Cross-coupling Negishi-type

When the metallic additive to the intermediate 374 was zinc dihalide (or another Lewis acid, such as aluminum trichloride, iron trichloride or boron trifluoride), a conjugate addition to electrophilic olefins affords 381 . In the case of the lithium-zinc transmetallation, a palladium-catalyzed Negishi cross-coupling reaction with aryl bromides or iodides allowed the preparation of arylated componnds 384 ° in 26-77% yield. In addition, a Sn2 allylation of the mentioned zinc intermediates with reagents of type R CH=CHCH(R )X (X = chlorine, bromine) gave the corresponding compounds 385 in 52-68% yield. ... 

The insight that zinc ester enolates can be prepared prior to the addition of the electrophile has largely expanded the scope of the Reformatsky reaction.1-3 Substrates such as azomethines that quaternize in the presence of a-halo-esters do react without incident under these two-step conditions.23 The same holds true for acyl halides which readily decompose on exposure to zinc dust, but react properly with preformed zinc ester enolates in the presence of catalytic amounts of Pd(0) complexes.24 Alkylations of Reformatsky reagents are usually difficult to achieve and proceed only with the most reactive agents such as methyl iodide or benzyl halides.25 However, zinc ester enolates can be cross-coupled with aryl- and alkenyl halides or -triflates, respectively, in the presence of transition metal catalysts in a Negishi-type reaction.26 Table 14.2 compiles a few selected examples of Reformatsky reactions with electrophiles other than aldehydes or ketones.27... 

Negishi-type cross-coupling reactions of primary and secondary alkyl iodides 1 and alkylzinc bromides 2 proceeded with 10 mol% of Ni(py)4Cl2/(sBu)-PyBOX 5a (entry 6) [48]. Based on calculations, an alkylNi(I)(PyBOX) complex is formed by initial SET reduction, which carries much of the spin density in the ligand, similar to Vicic s catalysts 9. Based on this result a Ni(I)-Ni(II)-Ni(III) catalytic cycle was proposed to operate. 

A cross-coupling methodology was also used by Banwell et al. to build the lamellarin framework around the pyrrole core 122 using Negishi and double-barrelled Heck-type reactions to establish key carbon-carbon bonds from 121 <99AJC755>. 

Utilization of stereodefined alkenylalanes or alkenylzirconium reagents in palladium-catalyzed cross-coupling reactions greatly enhances the versatility of Negishi-type coupling reactions. These organometallics are readily available by hydroalumi-nation, carboalumination, and hydrozirconation of alkynes, respectively. 

As was observed with the Kumada and Negishi reactions, the reactions conditions required to conduct the cross-coupling reaction may not be compatible with a wide variety of functional groups. The mild nature of the Suzuki reaction has been demonstrated by the types of functional groups that can be retained unprotected or via methods to modulate the reaction [65]. The coupling of 184 and 185 to generate 186 provided evidence that carboxylic acids and aldehydes are compatible with the Suzuki reaction. 

In efforts to prepare substituted methylthio-2V-heterocycles, researchers at Dupont discovered a new type of Negishi coupling reaction in which benzylic zinc reagents were found to undergo a Pd-catalyzed cross-coupling reaction at the C—S site. 2-(Methylthio) pyrimidine 50 was found to be a particularly reactive substrate for this reaction. Indeed, a 71% isolated yield using 1 mol% Pd( PPh J was obtained with benzyl zinc bromide and 2-(methylthio)pyrimidine in THF. This new cross-coupling method provides a convenient alternative to the use of pyrimidine halides [24]. 

Negishi cross-coupling was used for synthesis of pyridylpyrimidines using classical thermal or microwave-assisted conditions [66]. Distribution and yield of desired compounds and possible by-products proved to be very dependent on the type of energy input. In contrast with thermal conditions, the microwave-assisted method enabled efficient access to dicoupled compounds (Scheme 10.30). 

Zinc Derivatives. 2-(Benzopyran-4-yl)pyridine Al-oxide has been prepared from 2-chlorozinciopyridine 7V-oxide and benzopyran-4-yl triflate in a Negishi-type coupling from 2-chlorozinciopyridine N-oxide (Scheme 66). A five-fold excess of the the zincated pyridine A-oxide had to be used for optimal formation of the cross-coupled product 161. 

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