Kojic acid, reactions

Gomes, A.J. Lunardi, C.N. Gonzales, S. Tedesco, A.C. (2001) The antioxidant action of Polypodium leucotomos extract and kojic acid reactions with reactive oxygen species. Braz. /, Med. Biol Res. Vol.34, pp.1487-1494. 

Kojic acid — see also Pyran-4-one, 5-hydroxy-2-hydroxymethyl-, 3, 611 acylation, 3, 697 application, 3, 880 occurrence, 3, 692 reactions, 3, 714, 715 with amines, 3, 700 with phenylhydrazine, 3, 700 synthesis, 3, 810 Kokusagine occurrence, 4, 989 Kokusaginine occurrence, 4, 989 synthesis, 4, 990 Koopmans theorem, 2, 135 Kostanecki-Robinson reaction chromone and coumarin formation in, 3, 819-821 mechanism, 3, 820 flavones, 3, 819... 

The chemical reactions and derivatives of kojic acid will be grouped according to these centers of its reactivity. 

Kojic acid was brominated at position 6 with bromine water4 the 2-(chloromethyl) derivative of kojic acid was brominated with N-bromo-succinimide,87 and chlorinated with sulfuryl chloride and aluminum chloride,88 in both cases probably at C6. The C-benzoylation89 and C-acetylation90 of kojic acid, likewise at C6, was accomplished by Woods using a modification of the Friedel-Crafts reaction. The 2-carboxyethyl side chain was introduced at C6 in a reaction with 2-bromopropionic acid.91... 

Another series of nuclear substitution reactions of kojic acid might be represented as the addition of kojic acid to reactive multiple bonds, follow-... 

A more general reaction between kojic acid and aldehydes is a trimolecu-lar condensation discovered by Barham and Reed." By a process of elimination, they arrived at the conclusion that C6 of kojic acid was most probably the point of attack two molecules of kojic acid reacted with one molecule of the aldehyde, with the elimination of one molecule of water, giving a product of structure LXXV. Such compounds were prepared from kojic acid and the following aldehydes the normal alkanals from formaldehyde to heptanal, benzaldehyde, cinnamaldehyde, hydrocinnamaldehyde, 2-furaldehyde, and acrolein. The compound derived from kojic acid and benzaldehyde (LXXV, R = phenyl) was also obtained by treating LXXII (R = phenyl) with hot, aqueous sodium carbonate.92... 

In most of these nuclear substitution reactions, kojic acid did indeed react as a phenol. An exception was the reaction with acrylonitrile, as noted by Woods.97 Phenols usually form cyanoethy ethers under similar conditions, but the reaction of acrylonitrile with ketones leads to substitution of the a-hydrogen atom.100 This consideration points to a predominance of the diketo form of the kojate anion (LXIV) in these reactions. There are many good reasons for believing that, in the formation of all these derivatives, substitution actually takes place at C6 it should, however, be pointed out that this assumption still lacks confirmation by synthesis or by appropriate degradation studies. The nuclear mono-substitution products of kojic acid are listed in Table IV, and their functional derivatives in Tables V and VI. 

A three-component reaction of lactone 178 with cyanoacetic derivatives in ethanol or ionic liquid (bmimlPFg proceeds smoothly with formation of 2-aminopyrans 221 in high yields (04RCB724, 08JCO741, 08RCB2373), while kojic acid 181 acts in the same manner (04RCB724) (Scheme 83). 

Quinolone (122), 2-pyridone (123), kojic acid (124) and 4-hydroxycoumarin (125) couple with diazonium salts (to form azo compounds, e.g. 126) and undergo Mannich reactions (e.g. with HCHO + HNMe2 to form -CH2NMe2 derivatives) at the positions indicated. Chromones undergo the Mannich reaction to give, for example, (127). 

Reaction of pyran-4-ones with hydroxylamine or hydrazine causes ring opening followed usually by cyclization to a different ring substituents on the pyran-4-one often play a part in determining the course of the cyclization (Scheme 22) (79AP591, 62CJC2146). Kojic acid (427) is converted into pyrazoles by an excess of phenylhydrazine (74MI22302). 

Some reactions of the hydroxymethyl group of kojic acid are discussed in Section 2.23.9.5. 

Kojic acid has two hydroxyl groups and their reactions have been well studied as befits an important natural product. Until recently it was difficult to obtain the individual monoacyl... 

Stacey and Turton61 objected to Isbell s mechanism on two counts first, that he did not specify that a proton acceptor must be used to promote the reaction and second, that the orthoacetate intermediate would not be applicable in the conversion which they demonstrated (by absorption spectra data) to take place on treatment with dilute, aqueous sodium hydroxide. (The presence of the proton acceptor seems implicit in Isbell s general description of the process of enolization.) The mechanism of Stacey and Turton is shown in Formulas XXIV to XXVIII it calls for the donation of electrons by pyridine to the incipient, ionic proton at C2 and elimination of acetic acid between C2 and C3 with the formation of the partially acetylated enediol-pyridinium complex. The pyridinium ion is removed by acetic acid. Electronic readjustment results in the elimination of acetic acid from positions 4 and 5. The final step, conversion of XXVII to XXVIII, was not explained. Stacey and Turton considered that with sodium hydroxide the reaction proceeds after deacetylation by a similar mechanism except that hydroxyl groups take the place of acetyl groups. Neither mechanism requires a free hydroxyl group at Cl, a condition considered by Maurer to be essential to kojic acid formation. 

In the total synthesis of ( )-WS75644B 360, a biaryl endothelin converting enzyme inhibitor, pyrone 357 derived from kojic acid was converted to pyridone 358 by reaction with concentrated ammonium hydroxide in a sealed flask at 90 °C. The resulting pyridine was subsequently converted to 2,4,5-trisubstituted pyridine 359 and ultimately elaborated to complete the total synthesis (Scheme 54) <1997TL1297>. 

Ketosis, relation to carbohydrate oxidation, II, 145-159 theory of, II, 146 a-Ketovaleric acids, V, 50 Konigs-Knorr reaction, I, 79, 114 a-glycoside formation in, I, 84 Kojic acid, III, 373 from sucrose, IV, 322, 324... 

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