Chromone Mannich reaction

A The Mannich reaction proceeds through the intervention of the N,A dimethylmethyleniininium cation [Me N =CHJ, This is insufficiently electrophilic to react with the benzene ring under the mild reaction conditions. Similarly, were the electrophile to react with the carbonyl oxygen atom of the heterocycle, this reaction would be reversible, as an aminomethyl ether is relatively unstable in acidic media. Thus, it seems plausible that the chromone utilizes enol or enolate character to trap the electrophile at C-3, followed by deprotonation of the adduct to reform the chromone ring system ( heme 5.9). 

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). 

This is a Mannich reaction (see Chapter 2) and is an unusual example of an electrophilic substitution on a chromone. 

Deactivation of C-3 by the carboxyl group at C-2 prevents attack by electrophiles, for example, the Mannich reaction results in substitution at C-3 in many chromones [16] but not with chromone-2-carboxylic acid or ester. Radical (homolytic) chlorination of the ester or nitrile using sulphuryl chloride and a trace of benzoyl peroxide gives the 3-chloro derivative (84) [57, 149, 167]. 

Irgashev RA, Sosnovskikh VY, Sokovnina AA, Roschenthaler G-V (2010) The first synthesis of 3-hydroxy-2-(polyfluoroalkyl)chromones and their ammonium salts. 3-hydroxychromone in the Mannich reaction. J Heterocycl Chem 47 944-948... 

Polyhaloalkyl-substituted chromones and 7-pyrones react with salicylaldehydes in the presence of piperidine to give a variety of fused 277-chromenes in good yields (Scheme 58) <2006JOC4538>. Although it is conceivable that this reaction could proceed through a Baylis-Hillman reaction pathway, studies of this reaction point to the mechanism being a tandem intramolecular oxa-Michael addition and subsequent Mannich condensation. 

Chromones and flavones show analogies in their reactions to 4i/-pyran-4-one, i.e. they behave as masked 1,3-dicarbonyl systems. Protonation and alkylation occur on oxygen. Electrophilic attack takes place at the deactivated pyran-4-one ring in the 3-position, e.g. aminomethylation can be brought about under Mannich conditions. 

There is no record of a successful Friedel-Crafts acylation of a chromone-2-carboxylic acid the 6-acetyl acid was prepared from 2,4-diacetyl phenol and the acetyl group undergoes the usual Mannich and Claisen reactions [32]. 

We also found that 2-R -chromones 130 react with salicylaldehydes in the presence of piperidine to afford 207 via oxa-Michael addition followed by intramolecular Mannich condensation [27], Treatment of 130 with pyridoxal hydrochloride in the presence of NaOH (2.6 equiv.) gave oxepines 208 in moderate yields. In this case, the reaction proceeded at the alcoholic hydroxyl. Interestingly, using 1.3 equiv. of NaOH, it was possible to obtain 209 [103] (Scheme 67). 

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