Transition metal catalyzed nucleophilic allylic substitution: activation of allylic alcohols via π-allylic species

Modern organic synthesis now requires efficient atom economical synthetic methods operating under greener pathways to achieve C-C and C-heteroatom bond formation. Direct activation of allylic alcohols in the presence of transition metal catalysts leading to electrophilic π-allyl metal intermediates represents such a promising target in the field of nucleophilic allylation reactions. During the last decade, this topic of recognized importance has become an emerging area, and selected transition metals, sometimes associated with alcohol activators, have brought elegant solutions for performing allylic substitution directly from alcohols in a regio, stereo and enantioselective manner.     

Palladium-catalyzed allylic nucleophilic substitution reactions of (E)-γ-acetoxy-α,β-unsaturated p-tolylsulfoxides

Regio- and diastereoselective nucleophilic allylic substitutions of optically pure (E)-γ-acetoxy-α,β-unsaturated p-tolylsulfoxides 2 and 3 with sodium dimethyl malonate have been carried out. The reactivity of these substrates is controlled by both the chiral sulfinyl group and the size of the alkyl group attached at the γ-terminus of the allylic system. This process constitutes an example of palladium-mediated resolution of a 1:1 mixture of acetates 2 and 3.     

Allylic activation across an Ir–Sn heterobimetallic catalyst: nucleophilic substitution and disproportionation of allylic alcohol

A nucleophilic substitution of allylic alcohols with carbon (arene, heteroarene, allyltrimethylsilane, and 1,3-dicarbonyl compound), sulfur (thiol), oxygen (alcohol), and nitrogen (sulfonamide) nucleophiles has been demonstrated using an in house developed [Ir(COD)(SnCl₃)l(μ-Cl)]₂ heterobimetallic catalyst in 1,2-dichloroethane to afford the corresponding allylic products in moderate to excellent yields. In 4-hydroxycoumarin, allylation occurs at the 3-position. The diaryl-substituted allylic alcohols undergo disproportionation in presence of the heterobimetallic catalyst to provide the corresponding alkenes and chalcones. An electrophilic mechanism is proposed from Hammett correlation study.     

Vicarious nucleophilic substitution of hydrogen in aldehydes and Knoevenagel reaction of iminium salts with α-halocarbanions

Iminium salts derived from aromatic aldehydes react with -chlorocarbanions via two different pathways: reaction with secondary carbanion of halomethyl sulfones proceeds as the Knoevenagel condensation, while tertiary -chlorocarbanions gave products of vicarious nucleophilic substitution of hydrogen in parent aldehydes.     

Palladium-catalyzed nucleophilic allylic substitution of Morita–Baylis–Hillman adducts with enamines: Synthesis of 1,5-dicarbonyl compounds

An efficient nucleophilic allylic substitution of a variety of Morita–Baylis–Hillman adducts with enamines catalyzed by Pd(OAc)₂ in the presence of ZnBr₂ as a promoter is described in the present study. The reaction gives S_N2-type 1,5-dicarbonyl compounds that may subsequently undergo an intramolecular conjugate addition onto the enone moiety affording the corresponding 1,4-adducts. All the synthesized compounds have been isolated in moderate to good yields and fully characterized.     

Novel synthesis of 1α,25-dihydroxy-19-norvitamin D from 25-hydroxyvitamin D

19-Norvitamin D analogs 3a and 3b were synthesized from 25-hydroxyvitamin D, obtained via a bioconversion method. The synthetic route features a highly regio- and stereoselective hydroboration reaction to afford 25-hydroxy-3,5-cyclopropyl-vitamin D derivatives 12 having olefin at the C1-10-position.     

Synthesis of fused benzimidazole–quinoxalinones via UDC strategy and following the intermolecular nucleophilic substitution reaction

A series of fused benzimidazole–quinoxalinones were synthesized utilizing a one-pot UDC (Ugi/de-protection/cyclization) strategy to form a benzimidazole group with subsequent intermolecular nucleophilic substitution reaction to form quinoxalinone functionality. Using combinations of either a tethered ketone acid or aldehyde acid input the Ugi reaction was shown to afford (1) a ring system through lactamization, (2) a benzimidazole through de-protection and cyclization, and (3) a quinoxalinone through the nucleophilic substitution reaction. Scaffolds were produced in good yields and facile operation.     

A short,enantiospecific synthesis of the 1α-hydroxyvitamin D enyne A-ring synthon

The vitamin D A-ring synthon, the enyne 3b, was synthesized in 5 steps (37% overall yield) from (S)-(+)-carvone (5). The key step was the SmI₂-Pd₀ mediated transformation of epoxypropargyl ester 6 to 3b.     

A multimetallic piano-stool Ir-Sn3 catalyst for nucleophilic substitution reaction of γ-hydroxy lactams through N-acyliminium ions

A multimetallic piano-stool complex [Cp*Ir(SnCl(3))(2){SnCl(2)(H(2)O)(2)}] (1) having Ir-Sn(3) motif has been synthesized from [Cp*IrCl(2)](2) and SnCl(2). The multimetallic complex catalytically promotes the nucleophilic substitution reaction (here after α-amidoalkylation reaction) of γ-hydroxylactams generated from phthalimidals to obtain decorated isoindolinones in excellent yields. Succinamidals, however, lead to the substituted pyrrolidinones (thermodynamic control product) via S(N)1-type path as well as eliminated pyrrolinones (kinetic control product) via an E1-type path, depending on the reaction parameters. A straightforward application of this methodology is to synthesize benzo-fused indolizidine alkaloid mimics.     

Synthesis, characterization and application of β-cyclodextrin-silica nanocomposite as potential microvessel in nucleophilic substitution reaction of phenacyl halides

In the present study, β-cyclodextrin-silica hybrid is synthesized as a novel, efficient and eco-friendly microvessel and solid–liquid phase-transfer catalyst. This molecular host system was applied for nucleophilic substitution reaction of phenacyl halides in water. No evidence was observed for the formation of by-product for example isothiocyanate or alcohol. Also the products were obtained in pure form without further purification. The structure and morphology of the obtained system were investigated by infrared spectroscopy, powder X-ray diffraction, scanning electron microscopy, transmission electron microscopy, thermogravimetric analysis and differential thermal analysis techniques. The surface porosity of the synthesized catalyst was evaluated from the nitrogen adsorption isotherm. All the results provided evidence for incorporation of β-cyclodextrin inside silica pores.     

α-Amino esters as nucleophiles in diastereoselective palladium catalysed allylic substitution reactions

Allylic acetates undergo palladium catalysed allylic substitution with amino ester nucleophiles. Using enantiomerically pure α-amino esters, the substitution products are obtained with moderate diastereoselectivity (up to 85:15: 70% d.e.). The reactions could also be performed using an enantiomerically pure ligand, which was found to exert a stronger influence over the stereochemical outcome.     

2,2′-Dialkoxy, 2,2′-dihydroxy,and 2,2′-diamino derivatives of 1,1′-azobenzimidazole. The first synthesis of heterocyclic tetrazenes by means of a nucleophilic substitution reaction

2,2-Dimethanesulfonyl-1,1-azobenzimidazole is prepared by the oxidation of 1-amino-2-methanesulfonylbenzimidazole with lead tetraacetate. The reaction of this tetrazene with alkali in DMSO, with sodium alkoxides in the corresponding alcohol or ammonia, or with primary or secondary amines leads to the formation of 2,2-dihydroxy, 2,2-dialkoxy, or 2,2-diamino derivatives of 1,1-azobenzimidazole.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 190–193, February, 1992.     

SN2-Selective allylic substitution of chiral γ-aryl substituted allylic picolinates with alkynylcopper reagents

Substitution of γ-aryl secondary allylic picolinates with alkynyl copper reagents was studied. The copper reagent, prepared from TMSCCMgBr and CuBr·Me₂S in 2:1, was subjected to substitution of the picolinate derived from (E)-3-phenyl-1-methyl-2-propenyl alcohol at 0 °C for 1 h in THF to produce a mixture of α- and γ-products and the alcohol in 67:20:13, while the reagent in 3 or 4:1 ratio gave the α-product with 90-91% selectivity. On the contrary, reaction in CH₂Cl₂-THF (6-8:1) at 0 °C for 1 h furnished the α-product with 99% regioselectivity. The effect of CH₂Cl₂ was also demonstrated with eight more examples. Furthermore, 99% inversion was determined by transformation to the literature compound and by chiral HPLC.     

An efficient synthesis of N-hydroxy-α-amino acid derivatives of high optical purity

Conversion of α-hydroxy esters via triflates into compounds 3 proceeds in chemical yields ranging from 78 to 89% and with optical purities ranging from 76 to 100%.     

An improved synthesis of 1α, 25-dihydroxyvitamin D A synthons

A new improved preparation of key intermediates ($\text{9b, 11}$) for the synthesis of 1α, 25-dihydroxyvitamin D is described.     

Vicarious nucleophilic substitution of α-hydrogen of BODIPY and its extension to direct ethenylation

Direct, oxidizer-free substitution of the 3-hydrogen of BODIPY derivatives has been established through a vicarious nucleophilic substitution procedure. This methodology has been combined with a reversible Michael addition on nitrostyrenes to provide a novel, highly efficient entry to the valuable 3-styrylated BODIPY dyes.     

Dual Brønsted acid/nucleophilic activation of carbonylimidazole derivatives

Carbonylimidazole derivatives have been found to be highly active acylation reagents for esterification and amidation in the presence of pyridinium salts. These reactions are thought to involve both Br?nsted acid and nucleophilic catalysis. This mode of activation has been applied to the synthesis of difficult to access oxazolidinones, as well as esters and amides. Finally, the use of pyridinium salts has been shown to accelerate the esterification of carboxylic acids with imidazole carbamates.     

α-Sulfonyl succinimides: versatile sulfinate donors in Fe-catalyzed, salt-free, neutral allylic substitution

Allyl sulfones are versatile intermediates in organic chemistry. The presence of two distinct functional groups sets the stage for a plethora of subsequent transformations. However, despite these advantages the preparation of regioisomerically enriched sulfones is not easy. The use of sulfinate salts as nucleophiles in substitutions is frequently accompanied by side reactions such as π-bond migration, β-elimination, and so on. Herein we present a preparatively simple way to synthesize a variety of different aryl or alkyl allyl sulfones starting from readily accessible allylic carbonates. By employing aryl or alkyl α-sulfonyl succinimides as sulfinate synthons, mild and regioselective ipso substitution of diverse allylic carbonates was realized.     

RuCl3-TBHP mediated allylic oxidation of Δ lanosterol derivatives

A variety of Δ⁸⁽⁹⁾-lanosterol derivatives were converted into 7,11-dienones using t-butyl hydroperoxide in the presence of ruthenium chloride (RuCl₃) in good yields.