Oxidative addition, zinc metal bromides

The cyclohexene 121, which was readily accessible from the Diels-Alder reaction of methyl hexa-3,5-dienoate and 3,4-methylenedioxy-(3-nitrostyrene (108), served as the starting point for another formal total synthesis of ( )-lycorine (1) (Scheme 11) (113). In the event dissolving metal reduction of 121 with zinc followed by reduction of the intermediate cyclic hydroxamic acid with lithium diethoxyaluminum hydride provided the secondary amine 122. Transformation of 122 to the tetracyclic lactam 123 was achieved by sequential treatment with ethyl chloroformate and Bischler-Napieralski cyclization of the resulting carbamate with phosphorus oxychloride. Since attempts to effect cleanly the direct allylic oxidation of 123 to provide an intermediate suitable for subsequent elaboration to ( )-lycorine (1) were unsuccessful, a stepwise protocol was devised. Namely, addition of phenylselenyl bromide to 123 in acetic acid followed by hydrolysis of the intermediate acetates gave a mixture of two hydroxy se-lenides. Oxidative elimination of phenylselenous acid from the minor product afforded the allylic alcohol 124, whereas the major hydroxy selenide was resistant to oxidation and elimination. When 124 was treated with a small amount of acetic anhydride and sulfuric acid in acetic acid, the main product was the rearranged acetate 67, which had been previously converted to ( )-lycorine (108). 

Early preparations of active zinc utilized the potassium or sodium metal reduction of anhydrous zinc salts in refluxing THF or DME (Protocol l).3,8 These highly divided zinc powders displayed high reactivity towards organic halides in oxidative addition. Alkyl iodides and bromides reacted with the zinc powders at room temperature. Even aryl bromides and iodides would react to form the corresponding arylzinc iodides or bromides at refluxing... 

Mixed bimetallic reagents possess two carbon-metal bonds of different reactivity, and a selective and sequential reaction with two different electrophiles should be possible. Thus, the treatment of the l,l-bimetailic compound 15 with iodine, at — 78"C, affords an intermediate zinc carbenoid 16 that, after hydrolysis, furnishes an unsaturated alkyl iodide in 61% yield [Eq. (15) 8]. The reverse addition sequence [AcOH (1 equiv), —80 to — 40 C iodine (1 equiv)] leads to the desired product, with equally high yield [8]. A range of electrophile couples can be added, and the stannylation of 15 is an especially efficient process [Eq. (16) 8]. A smooth oxidation of the bimetallic functionality by using methyl disulfide, followed by an acidic hydrolysis, produces the aldehyde 17 (53%), whereas the treatment with methyl disulfide, followed by the addition of allyl bromide, furnishes a dienic thioether in 76% yield [Eq. (17) 8]. The addition of allylzinc bromide to 1-octenyllithium produces the lithium-zinc bimetallic reagent 18, which can be treated with an excess of methyl iodide, leading to only the monomethylated product 19. The carbon zinc bond is unreactive toward methyl iodide and, after hydrolysis, the alkene 19... 

Monoorganozinc halides (RZnX) can be synthesized by oxidative addition of organic halides to zinc metal. The oxidative addition rate is strongly affected by the reaction conditions (solvent, concentration) [16] and by activation of the zinc [15,17]. Zinc powder or zinc foil, which is activated by treatment with 1,2-dibromoethane and then with trimethylsilyl chloride, will oxidatively add alkyl iodides [18]. The reaction of alkyl bromides, on the other hand, requires more active zinc, which may be prepared by the reduction of zinc chloride with either lithium naphthalenide [19] or lithium metal under ultrasonic.irradiation [20, 21]. 

When studying the same reaction with a variety of allylic bromides it was found that the addition of metallic aluminium dramatically improved the yield (aluminium chloride, aluminium oxide and metalUc zinc were ineffective). 

The first report of the oxidative addition of zinc metal to organic halides dates back to the work of Frankland [1-4] around 1850. He discovered that dialkylz-inc compounds could be prepared from zinc metal and methyl iodide or ethyl iodide. However, the reaction did not proceed with alkyl bromides or chlorides. Also, no aryl halides were found to undergo the oxidative addition reaction. Several approaches have been reported since that time to increase the reactivity of the zinc metal. The majority of these modifications have employed zinc-copper couples [5-8] or zinc-silver couples. However, all of these procedures still only worked with alkyl iodides. Noller used a mixture of alkyl iodides and bromides but found that the mixture must contain a large percent of alkyl iodide [9]. 

In general, the preparation of 2-pyridyl organometallics is mostly performed by lithiation of 2-halopyridine at cryogenic conditions followed by transmetal-lation with an appropriate metal halide. As mentioned previously, this procedure causes some limitations on the use of the 2-pyridyl organometallics. In our study, readily available 2-bromopyridine was treated at it with active zinc prepared by the Rieke method [138]. The oxidative addition of the active zinc to carbon-bromine bond was completed in an hour at refluxing temperature to give rise to the corresponding 2-pyridylzinc bromide (PI). 

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