The structure of the products resulting from dehydroacetic acid and hydrazines

: Dehydroacetic acid, 3-acetyl-4-hydroxy-6-methyl-2H-pyran-2-one, a biologically active compound, undergoes a variety or reactions with alkyl, aryl and heteroaf) lhydrazines producing various products (pyranopyrazoles, bipyrazoles, pyrazolyl 1,3-diketones, pyrazolones, etc.) under dirferent experimental conditions. The structure of these products has been establi~hed by employing NMR spectroscopy, mass spectrometry, theoretical calculations and X-ray cr~stallogra­ phy.

Dehydroacetic acid (1, 3-acetyl-4-hydroxy-6-methyl-2Hpyran-2-one, DHAA), a biologically active compound, has shown to have good antibiotic and fungicidal effects 1 besides showing strong antiseptic properties 2 . It has also been used to enhance vitamin C stability, in vegetable food processing 3 and as a preservative 4 . Dehydroacetic acid, having several reactive sites, is very susceptible to attack by the nucleophilic reagents at the carbonyl of the acetyl group, carbon atom terminating the conjugated carbon chain at 6-position, the lactone carbonyl and the carbonyl of the 4-position. A study of the tautomerism of dehydroacetic acid using 1 H, 13 C (solution and CPMAS), gated 1 H-decoupling techniques, deuterium-induced isotope effects on 13 C chemical shifts, fully coupled C, H correlation (FUCOUP) and molecular modeling with AMI has established that the compound exists as the 3-acetyl-4-hydroxy-6-methyl-2H-pyran-2-one in solution and also in the solid state 5 .

'i
Dehydroacetic acid can be obtained from ethyl-acetoacetate6, t-butylacetoacetate 7 , acetyl acetic acid 7 and cx.-oxo-ketone 8 . It continues to remain the most inexpensive starting material for the synthesis of a variety of compounds e.g. natural products 9 • 10 , benzodiazepines 11 -13 , metal chelates of Schiff bases for biological properties such as antitumor, antibacterial and antiviral 14 - 16 and a host of compounds with diverse chemical structures 17 -19 • In view of growing interest in the reactions of significance available in the literature, we herein report a de-tailed account of the structure of the products resulting from the reaction of dehydroacetic acid with alkyl, aryl and heteroarylhydrazines under various experimental conditions.
Russian group 23 reported the reaction between methyl ether of 1 (5) (6) as the exclusive product. They also reported that 1 reacts with phenylhydrazine hydrochloride in methanol producing 3 and 4, besides a keto ester (7) as a by-product (Scheme 2). A keto ester (7) as a by-product was shown to be methanolysed product of 3 as proved by refluxing 3 in methanolic solution containing a few drops of hydrochloric acid. The reaction of 1 with phosphorus oxychloride furnished 4-chloro-3-(l-chlorovinyl)-6-methyl-2H-pyran-2-one (8), which on treatment with alkylhydrazines resulted in the formation of 3 (R = CH 3 , CH 2 CH 2 0H). However, the reaction of 8 with aryl/heteroarylhydrazines resulted in the formation of 6 which are isomeric with 3 24 (Scheme 3). The formation of products (3 and 6) may be explained on the basis of initial attack of more nucleophilic, substituted nitrogen of the hydrazine on the more reactive C 4 420 of pyrone ring of 8. It was reported thllJ reaction of 1 with phenylhydrazine in methanol followed by refluxing in xylene in presence of p-toluenesulphonic acid resulted in the formation of 3 along with a compound identified as 11 (discussed later). The structure assignment was unambiguously made by homonuclear 13 C{ 1 H} NOE measurements, including long-range selective heteronuclear Bq l H} NOE enhancement measurements. The reaction of l with phenylhydrazine was investigated (Scheme 4) and the product was incorrectly characterized as S-anilino-3,6-dimethyl-l-pyrazolo [4,3-c]pyridin-4-one (9, also called pyridinopyrazole) on the basis of elemental analysis, IR and mass spectral data 25 . Probably, the authors were not aware of the earlier work of Stolle 21 and Benary 2 2 and did not even consider the isomeric structure 4 (bipyrazole). It was explained that hydrazone 2 underwent cyclization to the corresponding pyranopyrazole (3) as well as the hydrolysed to generate the starting materials (dehydroacetic acid and phenylhydrazine) (path a). Compound 3 on reaction with phenylhydrazine (generated in situ via path a) resulted in the formation of9 (path b). The formation ofpyridinopyrazole (9) and other derivatives was also subsequently reported by Hassan et al. 26 . Gelin et al. 27 in 1983 studied the reaction of 1 with phenylhydrazine and established as 4,5'-bipyrazole structure ( 4) instead of the previously reported pyridinopyrazole (9)25,26. The structure revision was based on the isolation of the key intermediate 1-(S-hydroxy-3-methyl-1phenylpyrazol-4-yl)-l ,3-butanedione (10, also called 4-u::"· ~-. ""' ' """· H'"·  (13) which is analogous to compound 10. The mechanism proposed for its formation consists of a rearrangement of 12 involving a nitrogen nucleophilic attack at the C 2 lactone carbonyl with ring opening, thus generating 13. The mechanism was also supported by deuterium labeling studies experiments and 1 H NMR spectroscopy. A significant aspect of this work 28 was the treatment of 13 with 2-hydrazino-6-methoxy-4-methylquinoline under different reaction conditions (ethanol-hydrochloric acid or ethanol-sodium acetate-acetic acid), which resulted in the formation of either 4,5'-bipyrazole (14) (path a) or the product of C-C bond cleavage generating two molecules of 1-(6-methoxy-4-methyl-2-quinolyl)-3methylpyrazol-5-ol (15)  using electron-impact mass spectrometry and the major process were interpreted. The common features were the loss of ketene, acetonyl radical, acetone and two molecules of ketenes from the molecular ion (Scheme 8). All the processes were substantiated with the help of accurate mass measurements of the fragment ion and by a study of the 1st field-free region (FFR) metastable ions which were obtained by linked scans. 10.13. 16 17 Although the reaction led to the formation of only one compound (17) and not to a mixture of isomers (17,18), its structure assignment appeared to be a complex problem. This structure may present isomerism, tautomerism (OH/NH) and rotational isomerism (atropisomerism) thereby generating sixteen possible structures for discussion.
The structure, 17d (NH-Z), was eventually established by a combined use of X-ray crystallography, NMR ( between OH tautomer probably in the Z conformation and the NH tautomer probably in the E conformation. The structure of the type 17a, was also reported in the case of hydrazine itself (R = H) 33 and phenylhydrazine (R = C 6 H 5 ) 27 . Nevertheless, these two works lacked a convincing spectroscopic support. Surprisingly. Djerrari et al. 34 proposed structure 19a m solution (NMR) and 19c in gas phase (mass spectrometry). ppm) was clearly shielded as compared to the one in simple pyrazolinones (-2.1 ppm). This shielding was assigned to the proximity of the I 1 -phenyl ring which was confirmed by the NOE experiments as summarized below.
It was found that if 1 1 -phenyl ring is replaced by some other moiety such a signal of 3-methyl jumps to about 8 2.4 ppm which provided another proof that the methyl protons are shielded by the phenyl group. The fact that the signal at 1.791 ppm shows both NOE's with phenyl protons and H 4~, further indicated that 17 exists in two conformations 32 . While treating 10/13/16 with a variety of hydrazines and employing different reaction conditions, an interest- ing observation concerning the mechanism of formation bipyrazoles became known. Whereas all the hydrazines provided the expected bipyrazole on treatment with 10 in the presence of strong acid; unexpected formation of pyrazol-5-ols was observed with some hydrazines on performing the reaction in ethanol-acetic acid/sodium acetate (Scheme 9). The hydrazine attacked on the terminal carbonyl carbon of the side chain giving rise to the corresponding hydrazone (20) followed by ring closure to produce an intermediate. This intermediate then underwent (i) dehydration in the presence of strong acid yielding 4,5'-bipyrazole (21) and/or (ii) C-C bond cleavage resulting in the formation of pyrazol-5-ols (22,23) in ethanol-acetic acid/sodium acetate. Formation of pyrazol-5ols (22,23) clearly indicated the cleavage of C-C bond in the proposed intermediate. The mechanism for these processes has been postulated in Scheme 9.

Conclusions
Presence of several electrophilic site in the molecule of dehydroacetic acid (3-acetyl-4-hydroxy-6-methyl-2Hpyran-2-one) makes it an attractive target for nucleophilic attack. In particular, reactions of DHAA with hydrazines provide useful synthesis involving rearrangements. These compounds undergo a wide variety of reactions leading to the formation of products, which display interesting structural features.