Palladium-catalyzed cross-coupling substitution

Heck reaction, palladium-catalyzed cross-coupling reactions between organohalides or triflates with olefins (72JOC2320), can take place inter- or intra-molecularly. It is a powerful carbon-carbon bond forming reaction for the preparation of alkenyl- and aryl-substituted alkenes in which only a catalytic amount of a palladium(O) complex is required. 

Dipolar cycloaddition reaction of trimethylstannylacetylene with nitrile oxides yielded 3-substituted 5-(trimethylstannyl)isoxazoles 221. Similar reactions of (trimethylstannyl)phenylacetylene, l-(trimethylstannyl)-l-hexyne, and bis (trimethylsilyl)acetylene give the corresponding 3,5-disubstituted 4-(trimethyl-stannyl)isoxazoles 222, almost regioselectively (379). The 1,3-dipolar cycloaddition reaction of bis(tributylstannyl)acetylene with acetonitrile oxide, followed by treatment with aqueous ammonia in ethanol in a sealed tube, gives 3-methyl-4-(tributylstannyl)isoxazole 223. The palladium catalyzed cross coupling reaction of... 

Murakami and co-workers have shown that phenyl- and vinyl-substituted vinylallenes react in a palladium-catalyzed intermolecular [4+ 4]-cycloaddition in the presence of a palladium complex to give the cyclooctadiene cycloadducts in moderate to good yields (Scheme 29).103 In a method reported by Lee and Lee, bicyclo[6.4.0]-dodecatrienes are prepared in good overall yields via a two-step, one-flask procedure that involves a serial palladium-catalyzed cross-coupling/[4 + 4]-cycloaddition followed by [4 + 2]-cycloaddition (Scheme 30). Overall, this two-step process impressively brings together five simple components to form relatively complex bicyclic products.1... 

Palladium catalyzed cross-coupling reactions of 1-substituted glycals have not only been limited to tributylstannyl derivatives. In fact, the versatility of this approach is significantly enhanced by the fact that C-l zinc-, indium-, or iodine-substituted glycals (easily accesible from glycals, see Scheme 7)... 

In the early 1980s, one of the first preparations of substituted allenes was reported, which employed a palladium-catalyzed cross-coupling reaction of allenyl halides [9]. In this study, allenyl bromides 13 and various Grignard reagents 14 were coupled in the presence of catalytic amounts of a Pd(0) species, generated in situ by reduction of a Pd(II) salt. Trisubstituted allenes 15 were obtained with high regioselectivity (allene 15 alkyne 16 = 90 10 to 99 1) (Scheme 14.5). 

Additional examples of palladium-catalyzed cross-couplings, in particular with allenylzinc compounds, can be found elsewhere [11, 15, 36]. A systematic study comparing several chiral palladium phosphine catalysts in the reaction of 4,4-di-methyl-1,2-pentadienylzinc chloride and iodobenzene revealed that an enantiomeric excess of only 25% was obtained from the best catalyst combination PdCl2 and (R,R)-DIOP [15]. The synthetic value of these transformations of donor-substituted allenes as precursors is documented by the preparation of a/l-unsaturatcd carbonyl... 

Disubstituted 4-chloro-2-cyclobutenones 75 undergo the palladium-catalyzed cross-coupling reaction with vinyl- and arylstannanes 76 or vinylzir-conium reagents to give the 4-R sa,-2-cyclobutenones 77. Without isolation, these cyclobutenones 77 are rearranged to the substituted phenols 78 on thermolysis [38], Application of this method to the stannylated heteroaromatics 79 provides a synthetic route to the aromatic benzoheterocycles 80 [39]. (Scheme 27 and 28)... 

Palladium-catalyzed cross-coupling reactions are not restricted to stannane derivatives, however, and other azaheterocyclic carbanion derivatives to have been investigated include l-methyl-2-pyrrolylmagnesium bromide and l-methyl-2-pyrrolylzinc chloride (81TL5319), l-methyl-2-indolymagnesium bromide (81TL5319), l-substituted-2- and 5-imidazolyl-... 

Although there have been few new developments in the period since 1993, halogenopyrazines 42 have been convenient precursors for a variety of pyrazine derivatives. For example, the halogenopyrazines 42 are cyanated by palladium-catalyzed cross-coupling with alkali cyanide or by treatment with copper cyanide in refluxing picoline, to yield cyanopyrazines 48. Alkoxypyrazines 49 are produced by treatment with alkoxide-alcohol, and aminopyrazines 50 are prepared by amination with ammonia or appropriate amines. The nucleophilic substitution of chloropyrazine with sodium alkoxide, phenoxide, alkyl- or arylthiolate is efficiently effected under focused microwave irradiation <2002T887>. 

Pyrazines undergo nearly all of the same reactions as pyrimidines, from nucleophilic substitution (SnAt) to palladium-catalyzed cross coupling reactions. Displacement of the chlorides via SnAt reactions with nitrogen (157 158) and sulfur-based nucleophiles (158... 

The 4- and 6-positions of pyrrolo[2,3-3]pyridines can be substituted via palladium-catalyzed cross-coupling reactions with the 4- or 6-halo-substituted derivatives (Scheme 3) <2001SL609>. Nucleophilic displacement of the 4-substituent of 6-chloro-4-nitro- and 4,6-dichloro-pyrrolo[2,3-/ ]pyridines takes place with phenols. Protection of the pyrrole nitrogen with a /3-trimethylsilylethoxymethyl (SEM) group affords good yields of the aryl ethers (Equation 3) <2006TL2069>. 

By contrast, for iodide 18 having the triple bond activated by a phenyl group, conversion to the cyclic organozinc species 25 occurred effectively and the latter could be efficiently functionalized, provided that traces of moisture were excluded by pre-treatment of zinc powder with Mel. The substituted benzylidene cyclopentanes 26 and 27 were respectively obtained after iodinolysis and palladium-catalyzed cross-coupling reaction with benzoyl chloride (equation 10). However, it could not be assessed whether the formation of organozinc 25 was attributable to an anionic or a radical cyclization pathway (or both) as, had iodide 26 been produced by a radical iodine atom-transfer, it would have been converted to 25 by reaction with metallic zinc due to the presence of the activating phenyl group21. 

A 1,3-substituted allene, which has axial chirality instead of carbon central chirality, has been prepared by a palladium-catalyzed cross-coupling of 4,4-dimethylpenta-l,2-dienylzinc chloride (83) with phenyl iodide (5c) or by that of l-bromo-4,4-dimethylpenta- 1,2-diene (84) with phenylzinc chloride [60] (Scheme 8F.20). The highest enantiomeric purity (25% ee) of the allene (S)-85 was obtained in the former combination with (f ,/ )-diop (1) as chiral ligand. It is interesting that the enantiomeric purity was independent of the ratio of the reagents though the reaction seems to involve a kinetic resolution of the racemic 83. 

The benzene derivatives containing the fluorinated sulfone have been prepared either by nucleophilic substitution of the 4-fluorophenyl derivative (e.g. 1) or by starting with the appropriately substituted sodium thiophenoxide and reacting with perfluoroalkyl iodide follow by oxidation with either MCPBA or chromium oxide (12. li.) The biphenyl derivatives have been prepared by palladium catalyzed cross coupling chemistry of the 4-bromophenyl derivative (e.g. 2) with substituted phenyl boronic acid (yields 37-84%) (JLH, .). Compound 16 has been prepared by palladium catalyzed cross coupling of (4-bromophenyl)perfluorohexyl sulfone with vinyl anisole in 37 % yield (JJL). The vinyl sulfones, 7 and 9, have been prepared by condensation of CH3S02Rf (JJL) with the appropriate aldehyde (yields 70,and 73%) following a literature procedure (1 ). Yields were not optimized. 

Stannylquinones.1 The quinone synthesis based on addition of alkynyllithiums to substituted cyclobutenediones (13, 209-210, 284) can provide stannylquinones. Thus thermolysis of the alkynylcyclobutenol 1 with Bu3SnOCH3 results in rearrangement to the stannylquinone 2. As expected, these stannylquinones undergo palladium-catalyzed cross-coupling with organic halides (Stille reaction, 14, 35), particularly with allylic halides. 

Quinoline derivatives have been substituted by nucleosides <94JCS(P1)2931> and by ert-butyl groups <95JOC(60)5390> via radical substitution reactions. Palladium-catalyzed cross coupling method has been used to couple quinoline triflates with acetylene <95T(51)3737>. 4-Quinolones, in contrast to 2-quinolones, react with peroxodisulfate anions in aqueous base to form 3-hydroxyquinolines via the 3-sulfate ester <95JCR(S)164>. 

Scheme 16 shows parallel syntheses of cyclic and acyclic amide compounds. Fluorous benzaldehydes were first subjected to reductive amination reactions. The resulting amines were then reacted with isocyanates to form substituted hydantoin rings 14 or with benzoyl chlorides to form amides 15. Purified F-sulfonates were used for palladium-catalyzed cross-coupling reactions to form corresponding biaryl 16 [31] and arylsulfide 17 [32] products, respectively. 

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