Palladium catalysis vinylation

Synthesis of isomeric chiral protected (63 )-6-amino-hexahydro-2,7-dioxopyrazolo[l,2- ]pyrazole-l-carboxylic acid 280 is shown in Scheme 36. Crude vinyl phosphonate 275, obtained by treatment of diethyl allyloxycarbonylmethyl-phosphonate with acetic anhydride and tetramethyl diaminomethane as a formaldehyde equivalent, was used in the Michael addition to chiral 4-(f-butoxycarbonylamino)pyrazolidin-3-one 272. The Michael addition is run in dichloro-methane followed by addition of f-butyl oxalyl chloride and 2 equiv of Huning s base in the same pot to provide 276 in 58% yield. The allyl ester is deprotected using palladium catalysis to give the corresponding acid 277, which is... 

Allyl sulphones can be converted to dienes by alkylation and elimination of sulphinic acid under basic conditions (equation 64)105. Several vitamin A related polyenes have been synthesized following this two-step protocol (Table 10)106. The poor leaving-group ability of the arylsulphonyl group requires treatment with strong base for elimination. However, elimination of the allylsulphonyl group takes place readily under palladium catalysis (equation 65)107. Vinyl sulphones can be converted to dienes via Michael addition, alkylation with allyl halides and elimination of sulphinic acid sequence (equation 66)108. 

Bromoalkynes also couple with vinylstannanes readily to result in enynes. Synthesis of protected enynals via cross-coupling of vinylstannanes with 1-bromoalkynes in the presence of a catalytic amount of Pd(II) has been reported (equation 143)252. Hiyama and coworkers extended the Stille methodology for sequential three-component coupling of trimethylstannyl(trimethylsilyl)acetylene with a vinyl iodide in the first step and cross-coupling of the intermediate trimethylsilylethyne with another alkenyl iodide in the presence of tris(diethylamino)sulphonium trimethyldifluorosilicate in the second step to generate a dienyne (equation 144)253. Both steps occur under palladium catalysis, in one-pot, to result in stereodefined l,5-dien-3-ynes. 

Similar results for the replacement of halogen on an olefinic linkage by phosphorus have been accomplished using dialkyl phosphites with palladium(O) catalysts.4179 Another reaction involving replacement of a vinylic halide by phosphorus utilizes palladium catalysis with a trimethylsilyl-substituted phosphine (Figure 6.19).80... 

The a-arylation of carbonyl compounds (sometimes in enantioselective version) such as ketones,107-115 amides,114 115 lactones,116 azlactones,117 malonates,118 piperidinones,119,120 cyanoesters,121,122 nitriles,125,124 sul-fones, trimethylsilyl enolates, nitroalkanes, esters, amino acids, or acids has been reported using palladium catalysis. The asymmetric vinylation of ketone enolates has been developed with palladium complexes bearing electron-rich chiral monodentate ligands.155... 

A few synthetic applications of palladium catalysis appeared this year. The palladium-catalyzed cyclization of amino allenes 58 occurs with coupling of aryl iodides or vinyl triflates at the 3-position <990L717, 99SL324>. The cyclization can also proceed by the exo-trig pathway, but under suitable reaction conditions the piperidine 59 is prepared selectively. The intramolecular cyclization of amines onto N-allylbenzotriazoles similarly affords piperidines <99JOC6066>. 

The zinc reagents described above have shown extensive utility in coupling reactions with palladium catalysis. For example, coupling with heterocyclic iodides provides the corresponding fluorinated vinyl derivatives, as illustrated in equations 9-11. 

Clarke recently published the first microwave-accelerated Hiyama coupling [163,164]. It was noted that the availability and nontoxic attributes of the organosilicon reactants make them very attractive in synthesis, but their low nucleophilicity limits their potential. Microwave heating allowed aryl bromides and activated aryl chlorides to react under palladium catalysis using an electron-rich N-methyl piperazine/cyclohexyl phosphine ligand (Scheme 75). A vinylation reaction with vinyltrimethoxysilane was also reported [164],... 

The cyclization of alleneamines under palladium catalysis proceeds with coupling at the 3-position with aryl iodides and vinyl triflates <19990L717, 1999SL324>. The cyclization can also proceed by the 4-a o-/ttg-pathway, and, under suitable conditions, piperidines are produced exclusively (Equation 28). 

The coupling of terminal alkynes with aryl or vinyl halides under palladium catalysis is known as the Sonogashira reaction. This catalytic process requires the use of a palladium(0) complex, is performed in the presence of base, and generally uses copper iodide as a co-catalyst. One partner, the aryl or vinyl halide, is the same as in the Stille and Suzuki couplings but the other has hydrogen instead of tin or boron as the metal to be exchanged for palladium. 

While the major use for palladium catalysis is to make carbon-carbon bonds, which are difficult to make using conventional reactions, the success of this approach has recently led to its application to forming carbon-heteroatom bonds as well. The Overall result is a nucleophilic substitution at a vinylic or aromatic centre, which would not normally be possible. A range of aromatic amines can be prepared direcdy from the corresponding bromides, iodides, or triflates and the required amine in the presence of palladium(O) and a strong alkoxide base. Similarly, lithium thiolates couple with vinylic triflates to give vinyl sulfides provided lithium chloride is present. 

Among common carbon-carbon bond formation reactions involving carbanionic species, the nucleophilic substitution of alkyl halides with active methylene compounds in the presence of a base, e. g., malonic and acetoacetic ester syntheses, is one of the most well documented important methods in organic synthesis. Ketone enolates and protected ones such as vinyl silyl ethers are also versatile nucleophiles for the reaction with various electrophiles including alkyl halides. On the other hand, for the reaction of aryl halides with such nucleophiles to proceed, photostimulation or addition of transition metal catalysts or promoters is usually required, unless the halides are activated by strong electron-withdrawing substituents [7]. Of the metal species, palladium has proved to be especially useful, while copper may also be used in some reactions [81. Thus, aryl halides can react with a variety of substrates having acidic C-H bonds under palladium catalysis. 

Besides such homocoupling of alkynes, adduct (58) may be heterocoupled, under palladium catalysis, with a vinylic bromide that itself may have been formed by the hydroalumination of a different alkyne (equations 65 and 66). ... 

Previous preparations by Scolastico were based on the Strecker synthesis of aminonitrile and lacked steroselectivity [74,75]. More recently, two formal syntheses were reported from the same ketone 71. In Rama Rao s synthesis (Scheme 11.19) [76], 71 was condensed with vinyl magnesium bromide to give the tertiary alcohol 72 as a single isomer. This compound was then transformed into the vinyl epoxide 73 that, under palladium catalysis, reacted with 4-methoxyphenyl isocyanate to produce the oxazohdinone 74 with retention of its configuration. The remainder of the synthesis consisted of heterocycle opening and adjustment of the oxidation level to provide the lactone 75. Excision of two carbons was necessary to form the known aldehyde 76, previously transformed into myriocin [74]. 

Tanaka et al. have made the intef ting discovery that when cephems undergo vinylation with vinyltributyltin the nature of the product depends on the metal used [214] thus palladium catalysis afford the ipso product while the use of l.Sequiv. of CuCl in N-methylpyrrolidone leads to a double-bond shift in the cephem moiety (Scheme 4-54),... 

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