Cyanation reactions, heterocyclic compound

Thiourea (98) was first prepared in 1870 by heating ammonium thiocyanate (99) (Scheme 54). The reaction is analogous to the historic preparation of urea (Wohler, 1828) which involved heating ammonium cyanate. Thioureas generally are stable crystalline solids which are useful in the synthesis of heterocyclic compounds. Symmetrical thioureas (100) may be obtained by the action of amines on carbon disulfide, and the procedure can be extended to the synthesis of cyclic thioureas (101) (Scheme 55). The reaction occurs via the intermediate (102) which on subsequent treatment with either ammonia or an amine yields the corresponding... 

Other reactions of synthetic utility can be observed when suitable nucleophiles are added to the reaction system. Typical examples of these nucleophiles are azide, cyanate, thiocyanate, and cyanide anions and thioanisole. Reactions using these nucleophiles provide a reaction path to functionalized vinyl derivatives. The transformations are successfully achieved by using triaryl-substituted alkenyl halides. The reactions with such nucleophiles provide an efficient path to heterocyclic compounds, among others. Some examples, such as the pyrroHnes, isoxazoHnes, isoquinolones, and thio derivatives, are prepared by this method and are shown in Equation 11.11. 

The iron-catalyzed [3 + 2]-cycloaddition (Huisgen reaction) of nitriles and carbonyl compounds as reported by Itoh et al. is one of the rare examples reported where an iron reagent can be utilized for the synthesis of 1,2,4-oxadiazoles (Scheme 9.35) [93]. In this reaction, methyl ketones are nitrated at the a-position by Fe(N03)3 to generate an a-nitro ketone. This intermediate rearranges to an acyl cyanate, which reacts further with the nitrile to give the heterocyclic product 48 in good to excellent yields (R1 = Ph, R2 = CH3 95% yield). 

Strecker reactions are among the most efficient methods of synthesis of a-amino nitriles, useful intermediates in the synthesis of amino acids [73] and nitrogen-containing heterocycles such as thiadiazoles, imidazoles, etc. [74]. Although classical Strecker reactions have some limitations, use of trimethylsilyl cyanide (TMSCN) as a source of cyano anion provides promising and safer routes to these compounds [73b,75]. TMSCN is, however, readily hydrolyzed in the presence of water, and it is necessary to perform the reactions under strictly anhydrous conditions. BusSnCN [76], on the other hand, is stable in water and a potential source of cyano anion, and it has been found that Strecker-type reactions of aldehydes, amines, and BuaSnCN proceed smoothly in the presence of a catalytic amoimt of Sc(OTf)3 in water [77]. No surfactant was needed in this reaction. The reaction was assumed to proceed via imine formation and successive cyanation (it was confirmed that imine formation was much faster than cyanohydrin ether formation under these reaction conditions) again the dehydration process (imine formation) proceeded smoothly in water. 

The yields of isolated products varied from 45 to 95%. It is not totally proven whether an iminium ion is involved in the formation of 7-morpholinobicyclo[4.1. OJheptane 14. All primarily formed compounds were shown to be ent/o-morpholino isomers. Some derivatives isomerized to the corresponding ejfo-isomers on heating with acidic catalysts. Starting from 13 pure endo-and exo-morpholino compounds could be obtained in the case of the azide 14f and aminal 14k with benzotetrazole as the heterocycle. Reaction of potassium cyanate with 13 gave a trimer of 14e at ambient temperature or the exo-morphohno diastereomer of 14e at higher temperature. ... 

The reaction has been shown to be of very broad scope with a multitude of nucleophiles Nu such as imides.23,24,29,32,33,36,37,42 amines,10,32 cyanide,25,32 hydroxide,10,32 alkox-ide,10,26,32 electron-rich isocyclic or heterocyclic aromatic compounds,28 carboxamides,31 lactams,31 ureas,31 sulfonamides,31 cyanate,31 formate (to give products with Nu = H),34 C-H acidic compounds,35 hydrazines and hydrazides,38 and sulfinates.38 The amino group NR R2 of cyclopropane-1,1-diamines and the nucleophile Nu in bicycles 8, 9 or 12, respectively, can be easily replaced with other nucleophiles Nu, such as water,10,32,33 alkoxide,10,32-34,42 Grignard compounds,27,42 amines,29,30,36,37,42,43 cyanide,29,33,42,44 hydride,34,42,44 and C-H acidic compounds39-41,43,44 (see Section 5.2.1.). Therefore, it is currently the most important method for the preparation of substituted bicyclic cyclopropylamines. The toxic and costly reagent methyl fluorosulfate can be avoided in a modified synthetic route, which instead of the fluorosulfate 5 proceeds via the corresponding tetraphenylborate, hexafluorophosphate, or (most conveniently) via the tosylate.23 The different steps of the method can often be combined in a one-pot procedure. Results are summarized in Table 3. 

Benzimidazol-2-amine reacts with cyanates to give selectively the 2-aminobenzimidazole-l-carboximidic esters l.56 2-Guanidinobenzimidazole 4 is prepared by reaction of ammonia with AT-cyanobenzimidazol-2-amine. Compounds 1 and 4 react with JV-sulfinylarenesulfonainides to give the corresponding unstable /V-sulfinyl derivatives 2 and 5 of the heterocyclic bases.34,31... 

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