Green synthesis of new chiral 1-(arylamino)imidazo[2,1-a]isoindole-2,5-diones from the corresponding α-amino acid arylhydrazides in aqueous medium

New chiral 1-(arylamino)imidazo[2,1-a]isoindole-2,5-dione derivatives were obtained in good to excellent yields via the cyclocondensation of 2-formylbenzoic acid and various α-amino acid arylhydrazides using water as the solvent in the presence of sodium dodecyl sulfate as the surfactant and under simple and minimum manipulation, without purification. The reaction is totally diastereoselective and gives access to the nitrogenated tricyclic core with a relative trans stereochemistry.

To prepare the new chiral 1-(arylamino)imidazo[2,1-a]isoindole-2,5-diones 5a-m under greener conditions, we investigated the reaction in nontoxic solvents such as water and dimethyl carbonate (DMC). Indeed, DMC is well-known as safe reagent and solvent that has been used for many green applications [31][32][33]. On the other hand, water is a simply and environmen-tally benign solvent and interest has increasingly turned to it as the greenest solvent of chemical reactions [34]. In order to find the best reaction conditions, a model reaction was chosen using (L)-alanine phenylhydrazide (3a, Scheme 3), and the results of these optimized studies were summarized in Table 2.
The best result was obtained when a mixture of hydrazide 3a and formylbenzoic acid 4 was heated at 120 °C (oil bath) using water as the solvent in the presence of SDS (10%) as the surfac- tant for 10 h leading to a 90% yield in 5a. To demonstrate the generality of this method, we next investigated the scope of this reaction under the optimized conditions. A variety of the 1-(arylamino)imidazo[2,1-a]isoindole-2,5-diones 5b-m were prepared and the obtained results are summarized in Scheme 4. The mild conditions of the reaction gave access to the tricyclic compounds 5a-m providing similar yields, regardless the amino acid residue is. A weak acidic function was well-tolerated yielding 5j with 66%. Bulky groups did not roughly affect the efficiency of the reactivity (5b, 5c).
The new approach described in this work for the preparation of compounds 5a-m has the following advantages: (i) notably, under the reaction conditions described above, we have never observed the formation of degradation products. (ii) The reaction was performed in water, in the presence of SDS (sodium dodecyl sulfate) as the surfactant. Based on previous studies [35], the most effective method for ensuring the solubility of reactants in water is the use of surfactants that can form micelles with a hydrophobic core and a hydrophilic corona.
(iii) This clean method afforded compounds 5a-m without the need of additional purification such as column chromatography or recrystallization. (iv) The use of a sealed tube [36][37][38][39][40][41][42][43] obeys to four out of the twelve green chemistry principles: a cleaner and eco-friendly reaction profile with minimum of waste, solvent without negative environmental impact, shorter reaction time and safely work with a pressure tube canning prevent fires and emissions of hazardous compounds and toxic gas. (v) The reaction described in this work occurred with high atom efficiency (atom economy of 90%) and produced only stoichiometric H 2 O as waste (E-factor of 0.1).
The dihedral angle value of −163.1° for H(1)-C(1)-C(4)-H(4) close to the anti-planarity corroborates the expected non correlation between H(1) and H(4) in the NOE experiment. The structure contains two carbonyl moieties C(6)-O(2) and Analyzing the mechanism of the reaction between the 2-formylbenzoic acid 4 and α-amino acid arylhydrazides 3, we assumed that the first steps lead to the formation of the imine intermediate A, which is the result of the nucleophile addition of the α-amino group on the most electrophilic center in 4. This iminocarboxylic acid form likely evolves to its iminium-carboxylate form B [50]. This last intermediate involves the existence of two possible transition states for the cyclization of the imidazolidinone core of which one of them is favored by an intramolecular hydrogen bond (Scheme 5). This control is the main difference with the known reaction [51] between the hydrazides 3 and the phthalaldehydes in which two diasteroisomers have been observed. If the amino acid residue (R on the Scheme 5) enough implicates steric hindrance with the carboxyaromatic part of B, the pathway with disfavored transition state becomes unlikely and then the selectivity is important. Our model is in agreement with the diasteroisomeric ratio results. In fact, a total diastereoselectivity was observed, including 5d (R = Ph) since an epimerization of the initial asymmetric center was observed, therefore racemic trans-isomers were obtained in this case. Interest-Scheme 5: Proposed partial mechanism with a selectivity model.
ingly, acidic (phenolic 5j) and basic moieties (as indolyl 5i) on the amino acid residue did not affect the selectivity.

Conclusion
In summary, we have developed environmentally safe conditions for the synthesis of new chiral 1-(arylamino)-1Himidazo[2,1-a]isoindole-2,5(3H,9bH)-diones in good yields using water as the solvent in sealed tube. The aspects of greenness and good results make this methodology a practical and atom economical alternative in the whole of the processing since the syntheses of the α-amino acid arylhydrazide precursors behave this greener aspect. Once more, the processing includes this eco-friendly way up to have the compounds in hand since simple precipitation allows to isolate the nitrogenated tricyclic compounds; no purification is needed. The model for the key step of the cyclization clearly explains the stereochemistries, which are observed with a total trans-diastereoselectivity controlled by intramolecular hydrogen bonds.

Supporting Information
Supporting Information File 1 Experimental procedures, spectroscopic and analytical data and copies of spectra of the products.