PHARMACEUTICALS
excess of base is used to suppress possible cyclodimerisation reactions involving TosMIC . 9 - 12
Reaction temperatures are in the range from 0-50 ° C , depending on the ketone ’ s reactivity . Structurally , the cyano group ’ s carbon atom is TosMIC ’ s α-carbon . 10 TosMICbased reductive cyanation of ketones has seen considerable use in generating precursors to pharmaceutical compounds .
Reductive cyanation also works on aldehydes but changing the ketonic reaction conditions is necessary to avoid low yields . The aldehyde should still be reacted with TosMIC under basic and aprotic conditions , but at low temperatures ( -50 to -20 ° C ). 4 Upon addition of excess methanol , the reaction can then be completed by heating ( e . g . under reflux ). 13 , 14
In addition to pharmaceuticals , TosMIC-based reductive cyanation processes have found use in flavours
Glass-lined chemical reactors for speciality chemical synthesis
and fragrances for preparing active perfuming ingredients , among other industries . The reaction mechanism for reductive cyanation of ketones and aldehydes may be found in the literature . 9 , 10 , 15
Direct synthesis of heterocycles
TosMIC-based van Leusen synthesis methods for oxazole- , imidazoleand pyrrole-based compounds , all of which involve a base-mediated [ 3 + 2 ] ( or 1,3-dipolar ) cycloaddition reaction , are some of the most convenient and attractive . due to simple operation , easily obtained raw materials and a broad substrate scope . 16 - 18 The van Leusen method for oxazoles involves reacting TosMIC ( or TosCHR 1 NC ) in alcoholic solvents with aldehydes and base . 4
One procedure generally used to synthesise oxazoles involves reacting the aldehyde , TosMIC and the base K 2
CO 3 in methanol solvent and heating to reflux . 19 , 4 This process was noted as being suitable for the manufacturing of oxazole precursors to spleen tyrosine kinase ( Syk ) inhibitors . 20 Figure 2 shows an approximate reaction scheme , in which the final step is a basepromoted elimination . 21
Closely related to the abovementioned method for oxazole generation is the van Leusen method for synthesising imidazoles from imines and TosMIC . The reaction of TosCHR 1
NC with aldimines , usually prepared from aromatic aldehydes and aliphatic amines in the context of van Leusen synthesis , yields the otherwise-elusive 1,4,5-trisubstituted imidazoles . 11 , 22
A method suitable for industrial processes , in which TosMIC does not have to be isolated ( and a safer method for obtaining 5-substituted oxazole and imidazole compounds ), involves reacting TosMIC with the aldehyde or imine ( e . g . aldimine ), along with base , in a mixed aproticprotic solvent . 19 Oxazole- and imidazole-based compounds are useful in agrochemicals and pharmaceuticals .
To prepare pyrroles , TosMIC ( or TosCHR 1 NC ) undergoes cycloadditions with Michael acceptors prepared from aldehydes and activated methyl or methylene groups . It is sometimes advantageous to increase the Michael acceptor reactivity by using two electron-withdrawing groups instead of just one . To form a pyrrole , the stronger leaving group of the two ( located at the same carbon atom ) is removed during the reaction . 4
This leaving group procedure has been followed in the preparation of certain industrially relevant agrochemicals . Pyrroles have otherwise found use in pigments and materials science applications , and heterocycles , in general , have many applications in various industries , such as pharmaceuticals , cosmetics , reprography , information storage , plastics , solvents , antioxidants and corrosion inhibition . 23 , 3
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