Amino heterocycles preparation

A novel method for preparing amino heterocycles is illustrated by the preparation of 2-amino-5-methylthiophene (159). In this approach vinyl azides act as NH2 equivalents in reaction with aromatic or heteroaromatic lithium derivatives (82TL699). A further variant for the preparation of amino heterocycles is by azide reduction the latter compounds are obtained by reaction of lithio derivatives with p- toluenesulfonyl azide and decomposition of the resulting lithium salt with tetrasodium pyrophosphate (Scheme 66) (82JOC3177). 

Cyclization reactions effected by intramolecular attack of a heteroatom on a nitrile group provide a useful source of 2-amino heterocycles, e.g. (120) —> (121), and numerous syntheses employ this strategy (vide infra). Thus, the reaction of a,(3-unsaturated nitriles (122) with elemental sulfur in basic media, the Gewald synthesis, provides a most convenient route to 2-aminothiophenes (123), many of which are a useful as intermediates in the preparation of dyestuffs and pharmaceuticals. 

A variety of the structures is observed for the complex compounds prepared from ligands 196 and 197 containing the O (OH) exocyclic framework. Compared to the amino heterocycles, they are characterized predominantly by the chelate structures 227 and 228. The coordination... 

Fused ring heterocycles, prepared by cyclization of substrates with a tethered nitrogen nucleophile, have been used in the synthesis of amino sugars and aminocyclitols. The examples shown in Table 28 make use of imidate-type functionality (equation 101) to insure nucleophilic attack by nitrogen. The bro-mocyclization of N,W-dialkylaminomethyl ethers of 2-cyclohexen-l-ol to form bicyclic oxazolidine derivatives has been reported also.228b... 

The reaction of a-mercapto-A-amino heterocycles with acylating agents leads to fused 1,3,4-thiadiazoles. In general, the dehydration step is carried out with phosphorus oxychloride. The method has been used to prepare imidazo[2,l-6][l,3,4]thiadiazoles (63LA(663)113) and s-triazolo[3,4-6][l,3,4]thiadiazoles (64CI(L)1919> (equation 29). 

Isoxazolo[5,4-Z>]pyridines 47 and their N-oxides 48 were prepared by condensation of 3-phenyl -5-aminoisoxazole-4-carbaldehyde with amidines or its oxime 49 with triethyl orthoacetate (77H51, 80CPB1832). These and methods mentioned below, that were used in the syntheses of isoxazolo[5,4-c/]pyrimidines, are very similar to the methods described previously in detail for other amino heterocycles (82AHC1) (Scheme 21). 

Lactim ethers and thioethers are reported to react with imides <93H(35)1055>, amino ketones and acetals <82jhci93>, amino acids <90JHC1973>, active methylene compounds <82JHC193, 82JHC43I, 88T3309), and diethyl ethoxymethylenemalonate <84H(22)2285>. 7,8,9,10-Tetrahydro-6//-l,3,5-tri-azino[l,2-fl]azepine-2,4(3/f)-dione has been prepared from 7-amino-3,4,5,6-tetrahydro-2(//)-azepine and diphenyl imidodicarboxylate <93JHC55l>, and caprolactam acetals are reported to react with amino heterocycles <938521 > and ureas and urethanes <82KGS1553>. Most of these reactions lead to fused azepines either directly or after subsequent treatment of the isolated intermediate. 

A different conceptual approach to amino-alcohol preparation Involved use of chiral N,0-heterocycles as templates for enantiospecific syntheses of these compounds. Alkylations of the carbanion derived from 2-cyano-6-oxazolopiperidine (36) had been successfully applied to the synthesis of a number of alkaloids. 

SCHEME 13.83 Preparation of tricyclic dihydropyridine derivatives by amino-heterocycles and various cyclic CH acids different from Meldrum s acid [140, 143, 160, 161],... 

More than a third part of all the described principal syntheses of pyrimidines bearing fluorinated alkyl at C-4 atom commences from fluorinated p-dicarbonyl compounds 699. The chemistry of these bis-electrophiles was reviewed recently [411, 412] therefore, their preparation is not discussed herein. This synthesis of pyrimidines is fairly general (Table 34) it allows for introducing aliphatic, alicyclic and aromatic p-diketones (Entries 1-10), p-ketoesters (Entries 11-16), and cyclic P-ketoamides (Entry 17). Presence of some functional groups, such as additional ester moiety (Entry 15), is more or less tolerated, whereas increasing steric hindrance results in lowered yields of the products (Entry 10). A scope of conunon NCN binucleophiles include amidines (Entries 1, 11, 12, 17), (thio)urea and its derivatives (Entries 2-4), guanidines (Entries 5,16) and biguanides (Entry 6). Electron-rich amino heterocycles e.g. aminoazoles and even 2,6-diaminopyridine) are excellent NCN binucleophiles for the principal synthesis of fused pyrimidine derivatives (Entries 7-10, 13-15). 

A group of methods for the preparation of fluoroalkyl-substituted pyrimidines relied on CNCh-CCN connection of the aromatic ring. A variety of fluorinated 1,3-dielectrophiles was used for the annulations of CNC triade to CCN binucleophiles (i.e. anilines, enamines and electron-rich amino heterocycles). The most widely used among such 1,3-CNC-dielectrophiles are functionalized heterocumulenes 845-847 (Fig. 26) trifluoromethyl substituted imine derivatives 848, 849 and 850 can be also mentioned. 

An unusual approach to the synthesis of chain-fluorinated diazines relies on the inverse-electron-demand hetero-Zretro-Diels - Alder ihDA/rDA) sequence. The background of this method for the preparation of nitrogen-containing heterocycles in general has been reviewed recently [674], Typical dienes used for the synthesis of chain-fluorinated diazines are given in Fig. 29. Since electron-deficient dienes are necessary for the first step of the sequence - inverse-electron-danand hetero-Diels -Alder reaction, fluoroalkyl substituents of tri- and tetrazines 1111-1112 are favorable for the process. Typical electron-rich dienophiles for the reactions with 1111-1112 are enamines (including amino heterocycles) and alkynes, although other examples are also known. 

Oxidative Couplings of Heterocyclic Hydrazones. This method has opened the way to the preparation of azo derivatives of diazo compounds unobtainable by other means, ie, heterocycHc compounds ia which the diazotizable amino group is conjugated with the heterocycHc nitrogen atom as ia 2- and 4-amiQopyridine, compounds which do not normally yield stable diazonium salts (38). The reaction occurs as illustrated by equation 7 for the iateraction of (A/-methylcarbostyryl)hydrazone [28219-37-6] and dimethyl aniline the overall process is oxidation. 

Preparation of Heterocyclic Enamines from y- and h-Amino Ketones... 

Subsequent to Hantzsch s communication for the construction of pyridine derivatives, a number of other groups have reported their efforts towards the synthesis of the pyridine heterocyclic framework. Initially, the protocol was modified by Beyer and later by Knoevenagel to allow preparation of unsymmetrical 1,4-dihydropyridines by condensation of an alkylidene or arylidene P-dicarbonyl compound with a P-amino-a,P-unsaturated carbonyl compound. Following these initial reports, additional modifications were communicated and since these other methods fall under the condensation approach, they will be presented as variations, although each of them has attained the status of named reaction . 

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