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Domino Synthesis of Thioflavones and Thioflavothiones by Regioselective Ring Opening of Donor−Acceptor Cyclopropane Using In-Situ-Generated Thiolate Anions Nallappan Sundaravelu and Govindasamy Sekar* Department of Chemistry, Indian Institute of Technology Madras, Chennai-600036, Tamil Nadu, India

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S Supporting Information *

ABSTRACT: A copper-catalyzed intramolecular ring opening of donor−acceptor cyclopropane is developed for the synthesis of 3-alkyl-carbonated thioflavones and further extended to 3-alkyl-carbonated thioflavothione, using xanthate as a sulfur surrogate. This reaction proceeds through thiolate formation/ring opening/Krapcho decarboxylation, followed by hydrogen abstraction, to give thioflavanone, which is further oxidized by in-situ-generated iodine from waste byproduct KI. Experimental studies prove that the chargetransfer complex is responsible for the conversion of thioketone to ketone.

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Scheme 1. Lewis-Acid-Catalyzed D−A Cyclopropane Ring Opening Reaction Using a Sulfur Nucleophile

onor−acceptor (D−A) cyclopropanes have become an important class of building blocks for the construction of cyclic and acyclic compounds.1 The polarization of the bond between donor and acceptor, in conjunction with the high ring strain of cyclopropanes, forces the system to rearrange or undergo ring-opening or cycloaddition reactions, thereby paving the way for the efficient synthesis of heterocycles and natural products.2 The ring opening is induced by the attack of nucleophile to the emerging positive charge next to the donor. The resulting negative charge at the carbon substituted by the acceptor is neutralized by an electrophile or proton.3 However, the ring-opening reactions of D−A cyclopropanes with carbon, and other heteroatoms as nucleophiles are well-explored.4 Albeit, compared to other heteroatoms, sulfur heterocycles have been less explored in the literature,5 because of deactivation of the catalyst and also the stinking nature of sulfur compounds. On the basis of these reports, we are keen in exploring D−A cyclopropane ring opening reactions using sulfur nucleophiles. Seminal work in this field was reported by Werz, using chalcogenyl halides to accomplish the first 1,3halochalcogenation of D−A cyclopropanes via ring opening reaction (Scheme 1a).6,6a The same research group later reported the formal insertion of thioketone into cyclopropane for the synthesis of tetrahydrothiophenes (Scheme 1b).6b In the course of our studies, Trushkov have reported Lewis-acidcatalyzed intramolecular ring opening reaction for the synthesis of benzannulated five-membered heterocycles.7 3-Alkyl-substituted thioflavones8 and 3-alkyl-substituted thioflavothione9 are widely present in naturally occurring molecules and can be used in materials science, as well as in the pharmaceuticals industry. In addition, 3-alkyl-substituted thioflavones have evolved as photo labile protecting groups for different types of functional © XXXX American Chemical Society

groups.10 The importance of this moiety has triggered many research groups to focus on the synthesis of 3-alkyl-substituted thioflavones and thioflavothione.11 However, very few reports are available on the synthesis of 3-alkyl-substituted thioflavones, and, to the best of our knowledge; no reports are available for the synthesis of 3-alkyl-carbonated thioflovones. In consequence of the above-mentioned considerations, the development of novel synthetic approaches for the synthesis of Received: June 26, 2019

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DOI: 10.1021/acs.orglett.9b02210 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters thioflavone and thioflavothione is our prime interest. In this note, we report very convenient and efficient domino synthesis of 3-substituted thioflavones and thioflavothione bearing 1,4dicarbonyl backbone using xanthate as an odorless thionating reagent. As part of our ongoing research toward Cu-catalyzed in situ generation of thiol using xanthate as a sulfur surrogate,12 we postulated that Cu-catalyzed intramolecular nucleophilic ring opening of D−A cyclopropane using in-situ-generated thiolate anion will result in the synthesis of ethyl 2-(4-oxo-2phenylthiochroman-3-yl)acetate. To execute our hypothesis, the very first reaction was performed with cyclopropane obtained from 2′-iodochalcone and diethyl malonate (1a), treated with xanthate, AgOAc as an additive, and CuI as a catalyst. The reaction was allowed to proceed until complete consumption of the starting material. Delightfully, we got the desired product (3a) in 48% yield, along with the thioflavothione (2a) in 18% yield. Having the preliminary result in hand, after performing the rigorous studies, the optimal conditions were found for both 2a and 3a separately (see the Supporting Information for details). The resultant optimized conditions for 3-alkylcarbonated thioflavones uses 1a (1 equiv), xanthate (3 equiv), Cu(OAc)2 (10 mol %), and Na2O3S2·5H2O (2 equiv) in dimethylsulfoxide (DMSO) as a solvent to yield 99% of the product in 16 h, whereas for 3-alkyl-carbonated thioflavothione 1a (1 equiv), xanthate (3 equiv), Cu(OAc)2 (10 mol %), and AcOH (2 equiv) in dimethylformamide (DMF) as a solvent at 110 °C after 4 h gave 82% yield (see Scheme 2).

Scheme 3. Scope for the Synthesis of 3-Alkyl-Substituted Thioflavothionesa

a

Reaction conditions: 1 (0.2 mmol), xanthate (3 equiv), Cu(OAc)2 (10 mol %), AcOH (2 equiv), and DMF (2 mL) at 110 °C.

Scheme 4. Scope for the Synthesis of 3-Alkyl-Substituted Thioflavonesa,b

Scheme 2. Optimized Reaction Conditions for 2a and 3a

Having acquired two different optimized reaction conditions in hand (Scheme 2), we have studied the scope of the various 2′-iodosubstituted cyclopropanes. Initially, the scope of regioselective and chemoselective synthesis of 3-alkyl-carbonated thioflavothiones, using xanthate as a thionating reagent, under the optimal conditions, was studied. The scope of this methodology was studied thereof having electron-donating as well as electron-withdrawing substitutions in the aryl ring effectively participated in this reaction to produce desired products (2a−2l) in good yields (see Scheme 4). Even sterically crowded trisubstituted methoxy substituents also gave moderate yield (2m). Using dimethyl malonate under optimal conditions also produced an encouraging yield (2n). Furthermore, bromo substitution on phenyl ring attached with ketone was also well-tolerated in the reaction condition and gave (2o) in good yield. 3-Alkyl-carbonated thioflavothione products containing ortho- substitution gave the axial chirality, and the results are summarized in Scheme 3. Furthermore, the scope of the 3-alkyl-carbonated thioflavones was studied with EDG such as methyl (3b), ethyl (3c), methoxy (3d), and thiomethyl (3e) were well-tolerated and gave the sole thioflavone products in excellent yield (see Scheme 4). Electronegative functional groups such as bromo and fluoro substituents were found to be suitable for this domino reaction (3f, 3g). The electron-withdrawing-groupsubstituted 2′-iodocyclopropane was also well-tolerated and

a

Reaction conditions: 1 (0.2 mmol), xanthate (3 equiv), Cu(OAc)2 (10 mol %), Na2S2O3·5H2O (2 equiv), DMSO (2 mL) at 110 °C. b1Benzoyl-2-(2-iodobenzoyl)-3-phenylcyclopropane-1-carboxylate is used as starting material.

corresponding products 3h were isolated in good yield. In addition aryl groups, substrates with a fused ring (such as naphthyl) and a heteroaryl ring (such as thiophene) were found to be suitable for this domino reaction, and the corresponding products (3i, 3j) were obtained in notable yield. Even changing the substitution of phenyl ring attached to ketone also gave desired products in good yields (3k). Utilizing dimethyl malonate instead of diethyl gave the desired products in good yields (3l). B

DOI: 10.1021/acs.orglett.9b02210 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Note that, when the reaction was performed with sterically hindered ortho-substituted 2′-iodocyclopropane, smooth conversion to corresponding 3-alkyl-carbonated thioflavones was observed with excellent yields (see Scheme 3). Interestingly, ortho-substituted molecules (3m, 3n) showed axial chirality. However, while performing the reaction with ethyl 1-benzoyl2-(2-iodobenzoyl)-3-phenylcyclopropane-1-carboxylate as starting material, the benzoyl group was removed selectively in a very short reaction time (3a). Later, an effort was made to achieve the domino synthesis of 3-alkyl-carbonated thioflavones from less-reactive 2′-bromocyclopropanes 4. When the optimized reaction condition was applied to 2′-bromocyclopropane 4a, gratifyingly, we observed 95% product formation without changing any parameters. Also, other substituted 2′-bromocyclopropanes were found to be suitable substrates for this domino intramolecular ring opening reaction and provided the corresponding 3-alkylcarbonated thioflavones and thioflavothione 3d, 3h, 2e, and 2k in moderate to excellent yield (see Scheme 5).

Scheme 7. Control Experiments To Predict the Reaction Pathway for 2a and 3a

reaction was found to be slow and also the yield reduced drastically (Scheme 7a). This result suggests that the iodine plays a key role in the oxidation of thioflavanone to thioflavone. To substantiate this, the next reaction was performed with compound 5, using a catalytic amount of iodine, which afforded 98% of 3a in just 6 h (Scheme 7b). Furthermore, in both reactions, we did not find the trace of 2a, which proves that product 3a can attained directly without the formation of 2a. Based on the reaction observation, we surmised that the thioketone to ketone (2a to 3a) transformation is catalyzed by a halogen bonding catalyst. To prove this hypothesis, a few more reactions were performed from thioflavothione 2a. When compound 2a was performed with catalytic iodine in a DMSO medium led to the formation of product 3a in a very short reaction time (Scheme 7c). Nevertheless, replacing DMSO with DMF did not yield 3a, which shows that the DMSO plays a pivotal role, other than a solvent (Scheme 7d). Also, the reaction did not occur when the reaction was performed without iodine (Scheme 7e). However, replacing iodine by Cu(OAc)2 (10 mol %) leads to the completion of the reaction after 48 h (Scheme 7f). The iodonium ion formed in the reaction may be stabilized by DMSO via a charge-transfer catalyst. Next, we attempted to understand the formation of 2a in the reaction sequence. When 3-alkyl-carbonated thioflavone 3a was subjected to the optimized condition; no trace of thioflavothione 2a was observed (Scheme 7g). Similarly, when ketone 6a was treated under the optimized condition, the starting material was sustained (Scheme 7h); this result was evidence that the thionation of ketone may occur simultaneously with the cyclopropane ring opening step. Moreover, while 5a was treated under the optimized conditions, the thioflavothione 2a observed in 89% after 6 h (Scheme 7i). In an acid medium, potassium ethyl xanthate is known to decompose to carbon disulfide, which could be the reason for the thionation. Therefore, we replaced the xanthate by CS2 under the optimized conditions; however, the reaction ended with the formation of 3a (22% yield), which clearly indicates that the xanthate is the source of thionation of ketone (Scheme 7j). Based on the results of the control experiments and literature precedent,13,14 a plausible reaction mechanism is depicted in Scheme 8. The reaction is initiated by oxidative addition of 1 with copper acetate to give intermediate A, which

Scheme 5. Synthesis of 3-Alkyl-Carbonated Thioflavones and Thioflavothiones from 2′-Bromocyclopropanesa

a

Reaction conditions: 4 (0.2 mmol), xanthate (3 equiv), Cu(OAc)2 (10 mol %). For compounds 3d and 3h (Scheme 2a), optimal conditions were used, whereas, for 2e and 2k (Scheme 2b), optimized conditions were used.

In order to showcase the efficacy of domino synthesis of thioflavones and thioflavothiones on a gram scale, the reaction was performed in 3 mmol (1.48 g) scale under standard optimized conditions without altering any reaction parameters. The reaction proceeded smoothly and provided the corresponding thioflavone 3a and thioflavothione 2a in yields of 96% (946 mg) and 83% (851 mg), respectively. (See Scheme 6.) Scheme 6. Gram Synthesis of 3-Alkyl-Carbonated Thioflavone and Thioflavothione

To explore the mechanism, a series of control experiments were performed (see Scheme 7). Initially, to delve into the role of in-situ-generated halogen and thionation of ketone to the formation of 3a, we have chosen 5 as the starting material. When compound 5 was exposed to the optimized conditions with the replacement of xanthate by NaOAc as mild base, the C

DOI: 10.1021/acs.orglett.9b02210 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

brings the axial chirality to the molecule. Also, we expect the charge-transfer complex formed from in-situ-generated iodine and DMSO to catalyze the conversion of thioketone to simple ketones via the halogen bond.

Scheme 8. Proposed Catalytic Cycle for 2a and 3a

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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.orglett.9b02210. Experimental procedures, characterization data for all products, NMR spectra (PDF) Accession Codes

CCDC 1903394 and 1903395 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

subsequently undergoes ligand replacement by xanthate, leading to the formation of intermediate B and KI as a byproduct. The liberated byproduct KI may be oxidized to iodine by using DMSO. Intermediate B will be converted to intermediate C by reductive elimination. The intermediate C will generate thiolate anion intermediate D via base hydrolysis. There are two possibilities for the formation of product 3 from intermediate D. In path a in Scheme 8, intermediate D may undergo nucleophilic ring opening of cyclopropane, followed by Krapcho decarboxylation in the presence of halide anion in DMSO, by expelling CO2 as a gas to form intermediate E. Intermediate E then undergoes direct oxidation by halogen, which leads to the formation of 3. Alternatively, the addition of a stoichiometric amount of acetic acid to intermediate D will give intermediate F via rapid thionation of ketone chemoselectively over the ester. Intermediate F will be oxidized to thioflavothione 2 by insitu-formed halogen. Because of the poor orbital overlap between two elements that differ significantly in size, the carbon−sulfur π-bond has high reactivity; also, the enethiol tautomer is favored to a greater extent than in keto−enol tautomerism. Upon comparison, the rate of the transformation from F to 2 is rapid, compared to the rate of the transformation from E to 3. Finally, compound 2 will be immediately converted to 3 in the presence of an in-situgenerated charge-transfer complex. It is important to mention that we were able to isolate the thioflavothione 2 by performing this reaction in DMF, instead of DMSO. The driving force for the rapid conversion of intermediate 2 to 3 is the CT complex formation between the in-situ-generated halogen with DMSO. Hence, the formation of both 2 and 3 primarily follows path b in Scheme 8. In summary, we have disclosed an efficient Cu-catalyzed domino strategy for the synthesis of 3-alkyl-carbonated thioflavones via intramolecular ring opening of easily accessible 2′-halosubstituted D−A cyclopropane, using xanthate as a sulfur surrogate. To the best of our knowledge, this is the first example that takes advantage of intramolecular D−A cyclopropane ring opening reaction via in-situ-generated thiolate anions, followed by oxidation using I2 that is generated from waste byproduct KI using DMSO as an oxidant. Furthermore, this methodology is extended for the domino synthesis of chemoselective 3-alkyl-carbonated thioflavothione using xanthate and AcOH as thionating reagents. This can be a better alternative for existing thionating reagents. Also, we found that the substitution of ortho and meta position of phenyl ring

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Govindasamy Sekar: 0000-0003-2294-0485 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS G.S. thanks IIT Madras (No. CHY/17-18/847/RFIR/GSEK) for financial support. N.S. thanks CSIR, New Delhi for a senior research fellowship. We thank DST and Department of Chemistry, IIT Madras for Instrumentation facilities.

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DEDICATION Dedicated to Prof. H. Ila on the occasion of her 75th birthday. REFERENCES

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DOI: 10.1021/acs.orglett.9b02210 Org. Lett. XXXX, XXX, XXX−XXX