2-Aminobenzaldehydes from quinolinium salts and alkaline hydrogen peroxide

2-Formylanilines are very handy. For building various heterocyclic rings. But making them is not so very dandy. Low yields and multi-step ‘mongst other things. N-Alkylquinoliniums cleave with great ease. With hydrogen peroxide / aqueous base. (The mechanism’s clear to such as Charles Rees). To give these anilines – good yields, good pace.


Introduction
2-Aminobenzaldehyde and its derivatives are key intermediates in heterocyclic synthesis.Thus the Friedländer synthesis of quinolines 1 (base-catalysed condensation of 2aminobenzaldehyde with aliphatic aldehydes and ketones) is a widely used method.Both 2-and 4-quinolones 2 as well as acridines and acridones 3 are easily made from these versatile precursors as are indoles, 4 while dimerisation of N-methyl-2-aminobenzaldehyde yields oxa-analogues of Tröger's base. 5Various other macrocyclic applications have been described. 6Numerous quinazolines have been made efficiently 7 while Michael additions of 2-aminobenzaldehydes to alkenes and alkynes present a versatile route to quinolines and fused quinolines. 8ost syntheses of 2-aminobenzaldehydes involve more than one step and at best are moderate in yield.For example, the synthesis of 2-aminobenzaldehyde itself has been reported from easily derived precursors such as 2-nitroaniline (by way of the Beech reaction, employing formaldoxime coupling with the derived diazonium salt in 33% yield 9 ) or from 2-nitrotoluene (oxidation with CrO 3 /Ac 2 O followed by hydrolysis of the derived aldehyde diacetate in 24% yield 10 ) (Scheme 1).

Scheme 1
Other approaches are from condensation of 2-nitrobenzaldehyde to give 2-nitrocinnamic acid followed by oxidation, 11 or from several other multi-step reactions from aniline (40-50%).It is clear that there is a need for a simple and potentially large scale route to these versatile intermediates.In this paper we explore just such a route to N-alkyl-2-aminobenzaldehydes, utilising easily made quinolinium salts and their reaction with alkaline hydrogen peroxide(Scheme 2).

Discussion
The initial 'standard' process.When N-methylquinolinium salts (1) are treated with cold aqueous sodium hydroxide and hydrogen peroxide, a fast and mildly exothermic reaction takes place, to give on work-up 2-methylaminobenzaldehyde (2a) together with its N-formyl derivative (2b).By varying ratios of reagents, the optimal stoichiometry for this process was found to be 2 moles each of the base and of hydrogen peroxide (33-35% aqueous) per mole of quinolinium salt.Furthermore, the most effective method under these conditions was the dropwise addition of the base over 5 minutes to the other components in water maintained at about room temperature with stirring, when after 2 hours reaction, no salt 1 remained.On work-up the two products 2a and 2b were isolated in 30 and 39% respectively.Longer reaction times allowed the sole formation of 2-methylaminobenzaldehyde 2a, presumably by hydrolysis of any 2b.Complete reaction of the salt is easily monitored by addition of ammonium hexafluorophosphate to an aliquot, the quinolinium hexafluorophosphate precipitating.
Variation of the base.Similar results were observed if triethylamine was employed instead of sodium hydroxide, though more reagent was required (4:3:1 moles of base:peroxide:salt), probably due to triethylamine N-oxide formation.Sodium carbonate proved less effective while very useful results derived from the use of sodium phosphate (Na 3 PO 4 ) as the base when a combined yield of over 70% of the two products could be isolated.
Variation of the peroxidic agent.A variety of peroxidic reagents were also examined but none were as effective as aqueous hydrogen peroxide.Thus while sodium perborate reacted slowly to give solely 2a in 30% yield, using Na 3 PO 4 as base after 16 hours reaction, t-butyl hydroperoxide, performic acid, trifluoroperacetic acid and potassium monopersulfate were totally ineffective.
Variation of the solvent.Solvents other than water (including methanol, aqueous methanol, DMSO, aqueous DMSO, acetonitrile, dioxane, and DMF) were of no benefit whatever, the more water present the better the reaction yields.However, use of a 2-phase system did prove of interest.For example, use of DCM/aqueous sodium phosphate at 0-5 0 C for 16 hours, gave up to 80% combined yield of products 2a and 2b.Tetrachloromethane/water also proved particularly useful in that solely 2-methylaminobenzaldehyde 2a was formed in 78%.The optimal 2-phase reaction conditions, allowing solely the formation of 2-methylaminobenzaldehyde 2a in 84 % yield on a 20g scale (and of at least 62% on an 80g scale) were use of 1,2-dichloroethane/water with dropwise addition of the salt in water to the other well stirred reactants, initially at 0-5 0 C and then finally at ambient for 18-72h.In some cases a co-solvent aided dissolution of the salt (see below and Experimental).
Variation of the N-substituent of the quinoline.The reaction is effective with other Nsubstituted quinolines including ethyl (29 and 37% yield of the amino-benzaldehyde 2a and its formyl derivative 2b respectively under the 'standard' conditions) and allyl (73% of the 2allylaminobenzaldehyde with only a trace of its formyl derivative; even on a 20g scale this yield was maintained, again, under the 'standard' conditions).Several 1-substituents were readily cleaved under the reaction conditions including -methoxymethyl and -4-toluenesulfonyl.
Effect of C-substituents in the quinoline.(a) 2-Methylquinolinium salts.Initial studies with sodium hydroxide and aqueous hydrogen peroxide indicated that red dye formation (presumably a cyanine-type dye from deprotonation of the 2-methyl group followed by coupling of this derived enamine with unreacted salt) was a significant pathway.Lowering the reaction temperature helped slightly.TLC suggested that both 2-methylaminobenzaldehyde and its Nacetyl derivative were also formed but chromatographic work-up gave solely the former product in 30% yield.Even using weaker bases such as triethylamine, dye formation still occurred.
However, using sodium phosphate and aqueous hydrogen peroxide in a 3:3 ratio per mole of the salt, satisfactory yields of mostly the aminobenzaldehyde 2a (73%) with a little of its acetyl derivative were achieved after 16 hours reaction at 0-5 0 C. Similarly, using the 2-phase system with tetrachloromethane and water, the yield was increased to 80%, this being achievable on any scale from 2-20g of the salt and, if allowed to stir for 72 hours, produced solely 2methylaminobenzaldehyde 2a.(b) 4-Methylquinolinium salts.In a similar way to that observed with 2-methylquinolinium salts, the standard reaction conditions using sodium hydroxide as base caused red dye formation from the 4-methylquinolinium salt, together with up to 30% yield of 2methylaminoacetophenone and by-products.No further work was done to optimise this reaction.
(c) 6-Substituted 1-methylquinolinium salts.Only limited studies of 6-substituents was undertaken.A small amount of ethanol was necessary as a co-solvent in this series owing to the lower aqueous solubility of the salts.Thus while 6-methoxy-and 6-methyl-quinolinium salts rapidly gave reasonable yields of the corresponding 2-methylaminobenzaldehyde under the standard conditions (39 and 54% respectively, together with the corresponding N-formyl derivative in 20 and 8 % yield respectively) the yield of 5-methoxy-2-methylaminobenzaldehyde increased to 79% under the optimised 2-phase conditions.However, the 6-nitroquinolinium salt gave no ring opened products but solely the corresponding 2-quinolone in 33% yield.Mechanism of the ring opening.The most reasonable explanation for this interesting ringopening reaction is depicted in Scheme 3. It is well known that quinolinium salts form carbinolamines ('pseudo bases') with base, which are in tautomeric equilibrium with 2aminocinnamaldehydes.This latter electrophilic alkene can then epoxidise with the peroxide and the epoxide is oxidatively degraded to give the products 2 in accord with known literature precedent. 12Some new reactions of 2-methylaminobenzaldehyde. (a) 1,2-Dimethylquinolinium salt formation.-Theaction of acetone on 2-methylaminobenzaldehyde and base gives a yellow solution, presumably the dehydrated aldol adduct, which on heating at 70-80 0 C yields a 1,2dimethylquinolinium salt (precipitated as its hexafluorophosphate) in 70% yield.(c) Darzens reactions.The interaction of 2-methylaminobenzaldehyde with ethyl chloroacetate and sodium hydride in THF solution gratifyingly gave the known 13 4-hydroxy-1-methyl-2quinolone in 65% yield.

Table 1 .
Reactions of quinolinium salts with base and peroxide