Nitriles, Reformatsky reactions

The Reformatsky reaction can also be performed electrochemically either directly or using a mediator. Ni-catalysis has proven to be an efficient way to prepare j3-hydroxy ester or nitrile from the corresponding a-chlorocompounds (Table 14) [94]. Here again the first step is the oxidative addition of the cathodically generated Ni°bpy to the halocompound. The nature of the sacrificial anode also plays a crucial role in this reaction, though the formation of an organozinc intermediate has not been fully demonstrated. 

A new preparation of the C g ketone, an important synthon for the synthesis of vitamin A had also been published by Valla et al. [71]. Hence p-ionone and acetonitrile were condensed in the presence of KOH, to afford the nitrile (80%, E/Z isomers 80/20). A Reformatsky reaction of ethyl bromoacetate with the nitrile provided the ethyl P-ionylideneacetoacetate in 70% yield. Subsequent reduction with NaBH4, followed by esterification (MeSC Cl) and desulfonation of the unstable... 

Hydroxy nitriles, via indium-mediated Reformatsky reactions, 9, 708... 

The electrosynthesis of /Miydroxy esters (220), 2,3-epoxy esters (221) and /Miydroxy nitriles (222) was achieved under nickel-catalyzed conditions, obviating Reformatsky reaction 70(equation 112-114). The reaction proceeds in excellent yield when a sacrificial zinc rod is used as the anode. A mechanism has been proposed which involves reduction of a Ni(II) complex to a Ni(0) complex, oxidative addition of the a-chloroester to the Ni(0) complex, and a zinc (II)/Ni(II) exchange, leading to an organozinc reagent, in analogy to the Reformatsky reactions. 

Orsini reported the use of a 10 mol % Sml2-Mg reagent system in the Reformatsky reactions of a-halocarbonyl compounds, nitriles and phospho-nates with ketones, aldehydes and imines.29... 

Reductive oxidation of />-nitrotoluene to -aminobenzaldehyde, 31, 6 Reformatsky reaction, 37, 38 Reissert s compound, 38, 58 Reissert reaction, 38, 58 Replacement, benzenesulfonate groups by bromine atoms, 31, 82 bromine, by a thiol group, 30, 35 by fluorine, 36, 40 chlorine, by an amino group, 31,45 by a thiol group, 32, 101 by iodine, 30, 11 by methoxyl, 32, 79 by nitrile, 36, 50 in an imido-chloride group by an anilino group, 31, 48 chlorine and nitro by ethoxyl radicals, 32,68... 

In addition to aldehydes and ketones, organic compounds which are known to react with Reformatsky reagents include esters,nitriles, acid chlorides, organic halides,epoxides, nitrones, azirenes" and imines. This section describes the selectivity reported for Reformatsky reactions with functionally substituted aldehydes or ketones. 

The most successful acylations of Reformatsky reagents have been obtained with nitriles. This reaction, first reported in 1901 by Blaise, was little used until Kagan and Suen reported that slow addition of a benzene solution of a-bromo esters to a refluxing mixture of zinc and the nitrile gave good yields (70-83%) of a,a-disubstituted 3-keto esters. Hannick and Kishl reported that a similar proce-... 

Regioselective opening of epoxide 228 with potassium cyanide in ethanol—buffer furnishes the jS-hydroxy nitrile 235. This undergoes a Reformatsky reaction [83] with tert- mXy bro-moacetate/zinc followed by a highly stereoselective ketone reduction with sodium borohy-dride/diethylmethoxyborane to provide the chiral ester 236. Subsequently, 236 is converted in four steps to optically active NK-104 (237), a highly potent HMG-CoA reductase inhibitor [84] (Scheme 55). 

There was no problem with selectivity in the second aldol reaction because the aldehyde is not enolizable. The Reformatsky reaction in this sequence illustrates the fact that, as you saw in Chapter 26, aldol-type reactions happen at the ester oxidation level as well, and you should equally look to disconnect P-hydroxy or a,P-unsaturated esters, acids, or nitriles in this way. Just remember to look for 1,3-relationships, convert the functional groups to oxygen-based ones, and disconnect them to d plus a synthons. 

This reaction is believed to proceed by a mechanism analogous to that of the Reformatsky Reaction involving an initial condensation of the nitrile with the Reformatsky reagent the intermediate is finally transformed into 0-keto ester via acidic hydrolysis,as illustrated here. 

P-Ketoesters from nitriles, a-haloesters and Zn. Cf. Reformatsky reaction. 

Some papers mention the improvement of the Reformatsky reaction applied to nitriles (the Blaise reaction) by sonication. The presence of a chemical activator for zinc seems useful. This can be zinc oxide or silver. In the latter example, a cyclization between a bromoester moiety and a nitrile group was used in the synthesis of corynantheidol (Eq. 76). 2... 

Reformatsky reaction with nitriles leads to the formation of imine, which readily hydrolyse to the ketones. Using appropriate nitrile, keto-y-butyrolactone is obtained in good yield (Scheme 31). 

A tandem one-pot method for the construction of highly substituted pyridine derivatives from nitriles, Reformatsky reagents, and 1,3-enynes was developed by Lee and coworkers in 2011 [64], The reaction sequential consisted of the reaction of nitrile with a Reformatsky reagent and then selective addition of the Blaise reaction intermediate to 1,3-enyne, followed by isomerization, cyclization, and an aromatiza-tion cascade to give the final pyridines in moderate to excellent yields. 

Solid zinc activation has been used with success for the formation of stable organozinc compounds from functionalized benzylic bromides [8] and has been applied to the condensation of activated halides with nitriles [9] (Blaise reaction) or carbonyl compounds (10] (Reformatsky reaction). In this case, solid zinc is activated by catalytic generated zinc formed by electroreduction of anhydrous ZnBr2 solution in acetonitrile as solvent. Results and practical approaches have been reported [llj. 

The reaction of a nitrile with a Reformatsky reagent is known as the Blaise reaction and when applied to (9-trimethylsilyl cyanohydrins leads to the formation of tetronic acids with high ee [79]. By working-up the Blaise reaction with ammonium chloride it is possible to isolate... 

The starting reagent is the Reformatsky-typt. In this case, instead of adding to a carbonyl group, addition is to the nitrile. See Reformatskv Reaction for a discussion of reagent. 

Reformatsky first introduced electron-withdrawing substituents on the a-carbon of an organozinc halide, leading to the more reactive and thermally stable a-(alkoxycarbonyl)alkylzinc halides (123).107 Typically these reagents react with aldehydes or ketones to afford 3-hydroxy esters while nitriles afford 3-keto esters (Blaise reaction),l07b>c but 1,4-conjugate additions to select a,3 unsaturated ketones are precedented (Section 1.2.2.2.2). 

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