Schiff formation

Schiff s reagent. Add about 1 ml. of SchifTs reagent to about 1 ml. of acetone and note the very slow formation of a magenta colour. Neither acetophenone nor benzophenone reacts in this way. 

This is an example of the Doebner synthesis of quinoline-4-carboxylic acids (cinchoninic acids) the reaction consists in the condensation of an aromatic amine with pyruvic acid and an aldehj de. The mechanism is probably similar to that given for the Doebner-Miller sj nthesis of quinaldiiie (Section V,2), involving the intermediate formation of a dihydroquinoline derivative, which is subsequently dehydrogenated by the Schiff s base derived from the aromatic amine and aldehyde. 

N substituted imines are sometimes called Schiff s bases after Hugo Schiff a German chemist who de scribed their formation in 1864... 

Formation of Schiff-Bases. Reaction of an amino acid and an aldehyde oi ketone gives a Schiff-base in neutral or alkaline solution, and following reduction gives the corresponding Ai-alkylamino acid. 

Pomeranz-Fntsch Synthesis, Isoquinolines aie available fiom the cycUzation of benzalamiaoacetals undei acidic conditions (165). The cyclization is preceded by the formation of the Schiff base (33). Although the yields ate modest, polyphosphoric acid produces product in all cases, and is especially useful for 8-substituted isoquinolines (166). 

A cost-efficient synthesis of foHc acid via Schiff base formation is feasible only if 6-formylpterin (23) is readily available. This compound is prepared by the reaction of 2-bromomalondialdehyde dimethylacetal [59453-00-8] (25) with trianainopyrimidinone (10), followed by acetylation and cleavage of the acetal to give compound (23) in 51% overall yield (38). 

Pyridoxal Derivatives. Various aldehydes of pyridoxal (Table 3) react with hemoglobin at sites that can be somewhat controlled by the state of oxygenation (36,59). It is thereby possible to achieve derivatives having a wide range of functional properties. The reaction, shown for PLP in Figure 3, involves first the formation of a Schiff s base between the amino groups of hemoglobin and the aldehyde(s) of the pyridoxal compound, followed by reduction of the Schiff s base with sodium borohydride, to yield a covalendy-linked pyridoxyl derivative in the form of a secondary amine. 

There are two distinct groups of aldolases. Type I aldolases, found in higher plants and animals, require no metal cofactor and catalyze aldol addition via Schiff base formation between the lysiae S-amino group of the enzyme and a carbonyl group of the substrate. Class II aldolases are found primarily ia microorganisms and utilize a divalent ziac to activate the electrophilic component of the reaction. The most studied aldolases are fmctose-1,6-diphosphate (FDP) enzymes from rabbit muscle, rabbit muscle adolase (RAMA), and a Zn " -containing aldolase from E. coli. In vivo these enzymes catalyze the reversible reaction of D-glyceraldehyde-3-phosphate [591-57-1] (G-3-P) and dihydroxyacetone phosphate [57-04-5] (DHAP). 

Most ring syntheses of this type are of modern origin. The cobalt or rhodium carbonyl catalyzed hydrocarboxylation of unsaturated alcohols, amines or amides provides access to tetrahydrofuranones, pyrrolidones or succinimides, although appreciable amounts of the corresponding six-membered heterocycle may also be formed (Scheme 55a) (73JOM(47)28l). Hydrocarboxylation of 4-pentyn-2-ol with nickel carbonyl yields 3-methylenetetrahy-drofuranone (Scheme 55b). Carbonylation of Schiff bases yields 2-arylphthalimidines (Scheme 55c). The hydroformylation of o-nitrostyrene, subsequent reduction of the nitro group and cyclization leads to the formation of skatole (Scheme 55d) (81CC82). 

It was reported only recently that A-methyl transfer from an oxaziridine to an amine occurs with formation of an N—N bond (79JA6671). N—N bond forming reactions with A-unsubstituted oxaziridines had been found immediately after discovery of this class of compound (64CB2521) and have led to simple hydrazine syntheses (79AHC(24)63). Secondary amines like diethylamine or morpholine are A-aminated by (52) in the course of some minutes at room temperature with yields exceeding 90% (77JPR195). Further examples are the amination of aniline to phenylhydrazine, and of the Schiff base (96) to the diaziridine (97). 

Oxaziridines are generally formed by the action of a peracid on a combination of a carbonyl compound and an amine, either as a Schiff base (243) or a simple mixture. Yields are between 65 and 90%. Although oxygenation of Schiff bases is formally analogous to epoxidation of alkenes, the true mechanism is still under discussion. More favored than an epoxidation-type mechanism is formation of a condensation product (244), from which an acyloxy group is displaced with formation of an O—N bond. 

Formation of mixtures of (E)- and (Z)-oxaziridines from sterically defined Schiff bases fits a two step mechanism through (244) (70CC745). 

This type of amination by an oxaziridine is assumed to be the key step of a novel process for hydrazine manufacture, in the course of which butanone in solution with ammonia is reacted with hydrogen peroxide and acetonitrile. The smooth formation of oxaziridines from Schiff bases and hydrogen peroxide-nitrile mixtures is as well known as NH transfer from an oxaziridine like (300), suggesting the intermediacy of (300) as the N—N forming agent (72TL633). 

As will be pointed out in Section 5.11.3.8.4, epimerization at C(6) under basic conditions involves the formation of a carbanion at C(6). Using Schiff bases to activate the C(6) proton. 

The Schiff base intermediate (57) permits the oxidative formation of an imino intermediate which can then be converted to the 6a-methoxy derivative (Scheme 45) (76MI51100). 

The 6/3-amino group of 6-APA may be alkylated either with diazoalkanes <67LA(702)163) or by the reduction of Schiff bases (Scheme 50) (65JCS3616). Two special cases of N-alkylation are also shown in Scheme 50 the formation of an imidazolidinone ring upon treating ampicillin with acetone (66JOC897), and the formation of a 6/3-amidinopenicillanic acid from 6-APA (77MI51105). 

Macrocycles have been prepared by formation of macrocyclic imines as well as by using variations of the Williamson ether synthesis ". Typically, a diamine or dialdehyde is treated with its counterpart to yield the Schiff s base. The saturated macrocycle may then be obtained by simple reduction, using sodium borohydride, for example. The cyclization may be metal-ion templated. In the special case of the all-nitrogen macrd-cycle, 15, the condensation of diamine with glyoxal shown in Eq. (4.14), was unsuccess-ful ... 

Quite a number of mixed sulfur-nitrogen macrocycles have been prepared, but these have largely been by the methods outlined in Chaps. 4 and 5 for the respective heteroatoms. An alternative method, involves the formation of a Schiff base, followed by reduction to the fully saturated system, if desired. An interesting example of the Schiff base formation is found in the reaction formulated in (6.12). Dialdehyde 14 is added to ethylenediamine in a solution containing ferrous ions. Although fully characterized, the yield for the reaction is not recorded. To avoid confusion with the original literature, we note the claim that the dialdehyde [14] was readily prepared in good yield by reaction of the disodium salt of 3-thiapentane-l, 5-diol . The latter must be the dithiol rather than the diol. 

Aromatic nitro compounds are often strongly colored. They frequently produce characteristic, colored, quinoid derivatives on reaction with alkali or compounds with reactive methylene groups. Reduction to primary aryl amines followed by diazotization and coupling with phenols yields azo dyestuffs. Aryl amines can also react with aldehydes with formation of Schiff s bases to yield azomethines. 

Sugars react with the reagent probably with the formation of Schiff s bases ... 

While enamines can usually be obtained directly from ketones and secondary amines their formation by an indirect route may bo advantageous. The previously mentioned condensation of rnethyl ketones during azeotropic enamine formation has prompted the alklyation (J) or acylation and reduction (59) of Schiff s bases. A parallel method uses the formation and desulfurization of N-acylthiazolines followed by hydride reduetion (60,61). 

Two classes of aldolase enzymes are found in nature. Animal tissues produce a Class I aldolase, characterized by the formation of a covalent Schiff base intermediate between an active-site lysine and the carbonyl group of the substrate. Class I aldolases do not require a divalent metal ion (and thus are not inhibited by EDTA) but are inhibited by sodium borohydride, NaBH4, in the presence of substrate (see A Deeper Look, page 622). Class II aldolases are produced mainly in bacteria and fungi and are not inhibited by borohydride, but do contain an active-site metal (normally zinc, Zn ) and are inhibited by EDTA. Cyanobacteria and some other simple organisms possess both classes of aldolase. 

The transaldolase functions primarily to make a useful glycolytic substrate from the sedoheptulose-7-phosphate produced by the first transketolase reaction. This reaction (Figure 23.35) is quite similar to the aldolase reaction of glycolysis, involving formation of a Schiff base intermediate between the sedohep-tulose-7-phosphate and an active-site lysine residue (Figure 23.36). Elimination of the erythrose-4-phosphate product leaves an enamine of dihydroxyacetone, which remains stable at the active site (without imine hydrolysis) until the other substrate comes into position. Attack of the enamine carbanion at the carbonyl carbon of glyceraldehyde-3-phosphate is followed by hydrolysis of the Schiff base (imine) to yield the product fructose-6-phosphate. 

Cook and Heilbron report the formation of highly crystalline Schiff bases via the reaction of 5-aminothiazoles and acetone, aldehydes such as cinnamaldehyde, or ketones such as... 

The mechanism is postulated to involve the initial formation of a Schiff base 17 from the condensation of the anilinic amine 16 with the carbonyl-containing substrate. This is followed by a Claisen condensation between the benzylic carbonyl and the activated a-methylene of the imine. ... 

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