Imidate salts

The mono K-a, 3,f3-Trinitro-Propionaldehyde-methyl imide salt bright yel cryst explds on heating... 

Following resolution with (—)-quinine, (+)-465 was transformed into the (-l->2-formamido derivative which was condensed with the acid chloride of (+)-465 to give the secondary amide 468. From this point, the cyclic imidate salt 469 was prepared, but cyclization to the dodecahedrane nucleus could not be realired With Thiele s add as starting material, several routes to triquinacene and 2,3-dihydrotriquinacen-2-one 462) have been developed Triquinacene reacts with Mo(CO)g to give tricarbonyl(triquinacene)molybdenum (470) and with (CHjCI -... 

The synthesis of eprosartan mesylate (6) by SmithKline Beecham Pharmaceuticals is described in Scheme 9.9. The synthesis of the precursors 43 and 45 were required for imidazole formation. Thus, valeronitrile (40) was converted to the imidate salt 41 with... 

The constrained bis(oxazolines) 9a and 9b can be constructed beginning with malononitrile 32 as shown by Ghosh and co-workers. Thus, treatment of 32 with anhydrous hydrochloric acid in dioxane, as shown by Lehn and co-workers, yielded imidate salt 33 (Fig. 9.9). Condensation of the imidate salt with commercially available (15,2/ )-l-aminoindan-2-ol afforded the conformationally constrained bis(oxazoline) inda-box 9a. Alkylation at the bridging methylene of 9a was carried out by Davies and co-workers.Treatment of 9a with lithium diisopropylamide followed by alkylation with methyl iodide afforded 9b. Alternatively, alkylation with diiodoalkanes incorporated ring systems at the bridging position (structures 34a-d). 

Later investigators alcoholyzed imidate salts of other monobasic acids to obtain ortho esters of acetic [13, 14], propionic [15], butyric, valeric, caproic, isocaproic, benzoic [16], and phenylacetic acids [17]. For the latter alcoholysis reactions, the reaction time varies from a few days for the production of methyl orthopropionate to six weeks for ethyl orthobenzoate. McElvain reported that the reaction time is drastically cut by carrying out the reaction in boiling ether [18] or petroleum ether [19]. These conditions provide a reaction temperature below the decomposition point of the imidate salt to the amide. 

Electrophilic N-aminations of imide salts have been performed with hydroxylamine-0-sulfon1c acid (HOSA),8 9,1 0-(2,4-dinitrophenyl)-hydroxylamine,11,1 and O-mesitylenesulfonylhydroxylamine (MSH),11 The use of HOSA 1s mainly restricted to aqueous reaction media.8,9 0-(2,4-... 

Where there are two carbonyl groups to stabilize the amide anion, as in the l,2-benzenedicarboximide (phthalimide) anion (Section 18-IOC), the acidity increases markedly and imides can be converted to their conjugate bases with concentrated aqueous hydroxide ion. We have seen how imide salts can be used for the synthesis of primary amines (Gabriel synthesis, Section 23-9D and Table 23-6). 

Imidate-derived dipoles have played a prominent role in the synthesis of the pyrrolizidine alkaloid retronecine (121).119 The imidate salt derived from lactam (118) was found to undergo a smooth desilylation reaction to produce azomethine ylide (119). Trapping of this dipole with methyl acrylate affords... 

The mechanism of the caprolactam polymerization, i. e. the transamid-ation reaction catalysis by the system imide + salt can be interpreted by a nucleophillic attack of the amide anion on the carbonyl group of the imide which represents the strongest electrophillic reagent in the polymerizing system. 

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. 

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 43 reacts with sodium hydroxide, it gives sodium fluoro-borate and the tetrahedral intermediate 44 which breaks down in an irrevers-... 

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. 

The stereoelectronically controlled reaction of the syn imidate salt 58 (Fig. 5) with hydroxide ion must give specifically conformer 59, in which the nitrogen and the oxygen of the OR group have each an electron pair anti peri planar to the C— OH bond also, the R groups on the central carbon and on the oxygen atom which were syn in 58 are gauche in 59. 

Similar studies were carried out (33) with cyclic imidate salts 94 (R=CgHg or CH3 ). They behaved like imidate salt 89, yielding first the aminoester 95 followed by the slow formation of the thermodynamic product, j, e. the corresponding amidoalcohol 96. 

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. 

These syn salts give a mixture of products as predicted. Thus, for instance, the imidate salt 128 (Fig. 9) must react to produce first the intermediate... 

Consequently, each unsymmetrical imidate salt must first produce a tetrahedral intermediate which has a specific conformation, then equilibration occurs to give a mixture of different tetrahedral conformers which can then break down to give the reaction products. 

The direct formation of the equilibrium mixture of amide rotamers from the fragmentation of tetrahedral intermediates for imidate salts 138A and 138B is thus rationalized. The same explanation is also valid for the formation of the equilibrium mixture of the amide rotamers 139A and 139B from imidate salts 137A and 137B. 

Kaloustian and co-workers (37) have reported that the kinetic breakdown of hemi-orthothioamide tetrahedral intermediates (156) was found to involve the preferential cleavage of the C-N bond ( H>8) rather than the C-0 bond (->157). The intermediate J56 were produced in situ by the reaction of sodium hydrosulfide on an imidate salt (J55) in acetone. 

In a study on the aminolysis of O-acetylethanolamine (185, R =H) and 0-acetylserine (185, R =COOH), it was observed (41) that the kinetics of acetyl-transfer reaction of these two aminoesters indicate that the breakdown of 186 yields mainly the amidoalcohol 187 only 1.5-3% of aminoester 185 was detected. The breakdown of 186 was compared with that of 188 obtained from imidate 94 (cf. p. 130) which gave only the aminoester 95 by C-N bond cleavage. Contrary to the conclusion reached by these authors (41), the difference in behavior between 186 and 188 can be readily understood. Imidate salt 94 reacts with hydroxide ion to give conformer J89 (R=CH3) which can only give the aminoester 95 with stereoelectronic control the amino-... 

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... 

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). 

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