Iodides vinyl substitutions

Normally, the most practical vinyl substitutions are achieved by use of the oxidative additions of organic bromides, iodides, diazonium salts or triflates to palladium(0)-phosphine complexes in situ. The organic halide, diazonium salt or triflate, an alkene, a base to neutralize the acid formed and a catalytic amount of a palladium(II) salt, usually in conjunction with a triarylphosphine, are the usual reactants at about 25-100 C. This method is useful for reactions of aryl, heterocyclic and vinyl derviatives. Acid chlorides also react, usually yielding decarbonylated products, although there are a few exceptions. Likewise, arylsulfonyl chlorides lose sulfur dioxide and form arylated alkenes. Aryl chlorides have been reacted successfully in a few instances but only with the most reactive alkenes and usually under more vigorous conditions. Benzyl iodide, bromide and chloride will benzylate alkenes but other alkyl halides generally do not alkylate alkenes by this procedure. 

Alkyl halides with (3-hydrogens generally undergo only elimination reactions under the conditions of the vinyl substitution (100 C in the presence of an amine or other base). Exceptions are known only in cases where intramolecular reactions are favorable. Even alkyl halides without (3-hydrogens appear not to participate in the intermolecular alkene substitution since no examples have been reported, with the exception of reactions with benzyl chloride and perfluoroalkyl iodides. 

The same reactions, carried out with potassium carbonate as base in place of a secondary amine, yield exocyclic dienes in good yield, although double-bond isomerization sometimes occurs (equation 38).93 Inclusion of tetra-zi-butylammonium chloride in the reaction mixture stops the double-bond isomerization. Thus, the reaction in equation (38) with the chloride yields only the bis(exomethylene) product in 45% yield in a slow reaction. Some N- and O-heterocyclic products, also, have been prepared by the intramolecular vinyl substitution reaction.94 A 16-membered ring lactone was made by the ring closure of a vinylic iodide group with a vinyl ketone group. The yield, based upon the reactant, was 55% but a stoichiometric amount of bis(acetonitrile)palladium dichloride was employed. The catalyst was prereduced with formic acid so that the reaction proceeded at 25 C (equation 39).95... 

The direct metalation of 1,3-ditellurole (60 E = H) gave quite different results than the direct metalation of 4-phenyl-1,3-ditellurole (61 E = H) with lithium diisopropylamide (LDA) (83TL237). The parent system was lithiated at a vinylic position to give vinyl substituted products of structure (60) following electrophilic capture with benzaldehyde, methanol-O-d and methyl iodide. Identical results were obtained with 1,3-dithiole and 4-phenyl-l,3-dithiole with LDA. 

In the presence of a fluoride ion generating reagent such as tris(diethylamino)sulfonium difluorotri-methylsilicate (TASF, 99) and a palladium catalyst, vinyltrimethylsilane couples with vinyl and aryl iodides." For substituted vinylsilanes, the fluorodimethylsilyl group is particularly effective in the coupling reaction, which takes place with retention of configuration of both substrates (Scheme 17). Silicon-based C—C bond formation is as useful as that which employs organoborons " for the synthesis of stereo-defined conjugated dienes. 

Numerous aryl bromides, iodides [203], borates [204] and triflates [205, 206] have been successfully carbonylated. Triflates could serve as a route for the synthesis of arenecarboxylic acid derivatives from phenols. This carbonylation using dppf in a catalytic mixture generally shows higher efficiency than PPhj or P(o-Tol)3 [207]. Poor performance is also noted for PPhj in a Pd-catalyzed vinyl substitution of aryl bromides [208]. Side-reactions involving the formation of [PPhjAr]Br and ArH are responsible. A system which is catalyzed effectively by PdCljfdppf) under 10 atm CO is the desulfonylation of 1-naphthalenesulfonyl chloride 58 in the presence of Ti(OiPr)4. Formation of isopropyl 1-naphthoate 59 can be explained in a sequence of oxidative addition, SOj extrusion, carbonylation and reductive elimination (Fig. 1-27) [209]. A notable side-product is di-l-naphthyl disulfide. 

A more versatile palladium-catalyzed formylation of organic halides takes place using tributyltin hydride and carbon monoxide (equation 7). The reaction works for a variety of substrates — aryl, benzyl and vinyl iodides, vinyl triflates and allyl halides. Reaction conditions are mild (1-3 bar CO, 50 °C), and a variety of functional groups can be tolerated. With unsymmetrical allyl halides formylation is regio-selective, taking place at the less-substituted allylic position with retention of geometry at the allylic double bond. 

Further substitution possibilities are available from 2-(trimethylsilyl)methyl-2-propenal, prepared in 71 % yield by Swern oxidation of 2-(trimcthylsilyl)methyl-2-propenol23. Reaction with trimethylsilyl cyanide/zinc(II) iodide, aryl- or vinyllithium followed by acetyl chloride, allows access to cyano-, aryl- or vinyl-substituted congeners. 

Asymmetric synthesis of N-methyl-a-amino esters.2 This morpholine can be used as a chiral template for synthesis of N-methyl-a-amino esters. Thus reaction with an alkylcopper involves displacement of the phenylthio group by an alkyl group by the usual Sn2 process with inversion (about 90 10). In contrast, reaction with an alkylzinc iodide involves substitution with essentially complete retention, possibly via an iminium intermediate. The alkylated product (2) is then oxidized to an oxazinonc (3), which on treatment with vinyl chloroformate followed by hydrolysis provides N-methyl-a-amino esters (4) in high optical purity. This approach to chiral amino acids is unusual in that eiiher enantiomer can be formed from the same template depending on the choice of the organometallic reagent. Unfortunately, the chiral auxiliary (expensive) is not recovered for reuse. 

Arylation of olefins (6, 156).° The vinylic substitution of aryl bromides with diacetatobis(triphenylphosphine)palladium(II) as catalyst is not satisfactory with bromides containing strongly electron-donating groups (OH, NHa). Two solutions have been reported. One is to use an aryl iodide rather than the bromide and palladium acetate alone as catalyst. 

The cross-metathesis of the allylic phosphonate (480) and hydroxyalkenes (481) using the second generation Grubbs catalyst (482) and copper(I) iodide afforded substituted allylic phosphonates (483) in good yields (Scheme 123). Further stereospecific palladium(0)-catalyzed cyclization gave tetrahydrofuran (n = 1) and tetrahydropyran (n = 2) vinyl phosphonates (484). ... 

This is in sharp contrast with the mechanistic picture emerging for the carbopallada-tion of electron-deficient alkenes, which appears to be controlled primarily by electronic factors. For example, electronically biased carbopaUadation adducts are most probably involved in the Pd-catalyzed reaction of methyl cinnamate with aryl iodides. This reaction in fact produces vinylic substitution products containing the added aryl unit exclusively attached to the /3-carbon (Scheme 11).The same trend has been observed in the vinylic substitution Pf" and hydroarylationf" Pf" of /3-substituted-a, /3-enones. 

A key driver for the development of the DBR has been the increased availability of the requisite chromium carbene. Fischer carbenes undergo a wide variety of useful reactions and a significant effort has been devoted to their synthesis. These carbenes undergo many of the same reactions as esters. The a-hydrogens in 13 are quite acidic, with a pKa of approximately 8, that allows for application of the Aldol condensation to form the vinyl-substituted carbene 14. Of course, alkynes insert into these carbenes to form new vinyl substituted carbenes 15. However, the absence of a heteroatom on the carbene center makes these poor substrates for the DBR. The classical route to Fischer carbenes is the Fischer route addition of an organolithium to hexacarbonyl chromium and alkylation with a hard electrophile. Hoye has also shown that alkyl iodides under phase-transfer conditions can be used to alkylate the lithium alkoxide. Thus reaction of vinyl lithium 16 provides the carbene 17 in 53% over two steps. 

IV-Vinylimides readily undergo palladium-catalyzed vinylic substitution with aryl bromides to yield 2-styryl- and 2-phenylethylimines. With aryl iodides (eq 16), the reaction proceeds even in the absence of added phosphine, which opens the possibility of a sequential disubstitution of bromoiodoarenes. 

A variety of 3-vinyl-substituted imidazo[l,5-a]indole derivatives were synthesized by intramolecular Pd catalyzed cyclization of the indole-2-carboxylic acid al-lenamides through either a domino carbopalladation/exo-cyclization process or a novel hydroamination reaction that proceeds smoothly under microwave irradiation. Both the observed pathways involve a Tu-allyl-palladium (II) complex arising from insertion of the allene group into a palladium (II) species, the latter being formed in situ by the intervention of an aryl iodide or of the N-H group. In both these cases, the role of nucleophile is covered by the indole nitrogen (Beccalli et al., 2010). 

Aryl and vinylic bromides and iodides react with the least substituted and most electrophilic carbon atoms of activated olefins, e.g., styrenes, allylic alcohols, a,p-unsaturated esters and nitriles. 

Other Radioprotective Chemicals. The bis-methylthio- and methylthioamino-derivatives of 1-methylquinolinium iodide and l-methylpyridinium-2-dithioacetic acid provide reasonable protection to mice at much lower doses than the aminothiols, which suggests a different mechanism of action (139). One of these compounds, the 2-(methylthio)-2-piperidino derivative of the l-methyl-2-vinyl quinolinium iodide (VQ), interacts with supercoUed plasmic DNA primarily by intercalation. Minor substitutions on the aromatic quinolinium ring system markedly influence this interaction. Like WR-1065, VQ is positively charged at physiological pH, and the DNA-binding affinities of VQ and WR-1065 appear to be similar. 

A valuable feature of the Nin/Crn-mediated Nozaki-Takai-Hiyama-Kishi coupling of vinyl iodides and aldehydes is that the stereochemistry of the vinyl iodide partner is reflected in the allylic alcohol coupling product, at least when disubstituted or trans tri-substituted vinyl iodides are employed.68 It is, therefore, imperative that the trans vinyl iodide stereochemistry in 159 be rigorously defined. Of the various ways in which this objective could be achieved, a regioselective syn addition of the Zr-H bond of Schwartz s reagent (Cp2ZrHCl) to the alkyne function in 165, followed by exposure of the resulting vinylzirconium species to iodine, seemed to constitute a distinctly direct solution to this important problem. Alkyne 165 could conceivably be derived in short order from compound 166, the projected product of an asymmetric crotylboration of achiral aldehyde 168. 

The C-Se and C-Te bonds are formed by an internal homolytic substitution of vinyl or aryl radicals at selenium or tellurium with the preparation of selenophenes and tellurophenes, respectively. An example is shown below, where (TMSIsSiH was used in the cyclization of vinyl iodide 65 that affords... 

---