacts with excess lithium metal in tetrahydrofuran to give “[N3N]TaPLi”, as judged by NMR studies and by reactions with RX at −35 °C to afford the phosphinidene complexes [N3N]TaPR (R = Me, n-Bu, SiMe3, SiMe2Ph). [N3N]TaCl2 reacts with 2 equiv of LiN(H)R (R = H, CMe3, Ph) to produce 1 equiv of RNH2 and imido complexes [N3N]TaNR and with 2 equiv of benzylmagnesium chloride or ((trimethylsilyl)methyl)lithium to afford the alkylidene complexes [N3N]TaCHR (R = Ph or SiMe3). The ethylene complex [N3N]Ta(C2H4) is formed quantitatively upon addition of 2 equiv of ethylmagnesium chloride to [N3N]TaCl2. [N3N]Ta(C2H4) decomposes in a first-order manner in solution over a period of days at room temperature to give a complex in which a C−N bond in the TREN backbone has been cleaved. Alkylation of [N3N]TaCl2 with 2 equiv of RCH2CH2MgX (R = CH3, CH2CH3, CH(CH3)2, C(CH3)3; X = Cl or Br) produces a mixture of alkylidene and products derived from decomposition of the incipient ...

Highly chemoselective and stereoselective conjugate addition of benzyl copper reagents to α-oxoketene dithioacetals

Benzyl copper reagents derived by transmetallation between benzylmagnesium chloride and Cu(I) species are shown to undergo conjugate addition - elimination with acyclic and cyclic α -oxoketene dithioacetals to afford the corresponding β-benzyl vinylogous thiolesters in highly stereo- and chemoselective manner.

In 2‐ und 3‐Stellung verzweigte, enantiomerenreine 4,4,4‐Trifluor‐3‐hydroxy‐buttersäure‐Derivate aus 6‐Trifluormethyl‐1,3‐dioxan‐und ‐dioxin‐4‐onen

Preparation of Enantiomerically Pure 4,4,4‐Trifluoro‐3‐hydroxy‐butanoic Acid Derivatives, Branched in the 2‐ or 3‐Position, from 6‐Trifluoromethyl‐1,3‐dioxan‐ and ‐dioxin‐4‐onesEnantiomerically pure 3‐hydroxy‐3‐trifluoromethyl‐propionic acid and esters, substituted in the 2‐ or 3‐position, are prepared (13 examples) from (R)‐ or (S)‐4,4,4‐trifluoro‐3‐hydroxy‐butanoic acid. Key intermediates are the 2‐t‐butyl‐6‐trifluoromethyl‐1,3‐dioxan‐ and ‐dioxin‐4‐ones. The Li enolate of the cis‐dioxanone is generated with t‐BuLi and reacts with electrophiles (alkyl halides, aldehydes, imines, nitroolefins, Br2, I2) with predominant formation of trans,trans‐2,5,6‐trisubstituted dioxanones (9 examples). Elimination of HBr from the 5‐Br‐substituted dioxanone gives the (R)‐ or (S)‐dioxinone, a chiral derivative of 4,4,4‐trifluoro‐3‐oxo‐butanoic acid (trifluoro‐acetoacetate). Michael additions of cuprates or of CuCl‐doped Grignard reagents to the dioxinone produce 6,6‐disubstituted dioxanones (10 examples) bearing a CF3 group in the 6‐position. In most cases this addition is highly diastereoselective, with the new substituent winding up in the trans position. There are, however, surprising exceptions, such as the product formed with benzylmagnesium chloride which is an abnormal adduct with a p‐quinoid structure (26) and with the newly introduced group in the cis position with respect to the t‐Bu group. The structures of four trisubstituted dioxanones bearing CF3 groups are determined by X‐ray crystal structure analysis (Figure 1, Table 1), one of them including the absolute configuration (by anomalous diffraction). Besides the well‐known sofa, a twist‐boat conformation of dioxanones appears to be favorable. The solution conformations of the different types of CF3‐substituted dioxanones are derived from Nuclear Overhauser NMR measurements and compared with the crystal structures (Figure 3).

Reaction of Glycosyl Halides with Benzyl Grignard Reagents: Unexpected o-Tolyl Alkylation of Tetra-O-acetylglucopyranosyl Bromide and Direct Synthesis of (B-Glycosyl)phenylmethanes

Abstract The synthesis of (β-glycosyl1)phenylmethanes by Grignard alkylation of glycosyl halides is investigated. Reaction of tetra-O-acetylglucopyranosyl bromide with benzylmagnesium chloride gave a good yield of a 3:1 mixture of 2-(β-d-glucopyranosyl)toluene and (β-glucosyl)phenylmethane. The requirement for an equatorial 2-acetoxy group and 6-acetoxymethyl group for the formation of the unexpected o-tolyl rearrangement product is explored by using xylosyl, mannosyl, and 2-deoxyglucosyl halides as substrates for the alkylation. Synthesis of (β-glucosyl)phenylmethane by alkylation of 2,3,4,6-tetra-O-benzylglucosyl bromide with benzylmagnesium chloride is also presented.

A convenient synthesis of 2-methoxy-1-naphthyl sulfoxides in high enantiomeric purity. A new asymmetric synthesis of 1-benzyl-1,2,3,4-tetrahydroisoquinolines

The synthesis of diastereomerically pure (-)-(S) menthyl 2-methoxy-1-naphthalenesulfinate (5) is reported. The reaction of (5) with methylmagnesium iodode or benzylmagnesium chloride gives (+)-(R) methyl and (+)-(R) benzyl 2-methoxy-1-naphthyl sulfoxide, (7) and (8) respectively, in high enantiomeric purity (98% ee). Lithiated (8) undergoes addition to 6,7-dimethoxy-3,4-dihydroisoquinoline N-oxide (2) to give a 1-benzyl-1,2,3,4-tetrahydroisoquinoline derivative (9) with high product diastereoselection (d. r. 96 : 4). The stereochemistry of (9) was determined by a single crystal X-ray structure determination.

α-Oxoketene Dithioacetals as Intermediates for Aromatic Annelation

Abstract The α-oxoketene dithioacetals of general formula 1 (Scheme 2), undergo regioselective 1,2-addition with allyl anions to afford the corresponding carbinol acetals 6 in quantitative yields, which on treatment with BF3.Et2O in refluxing benzene yield the corresponding aromatic systems. The method has been shown to be widely applicable as exemplified by a large number of allyl anions (Scheme 3) reacting with α-oxoketene dithioacetals with wide structural variation. However, when 1 carry the α-substituent the intermediate carbinol acetals 14 (Scheme 4) follow, different path to yield the corresponding indenes 15 in good yields. The cinnamoylketene dithioacetals 16 react with allyl anions to afford the corresponding methylthiostilbenes 18 (Scheme 5), while the homologous dithioacetal 20 failed to yield the corresponding 1,4-biaryl-1,3-diene 22 (Scheme 6). This limitation was circumvented by reacting 23 with allyl anions to afford the corresponding stilbenes 24, dienes 25 and triene 26 respectively. The method was successfully extended for naphthoannelation. Thus naphthalenes 28 (Scheme 7) were prepared by reacting benzylmagnesium chloride with 1. In this case the reaction followed a sequential 1,4-and 1,2-addition mode and yielded the corresponding benzyl substituted naphthalenes. This problem was solved by reacting benzylmagnesium chloride with 8 to afford the corresponding naphthalenes 31 (Scheme 8) in excellent yields. Similarly the lithio derivatives derived from toluene followed 1,2-addition mode with 1 to afford the derived methylthionaphthalenes 39 (Scheme 9) in high yields. The other alkyl substituted naphthalenes 41,43 (Scheme 9), 45,47 (Scheme 10) were similarly prepared. Also 1 and β-oxodithioacetals 8 reacted with 1-naphthylmethylmagnesium chloride to afford the corresponding phenanthrenes 49 and 51 respectively in good yields. The method was extended to benzanthracene 56 (Scheme 11) synthesis successfully. The 2-naphthylmethyl magnesium chloride reacted in a sequential 1,4- and 1,2- fashion to afford the corresponding naphthylmethyl hydrocarbons 58 while it reacted with β-oxodithioacetals to give expected condensed aromatics 60, 61 and 62 (Scheme 12) in high yields. The 1-naphthylmethylmagnesium chloride also reacted with β-oxodithioacetals 23 to afford the corresponding styrylphenanthrenes 65, dienes 66 and triene 67 respectively in high yields. The intermediate 69 precursor in the synthesis of hexahelicine was also obtained by reacting 68 with 1-naphthylmethylmagnesium chloride (Scheme 13). The oxygenated benzylmagnesium halides reacted with 1 in 1,2-fashion (Scheme 14) with the exception of the formation of 79. Five fold excess of Reformatsky reagent reacted with 1 to afford the corresponding salicylates 82 (Scheme 15) in high yields. Similarly 84 (Scheme 16) was formed. Propargylmagnesium chloride also reacted with 1 with the participation of solvent methanol to afford the corresponding thioresorcinol dimethylethers 86 (Scheme 17) in high yields. However, intermolecular solvent participation did not occur with open chain α-oxoketene dithioacetals (Scheme 18) and the possible mechanism for this transformation is proposed (Scheme 19). The anion derived from aminocrotonate 97 (Scheme 20) reacted with 1 to afford the corresponding aminosubstituted aromatics 100. To prepare totally unsubstituted aromatics the allylanion was reacted with phenylthioacrolein 101 as exemplified by the synthesis of benzene 108a (Scheme 23), naphthalenes 109,110 and phenanthrene 111 (Scheme 24). In general our new method of aromatic annelation is a versatile, efficient and widely applicable for creating a large number of aromatics from easily accessible open chain precursors.

Ein einfacher Weg zur Herstellung von Alkylpalladium‐Verbindungen durch PdO‐Bindungs‐Spaltung in kationischen Bis(ether‐phosphan)palladium(II)1‐Komplexen mit Grignard‐Reagenzien

A Simple Method for the Preparation of Alkylpalladium Compounds by PdO Bond Cleavage in Cationic Bis(etherphosphane)palladium(II) Complexes with Grignard ReagentsHerrn Professor Heinrich Nöth zum 65. Geburtstag gewidmet. The bis(chelate) complexes [Pd(P∩O)2][ClO4]2 (3a – e) react with methylmagnesium chloride with a concomitant cleavage of two weak PdO bonds to give the methyl complexes trans1‐ClPd(P∼O)2(CH3) (4a – e) (P ∼ O; η1‐P1‐coordinated; P∩O: η21‐O, P1‐chelated; Scheme 1). Diffusion of pentane into the reaction mixture of 4a–e in the presence of the formed magnesium salts yields the cationic complexes trans‐[Ch3Pd(P∼O)1‐(P∩O)][ClO4] (6a, c). The reaction of 3a–e with benzylmagnesium chloride affords the cationic benzyl complexes cis‐[PhCh2Pd(P∼O)(P∩O)][ClO4] (8a–e) in which only one PdO bond has been cleaved. In the presence of carbon monoxide 4a–e adn 6a, c are transformed into the corresponding acyl complexes CH3C(O)Pd(P∼O)2Cl (5a–e and [CH3C(O)Pd‐(P∼O)(P∩O)][ClO4] (7a, c). Whereas at 183 K variable‐temperature 31P{1H}1‐NMR measurements of 6a, c, 7a, c indicate a non‐rigid behavior of the two differently bound ether‐phosphanes, the dynamic process is frozen out for 8a–e. By a lineshape analysis of the spectra the thermodynamic parameters ΔG≢, ΔH≢, and ΔS≢ are obtained. According to a crystal structure analysis 3d and 6c crystallize in the monoclinic space group P21/c with Z4.

Conformational study on indoline compounds. Structures of 2‐phenyl‐3‐arylimino‐3H‐indole 1‐Oxide, 1,2‐dihydro‐2‐phenyl‐2‐benzyl‐ and 2‐tert‐Butyl‐3‐phenylimino‐3H‐indole 1‐oxyls

AbstractReacting 1‐hydroxy‐2‐phenylindole with nitrosobenzene, 2‐phenyl‐3‐phenylimino‐3H‐indole 1‐oxide (1) is produced in only one of the two possible diastereomers. The latter reacts with tert‐butylmagnesium chloride and benzylmagnesium chloride giving, after oxidation, the corresponding aminoxyls which show the same configuration of the phenylimino group at C‐3 as in 1. This has been demonstrated by means of nmr spectros‐copy and X‐ray crystal structure and represents an unexpected stereospecific reaction.

New 1H-benzotriazole-mediated synthesis of N,N′-disubstituted thioureas and carbodiimides

1H-Benzotriazole reacts with an aldehyde and thiourea or an N-substituted thiourea to form Mannich-type condensation products which on treatment with sodium borohydride or benzylmagnesium chloride yield N,N′-disubstituted thioureas or carbodiimides, respectively.

An Approach to 3-Benzylfuran-2-Carboxylic Acid

Abstract 3-benzylfurfural was prepared from furfural and benzylmagnesium chloride and it was then oxidized to 3-benzylfuran-2-carboxylic acid with silver oxide in 40% overall yield.

A new synthesis of anthraquinones using dihydro-oxazoles and Grignard reagents derived from Mg(anthracene)(THF)3

A general synthesis of anthraquinones which depends on the displacement of the methoxy group from an o-methoxyaryldihydro-oxazole by a methoxy substituted benzylmagnesium chloride, generated by using a magnesium–anthracene complex, has been developed. The masked benzylbenzoic acids which result from these reactions are deprotected and then ring-closed to anthrones which on oxidation yield anthraquinones. In this way, the following naturally occurring anthraquinones (or derivatives thereof have been synthesized): chrysophanol (9), islandicin (19), digitopurpone (21), tri-O-methylemodin (26), and di-O-methylsoranjidiol (29).

Reactive intermediates in asymmetric cross-coupling catalysed by palladium P-N chelates

The palladium dibromide complexes of ( S,R)-(1,1′-bis-diphenylphosphino)-2-ferrocencylthyldimethylamine and ( S,R)-(1-diphenylphosphino)-2-ferrocenylethyldimethylamine have been reduced with dilithiocyclooctatetraene to form the corresponding Pd 0 cyclooctatetraene complexes. Their reactions with E-4-methoxy-2′-bromophenylethene, and then benzylmagnesium chloride at −60 to −30°C, provide information on the structure of intermediates in asymmetric cross-coupling.

ChemInform Abstract: A New Synthesis of Anthraquinones.

AbstractThe dimethoxyphenyloxazoline (I) is coupled with the benzylmagnesium chloride (II) to give the diphenylmethane (III).

Reactivity of the secondary benzylic Grignard reagent from 1-phenylethyl chloride with aldehydes and ketones. More evidence for the rearrangement mechanism in benzyl Grignard reactions

Additional evidence for the mechanism proposed previously to account for diol formation in the reaction of the Grignard reagent from benzyl chloride with aldehydes has been obtained from a study of the interaction of the Grignard reagent from 1-phenylethyl chloride with carbonyl compounds. This Grignard reagent reacts with ketones (except non-enolisable ketones) to give normal alcohols in low yields, and with aldehydes to give diols. However, in contrast to that formed in the reaction of benzylmagnesium chloride, an unstable trienic alcohol formed from the rearrangement of the corresponding alkoxide could be isolated in some case as the major product, providing confirmatory evidence for the existence of an initial reversible rearrangement in the reaction of the benzylic Grignard reagents with carbonyl compounds.

A Novel Synthesis of Ketoprofen, Important Non-Steroidal Antiinflammatory Agent

Abstract The α-propionic acid moiety in. ketoprofen is attached through Wittig Homer reaction of ethyl-phosphono propionate on 3-benzyl cyclohexanone, prepared by G. reaction of benzylmagnesium chloride with 2-cyclohexenone (in presence of cuprous chloride)

A New Method for the Synthesis of α-Substituted Phenethylamines via Titanium Amide Complexes

Substituted phenethylamines (1-substituted 2-phenylethylamines) 4 are obtained in high yields by a new, facile reaction of titanium amide complexes with aldehydes and benzylmagnesium chloride.