Simple synthesis of new imidazopyridinone, pyridopyrimidinone, and thiazolopyridinone derivatives and optimization of reaction parameters using response surface methodology

The reaction between ketene animal/ketene N,S-acetals (derived from diamines/cysteamine hydrochloride and 1,1-bis(methylthio)-2-nitroethene) with aromatic aldehydes, and Meldrum's acid led to the title compounds. The reaction conditions were optimized using response surface methodology (RSM). The two independent variables (temperature and water content of aqueous ethanol), and the responses (yield of product and reaction time) were studied. The range of each parameter selected was: T = 25–100 °C and water = 0–100%. The optimal values were: T = 72 °C and water = 33%. This work offers significant advantages including use of a green solvent, experimental simplicity, absence of catalyst, a simple work-up and purification process, moderate to good yields, and preparation of potentially bioactive compounds.


Introduction
Response surface methodology (RSM) is the most popular optimization method used in recent years. RSM is a powerful mathematical and statistical technique which has been widely used for designing experiments and empirical building models with minimal experimental number. This method is exclusively used to examine the surface, or the relationship between the response and the factors affecting the response. The application of RSM to design optimization is aimed at reducing the cost of expensive analysis methods and their associated numerical noise. [1][2][3][4][5][6] Nitrogen and sulfur containing heterocyclic compounds broadly exist in various natural and synthetic products, and play vital roles in medicinal chemistry. [7][8][9][10] Among these heterocycles, pyridine derivatives, such as imidazopyridine, pyridopyrimidine, and thiazolopyridine derivatives have received considerable attention over the past years due to their diverse biological activities and clinical applications. 11,12 Imidazopyridine derivatives have shown a broad range of interesting biological activities, such as antifungal, antitumor, antiviral, antibacterial, anti-HIV, 13 antipyretic, analgesic, hypnoselective, anxioselective, anti-inammatory, anticonvulsant, antiulcer, immunomodulatory 14 activities; also pyridopyrimidine derivatives 15 are found to exhibit a broad spectrum of potent antibacterial, antiallergic, antimicrobial, 12 anti-inammatory, analgesic, 16,17 tyrosine kinase, calcium channel antagonists, 8,18 tuberculostatic, antileishmanial, antitumor, 19 antifolate, antihypertensive, hepatoprotective, 20 anticancer 21 properties; and thiazolopyridine derivatives are associated with a wide range of biological activities such as analgesic, antioxidant, 11 anticancer, 22 anti-inammatory, 23 antihypertensive, 24 antibacterial, and antifungal 25,26 properties.
A reaction condition is optimized using response surface methodology (RSM). A central composite design with ve replicates at the center point requiring 13 treatments was used. The two independent variables (temperature (A) and water content of aqueous ethanol (B)), levels (Table 1), and the results obtained aer running the experiments are represented in Table 2. The following responses were analyzed: yield of product (R 1 ) and reaction time (R 2 ).
Optimum conditions with respect to yield, purity of product and reaction time were as follow: temperature 72 C, water content of aqueous ethanol 33%. Verication experiments, carried out at the predicted conditions showed values reasonably close to those predicted and further conrmed the adequacy of predicted models.
On the basis of the central composite design, the cubic model relationship between the experimental yield (R 1 ) and the process variables (temperature (A) and water content of aqueous ethanol (B)) in coded units is obtained from eqn (1).
where R 1 represents the experimental yield of the reaction, then A (temperature) and B (water content of aqueous ethanol) are the coded variables in the reaction. Fig. 1 illustrates the good linear correlation between the actual and predicted yield and sufficient accuracy of the forecast values. Therefore, the models can be used to predict the yield of product successfully.
The ANOVA for response surface cubic models are reported in Table 3. The model F-value of 189.50 implies the model is signicant. The "Lack of Fit F-value" is 0.71 then it is not signicant relative to the pure error. Non-signicant lack of t is good and we want the model to t. The "Pred R-Squared" of 0.9586 is in reasonable agreement with the "Adj R-Squared" of 0.9910; i.e., the deviation is about 0.3.
The effects of temperature and water content of aqueous ethanol on the total reaction yield are shown in Fig. 2. The total yield varied from 37% to 90%. As temperature increased, the yield increased. The changes in yield versus the water content of aqueous ethanol is minor compared to that of temperature. The highest yield (90%) was obtained at 62.5 C and at 0% water. The lowest yield (37%) was at 62.5 C and at 100% water.
The effects of temperature and the water content of aqueous ethanol on the total reaction time are shown in Fig. 3. The analysis of total reaction time (R 2 ) showed the signicant Lack of t and it is not good. So the temperature and water content of aqueous ethanol have no effect on the reaction time and the total reaction time was almost identical and short in any case.  The scope of the reaction substrate was explored under optimized conditions. Several kind of aromatic aldehydes, and various diamines were tolerated. The reaction was completed aer 5-180 min to afford corresponding S-and N-heterocyclic systems 5a-p, in moderate to good yields (50-89%). As shown in Table 4, reactions with diamines, usually resulted in good yields and short reaction times. Reactions with cysteamine hydrochloride, resulted in low yields and long reaction times. Also the structures of the aldehydes had obvious inuence on the yield of product and reaction time. Reactions involving aromatic aldehydes usually went smoothly and resulted in good yields and short reaction times. Reaction involving heteroaromatic aldehyde (such as furfural) and aliphatic aldehyde (such as butyraldehyde), on the other hand, were normally slow and resulted in low and trace yields, respectively. When the 4-pyridinecarboxaldehyde was used the reaction did not work. The substitutions of the aromatic aldehydes had some inuence on the yields and reaction times. Reaction with aromatic aldehydes carrying an electron-withdrawing group, such as chloro and nitro groups, usually resulted in good yields and short reaction times; those carrying electron-donating groups such as methoxy group, resulted in relatively poorer yields. The reaction did not work, when the reaction was performed using ethanolamine, cyclohexane-1,2-diamine and benzene-1,2diamine.
The structures of products were fully characterized using their infrared (IR), mass spectrometry, proton hydrogen-1 nuclear magnetic resonance ( 1 H NMR), carbon-13 nuclear magnetic resonance ( 13 C NMR) spectra. For example, the mass spectrum of 5a displayed the molecular ion peak at m/z 293 with frequency of 53% which was in accordance with the proposed structure. The IR spectrum of this structure indicated absorption bands due to the NH stretching (3231 cm À1 ) as well as bands at 2922, 1704, 1623, 1486 and 1337 cm À1 due to the CH, C]O, C]C and NO 2 groups.  4 Hz) and one singlet for NH group (d 9.74 ppm). The 1 H-decoupled 13 C NMR spectrum of 5a showed 11 distinct resonances. There are three signals for CH and CH 2 groups (d 37.0, 43.0, 43.9 ppm), and signals at 106.3 and 167.6 ppm, which were assigned C-NO 2 and C]O groups, respectively. The 1 H and 13 C NMR spectra of 5b-p are similar to those of 5a except for the aryl and diamine moieties, which exhibited characteristic signals with appropriate chemical shis (see the ESI †).
An acceptable reaction mechanism for this one-pot, multicomponent reaction is designated in Scheme 3. The one-pot  General procedure for the synthesis of product 5 Synthesis of imidazopyridinone and pyridopyrimidinone derivatives. The mixtures of various diamines (1 mmol), 1,1bis(methylthio)-2-nitroethene (0.165 g, 1 mmol) and 10 mL EtOH/H 2 O (2 : 1) at 72 C in a 50 mL ask was stirred for 6 h. Aer completion of the reaction (monitored by thin-layer chromatography, hexane/ethyl acetate 1 : 1), aromatic aldehyde (1 mmol), 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid) (0.144 g, 1 mmol) were added to the reaction mixture, and it was stirred under optimized condition for the time given in Table 4. Then, the reaction mixture was cooled to room temperature and ltered to give the crude product. The solid was washed with ethanol to give product in good yields.

Conclusion
We have reported a simple and clean synthesis of imidazopyridinone, pyridopyrimidinone, and thiazolopyridinone derivatives. We were able to optimize the reaction conditions using RSM in conjunction with a central composite design. Further experimentation revealed the optimal values of the water content of aqueous ethanol (33%), and reaction temperature (72 C). Also good yield of product in mild conditions show that the experimental results are in good agreement with the predicted values, and the model successfully can be used to predict the synthesis of such heterocyclic compounds.

Conflicts of interest
The authors declare no competing nancial interest.