Imino ether

Amidines are best made in two stages a nitrile reacts with dry HCl and anhydrous alcohols to give an imidic ester (imino-ether) which yields an amidine with NH3. 

Acyl carbonates (234), alkoxyquinones (235) as vinylogous esters, imino ethers (236), and diketene (237) react with ethyleneimine to give the corresponding acylated ethyleneimines. 

A -Imidazolines (294 Z = NH) are cyclic amidines and exhibit the characteristic resonance stabilization and high basicity. A -Oxazolines (294 Z = 0) are cyclic imino ethers, and A"-thiazolines (294 Z = S) are imino thioethers both are consequently easily hydrolyzed by dilute acid. 

Direct proof of an oxaziridine intermediate was achieved in photolysis experiments in an organic glass at 77 K (80JA5643). Oxaziridine (75), formed by photolysis of A/-oxide (74) and evidenced by UV spectroscopy under the above conditions, decomposed at higher temperature to form the imino ether (76) by N—O bond cleavage and C -> O migration of an aryl group. 

Alkyl-/l -piperideines were obtained on treatment of imino ethers with Grignard reagent (37,38). 

The low structural specificity in the local anesthetic sell cs is perhaps best illustrated by phenacalne (91), a local an-I -.lhetic that lacks not only the traditional ester or amide func-I ion but the basic aliphatic nitrogen as well. First prepared at I lie turn of the century, a more recent synthesis starts by con-ili iusation of p-ethoxyaniline with ethyl orthoacetate to afford I he imino ether (90), Reaction of that intermediate with a sec-I liil mole of the aniline results in a net displacement of ethanol, iiobably by an addition-elimination scheme. There is thus ob-I.lined the amidine, 91, phenacalne. 

In an interesting variation on this theme, the bis acid chloride of diethylmalonate (138) is condensed with the 0-methyl ether of urea to afford the imino ether of the barbituric acid (139). Heating this ether at 200°C results in 0 to N migration of the methyl group and formation of metharbital (140). ... 

Pentylenetetrazol (188) is a drug with profound stimulatory activity on the central nervous system. As such, the agent was at one time used in shock therapy for treatment of mental disease. Although it has since been supplanted by safer methods, the agents still occupy an important role in various experimental animal models in pharmacology. Addition of hydrazine to the imino ether (186) obtained from caprolactam affords 187. Treat-... 

Yet another compound that exhibits antidepressant properties, that does not fit the classical mold, is a rather simple substituted ami dine. Reaction of amide with triethyloxoniurn fluoroborate (Meerwein reagent) affords the corresponding imino ether Exposure of this inter-... 

The pharmacological versatility of this general substitution strategy is further illustrated by diazonium coupling of 14 with 2-nitrobenzenediazonium chloride to produce biarylal-dehyde 18. Formation of the oxime with hydroxylamine is followed by dehydration to the nitrile. Reaction with anhydrous methanolic hydrogen chloride leads to imino ether and addition-elimination of ammonia leads to the antidepressant amid-ine, nitrafudam (20). ... 

Preparation of 2-Hydroxy-4,4 -Diamidinostilbene Dihydrochloride 10 grams of 2-hydroxy-4,4 -dicyanostilbene were suspended in 250 cc of absolute ethyl alcohol and the mixture saturated with dry hydrogen chloride at 0°C. The whole was left for eight days at room temperature. The imino-ether hydrochloride formed was filtered off, washed with dry ether and dried in the air for a short time. It was then added to 250 cc of 10% ethyl alcoholic ammonia and the whole heated for 5 hours at 45°C. The 2-hydroxy-4,4 -diamidino-stilbene dihydrochloride which separated was crystallized from 10% hydrochloric acid. It forms pale yellow needles, MP 357°C (decomposition). 

A solution of 100 g. of c. p. concentrated sulfuric acid in 700 cc. of water is prepared in a 5-I. flask, 1500 cc. of cracked ice added, and the mixture shaken until ice forms on the outside of the flask. After about half of this solution has been poured into the cold ether solution of the imino ether, using a funnel to remove the excess ice, the mixture is shaken for exactly fifteen seconds (Note 4), allowed to settle, and the layers separated. The remaining acid is added to the ether layer in two portions, the mixture each time being shaken for fifteen seconds, and separated. Since the ether solution, although now free of the imino ether, still contains a small amount of ethyl phenylaceto-acetate, it is saved to be combined with the main portion later. 

The sulfuric acid solution of the imino ether sulfate quickly... 

Any delay at this point results in hydrolysis of some of the imino ether to the product, which stays in the ether layer. 

Ethyl a-phenylacetoacetate can be prepared by the hydrolysis of a-phenylacetoacetonitrile in absolute alcohol with dry hydrogen chloride.1 The present method differs in specifying neutralization of the hydrogen chloride with sodium carbonate and hydrolysis of the imino ether in aqueous sulfuric acid, so that the product separates as fast as it forms, thus being protected from further decomposition, with a considerably increased yield as the result. 

The addition of dry HCl to a mixture of a nitrile and an alcohol in the absence of water leads to the hydrochloride salt of an imino ester (imino esters are also called imidates and imino ethers). This reaction is called the Pinner synthesisThe salt can be converted to the free imino ester by treatment with a weak base such as sodium bicarbonate, or it can be hydrolyzed with water and an acid catalyst to the corresponding carboxylic ester. If the latter is desired, water may be present from the beginning, in which case aqueous HCl can be used and the need for gaseous HCl is eliminated. Imino esters can also be prepared from nitriles with basic catalysts. ... 

Conventional conversion of amide, lactam, imide, and urea carbonyl groups into enaminones, enamino esters, or enamino nitriles requires prior activation of the carbonyl groups either by alkylation to imino ethers, followed by reaction with activated methylene groups, or by thiation, e.g. with P2S5, to thiocarbonyl groups followed by alkylation (and possibly also oxidation), and, again, subsequent reac-... 

Imino ethers and, in particular, lactim ethers [141] such as O-ethylpyrrolidone 384a [142] or O-trimethylsilylcaprolactam 384b, which is formed, in equilibrium with N-trimethylsilylcaprolactam, on treatment of caprolactam with HMDS 2, condense readily with activated methylene compounds such as methyl or ethyl cyanoacetate to the y9-enamino esters 385 a and 385 b [140] whereas O-alkylureas such as 2-methoxyimidazoline 386 [143-146] afford products such as 387. 

Whereas primary amides such as butyric acid amide, on heating to 140-150 °C with triethylsilane 84b and ZnCl2, give, e.g., 78% butyronitrile 1853 and 95% HMDSO 7 [79], the secondary amide benzanilide is readily converted into 90% O-triethylsilyl imino ether 1854 [80] whereas the tertiary amide N,N-diethylacetamide... 

MeCH=CH, Ph) in the presence of Na2C03 (Eq. 6.41). The methanolysis of benzonitrile also proceeded to give the imino ether in the presence of [Cp Ir(T -CH2CHCHPh)(NCPh)]OTf and Na2C03 (Eq. 6.42). The methanolysis of benzonitrile proceeded much more rapidly than the hydration. Based on the isolated or detected intermediate complexes, plausible reaction mechanisms are suggested. 

As early as 1899, 8tieglitz proposed a tetrahedral intermediate for the hydrolysis of an imino ether to an amide. Thns it was clear qnite early that a complicated overall transformation, imino ether to amide, would make more sense as the result of a series of simple steps. The detailed mechanism proposed, althongh reasonable in terms of what was known and believed at the time, wonld no longer be accepted, but the idea of tetrahedral intermediates was clearly in the air. 8tieglitz stated of the aminolysis of an ester that it is now commonly snpposed that the reaction takes place with the formation of an intermediate prodnct as follows referring to work of Lossen. (Note that the favored tautomer of a hydroxamic acid was as yet unknown.)... 

Pentenyl amides such as 15A cyclize to lactams 15B on reaction with phenyl selenenyl bromide. The 3-butenyl compound 15C, on the other hand, cyclizes to an imino ether 15D. What is the basis for the differing reactions ... 

Nitroimidazoles substituted by an aromatic ring at the 2-position are also active as antitrichomonal agents. Reaction of p-fluorobenzonitrile (83) with saturated ethanolic hydrogen chloride affords imino-ether 84. Condensation of that intermediate with the dimethyl acetal from 2-aminoacetaldehyde gives the imidazole 85. Nitration of that heterocycle with nitric acid in acetic anhydride gives 86. Alkylation with ethylene chlorohydrin, presumably under neutral conditions, completes the synthesis of the anti-... 

The initial product from this reaction (100) is not observed as it undergoes spontaneous internal displacement to the cyclic imino ether salt 101. Treatment... 

While screening for p-lactam antibiotics stable to p-lactamases, a strain of Streptomyces lactamdurans was found to contain several such agents which have a 6-a-methoxy group whose electronic and steric properties protect the antibiotic from enzymatic attack. Cephamycin C (29a), one of these substances, is not of commercial value, but side chain exchange has led to much more potent materials. Of the various ways of effecting this transformation, one of the more direct is to react cephamycin C with nitrous acid so that the aliphatic diazo product (29b) decomposes by secondary amide participation giving cyclic iminoether 30. The imino ether moiety solvolyzes more readily than the p-lactam to produce 7-aminocephamycinic... 

Reductive cleavage experiments on a series of synthetic -substituted imino ethers have shown that different results would be obtained depending on the nature of the imino system (45). Thus, /3-aryl-substituted imino ethers can be reduced and cleaved with sodium in boiling alcohol whereas /3-aliphatic imino ethers are not susceptible to this kind of reductive fission. The /3-imino ethers synthesized include types 52 and 53. It appears that this kind of reductive cleavage might be developed into a common degradative method for the similar indolenene alkaloids. 

The first conversion of protoberberines to phthalideisoquinoline alkaloids was achieved by Moniot and Shamma (88,89). 8-Methoxyberberinephenol-betaine (131), derived from berberine (15) (Section III,B,2), is an attractive compound having a carboxyl group masked as an imino ether in ring B. The masking was uncovered by hydration with water-saturated ether to furnish dehydronorhydrastine methyl ester (367) (Scheme 65). On N-methylation (68%) and subsequent sodium borohydride reduction (90%), 367 provided (+ )-/ -hydrastine (368) and ( )-a-hydrastine (369) in a 2 1 ratio. Compound 367 was converted to dehydrohydrastine (370), which also afforded 368 and 369 by catalytic hydrogenation. 

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