Journal of Molecular Structure 1036 (2013) 216–225

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Journal of Molecular Structure

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Experimental and theoretical study on one-pot, three-component route to2H-indazolo[2,1-b]phthalazine-triones catalyzed by nano-alumina sulforic acid

Ali Reza Kiasat ⇑, Siamak Noorizadeh, Mahboubeh Ghahremani, Seyed Jafar SaghanejadChemistry Department, Faculty of Science, Shahid Chamran University, Ahvaz, Iran

h i g h l i g h t s

" 2H-indazol [2,1-b]phthalazine-triones synthesized using nano-alumina sulforic acid." The protocol extended for 1H-pyrazolo[1,2-b]phthalazine-diones synthesis." The nature of each step of suggested mechanism investigated." Theoretical spectra and structural analysis performed for synthesized compounds.

a r t i c l e i n f o

Article history:Received 31 July 2012Received in revised form 6 November 2012Accepted 7 November 2012Available online 24 November 2012

Keywords:2H-indazolo[2,1-b]phthalazine-trione1H-pyrazolo[1,2-b]phthalazine-dionesMulticomponent condensation reactionNano-c-alumina sulforic acidDFT calculationsFukui functions

0022-2860/$ - see front matter � 2012 Elsevier B.V. Ahttp://dx.doi.org/10.1016/j.molstruc.2012.11.014

⇑ Corresponding author. Tel./fax: +98 611 3331746E-mail address: akiasat@scu.ac.ir (A.R. Kiasat).

a b s t r a c t

A simple, efficient, and high yielding one-pot protocol for the synthesis of 2H-indazolo[2,1-b]phthal-azine-trione derivatives has been developed by three-component coupling of phthalhydrazide, dimedoneand some aromatic aldehydes in ecofriendly neat conditions promoted by nano-c-alumina sulforic acid.This protocol avoids the use of expensive catalysts, toxic solvents and chromatographic separation. Alsothe proposed protocol was extended to the linear b-diketone (acetylaceton) instead of cyclic diketone(dimedone). The generality and functional tolerance of this convergent and environmentally benignmethod is demonstrated. The nature of each step of the suggested mechanism for this condensation reac-tion is also identified through Density Functional Theory (DFT) calculations using B3LYP/6-31G�� level oftheory. It is shown that the first step is charge controlled; whereas the second one is controlled by fron-tier molecular orbitals. The 1H and 13C chemical shift values together with the structural parameters ofthe title compound have been also computed and the scaled values have been compared with the corre-sponding experimental NMR and X-ray spectra. As a result, the calculated spectroscopic data and opti-mized geometry show a good agreement with the experimental results.

� 2012 Elsevier B.V. All rights reserved.

1. Introduction

Over the years, the fast assembly of molecular diversity utilizingmulticomponent reactions (MCRs) has received a great deal ofinterest because of their atom-economy and straightforward reac-tion design due to substantial minimization of waste, labor, time,and cost [1–4]. MCRs lead to interesting heterocyclic scaffoldswhich are particularly useful for the construction of various chem-ical libraries of privileged medicinal molecules [5–13].

In the past few decades, the main restrictions for the syntheticchemists are the use of hazardous solvents, expensive and toxicreagents, multistep protocols and generation of unwantedside-products. Nowadays, neat condition, which is providing anecofriendly system, has attracted a lot of interest due to manyadvantages such as reduced pollution, low costs and simplicity in

ll rights reserved.

.

process and handling [14]. The possibility of performing multicom-ponent reactions under neat condition with a heterogeneous cata-lyst could enhance their efficiency from an economic as well asecological point of view [15].

The applications of heterocyclic compounds in our life are unde-niable. Therefore there is an increasing demand for synthesizingnew heterocyclic compounds and this has stimulated researchactivities in the field of heterocyclic compound chemistry. Amonga large diversity of heterocyclic compounds, those containingnitrogen atom are prevalent in nature, and their biological applica-tions distinguish them [16,17]. 2H-indazolo[2,1-b]phthalazine-tri-ones which are important N-heterocycles, comprise a keystructural of numerous natural and synthetic bioactive molecules[18]. They possess multiple pharmacological and biological activi-ties such as anticonvulsant [19], cardiotonic [20], vasorelaxant[21], antimicrobial [22], antifungal [23], anticancer [24] and anti-inflammatory [25] together with unique electrical and opticalproperties [26,27]. These compounds also could be promising

NH

NH

O

O O

O

H

O

+ +

R

N

N

O

O

O

R

Nano-ASA

neat/ 110 0C

Scheme 1.

A.R. Kiasat et al. / Journal of Molecular Structure 1036 (2013) 216–225 217

materials for new luminescence or fluorescence probes [28]. De-spite many proposing methods for the synthesis of phthalazinederivatives [18,28,29–34] their wide utility has accentuated theneed to develop eco-compatible and clean synthetic routes. Re-cently, Ghorbani-Vaghei et al. proposed an efficient and valuablecatalytic system for synthesis of the titled compound [32]. Alsothe synthesis of 2H-indazolo[2,1-b]phthalazine-triones and theirrelated compound have been reported using different catalystssuch as Dodecylphosphonic acid [35], heteropoly acid in ionic li-quid [36], Ce(SO4)2�4H2O [37], sulfuric acid-modified PEG-6000[38], trimethylsilyl chloride (TMSCl) [39], Phosphomolybdic acid(PMA)-SiO2 [40], silica supported polyphosphoric acid [41], silicasulfuric acid [42] H2SO4 in water-ethanol or ionic liquid [43],Mg(HSO4)2 [44] heteropoly acids [45], wet cyanuric chloride [46],nanosilica sulfuric acid [47], p-toluenesulfonic acid (p-TSA) [48].Also recently Shekouhy and Hasaninejad proposed a catalyst-freeone-pot four component methodology for the synthesis of 2H-indazolo[2,1-b]phthalazinetriones under ultrasonic irradiation atroom temperature using 1-butyl-3-methylimidazolium bromide([Bmim]Br) [49]. However due to the multiple pharmacologicaland biological activities of these compounds, it seems that it is nec-essary to design new, easy and clean protocol and catalytic systemfor their synthesis.

Our literature survey at this stage revealed that, there is no reportyet available on the synthesis of 2H-indazolo[2,1-b]phthalazine-tri-one derivatives using c-nano-alumina sulforic acid as an efficientnanoacid catalyst under neat conditions in one-pot via three compo-nent coupling of phthalhydrazide, dimedon and an aromatic alde-hyde; see Scheme 1. Nano-alumina sulforic acid could be easilyprepared at room temperature using easy and clean reactions.

The utility of multicomponent reactions has been significantlyexpanded if they are conducted under neat condition. The purposeof the present study is to highlight the use of MCRs under neat con-ditions using nano-catalyst for the development of new ecocom-patible strategy for heterocyclic synthesis together withinvestigating the nature of each step of the reaction mechanism,theoretical structural and spectroscopic parameters.

2. Computational details

Nowadays many attempts have been made to investigate mol-ecules from theoretical point of views. Among different quantummechanical methods, Density Functional Theory (DFT) provides apowerful theoretical framework for the study of both reactivityand selectivity of molecular systems [50]. One of the key conceptsin selectivity studies is Fukui function [51] defined as:

f ðrÞ ¼ @qðrÞ@N

� �mðrÞ

ð1-1Þ

This function measures the differential changes in the electrondensity, q(r), induced by a change in the number of electrons (N)at fixed molecular geometry (m(r)). It is shown that the highly elec-trophilic/nucleophilic center is a site presenting a high value of the

associated Fukui functions. In the frozen core approximation Fukuifunction represents the density of the relevant frontier molecularorbital involved in electron receiving (nucleophilic attack) or with-drawing (electrophilic attack) processes. The condensed Fukuifunction at the kth atom using finite difference approximation isdefined as:

fþk ¼ qkðN þ 1Þ � qkðNÞ for nucleophilic attack ð2-1Þ

f�k ¼ qkðNÞ � qkðN � 1Þ for electrophilic attack ð3-1Þ

where qk(N), and qk(N � 1) are the charges of the kth atom of theconsidered molecule in neutral, anionic and cationic forms, respec-tively. At point r, f+(r) measures the reactivity toward a nucleophilicattack that leads to an electron increment in the system; whereasf�(r) measures the reactivity toward electrophilic attack which re-sult electron depletion in the system.In order to investigate the sitereactivity of a chemical system, the global descriptors of reactivityshould be included. The local softness s(r) is an appropriate localdescriptor for investigating site reactivity which is defined as [51–53]:

s�ðrÞ ¼ f�ðrÞS ð4-1Þ

where S is the global softness of the considered system which couldbe evaluated using the obtained energies of HOMO and LUMOmolecular orbital from density functional calculations (eH and eL)as:

S ¼ 1eL � eH

ð5-1Þ

To investigate the nature of the each step of the reaction mech-anism from theoretical point of views, the geometries of the reac-tants (aldehydes, phthalhydrazide, dimedone and adduct A) werefully optimized at B3LYP/6-31G�� level of theory in order to calcu-late the charges, Fukuies and local softnesses of the correspondingreactive sites. This level of theory was selected because it gives agood description for electron densities and orbital energies of thecompounds studied here [54]. In all cases the vibrational frequen-cies of the optimized structures were also calculated in order tocheck if there was a true minimum on the potential energy surface.All calculations were performed using Gaussian03 program revi-sion A.02 [55]. Atomic coordinates of the equilibrium structuresas well as the corresponding energies are also summarized in theSupplementary information.

1H and 13C NMR chemical shifts of the title compound togetherwith tetramethylsilane (TMS), were calculated within the GIAO ap-proach using HF/6-311++G�� and B3LYP/6-311++G�� levels of the-ory. The 1H and 13C NMR chemical shifts were scaled to the TMSwith the values of 32.1718 (1H) and 194.6031 (13C) ppm for HF/6–311++G�� as well as 31.9260 (1H) and 183.7553 (13C) ppm forB3LYP/6–311++G��, respectively.

218 A.R. Kiasat et al. / Journal of Molecular Structure 1036 (2013) 216–225

3. Results and discussion

3.1. Chemical synthesis

Nano-alumina sulforic acid was easily prepared by simple mix-ing of nano-alumina and chlorosulfonic acid in CH2Cl2 at roomtemperature (Scheme 2). This reaction was easy and clean, becauseHCl gas was evolved from the reaction vessel immediately.

In order to determine the acidic capacity of nano-alumina sulfu-ric acid, back titration of catalyst was applied. Hence, NaOH solu-tion (10 ml, 0.1 M) was added to the catalyst (100 mg) in anErlenmeyer flask. Excess amount of the base was neutralized byaddition of HCL solution (0.1 M) to the equivalence point of titra-tion. The required volume of HCl to this point was 4.20 mL. There-fore 5.8 mmol H+/g of solid acid was calculated for the obtainedcatalyst.

The morphology and particle size distribution of prepared alu-mina sulforic acid nanostructure was performed by measuringSEM using a Philips XL30 scanning electron microscope. Accordingto Fig. 1, nano-alumina sulforic acid with spherical shape and aver-age distribution particle size 58 nm was obtained. FT-IR spectra ofthe prepared nano-alumina sulforic acid presented in Fig. 2 showscharacteristic adsorption bands at 1010–1080 cm�1 and 1120–1230 cm�1 corresponded to asymmetric and symmetric stretchingmodes of O@S@O groups. The spectrum also shows a broad OHstretching absorption around 2800–3700 cm�1.

To evaluate the catalytic activity of nano-alumina sulforic acidin the preparation of 2H-indazolo[2,1-b]phthalazine-1,6,11(13H)-triones derivatives, the three-component coupling reaction ofphthalhydrazide (1 mmol), dimedone (1 mmol) and bezaldehyde(1.1 mmol) under thermal neat (110 �C) conditions in the absenceand presence of nano-alumina sulforic acid were examined. It wasfound that in the absence of solid acid catalyst (entry 1 in Table 1)and in the presence of nano-alumina (entry 2 in Table 1) just atrace amount of the desired product was observed on TLC plate.Also the effect of temperature on the conversion and reaction timeis checked and the results are given in Table 1. It is obvious that atroom temperature (25 �C) no considerable conversion is observedand setting the reaction temperature at 60 �C and 80 �C cause along reaction time. Therefore 110 �C is chosen as optimum temper-ature for the reaction. As it is shown in Table 1, this transformationrequires acidic catalyst; and also 0.04 g of nano-alumina sulforicacid at 110 �C could be chosen for the facile preparation of 2,2-di-methyl-13-phenyl-2,3-dihydro-1H-indazolo[2,1-b]phthalazine-4,6,11(13H)-trione. In order to establish the true effectiveness ofthe nanostructure of catalyst, the condensation reaction was alsotested using alumina sulforic acid under the same reaction condi-tion. The results presented in Table 1 clearly show that althoughthe reaction proceeded in the presence of alumina sulforic acid,the best result was obtained in the presence of nano-alumina sulf-oric acid. This may due to considerable ratio of surface to volume innanoparticles.

These remarkable results encouraged us to investigate thescope and generality of the protocol for various aromatic aldehydesunder the optimized condition. A series of aromatic aldehydes (seeTable 2) containing either electron-withdrawing or electron-donating substituents successfully react with phthalhydrazideand dimedone in the presence of nano-alumina sulforic acid at

Al2O3 OHOH

OHClSO3H

CH2Cl2/ r. t.Al2O3 OSO3H

OSO3H

OSO3H

Scheme 2.

110 �C under neat conditions and afforded good to high yields ofthe corresponding products with high purity.

With these promising results in hand and establishing theadvantages of nano-alumina sulforic acid as solid acid catalyst un-der thermal neat conditions, we focused our attention on the linearb-diketone instead of cyclic diketone. Hence, acetyl acetone waschosen and its coupling with phthalhydrazide and aromaticaldehydes under the above optimized condition and in the pres-ence of nano-alumina sulforic acid were also examined (Scheme 3).Table 3 summarizes the obtained data and clearly shows that thedesired products were formed in good isolated yields and no sideproducts were observed.

A probable mechanistic rationale portraying sequence of eventsfor this coupling reaction is postulated [32,42,48], which is shown inScheme 4. The first step is suggested to be the acid-catalyzed Knoe-venagel condensation between the corresponding aldehyde anddimedone to generate adduct A, which acts as Michael acceptor.Note that the nanoacidic catalyst protonats the aldehyde and alsoit cause enol–keto tautomerism of dimedone in the acidic conditionwhich promote the reaction. These increase the nucleophilic activ-ity of dimedone in the first step of reaction. Also the nanocatalystshave considerable active sites with respect to the ordinary catalystsdue to their considerable ratio of surface to volume. In the secondstep the phthalhydrazide attacks to adduct A in a Michael-typefashion to produce an open chain intermediate B. Intermediate Bundergoes intramolecular cyclization by the reaction of nucleo-philic amino function to carbonyl group followed by dehydrationto form 2H-indazolo[2,1-b]phthalazine-triones. The characteristicof these steps are discussed in detail in the theoretical section.

3.2. Theoretical section

3.2.1. Investigating the nature of each step of the suggestedmechanism

The chemical reactions are charge or frontier molecular orbitalcontrolled and therefore the characteristic of a given reaction couldbe determined by evaluating the charges, Fukui functions and localsoftnesses of the reactive sites in the reactants. It is shown that theelectronic charges provide the site reactivity information of ionicsystems (for charge controlled reactions; i.e. hard–hard interac-tions), while the Fukui functions are better suited where dealingwith neutral species (for frontier molecular orbital controlled reac-tions; i.e. soft–soft interaction) [56]. It should be mentioned that incharge controlled reactions those sites which have considerablecharge difference interact with each other; whereas in frontiermolecular orbital controlled reactions the sites with smallest dif-ference in their Fukui functions are interacted.

In the first step of the considered reaction, the carbon atom ofthe protonated aldehyde molecule (site I in Scheme 4) may attackby carbon atom of the dimedone (site II in Scheme 4) or the nitro-gen atom of phthalhydrazide molecule (site III in Scheme 4). Thesereactive sites are stared and numbered in Scheme 4. According tothe suggested mechanism, it is the carbon atom of dimedone (siteII) which attacked to the carbon atom of the aldehyde molecule(site I) to produce the adduct A in this step. In the second stepthe carbon atom of this adduct (site IV) may attack by site II orIII. But the obtained product verifies the interaction between sitesIII and IV in this step.

The calculated Hirshfeld charges for both neutral and cationicforms together with the evaluated condensed Fukui functions aswell as the obtained local softnesses for the reactive sites of dime-done (II) and phthalhydrazide (III) are gathered in Table 4. It isnoteworthy that the Hirshfeld [57] is a very popular populationmethod based on deformation density partition in which the ob-tained Fukui functions from this population are more reliable thanthose calculated from the other population analysis approaches

Fig. 1. The SEM images of nano-alumina at (a) 500 nm and (b) 300 nm.

Fig. 2. FT-IR spectra of the prepared nano-alumina sulforic acid.

Table 1Optimum conditions for the three-component coupling reaction of phthalhydrazide(1 mmol), dimedone (1 mmol) and benzaldehyde (1.1 mmol) under thermal neatconditions.

Entry Catalyst (g) Temperature (�C) Time (min) Conversion (%)

1 None 110 60 Trace2 Nano-alumina 110 30 Trace3 Nano-ASA (0.01) 110 19 1004 Nano-ASA (0.015) 110 16 1005 Nano-ASA (0.025) 110 14 1006 Nano-ASA (0.04) 110 12 1007 Nano-ASA (0.05) 110 10 1008 ASA (0.04) 110 50 1009 Nano-ASA (0.04) 25 120 Trace

10 Nano-ASA (0.04) 60 50 10011 Nano-ASA (0.04) 80 35 100

ASA: alumina sulforic acid.

Table 2Preparation of 2H-indazolo[2,1-b]phthalazine-triones derivatives.

Entry Aromatic aldehyde Time(min)

Isolatedyield (%)

mp (�C)a

1 C6H5CHO 14 85 205–207(204–206)

2 p-Cl C6H4CHO 12 98 264–266(262–264)

3 p-OCH3C6H4CHO 10 94 219–221(218–220)

4 p-NO2C6H4CHO 15 72 221–223(223–225)

5 p-CH3C6H4CHO 15 70 228–230(227–229)

6 p-CNC6H4CHO 20 89 226–2287 p-CF3C6H4CHO 15 78 255–2578 o-NO2C6H4CHO 15 87 251–253

(227–229)

9 o-Cl C6H4CHO 18 70 265–267(264–266)

10 m-NO2C6H4CHO 15 83 271–273(270–272)

11 p-BrC6H4CHO 20 80 263–265(265–267)

12 p-OCH3CH2C6H4CHO 20 70 228–230

a The values in parantheses are from Refs. [32,41].

A.R. Kiasat et al. / Journal of Molecular Structure 1036 (2013) 216–225 219

[58]. These quantities were also calculated for some of the consid-ered aldehydes containing electron withdrawing or electron donat-ing substitutes; which are shown in Table 5. Note that f�k =fþk wascalculated for dimedone and phthalhydrazide/aldehyde usingEqs. (3-1)/(2-1). The obtained results in Table 5 shows that in thefirst step, of all reactions Dq(I–II) > Dq(I–III); while Df(I–II) > D-f(I–III). Since according to the suggested mechanism sites I and II(those with more charge difference) were reacted to each otherto produce adduct A, therefore it seems that this step should becharge controlled. It may arise from this fact that in the first step

the aldehyde molecule is protonated and therefore it is a hard–hard interaction; which is controlled by charges. On the otherhand, in the second step of those reactions Dq(VI–II) > Dq(VI–III)but Df(VI–III) < Df(VI–II). According to the obtained product forthis reaction, sites IV and III are reacted to each other and sincethese sites have less Fukui function difference, this step shouldbe frontier molecular orbital controlled. Note that in this step thereactants are neutral and therefore a soft–soft interaction isexpected.

It is noteworthy that for reacting different molecules whichthey have different global characteristics, the analysis based on lo-cal softnesses are more reliable than those based on Fukui func-tions. Therefore the local softness values are also calculated usingEqs. (4-1) and (5-1) which are summarized in Table 6 for the con-sidered aldehydes and adduct [A]. It is obvious from Tables 4 and 6that the higher the Fukui function, the higher the local softness.Hence local softness values are also successfully predict the

Table 3Preparation of 1H-pyrazolo[1,2-b]phthalazine-diones derivatives.

Entry Aromaticaldehyde

Time(min)

Isolated yield(%)

mp

10 C6H5CHO 60 88 288–29020 p-Cl C6H4CHO 60 60 178–18030 p-OCH3C6H4CHO 120 81 159–16240 p-NO2C6H4CHO 45 77 215–217 (217–

218)a

50 p-CNC6H4CHO 60 70 183–18560 o-Cl C6H4CHO 60 67 285–287

a The values in parantheses are from Ref. [18].

NH

NH

O

O

H

O

+ +

R

N

N

O

O

O

R

Nano-ASA

neat/ 110 0C

O

O

Scheme 3.

Table 4The calculated Hirshfeld charges, the evaluated condensed Fukui functions and localsoftnesses for the reactive sites of dimedone (II) and phthalhydrazide (III) as well asthe calculated frontier molecular orbital energies and global softnesses (seeScheme 4).

Site q(N) q(N � 1) f�k eL eH S s�

II �0.0957 �0.0286 0.0672 �0.0309 �0.2269 5.1020 0.3429III �0.0350 0.1032 0.1382 �0.0574 �0.2284 5.8459 0.8079

220 A.R. Kiasat et al. / Journal of Molecular Structure 1036 (2013) 216–225

interacting sites in the second step of reaction, which is frontiermolecular orbital controlled.

3.3. 1H and 13C NMR study

The product of reaction between p-CNC6H4CHO, dimedone andphthalhydrazide (entry 6 in Table 2) was selected to compare theexperimental and the obtained theoretical NMR spectra with eachother and assigning each peak to the corresponding atom. The opti-mized geometry for this compound (using B3LYP/6-31G�� level of

OOOHO

Ar-C-H

OH+

Knoeveconden

-H3O

OO

Ar N

HNO

O

Intramolecularcyclization O

[B]

I*

*II

-H2O

Scheme 4. The suggested mechanism for the considered

theory) is presented in Fig. 3. Both of the experimental and theoret-ical 1H and 13C NMR spectra for the considered compound are gi-ven in Fig. 4 and the evaluated chemical shifts are alsosummarized in Table 7.

All of the calculated 1H/13C chemical shifts with respect to TMSare in the range of 0.663–9.949/25.133–199.292 ppm; whereas theexperimental values are observed at 1.211–8.402/28.43–192.08 ppm. The correlations between the experimental andcomputed 1H and 13C chemical shifts are depicted in Fig. 5. It isclear that although significant correlations are observed betweenthe experimental and calculated spectra, the correlation for 13Cchemical shifts (R2 = 0.998) is to some extent better than those ofprotons (R2 = 0.992). This may arise from this fact that the protonshifts are more sensitive to the solvent effects rather than 13Cshifts, whereas all of these calculations were performed in the

nagelsation

+

OO

ArHN

HNO

O

Michael-typefashion

Ar N

N

O

O

H

[A]

*III

* IV

reaction. The reactive sites were assigned by stars.

Table 5The calculated Hirshfeld charges and the evaluated condensed Fukui functions for the reactive sites of some selected aldehydes (see Scheme 4). The bold values identify thecharge controlled and frontier molecular orbital controlled nature of first and second steps, respectively.

Molecule q(N) q(N + 1) fþk Df(X-II) Dq(X-II) Df(X-III) Dq(X-III)

First step-site X = IC6H5CHO 0.1234 �0.0252 0.1486 0.0814 0.2192 0.0104 0.1584p-Cl C6H4CHO 0.1249 �0.0152 0.1400 0.0729 0.2206 0.0018 0.1598p-OMeC6H4CHO 0.1166 �0.0326 0.1492 0.0820 0.2123 0.0110 0.1515p-CNC6H4CHO 0.1299 0.0152 0.1147 0.0475 0.2256 0.0235 0.1649

Second step-site X = IVC6H5CHO 0.0193 �0.0867 0.1060 0.0388 0.1150 0.0322 0.0542p-Cl C6H4CHO 0.0180 �0.0868 0.1048 0.0377 0.1138 0.0334 0.0530p-OMeC6H4CHO 0.0161 �0.0895 0.1056 0.0384 0.1118 0.0326 0.0511p-CNC6H4CHO 0.0180 �0.0854 0.1034 0.0363 0.1137 0.0348 0.0530

Table 6The calculated local softnesses for the reactive sites of some selected aldehydes aswell as the calculated frontier molecular orbital energies and global softnesses (seeScheme 4).

Molecule eL eH S fþk s+

First step-site X = IC6H5CHO �0.0634 �0.2552 5.2138 0.1486 0.7748p-Cl C6H4CHO �0.0734 �0.2629 5.2770 0.1400 0.7388p-OMeC6H4CHO �0.0520 �0.2337 5.5042 0.1492 0.8212p-CNC6H4CHO �0.0972 �0.2757 5.6022 0.1147 0.6426

Second step-site X = IVC6H5CHO �0.0903 �0.2393 6.7114 0.1060 0.7114p-Cl C6H4CHO �0.0972 �0.2428 6.8700 0.1048 0.7200p-OMeC6H4CHO �0.0822 �0.2213 7.1896 0.1056 0.7592p-CNC6H4CHO �0.1117 �0.2528 7.0847 0.1034 0.7326

Fig. 3. The optimized geometry of entry 6.

A.R. Kiasat et al. / Journal of Molecular Structure 1036 (2013) 216–225 221

gas phase. However these slight different is negligible. Note thatthe evaluated slopes for both graphs are close to unity (0.952and 1.059 for 1H and 13C spectra, respectively) which indicatesthe similarity between the experimental and the correspondingcalculated spectra.

In Fig. 4 all of the observed peaks in simulated 1H and 13C spec-tra are assigned to the corresponding atoms. In the previous re-ports [29–34] the observed 1H peak at 3.2–3.4 ppm was assignedto the hydrogen atoms of dimedone molecule; i.e. those hydrogenwhich are close to the carbonyl group (H36 and H37 in Fig. 3). Butthe presented calculations show that this peak is corresponded tothe H38 (observed at 3.677 and 3.522 ppm using B3LYP and HFmethods respectively), which because of its closeness to the nitro-gen atom (N9) has a different chemical environment with respectto H39 (observed at 2.715 and 2.652 ppm using B3LYP and HFmethods respectively) and therefore appears in the up field.Fig. 3 shows that H36 and H37 are far from the carbonyl groupand therefore they appear at 2.147 and 2.238 ppm using B3LYP,respectively. It should be mentioned that assigning the observedpeak at 3.677 to H36 or H37 reduces the correlation coefficientof experimental vs. calculated curve to 0.971 and 0.969 from0.991and 0.990 for HF and B3LYP methods, respectively.

3.4. Structural study

The optimized geometry for the product of reaction between p-BrC6H4CHO, dimedone and phthalhydrazide (entry 11 in Table 2)using B3LYP/6-311++G�� level of theory is presented in Fig. 6. Tocheck the reliability of the optimized structure, it is attempted tofind the correlation between the obtained bond lengths from thiscalculation and those which are reported in the X-ray data [48].The calculated values for some selected bond lengths and the cor-responding experimental data are given in Table 8 for comparison;and the correlation between these bond lengths are also shown inFig. 7. The closeness of the obtained slope to unity (0.996) and neg-

ligible intercept (0.007) imply to significant correlation betweenthe optimized structure and the reported experimental data.

4. Conclusion

Efficient one-pot condensation of aldehyde, dimedone, andphthalhydrazide has been achieved in the presence of a catalyticamount of nano-alumina sulfuric acid under neat conditions. Avariety of 2H-indazolo-[1,2-b] phthalazinetrione derivatives wereprepared in high to excellent yields in short time. Also the pro-posed protocol was extended to the linear b -diketone (acetylace-ton) instead of cyclic diketone (dimedone). Moreover, DFTcalculations are applied to identify the nature of each step of thesuggested mechanism for this condensation reaction. The obtainedresults show that the first step is charge controlled; whereas thesecond one is controlled by frontier molecular orbitals. The calcu-lated 1H and 13C chemical shifts and some structural parameters(bond lengths) for the titled compound show a good agreementwith the experimental data.

5. Experimental

5.1. General

All commercially available chemicals were purchased from Flu-ka and Merck companies and used without further purification. IR

Fig. 4. The obtained experimental (a) 1H NMR and (b) 13C NMR spectra together with theoretical (c) 1H NMR and (d) 13C NMR spectra simulated at HF/6-311++G�� togetherwith (e) 1H NMR and (f) 13C NMR spectra simulated at B3LYP/6-311++G�� for the entry 6 (see Fig. 3).

222 A.R. Kiasat et al. / Journal of Molecular Structure 1036 (2013) 216–225

spectra were recorded on a BOMEM MB-Series 1998 FT-IR spectro-photometer. 1H and 13C NMR spectra were recorded in CDCl3 on aBruker Advanced DPX 400 MHz spectrometer using TMS as inter-nal standard. Reaction monitoring were accomplished by TLC onsilica gel polygram SILG/UV 254 plates.

5.2. Preparation of nano-c-alumina-sulforic acid (nano-ASA)

A 50 mL suction flask which is equipped with a constant pres-sure dropping funnel was applied. It contained nano-c-alumina(3 g) and charged with chlorosulfonic acid (0.8 mL, 12 mmol) indry CH2Cl2 (3.5 mL) which was added dropwise over a period of30 min at room temperature. Note that during this process HClgas was evolved immediately, hence the gas outlet was connectedto a vacuum system through an alkali trap. The obtained mixturewas shaken for 1 h. Then the mixture was washed with excess

dry CH2Cl2 to remove the unreacted chlorosulfonic acid. Finally, awhite solid powder was obtained.

5.3. Typical procedure for the preparation of 2H-indazolo[2,1-b]phthalazine-triones

A mixture of dimedone (0.14 g, 1 mmol), phthalhydrazide(0.16 g, 1 mmol), aromatic aldehyde (1 mmol) or acetyl acetone(0.20 g, 2 mmol), phthalhydrazide (0.16 g, 1 mmol), aromatic alde-hyde (1 mmol) together with Nano-ASA (0.04 g) was heated at110 �C for the corresponding time (see Table 2 and 3). Completionof the reaction was indicated by TLC [TLC acetone/n-hexane(3:10)]. After completion of the reaction, the solid residue was dis-solved in ethanol and nano-alumina sulfuric acid was filtered. Thecrude product was purified by recrystallization in aqueous ethanolto afford the pure product.

Table 7The calculated (dCalc.) and experimental (dExp.) chemical shift values of 1H NMR and 13C NMR for the entry 6.

Atom dCalc. dExp. Atom dCalc. dExp.

HF B3LYP HF B3LYP

C-16 199.292 202.941 192.080 33-H 9.149 8.745 8.262–8.402 (8.332)C-10 163.000 170.355 155.970 31-H 9.006 8.631C-7 160.087 168.365 154.550 34-H 8.185 7.932 7.891–7.914 (7.903)C-15 158.761 166.988 151.610 32-H 8.213 7.921C-22 150.278 155.969 141.590 49-H 8.177 7.786 7.646–7.666 (7.565)C-2 140.430 143.908 134.820 48-H 7.900 7.621C-27 139.948 143.539 133.950 46-H 8.483 8.283 7.553–7.574 (7.564)C-6 139.322 141.470 132.620 47-H 7.383 7.030C-25 139.628 141.470 132.620 35-H 6.300 6.589 6.476C-23 137.883 139.140 128.950 38-H 3.522 3.677 3.244–3.440 (3.342)C-3 135.744 138.432 128.670 39-H 2.652 2.715C-5 135.122 138.008 128.230 37-H 2.064 2.238 2.356C-4 135.632 138.008 128.230 36-H 2.145 2.147C-1 134.929 136.140 127.900 40-H 1.097 1.237 1.211–1.256 (1.234)C-24 129.412 130.403 127.790 43-H 1.124 1.223C-14 125.750 126.363 118.450 44-H 1.265 1.206C-26 123.982 120.331 117.400 45-H 1.065 1.025C-29 118.918 119.932 112.530 41-H 0.765 0.671C-13 70.113 59.902 64.420 42-H 0.663 0.638C-17 54.623 47.690 50.840C-19 41.615 35.559 38.040C-18 41.319 31.245 34.750C-21 34.908 30.055 28.690C-20 26.101 25.133 28.430

Fig. 5. The correlations between the experimental and calculated (a) and (b) 13C NMR together with (c) and (d) 1H NMR chemical shifts of the entry 6 using HF and B3LYPmethods.

A.R. Kiasat et al. / Journal of Molecular Structure 1036 (2013) 216–225 223

– 13-(4-Cyanophenyl)-3,3-dimethyl-3,4-dihydro-2H-indazol-o[1,2-b]phthalazine-1,6,11(13H)-trione (Table 2, entry 6). Yel-low powder (89%); mp 226–228 �C; Rf (23% acetone/n-hexane)0.25; IR (KBr) (mmax, cm�1) 2961, 2227, 1667, 1623, 1473; dH

(400 MHz, CDCl3) 1.23 (6H, s, 2Me), 2.35 (2H, s,CH2CO), 3.24–3.414 (2H, AB system, CHaHbCH2), 6.47 (1H, s, CHN), 7.29–7.66 (4H, dd, ArCN), 7.89–8.40 (4H, m, Ph); dc (400 MHz,

CDCl3); 28.43, 28.69, 34.75, 38.04, 50.84, 64.42, 112.53, 117.4,118.45, 127.79, 127.9, 128.23, 128.67, 128.67, 128.95, 132.62,133.95, 133.95, 134.82, 141.59, 151.61, 154.55, 155.97, 192.08.

– 3,3-Dimethyl-13-(4-trifluoromethylphenyl)-3,4-dihydro-2H-indazolo [1,2-b]phthalazine-1,6,11(13H)-trione (Table 2, entry7). Yellow powder (78%); mp 255–257 �C; Rf (23% acetone/n-hexane) 0.25; IR (KBr) (mmax, cm�1) 2961, 1654, 1667, 1357,

Fig. 6. The optimized geometry of entry 11.

Table 8Some of the optimized (B3LYP/6-311++G��) and experimental bond lengths of theentry 11(see Fig. 6).

Bond RCalc. RExp. Bond RCalc. RExp.

C26ABr48 1.904 1.891 C1AC3 1.400 1.400C18AC19 1.555 1.541 C24AC22 1.399 1.387C17AC18 1.548 1.527 C15AN9 1.398 1.390C18AC20 1.544 1.534 C22AC23 1.397 1.379C18AC21 1.539 1.528 C23AC27 1.396 1.377C16AC17 1.526 1.510 C25AC24 1.395 1.384C13AC22 1.526 1.514 C26AC25 1.394 1.367C13AC14 1.512 1.449 C27AC26 1.393 1.380C19AC15 1.497 1.488 C1AC2 1.392 1.362C3AC7 1.483 1.476 N9AC10 1.392 1.381N8AC13 1.480 1.480 C6AC5 1.391 1.387C14AC16 1.457 1.449 C7AN8 1.372 1.356N8AN9 1.418 1.419 C14AC15 1.356 1.344C3AC4 1.407 1.386 C7AO11 1.230 1.221C2AC6 1.403 1.380 C16AO28 1.229 1.223C4AC5 1.403 1.404 C10AO12 1.228 1.216

Fig. 7. The correlation between the calculated and experimental values of someselected bond lengths in the backbone of the entry 11.

224 A.R. Kiasat et al. / Journal of Molecular Structure 1036 (2013) 216–225

1261; dH (400 MHz, CDCl3) 1.25 (6H, s, 2Me), 2.36 (2H,s,CH2CO), 3.25-3.46 (2H, AB system, CHaHbCH2), 6.51 (1H, s,CHN), 7.29–7.63 (4H, dd, ArCN), 7.88–8.41 (4H, m, Ph); dC

(400 MHz, CDCl3); 28.44, 28.71, 34.73, 38.06, 50.88, 64.44,117.86, 125.82, 125.85, 127.49, 127.80, 128.16, 128.82,128.98, 133.83, 134.74, 140.36, 151.36, 154.49, 192.12.

– 2-Acetyl-3-methyl-1-(4-Cholorophenyl)-1H-pyrazolo[1,2-b]phthalazine-5,10-dione: (Table 3, entry 20)Yellow powder(60%); mp 178–180 �C; Rf (23% acetone/n-hexane); 0.25; IR(KBr) (mmax, cm�1) 2938, 1660, 1624, 1362, 1310; dH

(400 MHz, CDCl3) 2.28 (s, 3H, CH3), 3.09 (s, 3H, COCH3), 6.49(s, 1H, CH), 7.35–7.45 (dd, 2H, ArH), 7.83–7.86 (m, 2H, ArH),8.23–8.26 (dd,3H, ArH), 8.35–8.36 (m, 1H, ArH). dC (400 MHz,CDCl3); 14.65, 30.69, 65.45, 118.83, 127.36, 128.10, 128.67,129.16, 129.50, 129.63, 133.62, 134.34, 134.97, 135.07,146.33, 154.24, 156.28, 193.02.

– 2-Acetyl-3-methyl-1-(4-Cyanophenyl)-1H-pyrazolo[1,2-b]phthalazine-5,10-dione: (Table 3, entry 5) Yellow powder(70%); mp 183–185 �C; Rf (23% acetone/n-hexane); 0.25; IR(KBr) (mmax, cm�1) 2964, 2230, 1665, 1630, 1494; dH

(400 MHz, CDCl3) 2.22 (s, 3H, CH3), 3.09 (s, 3H, COCH3), 6.52(s, 1H, CH), 7.60–769 (dd, 2H, ArH), 7.85–7.88 (m, 2H, ArH),8.22–8.24 (dd, 3H, ArH), 8.36–8.39 (m, 1H, ArH).

Acknowledgment

We are grateful to the Research Council of Shahid Chamran Uni-versity for financial support.

Appendix A. Supplementary material

Supplementary data associated with this article can be found, inthe online version, at http://dx.doi.org/10.1016/j.molstruc.2012.11.014.

References

[1] A. Basso, L. Banfi, R. Riva, G. Guanti, J. Org. Chem. 70 (2005) 575.[2] S.T. Staben, N. Blaquiere, Angew. Chem. Int. Ed. 49 (2010) 325.[3] T. Yue, M.X. Wang, D.X. Wang, G. Masson, J. Zhu, J. Org. Chem. 74 (2009) 8396.[4] N. Ma, B. Jiang, G. Zhang, S.J. Tu, W. Wever, G. Li, Green Chem. 12 (2010) 1357.[5] C. Hulme, V. Gore, Curr. Med. Chem. 10 (2003) 51.[6] J.D. Sunderhaus, C. Dockendorff, S.F. Martin, Org. Lett. 9 (2007) 4223.[7] F.L. Muller, T. Constantieux, J.J. Rodriguez, J. Am. Chem. Soc. 127 (2005) 17176.[8] C. Haurena, E.L. Gall, S. Sengmany, T. Martens, M.J. Troupel, J. Org. Chem. 75

(2010) 2645.[9] L.F. Tietze, M.E. Lieb, Curr. Opin. Chem. Biol. 2 (1998) 363.

[10] S. Kanakaraju, B. Prasanna, S. Basavoju, G.V.P. Chandramouli, J. Mol. Struct.1017 (2012) 60.

[11] M.M. Heravi, B. Baghernejad, H.A. Oskooie, R. Hekmatshoar, Tetrahedron Lett.19 (2008) 6101.

[12] Z. Khodaee, A. Yahyazadeh, N.O. Mahmoodi, M.A. Zanjanchi, V. Azimi, J. Mol.Struct. 1029 (2012) 92.

[13] W.B. Chen, Z.J. Wu, Q.L. Pei, L.F. Cun, X.M. Zhang, W.C. Yuan, Org. Lett. 12(2010) 3132.

[14] K. Tanaka, F. Toda, Chem. Rev. 100 (2000) 1025.[15] A. Kumar, R.A. Maurya, Tetrahedron 63 (2007) 1946.[16] E.C. Franklin, Chem. Rev. 16 (1935) 305.[17] F.W. Lichtenthaler, Acc. Chem. Res. 35 (2002) 728.[18] G. Shukla, R.K. Verma, G.K. Verma, M.S. Singh, Tetrahedron Lett. 52 (2011)

7195.[19] L. Zhang, L.P. Guan, X.Y. Sun, C.X. Wei, K.Y. Chai, Z.S. Quan, Chem. Bio. Drug

Des. 73 (2009) 313.[20] Y. Nomoto, H. Obase, H. Takai, M. Teranishi, J. Nakamura, K. Kubo, Chem.

Pharm. Bull. 38 (1990) 2179.[21] N. Watanabe, Y. Kabasawa, Y. Takase, M. Matsukura, K. Miyazaki, H. Ishihara,

K. Kodama, H.J. Adachi, J. Med. Chem. 41 (1998) 3367.[22] S.S. El-Sakka, A.H. Soliman, A.M. Imam, Afinidad 66 (2009) 167.[23] C.K. Ryu, R.E. Park, M.Y. Ma, J.H. Nho, Bioorg. Med. Chem. Lett. 17 (2007) 2577.[24] J. Li, Y.F. Zhao, X.Y. Yuan, J.X. Xu, P. Gong, Molecules 11 (2006) 574.[25] J. Sinkkonen, V. Ovcharenko, K.N. Zelenin, I.P. Bezhan, B.A. Chakchir, F. Al-

Assar, K. Pihlaja, Eur. J. Org. Chem. (2002) 2046.[26] V.P. Litvinov, Russ. Chem. Rev. 72 (2003) 69.

A.R. Kiasat et al. / Journal of Molecular Structure 1036 (2013) 216–225 225

[27] Y. Xu, Q.X. Guo, Heterocycles 63 (2004) 903.[28] H. Wu, X.M. Chen, Y. Wan, H.Q. Xin, H.H. Xu, R. Ma, C.H. Yue, L.L. Pang, Lett.

Org. Chem. 6 (2009) 219.[29] Y.K. Ramtohul, M.N.G. James, J.C.J. Vederas, J. Org. Chem. 67 (2002) 3169.[30] A. Csampai, K. Kormendy, F. Ruff, Tetrahedron 47 (1991) 4457.[31] R. Ghahremanzadeh, G.I. Shakibaei, A. Bazgir, Synlett (2008) 1129.[32] R. Ghorbani-Vaghei, R. Karimi-Nami, Z. Toghraei-Semiromi, M. Amiri, M.

Ghavidel, Tetrahedron 67 (2011) 1930.[33] R. Ghahremanzadeh, S. Ahadi, M. Sayyafi, A. Bazgir, Tetrahedron Lett. 49

(2008) 4479.[34] L.P. Liu, J.M. Lu, M. Shi, Org. Lett. 9 (2007) 1303.[35] M. Kidwai, A. Jahan, R. Chauhan, N. Mishra, K. Neeraj, Tetrahedron Lett. 53

(2012) 1728.[36] R. Fazaeli, H. Aliyan, N. Fazaeli, Open Catal. J. 3 (2010) 14.[37] E. Mosaddegh, A. Hassankhani, Tetrahedron Lett. 52 (2011) 488.[38] A. Hasaninejed, M.R. Kazerooni, A. Zare, Catal. Today, 2012. <http://dx.doi.org/

10.1016/j.cattod.2012.05.026>.[39] L. Nagarapu, R. Bantu, H.B. Mereyala, J. Heterocy. Chem. 46 (2009) 728.[40] G. Sabitha, C. Srinivas, A. Raghavendar, J.S. Yadav, Helv. Chim. Acta 93 (2010)

1375.[41] H.R. Shaterian, A. Hosseinian, M. Ghashang, ARKIVOC 2 (2009) 59.[42] H.R. Shaterian, M. Ghashang, M. Feyzi, Appl. Catal. A: Gen. 345 (2008) 128.[43] J.M. Khurana, D. Magoo, Tetrahedron Lett. 50 (2009) 7300.[44] H.R. Shaterian, F. Khorami, A. Amirzadeh, R. Doostmohammadi, M. Ghashang, J.

Iran. Chem. Res. 2 (2009) 57.[45] H.J. Wang, X.N. Zhang, Z.H. Zhang, Monatsh. Chem. 141 (2010) 425.[46] X. Wang, W.W. Ma, L.Q. Wu, F.L. Yan, J. Chin. Chem. Soc. 57 (2010) 1341.

[47] H. Hamidian, S. Fozooni, A. Hassankhani, S.Z. Mohammadi, Molecules 16(2011) 9041.

[48] M. Sayyafi, M. Seyyedhamzeh, H.R. Khavasi, A. Bazgir, Tetrahedron 64 (2008)2375.

[49] M. Shekouhy, A. Hasaninejad, Ultrason. Sonochem. 19 (2012) 307.[50] W. Kohn, A.D. Becke, R.G. Parr, J. Phys. Chem. 100 (1996) 12974.[51] R.G. Parr, W. Yang, J. Am. Chem. Soc. 106 (1984) 4049.[52] Y. Yang, R.G. Parr, Proc. Natl. Acad. Sci. USA 82 (1985) 6723.[53] K.R.S. Chandrakumar, S. Pal, J. Phys. Chem. A 106 (2002) 5737.[54] R.K. Roy, S. Krishnamnrti, P. Geerlings, S. Pal, J. Phys. Chem. A 102 (1998) 3746.[55] M.J. Frisch, G.W. Trucks, H.B. Schlegel, G.E. Scuseria, M.A. Robb, J.R. Cheeseman,

V.G. Zakrzewski, J.A. Montgomery Jr., R.E. Stratmann, J.C. Burant, S. Dapprich,J.M. Millam, A.D. Daniels, K.N. Kudin, M.C. Strain, O. Farkas, J. Tomasi, V.Barone, M. Cossi, R. Cammi, B. Mennucci, C. Pomelli, C. Adamo, S. Clifford, J.Ochterski, G.A. Petersson, P.Y. Ayala, Q. Cui, K. Morokuma, D.K. Malick, A.D.Rabuck, K. Raghavachari, J.B. Foresman, J. Cioslowski, J.V. Ortiz, A.G. Baboul,B.B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaromi, R. Gomperts, R.L.Martin, D.J. Fox, T. Keith, M.A. Al-Laham, C.Y. Peng, A. Nanayakkara, C.Gonzalez, M. Challacombe, P.M.W. Gill, B. Johnson, W. Chen, M.W. Wong, J.L.Andres, C. Gonzalez, M. Head-Gordon, E.S. Replogle, J.A. Pople, Gaussian 03;Revision A.02 Gaussian, Inc.: Pittsburgh, PA, 2003.

[56] J. Melin, F. Aparicio, V. Subramanian, M. Galván, P.K. Chattaraj, J. Phys. Chem. A108 (2004) 2487.

[57] F.L. Hirshfeld, Theor. Chim. Acta. 44 (1977) 129.[58] F. De Proft, C. Van Alsenoy, A. Peeters, W. Langenaeker, P. Geerlings, J. Comput.

Chem. 23 (2002) 1198.