Imino ester hydrochlorides

By the condensation of a nitrile with a phenol or phenol ether in the presence of zinc chloride and hydrogen chloride a hydroxyaryl- or alkoxyaryl-ketone is produced. The procedure is termed the Hoesch reaction and is clearly an extension of the Gattermann aldehyde reaction (Section IV,121). The reaction gives the best results with polyhydric phenols and their ethers with simple monohydric phenols the imino ester hydrochloride is frequently the sole product for example ... 

The synthesis of ortho esters from nitriles is usually a two-step process involving first the formation of the imino ester hydrochloride and subsequent reaction with an alcohol. Several examples are described in Table I, even a glycol such as ethylene glycol can be used to obtain heterocyclic ortho esters, as shown in Eq. (11). 

McElvain and Nelson [18] reported that several factors can optimize the yield of imino ester hydrochlorides from the nitrile (see Table II and Eq. 12). 

The ortho esters are prepared as described in Table III starting with 0.2 mole of the imino ester hydrochloride and 3.0 moles of absolute alcohol (Eq. 13). It is... 

The most serious competing reaction involved in the conversion of nitriles to imino ester hydrochloride is the decomposition of the latter to an amide and an alkyl chloride [28]. This decomposition can be avoided or minimized by using low reaction temperatures (preferably below about 60°C). The decomposition is favored in highly polar solvents [28]. 

This is the best reaction for the preparation of ortho esters. The imino ester hydrochlorides are available in excellent yields by partial alcoholysis of nitriles (method 402). In early procedures, the hydrochlorides and excess alcohol were allowed to stand at room temperature for 5 to 40 days. The time of reaction can be reduced to 6 to 28 hours by carrying out the alcoholysis in refluxing ether solution. Good yields are common for both steps in the process. The principal side reaction is the thermal... 

Aliphatic and aromatic imino ester hydrochlorides are most easily obtained by passing dry hydrogen chloride into an equimolar mixture of a nitrile and an alcohol in ether solution. Strictly anhydrous conditions ate essential for successful conversions. The time of reaction is greatly reduced by refluxing the ether solution. Dioxane is superior as a solvent in certain cases. At temperatures above 60-80°, decomposition of the imino ester hydrochloride to an alkyl chloride and an amide occurs. The free imino esters are obtained by neutralization of the hydrochlorides with sodium bicarbonate or potassium carbonate under ether. 

Excellent examples of this reaction are found in the preparations of acetamidine (91%) and nicotinamidine (60%). The conversion is accomplished by treatment of the imino ester hydrochloride with alcoholic ammonia or by the action of ammonium chloride on the free imino ester. The amidines are frequently isolated as salts such as the sulfates or picrates. N-Substituted amidines result when amines are used in place of ammonia. ... 

Carboxylic acid amides from nitriles via imino ester hydrochlorides... 

A soln. of oxalyl diloride in CCI4 added dropwise with stirring to a soln. of ethyl nicotinimidate in the same solvent, warmed 0.5 hr. at 50°, the solvent distilled off in vacuo, and the remaining N-(diloroglyoxyloyl)iminoester heated at 110-130° until gas evolution ceases nicotinoylisocyanate. Y 77%. F. e., also from imino-ester hydrochlorides, s. L. I. Samarai et al., Zh. Org. Khim. 6, 85 (1970) C. A. 72, 90006 review of acylisocyanates s. K. A. Nuridzhanyan, Russ. Chem. Rev. 39, 130 (1970) (Eng. transl.). 

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. ... 

Acidic treatment of prechilenine (139) (Section III,C) afforded the imino keto acid 377 via the imminium salt 140 (Scheme 68). Neutralization and work-up furnished the known y-lactol 371 in 90% overall yield from 139 (96, 181). Kondo et al. (183) obtained 139 from the epidioxide 122 by treatment with pyridine hydrochloride in pyridine along with 377 and norhydrastine. The acid 377 was converted to the known imino ester 373 through N,0-dimethylation. 

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... 

Under optimized reaction conditions this two step synthesis for asymmetric preparation of /1-lactams is performed as follows. First, the organocatalyst 46 is added as a shuttle base to a solution of the acid chloride, 47, and the proton sponge , 49, at low temperature. Within a few minutes the soluble ketene and the hydrochloride salt, 49 HC1, as a white precipitate, are formed. Subsequently, the imino ester 44 is added to this solution at —78 °C, which results in the asymmetric formation of the /Mactam. Thus, the alkaloid 46 acts both as a dehydrohalogena-tion agent and as an organocatalyst for subsequent lactam formation [49, 52]. 

N-TFA-L-prolyl methyl esters have been most frequently used for the separation of diastereoisomers of amino acids [295,296], although other procedures have been suggested for blocking the imino group of Pro using functional groups such as a-chloro-propionyl and a-bromopropionyl. The preparation of the derivatives consists in conversion of amino acids into methyl ester hydrochlorides by the action of methanol and thionyl chloride and subsequent reaction with TFA-L-prolyl chloride in dichloromethane... 

Carbodiimides are known to react with primary amines to form guanidines.f In the case of amino acid esters, a subsequent elimination of alcohol is possible with formation of an imino-hydantoin species (Scheme 8). However, these reactions usually require higher temperatures or the occurrence of acid catalysis and therefore can be neglected when unprotonated amino acid derivatives are acylated using carbodiimides. On the other hand, this side reaction becomes more important when protonated amino acids (i.e., amino acid ester hydrochlorides) are coupledf and these byproducts may occur. 

Several nitriles (RCN, where R = Me, Et, Bn, Ph, and r -Pr) were treated with HCl(g) in EtOH to form the corresponding imino ethers, which were subsequently condensed with (R)-cysteine methyl ester hydrochloride to form the variously substituted A -thiazolines in 73%, 79%, 83%, 91% and 83% yields, respectively <2001JOC6756>. 

Imino esters, catalyzed by trifluoroacetic acid, are trimerized in 81-85% yield with loss of alcohol. The iminoester hydrochloride salt gave the corresponding triazines in 72-78% yield in the presence of sodium acetate <92ZOR1750>. 

Ihe esterification of the nitrile presents no great difficulty. An amount of acid catalyst greater than that required to combine with the ammonia that is formed must be used. Higher reaction temperatures and longer reaction times are required than for simple esterification. A common procedure is to dissolve the nitrile in the appropriate alcohol and to saturate the resulting solution with hydrogen chloride. Under these conditions imino ether hydrochlorides are formed [reaction (21)]. When the imino ethers are caused to react with water, esters are formed (reaction (22)]. 

Ehrler and Farooq" prepared 1187 via a stepwise construction of the three thiazoline rings, introduction of the styryl group, and preparation of the oxazole ring (Scheme 1.333). Condensation of L-cysteine ethyl ester hydrochloride 1284 (R = C2H5) with an imino ether derived from cinnamamide was unsuccessful, owing to complications from Michael addition. This necessitated a strategy in which the styryl double bond was introduced after assembly of thiazoline rings. 

A solution of 1.50 g heptanoic acid 7-[[(5-cyano-l/f-indol-2-yl)carbonyl]-amino] ethyl ester (4.18 mmol) in 250 mL EtOH was treated with a stream of HCl gas for 30 min. The reaction vessel was sealed, and the solution was stirred for 48 h until NMR indicated the completion of conversion to the imino ether. The reaction was concentrated in vacuo, reconstituted in EtOH, and evaporated in vacuo again. The residue was taken up in 250 mL EtOH, and the mixture was treated with a stream of NH3 gas for 30 min. The vessel was sealed, and the contents were stirred for 24 h for the consumption of imino ether. The reaction mixture was concentrated in vacuo to afford 820 mg of the corresponding amidino ester hydrochloride as a white solid, in a yield of 50%. 

A 0.38 N soln. of Ag-tetrafluoroborate in methylene chloride-benzene added dropwise at —20 with agitation to a soln. of ( + )-Na-(y-chlorobutyryl)-L-tryptophan methyl ester in abs. methylene chloride, kept 1 hr. at —20 , agitated 1 hr. at 0°, after an additional 1.5 hrs. at room temp, excess Ag-tetrafluoroborate decomposed with triethylamine hydrochloride, the resulting crude imino-lactone dissolved in acetonitrile treated with methyl iodide, stored 41 hrs. at 30 , excess methyl iodide and 2/3 of the acetonitrile evaporated in vacuo at room temp., the residual soln. allowed to stand 2 hrs. at 20 with 2 N KHGO3-soln., and the product isolated as the hydrochloride (+)-Ngj-methyl-L-trypto-phan methyl ester hydrochloride. Y 84.5%. H. Peter et al., Helv. 46, 577 (1963). 

The synthesis begins with imino ethers, produced fiom nitriles, that ate condensed with racemic cysteine methyl ester hydrochloride to give a set of substituted thiazolines (Scheme )(11,12). 

Interestingly, 4-nitrobenzyl esters of 2-amino, 4-amino-, or 6-aminonicotinates exist in their amino form in DMSO-< /6 solution, whereas their hydrochlorides favor the imino tautomeric form (94CCC2057). 

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