Unmasking Dipole Character of Acyl Ketene Dithioacetals via a

7 days ago - In summary, we have developed a transition-metal-free, expeditious reaction for the synthesis of 2,3-disubstituted benzo[b]thiophenes. Ke...
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Unmasking Dipole Character of Acyl Ketene Dithioacetals via a Cascade Reaction with Arynes: Synthesis of Benzo[b]thiophenes Parul Garg and Anand Singh* Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur, UP-208016, India S Supporting Information *

ABSTRACT: An unusual strategy toward novel substituted benzo[b]thiophenes has been developed. The generation of arynes in the presence of acyl ketene dithioacetals resulted in a cascade reaction involving [3 + 2] cycloaddition, and a dealkylative arylation of a thioether moiety to afford 2,3disubstuted benzo[b]thiophenes. This route represents an expeditious approach to benzothiophenes that employs acyl ketene dithioacetals as dipoles.

T

Scheme 1. Synthetic Strategies toward Benzo[b]thiophenes and Our Hypothesis

he benzothiophene scaffold is of significant interest because of its occurrence in bioactive molecules.1 Examples of related commercial drugs include Raloxifene2 and Arzoxifene3 (selective estrogen receptor modulators),4 Zileuton5(inhibitor of 5-lipoxygenase), Ipragliflozin6 (type 2 diabetes), and Sertaconazole7 (antifungal agent) (Figure 1).

Figure 1. Biologically active benzothiophene derivatives.

Recent studies have also identified benzo[b]thiophene containing compounds possessing antitubulin,8 antimitotic,9 urotensin-II receptor antagonistic,10 S1PR4 agonistic,11 antitubercular,12 and antinociceptive13 activities. Additionally, many benzothiophenes have potential applications in material science.14 Classical methods for the synthesis of benzothiophenes from thiophenol derivatives15 have been given a new dimension via modern approaches that employ transition metal catalysts such as Cu,16 Pd,17 Mn,18 Hg,19 Ag,20 and Au.21 Our method involves an unusual arylative annulation of arynes22,23 with acyl ketene dithioacetals to afford 2,3-disubstituted benzothiophenes in an expeditious manner under mild conditions.24 Known cyclization reactions proceeding via the fragmentation of the dithialane moiety utilize a base mediated ring opening at elevated temperatures for initiating the reactivity (Scheme 1b).20,25 Dithialanes are also known to react as dipolarophiles in formal [3 + 2] cycloadditions (Scheme 1c), acting as two-atom donors in ionic reactions that lead to five-membered rings.26 We envisaged that generation of a reactive electrophilic species © XXXX American Chemical Society

(aryne) in the presence of acyl ketene dithioacetals would elicit the innate nucleophilic reactivity of the β-carbon atom thereby revealing their dipole character, and engaging them as threeatom donors in formal cycloadditions (Scheme 1d). During our studies on the cycloaddition chemistry of the acyl ketene dithioacetal 1a with benzyne, we discovered that the Received: January 5, 2018

A

DOI: 10.1021/acs.orglett.8b00053 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters benzothiophene derivative 3a was formed in low yield (Table 1, entry 1). At the outset, it was clear that 2 equiv of the benzyne Table 1. Preliminary Experiments and Optimizationa

entry

2 (equiv)

fluoride (equiv)

additive

solvent

yield (%)

1 2 3 4 5 6 7b 8b 9 10b 11b,c 12b,d

1.5 2.5 3.0 4.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0

CsF (1.5) CsF (3.0) CsF (4.0) CsF (5.0) TBAF (4.0) TBAF (4.0) KF (4.0) CsF (4.0) CsF (4.0) CsF (4.0) CsF (4.0) CsF (4.0)

− − − − − − 18-C-6 18-C-6 18-C-6 18-C-6 18-C-6 18-C-6

MeCN MeCN MeCN MeCN MeCN THF MeCN MeCN PhMe DMF MeCN MeCN

24 50 64 66 20 14 63 76 50 35 59 52

a

Reactions were conducted with 0.21 mmol of 1a in the presence of a fluoride source and an additive (4.0 equiv) in solvent (2.0 mL) at room temperature under an argon atmosphere for 24 h. bReaction was run for 1 h. cReaction was heated at 60 °C for 1 h. dReaction was heated at 100 °C for 1 h.

precursor were required, and subsequent optimization studies concluded that the best results were obtained using 3 equiv of 2 (Table 1, entry 3), although the reaction time was still 24 h (as indicated by the consumption of 1a). Further increasing the amount of 2 and CsF did not have a beneficial effect on the reaction. Exploring other fluoride sources such as TBAF and KF also failed to provide any improvement in the yield of the product. Addition of 18-crown-6 along with CsF improved the yield to 76% and also reduced the reaction time significantly to 1 h (Table 1, entry 8). Use of other phase transfer additives27 did not improve the yield further.28 It was found that the yield of the product was significantly lower in toluene and dimethylformamide (DMF) solvents (Table 1, entries 9 and 10). Performing the reaction at elevated temperatures also led to lower yields (Table 1, entries 11 and 12). We explored the scope of the reaction and found that a wide variety of acyl ketene thioacetals underwent the reaction smoothly. Electronic variations in the aryl substituent on the ketone were well tolerated (Figure 2). Electron-rich as well as electronically neutral substituents on the aryl group afforded products (3a−g) in good yields. Weakly electron-withdrawing substituents were well tolerated (3h−j, 3l−m) and provided the product benzothiophenes in good yields. A comparison between the 3,4-dichloro derivative 3k and the 4-chloro derivative 3j indicated that incorporation of more electronwithdrawing substituents leads to a reduction in the yield. This was further substantiated by the 4-cyano derivative 3n which was obtained in moderate yield (52%). Among heterocyclic substituents, the thiophene derived ketene dithioacetal afforded the product 3o in higher yield (61%) than the 2-pyridyl derivative (3p, 35%). It was observed that acyl ketene thioacetals with alkyl substituents were also suitable in the reaction as demonstrated by the formation of the methyl and cyclopropyl derivatives 3q and 3r in 43% and 56% yield, respectively. Employing α-alkenoyl ketene dithioacetal also

Figure 2. Reaction scope: synthesis of 2,3-disubstituted benzo[b]thiophenes.

furnished the product 3s in good yield (52%). We also studied the reaction of 3,4-dimethyl benzyne with two acyl ketene acetals and found that the products were obtained in good yields (3t and 3u′29). The structure of the product was further confirmed by X-ray crystal structure analysis of 3q. The reaction was also performed on a gram scale (1a; 1.00 g) affording the product 3a (1.13 g) in 74% yield.30 With easy access to the benzothiophene scaffold, we turned our attention to leverage it toward the generation of the triarylmethane motif. The triarylmethane motif has been the subject of numerous synthetic studies31 due to its occurrence in compounds of medicinal importance,32 their use as templates for supramolecular architectures,33 and applications as functional materials.34 Thus, the benzothiophene derivative 3a was reduced with NaBH4 to afford the corresponding alcohol 4a in 78% yield (Scheme 2). FeCl3 catalyzed the C−C bond formation reaction with phenyl ketene thioacetal affording the alkylated product 5 in 78% yield. Employing pyrrole and indole as nucleophiles, the corresponding triarylmethane derivatives 6 and 7 were obtained in 81% and 92% yield, respectively. B

DOI: 10.1021/acs.orglett.8b00053 Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

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Scheme 2. Elaboration of Benzothiophene Products

Letter

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b00053. Full experimental procedures, analytical data, and NMR spectra of all novel compounds (PDF) Accession Codes

CCDC 1576914 contains 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 data_ [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

Although the reaction between arynes and acyl ketene dithioacetals is unprecedented, a reasonable mechanistic picture can be constructed based on the present investigation and the reactivity of acyl ketene thioacetals reported previously.20,25 In the presence of benzyne, the acyl ketene dithioacetal undergoes a [3 + 2] cycloaddition leading to the adduct 9 which is benzo[b]thiophene-2(3H)-thione represented by the resonance form 9′ (Scheme 3, path A). Tautomerization to the aromatic

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Scheme 3. Mechanistic Studies and Proposal

Anand Singh: 0000-0001-9703-6306 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS A.S. gratefully acknowledges funding from IIT Kanpur SERB (SERB/CHM/2015202) and BRNS (BRNS/CHM/2014118). P.G. thanks IIT Kanpur, for a research fellowship. The authors thank Ms. Sonam Mehrotra (IIT Kanpur) for solving the crystal structure of 3q.

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REFERENCES

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DOI: 10.1021/acs.orglett.8b00053 Org. Lett. XXXX, XXX, XXX−XXX

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DOI: 10.1021/acs.orglett.8b00053 Org. Lett. XXXX, XXX, XXX−XXX