Pinner synthesis

Transformation of a nitrile into an imino ether, which can be converted to either an ester or an amidine. 

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Nitriles react with alcohols in the presence of hydrochloric acid to form iminoester hydrochlorides, which are hydrolyzed to the esters (Pinner synthesis). Heitz and coworkers [21-23] published several fine papers on the polyazoester synthesis from the reaction of a series of poly(oxyethylene) glycol or poly(oxypropylene) glycol and AIBN in the presence of dry hydrochloric acid at 0-5°C according to Pinner synthesis. Condensation reactions of ACPC and dihydroxy terminated poly(oxy-ethylene) glycol yield polyazoesters [24,25]. 

The chemistry of imidates and their methods of synthesis have been reviewed [32], Imidates are mainly available via the Pinner synthesis, via iminochlorides, from amides, from aldehydes and ketones, and via unsaturated systems [32]. 

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... 

Amidines can react with a wide range of carboxylic acid derivatives the reactions work on similar principles to the original Pinner synthesis. Typical examples are shown in equations (85)—(89) (B-61MI22000, p. 662, 72HCA1566, 72GEP2145174, 63CB3265, 68BCJ1368). 

This reaction is known as the Pinner synthesis. The salt formed may be converted to the free imino ester by treatment with a weak base. It may also be converted to the corresponding ester by an aqueous acid catalyzed hydrolysis. The Pinner reaction is of a general nature and is applicable to aliphatic, aromatic and heterocyclic alcohols. 

Fischer indole cyclization and transformation of a nitrile to an ester (Pinner synthesis) to yield diethyl 5-hydroxy-1 T/-pyrrolo[2,3-/]quinoline-2,7-dicarboxylate (183) was performed in one step by... 

Not only the Pinner synthesis provides alkoxymethyleneiminium salts the action of chloroformic acid esters on primary or secondary amides or thioamides ° as well as on lactams is a versatile method to get these salts and from them the imino esters, e.g. (230 equation 125). Primary and secondary amides have been alkylated by several reagents and the iminium salts thus formed were converted to imino esters with the aid of bases. A collection of imino esters prepared by this method can be found in a review the more recent results listed in Table 5 demonstrate the scope of this procedure. 

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. 

Pinner synthesis of orthoesters starting from alkoxymethyleneiminium salts (410 equation 192) (imino ester hydrohalides) is a standard procedure, which has been reviewed several times.For some more recent results see ref. 7. Closely related to this reaction is the alcoholysis of IV-alkyl- and NJ -di-alkyl-alkoxymethyleneiminium salts or acid amide-acid halide adducts. Orthoesters are formed via N//-dialkylalkoxymethyleneiminium salts when amide acetals (411 Scheme 74) are alcoholyzed in the presence of acetic acid. - ... 

This original Pinner method shown in Equation (1) is still widely used. Solvents such as ether, dioxane, dichloromethane, chloroform, benzene, and nitrobenzene are often used as diluents and as an aid to crystallization of the imidate salt. Methanol and ethanol are the most widely used alcohols in the Pinner reaction, but other alcohols have also been employed and have given satisfactory results. However, the use of substituted nitriles in the Pinner synthesis has some limitations, and some nitriles cannot be converted into corresponding imidates but form amides instead. Fortunately, it has been found that those nitriles which give poor yields under the acidic conditions of the Pinner synthesis give good yields under base-catalyzed conditions (Equation (2)) reported first by Nef, etc.146,147 The base-catalyzed and acid-catalyzed processes therefore complement each other. 

Amidines themselves also cyclize with carboxylic acid anhydrides or esters to give the corresponding 1,3,5-triazines 322 323 the reactions have a mechanism similar to the Pinner synthesis. 

The usual procedure36 is to add a slight excess of a secondary amine to an ethereal solution of ethylmagnesium bromide (50% excess relative to the nitrile) and, when evolution of ethane ceases, to heat the mixture under reflux for about 20 min before adding an ethereal solution of the nitrile the whole is then boiled under reflux for 2-3 h, then decomposed with ice. In many cases this method is superior to the Pinner synthesis of amidines from imidoyl esters. 

In a standard method, 1,3-diketones are cyclocondensed with amidines, ureas, thioureas and guanidines giving 4,6-di- and 2,4,6-trisubstituted pyrimidines 4, 2-pyrimidones 5, 2-thiopyrimidones 6 and 2-aminopyrimidines 7 respectively Pinner synthesis) [140] ... 

Following the well-known Pinner synthesis of imidates by the reaction of nitriles with alcohols, there has been considerable interest in recent years in treating a nitrile bond within the coordination sphere of metal ions with water or alcohols. It has been suggested that the initial step consists of nucleophilic attack of an external or coordinated hydroxide or alkoxide anion on the nitrile carbon atom. A number of imidate complexes have been isolated from the reactions of 2-cyanopyridine with metal [Cu", Ni , Co" and Fe"] salts in alcohols, of frans-PtMeClL with pentafluorobenzonitrile and silver hexafluorophosphate in alcohols," and of o-cyanobenzylplati-num complexes. "... 

Although this reaction was first reported by Beckurts and Otto in 1876, the extensive studies on this reaction appeared in Pinner s work in 1877. It is the transformation of nitriles into imidines or their salts by the treatment of nitriles with an excess of strong acid and one equivalent of alcohol followed by an excess of ammonia or amines. Therefore, it is generally known as the Pinner synthesis, " or Pinner reaction. " This reaction is generally carried out at with anhydrous ethanol and an excess amount of hydrochloric... 

This section is concluded with a different type of reaction that gives products similar to those observed above. In this study, acetonitrile was first reacted with HCl and then with Meldrum s acid (1.141) to give 1.142 in a Pinner synthesis. Hydrolysis was followed by decarboxylation (in situ) to give ethyl 3-aminobut-2-enoate, 1.143 This reaction used a nitrile as an amine surrogate (acetonitrile) and... 

Unsubstituted and A -monosubstituted alkoxymethyleneiminium salts are readily deprotonated by bases like tertiary amines, carbonates, alkoxides etc. to give the corresponding imidates (227 Scheme 32). By the same procedure cyclic imidates (lactim esters) (228) can be prepared. The iminium salts needed are readily available (see Section 2.7.2.S) often they were synthesized and transformed to the imidates without further purification. The Pinner synthesis, which pn uces the M-unsubstituted salts, is widely applicable and has been reviewed several times - " (for some mote recent examples see Section 2.7.2.3.7). To demonstrate the range of the reaction, a selection of nitriles, which have been transformed via Pinner synthesis to the corresponding imidates (229 equation 124) is compiled in Table 4. 

Table 4 Nitriles which are Suited for Pinner Synthesis...

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