Substitution a-alkylations

Another application was investigated by Olson and coworkers (99HCA(82) 2432). 4-Substituted-A-alkyl- and A-aryl-l,2,5-thiadiazolidin-3-ones 247-249 were prepared and evaluated for their MHC class-II inhibitor activity. 

Roberts et al. [74] took advantage of the rapid and selective p-scissions of phosphoranyl radicals, to develop a radical chain desulfurization affording new substituted a-alkyl acrylates in good to moderate yields (Scheme 37). 

Alkyl radicals. Alkyl radicals produced by oxidative decarboxylation of carboxylic acids are nucleophilic and attack protonated azoles at the most electron-deficient sites. Thus, imidazole and 1-alkylimidazoles are alkylated exclusively at the 2-position. Scheme 72 shows the substitution of a protected histidine <2001BML1133>. Similarly, thiazoles are attacked in acidic media by methyl and propyl radicals to give 2-substituted derivatives in moderate yields, with smaller amounts of 5-substitution. A-Alkyl-1,2,-4-triazoles can be radical substituted at C(5) <2001TL7353>. 

Benzo-fused isoquinuclidines have been synthesized via benzyne (generated from anthranilic acid) addition to the appropriate N-substituted-A -alkyl-2-pyridones to produce benzomorphan-type analgesics (e.g., 28a,b) [28,78]. 

Intramolecular Diels Alder reaction of the 2-cyano-substituted A-alkyl azadiene 221 to indolizidine 222 (70%) was carried out under MWI within 14 min (Scheme 47). This conversion took place on heating in benzene overnight in a sealed tube to give a 90% yield (97JOC2098). 

Reaction of 5-substituted isatoic anhydride 761 with allylamines 762 in DMF under MWI for 5-50 min gave 2-amino-5-substituted-A-alkyl-iV-(2-propenyl)... 

Quatemization is sometimes difficult to avoid but can be used positively. Quatemization can provide entry into 5-substituted A-alkylated imidazoles. For example, A-ethylation of iV-benzoyl-4-phenylimidazole with a powerful alkylating agent like triethyloxonium tetrafluoroborate provides the salt that undergoes hydrolysis under mildly basic conditions to provide 5-phenyl-iV-ethylimidazole. ... 

Remarkably, the reaction also tolerated the use of differently substituted a-alkyl-p-ketoesters as Michael donors, leading to the formation of compounds containing two contiguous stereogenic centers, one of them a quaternary one, in good diastereo- and enantioselectivities (Scheme 4.6). Masked cyclic 1,3-diketones such as 2-hydroxy-1,4-naphthoquinols have also been successfully applied in this context also showing the extraordinary performance of catalyst 68a in terms of both yields and enantioselectivities. There is also one example of a vinylogous Michael reaction between a,a-disubstituted dicyanoacrylates and nitroalkenes for which Takemoto s catalyst has also been identified as the most efficient promoter of the reaction. Moreover a solid-supported version of this catalyst has also been developed by Takemoto himself and tested in the reaction of diethylmalonate with nitrostyrene with success. ... 

Under the optimal reaction conditions, various a-alkyl styrenes were successfully hydrovinylated to afford the corresponding products bearing an all-carbon quaternary center. However, when the ort/ o-substituted a-alkyl styrenes were tested under the same conditions, no reaction was observed, indicating that the steric hindrance of the substrate has a remarkable negative effect on the reactivity (Scheme 9.6). 

It is of interest to note that by substituting alkyl bromides for cyciohexyl bromide the corresponding a-phenyl-a-alkyl-acetonitriles are obtained, which may be hydrolysed to the a-phenylaliphatic acids thus with ethyl iodide a-phenyl-lwt3Tonitrile is produced, hydrolysed by ethanoUo potassium hydroxide to a-phenylbutyric acid. 

There are a wide variety of methods for introduction of substituents at C3. Since this is the preferred site for electrophilic substitution, direct alkylation and acylation procedures are often effective. Even mild electrophiles such as alkenes with EW substituents can react at the 3-position of the indole ring. Techniques for preparation of 3-lithioindoles, usually by halogen-metal exchange, have been developed and this provides access not only to the lithium reagents but also to other organometallic reagents derived from them. The 3-position is also reactive toward electrophilic mercuration. 

Nitriles contain the —C=N functional group We have already discussed the two mam procedures by which they are prepared namely the nucleophilic substitution of alkyl halides by cyanide and the conversion of aldehydes and ketones to cyanohydrins Table 20 6 reviews aspects of these reactions Neither of the reactions m Table 20 6 is suitable for aryl nitriles (ArC=N) these compounds are readily prepared by a reaction to be dis cussed m Chapter 22... 

Alkyl azides prepared by nucleophilic substitution of alkyl halides by sodium azide as shown m the first entry of Table 22 3 are reduced to alkylammes by a variety of reagents including lithium aluminum hydride... 

In contrast to nucleophilic substitution m alkyl halides where alkyl fluorides are exceedingly unreactive aryl fluorides undergo nucleophilic substitution readily when the ring bears an o or a p nitro group... 

There is a wide variety of dyes unique to the field of hair coloring. Successive N-alkylation of the nitrophenylenediamines has an additive bathochromic effect on the visible absorption to the extent that violet-blue dyes can be formed. Since the simple A/-alkyl derivatives do not have good dyeing properties, patent activity has concentrated on the superior A/-hydroxyalkyl derivatives of nitrophenylenediamines (29,30), some of which have commercial use (31). Other substituents have been used (32). A series of patents also have been issued on substituted water-soluble azo and anthraquinone dyes bearing quaternary ammonium groups (33). 

Another useful reagent for the 3-aLkylation of indole is the /V,/V-dimethy1foTma1 diminium ion, which forms the useful intermediate gramine [87-52-5] (9). The C-3 substituent can subsequendy be modified by displacement of the dimethylarnino group by a nucleophile. Alternatively, gramine can be converted to its quaternary salt prior to substitution. A variety of carbanions can function as the nucleophile. 

A AlI lation. 1-Substitution is favored when the indole ring is deprotonated and the reaction medium promotes the nucleophilicity of the resulting indole anion. Conditions which typically result in A/-alkylation are generation of the sodium salt by sodium amide in Hquid ammonia, use of sodium hydride or a similar strong base in /V, /V- dim ethyl form am i de or dimethyl sulfoxide, or the use of phase-transfer conditions. 

The (A/-alkylated) lactam of 8-aminonaphthalenecarboxylic acid (47) also is a valuable dye iatemiediate, eg, for cyclometbine-type dyes used for dyeiag polyacrylonitrile fibers and other synthetics. 1,8-Naphtholactams are prepared in high yield and purity by the reaction of naphtholactones with RNH2 (R = H, Cl—4 alkyl, cycloalkyl, or optionally substituted aryl) in aqueous medium, usually in the presence of bisulfite at 150°C over a period of 15 h (143). 

Future Trends. In addition to the commercialization of newer extraction/ decantation product/catalyst separations technology, there have been advances in the development of high reactivity 0x0 catalysts for the conversion of low reactivity feedstocks such as internal and a-alkyl substituted a-olefins. These catalysts contain (as ligands) ortho-/-butyl or similarly substituted arylphosphites, which combine high reactivity, vastiy improved hydrolytic stabiUty, and resistance to degradation by product aldehyde, which were deficiencies of eadier, unsubstituted phosphites. Diorganophosphites (28), such as stmcture (6), have enhanced stabiUty over similarly substituted triorganophosphites. 

Extension of the Phosphorane Route. Ample evidence of the versatihty of the phosphorane synthesis strategy is provided by the proliferation of penems that followed. Nucleophilic displacement of the acetate function of the acetoxy-azetidinone (51, R = OCOCH ) [28562-53-0] (86) provided azetidinones where R = SCOCH, SCSSC2H, and SCSOC2H, which on elaboration gave the penems (52, R = CH ) (87), (52, R = SC2H ) (88), (52, R = 0C2H ) (89). Similar treatment of 3-substituted (or disubstituted) acetoxyazetidinones allowed the synthesis of a number of 2-substituted- 6-alkyl-and 6,6-dialkylpenems (90). 

An interesting method for the substitution of a hydrogen atom in rr-electron deficient heterocycles was reported some years ago, in the possibility of homolytic aromatic displacement (74AHC(16)123). The nucleophilic character of radicals and the important role of polar factors in this type of substitution are the essentials for a successful reaction with six-membered nitrogen heterocycles in general. No paper has yet been published describing homolytic substitution reactions of pteridines with nucleophilic radicals such as alkyl, carbamoyl, a-oxyalkyl and a-A-alkyl radicals or with amino radical cations. 

Acyl-pyrroles, -furans and -thiophenes in general have a similar pattern of reactivity to benzenoid ketones. Acyl groups in 2,5-disubstituted derivatives are sometimes displaced during the course of electrophilic substitution reactions. iV-Alkyl-2-acylpyrroles are converted by strong anhydrous acid to A-alkyl-3-acylpyrroles. Similar treatment of N-unsubstituted 2- or 3-acyIpyrroles yields an equilibrium mixture of 2- and 3-acylpyrroles pyrrolecarbaldehydes also afford isomeric mixtures 81JOC839). The probable mechanism of these rearrangements is shown in Scheme 65. A similar mechanism has been proposed for the isomerization of acetylindoles. 

Diaziridines also show slow nitrogen inversion, and carbon-substituted compounds can be resolved into enantiomers, which typically racemize slowly at room temperature (when Af-substituted with alkyl and/or hydrogen). For example, l-methyl-3-benzyl-3-methyl-diaziridine in tetrachloroethylene showed a half-life at 70 °C of 431 min (69AG(E)212). Preparative resolution has been done both by classical methods, using chiral partners in salts (77DOK(232)108l), and by chromatography on triacetyl cellulose (Section 5.08.2.3.1). 

X-ray analysis of an optically active oxaziridine substituted at nitrogen with the 1-phenylethyl group of known configuration led to the absolute configuration (+)-(2R,3R)-2-(5-l-phenylethyl)-3-(p-bromophenyl)oxaziridine of the dextrorotatory compound as expected, C-aryl and A-alkyl groups were trans to each other (79MI50800). 

Aromatic ethers and furans undergo alkoxylation by addition upon electrolysis in an alcohol containing a suitable electrolyte.Other compounds such as aromatic hydrocarbons, alkenes, A -alkyl amides, and ethers lead to alkoxylated products by substitution. Two mechanisms for these electrochemical alkoxylations are currently discussed. The first one consists of direct oxidation of the substrate to give the radical cation which reacts with the alcohol, followed by reoxidation of the intermediate radical and either alcoholysis or elimination of a proton to the final product. In the second mechanism the primary step is the oxidation of the alcoholate to give an alkoxyl radical which then reacts with the substrate, the consequent steps then being the same as above. The formation of quinone acetals in particular seems to proceed via the second mechanism. ... 

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