Hydrolysis of imidate salts

Imidate salts are 0-alkyl derivatives of tertiary amides. Being activated tertiary amides, they are extremely reactive towards nucleophiles. There is instantaneous reaction with hydroxide ion they also react rapidly at room temperature with water under acidic conditions. When an imidate fluoro-borate salt such as A3 reacts with sodium hydroxide, it gives sodium fluoro-borate and the tetrahedral intermediate AA which breaks down in an irrevers- 

The hydrolysis of imidate salts is a technique to generate in situ hemi-orthoamide tetrahedral intermediates (44). and to observe their breakdown to yield the reaction products under kinetically controlled conditions. Such conditions can be ascertained by verifying that the reaction products are not iriterconverted (amide + alcohol ester +amine) during the reaction. This technique can therefore be used to test the principle of stereoelec-tronic control in the cleavage of tetrahedral intermediates derived from amides. 

A hemi-orthoamide tetrahedral intermediate can take several ionic forms. T, T , T°, and T, depending on the pH of the reaction medium. In acidic medium, it will exist in the T form, in slightly basic medium (near the pKa of the intermediate, pH =10), it will exist as T and in basic medium (pH 11), as T . In systems where the nitrogen can be readily protonated, T° is neglected since it is rapidly converted into the T form which has a low energy barrier for fragmentation. 

Ue have already discussed (p. 106) that T and T ionic forms can give the ester and amine products only. Thus, in acidic and neutral media which favor the formation of T and T , imidate salts should always give the ester and amine products. In basic medium, which favors the formation of T , there is the possibility for the formation of both types of products, i. e., ester and amine or amide and alcohol. The cleavage of the C—N bond in the T tetrahedral intermediate will take place only if the nitrogen electron pair can form a hydrogen bond with a solvent molecule. Thus, experimental evidence in favor of the principle of stereoelectronic control can be obtained with imidate salts, only when the hydrolysis is carried out under basic conditions. 

As in tertiary amides, the primary electronic effect (n- ) in imidates corresponds to the delocalization of two electron pairs, one from the nitrogen and one from the oxygen atom, which is normally represented by resonance structures and 47. The central atoms (C, M, and 0) of the imidate function are therefore sp hybridized and this is confirmed by X-ray analysis (32) which shows that this function is planar. As a consequence, an imidate function can exist in two different conformations, the anti or the syn form. 

---

Further experimental evidence supporting the principle of stereoelectronic control in the cleavage of hemi-orthoamide tetrahedral intermediates has been obtained from studies on the carbonyl-oxygen exchange during the basic hydrolysis of amides, and from the hydrolysis of imidate salts. These experiments are described next. 

These results confirm that under acidic or neutral conditions, the hydrolysis of imidate salts yield only the ester and amine products via the T+ and T4 ionic form. They also show that under basic conditions some imidate salts (56 and 57) yield only the ester and amine product whereas others (54 and 55) give a mixture of ester and amine plus amide and alcohol products. This difference in behavior of imidate salts can be readily explained by taking into account the principle of stereoelectronic control and by assuming that imidate salts 56 and 57 exist in the anti conformation whereas imidate salts 54 and 55 exist either in the syn conformation or as a mixture of the syn and anti conformations. 

Imidate salt 97 also gave the aminoester 99 (33). Allen and Ginos (34) have reported that the basic hydrolysis of imidate salts 100 (R=CH3, C2H5 or (CH3)3C) yielded only the corresponding aminoester 102. 

The basic hydrolysis of imidate salt 118 takes a different course from that of imidate salt 112, yielding first only the amide rotamer 120B which is then slowly isomerized to the equilibrium mixture (ratio 3 1) of 120A and 120B. Treatment of the ester ammonium salt 119 under the same basic conditions gave directly the aminoalcohol 123. This result shows that the amino-ester 122 is not an intermediate in the basic hydrolysis of imidate 118. The formation of the amide rotamer 120B is therefore the result of the direct fragmentation of a tetrahedral intermediate whidh is formed from 118. 

Imidate salts having a syn conformation were also studied (33). Imidate salt 128 which has a syn conformation due to its cyclic structure, gave on basic hydrolysis a mixture of amidoalcohol 129 (66%), s-valerolactone (130, 33%) and dimethyl amine (33%). Likewise, the hydrolysis of imidate salt 131 gave a one to one mixture of the corresponding amidoalcohol 132 and y-butyro-lactone 133 plus dimethyl amine. 

When the R group linked to the carbon atom is a large group (such as a t -butyl or a phenyl group conjugated with the imidate function), it is assumed that the anti form predominates. When that R group is of an intermediate size (R=CH3 or cyclohexyl), it is assumed that there is a mixture of the syn and the anti forms. These assumptions are supported by the results obtained from the hydrolysis of imidate salts 54-57 (11). 

The basic hydrolysis of imidate salt 64 was carried out (33), and it gave a mixture of aminoester 65 (83%) and N-methylpiperidone (66) (17%). This result can be explained in the following way. Assuming that this salt exists as a mixture of the syn and anti forms 67 and 68 (Fig. 6), these two isomeric forms would give the tetrahedral conformers 69 and 70 respectively. Conformer 70 can yield the aminoester 65 with stereoelectronic control whereas conformer 69 cannot break down. Thus, 69 would either be converted into 70 and 71 by rotation of the ethoxy group or undergo a chair inversion to conformer 72. Interestingly, 71 as well as 70 which come from the rota-... 

The basic hydrolysis of imidate salt 86 was also reported (33). This salt gives a mixture of aminoester 87 (65%) and lactam 88 (35%). This result can be interpreted in the same manner as that of imidate salt 64. 

TABLE 3 Hydrolysis of Imidate Salts 148 and as a Function of pH at Room Temperature... 

Under basic conditions, the hydrolysis of imidate salt UZ, at 0°C gave a mixture (2 B) of the amidoalcohol rotamers 115A and USB as the kinetic products of the reaction. Isomerization followed to yield the equilibrium ratio (4 6) of USA and USB. Imidate first anti imidate salt which does not give the anticipated product, i.e. the aminoester U4. However, being a formate, thus a reactive ester, it is possible that under the reaction conditions. U recyclizes rapidly to give new tetrahedral intermediates which then yield a 2 B mixture of amide rotamers USA and USB. This was proven by showing that the treatment of ester ammonium salt U1 under the same basic conditions at 0°C led directly to a 2 8 mixture of USA and USB. 

---