Imino ethers synthesis

This is an example of the Pinner imino ether synthesis (1). In the presence of an aqueous medium, the intermediate is hydrolyzed to the benzoic acid derivative. 

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. 

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-... 

Almqvist and coworkers have developed a two-step synthesis of optically active 2-pyridones via thiazolines (Scheme 6.216) [388]. Thus, heating a suspension of (R)-cysteine methyl ester hydrochloride with 2 equivalents of an imino ether and 2 equivalents of triethylamine base in 1,2-dichloroethane at 140 °C for 3 min furnished the desired thiazolines in near quantitative yield with limited racemization. Purification by filtration through a short silica gel column and concentration of the filtrate gave a crude product, which was used directly in the next step. Thus, after... 

Some particularities of the extraction of ions from an aqueous organic phase, and of the phase catalyzed polyetherification will be summarized. These will represent the fundamentals of our work on the synthesis of some novel classes of functional polymers and sequential copolymers. Examples will be provided for the synthesis of functional polymers containing only cyclic imino ethers or both cyclic imino ethers as well as their own cationic initiator attached to the same polymer backbone ABA triblock copolymers and (AB)n alternating block copolymers and a novel class of main chain thermotropic liquid crystalline polymers containing functional chain ends, i.e., polyethers. 

Three major topics of research which are based on phase transfer catalyzed reactions will be presented with examples. These refer to the synthesis of functional polymers containing functional groups (i.e., cyclic imino ethers) sensitive both to electrophilic and nucleophilic reagents a novel method for the preparation of regular, segmented, ABA triblock and (A-B)n alternating block copolymers, and the development of a novel class of main chain thermotropic liquid-crystalline polymers, i.e., polyethers. 

One of the most famous examples of intramolecular attack of oxygen on the nitriUnm ion intermediate was observed in the Beckmann rearrangement of Erythromycin oxime derivatives and was used in the discovery and synthesis of the commercial macrolide antibiotic Azithromycin 464. In fact, the Beckmann rearrangement of Erythromycin A 9( )-oxime 460 produced only small amounts (5%) of the expected amide 463, along with two isomeric imino ethers (461 and 462) in a fair yield (38 and 43%) (equation 198). 

The addition of dry HCI 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 synthesis.103 The 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 HCI can be used and the need for gaseous HCI is eliminated. Imino esters can also be prepared from nitriles with basic catalysts.104... 

MacrocycBc lactams. Two key steps in a synthesis of the polyamine alkaloid dihydroperiphylline (4) involve ring expansion of the cyclic imino ether 1 by reaction with the /3-lactam 2 to form 3. Sodium cyanoborohydride in acetic acid reduces 3 in high yield to 4, probably by way of intermediates a and b.2... 

Trichloroacetimidates are the only type of imino ethers to have found some application in solid-phase synthesis. Trichloroacetimidates can readily be prepared from support-bound alcohols by treatment with trichloroacetonitrile and a base (Entry 6, Table 13.18). Because trichloroacetimidates are good alkylating agents, this reaction offers a convenient alternative for converting support-bound aliphatic alcohols into alkylating agents. Trichloroacetimidates prepared from Wang resin or from hydroxymethyl polystyrene are quite stable and can be stored for several months without decomposition [253],... 

Cationic methylplatinum(II)-nitrile complexes of the type m is-PtMeL2(NCR)+X have been isolated by the reaction of //vms-PtMeClL2, where L = dimethylphenylphosphine or trimethyl-arsine, with an aryl nitrile and AgX, where X = BF4, PF. Use of pentafluorobenzonitrile and 2,3,5,6-tetrafluorotetraphthalonitrile in alcohol has led to the synthesis of a series of imino ether complexes. A mechanism for imino ether formation, involving nucleophilic attack by an alcohol at a coordinated nitrile, is suggested and the course of the reaction is shown to be dependent not only on the alcohol but also on the size of the anion used.110... 

As an alternative to the alkylation of 113 for the preparation of compounds of type 103-105, 110, and 111, Meyers et al. developed a variant of the Com-forth oxazole synthesis. This had been used previously to prepare 113-115 (67, 70). In this scheme, the imino ether 128, the adduct of methanol, HC1, and acetonitrile, is condensed with methyl glycinate (129) to yield 130, which is for-mylated to 131. Deprotonation of the formyl anion 131 at the incipient 2-methyl position of the oxazole followed by alkylation with the electrophile of choice [in this case the acetonide 132 derived from (S)-malic acid] and Lewis acid-... 

Synthesis of the pyrrocorphin 122 (Scheme 13) was rendered difficult by the instability of the intermediates, as well as of the product. Sulfur contraction of 120 and imino ether condensation of 121 could be effected only by using appropriate complexes (82HCA600). 

A total synthesis of (+)-dihydroperiphylline (27) has been achieved, starting from piperidazine and utilising a ring-expansion reaction by a transamidation with the imino-ether (28) and a /Mactam.21 This procedure has also been used to synthesize celacinnine.22... 

The application of lactams in heterocyclic synthesis depends on the activation of their amide function.5 Similar activation of other functional groups, e.g., the conversion of ketones to enamines6 and of carboxylic acid amides to imino ethers,7 presented new applications for these compounds. Similarly, the conversion of lactams into lactim ethers offers a greater scope for the use of lactams in organic synthesis. 

This is an example of the Pinner imido ether synthesis. The intermediate imido ester hydrogen chloride salt can be hydrolyzed to the ester or neutralized to the imino ester... 

The photoreactions of azides can in most cases be rationalized in terms of the initial formation of nitrenes which then undergo rearrangement, insertion or addition reactions. Nitrene rearrangement is thought to be responsible for the conversion of the a-azido ethers (81) into the imino ethers (82), and the first silanediimine (83) to be described has been prepared in a similar fashion from the diazide (84) as shown in Scheme 4. Intramolecular nitrene addition to suitably aligned nitrogen-nitrogen double bonds has been employed in the synthesis of triaziridines. 

This Cl homologation of osones proved to be valuable in the preparation of L-ascorbic acid analogues (16) as well as in the preparation of radiolabeled L-ascorbic acid (17-20), This synthesis was greatly improved when aldoses were discovered to be directly oxidized to osones with cupric acetate (Equation 1) (21), Subsequently, the conditions were modified so that D-xylose could be oxidized to D-xylosone in 50-55% yield with cupric acetate in methanol. The intermediacy of the imino ether was proved by the isolation of 7 when D-glucosone was treated with potassium cyanide (16), The initial cyanohydrin adduct (3a) easily undergoes cyclization to the imino ether intermediate (aqueous solution for 10 min at room temperature. Scheme 5). This feature will be compared with the conditions required for the lactonization of other intermediates. 

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