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Highly Efficient Regioselective Synthesis of 2‑Imino-4-oxothiazolidin5-ylidene Acetates via a Substitution-Dependent Cyclization Sequence under Catalyst-Free Conditions at Ambient Temperature Yogesh B. Wagh,† Anil S. Kuwar,† Dipak R. Patil,† Yogesh A. Tayade,† Asha D. Jangale,† Santosh S. Terdale,‡ Darshak R. Trivedi,§ Judith Gallucci,∥ and Dipak S. Dalal*,† †

School of Chemical Sciences, North Maharashtra University, Jalgaon 425 001, Maharashtra, India Department of Chemistry, Savitribai Phule Pune University, Pune 411 007, India § Supramolecular Chemistry Laboratory, Department of Chemistry, National Institute of Technology Karnataka (NITK), Srinivasnagar, Surathkal, Mangalore 575025, Karnataka, India ∥ Department of Chemistry and Biochemistry, The Ohio State University, Columbus, Ohio 43210, United States ‡

S Supporting Information *

ABSTRACT: A green and efficient method for the synthesis of newer 2-imino-4-oxothiazolidin-5-ylidene acetate derivatives under catalyst-free conditions by simply stirring symmetrical and unsymmetrical 1,3-diarylthioureas with dialkyl acetylenedicarboxylates in ethanol at room temperature has been developed. Interestingly, the regioselective synthesis affords the 2-imino-4-oxothiazolidin-5-ylidene acetate derivatives: the amine nitrogen bonded to an electron-withdrawing substituent becomes part of the imino component, and the amine nitrogen bonded to an electron-donating substituent becomes the heterocyclic nitrogen. This is the first report wherein the impact of substituents in directing the regiocyclization has been explained and the structure conflict resolved by single-crystal X-ray analysis.

1. INTRODUCTION Green, sustainable chemistry involves the design of chemical processes with a view to reduce or even eliminate the use and production of hazardous materials.1 Five-membered rings containing two heteroatoms are privileged structures because they belong to a class of compounds with proven utility in chemistry.2 As an example, the 2-iminothiazolidin-4-one core is a crucial privileged heterocyclic scaffold3 in numerous biologically active pharmacophores,4 and their synthesis has emerged as one of the most important topics in the field of heterocyclic chemistry. Compounds carrying the 2-iminothiazolidin-4-one core are reported to have a wide range of biological activities as in Figure 1, which include anticancer5 (autoimmune disorders5b ACT-128800 and orally active S1P1 receptor agonist5c), anti-HIV agents,6 antidiabetic,7 potent antiproliferative agents,8 antitumor,9 antiinflammatory,10 cardiovascular effect,11 antimicrobial,12 antitubercular,13 antihypertensive agents,14 antibacterial,15 with antibiofilm activities,16 etc. A general method involved in the prevailing synthetic protocols for 2-iminothiazolidin-4-ones is the cyclization of thioureas with β-nitroacrylates,17 bromoketones,18 carboxylic esters,19 acyl halides,20 and α-halocarboxylic acids.21 In the literature, reactions of thioureas with dialkyl acetylenedicarboxylates have been reported to produce both five-22 and sixmembered23 heterocyclic systems by using acetone,24a anhydrous CH2Cl2,24b tetrahydrofuran (THF),24c and ethyl lactate25 as reaction media. However, all of these methods have certain limitations, such as confinement to limited examples, availability of conditions, suffering from step efficiency, and importantly no © 2015 American Chemical Society

attempt by unsymmetrical thioureas to explain the regioselectivity. In a continuation of our studies on heterocyclic synthesis,26 recently, we have reported the regioselective synthesis of (Z)ethyl-2-[(Z)-2-(benzo[d]thiazol-2-ylimino)-4-oxo-3-phenylthiazolidin-5-ylidene acetate, which shows metal sensing as well as antidiabetic activity.26e Herein, we report a highly efficient, straightforward regioselective synthesis of (2Z)-ethyl/methyl-2[(Z)-4-oxo-3-aryl/alkyl-2-(arylimino)thiazolidin-5-ylidene] acetate derivatives from various symmetrical and unsymmetrical aryl/alkylthioureas with dialkyl acetylenedicarboxylates (DAADs) under catalyst-free conditions in an innocuous solvent, ethanol (Scheme 1). Such a regioselective synthesis of the 2-iminothiazolidin-4-one core through the substitutiondependent transformations has not yet been reported.

2. EXPERIMENTAL SECTION 2.1. Methods and Materials. Melting points were measured in open capillary tubes and are uncorrected. Fourier transform infrared (FT-IR) spectra were obtained on a Shimadzu IR-Affinity spectrometer (KBr pellets). The 1H and 13 C NMR spectra were recorded on an Advance-II FT-NMR spectrometer model (Bruker). The instrument is equipped with a cryomagnet of field strength 9.4 T. Its 1H frequency is 400 and 300 MHz, while its 13C frequency is 100 and 75 MHz; the Received: Revised: Accepted: Published: 9675

May 11, 2015 September 19, 2015 September 23, 2015 September 23, 2015 DOI: 10.1021/acs.iecr.5b01746 Ind. Eng. Chem. Res. 2015, 54, 9675−9682

Article

Industrial & Engineering Chemistry Research

Figure 1. Selected representative examples of bioactive 2-iminothiazolidin-4-one cores.

Scheme 1. Synthesis of Various Substituted 2-Imino-4-oxothiazolidin-5-ylidene Acetates

3. RESULTS AND DISCUSSION For our initial investigation, 1,3-diphenylthiourea with DEAD was taken as the model reaction. We began this study by performing the reaction of an equimolar mixture in ethanol at room temperature as well as at reflux temperature, which afforded exclusively compound 4b within a few minutes. Encouraged by this result, we further investigated the effect of the solvent and temperature on the model reaction with an equimolar quantity. As shown in Table 1, various yields of the target product 4b (44−90%) were obtained when the mixture of 1, 3-diphenyl thiourea with DEAD was stirred under given conditions in various solvents. The reaction using EtOH and MeOH gave the corresponding product 4b in high yields (Table 1, entries 1−4). While the results with other solvents as MeCN, Water, CHCl3, DCM and THF were not much impressive (Table 1, entries 5− 8 respectively). Similarly, isolation problem of solid products was occurs when we employed DMF and DMSO as solvent in the above reaction (Table 1, entries 9 and 10). The isolated solid was sticky in nature and dark orange colored. Therefore, the economical and environmental point of view and toxicity of methanol, ethanol was chosen as the reaction medium for all reactions. Furthermore, the relation between the yields of the model reaction and temperature was also studied. We carried out the reaction at room and reflux temperatures using ethanol as the reaction solvent (Table 1, entries 1−2), and found that the yields of the desired product 4b were not improved at the reflux temperature. Therefore, the best reaction conditions were optimized in ethanol at room temperature.

NMR instrument uses tetramethylsilane as an internal standard and CDCl3 as a solvent. Chemical shifts are given in parts per million (δ-scale), and the coupling constants are given in hertz. Mass spectra were performed on an Ultima Global spectrometer with an E source. Silica gel (60−120 mesh size) was used for column chromatography, and silica gel-G plates (Merck) were used for thin-layer chromatography (TLC) analysis with a mixture of acetone in n-hexane (15%) as the eluent. Dimethyl acetylenedicarboxylates (DMADs) and diethyl acetylenedicarboxylates (DEADs) were obtained from SigmaAldrich Chemical Co. and used without further purification. 2.2. General Preparation of 4-Oxo-2-(phenylimino)thiazolidin-5-ylidene Acetate Derivatives. To a magnetically stirred solution of 2 mmol of 1,3-diphenylthiourea and 5 mL of ethanol in a 25 mL round-bottom flask was added dropwise at room temperature (rt) 2 mmol of DAADs (for 5j− 5m using a 1:2 ratio in 7 mL of ethanol). After the complete addition of DAADs, the reaction mixture was stirred and monitored by TLC (hexane/acetone, 15%); during the reaction, a solid appears in the solution. After completion of the reaction, excess solvent was removed under reduced pressure and the residue recrystallized from ethanol and a few drops of water, affording the desired product as pale-yellow crystals. Similarly, the products were further identified by FTIR, 1H and 13C NMR, and mass/high-resolution mass spectrometry (HRMS), which were all in good agreement with the assigned structures. 9676

DOI: 10.1021/acs.iecr.5b01746 Ind. Eng. Chem. Res. 2015, 54, 9675−9682

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yl)-4-oxo-2-(phenylimino)thiazolidin-5-ylidene] acetate or (Z)ethyl-2-[(Z)-2-[(4-methoxyphenyl)imino]-4-oxo-3-phenylthiazolidin-5-ylidene] acetate on the basis of 1H and 13C NMR and HRMS results. Interestingly, the compound crystallized out from a mixture of chloroform and hexane (1:9). X-ray crystallography of the product unequivocally confirmed the (Z)-ethyl-2-[(Z)-3-(4-methoxyphenyl)-4-oxo-2-(phenylimino)thiazolidin-5-ylidene] acetate structure with the 4-methoxyphenyl group bonded to the heterocyclic N1 atom in Figure S1 (see the Supporting Information). Similarly, the structure of compound 3d was resolved through the crystallization from a mixture of chloroform and hexane (2:8), and X-ray crystallography confirmed (Z)-ethyl-2-[(Z)-2-((3-nitrophenyl)imino)-4-oxo-3-phenylthiazolidin-5-ylidene] acetate, with the 3nitrophenyl group bonded to the imino group in Figure S2 (see the Supporting Information). While in 3e and 3h (Table 2) the unsymmetrical thiourea contains phenyl and p-nitrophenyl groups, when the pbromophenyl group attached to the thiourea reacted with DEAD, it gave a regio mixture of 2-imino-4-oxothiazolidin-5ylidene acetate in a ratio of 98:2. The effect of substitution on 1,3-diphenylthiourea was examined, and it was found that the nature of the substituent gave only minor variations in the rate of the reaction but a major effect in the reaction where it will react. In accordance with reports from the literature,27,28 we suggest that the sulfur atom (soft nucleophile) of the thiourea will preferentially attack activated alkynes (soft electrophile) and NH (hard nucleophile) will attack the carbonyl center (hard electrophile). Thus, we conceived of the following mechanism on the basis of electronic effects on the regioselectivity of the reaction in Scheme 2. Interestingly, the NH proton engaged between the phenyl moiety bearing an electron-donating group compared to the other NH proton from the phenyl moiety bearing electronwithdrawing substituents; therefore, enolization of thiourea from the phenyl side bearing an electron-withdrawing group of the substrate is facilitated. This regioselective cyclization of thiourea bearing an electron-donating substitutent results in that substituent becoming a part of the heterocyclic ring, and the amine bearing the electron-withdrawing substitutent becomes the imino nitrogen as the product in good yield. The formation of products was in accordance with the results of Patel et al.,28 who reported that regioselective formation of 5unsubstituted 2-iminothiazolidin-4-ones was observed for unsymmetrical thioureas in which the amine having higher pKa is part of the heterocyclic nitrogen of the five-membered ring and the amine attached to the thiourea having lower pKa is a part of the imino component. Another couple of reports suggest that the chelating effect29 of the substituent addresses the regiochemical result, while another investigation shows that the allylic strain30 on the substrate directs the regioselectivity. After the successful synthesis of a series of 2-imino-4oxothiazolidin-5-ylidene acetate from unsymmetrical thioureas, we turned our attention to the reaction for symmetrical thioureas. As can be seen, the reaction of DEAD and DMAD with the symmetric 1,3-diphenylthiourea bearing methyl, methoxy, fluoro, chloro, bromo, etc., substituents was well tolerated, and in all cases, the reactions proceed smoothly to afford the corresponding 2-imino-4-oxothiazolidin-5-ylidene acetate in good yield, as shown in Table S8 (see the Supporting Information). The purity of the product was high enough for spectroscopic analysis without any further purification, but all of the compounds were, nevertheless, crystallized from ethanol.

Table 1. Optimization of the Reaction Conditions for the Synthesis of 4b

entry

solvent

conditionsa

time

yield (%)b

1 2 3 4 5 6 7 8 9 10

EtOH EtOH MeOH MeOH CH3CN water CHCl3 THF DMF DMSO

rt reflux rt reflux rt rt rt rt rt rt

15 min 15 min 15 min 15 min 2h 30 min 4h 24 h 5h 5h

90 88 81 80 68 44c 68c 70 traced traced

a

Reaction conditions: 1,3-diphenylthiourea (1 mmol), DEAD (1 mmol), and solvent (3 mL). bIsolated yields. cSticky products. d Reaction was not completed.

With optimal conditions in hand, we commenced exploring the substrate scope, and the results are summarized in Table 2. When the reactions were proceeding toward the desired product formation, the color of the reaction mixture changed from white to yellow or pale yellow. Finally at the end of the reaction, we found the formation of a yellow precipitate. The obtained yellow precipitate was filtered, dried, and subjected to spectroscopic analysis. We were pleased to recognize that the yellow solid obtained in the reaction was the desired product just by filtration and recrystallization (Table 2, entries 1−8). Because the formation of 2-imino-4-oxothiazolidin-5-ylidene acetate is an addition with cyclization, the effect of the substituent on the phenyl ring is expected to play an important role of regioselectivity in product formation. In the case of the cyclization of unsymmetrical 1,3-diphenylthiourea, mixtures of regioisomeric products may be possible. However, with all unsymmetrical 1,3-diphenyl thioureas used, only one major regioisomer has been obtained in high yields under the present reaction conditions. This may be attributed to the fact that regiocontrol in the cyclization step is in general influenced by electronic factors that predispose the regioselective cyclization of thiourea having electron-donating as well as electronwithdrawing substituents to maintain conjugative stabilization with product formation. In order to evaluate the scope of the present protocol, the reaction was extended to electrondonating as well as electron-withdrawing substituents on 1,3diphenylthiourea. Interestingly, reactions proceeded easily under the present conditions to afford the corresponding regioselective 2-imino-4-oxothiazolidin-5-ylidene acetate derivatives in good yields in which an electron-donating (3a and 3b) substituent is bonded to the five-membered heterocyclic nitrogen in the products, while the electron-withdrawing substituent (3c and 3h) is a part of the imino component as the sole product. In entry 3, the phenyl ring is electronwithdrawing compared with the donating cyclohexyl ring; therefore, the phenyl ring bonded to thiourea nitrogen becomes part of the imino component and the cyclohexyl ring bonded to the thiourea nitrogen becomes part of the five-membered heterocyclic ring. For 3a, it was difficult to conclude whether the product obtained was (Z)-ethyl-2-[(Z)-3-(4-methoxyphen9677


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Table 2. Formation of 2-Imino-4-oxothiazolidin-5-ylidene Acetate Derivatives from Unsymmetrical 1,3-Disubstituted Thioureas and DEADa

a All reactions were conducted under conditions: 1,3-diphenylthiourea derivative (3.0 mmol), DEAD (3.0 mmol), and ethanol (8 mL) at rt. bYield of pure product. cRegio mixture (98:2).

tives from phenyl isothiocyanate, aniline, and DEAD. Interestingly, our method affords only (Z)-alkyl-2-[(Z)-4-oxo3-phenyl-2-(phenylimino)thiazolidin-5-ylidene] acetate. After the successful resolution of the structural conflict of unsymmetrical and symmetrical 2-imino-4-oxothiazolidin-5-ylidene acetate, to further broaden the scope of the regioselectivity, we also focused on employing aliphatic amine versus aromatic

The structures of the products were determined by spectroscopic analysis, and the structure of compound 4d was confirmed by single-crystal X-ray analysis in Figure S3 (see the Supporting Information). Previously, Das et al.31 reported a CuFe2O4-catalyzed regioselective one-pot synthesis of (E)-alkyl-2-[(E)-4-oxo-3phenyl-2-(phenylimino)thiazolidin-5-ylidene] acetate deriva9678


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Industrial & Engineering Chemistry Research Scheme 2. Probable Mechanism for the Formation of Regioselective 2-Imino-4-oxothiazolidin-5-ylidene Acetate

prepared from the reaction of various amines with phenyl isothiocyanate.33 It is worth noting that all of the precipitated products needed only to be washed with cold ethanol during filtration to afford the pure compounds. This ease of purification makes this methodology facile, practical, and rapid to execute. The present method is indeed superior to several of the others in terms of simplicity, regioselectivity through substitution-dependent transformations, and ease of isolation of the final products by a simple workup. The synthetic procedure was optimized on a small scale and subsequently transferred to a large scale for excellent yield. In a controlled experiment in our laboratory, when DEAD (8.5 g, 50 mmol) was slowly mixed with 1,3-diphenylthiourea (11.4 g, 50 mmol) in ethanol (50 mL) in ice cold conditions, the mixture began to convert into yellow solid within about 20 min. Thereafter, ethanol (20 mL) was added to the reaction mixture for the isolation of product 4b with 92% (16.21 g) yield. This is an exothermic reaction, and cooling is necessary for a largescale reaction. By using these optimized conditions and designed reactors, this process will be useful to industries for the larger-scale production of various 2-imino-4-oxothiazolidin5-ylidene acetates. No operational problems are foreseen for a large-scale version of this green process. This methodology is also applicable to a wide variety of pharmaceutically relevant heterocyclic systems, such as an illustrated plan for the formal synthesis of an orally active S1P1 receptor agonist selected for clinical development (ACT-128800).5b In addition, the biological properties of this rarely described class of new compounds are currently in progress and will be reported in due course.

amine of unsymmetrical 1,3-disubstituted thiourea in this protocol. The benzylamine, 2-phenylethanamine, 2-(thiophen2-yl)ethanamine, and furan-2-ylmethanamine substituents on unsymmetrical thioureas gave good results, as shown in Table S9 (see the Supporting Information). Furthermore, in the case of the alkyl substituents of thioureas, tert-butyl and isopropyl substituents showed moderate yields compared with other substituents (5a−5i). Next, to study the applicability of the present method, we employed aliphatic amine versus aromatic amine of dimeric unsymmetrical 1,3-disubstituted thiourea (5j−5m). To our delight, aliphatic amine versus aromatic amine substituents gave the corresponding series of bis(2imino-4-oxothiazolidin-5-ylidene) acetate derivatives in good yield. This allows regioselective cyclization of thiourea bearing aliphatic amine versus aromatic amine substitution in which aromatic amines become a part of the imino component and the aliphatic amines contribute to the heterocyclic fivemembered ring nitrogen as the sole product in good yield. This is clearly revealed from the X-ray structures of 5c, 5d, 5f, and 5k, which were crystallized from a mixture of ethyl acetate and hexane (2:8). Interestingly, the structures of all products show the geometry of imine (Z), as shown in Figures S4−S7 (see the Supporting Information). Thus, the difference in the reactivity of aliphatic and aromatic amines of 1,3-diphenylthiourea leads to the formation of a single regioisomer, and hence the present protocol can be considered as regioselective. Of the possible other diastereomeric forms, E and Z, only Z isomers were obtained in the reactions between symmetrical and unsymmetrical thioureas with DMAD/DEAD, and it is important to highlight that this methodology provides easy access to the formation of a single regioisomer through the proper tuning of the various 1,3disubstituted thioureas. For the synthesis of 2-imino-4oxothiazolidin-5-ylidene acetates by our method, we need a carboxylic ester group at the terminal. We tried to extend the substrate scope toward other alkyne-like ethyl propiolates, but the reaction does not proceed smoothly in optimized conditions, while the reaction of 1-benzyl-3-butylthiourea having aliphatic amine versus aliphatic amine substituents with DMAD shows the formation of regio isomers in product 6 (see the Supporting Information). We previously reported the reaction of anilines with carbon disulfide in the presence of sunlight in water to produce symmetric thiourea compounds32 used in the synthesis, and unsymmetrical thioureas were

4. CONCLUSION In conclusion, an efficient and facile regioselective synthesis of 2-imino-4-oxothiazolidin-5-ylidene acetate from symmetrical and unsymmetrical thioureas is reported. The regioselective reactions show that the amine nitrogen of thiourea bonded to an electron-withdrawing substituent becomes part of the imino component and the amine nitrogen of thiourea bonded to an electron-donating substituent becomes the heterocyclic nitrogen in the synthesis of 2-imino-4-oxothiazolidin-5-ylidene acetate derivatives, even in cases of challenging aliphatic amine versus aromatic amine substitution in which aromatic amines become a part of the imino component and the aliphatic amines contribute to the heterocyclic five-membered 9679


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ring nitrogen in good yield. The present method has simplified methodology, wider applicability, and easier workability and is environmentally friendly. The structures were unambiguously determined by X-ray crystallographic analysis. This approach could be easily applied to the synthesis with structure determination of more privileged structure-based analogues that are of interest in drug discovery.

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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/acs.iecr.5b01746. Spectral values of 1H and 13C NMR, HRMS spectra of selected compounds, and X-ray crystal data for compounds 3a, 3d, 4d, 5c, 5d, 5f, and 5k (PDF)

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AUTHOR INFORMATION

Corresponding Author

*Tel: +91-2572257432. Fax: +91-2572258406. E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors express their gratitude to UGC, New Delhi, India, for an SAP fellowship under the scheme Research Fellowship in Sciences for Meritorious Students. The authors are also grateful to SAIF, Panjab University, University of Pune, Chemistry Department for providing NMR, and LCMS facilities.

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REFERENCES

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