Zinc compounds benzylation reactions

Palladium catalysed coupling reaction of a heteroaromatic zinc compound with a functionalized aryl iodide preparation of N-benzyl-6-(4-ethylcarboxyphenyi)-purine33... 

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]. 

Benzyl halides and allyl (propargyl) halides are structurally similar but have drastically different chemical reactivities in the aqueous Barbier-Grignard-type reactions. Although tribenzyl and dibenzyltin derivatives have been prepared in aqueous conditions since the 1960s, they do not add onto carbonyls, most likely because it is not possible to form a six-membered cyclic transition state with the carbonyl group in a two-componenf fashion. Still, zinc-mediated benzylation of carbonyl compounds in aqueous media was reported by Bieber et al. recently. The benzylation of 4-nitrobenzaldehyde could be controlled chemoselectively by using various phase transfer catalysts and metal reductants in water (Eq. 4.41). 2... 

In an early example of this reaction aryl and benzyl zinc halides were coupled with aryl halides (equation 40) (102). Alkynyl zinc compounds cross-couple with aryl halides (iodides or bromides) in the presence of a Pd catalyst (equation 41) (103) or alkynyl iodides can be coupled with aryl and alkenyl zinc compounds (equation 42) (100). 

Although the preparation of benzyl carboxylate esters from benzyl bromide and carboxylate anions is not the most common route to these compounds, the reaction is possible when carried out in DMF or using zinc carboxylates. ... 

The chemistry of indium metal is the subject of current investigation, especially since the reactions induced by it can be performed in aqueous solution.15 The selective reductions of ethyl 4-nitrobenzoate (entry 1), 2-nitrobenzyl alcohol (entry 2), l-bromo-4-nitrobenzene (entry 3), 4-nitrocinnamyl alcohol (entry 4), 4-nitrobenzonitrile (entry 5), 4-nitrobenzamide (entry 6), 4-nitroanisole (entry 7), and 2-nitrofluorenone (entry 8) with indium metal in the presence of ammonium chloride using aqueous ethanol were performed and the corresponding amines were produced in good yield. These results indicate a useful selectivity in the reduction procedure. For example, ester, nitrile, bromo, amide, benzylic ketone, benzylic alcohol, aromatic ether, and unsaturated bonds remained unaffected during this transformation. Many of the previous methods produce a mixture of compounds. Other metals like zinc, tin, and iron usually require acid-catalysts for the activation process, with resultant problems of waste disposal. 

Functionalized organozinc halides are best prepared by direct insertion of zinc dust into alkyl iodides. The insertion reaction is usually performed by addition of a concentrated solution (approx. 3 M) of the alkyl iodide in THF to a suspension of zinc dust activated with a few mol% of 1,2-dibromoethane and MeaSiCl [7]. Primary alkyl iodides react at 40 °C under these conditions, whereas secondary alkyl iodides undergo the zinc insertion process even at room temperature, while allylic bromides and benzylic bromides react under still milder conditions (0 °C to 10 °C). The amount of Wurtz homocoupling products is usually limited, but increases with increased electron density in benzylic or allylic moieties [45]. A range of poly-functional organozinc compounds, such as 69-72, can be prepared under these conditions (Scheme 2.23) [41]. 

Several other alkylation reactions of benzyl chloromethyl ether have been reported using phosphorus compounds as nucleophiles. Hydrolysis and alcoholysis reactions of the reagent have been investigated along with the addition of the chloroether to propylene in the presence of zinc chloride. The alkylation of enamines with benzyl bromomethyl ether has been reported. ... 

Reduction of a range of allyl and benzyl chlorides at a stainless steel cathode in dimethylformamide in the presence of carbonyl compounds and using a sacrificial anode of aluminium or zinc, leads to a Reformatsky-type reaction in 40-80 % yields. Allyl halide give products by reaction at both the a- and y-positions. Tetra-chioromethane and bromotrifluoromethane take part in similar reactions provided a... 

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 . ... 

The massive zinc (rod or plate) reacts spontaneously with activated bromides provided the preliminary electroreduction of a catalytic amount of zinc salt (ZnBr2 or ZnCl2) occurs. Reactions are carried out in nitrile solvents (CH3CN, PhCN,. ..) or their mixture with dichloromethane. An undivided cell fitted with a zinc anode and an indifferent cathode (gold, nickel, carbon, zinc,. ..) is used. As observed with benzylic bromides, the activation leads to an organozinc compound able to react with either the nitrile solvent or an electrophile reagent. The process is depicted in equation 12. 

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