Transformation of phenolic hydroxyl into acyl group: a new tool in organic synthesis

The progress that has been made in organic synthesis via the transformation of a phenolic hydroxyl into the acyl group is presented in this review. This transformation involves the formation of a new C-C bond.


Introduction
Interconversion of functional groups has always played an important role in organic synthesis.There have been many developments in the last decade regarding this area and two excellent editions "Comprehensive Organic Functional Group Transformations I" and recently "Comprehensive Organic Functional Group Transformations II" have presented the vast subject of organic synthesis in terms of the introduction and interconversion of all known functional groups, providing thus a unique information source documenting all methods of efficiently performing a particular transformation. 1,2uring recent years our research has been focused on an unexpected new transformation of phenolic hydroxyl to a carbonyl group that we first found 3 in our laboratory in 1987.This transformation involves oxidation of o-hydroxy aryl ketones with lead tetraacetate (LTA) and allows the preparation of carbonyl compounds, formally unavailable, in high yields and in an easy experimental way.
The purpose of this review is to present all the findings regarding the transformation of phenolic hydroxyl into an acyl group as well as the progress that has been made in organic synthesis based on this transformation.The presentation will begin with a discussion of the substrates and the oxidants that have been used as well as of the suggested mechanism.The papers dealing with the oxidation of aryl ketones which are not substituted at ortho-position as well as of o-amino aryl ketones will also be covered.Finally, some of the applications and the importance of the derived products will be presented.It is hoped that this review will demonstrate the synthetic potential of the above transformation and generate some new ideas in this area.

Cyclisation reactions of o-unsubstituted arylketone N-acylhydrazones
It has been known [4][5][6][7] since 1966 that N-acylhydrazones of aryl ketones 1 which are not substituted at the ortho-position readily undergo cyclization to 1,3,4-oxadiazolines 2, which yield epoxides 3 with elimination of nitrogen on heating.Further heating at higher temperature leads to acetates 4. A characteristic example is given in Scheme 1.
In  o-Hydroxyarylketones are very interesting molecules both because of their potential to serve as starting materials in organic synthesis as well as because of their applications. 9The presence of a hydroxyl and a carbonyl group at ortho positions to each other at the benzene ring allows the formation of novel heterocycles as well as other non-heterocyclic aromatic compounds. 9urthermore, it is well known that lead tetraacetate reactions of hydrazones of carbonyl compounds lead to a variety of synthetically useful products. 10hus, we thought that the hydroxyl group could interact with the hydrazone moiety to lead to the formation of 1,2-benzisoxazole N-imines 11.However, we found that monoacylhydrazones of type 10 do not yield N-imines 11 or the corresponding 1,3,4-oxadiazolines that would be formed if the reaction proceeded according to the literature data [4][5][6][7] about the unsubstituted hydrazones (Scheme 1), but instead they undergo a rearrangement resulting in "replacement" of the phenolic hydroxyl with an acyl substituent to give 3 1,2-diacylbenzenes 12, in excellent yields 70-90%, Scheme 3.
o-Diacylbenzenes have been of interest primarily as fluorescence reagents for both qualitative and quantitative high sensitivity analyses for amines and amino acids. 11Having the two acyl substituents at ortho-positions they could also serve as precursors in the synthesis of several heterocycles.However, there were no general methods for their synthesis and only in isolated cases they have been prepared in many steps and low yields. 12

The Mechanism
Since no analogous transformations had been previously reported, the mechanism of this novel reaction was investigated. 13Crossover experiments demonstrated that the reaction is intramolecular.Furthermore, treatment of o-hydroxyacetophenone benzoyl- 18 O-hydrazone 13 with LTA resulted in incorporation of 18 O at the acetyl position of the labeled 2acetylbenzophenone 14 (Scheme 4).Scheme 4. Synthesis of labeled 2-acetylbenzophenone. 13 Based on this oxygen-labeling evidence we have suggested a possible reaction mechanism that is presented in Scheme 5.
Thus, the formation of the expected organolead intermediate 15, followed by acetoxy migration to the hydrazone carbon gives initially azoacetate 16 and subsequently 1,3,4oxadiazoline 17.Intermediate 17 is indeed the final product obtained [4][5][6][7] by LTA reactions with o-unsubstituted N-acylhydrazones as hydrazones 1 in Scheme 1.The presence of the hydroxy group seems to be crucial to the mechanism of the reaction.And at this stage we suggested that the o-hydroxyl group reacts with the oxadiazoline to give the 1,3-dioxane species 18. Elimination of nitrogen leads to the formation of epoxide

The Transformation of Hydroxyl into a Carbonyl Group in Benzene Derivatives via Lead Tetraacetate Oxidation
The reaction was further applied to N-ethoxycarbonyl hydrazones 20 and 23 which led to the synthesis of a series of o-acylarylcarboxylic esters 21 and 24 in good yields. 14The results are presented in Schemes 6 and 7.The simplicity of the experimental procedure gives this reaction a considerable synthetic value.Moreover, classical methods to approach such structures often result in ring-closed pthalan derivatives. 15Extension of the rearrangement led to the synthesis of o-acylbenzaldehydes as shown in Scheme 8. N-Formylhydrazones of o-hydroxyaryl ketones 25 as well as N-carbonylhydrazones of salicylaldehyde 27 both served as precursors to o-acylbenzaldehydes 28. 16terestingly, the transformation of a phenolic hydroxyl to a carbonyl group was also successful when 5-bromo-2-hydroxybenzoyl bromide N-benzoylhydrazone 31 was treated with LTA. 14 The result was the formation of 5-bromo-2-benzoylbenzoyl bromide 32 in 75% yield, and the reaction is presented in Scheme 10.It is worthy to note that there is only one prior available preparative procedure for o-acylbenzoyl bromides.Our desire to further extend the unusual transformation which was found in our laboratories, led us to use ketones bearing two acyl groups and one hydroxyl ortho to each other, as starting substrate. 19Thus, the starting ketones 33 were initially treated with the appropriate hydrazide, in 1:1 ratio to give monohydrazones 34 either as a single isomer (when R 1 =R 2 ) or as a mixture of two isomers 34 and 35 (when R 1 #R 2 ), Scheme 11.It was not necessary to separate the isomeric mixtures of 34 and 35 for the conversion to 36.LTA oxidation of the mixture afforded 1,2,3triacylbenzenes 36 in very good yields.

The Transformation of Hydroxyl into a Carbonyl Group in Heterocycles
Our continuous interest in the potentialities of the above "replacement" in organic synthesis led us to design the synthesis of 7,8-diacylcoumarins 53 applying this transformation in the coumarin substrate 51 that bears hydroxyl ana acetyl groups at ortho positions (Scheme 16).7-Hydroxy-8-acetylcoumarin N-acylhydrazones 52 were treated with LTA.The transformation of phenolic hydroxy to a carbonyl group worked out smoothly and 7,8-diacylcoumarins 53 were formed in very good yields, 73-90%. 23,24The transformation was also successfully applied to 7-hydroxy-8-acetylcoumarin N-ethoxycarbonyl hydrazone 52l and led to the formation of the corresponding angular 8-acetylcoumarin-7-ethoxycarboxylate 53l. 23 R 1 =Ph; b: R  23,24 It is well known that coumarin is a biologically active compound and its derivatives have been extensively used for the treatment of a variety of diseases.25 Because the pharmacological and biochemical properties and therapeutic alterations in the structures of coumarins depend 26 upon substitution pattern, we synthesized 27

Limitations
Treatment of o-hydroxyphenyl-1-propenyl ketone benzoylhydrazone 28 57 as well as the 1hydroxy-9H-fluoren-9-one benzoylhydrazone 58 led to very complicated mixtures. 29Both hydrazones 57 and 58 possess a double bond at the α-carbon of hydrazonyl group that possibly influences the mechanism of the reaction.

The Transformation of Hydroxyl into a Carbonyl Group via Phenyliodoso Diacetate Oxidation
It is well known that phenyliodoso diacetate (PID) is a mild oxidizing agent and a very useful reagent in organic synthesis.It shows reactivity similar to LTA and it is less hazardous, and toxic than lead(IV)compounds. 30However, although it is a mild oxidizing agent it has been not so often used for oxidations of hydrazones.In 1986 it has been reported that the PID oxidation of aldehyde carbo-t-butoxyhydrazones 59 affords 5-substituted-1,3,4-oxadiazolin-2-ones 60 in good yields as shown in Scheme 18.  Scheme 18. Cyclisation of aldehyde N-carbonylbutoxy hydrazones. 31 1990 the initial transformation of hydroxyl into a carbonyl group which is shown in Scheme 3 was performed using phenyliodoso diacetate (PID) instead of LTA and results analogous to those with LTA were obtained. 32It was suggested that the mechanism of this reaction should be analogous to the LTA mechanism. 32,9Alternatively, cross-linked [polystyrene(iodoso diacetate)] has been successfully used as an oxidative agent. 33roup was successful.However, the generality of this reaction as well as the optimisation of the yield should be further investigated.

Conclusions
The transformation of a hydroxyl into an acyl group works smoothly in several carbocyclic and heterocyclic substrates and gives the ability for the synthesis of ortho-diacylsubstituted carbocyclic and heterocyclic compounds respectively which were previously unavailable.Despite the difficulties for their preparation, both o-acylbenzaldehydes 37 or o-diacylbenzenes 12 have been shown to be useful starting materials in the synthesis of various compounds such as 1,3-diarylisobenzofurans, isoindoles, phthalimidines, isoindoloquinazolines, indanes, naphthols, olefins and they could be promising tools in organic synthesis in the future.The products could further serve also as useful intermediates to the synthesis of various derivatives with possible pharmaceutical properties.
The simplicity of the experimental procedure, the generality, the high yields and the low cost of the reagents add to the synthetic value of the method.

Scheme 5 .
Scheme 5. Mechanism of the transformation of hydroxyl into a carbonyl group.13

31
(OAc) 2 /MeOH/reflux/ N 2 / 25-30min /47-67% The Transformation of Hydroxyl into Carbonyl Group in Benzene Derivatives via Lead Tetraacetate Oxidation 5.The Transformation of Hydroxyl into Carbonyl Group in Heterocycles 6. Limitations 7. The Transformation of Hydroxyl into Carbonyl Group via Phenyliodoso Diacetate Oxidation 8.The Transformation of Hydroxyl into a Carbonyl Group via Sodium Oxidation 9. Conclusions 1986, Alexandrou et al. reported 8 that the oxidation of bis-aroylhydrazones of isophthalaldehyde and terephthalaldehyde with LTA afforded the oxadiazoles 6 and 8 in 30-95%, as shown in Scheme 2.