Amino esters from imides

As in 10-55 hydrazides and hydroxamic acids can be prepared from carboxylic esters, with hydrazine and hydroxylamine, respectively. Both hydrazine and hydroxylamine react more rapidly than ammonia or primary amines (the alpha effect, p. 445). Imidates, RC(=NH)OR, give amidines, RC(=NH)NH2. Lactones, when treated with ammonia or primary amines, give lactams. Lactams are also produced from y- and 5-amino esters in an internal example of this reaction. 

Microwave-induced 1,3-dipolar cycloadditions involving azomethine ylides have been widely reported in the literature. Bazureau showed that imidates derived from a-amino esters 120, as potential azomethine ylides, undergo 1,3-dipolar cyclo-additions with imino-alcohols 121 in the absence of solvent under microwave irradiation. This reaction leads to polyfunctionalized 4-yliden-2-imidazolin-5-ones 122 (Scheme 9.36) [87]. 

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. 

Alternatively, an electrochemical procedure was employed in the synthesis of amino acids from nitridomolybdenum complex 4 via nitrogen-carbon and carbon-carbon bond formations involving imide 5 and nitrogen ylides 6. trans-[MoCl(N)(Ph2PCH2CH2PPh2)] 4 reacted with methyl iodoacetate to give the cationic complex 5. Complex 6 was obtained by the deprotonation of 5 at the a-carbon followed by treatment with Mel to afford the cationic methyl derivative 7. Electrochemical cleavage of the Mo-N bond of the complex 5 or 7 proceeded in the presence of acetic acid to release amino acid esters in 70-80% yield (Scheme 2) [12]. 

Chiral oxazolidones are readily prepared from carbamates of a-amino esters by reduction with NaBHa-Lil in refluxing THF. Note that imides (A-acyloxazolidinones) are reduced to alcohols, therefore the reduction represents a method for recovery of both chiral products and auxiliaries. ... 

The solid phase synthesis of 1-substituted 4,5-dihydro-l,2,4-triazin-6-ones from imidate esters and substituted hydrazines has been reported <01TL6455>. The first reported solid phase synthesis of 3-amino-l,2,4-triazin-5(4W)-ones has been described. Reaction of polymer-bound isothiourea with 2,3-diaza-3-pentenedioic anhydride afforded the title compounds in... 

The most general protocol (eq 10) has therefore been based on potassium hexamethyldisilazide (KHMDS) as the base addition of trisyl azide at —78 °C and then acetic acid at the same temperature. Excellent levels of diastereoselectivity are ohsCTved with most substrates and the method has been used widely in the enantioselective synthesis of a-amino acids from chiral iniides. Chemoselective azidation of an imide enolate in the presence of an ester function has been demonstrated (eq 11). The product distribution is nevertheless finely balanced, as discovered with the respective dimethyl and dihenzyl ethers of the 3,5-substituted phenylacetyl imide (3) (eq 12). ... 

Tractable polymers can be prepared when amino and anhydride functions are not located on the same aromatic ring, and different strategies were employed to obtain soluble polymer. AB benzhydrol imide was prepared by polycondensation of 4-(3-amino-l-hydroxymethylene) phtlialic acid monomethyl ester in NMP. The polymer soluble in NMP has been used as adhesive and coating.56 A second approach was based on an ether imide structure. AB aminophenylether phthalic acids (Fig. 5.34) were prepared by a multistep synthesis from bisphenols.155 The products are stable as hydrochloride, and the polycondensation takes place by activation with triphenylphosphite. The polymers are soluble in an aprotic polar... 

The formation of tluorinated Q -hydroxy-jS-imino esters (180) by treatment of fluorinated imino ethers (179) with lithium 2,2,6,6-tetramethylpiperidide has been reported. A possible explanation for this interesting intramolecular rearrangement is proposed in Scheme 64. Acyclic imides derived from primary benzylic amines and amino acid esters have been found to undergo a novel nitrogen to carbon acyl migration via a base-generated carbanion to yield the corresponding a-amino... 

In solution-phase peptide synthesis, acylation of amino acids or peptides with N-protected azetidine-2-carboxylic acid is performed via the active esters, e.g. A-hydroxysuccin-imide 100 111-112 or pentachlorophenyl ester, m 117 as well as by the mixed anhydride 101114 or carbodiimide 118 methods. An attempt to prepare the A-carbonic acid anhydride by cycli-zation of A-(chloroformyl)azetidine-2-carboxylic acid with silver oxide in acetone or by addition of triethylamine in situ failed, presumably due to steric hindrance. 111 In SPPS, activation of the Fmoc-protected imino acid by HBTU 119,120 is reported. In solution-phase peptide synthesis, coupling of N-protected amino acids or peptides to C-protected azetidine-2-carboxylic acid or related peptides may be performed by active esters, 100 118 121 mixed anhydrides, 95 or similar methods. It may be worth mentioning that the probability of pip-erazine-2,5-dione formation from azetidine-2-carboxylic acid dipeptides is significantly reduced compared to proline dipeptides. 111 ... 

In analogy to proline dipeptides, A1-unprotected 2-carbonylpyrazolidine amino acid dipeptide esters 37 on storage at ambient temperature are prone to conversion into the related triazines 38 that correspond to the aza analogues of piperazine-2,5-diones (Scheme 5). 160 161 An additional side reaction is reported for the 2-azaproline peptides 161 which leads to formation of the cyclic imide 40 from methyl TV -lbenzyloxycarbonylj -carbonylpyra-zolidine glycinate (39) upon treatment with methanolic ammonia (Scheme 6). 

Intermediate 3-33 reacts by a route completely analogous to the previous steps to give 3-35, a tautomer of the product. That is, the proton removed from the amino nitrogen of 3-33 leads to a resonance-stabilized anion, 3-34. (The anion formed by removal of a proton from the imide nitrogen would not be resonance stabilized.) The nucleophilic anion, 3-34, adds to the remaining ester carbonyl. Elimination of ethoxide then gives 3-35. 

Dimethylamino-l-phenylphthalazine can in acid solution be reduced in a four-electron reaction to 2-(l -amino-1 -phenylmethyl)-A/, A/ -dimethylbenzamidine [310], which at higher pH forms l-phenyl-3-iminoisoindoline, which can be reduced to 1-phenylisoindoline (LII) in a four-electron reduction. From the reduction corresponding to the first wave of 4-methoxy-l-phenylphthalazine, the cyclic imidic ester 3-methoxy-l-phenylisoindole can be isolated it may be further reduced to LII. 

The base-catalyzed addition of alcohols to nitriles to give imidates proceeds well, if there are electron-attracting groups in the a-position. In such cases the Pinner synthesis is less effective, because nitrile basicity is less. TTiis shows that both methods are complementary. Recently attention has been paid to the long-known addition of alcohols to trichloroacetonitrile, since it was found that imidates prepared from protected saccharides, amino alcohols etc. and trichloroacetonitrile are useful reagents for the synthesis of nucleosides, disaccharides and other natural products. The trichloroacetimidic acid esters (240 equation 131) of fluorinated, unsaturated aliphatic alcohols °° and benzyl alcohol have been prepared for synthetic purposes. 

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