Imidate salts hydrolysis

Imidate salts hydrolysis, 118-144 syn and anti, 120 isomerization, 142 B-lactam, 142 Iminium salts, 211-221 Imino-ethers, 147 lodolactonization, 169 Ionic state of tetrahedral intermediates, 65, 105-106, 119 Ionophore A-23187, 13 Isochromane-3-one, 70 Isocyanate, 300 Isonitrile, 296... 

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. 

The results of hydrolysis of these imidate salts as a function of pH are the following at pH 8.5 or lower, the imidate salts 54 and 55 yield the ester and amine products exclusively. At pH greater than 8.5, they start to produce the amide and alcohol products which reach a maximum yield at pH 11 (20% for 54 and 25% for 55), and this yield remains unchanged at higher pH. The imidate salts 56 and 57 behaved completely differently as they give exclusively the ester and amine products over the entire range of pH values. 

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. 

Application of the principle of stereoelectronic control to the hydrolysis of syn and anti imidate salts leads to the following analysis. Syn imidate salts are first considered. 

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 acidic and basic hydrolysis of the cyclic imidate salt YW was investigated (16). Under acidic conditions, imidate salt 112 was slowly hydrolyzed to yield the ester ammonium salt 113 exclusively. This is the expected result for any imidate salt. 

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. 

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 ihterconverted (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. 

We 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 T1, 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. 

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). 

This is also consistent with the results obtained from the basic hydrolysis of formamide imidate salt 63 (33) for which there is evidence (cf 53) that this compound exists in the syn conformation. This salt gave a =1 1 mixture of ethyl formate and N,N-dimethylformamide. 

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. 

The basic hydrolysis of a series of cyclic anti imidate salts has been investigated (1, 33). For instance, the six-membered imidate salt 89 where the anti conformation is assured by its cyclic structure, gave first under basic conditions, only the aminoester 90. The aminoester 90 was then slowly converted into the thermodynamic product of the reaction, i,e. the benzamido-alcohol 91. The reaction of imidate salt 89 with hydroxide ion must first give intermediate 92 following the principle of stereoelectronic control. It can also be seen that 92 can only give the aminoester 90 by following... 

It should be pointed out (a) that the half-life of each rotamer in forma-mides 139 and 140 is several minutes at room temperature, (b) that the basic hydrolysis of the imidate salts 137 and 138 is completed in less than one minute at that temperature. Consequently, the production of the equilibrium mixture of the amides rotamers comes from the direct fragmentation of tetrahedral intermediates. It cannot come from a subsequent equilibration of the amide rotamers. 

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

Recently, Eschenmoser, Dunitz, and co-workers (48) have reported the hydrolysis of tricyclic ketene N,0-acetal 224 which yields only aminopropionic acid ester 225. The first step in this reaction must be the protonation of 224 which gives the anti imidate salt 226. Since anti imidate salts always... 

The white residue is next modified by treatment with a strong base in alcohol. It is known that bases can hydrolyze the imide ring of ULTEM polyetherimide (18). Figure 9 shows that both chemical and physical changes to the residue have occurred following immersion in methanolic potassium hydroxide. XPS results are consistent with imide ring hydrolysis and formation of the potassium salt of a carboxylic acid. 

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