Pyridines, 2-alkylamino-. reaction with

Various alkylamino-artemisinins 155 were synthesized by the nucleophilic displacement of bromoartemisin 149, which was prepared in situ from 148 (Scheme 19), followed by reaction with alkylamines <2004AGE1381>. A more direct route involved treatment of 29a firstly with a mixture of NaBr and TMSCl and then with the amine <2006AGE2082>. HFIP can be used as an additive in the amination step to increase the yield <2005AGE2060>. Similar aminoartemisinins 155 (where NRR = NHAr) were prepared by reacting 29a with anilines, in the presence of a catalytic amount of pyridinium sulfate in pyridine, in good yields (e.g., Ar = Ph, 93% 72% ... 

Since these early studies, numerous derivatives of 2-chloro- and 2-bromo ia, 672 and 4-chloro- and 4-bromo-pyridine 73 have been converted into amino- or alkylamino-pyridines under conditions differing little from those mentioned above. Modifications which have been used include the addition of copper sulphate as a catalyst a, 672a reaction in the presence of pyridine 64 and also, in the case of 4-chloropyridine, reaction with primary and secondary aliphatic amines in benzene 4 at 140-180 . The qualitative data from these numerous examples show the effect of other substituents upon 2- and 4-halogen atoms to be as expected. GarboxyM oa, 675, 9i8 and nitro-groups24ia markedly augment reactivity, and in a compound such as 2-chloro-3,5-dinitropyridine, much milder conditions than usual can be used for amination e ... 

Reaction of 2-[(benzotriazol-l-yl)alkylamino]pyridines 341 with open-chain electron-rich alkenes 342 in the presence of BF3-Et20 gave 4-substituted 1,2,3,4-tetrahydropyrido[l, 2-n]pyrimidinium tetrafluorobo-rates 343 (98S704). 

Only very powerful nucleophilic reagents such as HO-, NHJ, RLi, LAH, etc., react effectively at the ring carbon atoms of simple pyridines (c/. equation 22), and even then forcing conditions may be required. Oxidation of pyridine to 2-pyridone with potassium hydroxide, for example, requires a temperature of ca. 300 °C. Nevertheless, some of these reactions can be of very considerable synthetic importance, especially the classical Chichibabin reaction for the preparation of 2-amino, alkylamino and hydrazino heterocycles (equation 28). The sequence of substitution is C-2, then C-6 and finally C-4. The Chichibabin reaction also requires rather vigorous conditions and often proceeds in only moderate yield the simplicity of the approach, however, is such that it often represents the method of choice for the preparation of the requisite substituted heterocycle. 

By the reaction of 2-(alkylamino or benzylamino)pyridines with epichlorohydrin or l,3-dichloro-2-propanol, quaternary pyrido[l,2-a]pyrimidinium salts (132) were obtained.188... 

Reactions of 1,2,4-thiadiazoles with radicals and electron deficient species are virtually unknown. Catalytic and dissolving metal reductions usually result in S—N bond cleavage. For example, the 5-anilino-3-hydroxy derivative (51) gives a good yield of l-phenyl-2-thiobiuret (52) on Zn-HCl reduction (Scheme 27). Reduction of the diamino derivative (53) gives amidinothiourea (54) from which it may be prepared by oxidation (Scheme 28). Under similar conditions, cleavage of the 3,5-diphenyl derivative (55) results in loss of sulfur and formation of benzylbenzamidine (56 Scheme 29). Reduction of 5-alkylamino-or 5-arylamino-3-alkylthio derivatives (57) with H2S in pyridine-triethylamine or sodium in liquid ammonia yields 1-substituted dithiobiurets (58 Scheme 30). 

Various heteroaromatic alkylamines, such as (di)alkylamino derivatives of pyridine, quinoline and pyrimidine, which are difficult to prepare at normal pressure, have been obtained in good to high yields by high-pressure S nAi reactions of the corresponding heteroaromatic halides with various amines. 4-(Di)alkylaminopyridine derivatives 140 have been synthesized via the high-pressure-promoted (0.8 GPa) iS nAf of 4-chloropyridine hydrochloride (138) with primary and secondary amines 139 (Scheme 7.34). ... 

Reaction of 7-substituted 2//-benzo-l-thia-2,4-diazine-3(4//)-one 1,1-dioxides 133 (X = F, Cl, Br, I) with phosphorus pentasulfide in pyridine produces the 3-thioxo compounds 134 (Equation 21) <2003JME3342>, which are used subsequently to make 3-alkylamino derivatives (see Section 9.05.7.6). 

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