Heterocyclic zinc reagent

SCHEME 110. Negishi cross-coupling with heterocyclic zinc reagents... 

The reactions of a range of aryl, benzylic, and heterocyclic zinc reagents with iodo- and bromoarenes were reported at ambient temperature under biphasic conditions with [C4mmim][PF6] and toluene. The biaryl products were readily isolated by decanting the toluene phase, with yields of 70-92% achieved after several minutes. However, attempts to recycle the catalytic ionic liquid solution resulted in significantly decreased activities. 

Functionalized heterocyclic zinc reagents are quite usefiil for the preparation of polyfunctional heterocycles. The pyridylzinc derivative 400 has been prepared by reductive lithiation followed by a transmetalation with zinc bromide (Scheme 2-130, eq. (a)). Its cross-coupling with a quinolyl chloride provides the new polyheterocyclic compound 401 in 81% yield. The selective functionalization of positions 3 and 4 of... 

Functionalized heterocyclic zinc reagents are very useful building blocks for the preparation of polyfimctional heterocycles, as shown with the pyridylzinc derivative 430 prepared by reductive lithiation followed by a transmetallation with zinc... 

The formation of arylzinc reagents can also be accomplished by using electrochemical methods. With a sacrificial zinc anode and in the presence of nickel 2,2-bipyridyl, polyfunctional zinc reagents of type 36 can be prepared in excellent yields (Scheme 14) . An electrochemical conversion of aryl halides to arylzinc compounds can also be achieved by a cobalt catalysis in DMF/pyridine mixture . The mechanism of this reaction has been carefully studied . This method can also be applied to heterocyclic compounds such as 2- or 3-chloropyridine and 2- or 3-bromothiophenes . Zinc can also be elec-trochemically activated and a mixture of zinc metal and small amounts of zinc formed by electroreduction of zinc halides are very reactive toward a-bromoesters and allylic or benzylic bromides . ... 

Functionalized heterocycles such as 308 can be prepared in a one-pot synthesis, in which the key step is the addition-elimination of a functionalized copper-zinc reagent 309 to the unprotected 3-iodoenone 310, producing the annelated heterocycle 308 in 41% (Scheme 87) . ... 

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. 

Heterocyclic derivatives of a range of metals other than lithium have received considerable attention, especially as precursors for coupling reactions. These derivatives can be prepared either directly from halo compounds or from the lithio compounds. Thus, direct formation of the pyrrolylzinc compounds can be effected under very mild conditions by treatment of an iodide with a zincsilver couple deposited on graphite. The zinc reagents are formed in excellent yields and can be converted into acylated or allylated products (Scheme 140). For further discussion on this theme, see Section 3.3.3.8.8. 

The reaction of zinc-copper reagents with acid chlorides has a remarkable generality [7,19] and has found many applications in synthesis (Scheme 9-30) [16,59-64]. The treatment of silyl-protected o-aminated benzylic zinc-copper derivatives such as 33 with an acid chloride leads to a 2-substituted indole 34. Aromatic and heterocyclic zinc compounds provide polyfunctional aromatic or heterocyclic ketones like 35 (see Section 9.6.8 Scheme 9-31) [60]. 

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]. 

The heterocycles may be pyridine, pyridazine, pyrimidine (positional isomers) and the organo-zinc reagents 233 were made from the bromo-compounds. Six compounds such as 234 were made by Negishi coupling.34... 

Where a heterocyclic organometallic reagent is required, Grignard and zinc derivatives are often satisfactory complications sometimes attend the use of lithio derivatives. The use of boronic acids has become very popular on account of their clean reactions, general stability to air and water, and their compatibility with practically any functional group furan, thiophene, indole and pyridine boronic acids have all been used. " ... 

A modification of the Negishi cross-coupling has also been used for a wide range of nitrogen heterocycles. In accordance to that, the zinc reagent derived from protected iodoaniline can be treacted with a-substituted carbethoxy vinyl-triflates to produce quinolin-2-ones. ... 

Zinc Reagents. Coupling of heteroaryl iodides or bromides with ethynylzinc halides yields alkynylated heterocycles (Scheme 31). The ethynylzinc reagent can be prepared in situ by addition of a zinc halide to the ethynylmagnesium halide, which is either... 

The cross-coupling of heterocycles is also possible and thus, polyfunctional zinc reagent 331 obtained from the iodide 332 via a I/Mg exchange, followed by a transmetallation, reacts readily in the presence of the highly active palladium catalyst Pd( Bu3P)2 [180] under mild conditions, furnishing the biaryl 333 in 87% yield (Scheme 4.74) [181]. 

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