Nucleophilic substitution reduction conditions

Scheme 19.5 Transformation of methyl 2-oxo-D-gluconate into spiro-connected saccharidic heterocycles by protection, anomeric activation, nucleophilic substitution, reductive cyclisation and deprotection. Reagents and conditions a) Ac O, cat. H SO, 60 °C, 15 min b) HBr/AcOH ...

The growing importance of cyclopropane derivatives (A. de Meijere, 1979), as synthetic intermediates originates in the unique, olefin-like properties of this carbocycle. Cyclopropane derivatives with one or two activating groups are easily opened (see. p. 69f.). Some of these reactions are highly regio- and stereoselective (E. Wenkert, 1970 A, B E. J. Corey, 1956 A, B, 1975 see p. 70). Many appropriately substituted cyclopropane derivatives yield 1,4-difunctional compounds under mild nucleophilic or reductive reaction conditions. Such compounds are especially useful in syntheses of cyclopentenone derivatives and of heterocycles (see also sections 1.13.3 and 4.6.4). 

Under different conditions (in aqueous electrolyte) the selectivity of the cleavage reaction may be perturbed by the occurrence51-53 of a dimerization process. Thus, while the major process remains the two-electron reductive pathway, 20% of a dimer (y diketone) may be isolated from the cathodic reduction of PhC0CH2S02CH3. The absence of crosscoupling products when pairs of / -ketosulphones with different reduction potentials are reduced in a mixture may indicate that the dimerization is mainly a simple radical-radical coupling53 and not a nucleophilic substitution. 

The most plausible mechanism for the interconversion of la and Ih is shown in Scheme 2. Similar mechanism has been put forward for epimerization of a-substituted ketones under basic conditions and for the equilibration via an enolate prior to nucleophilic substitution was observed by Numazawa et al. (ref. 13). The same mechanism seems to operate in the reduction of some steroid a-haloketones (ref. 14) or tra/ty-3-chloroflavanone (ref. 15) with sodium borohydride where an inversion of configuration takes place at the a carbon parallel to the reduction of the... 

Additions to quinoline derivatives also continued to be reported last year. Chiral dihydroquinoline-2-nitriles 55 were prepared in up to 91% ee via a catalytic, asymmetric Reissert-type reaction promoted by a Lewis acid-Lewis base bifunctional catalyst. The dihydroquinoline-2-nitrile derivatives can be converted to tetrahydroquinoline-2-carboxylates without any loss of enantiomeric purity <00JA6327>. In addition the cyanomethyl group was introduced selectively at the C2-position of quinoline derivatives by reaction of trimethylsilylacetonitrile with quinolinium methiodides in the presence of CsF <00JOC907>. The reaction of quinolylmethyl and l-(quinolyl)ethylacetates with dimethylmalonate anion in the presence of Pd(0) was reported. Products of nucleophilic substitution and elimination and reduction products were obtained . Pyridoquinolines were prepared in one step from quinolines and 6-substituted quinolines under Friedel-Crafts conditions <00JCS(P1)2898>. 

Some strategies used for the preparation of support-bound thiols are listed in Table 8.1. Oxidative thiolation of lithiated polystyrene has been used to prepare polymeric thiophenol (Entry 1, Table 8.1). Polystyrene functionalized with 2-mercaptoethyl groups has been prepared by radical addition of thioacetic acid to cross-linked vinyl-polystyrene followed by hydrolysis of the intermediate thiol ester (Entry 2, Table 8.1). A more controllable introduction of thiol groups, suitable also for the selective transformation of support-bound substrates, is based on nucleophilic substitution with thiourea or potassium thioacetate. The resulting isothiouronium salts and thiol acetates can be saponified, preferably under reductive conditions, to yield thiols (Table 8.1). Thiol acetates have been saponified on insoluble supports with mercaptoethanol [1], propylamine [2], lithium aluminum hydride [3], sodium or lithium borohydride, alcoholates, or hydrochloric acid (Table 8.1). 

A convenient and efficient synthetic route to a new class of macrocyclic aryl ether ether sulfide oligomers was reported. The process is shown in Fig. 28. This new class of cyclic oligomers is prepared in excellent yield by quantitative chemical reduction of macrocyclic aryl ether ether sulfoxide oligomers with oxalyl chloride and tetrabutylammonium iodide. The cyclic sulfoxide oligomeric precursors are prepared in high yields by an aromatic nucleophilic substitution reaction from bis(4-fluorophenyl) sulfoxide with potassium salts of bisphenols under high-dilution conditions [99]. 

Preliminary work with model selenoester 54 revealed that the hexabutyldistannane protocol, previously used in the phenyl and pyridine series, now gave poor yields of cyclized products. However, treatment of 54 under reductive TTMSS conditions in the presence of AIBN as the initiator led to the calothrixin-related pentacycle 55 in 65% yield. This compound, which incorporated the 2-cyano-2-propyl moiety of the initiator, was converted into A -methylcalothiixin 56 by treatment with potassium hydroxide in methanol, through a process involving a gramine-type nucleophilic substitution and the oxidation of the resulting carbinol by air. 

Plasticised PVC sheets were surface modified by nucleophilic substitution of chlorine by azide in aqueous media under phase transfer conditions. The azidated PVC surface was then irradiated by UV light to crosslink the surface. It was found that considerable reduction in the migration of the plasticiser di-(2-ethylhexyl phthalate) could be achieved by this technique, depending on the extent of azidation of the PVC surface and the irradiation dose. After surface modification, there was around 30% reduction in the stress-strain properties of the PVC sheets but these values were still well above the minimum prescribed for PVC used in biomedical applications. 19 refs. 

Methyl-2-mercaptobenzimidazole 923 is oxidized with ozone to afford mainly sulfonic acid 924 at low temperature (Table 12, entry 1). The formation of desulfurized product 924 is most likely a result of partial oxidation, followed by intermolecular reduction by 923. At higher temperatures and in the presence of nucleophiles, substitution of the sulfonic acid group takes place <1996SC3241>. 2-Mercaptoimidazoline reacts similarly under these conditions. 

Examples of relevant chemical transformation processes in aqueous environment are hydrolysis, nucleophilic substitution, elimination, oxidation and reduction reactions (Schwarzenbach et al, 1993). Of these, hydrolysis is often considered the most important and it is the only chemical transformation process for which international test guidelines are generally available. The tests for abiotic degradation of chemicals are generally in the form of determination of transformation rates under standardized conditions. 

The relative extent of dialkylation depends on the electrophilicity of RX (and the nucleophilicity of AR ) when a realtively fast SET (AE i/2 < 0.5 V) is the primary reaction. Other mechanisms may also satisfactorily explain the distribution of products. For instance, adduct formation between the alkyl radical and the mediator (acting as a radical trap) is possible and must be considered in such a case, further reduction of AR may take place, either by electron transfer or by abstraction of a hydrogen atom from the solvent. However, let us keep in mind that radical anions or dianions may act as nucleophiles, since a partial inversion of configuration of some optically active secondary RX compounds has been found [222] after workup under experimental conditions similar or identical to those of the electrolyses. Table 8 exemplifies alkylation reactions following a SET. The reaction scheme may be complicated by the fact that reduced forms of the mediator may act as a reducing nucleophile toward RX. The SET may then be assumed as the rate-determining step in aliphatic nucleophilic substitutions [223], and/or R generated in solution may be added to an electrophilic mediator, such as an activated ketone [224]. 

As it is well known, nucleophilic substitution of a C-X bond, one of the key synthetic reactions with aliphatic compounds is severely limited with aromatic derivatives, where it occurs thermally only with electron-withdrawing substituted compounds and/or under severe conditions. Alternatives include time honored reactions involving the phenyl radical generated by decomposition of diazonium salts after a reductive step, such as the Meerwein and the Gomberg-Bachmann reactions, as well as the (often photoinitiated) SrnI reaction, where a (usually weak, e.g. carbon-iodine) bond is cleaved after monoelectronic reduction to give an aryl radical as the active inter-mediate that adds to an enolate, cyanide or other nucleophiles (and thus again with an aryl radical as the key intermediate. Scheme S). ... 

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