Don Wang of Varsal introduces a key reagent for applications in pharmaceuticals and other industries
TosMIC : A versatile reagent
Don Wang of Varsal introduces a key reagent for applications in pharmaceuticals and other industries
Figure 1 - Resonance structures of TosMIC
With three important chemical groups contained within its structure , tosylmethyl isocyanide ( TosMIC , CAS 36635-61-7 ) is a versatile synthetic reagent and building block in organic synthesis . This paper highlights three missioncritical industrial applications .
Background
TosMIC is a colourless solid that can be stored at room temperature without decomposing . Unlike other isocyanides , however , it is effectively odourless . 1 It has a melting point of 111 – 113 ° C and is insoluble in water but soluble in organic solvents such as dimethoxyethane ( DME ) and tetrahydrofuran ( THF ). 2 , 3
Structurally ( Figure 1 ), TosMIC ’ s versatility stems from three key components : the isocyanide ( blue ) and tosyl ( pink ) groups , and the acidic α-carbon ( red ). The isocyanide , which undergoes addition-type reactions , has a carbon atom that usually acts as an electrophilic centre for ringclosing reactions and may also double as an active methylene group for secondary reactions . 1 , 4 , 5
This carbon atom also typically exhibits carbene-like reactivity , which is reflected in the first resonance structure and its canonical hybrid on the right ( Figure 1 ). 6 The tosyl acts as a good leaving group in the generation of heterocycles . 4 Finally , the α-position ’ s reactivity stems from the strong electron-withdrawing effects of the other two groups ( although the α-position is also less sterically hindered ). 1 , 7
With pKa ≈ 14 , the acidic α-carbon is readily deprotonated under basic conditions to yield the carbanion TosC-HNC , on which this white paper ’ s TosMIC-based applications base their initial reactions . 8 , 4 Related anions may be derived from mono-substituted TosCHR 1 NC ( formed via SN 2 substitution reactions involving TosC- HNC and an alkyl halide electrophile ) and used to prepare di-substituted TosCR 1 R 2 NC TosMIC derivatives . 4 , 7
In this way , TosMIC can synthesise ketones via di-substitution at the α-position followed by hydrolysis ,
or act as a connecting reagent of two alkyl halides via di-substitution followed by reduction ( e . g . using Li and
NH 3
). Otherwise , in the presence of a dipolarophile ( e . g . alkene , carbonyl , imine ), the 1,3-dipolar character of TosMIC is exploited in a [ 3 + 2 ] cycloaddition reaction . However , TosCHR 1 NC cannot be used in the reductive cyanation or Knoevenagel procedures because those require both α-carbon hydrogens . 4 , 7
Reductive cyanation
The reductive cyanation of ketones to cyanides occurs upon reaction with TosMIC and base ( e . g . t-BuOK ) in aprotic solvents ( e . g . DME , THF ). 4 This process is sped up considerably in the presence of 1 – 2 eq . MeOH or EtOH , while an
Figure 2 - Van Leusen oxazole synthesis
32 SPECIALITY CHEMICALS MAGAZINE ESTABLISHED 1981