Solvent-free organic salt media mono symmetrical aza-Michael: synthesis of new N-mono substituted phthalhydrazide derivatives

ABSTRACT In this paper, C–N bond formation between 2,3-dihydrophthalazine-1(4H),4-dione (phthalhydrazide) and α,β-unsaturated esters was investigated and a new series of phthalazine derivatives was synthesized using an efficient and simple method under solvent-free conditions. An aza-Michael addition of phthalhydrazide to both acrylic and fumaric esters led to N-mono-substituted phthalhydrazides (as mono-Michael adduct) in the presence of tetrabutylammonium bromide as a high polar media, and 1,4-diaza-bicyclo[2,2,2]octane as an available organic base. In this reaction, the N1,N2-bis-Michael adduct was not observed at all. Also, reactions were performed at 90°C and yields of products were good to excellent. GRAPHICAL ABSTRACT

Although there are many reports of the synthesis of phthalazine derivatives (23)(24)(25)(26)(27), their broad utility range has accentuated the need to develop newer methods and the synthesis of novel derivatives of these compounds. Herein, in line with our interest in the aza-Michael addition reaction of amides and imides to α, β-unsaturated esters and the scientific interest in this method (28)(29)(30)(31)(32)(33)(34)(35)(36), and also in continuation of our previous work on the synthesis of nitrogen-containing heterocyclic compounds, using the Michael addition reaction of 4-phenylurazole to α,β-unsaturated esters (37,38),we decided to synthesize a new collection of biologically active compounds. Recently, we reported the synthesis of N1,N2-disubstituted 4-phenylurazole derivatives by Michael addition of this symmetric Michael donor to diverse acrylic esters (37). Also, we reported the reaction between 4-phenylurazole and symmetric fumaric esters that led to produce an unexpected product (38). In order to extend these reactions to other similar symmetrical Michael donors; herein, we report the addition of 2,3-dihydrophthalazine-1(4H ),4-dione (phthalhydrazide) to α,β-unsaturated esters under solvent-free conditions (Scheme 1).

Experimental
Phthalhydrazide and α,β-unsaturated esters were synthesized according to literature procedures (39,40 General procedure for the Michael addition of phthalhydrazide to α,β-unsaturated esters A well-ground mixture of phthalhydrazide (1.0 mmol), DABCO (1.0 mmol) and TBAB (1.0 mmol) was placed in a flask. α,β-Unsaturated ester (1.2 mmol) was added to this mixture and the flask was heated in the oil bath. When the oil bath temperature reached 90°C, a brown solution was formed. After keeping the reaction flask at this temperature for the stipulated time (Table 3), the reaction was completed as monitored by TLC. Then, the flask was allowed to cool down to room temperature and chloroform (20 mL) was added. The solution was stirred to dissolve all the solids. TBAB was recovered by the addition of water (3 × 20 mL) to this solution and then collected and dried under vacuum. The chloroform layer was washed with water (3 × 15 mL). After dried with sodium sulfate and the removal of the organic solvent, the residue was purified on short silica-gel column with n-hexane/ethyl acetate (8:2) as the eluent.  13

Results and discussion
Considering the above reports and our interest in applying the solvent-free system conditions, we first investigated aza-Michael addition of phthalhydrazide 1 to ethyl acrylate 2b as the model reaction, in the presence of TBAB and various organic and inorganic bases to evaluate their capabilities and selectivity (Scheme 2). In our initial study, we found that mono-substituted phthalhydrazide (mono-Michael adduct) 3b was the only product and no di-substituted phthalhydrazide (bis-Michael adduct) 4 was produced at all. The steric hindrance of the first alkyl group (at N1 or N2 atoms) prevents the addition of the second alkyl group. We tried to perform the reaction with twice the amount of ethyl acrylate to obtain bis-Michael adduct, but observed that mono-Michael adduct was the exclusive product of the reaction. These results indicated that in this reaction, the steric effects outweigh the electronic effects, so that further alkylation does not tend to occur. Among the tested bases, the best result was obtained when DABCO was used as base in the model reaction and afforded good yield of 85% after 10 h ( In another study, we investigated the effect of different solvents on this reaction ( Table 2). In this study, we observed that when TBAB was used instead of solvent, mono-Michael adduct was obtained in a good yield ( Table 2, entry 10). The model reaction failed in most organic solvents, for example DMF, CH 2 Cl 2 , MeOH, CH 3 CO 2 Et and H 2 O (Table 2, entries 1 , 4, 5, 8, 9) at their boiling points. After refluxing for 10 h, a trace amount of mono-Michael adduct was obtained in CHCl 3 and EtOH (Table 2, entries 3,6). Also, a low yield of product 3b was afforded in DMSO, acetone and no solvent media (Table 2, entries 2,7,11).
Next, we optimized the amount of phthalhydrazide, ethyl acrylate, TBAB and DABCO. The best result was obtained with 1.0 mmol of phthalhydrazide, TBAB, DABCO and 1.2 mmol of ethyl acrylate. With the optimized reaction conditions in hand, the scope and limitation of reaction were explored using phthalhydrazide and a variety of acrylic esters. The results are summarized in Table 3 (Table 3, entries 1-7).
It is seen from the results in Table 3 that the reaction with acrylic esters proceeded smoothly and afforded the corresponding products in good to excellent yields. Also, it was observed that the bulky alkoxy groups (-OR) of the acrylic esters did not have a significant effect on the reaction yields and times under the model reaction conditions (Table 3, entries 2-5, 7).
Since the reaction between 4-phenylurazole and fumaric esters produced unexpected products (38), we were interested in testing other similar symmetrical double-Michael      (38) and phthalhydrazide 1 with fumaric esters can be ascribed to the fact that the carbon atom of the carbonyl group in 4-phenylurazole is more reactive than the one in phthalhydrazide. Next, we investigated the generality of this reaction with other fumaric esters (Table 3, entries 8-22). From Table 3, it is clear that generally, in the reaction in which alkoxy fumarates were employed, the corresponding mono-Michael adducts 3 were produced in moderate to good yields within 15-20 h (Table 3, entries 9-13 and 15-18). However, when benzyloxy fumarates were employed as Michael acceptors, the TLC test did not show any progress in the reaction, even after a long time of 120 h (Table 3, entries 20-22). These results can be attributed to the increased steric hindrance of the Michael acceptors. The existence of hindered -OR groups on fumaric esters make them a weak Michael acceptor and hence, addition is much more difficult. Whereas the addition to cyclohexyl fumarate (bearing large -OR groups) provided a relatively low yield of product (Table 3, entries 18), the addition of Michael donor 1 to linear fumaric esters, for example ethyl, propyl, butyl, pentyl and hexyl fumarate afforded the related mono-substituted phthalhydrazide in good yields (Table 3, entries 9-13). However, when octyl fumarate was employed as a Michael acceptor, reactivity was low and no product was observed in the TLC test because of the long chain alkoxy group n-octyloxy (Table 3, entry 14). It is important to note that when α, β-unsaturated esters containing small alkoxy groups were used as Michael acceptors, the desired Michael adducts were not obtained and the related carboxylic acids of the employed esters resulted as the only product of these reactions (Table 3, entries 1,6,8). We believe that these α,β-unsaturated esters are more susceptible to hydrolysis due to their smaller alkoxy groups (-OMe) under the reaction conditions. Also, it was interesting that in the case of 2-methoxyethyl fumarate, the reaction was unsuccessful (Table 3, entry 19). This can be attributed to methoxy group at 2-position of the alkoxy moiety of this ester. Due to the electronegative oxygen atom at the 2-position of this moiety, the bond length is decreased and, consequently, a condensed Michael acceptor is provided that the nucleophilic attack becomes difficult on it.

Conclusions
In summary, we developed a novel, effective, clean, and environment-friendly procedure for the synthesis of new phthalazine derivatives in the presence of TBAB as a high polar media under solvent-free conditions. It was found that among the various organic and inorganic bases, DABCO was a more suitable base and mono-substituted phthalhydrazide (as mono-Michael adduct) was the sole product of the reaction. Also, we observed that in this reaction when fumaric esters were used as Michael acceptors, the structure of the alkoxy group had a significant effect on the reaction yield and time.

Disclosure statement
No potential conflict of interest was reported by the authors.

Notes on contributors
Zahra Soltanzadeh was born in 1984. She is studying for a doctorate at the University of Mahaghegh Ardabili. Her research has focused on the synthesis and development of new organic compounds under solvent-free conditions. Ertan Şahin is a professor in Atatürk University and mainly investigating on the structure of organic compounds. He received his Ph.D. degree in Engineering Physics.