An eco-compatible access to diversified bisoxazolone and bisimidazole derivatives

An efficient, straight-forward and eco-friendly synthetic strategy for the assembly of novel bisoxazolones via a four-component, sequential reaction of dialdehydes, glycine, benzoyl chloride and acetic anhydride, using ultrasound radiation, is described. Additionally, a diverse group of new bisimidazoles has been synthesized in good yields by the sonication of diamines and ( Z )-4-arylidene-2-phenyloxazol-5(4 H )-ones. These approaches have resulted in a number of successful routes for the facile synthesis of bis-oxazolone and bis-imidazole frameworks within minutes of irradiation. Excellent outcomes using these environmentally-friendly parameters make these synthetic schemes ideal, sustainable, green-chemistry procedures and provide simple access towards the preparation of bisheterocycles.


Introduction
2][3] They are convenient, significant intermediates and building blocks for the assembly of a variety of biologically-active compounds comprising peptides [4][5][6][7] and amino acids. 8,9Moreover, these compounds are valuable precursors for the design of photosensitive and biosensors devices for proteins. 10The best known strategy for the preparation of oxazolones is generally regarded to be the Erlenmeyer reaction, which involves the reaction of N-benzoylglycine (hippuric acid) with aldehydes in the presence of a basic catalyst (NaOAc) and dehydrating agent (Ac 2 O). 113][14][15] Nevertheless, several of these protocols have some disadvantages, including prolonged reaction times, poor yields, use of hazardous chemicals, and often harsh reaction conditions. 16,17Our group developed a new strategy for the assembly of arylideneoxazolones starting from arylidenemalononitriles using solvent-free conditions. 18Although several structural analogs have been prepared, a careful literature survey showed that only one synthetic method has been used for the construction of bisoxazolones. 19Hence, the development of more convenient and ecofriendly strategies for the preparation of oxazolones and bisoxazolones would be advantageous.
Imidazole is one of a number of remarkable N-heterocyclic structures which are present in a variety of synthetic pharmaceuticals and natural products. 20Regardless of the number of reaction protocols that have been established for the synthesis of imidazole moieties, [20][21][22][23][24][25] the development of a highly-efficient synthesis for the preparation of a series of novel bis-imidazoles from easily available substances in a one-step reaction, is one of the most intriguing challenges of modern synthetic chemistry.7][28][29] Ultrasonic irradiation, compared with other conventional techniques, has some inherent merits, e.g., milder reaction conditions, higher yields, shorter reaction times and simpler work-ups.As part of our efforts to prepare bis-heterocyclic systems using environmentally-benign conditions, [30][31][32][33][34] we describe, herein, efficient protocols for the preparation of bis-oxazolones and bis-imidazoles driven by ultrasonic irradiation.

Results and Discussion
As a continuation of our work towards developing novel protocols for the synthesis of oxazolones 18 and bisheterocycles from dialdehydes, 30,34 we have progressed with respect to the design and preparation of the bisoxazolones (2a-f).In this context, reactive precursors such as dialdehyde derivatives (1a-f) can react effectively with hippuric acid (HA) and acetic anhydride (Ac 2 O).We commenced our investigation using a model reaction of 2-hydroxy-5-methylisophthalaldehyde (1a) with HA and Ac 2 O in the presence of sodium acetate (NaOAc).Based on the results of our previous investigations, the reaction of HA with Ac 2 O should yield 2-phenyloxazol-5(4H)-one, which would subsequently interact with dialdehyde (1a) to afford the target bis-oxazolone product (2a) (Scheme 1).Scheme 1. Model reaction of 2-hydroxy-5-methylisophthalaldehyde (1a) with hippuric acid (HA) and acetic anhydride (Ac 2 O) in presence of sodium acetate (NaOAc).
The three-component reaction could be effected by blending all the substrates under ultrasonic irradiation (40 kHz).The reaction was achieved at room temperature (23 o C) in a sealed vial for 10 minutes (Table 1, entry 1).Regrettably, the reaction afforded the desired product in poor yield (15%) and the dialdehyde (1a) remained mostly unreacted.Slight improvements in yield were observed by increasing both temperature and time (Table 1, entries 2 and 3), however, multiple spots on the TLC plates indicated the presence of other compounds.These unsatisfactory outcomes prompted us to investigate the abovementioned three-component reaction in a sequential pattern of ultrasound radiation (US), ultrasound radiation plus heating (US/Conv.),and microwave radiation (MW).
We initially carried out the reaction between HA and Ac 2 O in the presence of NaOAc with sonication for 3 min at 40 o C. Interestingly, the formation of 2-phenyloxazol-5(4H)-one was completed within 2 min (confirmed by NMR analysis).The dialdehyde (1a) was then added and the resulting mixture was sonicated for an additional 3 min at 40 o C.After cooling, the, hitherto, unreported bisoxazolone derivative (2a) was obtained in 83% overall yield (Table 1, entry 4).Reaction analysis (by TLC) indicated the incomplete transformation of the intermediate 2-phenyloxazol-5(4H)-one into the final product (2a).Therefore, the reaction was repeated at elevated temperatures, viz.50 and 60 o C, which provided (2a) in 90% and 97% yields, respectively (Table 1, entries 5 and 6).It was also observed that a shorter irradiation period (4 min) diminished the yield slightly (Table 1, entry 7) while a longer period (8 min) provided no advantage (Table 1, entry 8).Next, a series of other catalysts, including piperidine (Pip.), zinc oxide (ZnO) and potassium phosphate (K 3 PO 4 ) were screened; of these, NaOAc was found to be the most efficient catalyst for this conversion (see Table 1, entry 8 vs. entries 9-11).In order to compare the effectiveness and applicability of ultrasonic irradiation on the template reaction, a control experiment was performed, utilizing thermal heating (100 o C) with the NaOAc catalyst (Table 1, entry 12).A good yield was acquired (67%), however, with longer time (2h).These results demonstrated that ultrasonic irradiation can make the current one-pot method occur efficiently and rapidly, while heating decreases the rate and yield of the reaction.Carrying out the model reaction under microwave irradiation produced the desired product (2a) in poor yield (Table 1, entry 13, 45%) and generation of a Perkincondensation product (4, Scheme 3).
Four-component reactions of dialdehydes (1a-f), glycine, benzoyl chloride, and Ac 2 O have also been studied, providing direct access to bis-oxazolones (Scheme 2, method B).Benzoyl chloride, glycine, Ac 2 O and fused NaOAc were sonicated at 60 o C for 3 min to furnish 2-phenyloxazol-5(4H)-one.Following that, dialdehydes (1a-f) were added and sonication was recommenced for another 3 min at the same temperature.The bis-oxazolones (2a-f) were obtained in excellent yields and high purity.Notably, this newly developed four-component reaction under sonication gave nearly similar yields compared with method A.
The proposed structures of the prepared bisoxazolones (2a-f) were confirmed based on the spectral analyses (mass spectra, IR and NMR spectroscopies).The IR spectra of (2a-f) exhibited sharp bands around ν 1790 cm -1 assigned to C=O.The constructed heterocyclic system was confirmed by the absence of any bands attributed to amidic NH or carboxylic OH functional groups.Despite the fact that there are two possible geometric isomers for derivatives (2a-f), we presumed that the configuration around the C=C double bond would be the thermodynamically more favourable Z-isomer, by analogy of the synthetic procedure utilized here with previously reported preparations of Z-oxazolones. 35In the 1 H NMR spectra of (2a-f), only one set of signals exists in each spectrum, demonstrating that only one of the geometric isomers, the thermodynamically-preferred Z-isomer, was formed.Furthermore, the signal patterns denote that the two oxazolone moieties are chemically equivalent, meaning that the oxazolone molecules are symmetric with respect to the central ring.
As presented in Scheme 4, a reasonable mechanism of this reaction at 190 o C would be an intramolecular aldol-type condensation of the initially formed O-acetyl derivative (5) to generate the non-isolable coumarin intermediate (6).This intermediate could then undergo a condensation reaction with the formed oxazolone anion (7), yielding the isolable derivative (3).Perkin-condensation compound (4) was also formed in this step.The formation of bisoxazolone (2a) may be due to the carbanion (7) attacking both carbonyl groups of the dialdehyde (1a).Scheme 4. Proposed mechanisms for the syntheses of derivatives (2a), ( 3) and (4).
To further expand the scope of the substrates, several aromatic carbonyl compounds (8a-f) were also investigated under these sequential protocols (Scheme 5, methods A and B).The reactions afforded the corresponding oxazolones (9a-f) in excellent yields.

Scheme 5. Syntheses of oxazolones (9a-f) using methods A and B.
From a green-chemistry perspective, it would be valuable to compare our new methods with a conventional solvent/heating method (C) for the construction of bis-oxazolones using several 'green' metrics; 36 for example, Process Mass Intensity (PMI), E-factor, Reaction Mass Efficiency (RME) and Yield Economy (YE), which would then enable us to assess the strength of our chemical procedures.To accomplish this, the reaction should be scalable to gram level.Therefore, we performed gram-scale preparations of derivative (2a) utilizing methods A, B and C (Scheme 6).Using Method A, reacting dialdehyde (1a) (5 mmol) with HA (10 mmol) under sonication at 60 o C for 5 min provided 2.41 g of (2a) (98% yield) (Table 2, entry 1).Using Method B, reacting dialdehyde (1a) (5 mmol) with glycine (10 mmol) and benzoyl chloride (10 mmol) under sonication at 60 o C for 6 min gave 2.36 g of (2a) (96% yield) (Table 2, entry 2).Using Method C, reacting dialdehyde (1a) (5 mmol) with HA (10 mmol) in a water bath (100 o C) for 2h afforded 1.70 g of (2a) (69% yield) (Table 2, entry 3).Scheme 6. Scaled-up synthesis of bis-oxazolone (2a) using ultrasonic and conventional methods., and smaller values of E-factor (0.020 and 0.041) and PMI (1.13 and 1.30), make the investigated ultrasound-assisted protocols A and B ideal sustainable green processes for construction of mono-and bisoxazolones vs. the reported moreconventional process (C) when comparable reaction chemistries are applied.
In the course of our investigations for developing novel protocols to construct bis-heterocycles, we have also established an efficient and simple methodology for the preparation of bisimidazoles.Bis-imidazoles (11a-i) were synthesized simply by reacting diamines (10a-c) with (Z)-4-arylidene-2-phenyloxazol-5(4H)-ones (9a-c), in the presence of catalytic amounts of NaOAc, using sonication for 10 min at 80 o C (Scheme 7).
The structures of products (11a-i) were fully characterized by NMR, IR, and MS.The IR spectrum of derivative (11a) displayed characteristic bands at 1697 and 1635 cm -1 which were attributed to oxo-imidazole carbonyl (C=O) and azomethine (C=N) stretching frequencies, respectively.The 1 H NMR spectrum of (11a) exhibited one down-field singlet at 7.27 ppm which was assigned to the methine-group proton (C=CH); this confirmed the isolation of the thermodynamically more favourable Z-isomer preferentially over the E-isomer.The protons of the phenyl rings displayed three multiplets in the range of 8.21-7.29 ppm.Additionally, for derivative (11a), the protons of the cyclohexane ring were observed as multiplets in the 4.24-1.72ppm range.Also, the 13 C NMR of derivative (11a) agreed with the number of carbons.These results were supported further by the mass spectrum which exhibited the molecular-ion peak at m/z 604.28 (M + , 1.6%), in agreement with the molar mass of the proposed structure.To assess our protocol on the "greenness" scale once again, we performed a gram-scale preparation of bis-imidazole (11g) (Table 3) by condensing oxazolone (9a) (10 mmol, 2.49 g) with ethylene diamine (5 mmol, 0.3 g) using either ultrasonic irradiation for 10 min at 80 o C or in refluxing ethanol for 10 min. 37(Scheme 8).Some green metrics were calculated for these reactions and the results are presented in Table 3.The sonication method achieved good scores in comparison with the conventional method, thus establishing the sonication methodology to be an ideal green, environmentallysustainable method.Scheme 8. Scale-up synthesis with yields of bisimidazole (11g) by ultrasonic (US) vs. conventional (Conv.)methods.

Conclusions
A rapid, scalable and multi-component protocol for the assembly of a novel series of mono-and bis-oxazolone scaffolds through sequential reactions was demonstrated using ultrasonic irradiation.(Z)-4-Arylidene-2phenyloxazol-5(4H)-ones underwent ring transformation on sonication with several diamines to afford a new series of bisimidazoles.Key merits of these eco-friendly protocols over conventional methods include excellent functional-group tolerance, high yields, scalability, short reaction times, and easy work-up.These protocols display distinct advantages in terms of green-chemistry/sustainability metrics that can be of potential use for therapeutic-chemistry purposes and parallel synthesis applications.

Experimental Section
General.All chemicals and solvents were received commercially from Merck and Sigma-Aldrich chemical companies.Derivatives (1a-c, 1e) and (1f) were prepared following our reported methods. 30,33All known organic products (2d), 35 (9a-c), 38,39 and (11g) 37 were confirmed by comparison of their physical and spectral data with those of authentic samples.All of the melting points of the prepared compounds were determined on an Electrothermal IA9100 apparatus (UK).IR spectra of the samples were run using KBr disks on a Perkin-Elmer Spectrum One spectrometer.The NMR spectra were measured on a Bruker Avance 400 MHz spectrometer using CDCl 3 or DMSO-d 6 .Ultrasonication was performed in a SY5200DH-T ultrasound cleaner (40 kHz).Microwave irradiation was carried out using Biotage® Initiator Classic (Biotage AB; Uppsala, Sweden) using sealed vessels.
General procedures for the preparation of mono-and bis-oxazolones (2a-f and 9a-f) Method A. A mixture of hippuric acid (HA) (1.0 mmol), and freshly fused NaOAc (1.1 mmol) was mixed in the presence of Ac 2 O (1 mL) and the mixture was sonicated for 3 min at 60 o C.Then, 0.5 mmol of dialdehydes (1af) or 1.0 mmol of carbonyl compounds (8a-f) were added and the sonication was resumed for 2 min at the same temperature.Upon completion of the reaction (monitored by TLC), the mixture formed a yellow solid, which was washed with water (2x10 mL), chilled in EtOH (2x10 mL), and recrystallized from EtOH containing a few drops of dioxane to obtain the desired mono-and bisoxazolones (2a-f and 9a-f).Method B. A mixture of glycine (1.0 mmol), benzoyl chloride (1.0 mmol) and freshly fused NaOAc (2.1 mmol) was mixed in the presence of Ac 2 O (1 mL) and the mixture was sonicated for 3 minutes at 60 o C. Then 0.5 mmol of dialdehydes (1a-f) or 1.0 mmol of carbonyl compounds (8a-f) were added and the sonication was resumed for another 3 min.Upon completion of the reaction (monitored by TLC), yellow solids separated out which were washed with water (2x10 mL), chilled in EtOH (2x10 mL), and recrystallized from EtOH containing a few drops of dioxane to obtain the desired mono-and bis-oxazolones (2a-f and 9a-f).

Table 1 .
Optimization of reaction conditions for the preparation of bis-oxazolone derivative (2a)

Table 2 .
Comparison of reaction efficiencies sustainability metrics ultrasonic methods (A, B) and conventional method (C) preparation of bis-oxazolone derivative (2a) The higher values of sustainability metrics YE(19 and 16)andRME (88.8 and 76.8)

Table 3 .
A comparison of reaction efficiencies of different methods for the preparation of derivative (11g) 37Ultrasonic irradiation.bConventional method.37