o -Acylbenzaldehydes in organic synthesis: a brief review

The progress that has been made in organic synthesis via the reactions of o -acylbenzaldehydes is presented in this review, along with the methods for their synthesis and some of their applications.


Introduction
o-Acylbenzaldehydes are very interesting molecules because of their potential to serve as starting materials in organic synthesis.The presence of the two ortho to each other carbonyl groups at the benzene ring allows the formation of novel heterocycles as well as other nonheterocyclic aromatic compounds.Furthermore, aromatic aldehydes have found significant applications in the fragrance, flavour and pharmaceutical industries. 1 However, o-disubstituted benzene derivatives are frequently difficult to prepare and cannot be synthezised by conventional methods.][4][5][6][7][8][9][10][11][12][13][14][15][16] The most of them are not general and often involve many steps with low yields.This is probably the reason for the limited number of references in the literature regarding their reactivity.Despite these difficulties a variety of products as isoindoles, phthalimidines, isoindoloquinazolines, indanes, naphthols, olefins have been prepared starting from o-acylbenzaldehydes.The products are usually obtained in good yields by using simple experimental conditions.Several years ago, we prepared o-diacylbenzaldehydes in high yields, via a general method which includes the reaction of either N-formylhydrazones of ohydroxyaryl ketones or N-acylhydrazones of salicylic aldehyde with lead tetraacetate (LTA). 15he purpose of this review is to present all the synthetic approaches for the preparation of odiacylbenzaldehydes as well as the progress that has been made in organic synthesis using them as starting materials.The presentation will begin with the methods of synthesis of oacylbenzaldehydes.The papers dealing with the reactivity of o-acylbenzaldehydes will follow.Finally, some of the applications of o-acylbenzaldehydes and their derivatives will be presented.
It is hoped that this review will demonstrate the synthetic potential of o-acylbenzaldehydes and generate some new ideas in this area.

Synthesis of o-acylbenzaldehydes
o-Disubstituted benzene derivatives are frequently difficult to prepare and cannot be synthezised by conventional methods.In the literature, there exist several methods dealing with the synthesis of o-acylbenzaldehydes.However, in most cases they are not general and they usually lead to the synthesis of either o-benzoylbenzaldehyde 3a (Schemes 1 and 8) or o-acetylbenzaldehyde 3b (Schemes 3-6 and 8).
4][5][6] However, yields are not available.Alternatively, oxidation of 2a with ceric ammonium nitrate led to the formation of 3a in 96% yield. 7Dialcohols 2 were usually obtained from the reaction of o-acylbenzoic acids 1 with lithium aluminum hydride.Furthermore, o-acylbenzaldehydes 3 were synthesized by the oxidation of lactols 6 using selenium oxide as oxidative agent (Scheme 2).Lactols 6 were produced in a rather complicated way and yields for most of the products are not available.
There exist also in the literature [8][9][10][11][12] a few methods of synthesis especially for oacetylbenzaldehyde 3b.One of them involves six steps and it is presented in Scheme 3.

Scheme 3
Treatment of pthalic anhydride 7 with malonic acid 8 yielded o-acetylbenzoic acid 1b in 28% yield.Subsequently, reaction of 1b with methyl iodide led to the formation of o-acetylbenzoic methylester 9 in 94% yield.Treatment of 9 with trimethylorthoformate and ethylene glycol in the presence of p-toluenesulfonic acid gave the ketal 10 in 74% yield, which was further added to a slurry of lithium aluminum hydride to form o-acetyl benzyl alcohol ethylene ketal 11 in 86% yield.Addition of 11 to a mixture of pyridinium chlorochromate absorbed on alumina, in methylene chloride and hexane led to the formation of o-acetyl-benzaldehyde ethylene ketal 12 as a faint yellow liquid in 87% yield.Finally, stirring of 12 in a mixture of acetic acid/water gave o-acetylbenzaldehyde 3b in 83% yield.

Scheme 5
In 1976, it was reported that the photo-oxidation of o-methylacetophenone 15 led to the formation of o-acetylbenzaldehyde 3b (Scheme 6). 12An analogous report appeared later in the literature about o-benzoylbenzophenones. 13 It has been suggested that the reaction proceeds via the intermediate enole 16 and the cyclic peroxide 17.The photo-oxidation of the ketone 15 in methanol was performed under three sets of conditions: (a) with no additive in yield up to 5%, (b) in the presence of copper(II) sulphate in yield up to 38% , and (c) in the presence of hydrochloric acid in yield up to 9%.There is also a reference 14

Scheme 7
In 1998, we reported a general, simple and efficient method for the synthesis of o- acylbenzaldehydes (Scheme 8). 15Formylhydrazones of arylketones bearing a hydroxy group at ortho-position 22 on treatment with lead tetraacetate underwent a rearrangement resulting in an unusual replacement of the phenolic hydroxyl with a formyl group to give o-acylbenzaldehydes 3, in excellent yields 70-86%.Alternatively, o-acylbenzaldehydes 3 were obtained by acyl group rearrangement of salicylaldehyde N-acylhydrazones 24.

22
C or OH The first route involves initial conversion of o-hydroxy ketones 21 to their Nformylhydrazones 22a,b,k, which upon LTA oxidation, loss of nitrogen and migration of the formyl group, give the corresponding o-acetylbenzaldehydes 3 in 70-86% yields.The alternative path starts with salicylaldehyde 23 which was condensed with N-acylhydrazines to give acylhydrazones 24a,k,l, and subsequent LTA treatment results in acyl group migration to give the corresponding o-acetylbenzaldehydes 3 in 77-82% yields.o-Acetylbenzaldehyde 3b has been also obtained in 71% yield when salicylic aldehyde acetylhydrazone 24b was oxidized with [(diacetoxy)iodo]benzene instead of lead tetraacetate. 16

Reactivity of o-acylbenzaldehydes
The main interest of the researchers on the reactivity of o-acylbenzaldehydes has been focused on their reactions with nitrogen compounds such as amines, hydrazides and amino acids.3][4][5] When the condesation of obenzoylbenzaldehyde with ethylenediamine was performed under anhydrous conditions the imidazoisoindole derivative 26 was formed in 43% yield. 1,17Furthermore, condensation of 3a with 1,3-propanediamine afforded the analogous pyrimidoisoindole derivative 27 in 73% yield (Scheme 9).

Scheme 9
Furtermore, the reaction of o-benzoylbenzaldehyde with primary diamine 28 in CD 3 OD led to the intensely fluorescing deuterated isoindoloquinazolines 29 and 30 in 27 and 23% yield respectively (Scheme 10).Treatment of o-acylbenzaldehydes with primary amines in the presence of thiol 7 has been reported to afford 1,2,3-trisubstituted isoindoles 31 as shown in Scheme 11.
Reaction of 3a with aniline led to the formation of phthalimidine 33 in 65% yield (Scheme 12). 19The same product 33 was obtained via treatment of o-benzoylbenzaldehyde 3a with aromatic isocyanates in 54-84% yield (Scheme 12). 19It was suggested that 2,3-disustituted phthalimidines 33 could be formed via o-benzylbenzylideneaniline intermediate 32 followed by migration of phenyl group.

Scheme 13
Treatment of o-benzoylbenzaldehyde 3a with β-alanin and malononitrile and subsequent reduction with sodium borohydride gave o-benzoylbenzylmalononitrile 37 in 77% yield.Reaction of 37 with guanidine afforded the pyrimidinetriamine 38 which was cyclised to pyrimidobenzazepin 39 upon heating in acetic acid in the presence of trifluoroacetic acid (Scheme 14). 21Furthermore, treatment of 37 with methanol or ethanol in the presence of the corresponding alkoxide afforded benzazepines 40.However yields are not available.Photooxidation of o-acetylbenzaldehyde 3b, in methanol with no additive, led to the formation of the lactone 42.In the presence of copper catalyst, the photoreaction of aldehyde 3b led to the formation of the acetal 44 whereas, in the presence of hydrochloric acid the peroxide 45 was obtained as the main product (Scheme 15). 12Further studies on the photochemical reaction of o-benzoylbenzophenone suggested that the main intermediate is a ketene derivative analogous to 43. 22,23  Furthermore, the main product of the reaction of o-acetylbenzaldehyde 3b with (CF 3 ) 2 CCl 2 and triphenylphosphine was the olefin 48 whereas, benzofuran 49 which was isolated in 7% yield was easily converted to 50 at room temperature (Scheme 17) The mechanism of the olefination reaction was studied and it was shown that it takes place not by Wittig-but by a Knoevenagel-type of reaction. 25Applications o-Acylbenzaldehydes have been of interest as fluorescence reagents for high sensitive detection and quantitative measurements of biological compounds bearing primary amino group, as amino acids and peptides. 6,7,27They have been also used for a high specific TLC-fluorescent detection of oxazepam and lorazepam. 27-Acylbenzaldehydes have also proven to be useful precursors to isoindoles, 2-6 phthalimidines, 19 isoindoloquinazolines, 18 naphthols, 24 indane derivatives, 26 and olefins.36 Recently, o-acetylbenzaldehyde has been used to synthesize glycosylporphyrins appropriate for cancer photochemotherapy.[28][29][30] Photodynamic therapy is based on the principal that porphyrins become concentrated in tumor cells and upon subsequent irradiation with visible light in the presence of oxygen, specifically destroy the cell.31,32 Finally, some organic peroxides as 45 (Scheme 15) derived from o-acylbenzaldehydes showed antibacterial activity 12,33 whereas, the imidazo and pyrimidoisoindole derivatives 26 and 27 (Scheme 9) were found to be psychostimulants at 0.03-50 mg/kg.They were found also to show analgesic, antipyretic, antiinflammatory and antifungal activity. 17

Conclusions
Despite the difficulties for their preparation, o-acylbenzaldehydes have been shown to be useful starting materials in the synthesis of various compounds such as isoindoles, phthalimidines, isoindoloquinazolines, indanes, naphthols, olefins and promising tools for the future.

CHO
in the literature about the formation of o-(o´hydroxyphenyl)benzaldehyde 3k in traces, via the thermal decomposition of phenylanthracene 9,10-photooxide 18, as shown in Scheme 7. It has been proposed that the initially formed isobenzofuran 20 is easily auto-oxidized.A: toluene or dichloromethane/reflux/3h Scheme 8