Zinc Bromide reduction

The stereospecific reduction of a 2-butyne-l, 4-diol derivative and silver( I)-mediated cyclization of the resulting allene were successively applied to a short total synthesis of (+)-furanomycin 165 (Scheme 4.42) [68], Stereoselective addition of lithium acetylide 161 to Garner s aldehyde in the presence of zinc bromide afforded 162 in 77% yield. The hydroxyl group-directed reduction of 162 with LiAlH4 in Et20 produced the allene 163 stereospecifically. Cyclization followed by subsequent functional group manipulations afforded (+)-furanomycin 165. 

Zinc promoted reduction of Baylis-Hillman adduct derived allylic bromides gave access to... 

Russian chemists [228] found that trimethylsilyl groups protect adjacent triple bonds against hydrogenation with poisoned Pd-catalysts. A similar effect is shown in reductions of trimethylsilylated 1,3-diynes with (activated) zinc powder [226]. One disadvantage of the zinc method is that the zinc salts present in the reaction mixture can cause cleavage of the =C-Si bond (this was shown in a separate experiment in which a trimethylsilylated 1,3-diyne was heated with a solution of zinc bromide or chloride in ethanol [2]). It seems therefore important to keep reaction times of the reductions with zinc as short as possible and to activate the zinc powder with a limited amount of dibromoethane. 

The concept (see Scheme 15) was introduced by Shue et al.,144-85-861 who used a zinc-induced reductive isomerization of diasteromeric allylic bromides which already contained the R2 side chain. Because of the lack of stereocontrol at the a-carbon, and of difficulties in obtaining the allylic bromide, this method has not been further developed instead, homochiral allylic acetates or mesylates have been used. 

The organoselenium-mediated intramolecular trapping of a hemiketal by a suitably disposed carbon-carbon double bond can lead to a spiroketal, although with low stereoselectivity. Thus, when 9-hydroxy-l-nonen-5-one (17) is treated with /V-(phenylsclcno)phthalimide and a catalytic amount of zinc bromide in dichloromethane at 20 °C, a 67 33 (ZjE) mixture of the seleno derivatives is obtained in 78% yield. After Raney nickel reduction, the corresponding spiroketals are recovered in 90% yield103-104. 

Lithium halides (bromide or Iodide) may well modify the Lewis character of the zinc atom, probably via a zincate species [53], and prevent the efficient coordination of the zinc atom to the double bond, coordination which is required for the carbocyclization. Thus, in the Rieke method, it is essential to wash the active zinc thoroughly since the lithium naphthalenide reduction of zinc bromide also generates lithium bromide, which is detrimental to the success of the reaction. Indeed, the insertion of Rieke s zinc in the presence of LiBr leads to the linear organozinc iodide but not to the cyclic product [52]. 

Dimethylaniline has been prepared by reduction of the corresponding nitro compound, either chemically or catalyti-cally. It has been prepared from 3,4-dimethylphenol by heating with ammonia, ammonium bromide, and zinc bromide from w-toluidine hydrochloride by alkylation with methanol at high temperatures from anhydro-4-amino-2-methylbenzyl alcohol by dry distillation from calcium hydroxide from 2-methyl-S-aminobenzyl alcohol by reduction with sodium from 2-methyl-5-nitrobenzyl chloride and 2-methyl-S-nitrobenzyl acetate by catalytic reduction from o-xylene by direct amination with hy-droxylamine hydrochloride in the presence of aluminum chloride and from 3,4-dimethylacetophenone by the Beckmann rearrangement of the oxime.i" The present method has been published. ... 

Rieke zinc is useful for the preparation of secondary and tertiary alkyl zinc bromides. The employment of activated zinc deposited on Ti02, which is obtained from reduction of ZnCU by sodium dispersed on TiOj, is another possibility (for sec-R and benzylic bromides). ... 

The s)mthesis of e /iro-L-j -hydroxyglutamic acid (844) makes use of the furan heterocycle as a carboxyl equivalent (Scheme 122) [185]. After reduction of 793a to 839 and acetylation (840), the aminal acetate and furan are coupled in the presence of zinc bromide and a catalytic amount of trimethylchlorosilane to give a 67 33 mixture of 841 and 842. In the absence of silane the reaction requires 12 h at room temperature for completion, but with silane present the reaction time is reduced to2hat —15°C. 

The cyclohexylidene protecting group has been employed in several syntheses. A preparation of 2,3-0-cyclohexylidene-4-deoxy-L-threose (445) fi om L-( + )-diethyltartrate (lb) in seven steps illustrates one synthetic application (Scheme 99). Conversion of the monobenzyl protected alcohol 443 to its tosylate followed by reduction with sodium borohydride provides the deoxy intermediate 444, which is reductively deprotected and Swem oxidized to 445 in good overall yield. Treatment with benzylamine provides an imine that undergoes a stereoselective carbon-carbon bond forming reaction with a-lithio-A, A -dimethylacetamide in the presence of the Lewis acid zinc bromide to furnish, after Cbz-amine protection, the j9-aminoamide 446. This is converted in four steps to A -acetyl-L-daunosamine (447), a sugar moiety particularly important as the carbohydrate constituent of the anthracycline antibiotics [149]. 

Diastereoselective hydride addition is quite versatile, and it provides facile synthetic access to ( —)-pinidine (661), an alkaloid isolated from several species of Pinus, as well as its unnatural isomer (+ )-pinidine (660b). The unstable aldehyde 655, prepared in four steps from 624 [202], undergoes Grignard addition with 4-pentenylmagnesium bromide followed by Swem oxidation to afford ketone 656 in 90% yield for the two steps. Stereoselective hydride addition with L-Selectride provides the -yn-alcohol 657 (91 9), while zinc borohydride reduction provides almost exclusively the anri-alcohol 658 (>99 1) (Scheme 144). 

The second starting material, mesylate 426, was synthesized from alcohol 422. Swern oxidation followed by addition of propargyl zinc bromide led to compound 423 in 79% yield, which was converted into thionocarbonate 424 (41% yield over three steps). Radical ring closure with tributyltin hydride and oxidation with Dess-Martin periodinane afforded ketone 425. Treatment with DMAP led to the rearrangement of the double bond and subsequent reduction with sodium borohydride and mesylation gave compotmd 426 (Scheme 8.6). 

Other methods for the preparation of 6.99 from leucine involved reduction of the acid moiety with borane and then oxidation to an aldehyde with chromium irioxide and pyridine. Another variation added zinc bromide to the enolate condensation reaction,75 which led to greater selectivity for the anti diastereomer. 

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