Cyanide displacement-reduction

Conversion of a Haloalkane into the Homologous Amine by Cyanide Displacement-Reduction... 

Although the biosynthetic cascade hypothesis predicts the co-occurrence of endiandric acids D (4) and A (1) in nature, the former compound was not isolated until after its total synthesis was completed in the laboratory (see Scheme 6). Our journey to endiandric acid D (4) commences with the desilylation of key intermediate 22 to give alcohol 31 in 95% yield. The endo side chain is then converted to a methyl ester by hydrolysis of the nitrile to the corresponding acid with basic hydrogen peroxide, followed by esterification with diazomethane to afford intermediate 32 in 92% overall yield. The exo side chain is then constructed by sequential bromination, cyanide displacement, ester hydrolysis (33), reduction, and olefination (4) in a straight-... 

Structure 190 has been converted into key intermediates 191a and 191b via bromination, cyanide displacement, and benzylation (Scheme 18). Cyclization of 191 occurs upon reduction of the nitro group to give 192 <2004BMC3187>. The A, iV -dibenzyl derivative of 190 leads to similar products <2004JME3187>. 

Sulfone 47 was prepared in nine steps from known iodide 69 by the sequence shown in Scheme 17.15. After initial conversion of 69 into aldehyde 70 by cyanide displacement and reduction with diisobutylaluminium hydride (DIBAL), a Corey-Fuchs alkynylation25 yielded alkyne 51, the key substrate needed for the proposed carboalumination-epoxide ring-opening step. Carboalumination26 was achieved by treating... 

The second synthesis is the most difficult because the double bond can easily slip into conjuga with the carbonyl group. Perhaps the easiest synthesis is a cyanide displacement on an allylic ha though there are other routes including alkyne reduction. 

The precursor of these lower homologous trienes, ( )-5,7-octadienal, was synthesized from 3-hydroxy-l,4-pentadiene9 via Johnson-Claisen rearrangement10, reduction, methanesulfon-ylation and cyanide displacement, followed by reduction using diisobutylaluminum hydride. 

The first step is chloromethylation (Chapter 2) at the most reactive position (less hindered). Cyanide displacement and reduction give (66) which cyclises with the aldehyde to give (65) in acid sojution. 

This gives the 4-pyrimidone ring, which is converted into the 4,5-dichloro-6-(l-fluoroethyl)pyrimidine by the action of sulfuryl chloride in the presence of dimethylformamide (DMF) [68]. The chlorine on the 4-position of the pyrimidine ring is substituted with the side chain 2-[4-(trifluoromethyl)phenyl]ethylamine through a nucleophilic substitution reaction [63]. The side chain 2-[4-(trifluoro-methoxy)phenyl]ethylamine is prepared by chloromethylation of trifluorome-thoxybenzene followed by displacement of the chlorine atom with cyanide and reduction of the nitrile with Raney nickel [69]. 

The reduction of [Co(CN)e] by hypophosphorous acid has also been investigated, effective cyanide displacement yielding Co(CN>2,2H20 as product. 

Indirect methods, such as displacements with azide or cyanide, or reductive amination, are superior to direct alkylation of ammonia for the synthesis of amines. 

In a similar vein, the keto bridge in 5 can be replaced by oxygen with retention of activity. Reduction of acetophenone derivative 19 by means of sodium borohydride leads to the corresponding alcohol (20). Reaction with phosphorus tribromide with cyanide gives... 

In the synthesis of 162, catalytic hydrogenation of lysergic acid proceeds from the less hindered side of the molecule to afford the derivative with the trans ring junction (158). As above, reduction of the methyl ester (159) gives the corresponding carbinol. This is then converted to the methane sulfonate (160), and that function is displaced with cyanide ion to afford the acetonitrile derivative 161. 

As a further illustration of the reactivity of the 3 position toward electrophiles, the methoxyindole (25-1) readily undergoes Mannich reaction with formaldehyde and dimethylamine to afford the aminomethylated derivative (25-2). Treatment of that intermediate with potassium cyanide leads to the displacement of dimethylamine and the formation of the nitrile (25-3), possibly by an elimination-addition sequence involving a 3-exomethylene-indolenine intermediate. The protons on the methylene group adjacent to the nitrile are quite acidic and readily removed. Reaction of (25-3) with methyl carbonate in the presence of sodium methoxide gives the carbo-methoxylated derivative (25-4). Catalytic hydrogenation leads to reduction of the nitrile to a primary amine. There is thus obtained the antihypertensive agent indorenate (25-5) [26]. 

A third route developed by this group started with the commercially available alcohol 32," a compound which has also been the subject of considerable process development due to its use as a common intermediate in the synthesis of several HMGR inhibitors.Conversion of 32 to the 4-halo or 4-nitrobenzenesulfonate 33 followed by displacement with sodium cyanide provided 34 in 90% yield, which is the z-butyl-ester analog of 29. It was noted that this procedure was most scaleable employing the 4-chlorobenzenesulfonate 33a due to the instability of the 4-bromo and 4-nitro-analogs to aqueous hydrolysis. Ra-Ni reduction as before provided the fully elaborated side-chain 35 as the f-butyl ester (Scheme 8). 

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