Molecular Iodine : A Versatile Catalyst for the Synthesis of 2 H-indazolo [ 2 , 1-b ] phthalazine-1 , 6 , 11 ( 13 H )-trione Derivatives in Ethanol

An efficient method for the synthesis of 2H-indazolo[2,1-b] phthalazine-1,6,11(13H)-trione derivatives by a three-component condensation reaction of dimedone, aromatic aldehydes and phthalhydrazide in the presence of a catalytic amount of molecular iodine in ethanol is described.


Introduction
Phthalazine derivatives have attracted considerable attention in recent years because of their wide range of pharmaceutical activities such as antimicrobial 1 , anticonvulsant 2 , antifungal 3 , anticancer 4 , and anti-inflammatory 5 activities.Therefore, a number of methods have been reported for the synthesis of phthalazine derivatives 6 .Nevertheless the development of new synthetic methods for the efficient preparation of heterocycles containing phthalazine ring fragment is therefore an interesting challenge.Recently, synthesis of 2H-indazolo[2,1-b]phthalazine-1,6,11(13H)-trione derivatives have been reported [7][8][9][10][11] using p-TSA, Me 3 SiCl, silica sulfuric acid, H 2 SO 4 , Mg(HSO 4 ) 2 and silica supported poly phosphoric acid 12 as catalysts.However, many of these methodologies are associated with one or more disadvantages such as use of expensive catalyst or toxic organic solvents, strong acidic conditions and harsh reaction conditions.
In recent years, the usage of molecular iodine has drawn considerable attention as an inexpensive, nontoxic, readily available catalyst for various organic transformations to afford the corresponding products in excellent yields with high selectivity.The mild Lewis acidity associated with iodine enhances its usage in organic synthesis to realize several organic transformations using stoichiometric levels or even catalytic amounts 13 .As a part of our studies to explore the utility of iodine-catalyzed reactions 14 , we proceeded to examine the synthesis of 2H-indazolo[2,1-b]phthalazine-1,6,11(13H)-trione derivatives in the presence of molecular iodine in ethanol (Scheme 1).

Experimental
NMR spectra were determined on Bruker AV-400 spectrometer at room temperature using TMS as internal standard, coupling constants (J) were measured in Hz; Elemental analysis were performed by a Vario-III elemental analyzer; Melting points were determined on a XT-4 binocular microscope and were uncorrected; commercially available reagents were used throughout without further purification unless otherwise stated.

Results and Discussion
In a preliminary study, the effect of amount of the catalyst on the reaction yield of 2H-indazolo [2,1-b]phthalazine-1,6,11(13H)-trione derivatives was investigated with the reaction of dimedone, benzaldehyde and phthalhydrazide as a model reaction in ethanol at reflux temperature.As shown in Table 1, in the absence of catalyst no product was obtained.We found that 10 mol% of the catalyst was sufficient to mediate the reaction toward the formation of the corresponding 2H-indazolo[2,1-b]phthalazine-1,6,11(13H)-trione in excellent yield.The lower quantities of the catalyst (i.e. 5 mol%) also gave moderate yield of the product at longer reaction time.To find the optimal solvent for this reaction, the synthesis of 4a was carried out at 80 °C or reflux temperature using ethanol, H 2 O, CH 2 Cl 2 , DMF and CH 3 CN as solvents, respectively.It is shown in Table 2 that the reactions with ethanol as solvent resulted in higher yield than other solvents.So ethanol was chosen as the solvent of this reaction.4) was synthesized by the reaction of dimedone (1, 1 mmol), aromatic aldehydes (2, 1 mmol) and phthalhydrazide (3, 1 mmol).The reaction proceeded at reflux within 30 min in excellent yields after the addition of 10 mol% I 2 .Table 3 shows that both electron-deficient and electron-rich aromatic aldehydeswere converted to the corresponding 2H-indazolo[2,1-b]phthalazine-1,6,11(13H)-trione derivatives in moderate yields.The structures of the products were established from their spectral properties ( 1 H NMR, 1 C NMR and elemental analysis).The plausible mechanism of the reaction is shown in Scheme 2. It is conceivable that molecular iodine is capable of binding with the carbonyl oxygen increasing the reactivities of parent carbonyl as it behaves as a mild lewis acid.First molecular iodine activates carbonyl group of aromatic aldehyde to give iodine-aldehyde complex I and thus increases the electrophilicity carbonyl carbon of aldehyde.Nuleophilic addition of dimedone to I to give II and followed by loss of H 2 O from II to afford III, which is further activated by iodine.Subsequent Michael-type addition of phthalhydrazide to the olefin afford the corresponding products 4a-4k.

Table 1 .
The amounts of catalyst optimization for the synthesis of 4a a b Isolated yield

Table 2 .
Solvent optimization for the synthesis of 4a a