Regioselectivity substitution

Regioselective nucleophilic substitution at the 5 position is proved to occur when 1-hydroxytryptophan and -tryptamine derivatives are treated with 85% HCOOH (99H1157). Truly amazing is the fact that only substrates carrying a C—C—N structure in the side chain at the 3 position can undergo this regioselective substitution. 

The primary OH group can be selectively blocked by the bulky triphenyl-methyl (trityl) moiety, followed by esterification at the secondary OH groups and removal of the protecting trityl group. Thus 2,3-di-O-acetyl cellulose has been obtained by this procedure. Moreover, regioselectively substituted mixed cellulose esters, acetate/propionate, were prepared by subsequent acy-... 

Tamura and coworkers have reported a related substitution reaction cyclic a-(nitroalkyl) enones undergo regioselective substitution of the nitro group by sulfinate ion, amino, and carbon nucleophiles (Eq. 7.23).24 Several reaction pathways are envisioned for this useful... 

The synthesis of the naphthoquinone 116 is shown in Scheme 3.24. Bromination of juglone (118) afforded the dibromojuglone derivative 134. Protection of the phenol group as its methoxymethyl ether formed the product 135 (50 % yield over two steps). Finally, the C-3 bromide substituent was regioselectively substituted with methoxide by heating 135 in methanol in the presence of sodium carbonate (96 %). The methoxy group was installed to impart electronic bias to the naphthoquinone in the TASF(Et) coupling (vide infra). 

Ford and co-workers reported regioselective substitutions of 2,3-dichloro-6-amino-quinoxaline 270 with various dialkylamines to study the biological properties of substituted quinoxalines <00TL3197>. For example, 2,3-dichloro-6-aminoquinoxaline 270 reacted with nucleophiles to give the opposite regioisomer to that seen with 2,3-dichloro-6-nitroquinoxalines 267. 

The intermediate enol silyl ether permits further regioselective substitutions such as bromination followed by dehydrobromination (Eq. 81)49> and alkylation (Eqs. 82 93) and 83 103)). Thus, in addition to activating the rearrangement, the oxygen substituent regioselectivity creates an enol silyl ether, a powerful enolate synthon. 

Regioselective Substitution of Unactivated CH Bonds CH bonds in cycloalkanes (decaline, steroids) and alkanes bearing electron-deficient groups in remote posihons (1,2-dichlorocyclohexane, decanoic acid) can be regioselectively subshtuted at the anode by trifluoroacetate, acetate, or methoxide (Figs. 1, 2) [12-14]. 

The 4-fluoro atom of 4,5-difluoro-7-oxo-2,3-dihydro-7//-pyrido[3,2,l-t ]-[2,l]benzoxazine-8-carboxylate (40) was regioselectively substituted by cyclic amines in DMSO at 100-110 C [92JAP(K)92/208288, 92JAP(K)92/ 210656],... 

The same process shown in Scheme 88 starting from different 2-substituted oxetanes and using biphenyl as the electron-carrier catalyst under THF reflux has been used to prepare regioselectively substituted primary alcohols. On the other hand, the combination of a DTBB-catalyzed ca 20%) lithiation with triethylaluminium in TFIF at —78 °C has been used for the transformation of strained oxetanes to substituted di- and triquinanes through a rearrangement process . An example is given in Scheme 89 for the transformation of oxetane 299 into the product 302 through radicals 300 and 301. 

A more attractive chemo-enrymatic approach for the production of he-mithiocyclodextrins has been developed. More than ten years ago, cyclodextrin glucosyltransferase (CGTase) was shown to use a-maltosyl fluoride for the synthesis of a-, p-, and y-cyclodextrins [47] and has been used for the chemoenzymatic synthesis of regioselectively substituted cyclodextrins [48]. For this purpose, 4-thio-a-maltosyl fluoride (58) was easily prepared from (45). Incubation of (58) in the presence of pure CGTases afforded hemithiocyclodex-trins (57a), (57b) and (57c) isolated in 14,16 and 15% yields respectively [49]. 

Aminolysis of active halogenopyrimidines is the normal route into 2-, 4-, and 6-aminopyrimidines. Regioselective substitutions in di- and tri-halo derivatives can be achieved in many cases. Ghloro, bromo, and iodo substituents undergo aminolysis at approximately the same rates, whereas a fluoro substituent reacts 60-200 times faster. 4(6)-Halo substituents react up to 10 times faster than 2-halo substituents. 

The 2-substituted 1,2,3-triazole 1-oxides 326 have been used for synthesis of 2- substituted 1,2,3-triazoles 382 and regioselectively substituted 1-hydroxy-1,2,3-triazoles 443 manipulating the substituent in the N-oxide... 

Substituted 1,2,3-triazole 1-oxides 448 have been used for and have a great potential for the synthesis of regioselectively substituted 1,2,3-triazoles 457 which possess their own virtues as mentioned in Section 4.1.7. However, no reports on the biological activity or on the application of 3-substituted 1,2,3-triazole 1-oxides 448 are available. The missing data may be due to the, until recently, lack of a simple synthesis of the 1-oxides 448 based on a direct cyclization. 

Many efforts have been directed to the regioselective substitution of either HO-2 or -3 and to stereocontrolled addition reactions to the double bond. The acylation and alkylation of such hydroxyl groups is fairly sensitive to the reaction conditions. It is reported that alkylation of ascorbic acid in solvents of high dielectric constant favors 2-C-alkylation when powerful alkylation agents were employed.346... 

Comins, D. L., O Connor, S., Regioselective Substitution in Aromatic Six-Membered Nitrogen Heterocycles, 44, 199. 

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