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Cite This: ACS Sustainable Chem. Eng. 2019, 7, 12044−12051

From Lossen Transposition to Solventless “Medicinal Mechanochemistry” A. Porcheddu,*,† F. Delogu,‡ L. De Luca,§ and E. Colacino*,∥

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Dipartimento di Scienze Chimiche e Geologiche, Cittadella Universitaria, Università degli Studi di Cagliari, SS 554 bivio per Sestu, 09042 Monserrato, Cagliari, Italy ‡ Dipartimento di Ingegneria Meccanica, Chimica, e dei Materiali, Università degli Studi di Cagliari, via Marengo 2, 09123 Cagliari, Italy § Dipartimento di Chimica e Farmacia, Università degli Studi di Sassari, via Vienna 2, 07100 Sassari, Italy ∥ Université de Montpellier & Institut Charles Gerhardt de Montpellier (ICGM), UMR5253 CNRS − UM − ENSCM, 8 Rue de l’Ecole Normale, 34296 Montpellier, Cedex 5, France S Supporting Information *

ABSTRACT: An environmentally friendly mechanochemical strategy for the preparation of unsymmetrical ureas and 3,5-disubstituted hydantoins by using safe starting materials in place of hazardous and toxic isocyanates has been designed. For the first time, the Lossen rearrangement was successfully applied to prepare a collection of relevant structures in medicinal chemistry via a one-pot mechanochemical approach and without a single drop of organic solvent including during the workup. The procedure was effective for the preparation of the Active Pharmaceutical Ingredient (API) ethotoin.

KEYWORDS: Lossen rearrangement, 1,1-Carbonyldiimidazole, Hydantoins, Medicinal mechanochemistry, Active pharmaceutical ingredients

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INTRODUCTION The public debate around climate changes has profoundly changed the way chemists think about chemistry, opening up new ways to design the organic synthesis.1,2 Pursuing this goal, many classic organic reactions need to be redesigned for making them ever more efficient from both the resource consumption and the economic points of view. Nowadays, most of the synthetic processes, including those that can be considered innovative, make use of solvents (often also highly toxic) so large that they can easily constitute up to 90% of the mass of the reaction system.3−7 In this regard, solvent-free reactions represent the ideal approach since they meet at least two of the 12 requirements of green chemistry: “safer solvents and auxiliaries” and “prevent waste”. Unfortunately, the high concentration of materials under neat conditions often makes these reactions proceed with the formation of significant amounts of byproducts requiring final tedious and costly chromatographic purifications. This problem has been recently overcome by using mechanochemistry,8−19 that allows performing reactions under solvent-free conditions, combining the advantages of neat reactions and homogeneous phase. In the mechanochemistry-assisted synthesis, reagents are distributed on the grinding surfaces of both grinding jar and balls, while individual ball-jar © 2019 American Chemical Society

impacts affect only a limited portion of overall reactive mass (in the unit of time). Following our interest in this methodology,20−24 the attention was focused on the ecofriendly solventless mechanochemical preparation of unsymmetrical ureas25−27 and from them, hydantoins,28,29 two scaffolds of significant importance in medicinal chemistry. In solution, ureas are commonly prepared by addition of amines on isocyanates.30 More recently, the suitability of solvent-free methodologies employing mortar and pestle31 or based on the use of a ball milling apparatus has also been demonstrated for the preparation of nonsymmetrical (thio)ureas27 and hydantoins32,33 from iso(thio)cyanates,26,34 which constitute a valid alternative to the shock-sensitive organic azides25 also for large scale preparations.35 However, although some isocyanates are commercially available, the classical rearrangement of amides (Hofmann reaction),36 acyl azides (Curtius reaction),36,37 and hydroxamic acids (Lossen reaction)36 provides broader and effective access to this class of compounds (Scheme 1). Received: February 2, 2019 Revised: June 16, 2019 Published: June 17, 2019 12044

DOI: 10.1021/acssuschemeng.9b00709 ACS Sustainable Chem. Eng. 2019, 7, 12044−12051

Research Article

ACS Sustainable Chemistry & Engineering Scheme 1. Classical Routes to Isocyanates in Solution Phasea

The “rearrangement” reaction is represented using the curly arrow formalism first introduced by Liebig;38 for mechanochemically activated reactions, the formalism recently proposed by Hanusa was used.39 a

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RESULTS AND DISCUSSION Having already disclosed an efficient mechanochemical protocol for preparing a wide range of hydroxamic acids40 (Scheme 2, pathway a), we extended our attention to the development of the Lossen transposition under mechanical activation conditions (Scheme 2, pathway b).

hydroxamic acid, followed by the addition of amines leading to the corresponding ureas (Scheme 2, pathway b).41 When amino esters are used in the second step, unsymmetrical ureas can be further mechanochemically cyclized in situ to the corresponding 3,5-disubstituted hydantoins, according to an elegant 4-fold cascade reaction (Scheme 2, pathway b). With this in mind, the model substrate benzhydroxamic acid and a slight excess of eco-friendly carbonyl equivalent 1,1′-carbonyldiimidazole (CDI) were ball milled together in a zirconia jar (45 mL) containing ZrO2 balls (5 mm × 40), using a highenergy SPEX mill equipment (Scheme 3). As soon as analysis by TLC confirmed the complete consumption of the starting hydroxamic acid (about 15 min), a slight excess of morpholine was added into the jar, and the resulting system was then ball milled for one additional hour (Scheme 3). Upon completion, aqueous 15% citric acid42 was added into the jar. The white precipitate was filtered off, washed with water, and dried to afford the desired urea 1 in high yield (91%), with no need of further purification, the only byproducts being water-soluble imidazolium salts and gaseous CO2.43 The mechanochemical Lossen rearrangement outperforms with respect to solution procedures in toluene starting from diphenylurea and morpholine, heated up in a sealed autoclave at 160 °C for 2 h and leading to urea 1 in 85% (after recrystallization to eliminate the toxic aniline generated as a byproduct).44 For the sake of comparison with the procedures in solution, the model reaction was reinvestigated using directly the phenyl isocyanate in place of benzohydroxamic acid. To our surprise, the reaction between phenyl isocyanate and morpholine afforded the target urea 1 in lower yield (40%) together with significant amounts of diphenylurea (due to a partial hydrolysis of phenyl isocyanate to aniline during milling) as a byproduct, clearly indicating that importance of mechanochemical Lossen transposition. Furthermore, the desired urea 1 could be isolated only after tedious chromatographic purifications, which required a large consumption of solvent making void

Scheme 2. General Mechanochemical Method To Access Dissymetrical Ureas and 3,5-Disubstituted Hydantoins by Lossen Transposition by a Sequential Mechanochemical: a) Preparation of Hydroxamic Acid40 Followed by b) Their Activation by CDI (This Work) To Afford Nonsymmetrical Ureas or 3,5-Disubstituted Hydantoins

The model reaction was set up in a one-pot/two-step fashion, consisting first of the activation/Lossen transposition of the Scheme 3. Benchmark Reaction for the Lossen Rearrangement

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ACS Sustainable Chemistry & Engineering

Scheme 4. Ball Milling Synthesis of Unsymmetrical Ureas Combining a Set of Structurally Diverse Hydroxamic Acids with a Collection of Primary and Secondary Amines

(Scheme 4). It is worth noticing that, with the exception of compounds 2 and 8, previously prepared by the Lossen rearrangement in solution,50 ureas 1, 3−7, and 9−18 were usually prepared by a “click” reaction involving isocyanates and amines. In both cases, solution procedures led to lower or somehow comparable yields (see Table S1 in the Supporting Information) and purification steps involving the use of organic solvents. In solution, the low solubility of the hydroxamic acids is a limiting factor for the exploitation of the full potential of the Lossen rearrangement, often leading to low yields together with an increase in reaction times. The current mechanochemical procedure overcomes any restriction due to solubility51 and worked well both with primary and secondary amines providing unsymmetrical ureas 2−17 in high yields, recovered by precipitation in acidified water by citric acid as previously described (Scheme 4). It is worth noting that for urea 2, as previously observed in other mechanochemically activated transformations,33,42,52 the in situ generation of the nucleophilic benzylamine from the corresponding hydrochloride salt was possible without addition of a base, without any significant drop in yield (Scheme 4). Moreover, contrary to what was observed in homogeneous phase, the ball milling procedure did not need a strong excess of amine (second step) in order to drive the reaction to completion. As expected, the presence of bulky or electron-withdrawing substituents on the aromatic ring of

this approach from the green chemistry point of view. Moreover, the milling of stoichiometric amounts of phenyl isocyanate and imidazole drastically reduced both the formation of symmetrical urea and the hydrolysis of the aryl isocyanates to aniline, usually observed in solution.45−47 In solution, the Lossen rearrangement usually requires an additional base or high temperature in order to trigger the nucleophilic migration from the carbon center to the electrondeficient nitrogen site of the nitrene (Scheme 1).48 However, by ball milling, the addition of a base was not necessary (reagent economy): CDI not only activated the hydroxamic acid but also released the basic imidazole, which promotes, in turn, both the transposition reaction49 and the final urea formation. Moreover, in the absence of an additional base, the selfsustaining Lossen rearrangement of benzhydroxamic acid to aniline, usually occurring in solution, did not proceed at all by mechanochemistry, thus suppressing the formation of undesired symmetrical diphenyl urea,48 never detected even in traces, as assessed by GC-MS analyses performed on the crude and LC-MS analyses of the precipitate recovered after precipitation in water/filtration, as already described. If present, the water-insoluble symmetrical biphenyl urea would have been detected when analyzing the precipitate. In order to verify the general applicability of the method, the one-pot/twostep procedure was applied to the preparation of a library of nonsymmetrical ureas, from structurally different amines 12046


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ACS Sustainable Chemistry & Engineering aniline derivatives resulted in lower yields in urea (Scheme 4, products 10 and 12). To enhance the molecular diversity of the final library, ureas 14−17 were also obtained with generally high yields from commercially available hydroxamic acid. In the case of urea 14, the so-called Bufexamac (Paraderm) hydroxamic acid, a topical nonsteroidal anti-inflammatory drug (NSAID) on the skin,53 was used. It is noteworthy that 1H and 13 C NMR analyses carried out on crude reaction between heptyl hydroxamate and CDI revealed the formation of the nitrene equivalent dioxazole A54−56 (cyclic carbonate with R = C7H15, Scheme 2) a nitrene equivalent before rearranging to the desired unsymmetrical urea 15. In contrast, the reaction between benzhydroxamic acid, previously activated with CDI and L-phenylalanine methyl ester hydrochloride, resulted in a 9:1 mixture of two compounds, in which the desired urea 18 was partially cyclized into the corresponding hydantoin 19 (Scheme 5). Full cyclization of urea 18 into hydantoin 19

Figure 1. Industrially important hydantoin-based Active Pharmaceutical Ingredients (APIs) previously prepared by mechanochemistry.

The reactions proceeded smoothly with good to excellent yields (after recovery of the products by the previously described precipitation/filtration workup) by combining together sets of various amino esters hydrochlorides and hydroxamic acids having both aromatic and aliphatic residues with carbon chains of different length in their backbone. The current method tolerates the presence of several protective groups located in the amino ester side chains. It is worth highlighting that this procedure allows synthesizing, in a cheap and straightforward way, N-arylated and N-alkylated 3,5dibustituted hydantoins, not accessible by other mechanochemical methods previously reported by us,32,59 using for example an excess of toxic phenyl isocyanate (e.g., compounds 19 and 31, see Supporting Information, Table S1) or by direct N-alkylation of hydantoin scaffold (e.g., ethotoin 21, see Supporting Information, Method C, Scheme S1). Indeed, the mechanochemical Lossen rearrangement (i) is an intrinsically sustainable approach avoiding the direct use of overstoichiometric quantities of toxic isocyanates, generated in situ instead and immediately reacted, thus avoiding their exothermically promoted polymerization side reaction encountered in solution, leading to lower yields and need of purifications; (ii) circumvents the lack of commercially available isocyanates, extending the access to a diversity of new compounds; (iii) allows access to inedited N-3-alkylated and arylated hydantoins not possible to be easily prepared in solution or by other mechanochemical methods,32 including the use of phenyl isocyanate to prepare hydantoins from α-amino-ester derivatives (see Supporting Information, Table S2); and (iv) allows an eco-friendly recovery of the final N-3-substituted hydantoins, scaffolds of particular interest in medicinal chemistry, by an aqueous precipitation/filtration workup. Direct N-alkylation reactions have been described is solution using sodium or potassium salt of the hydantoins with (harmful!) alkyl halides or dialkylsulfates. The reaction was not selective and both N-1 and N-3-dialkylated hydantoins were obtained, with yields ranging between 60 and 70% after recrystallization of the desired N-3-alkylated product. Alternatively, it was reported62 that the use of dimethylformamide dialkyl acetals afforded selectively the corresponding N-3 alkylated products (alkyl = CH3, CH3CH2, n-Bu) in good yields at 100 °C in 1 h. The direct N-3-arylation of hydantoins in solution was barely investigated and mainly restricted to nucleophilic aromatic substitution. Copper-mediated reactions were described63−67 in high boiling solvents (DMF, DMAc) at temperatures up to 160 °C for 7−72 h or at room temperature

Scheme 5. First Attempts To Prepare Hydantoin 18 by CDIMediated Mechanochemical Lossen Transposition57

could not be achieved by extending the reaction time (also increasing the number of balls in the jar). The use of an excess of KHCO3 or other organic bases (triethylamine or N,N′diisopropylethylamine) resulted in a mixture of compounds 18 and 19 with the hydantoin being the main component (18/19, 40/60). The addition of stoichiometric quantities of the ecocompatible K2CO3 (1.1 equiv) in the second step together with the amino ester hydrochloride promoted the complete cyclization of the intermediate urea 18 into the final hydantoin 19 within 3.5 h of grinding. Once the reaction was complete, aqueous citric acid (15% w/w) was added to the crude mixture, leading to the immediate precipitation of pure hydantoin 19 recovered after filtration as a white solid in good yields (90%) and with some erosion of the optical purity (er 85/15 in favor of the L-enantiomer) as shown by chiral HPLC analyses. Also in this case, the water-soluble byproduct imidazole and the unreacted amino ester were eliminated in the filtrate. We previously reported the mechanochemical preparation of several hydantoin-based Active Pharmaceutical Ingredients (APIs),57 such as the phenytoin 20,58 ethotoin 21,32 antibacterial agents for polymer textiles 22−24,32,59 nitrofurantoin 25,52 and dantrolene 2652 (Figure 1). Hydantoins were also used for preparing silicon-based biohybrid nanomaterials by the “mechanochemical sol-gel process”.60 With this background and because of our ongoing interest in the field of “medicinal mechanochemistry”,61 the mechanochemical Lossen rearrangement was also extended to the solvent-free one-pot/ three-step preparation (activation of hydroxamic acid by CDI/ urea synthesis/base-mediated intramolecular cyclization) of 3,5-disubstituted hydantoins, including the anticonvulsant ethotoin 21 (Scheme 6). 12047


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Scheme 6. Synthesis of a Library of 3,5-Disubstituted Hydantoins via Mechanochemical Lossen Transposition

in CH2Cl2 for 7 days.68 In all cases, high amounts of copper salts were necessary (0.5−1.0 equiv). In the case of the mechanochemical preparation of hydantoins 43 and 44, even if the yields by the Lossen rearrangement were similar to those previously reported by us, it avoids the use of an excess of toxic ethyl isocyanate (in neat conditions32 or by PEG-assisted grinding59) or workup procedures based on liquid−liquid extraction. In the same fashion, N-3-methylated hydantoins 45 and 46 avoided the use of highly flammable methyl isocyanate, responsible for one of the world’s worst industrial disasters in history known as the Bhopal disaster, having caused the death of nearly 4000 people. The mechanochemical Lossen rearrangement outperforms also for the one-pot/three-step preparation of the API ethotoin 21, of utmost importance in medicinal chemistry as an anticonvulsant drug.69,70 In this case, a better yield (52%) was obtained compared to three previously reported mechanochemical methods (35%, see Supporting Information, Scheme S1),32 the use of an excess of base and grinding additives such as poly(ethylene)glycols (PEGs) was avoided,32,59,71 and the workup was simplified. Indeed, our previous investigations32 for the N-3 ethylation reaction of 5-phenylhydantoin in the presence of a large excess of various alkylating agents (e.g., ethyl iodide, ethyl bromide, and diethylsulfate) in neat conditions at room temperature overnight were unsuccessful. In all cases, only traces of the corresponding N-3 ethylated 5-phenylhydantoin 21 were obtained, with a yield improvement up to 40% (determined by 1H NMR) when liquid poly(ethylene) glycol HO-PEG-400OH was added as the reaction solvent. Under neat

mechanochemical conditions, the N-3-ethylation reaction led to hydantoin 21 in traces as well, with an improved efficiency (yields ranging between 20% and 45%) when solid PEG polymers were used as additives.32 In order to investigate the potential for scaling up the process, the synthesis of hydantoin 19 initially performed on 1 mmol scale was repeated on a larger scale (3 mmol) without a significant change in the yield of isolated product, according to the usual precipitation/filtration workup. To evaluate and benchmark the sustainability of the Lossen transposition, green chemistry metrics such as the environmental factor (E-factor)72 and the Process Mass Intensity (PMI)73 were calculated for urea 1, 5-benzyl-3-phenyl hydantoin 19, and ethotoin 21 (Table 1) for both solution and mechanochemical procedures. In addition to the advantages already highlighted for the mechanochemical Lossen rearrangement, the E-factor and PMI metrics were much better compared to the reaction in solution (Table 1). When possible, the E-factor for both synthesis in solution and by mechanochemistry was calculated: (i) including the amount of solvents used for the isolation of the products and (ii) neglecting the amount of solvents necessary for the workup. Worthy of notice is that for procedures in solution, the recovery of the final products required large amounts of “organic” solvents (including a purification by column chromatography). On the contrary, the mechanochemical Lossen rearrangement presents also the advantage of an easier workup (precipitation/filtration steps), keeping the amount of “aqueous” solvent to the minimum. 12048


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ACS Sustainable Chemistry & Engineering Author Contributions

Table 1. Green Metrics for Urea 1, 5-Benzyl-3phenylhydantoin 19, and Ethotoin 21

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Only persons having made significant scientific contributions to the work reported and who share responsibility and accountability for the results were associated with this article.

in solution/by mechanochemistry E-factora with workup 1 19 21

74

1168 /124 na,75d/98 ≫288,76d/221

yields (%) without workupb 74

103 /1.21 3.0575/1.91 19376/4.84

PMIc 74

99 /91 7975/92 6576/52

125 99 222

Notes

The authors declare no competing financial interest.

a

E-factor = total waste (kg)/product (kg). bData refer to the recovery of products without any postsynthetic workup. cPMI = total mass (kg) used in the process/mass of product (kg); PMI = E-factor + 1. d na = not available. The amount of solvents and/or silica gel used for the purification of the product by column chromatography is not available in the original article.

CONCLUSIONS In conclusion, we developed a simple, general, and environmentally friendly method for preparing unsymmetrical ureas and 3,5-disubstituted hydantoins by using easily available, less hazardous starting materials in place of hazardous, toxic, and moisture sensitive isocyanates and based on a metal-free approach (compared to the direct N-3-arylation reaction in solution). In this study, competition experiments were performed by using almost equimolar amounts of each coupling partner in a one-pot multistep fashion reaction. The final products can be easily separated from the reaction mixture (and harmless byproducts) by trituration with inexpensive and eco-compatible citric acid, thus avoiding the use of solvents altogether. To our knowledge, this is the first example where the energy necessary to promote the Lossen rearrangement has been provided by mechanical activation. Easy operation underlying the mechanochemical synthesis, makes it suitable for the mechanochemical preparation of hydantoins, including the API ethotoin 21.

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REFERENCES

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acssuschemeng.9b00709. Experimental procedures (materials and methods), 1H and 13C NMR spectral data for compounds 1−19, 21, 27−46, and cyclic carbonate A, and chiral HPLC chromatograms for hydantoin 19; comparative yields for ureas 1−18 and 3,5-disubstituted hydantoins 19, 21, and 27−46 obtained by mechanochemical Lossen transposition versus solution synthesis (Tables S1 and S2); comparative mechanochemical methods for ethotoin 21 preparation (Scheme S1)(PDF)

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ACKNOWLEDGMENTS

The authors are grateful to MIUR (Italy, PRIN project: MultIFunctional poLymer cOmposites based on groWn matERials). A.P. is grateful to MIUR for “Finanziamento delle Attività Base di Ricerca (FABR 2017)“. The authors acknowledge the CeSAR (Centro Servizi d’Ateneo per la Ricerca) of the University of Cagliari, Italy for the NMR experiments at 600 MHz.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

A. Porcheddu: 0000-0001-7367-1102 F. Delogu: 0000-0003-2520-9057 L. De Luca: 0000-0001-7211-9076 E. Colacino: 0000-0002-1179-4913 12049


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