DEHYDROACETIC ACID (Part 1) : CHEMICAL and PHARMACOLOGICAL PROPERTIES

J.MAR.CHIM.HETEROCYCL. Volume 16, N° 1 Décembre 2017

DEHYDROACETIC ACID (Part 1) : CHEMICAL AND PHARMACOLOGICAL PROPERTIES

Alae Eddine Jilalat 1, Wedad Hashem Abdulhafedh Hassan Al-Garadi 1, Khalid Karrouchi 2& El Mokhtar Essassi 1,3 1 Laboratory of Heterocyclic Organic Chemistry, Faculty of Science, Mohammed V University, BP 1014, Avenue Ibn Batouta, Rabat, Morocco 2 Laboratoire National de Contrôle des Médicaments, Rabat, Morocco 3 Moroccan Foundation for Advanced Science,Innovation and Research (MASCIR), Rabat Design Center, Rue Mohamed Al Jazouli, Madinat El Irfane, Rabat, Morocco

E-mail address: [email protected] Reçu le 20 Novembre 2016, Accepté le 15 Janvier 2017

Abstract Dehydracetic acid and its derivatives are widely used as an intermediates in organic synthesis. In this paper, we report several methods used for synthesizing this acid. We will also describe, in more details, the reactivity of this pyrone against electrophilic and nucleophilic reagents and its biological properties. Keywords :Dehydroacetic Acid, Heterocycles, Synthesis, Reactivity, Biological Activity

Contents 1. Introduction 2. Structural study 3. Synthesis of dehydroacetic acid 4. Reactivityofdehydroacetic acid 4.1. Classical Reactions 4.2. Preparation of new heterocyclic systems 4.3. Transformations into other carbocyclic systems 5. Biological activity 6. Conclusion

1. Introduction Dehydracetic acid (1) , commercially abbreviated as DHA, is a monocyclic oxygenated [1] compound, derived from pyrone (Fig1), as molecular formula C 8H8O4. It isolated from natural sources ( solandra nitida )[2,3] and has an important role in the preparation of new active biologically compounds. [4,5]

Fig1 : Dehydracetic acid (DHA)

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Dehydroacetic acid is absorbed, rapidly and completely, by the human body, [6] used as a food additive, [7-9] as a stabilizer for cosmetics and pharmacokinetic products due to its fungicidal and bactericidal activities, [10 ,11 ] and also used as an antiseptic agent, [12 ,13 ]herbicide, [14 ]antimicrobial preservative, powerful against bacteria, yeasts and molds [15 ] and as a plasticizer in a variety of synthetic resins. [16 ] It is a colorless to white crystalline powder, [16 ] odorless, [17 ] unstable when heated to decomposition(it emits acrid smoke and irritating fumes), it sublimes when heated to 109- 111°C. [18 ] Dehydroacetic acid is a weak acid (pKa = 5.26 in water), [19 ,20 ]almost insoluble in water and moderately soluble in most organic solvents. [21 ]

2. Structural study

C8H8O4 is the molecular formula of more than 180 dehydroacetic acid isomers, which may be cyclic or linear (Fig2), therefore the determination of the correct structure of the isomer of dehydroacetic acid, has become very important due to the wide variety of well known and important compounds that may be readily prepared from this acid.

Fig2 : Examples of some (C 8H8O4) molecular formula isomers

Schibbye presented one of the first formulas of dehydroacetic acid as a tetraonic cyclooctatetraone (Fig3).[22 ]

Fig3 : Formula proposed by Schibbye

At one time, researchers have shown that dehydroacetic acid is a true acid containing a carboxyl group. Which implies that the form of Schibbye was excluded. For their part,Oppenheim and Precht [23 ] proposed a formula that represents this acidity, but the most satisfying form of this type was that suggested by Haitinger [24 ,25 ] and Perkin [26 ](Fig4).

Fig4 : Formula proposed by Oppenheim-Precht (Left)and Haitinger and Perkin (Right)

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Ostwald [27 ]pointed out that probably it was not a true acid, because of its abnormally small dissociation constant. He proposed as dehydroacetic acid in the form of 2,4,6-trihydroxy acetophenone (Fig 5).

Fig 5 : Formula proposed by Ostwald

Based on this hypothesis (DHA is not a true acid), Feist [28 ]criticized all existing formulas, and presented the idea that dehydroacetic acid is a δ-lactone acetylated (Fig6).

Fig6 : Formula proposed by Feist

A few months later, Collie [29 ,30 ]proposed another formula to dehydroacetic acid (6- acetonylpyronone) which slightly differs than that of Feist (Fig 7). This formula, however, rendered one or two reactions capable of explanation which could not be accounted for by the use of Feist’s. It was also based upon the assumption that dehydracetic acid is a lactone.

Fig 7 : Formula proposed by Collie

Forsen and Nilsson [31 ]concluded by spectral studies (infra-red and NMR) that dehydroacetic acid has a pyran structure. Similarly, Berson [32 ]and Billes [33 ]confirmed the formula for Feist by a spectral studies vibrational, infrared and Raman (Fig 8).

Fig 8 : Optimized molecular structure (Left) and atoms numbering (Right) of dehydroacetic acid

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Tautomeric forms Dehydroacetic acid exists in four principal tautomeric forms (Fig 9), and 3-acetyl-4- hydroxy-6-methyl-2H-pyran-2-one (1) is the most stable tautomer, [34 ] simply because it contains the most extended conjugated system of all tautomers, Also, this tautomer does not contain exocyclic carbon-carbon double bonds, and it is known that in six-member rings, endocyclic double bonds are usually more stable than exocyclic double bonds. [35 ]

Fig 9 : principal tautomeric forms of dehydroacetic acid

3. Synthesis of dehydroacetic acid Chemical access roads to DHA are numerous, give for examplethe controlled polymerization of diketene (5) in the presence of a small amount of basic catalyst (tertiary amines such as pyridine, triethylamine or methyl morpholine, or sodium alkoxides such as ethoxide and sodium butoxide) in aromatic hydrocarbons used as solvents, such as benzene and toluene. [16 ,36 ,37 ] On the other hand, the acylation of the triacetic acid lactone (6) by acetic acid (7a) ,[5,38 ]acetic anhydride (7b) [39 ]or acetyl chloride (7c) [40 ]in the presence of sulfuric acid, pyridine or sodium acetate gives dehydroacetic acid ( Scheme 1).

Scheme 1

Dehydroacetic acid can also be synthesized from acetoacetic acid (8a) ,[41 ] acetoacetic ester (8b) ,[42-47 ] acetoacetyl fluoride (8c) [48 ] or chloride (8d) [49 ] and also from diacetylacetone (8e) ,[50 ] or from condensation of (7b) ,[51 ,52 ] or (7c) [53 ] with 3-oxoglutaric acid (9) (Scheme 2).

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Scheme 2

Another reaction that should be included here is the cycloadition [4 + 2], or Hetero-Diels- Alder reaction, of two acetyl ketenes (10) ,[54 ,55 ] which are prepared from1,3-dioxinone (11) [56 ], 1-ethoxybutyn-3-one (12) ,[56 ]diacetone oxalyl (13) [57-60 ] 1,3-oxazine (14) [61 ] or others, [62-65 ]to synthesize dehydroacetic acid ( Scheme 3).

Scheme 3

4. Reactivityofdehydroacetic acid

Dehydroacetic acid possess many reactive sites. The carbon atoms C 2 , C 4, C 6and C 3a are [66-68 ] highly electrophilic centers. However, carbons C 3 and C 5 have a nucleophilic properties (Figure 10).[69 ]

Figure 10

Reactions with nucleophiles at C 2 and C 6 provoke the opening of the pyranic ring, which, in general, is followed by cyclization to give a new heterocyclic or carboxylic systems. On the other hand, the introduction of electrophilic reagents at C 3 and C 5 keeps the pyranic structure.

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C4 and C 3a positions undergo, generally, a substitution reactions, the methyl groups at C 6 and C 3a can be alkylated in different ways.

4.1. Classical Reactions 4.1.1. Acidification Acidification of (1) by sulfuric acid gives, after rearrangement, isodehydroacetic acid (1’) [70 ]and 2,6-dimethyl-4H-pyran-4-one-3-carboxylic acid (15) .[71 ] Moreover, triacetic acid [29 ] lactone (6) was prepared by deacetylation of dehydroacetic acid, in acidic medium (H 2SO 4). DHA can, also, gives by treatment with concentrated hydrochloric acid or 10% aqueous sulfuric acid (10% H 2SO 4), after heating and elimination of CO 2, 2,6-dimethyl-4H-pyran-4- one (16) [72-74 ] (Scheme 4).

Scheme 4

4.1.2. Basification The basification of dehydroacetic acid leads, usually, to the deprotonated intermediates (17) (Scheme 5).

Scheme 5

Dehydroacetic acid gives, in the presence of barium (or sodium) hydroxide, 2-acetyl-3,5- dioxohexanoic acid (18) as an intermediate, which cyclizes, thereafter, to give orcinol (19) (Scheme 6). [75 ]

Scheme 6

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4.1.3. Reduction

Selective reduction of acetyl groupat C 3 position of dehydroacetic acid was accomplished [76 ] [77 ] usingNaBH 3CN, borane-methyl sulfide complex (BMS) or triethylsilane (Et ₃SiH), [78 ]afforded 3-ethyl-4-hydroxy-6-methyl-2-pyrone (20) in good yields. Furthermore, hydrogenation of this acid in the presence of 10% alladium-charcoal in ethyl acetate, at 80°C, gives 3-ethyl-4-hydroxy-6-methyl-5,6-dihydro-2-pyrone (21) .[79 ]5,6-dihydrodehydroacetic acid (22) was prepared by the catalytic hydrogenation of DHA.[80 ,81 ] Another protocol leads, after hydrogenation, to a symmetrical heptanone (23) [82 ] (Scheme 7).

Scheme 7

4.1.4. Formation ofmetallic complexes Several studies have been reported on complexation of dehydroacetic acid with transition metals, we note, for example the complexation with Boron, Magnesium, Scandium, Vanadium, Crome, Manganese, Iron, Cobalt, Nickel, Copper, Zinc, Ruthenium, Palladium, Cadmium ... etc ( Scheme 8). [15 ,83-88 ]

Scheme 8

4.1.5. Halogenation Chlorination of dehydroacetic acid (1) by phosphorus pentachloride (PCl ₅) gives 3- (2- chloroacetyl)-6-methyl-2H-pyran-2,4-(3H)-dione (26) ,[89 ]and by phosphoryl trichloride [90 ] (POCl 3) gives4-chloro-3-(1-chlorovinyl)-6-methyl-2H-pyran-one (27) , 3-acetyl-4-chloro-6- methyl-2H-pyran-2-one (28) [91 ,92 ] and 3-chloro-4-hydroxy-6-methyl-2H-pyran-2-one (29) [93 ,94 ] (Scheme 9).

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Scheme 9

3-(bromoacetyl)-4-hydroxy-6-methyl-2H-pyran-2-one (30) could be obtained, as a single product, by a simple bromination (1) under acidic conditions [95 ,96 ] (Scheme 10 ). Bromination in C 3 position gives 3-acetyl-3-bromo-4-hydroxy-6-methyl-2H-pyran-2-one (3-Br- DHA) (31) .[97 ]

Scheme 10

[98 ] [99 ] C5 is much less active than C 3,Feist and Harris studied the bromination of (1) in thisposition for synthesizing 5-bromopyrone (5-BrDHA) (32) .This reaction gives, probably, an intermediate (obtained from addition of bromine on the C ₅-C₆ bond), followed by removal of hydrobromic acid for synthesizing 5-BrDHA (33) (Scheme 11 ). Treatment of this new brominated derivative with N-bromosuccinimide (NBS) in tetrachloromethane for 20 hours at room temperature, leads to the formation of (5,6a)-dibromo dehydroacetic acid (34) .[100 ] Harris and his team [99 ] have also shown that treatment of dehydroacetic acid with NBS under radical conditions leads to the formation of 3-acetyl-6-bromomethyl-4-hydroxy-2H-pyran-2-one (35) . This new 6a-BrDHAderivative can be hydrolized to alcohol (36) and transformed into the phosphonium bromide (37) [101 ] or into sulfides (38) .[102 ]

OH O OH O OH O

NBS Br 2 /I2 Br Br 7h Chloroforme O O O O Reflux 72h O O (32) (35) Br (1) i, ii ou iii O OH O OH O Br N OH O Br O Br (36-38) CCl X 4 (33) O O O O 20h O O i) NaOH 36 : X = OH Br H2O (34) PPh 3 + - ii) 37 : X = PPh 3 , Br

RSNa iii) 38 : X = SR Scheme 11

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4.1.6. Amination Generally, treatment of (1) with primary amines gives pyridine derivatives. [103-109 ] In the first step, the nitrogen atom attacks the carbonyl group of the acetyl function of DHA to form the Schiff base (39) .[110-116 ] This new base transformed after the attack by another equivalent of the primary amine (or with ammonia) in the C 6 position of DHA, to diamine (40) or amino acid (40’) , which turns upon heating, deamination or dehydration, to lutidone derivatives (41) .[117 ] Other studies have shown that the amine attacks the carbonyl groups(2 or 4) to form a new 2-aminopyrone (42) [118-120 ] or 4-aminopyrone systems (43) .[121 ] It can also condensed with N, N-dimethylformamide dimethylacetal to yield enaminones (44) [122 ,123 ] (Scheme 12 ).

Scheme 12

4.1.7. Acetylation DHA is successfully converted, in two steps, to 3,4-diacylpyran-2-ones (46) by conversion of hydroxyl group into an acyl group ( Scheme 13 ). [124 ]

Scheme 13

4.1.8. Alkylation Treatment of dehydroacetic acid with methyl tetrafluoroborate, under nitrogen atmosphere at-78°Caffords the formation of 3-acetyl-2-methoxy-6-methyl-4H-pyran-4-one (47) (Scheme 14 ). [125 ] 3-acetyl-4-methoxy-6-methyl-2H-pyran-2-one (48) was prepared by alkylation of [126 ,127 ] dehydroacetic acid with diazomethane. C5 position is not sufficiently activated to be attacked by electrophilic reagents, and very few reactions have been reported. Thus, the reaction of the cobalt (II) complex of dehydroacetic acid with Diphenylbromomethane gives

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3-acetyl-5-benzhydryl-4-hydroxy-6-methyl-2-pyrone (50) .[128 ] Also, the addition of dehydroacetic acid to two equivalents of sodium amide, in ammonia, affords, after treatment with methyl sulfate, 4-hydroxy-6-methyl-3-propionyl-2H-pyran-2-one (52) in low yield. [129 ]

Scheme 14

A new tri-anionic (53) molecule was obtained by the addition of three equivalents of sodium amide,in ammonia, to dehydroacetic acid ( Scheme 15 ). [130 ] The higher basicity of sodium amide (pKa = 38) makes it easy to remove three protons of dehydroacetic acid which helps to form the trianionic dehydroacetic acid (triso-DHA). This trianionic derivative has an exceptional reactivity at C 6 position towardsalkylating agents.

Scheme 15

Triso-DHA (53a,b) reacted with methyl chloride in acid medium to form 3-acetyl-6-ethyl- 2-methoxy-4H-pyran-4-one (alkylating C 6a )(55) or 3-acetyl-2-methoxy-5,6-dimethyl-4H- [131 ] pyran-4-one (methylation at C 5)(56) in a small quantity. Furthermore, treatment of this trianionic derivative with excess methyl iodide affords two new products (57,58) resulting from alkylation at both C 6a -C3b and C 5-C3b positions ( Scheme 16 ).

Scheme 16

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Evenly, alkylation with an equivalent of haloalkanes yielded 6a-alkylated DHA (59a-d) with good yields. [132 ,131 ] Otherwise, condensation of (53a) with methyl benzoate and methyl anisate gave corresponding phenacyl pyrones (60a-b) (Scheme 17 ).

Scheme 17

The addition of benzophenone (61) to the (53a) (aldol-type condensation) gives carbinolpyrone (62) , and treatment of this new DHA derivative with concentrated sulfuric acid gives an unsaturated pyrone (63) (Scheme 18 ). [131 ]

Scheme 18

On the other hand, condensation of trianionic dehydroacetic acid (53a) with (E)- chalcone (64) promotethe formation of two products (65-66) . The first results from the attack of the anion on the carbon beta of the carbonyl function, and the other on the carbonyl function directly ( Scheme 19 ).

Scheme 19

4.1.9. Condensation with aldehydes Condensation of dehydroacetic acid (1) with aromatic aldehydes considered as a good method for preparing chalcones (67) and cinnamoyl derivatives( Scheme 20 ). [79 ,133-137 ]

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Scheme 20

Condensation of (1) with various aromatic aldehydes (68a-m) , at the acetylic function (Claisen-Schmidt condensation), in chloroform catalyzed by piperidine, leads to cinnamoyl- pyrones (69a-m) .[79 ,138 ,139 ]Furthermore, the condensation of DHA-phosphonium bromide (37) [101 ] with 4-methoxycinnamaldehyde (70) gives a conjugate derivative (71) [140 ] (Scheme 21 ).

Scheme 21

On the other hand, the condensation of (1) with two equivalents of benzaldehyde (68n) in the presence of a small amount of N-benzylidenecyclohexylamine, in toluene reflux for 24 hours, gives a new dual condensed derivative (72) (Scheme 22 ). [141 ]

Scheme 22

4.1.10. Cycloaddition « Diels-Alder » Photochemical cycloaddition of dehydroacetic acid (1) with cyclohexane (73) in ethyl acetate produced a diastereomeric mixture (74a-b) (Scheme 23 ). [142 ] The other tautomer of dehydroacetic acid (4) can provides a new pyranic compound (75) in reaction with the same dienophile.

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Scheme 23

4.1.11. Opening of the pyranic ring Reactions resulting in opening of the pyrane ring of dehydroacetic acid without transformation into a different cyclic product are relatively uncommon, although some of them are quite important.Treatment of dehydroacetic acid with methoxide [143 ] or ethoxide [144 ] of magnesium in alcohols gives 3,5-dioxohexanoate methyl or ethyl (76a-b) . Hydrolysis and decarboxylation, by concentrated hydrochloric acid in presence of barium hydroxide solution, of dehydroacetic acid affords heptane-2,4,6-trione (77) [145-147 ] (Scheme 24 ).

Scheme 24

Since open-chain compounds directly arising from opening of pyrones ring are highly functionalized, they have a strong tendency to cyclize again, and this can be used to prepare different types of hetero and carbocycles.

4.2. Preparation of new heterocyclic systems 4.2.1. Synthesis of azetidine derivatives Treatment of dehydroacetic acid (1) with substituted primary aromatic amines (78a-g) yielded, under microwave irradiation, many Schiff bases (79a-g) . These bases are subsequently irradiated with dimethylformamide in the presence of triethylamine and chloroacetyl chloride to give finally azetidinone derivatives (80a-g) (Scheme 25 , Table 1). [148 ]

Scheme 25

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Entry R1 R2 R3 Prdt

1 OCH 3 H H 80a

2 CH 3 H H 80b 3 Br Cl H 80c 4 Br H H 80d 5 H H H 80e 6 OH H H 80f 7 H H Cl 80g

Table 1: Synthesis of azetidinone derivatives

4.2.2. Synthesis of pyrrole derivatives To prepare pyrrole derivative (81) , Fadda and his co-workers [149 ]have reacted an ethyl glycinate hydrochloride with an enaminone of DHA (44) (Scheme 26 ).

Scheme 26

Reaction of DHA-chalconsderivatives with nitromethane in the presence of more than one equiv. of 1,1,3,3-tetramethylguanidine (TMG) gives the corresponding nitro compound (82) (1,4-conjugate addition) in good to excellent yields. Chemoselective reduction of nitro function of thesecompound leads to 2(3)-(4-arylpyrrolidin-2-ylidene) derivatives (83a- b) (Scheme 27 ). [150 ]

Scheme 27

4.2.3. Synthesis of pyridine derivatives Pyridones or pyridine derivatives (41) , made from dehydroacetic acid, were prepared generally in the presence of a primary amine [106 ,107 ,103-105 ](Scheme 12).(84) can be synthesized, also, effectively in excellent yields from the reaction of DHA with sulfuric acid (hydrolysis of DHA), then ammonium hydroxide ( Scheme 28 ). [151-153 ]

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Scheme 28

Also, condensation of dehydroacetic acid (1) with aromatic aldehydes (85a-k) and ammonium acetate (Hantzsch condensation) in the presence of catalytic amounts of cerium (IV) ammonium nitrate in an aqueous medium gave a 2,4,6-trisubstituted pyridine (86a- k) (Scheme 29 , Table 2). [154 ,155 ]

Scheme 29

Entry R1 R2 R3 Prdt

1 H H NO 2 86a

2 H OCH 3 OCH 3 86b 3 H H Br 86c 4 H H Cl 86d e 5 H H CH 3 86

6 H H OCH 3 86f 7 H H OH 86g

8 H H N(CH 3)2 86h 9 OH H H 86i

10 H NO 2 H 86j 11 2-hydroxy-1-naphthaldehyde 86k

Table 2 : Synthesis of 2,4,6-trisubstituted pyridine

Enaminone of dehydroacetic acid (44) may also transform to pyranopyrdines (87-88) by reaction with hydroxylamine ( Scheme 30 ). [156 ]

Scheme 30

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4.2.4. Synthesis of diazole derivatives 4-acetoacetyl-5-hydroxy-3-methylpyrazol (90) was prepared from the reaction of dehydroacetic acid with hydrazines (89a-d) .[157 ] This pyrazole can gives, under acid conditions, pyrano[b]pyrazole derivatives (91a-d) (Scheme 31 ). [158-160 ]

Scheme 31

Moreover, treatment of (1) with hydrazines (89c-g) (Table 3), in acidic medium, gavespyrano[c]pyrazole derivatives (92) .[161 ,90 ,162 ]Kumar et al [92 ] are, also, tried to synthesize (93d,f,h-o) from a chlorination followed by an amination of dehydroacetic acid.Condensation of (1) with phenylhydrazine (89d) in acetic acid gave substituted pyrazolyl- pyrazolopyranes (94) [163 ]which were subsequently transformed, hereafter, into other heterocyclic systems. [164 ]The action of an excessof hydrazines derivatives (89d,i,p) on DHA (1) under reflux for 12h leads to the pyrazolopyridones (95 d,i,p) [165 ,166 ] (Scheme 32 ).

Scheme 32

Reaction of hydrazone derivatives (96d,f-i) with POCl 3 provided the corresponding pyranylpyrazole derivatives (97 d, f-i) [167 ](Scheme 33 ). Furthermore, reaction of DHA with hydrazines (89a,d) , in presence of pyridine, gave bipyrazole derivative (98a,d) in good yields. [168-170 ]

R R N N OH O OH NNHR OH N N RNH-NH 2 (89a,d) ArNH-NH 2 DMF N Base EtOH POCl N 3 HO O O O O O O R (98a,d) (96d,f-i) (97d,f-i) Scheme 33

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a H b Et c Me d Ph

e 4-Cl-Ph f 4-NO 2-Ph

g 2,4-(NO 2)2-Ph h 4-Me-Ph i 4-Cl-Ph j 4-Br-Ph k 4-MeO-Ph l 4-Me-2-quinolinyl m 4-phenyl-2-thiazolyl n 2-benzothiazolyl

o 4,6-(Me) 2-2- p 4-F-Ph pyrimidinyl

Table 3 : RHN-NH2 (89a-p) derivatives

Reaction of DHA-chalcons [171 ,172 ] with (89d) gave corresponding 1.3-diazine derivatives (99a-c) . Bromination of DHA-chalcons [173 ] gives (100) which were subsequently transformed, in presence of phenylhydrazine (89d,e,h) , into 1.2-diazolic derivatives ( Scheme 34 ).

Scheme 34

Amination of (1) by primary amines (101a-f) afforded a series of imine derivatives (102a- f) , which were converted to the corresponding imidazoles (103a-f) by treatment with p- Toluenesulfonylmethyl isocyanide (TosMIC) in the presence of bismuth triflate Bi(OTf) 3 as catalyst ( Scheme 35 ). [174 ,175 ]

Scheme 35

Aït-Bazizet al [176 ] developed a procedure to convertDHA into substituted imidazoles by four different methods ( Scheme 36 ).They condensed, in a first step, DHA (1) with aromatic aldehydes, in chloroform as solvent and in the presence of a small amount of pyridine and piperidine under thermal refluxing or under microwave (MW) irradiation, to afford the synthesis of enoyl and dienoylpyranones (104, 105) . These derivatives are selectively hydrogenated, by palladium on carbon (Pd/C: 10%) as catalyst and under a pressure of

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11Kg/cm 2 of hydrogen in ethyl acetate, to give,finally,an analogous of dehydroacetic acid derivatives (106, 107) . Treatment of these new derivatives with o-phenylenediamine (108a) in ethanol at room temperature for six hours (Procedure A), under reflux for 1h (procedure B) or under the microwave irradiation at 100 W for one minute (procedure C) gives (3E)-3-(1-[(2- aminophenyl)amino]-3-arylpropyl/pentylidene)-6-methyl-2H-pyran-2,4(3H)-diones (109, 110) , while treatment under microwave irradiation at 100 W for 4 minutes (Procedure D) gave 3-(1,3-dihydro-2H-benzimidazol-2-ylidene)-6-methyl-2H-pyran- 2,4(3H)-dione (111) . And when the reaction treated under reflux in toluene for 3h (procedure E) or under microwave irradiation at 200 W for 4 minutes in toluene (procedure F) gives 2-substituted benzimidazoles (112, 113) and (6) .

Scheme 36

Furthermore, condensation of an equimolar mixture of 3-(2-bromo acetyl)-4-hydroxy-6- methyl-2H-pyran-2-one (30) with various aromatic aldehydes (85b-d, f-j, l-p) , benzylamine (101d) and ammonium acetate in absolute alcohols gave the corresponding imidazole derivatives ( Scheme 37 ) in good yields (Table 4).[177 ]

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Scheme 37

Entry R1 R2 R3 Ald Prdt Yield

1 H OCH 3 OCH 3 85b 114a 80 2 H H Br 85c 114b 90 3 H H Cl 85d 114c 80

4 H H OCH 3 85f 114d 85 5 H H OH 85g 114e 80

6 H H N(CH 3)2 85h 114f 85 7 OH H H 85i 114g 80

8 H NO 2 H 85j 114h 80 9 H H H 85l 114i 75

10 OH OCH 3 H 85m 114j 85

11 H OCH 3 OH 85o 114k 75 12 OH H OH 85p 114l 70

Table 4 : Synthesis of imidazole derivatives

In a recent study, 3-acetyl-4-hydroxy-6-methyl-3H-pyran-2-one (1) on reaction with 5- bromopyridine-2,3-diamine (115) gives an imidazopyridine (116) (Scheme 38 ). [178 ]

OH O Br NH 2 H Br N N NH 2 O O (115) N N (1) (116) Scheme 38

4.2.5. Synthesis of diazine derivatives

Acidification of (1) by sulfuric acid (H 2SO 4) gave 4-hydroxy-6-methyl-2-pyrone (6) , which interacts with benzenediazoniumchloride (117a-n) to form hydrazones (118a-n) , pyridazine (119a-n) derivatives were synthesized via treatment of (118a-n) in acidic media( Scheme 39, Table 5). [179-182 ]On the other side, Tijou [183 ] et Claramunt [184 ] have isolated pyrazine derivatives (120) from condensation of DHA with aldehydes [185 ] and (108a) . Reaction of (30) with (89g) in ethanol gives 1,2-diazine derivative (121) , while the use of 1,2- diamines (108a-d) gives 1,4-diazine derivatives (122) .[95 ]

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NH 2 O2N NO 2 R R H NH N OH N 2 N (108a-d) (89g) N (30) a) R = H, b) R = Me O c) R = Cl, d) R = NO O O 2 O O (122) (121)

O H2SO 4 8a) / Ar (1) (6) (10 H + - H Reflux, 1h N2 Cl N O

N O O (117) Na 2CO 3 O O Ar OH H H O (120) O N 2 N Ref 3h R 0 - 10 C N N HCl (cc) (118) R O O (119) Scheme 39

a 4-F b 4-Cl c 4-Br d 4-CN

e 4-CH 3 f 4-OCH 3

g 4-CO 2H h 4-CONH 2

i 4-NO 2 j 4-CF 3 k 3-F l 3,5-di-F m 2,4-di-F n 3,4-di-F

Table 5 : (119a-n) derivatives

Kaur et al [186 ] have used S-benzylthiuronium chloride (SBT) (123) and 3-cinnmoyl-4- hydroxy-6-methyl-2-oxo-2H-pyranto form pyranyl-thiopyrimidine derivatives (124) . Condensation of 1,8-diaminonaphthalene (125) with (1) in methanol (Time= 3h) gave the corresponding 1.3-diazine derivative (126) .[187 ] Moreover, DHA can convert, also, to pyrimidine derivatives (129-130) by treatment with guanidine (127) and thiourea (128) under basic media ( Scheme 40 ). [188 ,189 ]

Scheme 40

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Djerrari [190 ], Bel-Ghacham [191 ]and El Otmani [192 ]reported the synthesis of pyridopyrimidine derivatives (132 and 132’a-d) by the reaction of pyridines (115-131a-c) and dehydroacetic acid (1) in refluxing of butanol ( Scheme 41 ).

Scheme 41

4.2.6. Synthesis of benzodiazepine derivatives Benzodiazepines are very interesting pharmaceutical compounds, [193 ]it would be interesting to cite a few examples of synthesis of this derivatives from dehydroacetic acid. There are many examples of transformations of DHA into pyronyl-1,5- benzodiazepines (134) ,give for example, the treatment of (1) with various aldehydes and cyclic or linear 1,2-diamines( Scheme 42 ). [171 ,184 ,185 ,194-200 ] Thus, 4-chloro-3-ethynyl-6-methyl- 2H-pyran-2-one (133) (derived from dehydroacetic acid) leads, after a condensation reaction with the 1,2-diamines, to corresponding diazepinic compounds (134) .[201 ]

Scheme 42

Heating of dehydroacetic acid with two moles of 1,2-diamine (108a) in a variety of alcohols (MeOH, EtOH, PrOH, PrOH, BuOH) for 12 to 18h, give a mixture of four separable products (135-138) .[202 ] Treatement of the same reaction in xylene at reflux yielded benzodiazepinone (138) , in 75%, besides 2-methyl benzimidazole (137) and benzimidazolone (136) . Thus, an higher excess of o-phenylenediamine afforded products (136-138) and an imino-benzodiazepinone (139), which leads, after heating in the presence of acid, 4-methylbenzodiazepin-2-one (140) . Similary, Minnih et al [203 ,204 ] tried, also, to synthesize (138) from a condensation of o-phenylenediamineswith dehydroacetic acid in reflux of xylene for 2 hours ( Scheme 43 ).

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Scheme 43

4.2.7. Synthesis of furan derivatives Most of furanic systems(derived from DHA) (141-142) are prepared via intramolecular cyclization of 3-bromoacetyl-4-hydroxy-6-methyl-2H-pyran-2-one (30) in basic media, [96 ,205 ] or from addition of amines on this DHA-Br in acetone ( Scheme 44 ). [206 ]

Scheme 44

Treatment of enolic form of dehydroacetic acid (4) with N-isocyanimino- triphenylphosphorane (Ph 3P=NNC) (143) followed by intramolecular cyclization yielded an iminofurane (144) , which on further reaction with aldehydes (Aza-Wittig reaction) providedthe corresponding furanopyrone derivatives (145) (Scheme 45 ). [207 ]

Scheme 45

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4.2.8. Synthesis of thiopyran derivatives The action of sulfuric acid on (1) gives, after rearrangement, 2,6-dimethyl-4-oxo-4H- pyran-3-carboxylic acid (146) . This new acid reacted with phosphorus pentachloride (PCl 5) in a mixture of diethyl ether and benzene to give methyl 2,6-dimethyl-4-thioxo-4H-pyran-3- carboxylate (147) . The ester obtained reacted, aftre, with aqueous potassium hydrogensulfide in ethanol to gave methyl 2,6-dimethyl-4-thioxo-4H-thiopyran-3-carboxylate (148) (Scheme 46 ). [71 ]

OH O S O S O

H2SO 4 OH OEt 2 O KHS (aq) O (1) Benzen EtOH O PCl 5 O S

(146) (147) (148) Scheme 46

4.2.9. Synthesis of dithiane derivatives Methylation, reduction, dehydration and oxidation of dehydroacetic acid affords a new aldehyde derivative (149) which evolves in presence of dithioacetal (150) to dithianic derivatives (151) (Scheme 47 ). [4]

Scheme 47

4.2.10. Synthesis of thiazole derivatives Singh et al [208 ] reported a simple synthesis for preparing thiazole derivatives (156) . They treated thiazolylhydrazoneof DHA (153) (prepared from (1) and thiosemicarbazone (152) at reflux in ethanol) with phenacyl bromide (154) ,or chloride (155) and sodium acetate in ethanol. Thiazolylhydrazones (153) can also converted to thiazide derivatives (160-162) in the presence of ethyl 2-bromopropionate (157) , ethyl phenyl bromoacetate (158) and also in the presence of maleimidic derivatives (159) (Scheme 48 ). [209 ]

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Scheme 48

Bromination of (1) by hydrogen bromide (HBr), bromine (Br 2), or with an excess of this bromine in chloroform and in the presence of a catalytic amount of iodine provides triBr- DHA (163) , thisnew compound was treated with thioamide (164) and thiocarbamide (152) to give thiazolyl-pyranderivatives (165-166) in good yields( Scheme 49 ). [205 ,210-217 ]

Scheme 49

4.2.11. Synthesis of oxazole derivatives Akhrem et al [161 ] have reported the synthesis of pyrano-isoxazole (167-168) compounds via reaction of (1) with hydroxylamine in methanol. Similarly, Somogyi et al [218 ] isolate the same compound (167) from a cleavage of the N-N bond of DHA-acylhydrazone. Enaminone of dehydroacetic acid (44) on reaction with hydroxylammonium chloride gives another oxazole derivative (169) in ethanol reflux condition. [149 ]Moreover, DHA can convert to bis-isoxazole (170) by treatment with two moles of hydroxylammonium chloride (Scheme 50 ). [169 ,219 ,220 ]

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Scheme 50

Treatment of thiazole derivatives (156) , which prepared from dehydroacetic acid, with hydrazine [221 ] or with hydroxylamine hydrochloride [222 ] in ethanol-acetic acid mixturegives tricyclic compounds (171a-b) (Scheme 51 ).

Scheme 51

In a recent study, condensation of an equimolar mixture of (30) with thiosemicarbazide (152) and 3-(acetoacetyl)coumarin derivatives (172) , in refluxing anhydrous ethanol delivered asubstituted series of thiazolyl-pyrazole derivatives (173) in good yields ( Scheme 52 ). [223 ]

Scheme 52

4.2.12. Synthesis of oxazine derivatives The reaction of phenylhydrazine (89d) with DHA (1) and amines (101b-l) gives an enaminonic pyrazole (174) . cyclisation of these new derivatives with triphosgene, [224 ] or thiophosgene [225 ] in dichloromethane and in the presence of trimethylamine leading to oxazine derivatives (175a-b) in a good yields ( Scheme 53 ).

Scheme 53

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4.2.13. Synthesis of thiazine derivatives Treatment DHA-chalcones [226 ]with o-aminothiophenol (176a) give the thiazinic derivatives (177) (Scheme 54).[227 ,228 ]

Scheme 54

1,4-thiazine derivatives (178-179) can be synthesized, also, from addition of (176a) on (30) (Scheme 55 ). [95 ]

Scheme 55

4.2.14. Synthesis of thiazepine and oxazepine derivatives Dehydroacetic acid on treatment with substituted aromatic aldehydes yielded α,β- unsaturated carbonyl compounds,which on further reaction with o- aminothiophenol (176a) ,[227 ]o-aminophenol (176b) [229 ]or cysteamine (1,2-aminoethanethiol) (176c) ,[230 ]provided a new oxazepinic and thiazepinic compounds(180-181) (Scheme 56 ).

Scheme 56

4.3. Transformations into other carbocyclic systems The self-condensation (path 1) of two equivalents of heptane-2,4,6-trione (77) leads to the formation of 1- (2-hydroxy-4-methyl-6- (2-oxopropyl) phenyl) butane-1,3-dione (182) and

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2-acetyl-3,6- dimethylnaphthalene1,8-diol (183) .[145 ] However, the condensation (path 2) provides the 3-acetonyl-2,6-diacetyl-5-methylphenol (184) , 7-acetyl-3,8-dihydroxy 3,6- dimethyl-1-tetralone (185) and (183) [231 ,232 ] (Scheme 57 ).

Scheme 57

Treatment of (1) with vinyl acetate (186) leads to the formation of (187). Hydrolysis, carboxylation and cyclization of of the latter compounds gave a mixture of acetyl-cresol (188) and diacetylic resorcinol (189) (Scheme 58 ). [142 ]

Scheme 58

At the end of the 19 th century, Collie reported the conversion of (1) into aromatic compound (19) by treatment with sodium hydroxide ( Scheme 59 ). [75 ]

Scheme 59

Treatment of DHA (1) with dimethoxytrimethylamine gives an enaminone (44) which leads after hydrolysis (of the lactone foncton), decarboxylation and cyclisation to 2,4- dihydroxyacetophenone (190) . Treatment of these enaminone with an ethanol solution of methylamine in acid media gives the same product( Scheme 60 ). [122 ]

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Scheme 60

5. Biological activity 5.1. Antimicrobial activity: The relationship between the molecular structure of DHAderivatives and their biological activity is a very importantproblem, because even unsubstituted DHA can form more than tautomer (Fig 9), each having different chemical and biological properties. Moreover, some derivatives of DHA (specially schiff-bases and their metal complexes) considered as an antimicrobial agents (antibacterial, anti-fungal, nematicidal and DNA-photocleavage agents). 5.1.1. Antibacterial and anti-fungal agents The antimicrobial activity of the complexes (192) is more as compared to the ligand (191) . Antibacterial activity shows that the copper complex is more biologically active in all complexes. Antifungal activity of these complexes is found to be increased in the similar order of increase in the stability constants of metal complexes, the activity of these complexes follow the order Cu(II) > Ni(II) > Co(II) > Fe(III) > Mn(II) which is exactly same as the order of stability constants of these complexes and the high antifungal activity of ligand and its metal complexes may be due to the fluoro substituents present in the ligand as shown in (Figure 11).[233 ]

F O O F

N N O N OH N M N O N

O O (191) F O O (192) Ligand Figure 11

In other study, ligand (193) and their metal complexes (194-195) were tested for in vitro antimicrobial activity against two bacteria Staphylococcus aureus and Escherichia coli at the concentration 500 ppm and 1000 ppm. The antifungal activity against Aspergillus niger and Trichoderma viride were carried out at the concentration of 250 ppm and 500 ppm respectively. Ligand and metal complexes were more active against Staphylococcus aureus and Trichoderma viride (Figure 12).[234 ,235 ]

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H3C H3C H3C O O O O O OH HO O O M H2O M H2O N O O N N O N H N N H H3C H C H3C 3 H (193) (194) (195) CH 3 CH 3 CH 3 Ligand M(II) = Cu(II) or Ni(II) M = Co(II), Mn(II) or Fe(II). Figure 12

Also, all complexes exhibit an irreversible oxidation (RuIII/RuII) and an irreversible reduction (RuII/RuI). Further, the free ligand and its ruthenium complexes (196a-b) have been screened for their antibacterial and antifungal activities. The complexes show better activity in inhibiting the growth of bacteria (Figure 13).[236 ]

Figure 13

The metal complexes of hydroxy-pyrones (197) have reasonable hydrolytic stability and significant lipophilicity. So, significant activities in synthesis, structural investigations biological activities, and density-functional studies of dehydroacetic acid complexes have shown. The antibacterial activity of Schiff base ligand, and complex were performed against E.coli and S. pyogenes at a concentration of 200 µM in DMSO by the agar diffusion method in (Figure 14).[237 ]

Figure 14

Ligands (198) and their organosilicon complexes (199) were evaluated for their antibacterial activity and the antimicrobial studies suggested that Schiff base ligands and their complexes contain the toxophorical group –CON = which is responsible for their antimicrobial activity. The probable mode of action of these complexes may be due to the formation of a hydrogen bond through azomethine or carbonyl groups with the active center of cell constituents (Figure 15).[238 ]

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Figure 15

Three Schiff' bases (200-202) retarded microbial activity with small variations against the bacterial species and this difference in activity could be attributed to the impermeability of the cells of the microbes. The observed results seem to conclude that the Schiff base (201) show better antibacterial activity when compared to other Schiff bases (200 and 202)(Figure 16) against the microbes Staphylococcus aureus , Bacillus subtilis , Escherichia coli and Pseudomonas aeruginosa . Bacterial species are also classified due to their differences in the ribosomes of the microbial cells. Also, experiments with standard antibiotic imipenem under identical experimental conditions show 100 % ability to retard the bacterial growth. [239 ]

Figure 16

Chalcones are important compounds because of their contribution to human health and their multiple biological effects. It is believed that the (>CO–C=C<), moiety imparts biological characteristics to this class of compounds. Such α, β unsaturated carbonyl compounds and their metal complexes possess interesting biochemical properties. Also, the ligand and its metal complexes were screened for in vitro antibacterial activity. The antibacterial results, showed that the ligand exhibited weak antibacterial activity, but its complexes showed moderate activity against the bacteria, it is known that chelation tends to make the ligands act as more powerful and potent bactericidal agents, thus killing more of bacteria than the non-chelated ligand. Here, the antifungal results showed that ligand exhibited moderate antifungal activity and its metal complexes show significant antifungal activity at the same concentration against the fungi. The complexes (204-205) are biologically active and exhibit enhanced antibacterial, antifungal activities compared to the parent ligand(203a) . The increased activity of the chelates can be explained based on the overtone concept and the Tweedy chelation theory (Figure 17).[240 ]

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Figure 17

Others compounds (203b-e) have been screened for antibacterial activity against Staphylococcus aureus, Bacillus subtillis, Escherichia coli and Salmonella typhi ,and for antifungal activity against Aspergillus niger, Penicillium chrysogenium, Fusarium moneliform and Aspergillus Flavus using potato-dextrose agar medium (PAD) (Figure 18).[139 ]

Figure 18

The antibacterial activities of bipyrazolopyrimidinones (206a-f) were evaluated against both Gram-positive Bacillus subtilis (A) and Bacillus stearothermophilus (B) and Gram- negative bacteria Escherichia coli (C) and Pseudomonas aeruginosa (D) at three different concentrations : 10, 50 and 100 µg/mL (Table 1) by using agar diffusion assay technique, and the antimicrobial activities of the compounds were compared with standard drugs ampicillin, and chloramphenicol (Figure 19, Table 6).[68 ]

Figure 19

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Diameter of zone of Concentration Compunds growth inhibition (µg/mL) (mm) (A) (B) (C) (D) 206a 10 - - - - R1 = H 50 - - - - R2 = Ph 100 - - 13 12 206b 10 - 10 11 09 R1 = Me 50 12 23 24 25 R2 = Ph 100 31 38 46 43 206c 10 - - - - R1 = p-Me Ph 50 - - - - R2 = H 100 10 11 13 - 206d 10 - - - - R1 = p-Cl Ph 50 - - - - R2 = H 100 11 14 12 - 206 e 10 - - - - R1 = p-Br Ph 50 - - - - R2 = H 100 - 13 11 10 206f 10 - - - - R1 = p-F Ph 50 - - - - R2 = H 100 10 12 13 12 Chloramphenicol 25 17 16 26 24 Ampicillin 25 34 35 39 41

Table 6 : In vitro antibacterial activity of compounds206a-f by using well diffusion method

pogostone (PO) and its analogues (207-208, 107) are considered as antimicrobial agents, the activity was related to the length of the side chain of the pyranoid ketone ring and the compound shown a strong antifungal activity. However, when the terminal carbon of the side chain was connected with benzene, the activity was vanished (Figure 20).[136 ,241 ]Also, the results indicate that PO could exert a gastro-protective effect against gastric ulceration, and the underlying mechanism might be associated with the stimulation of PGE2, improvement of antioxidant and anti-inflammatory status, as well as preservation of NP-SH. [242 ]

Figure 20 : Structure of Pogostone and its analogues

The compounds (209a–k) were screened for their in vitro antimicrobial activity against Gram-positive bacteria and Gram-negative bacteria compared with those of standard antibiotic kanamycin. Compounds (209a,c) were found to be most potent of this series showing the largest zone of inhibition against all the bacterial strains. Compound (209g) was highly active against E. coli and K. pneumoniae . Compound (209j) showed a good activity against B. subtilis . The remaining compounds exhibited a moderate activity ( Figure 21 , Table 7). [155 ]

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Figure 21

Comp R1 R2 R3

209a H H NMe 2

209b H OCH 3 OCH 3 209c H H Cl

209d H H CH 3 209e H H OMe 209f H H Br

209g H H NO 2 209h H H OH 209i H H H 209j OH H H 209k OH OMe H

Table 7 : (209a-k) derivatives

Other compounds (156, 210, 171) has been assayed for their in vitro antibacterial activity against Gram-positive Bacillus subtilis, Staphylococcus aureus and Gram-negative Escherichia coli and in vitro antifungal activity against Candida albicans and Aspergillus niger (Figure 22).[222 ]

Figure 22

Antimicrobial activity of (153a-d) ,(161a-d) and (162a-h) was evaluated against five microorganisms, [209 ] known to cause some infections in humans, and the results obtained from these compounds has shown in ( Figure 23 , Table 8).

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Figure 23

Comp S. A 1 S. A 2 Es. C Ps. A F. S. A 153a B. A - 12 - 20 153b B. A - - 20 18 153c - - - 17 - 153d - - - 20 18 161a - 20 - - - 161b 17 - - - 14 161c B. A 28 13 25 - 161d 26 22 - 13 22 162a B. A - 14 15 - 162b B. A - - 10 12 162c B. A - 15 18 - 162d B. A - 10 - - 162e B. A - - 25 - 162f 15 - - - 14 162g B. A - - - - 162h B. A - 10 - -

S. A 1 : Staphylococcus S. A 2 : Staphylococcus aureus aureu Ps. A : Pseudomonas Es. C : Escherichia coli aeruginosa B. A : Bactericidal F. S. A : Fungi aaaaa activity Staphylococcus aureus

Table 8 : Antimicrobial activity of (153a-d),(161a-d) and (162a-h) derivatives (diameter zones in mm)

Compound (211) was evaluated for their in vitro antimicrobial activity against gram- positive bacteria ( Staphylococcusaureus and Bacillussubtilis ), gram-negative bacteria (Escherichiacoli and Klebsiellapneumoniae ), antifungal activity against Candida albicans , and nematicidal activity against Meloidogyneincognita (Figure 24).[243 ]

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Figure 24

Others compounds (124) ,[186 ](212) [244 ]and (213) [245 ]have shown an activity against bacteria (Figure 25).

SCH 2Ph X H R N NO 2 OH N N O N N O R M Ar R M R O N O O O O O O (124) (212) O O (213) Ph, 4-FC H , 3-ClC H 6 4 6 4 M = Sn and Si 4-BrC 6H4, 4-OH-3-Et- C6H3 M = Sn and Si Ar = R = Me, Bu and Ph R = Me, Et, Bu and Ph 3-OCH3-4-OH-C 6H3, (CH3) 2NC 6H4 X = -CH 2-O-CH 2-CH 2-O-CH 2- (C2H5)2NC 6H4, 2-Thienyl, 4-Pyridyl Figure 25

5.1.2. DNA-photocleavage agents Many researchers have already been reported that Schiff bases complexes possess good DNA-cleaving activities. Also, all the remaining compounds Co(II),Ni(II), Cu(II), Mn(II) and Zn(II) complexes (214, 215) have shown moderate degree of DNA-cleaving activity(Figure 26).[246 ]

Figure 26

Others complexes (216, 217a and 217b) (synthesized via condensation of cyanoacetic acid hydrazide with dehydroacetic acid) have shown a good DNA-cleaving activities have been reported by Pal et al [247 ](Figure 27).

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Figure 27

The antibacterial activity of (218) was compared with Oxacillin as a standard drug as shown in (Figure 28), and also it was found that metal complexes (219) , where M = Co(II), Ni(II), Cu(II), Mn(II) and Zn(II), have good antibacterial activity than a free ligand under identical experimental conditions. All the compounds were also evaluated for their antibacterial and DNA photo-cleavage activities with an aim to explore the biological potential of the synthesized compound as a new chemotherapeutic agent. [247 ]

Figure 28

5.2. Analgesic & anti-inflammatory activity : Compounds (93d, h, i, m) and (93’d, h, m, n, o) have significant analgesic activity depend on immersion method, also compounds (93 h, k, l) and (93’ d, i, f, n, o) have nearly the same activity to the reference drug. The study revealed a close agreement between in vitro and in vivo analysis with some compounds (93k) and (93’ j, l, n) having dual analgesic and anti- inflammatory profile, and therefore become lead to molecules for further synthetic and biological evaluation [92 ](Figure 29).

Figure 29

Compounds (175a) and (208) have, also, shown a good analgestic and anti-inflammatory activities have been reported by Pal [224]and Li. [248 ]

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5.3. Anticancer activity: Compounds (165a-b) , and (220) displayed the highest anticancer activity against Ehrlich Ascites Carcinoma cells (Figure 30 ).[215 ]

Figure 30

The cytotoxicity on human liver carcinoma HEPG2 and breast carcinoma cells lines MCF7 of the ligand (221) and its Zn (II), Ru (III) and Pd (II) complexes (222) were determined (Figure 31 , table 9,10 Table 9-10) .[249 ]

Figure 31 conc: Drug Cytotoxicity (HEPG2) ug/ml DOX (221) Zn (II) Ru (III) Pd (II) 0.0 1.00000 1.00000 1.00000 1.00000 1.00000 5.0 0.33190 0.84139 0.83791 0.88626 0.09156 12.5 0.21193 0.68270 0.65672 0.68945 0.07306 25.0 0.18896 0.48655 0.37621 0.37138 0.06988 50.0 0.26213 0.23575 0.25923 0.27661 0.09347

IC 50 3.37 24 19.5 20.1 2.67

Table 9 : Anticancer liver HEPG2 activity data of the ligand (221) and its complexes conc: Drug Cytotoxicity (HEPG2) ug/ml DOX (221) Zn (II) Ru (III) Pd (II) 0.0 1.00000 1.00000 1.00000 1.00000 1.00000 5.0 0.19427 0.91682 0.88160 0.91217 0.16695 12.5 0.17171 0.80187 0.74334 0.77056 0.14666 25.0 0.18552 0.32318 0.35014 0.27811 0.11913 50.0 0.20133 0.20637 0.12391 0.21826 0.13681

IC 50 2.97 20.5 20.3 19.6 3.28

Table 10 : Anticancer effect breast MCF7 activity data of the ligand (221) and its complexes

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5.4. Anti-HIV / antiviral activity: Dehydroacetic acid derivatives and their boron diflouride complexes (223) were experimentally conformed by in vitro testing for their antiviral activity with respect to HIV- infected cells (Figure 32 ).[250 ]

Figure 32

Other compounds (224-226) have been assayed for their antiviral activity (Figure 33 ).[251 ]

Figure 33

Great efforts have been dedicated to the design of compounds acting as selective inhibitors of the HIV-1, and in this case a series of novel 2H-pyran-2-one structural way prepared by Defant et al. Of all the synthesized compounds, Only one compound (4-((2-(1H-indol-3- yl)ethyl)amino)-6-methyl-2H-pyran-2-one) (227) displayed inhibitory activity (EC50: 25– 50mM) (Figure 34 ).[252 ]

Figure 34

6. Conclusion The aim of this systematic literature review was to provide an overview of knowledge about how synthesis of dehydroacetic acid can be carried out in different ways, the higher reactivity towards electrophilic and nucleophilic reagents and thebiological activity of its derivatives.

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