Imine salt

The most generally useful method for acylation or formyl a ti on of pyrroles is the Vil smeier-Ha ack reaction (32,33). The pyrrole is treated with the phosphoryl complex of A/ A -dialkjlamide and the intermediate imine salt is hydroly2ed. 

The most useful general method for the C-acylation of pyrroles is the Vilsmeier-Haack procedure in which pyrrole is treated with the phosphoryl chloride complex (55a, b) of an AiA-dialkylamide (54). The intermediate imine salt (56) is hydrolyzed subsequently under mildly alkaline conditions to give the acylated pyrrole (57). On treatment of the imminium salt (56 R =H) with hydroxylamine hydrochloride and one equivalent of pyridine and heating in DMF, 2-cyanopyrrole (58) is formed (80CJC409). 

With imines, salts formation is accompanied by characteristic spectral changes (153) (a) a bathochromic shift in the ultraviolet region by as much as 50 m/i, according to compound type and to properties of any auxochrome present, and (b) a high frequency shift of the... 

Stretching vibration in the infrared region. The imine salts possess an active hydrogen, whereas their quaternization products exhibit the same spectral properties as the enamine salts (187). 

The reaction mechanism is complex and not completely settled. The first stage consists of an attack on the substrate by a species containing the nitrile and HCl (and the Lewis acid, if present) to give an imine salt (39). Among the possible attacking. species are 37 and 38. In the seeond stage, the salts are hydrolyzed to the products ... 

When enamines are treated with alkyl halides, an alkylation occurs that is analogous to the first step of 12-14. Hydrolysis of the imine salt gives a ketone. Since the enamine is normally formed from a ketone (16-12), the net result is alkylation of the ketone at the a position. The method, known as the Stork enamine reaction is an alternative to the ketone alkylation considered at 10-105. The Stork method has the advantage that it generally leads almost exclusively to monoalkylation of the ketone, while 10-105, when applied to ketones, is difficult to stop with the introduction of just one alkyl group. Alkylation usually takes place on the less substituted side of the original ketone. The most commonly used amines are the cyclic amines piperidine, morpholine, and pyrrolidine. 

The practical route for oxidizing leuco diphenylmethanes 15 demands inital conversion to an imine salt 16. The imine salt is obtained by heating a mixture of diphenylmethane, sulfur, ammonium chloride, and sodium chloride at 175°C in a current of ammonia or by heating a mixture of diphenylmethane, urea, sulfamic acid, sulfur, and ammonia at 175°C (Scheme 3). Dyes 16 can be represented as the quinonoid resonance structure 17. Dyes of this class, known as auramines, are all yellow, with the only commercial representative being auramine O 16a. Due to its poor lightfastness and instability to hot acids and bases, its use has been restricted to dyeing and printing cotton, paper, silk, leather, and jute. 

The imine salt can be converted into the free base by the method of Hantzsch and Kraft, which involves treating a solution of the salt in chloroform with dry ammonia. 

Nucleophilic addition of methyl- or phenylphosphite n -butyl- esters to oxo-imine salts, generated by nitrone alkylation of triethyloxoniumtetrafluoro borate (Meerwein salt), leads to a-aminophosphinic acid esters (Scheme 2.201) (691). 

When pyridinium A -imine salts 157 were reacted with methylphenyl-cyclopropenone (158, R = Ph, R = Me) in the presence of a base, dihydro-pyrido[l,2-h]pyridazin-3-ones (159) were formed, which subsequently underwent oxidation to produce 3//-pyrido[l,2-h]pyridazin-3-ones (160) under the reaction conditions [76JCS(CC)275 78JOC2892], In some cases the dihydro intermediates (159) could be isolated. 3-Substituted derivatives (157, R = 3-Me, 3-CN R = H) gave mixtures of isomers of 160 (R = 5-... 

C(R)=NR group with a nitrilium salt RCssNR .222 The acylation of the enamine can take place by the same mechanism as alkylation, but another mechanism is also possible, if the acyl halide has an a hydrogen and if a tertiary amine is present, as it often is (it is added to neutralize the HX given off). In this mechanism, the acyl halide is dehydrohalogenated by the tertiary amine, producing a ketene (7-14) which adds to the enamine to give a cyclobutanone (5-49). This compound can be cleaved in the solution to form the same acylated imine salt (27) that would form by the more direct mechanism, or it can be isolated (in the case of enamines derived from aldehydes), or it may cleave in other ways.223... 

One of the most spectacular and useful template reactions is the Curtis reaction , in which a new chelate ring is formed as the result of an aldol condensation between a methylene ketone or inline and an imine salt. The initial example of this reaction was the formation of a macrocyclic nickel(II) complex from tris(l,2-diaminoethane)nickel(II) perchlorate and acetone (equation 53).182 The reaction has been developed by Curtis and numerous other workers and has been reviewed.183 In mechanistic terms there is some circumstantial evidence to suggest that the nucleophile is an uncoordinated aoetonyl carbanion which adds to a coordinated imine to yield a coordinated amino ketone (equation 54). If such a mechanism operates then the template effect is largely, if not wholly, thermodynamic in nature, as described for imine formation. Such a view is supported by the fact that the free macrocycle salts can be produced by acid catalysis alone. However, this fact does not... 

Nitriles can be reduced to amines by lithium aluminum hydride. An imine salt is an intermediate product if the reaction is carried out under the proper conditions, this salt is the major product and provides an aldehyde on hydrolysis (see Section 16-4C) ... 

Similarly, all imines (imine salts) 3a-l were obtained quantitatively. The reaction of 2a provided a partially liquefied (deliquescent) 3a-HCl + H20 that lost the water and solidified upon evaporation. The reaction times with 2g and 21 were 2 and 3 days under these modest conditions. 

It may appear at first sight that tertiary amines cannot be made by reductive amination as an imine cannot be made. If a secondary amine such as piperidine 42 reacts with an aldehyde, the product is an enamine 44 not an imine. But reflect the enamine 44 is formed by deprotonation of the imine salt 45 and that is the species we need for reaction with NaB(CN)H3 or NaB(OAc)3H to give the tertiary amine 46. So there is no problem. 

We met enamines as specific enol equivalents in the last chapter and they are particularly good at conjugate addition. The pyrrolidine enamine from cyclohexanone 41 adds to acrylic esters 42 in conjugate fashion and the first-formed product 43 gives the enamine 44 by proton exchange.4 Acid hydrolysis via the imine salt 45 gives the 1,5-dicarbonyl compound 46. 

Scheme 14 Synthesis of Douthwaite s imidazolium-imine salts...

The mechanism involves the preliminary formation of an imine salt from the amine and formaldehyde. The amine is nucleophilic and attacks the more electrophilic of the two carbonyl compounds available. That is, of course, formaldehyde. No acid is needed for this addition step, but acid-catalysed dehydration of the addition product gives the imine salt. In the normal Mannich reaction, this is just an intermediate but it is quite stable and the corresponding iodide is sold as Eschenmoser s salt for use in Mannich reactions. 

This enol reacts with the imine salt we have previously made and it will be easier to see this reaction if we redraw the enol in a different conformation. The imine salt does not... 

This complex route to tropinone was imitated as long ago as 1917 in one of the most celebrated reactions of all time, Robinson s tropinone synthesis. Robinson argued on purely chemical grounds that the sequence of imine salts and enols, which later (1970) turned out to be Nature s route, could be produced under natural conditions (aqueous solution at pH 7) from a C4 dialdehyde, MeNH2 and acetone dicarboxylic acid. It worked and the intermediates must be very similar to those in the biosynthesis. 

Pyridoxal-media ted decarboxylation of dopa gives dopamine and this reacts with the keto-acid to form an imine salt. This is an open-chain inline salt unlike the cyclic ones we saw in the pyrrolidine alkaloids, but it will prove to have similar reactivity. 

The imine salt is perfectly placed for an intramolecular electrophilic aromatic substitution by the electron-rich dihydroxyphenyl ring. This closes the isoquinoline ring in a Mannich-like process (Chapter 27) with the phenol replacing the enol in the pyrrolidine alkaloid biosynthesis. 

You saw a carbonyl addition reaction forming a polymer right at the beginning of the chapter—the polymerization of formaldehyde. If an amine is added to formaldehyde, condensation to form imines and imine salts occurs readily. These intermediates are themselves electrophilic so we have the basis for ionic polymerization—electrophilic and nucleophilic molecules present in the same mixture. Reaction with a second molecule of amine gives an aminal, the nitrogen equivalent of an acetal. 

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