It has been mentioned that N-substituted glycines can be used in the formation of glyphosate via acidic Mannich condensation reactions. The most commonly used method incorporates the use of the N-phosphonomethyl derivative of iminodiacetic acid (IDA).The two-carbon carboxymethyl fragment can be easily removed as formate and formaldehyde in hot, fuming acid, or by a variety of oxidative conditions, eg. oxygen with activated carbon catalsyts, hydrogen peroxide in sulphuric acid, sodium chlorite, electrolysis,... This is a very widely used method because the carboxymethyl group in the IDA derivative is a relatively cheap protecting group.
Generally, any N-substituted glycine which is stable to the reaction conditions can be used to used in the synthesis of glyphosate, eg. sarcosine produces N-methyl-glyphosate and N-hydroxyglycine produces N-hydroxy-glyphosate under acidic conditions. Many glycinate esters, with removable N-alkyl protecting groups such as N-t-butyl, N-allyl, and N-benzyl have been used in this method.
The corresponding glyconitriles can, also, be used in the formation of glyphosate. When hydrolysed they first form the N-phosphonomethylglyconitriles and then on further hydrolysis they form glphosate.
The yield of glyphosate acheived by the acid cleavage (using HBr or HCl) of the the N-benzyl substituent from the corresponding glycine can be improved upon by the use of hydrogenolysis. In fact glyphosate can be gained in nearly quantitive yields via this method. The fact that glyphosate is thermally quite stable means that protecting groups which can only be removed under harsher conditions can also be used. As a result N-iso-propylglycine can be used to produce glyphosate in high yield. This reaction proceeds via the N-iso-propyl-glyphosate intermediate. Also, glyphosate can be gained in moderate to good yield from N-cyanomethylglycines.
Another rather novel preparation uses ethyl 2-azabicyclo[2.2.1]-hept-5-ene acetate to deliver the glycine aldimine component for the Mannich condensation by a thermal retro Diels-Alder reaction. Further reaction with phosphorous acid or dialkyl phosphite leads to the the formation of the glyphosate backbone in good yield.
Alternatively, N-acyl derivatives of glcine can be used as a protecting group in the form of 2,5-Piperazinediones. These heterocyclic compounds can be prepared by the cyclo-condensation reactions of glycine or it's esters and are reasonably stable. These undergo a standard Mannich condensation reaction in acidic conditions to form a cyclic compound. Basic hydrolysis of this cyclic compound leads directly to the formation of glyphosate, in moderate yield.
N-substituted-2,5-piperazinediones can be used in the formation of N-substituted glyphosate derivatives and are thought to undergo ring opening during the acidic Mannich reaction conditions. The N-substituted-2,5-piperazinediones can be conveniently generated from N,N'-dialkylglycinamides.
Hydantoin has, also, been used in a similar fashion to the 2,5-piperazinediones as a protected form of glycine.
