Synthesis of 2-Acylbenzo[b

Letter pubs.acs.org/OrgLett

Synthesis of 2‑Acylbenzo[b]thiophenes via Cu-Catalyzed α‑C−H Functionalization of 2‑Halochalcones Using Xanthate Subramani Sangeetha and Govindasamy Sekar* Department of chemistry, Indian Institute of Technology Madras, Chennai 600036, Tamil Nadu, India S Supporting Information *

ABSTRACT: An efficient protocol is described for the synthesis of 2acylbenzo[b]thiophenes from easily accessible 2-iodochalcones through α-C−H functionalization using Cu(OAc)2 catalyst and xanthate as sulfur source. Less reactive 2-bromochalcones also yielded the corresponding 2-acylbenzothiophenes in good yield. The reaction proceeds via in situ incorporation of sulfur followed by copper-catalyzed cyclization to generate 2-acylbenzothiophenes without external acyl source. The synthetic importance is showcased by synthesis of 1-(5-hydroxybenzothiophene-2-yl)ethanone, which is a known premRNA splicing modulator.

O

Scheme 1. Synthetic Methods of 2-Acylbenzo[b]thiophenes

rganic molecules containing benzo[b]thiophene moiety are quite significant due to their promising properties in pharmacology, catalysis, and application in material science.1 In particular, 2-acylbenzothiophenes are privileged scaffolds in medicinal compounds; for instance, they are used as potent antimitotic agents, inhibitors of tubulin polymerization,2 potent inhibitors of 17β-HSD1,3 and antitrypanosomal4 and antiproliferative agents5 (Figure 1). Apart from this, 2-acylbenzothiophenes are essential building blocks for numerous biologically active compounds.6

Figure 1. Selected 2-acylbenzo[b]thiophene derivatives with biological activities.

along with Pd catalyst.11 Notably, all of the aryl boronates utilized for palladium cross-coupling reactions have been generated from the 2-halo/carboxaldehyde of benzothiophene with pyrophoric n-BuLi at −78 °C. In addition, complexities of these methods include the use of moisture-sensitive and corrosive acylating agents, expensive metal catalysts, odor sulfur sources, limited substrate scope, multistep starting materials, and the requirement of external ligands. Similarly, elegant methods have been developed for the synthesis of the benzo[b]thiophene core by either electrophilic cyclization or coupling cyclization reactions using different sulfur sources in the presence of metal or under metal-free conditions.1b Simultaneously, aryl halides activated with Cu

In general, Brønsted or Lewis acid catalyzed direct Friedel− Crafts acylation of benzothiophene results in 3-acylbenzothiophene rather than 2-acylbenzothiophene (Scheme 1a, eq 1).7 However, 2-acylbenzothiophene can be selectively prepared through 2-lithiobenzothiophene using n-BuLi followed by reaction with an aldehyde and then oxidation of the corresponding alcohol (Scheme 1a, eq 2).8 Conversely, synthesis of 2-acylbenzothiophenes by cyclization of specific starting materials is also reported in which sulfur is either part of the molecule or added from an external source.9 Recently, palladiumcatalyzed cross-coupling reactions have been explored using a variety of benzo[b]thiophene-2-ylboronic acids10a with ligands like imidazolinium carbene10b or phosphine salts10c (Scheme 1b). Subsequently, iridium was used as a transmetalation agent © XXXX American Chemical Society

Received: February 15, 2017

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DOI: 10.1021/acs.orglett.7b00462 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

improve the yield of 2a, the reaction was screened with various bases and ligands, but the yield was not fruitful. When xanthate was added in two equal portions in 1 h time interval, it afforded 82% of 2a in DMF (entry 13). In DMSO solvent, the yield of 2a was increased to 87% in 4 h (entry 14). When the reaction was carried out under inert (N2) atmosphere, the yield was reduced to 23%. Increasing or decreasing the xanthate quantity under N2 atmosphere did not improve the yield (entries 15−17). Importantly, use of 5 mol % of Cu(OAc)2 reduced the product yield (entry 18). Finally, when the reaction was carried out with no catalyst, it yielded only 6% of 2a (entry 19).16 The optimized reaction conditions of the reaction (entry 14) were explored with various substrates, and the results are summarized in Scheme 2. Initially, 2-iodochalcones prepared

catalyst for Heck-type coupling reactions have been established by activated olefins with different coupling partners.12 However, to the best of our knowledge, examples of sulfur and its analogues contributing to Cu-catalyzed cyclization to generate the benzothiophene core for the synthesis of 2-acylbenzothiophene are unknown. As part of our ongoing research toward Cucatalyzed in situ C−S bond formation using potassium ethyl xanthate as a sulfur surrogate,13 herein we report Cu-catalyzed synthesis of 2-acylbenzo[b]thiophene from α-C−H functionalization of 2-halochalcones (Scheme 1c).14 Initially, 2-iodochalcone 1a was examined as a model substrate for the synthesis of 2-benzoylbenzothiophene 2a with 10 mol % of Cu(OAc)2 and potassium ethyl xanthate (2 equiv) as sulfur precursor in dimethyl sulfoxide at 80 °C. To our delight, the reaction yielded 58% of 2a in 5 h (Table 1, entry 1).15 Table 1. Optimization of Reaction Conditions

entry

Cu salt

xanthate (equiv)

1 2 3 4 5 6 7 8

Cu(OAc)2 Cu(OTf)2 CuBr2 CuCl Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2

2 2 2 2 2 2 2 2

9 10 11 12 13 14 15 16 17 18 19

Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2

2 2 1 3 1+1 1+1 1+1 0.7 + 0.7 1.5 + 1.5 1+1 1+1

solvent DMSO DMSO DMSO DMSO DMF DMA NMP DMF + toluene DMF DMF DMF DMF DMF DMSO DMSO DMSO DMSO DMSO DMSO

Scheme 2. Synthesis of 2-Acylbenzo[b]thiophenesa

a

temp (°C)

time (h)

yieldb (%)

80 80 80 80 80 80 80 80

5 6 7 8 5 6 4 7

58c 56c 57c 48 65 62 41 58

100 110 100 100 100 100 100 100 100 100 100

4 3 12 4 4 4 4 4 4 10 4

72 73 38d 68 82e 87 23f 16f 27f 52g 6

a

Reaction conditions: 1 (0.5 mmol), xanthate (0.5 + 0.5 mmol), Cu catalyst (10 mol %) in DMSO (2 mL) at 100 °C. All yields are isolated yields.

a Standard reaction conditions: 1a (0.5 mmol), xanthate, Cu catalyst (10 mol %) in 2 mL of solvent. bIsolated yield. cAverage yield of three repetitions. dStarting material remained. e1 equiv of xanthate was added after 1 h. fUnder N2 atm. g5 mol % of Cu(OAc)2 was used.

from acetophenones substituted with electron-donating groups reacted smoothly and gave products 2b, 2c, and 2d in good yields. Further, this methodology was employed for various 2iodochalcones substituted with halogen groups to afford moderate yields of 2e, 2f, and 2g, which are useful initial scaffolds for conventional coupling reactions. Subsequently, ortho-substituted 2-iodochalcones were well tolerated, and 61% of 2h, 84% of 2i, and 90% of 2j were obtained. Interestingly, dimethoxy- and methylenedioxy-substituted chalcones were more appropriate for the cyclization and provided 2k and 2l in appreciable yield. In addition, 2-acetylthiophene- and 3-acetylindole-derived 2iodochalcones progressed efficiently, and products 2m and 2n were isolated in 77% and 92% yield, respectively. Notably, 2iodochalcone substituted with an electron-withdrawing group was found to be a suitable substrate for this reaction, yielding 61% of 2o. Strikingly, 2-acetonaphthone and trimethoxy-substituted ketone derived chalcones produced 58% of 2p and 72% of 2q in 3 h. Next, the optimized reaction conditions were tested with

Encouraged by these results, we screened various copper salts to improve the efficiency of the reaction (entries 2−4). Though all of the copper salts provided 2a in more or less the same yield, copper acetate was chosen as it gave the highest yield (entry 1 vs 2−4). Then the effect of solvent was studied, and the results revealed that DMA and NMP produced lower yields of 2a than DMF (entries 5 vs 6 and 7). The reaction was also conducted in a mixture of DMF and toluene (1:1), and it provided a better yield of 58% compared to other mixtures of solvents (entry 8). When the reaction temperature was increased to 100 °C, the yield increased to 72%, but identical results were observed at 100 or 110 °C (entries 9 and 10). Next, the xanthate equivalent was evaluated, and using 1 equiv of xanthate gave only 38% yield (entry 11). Use of 3 equiv of xanthate reduced the yield of 2a to 68% (entry 12). In order to B

DOI: 10.1021/acs.orglett.7b00462 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

modulator, namely, 1-(5-hydroxybenzothiophene-2-yl)ethanone 6, by demethylation as shown in Scheme 4.18c Several experiments were conducted to reason out the increase in the yield of the product when xanthate was added portionwise (Scheme 5). The reaction was examined with a moderate polar

substituents on the iodo-attached benzene ring of 2-iodochalcone. Consequently, fluoro-, chloro-, and bromo-substituted 2iodochalcones underwent the cyclization reaction nicely, and the corresponding cyclized products 2r, 2s, 2u, and 2v were obtained in good yields. The structure of 2u was further confirmed by single-crystal XRD analysis (CCDC no. 1525720 with 30% probability ellipsoids). Importantly, nitro-substituted chalcone with 1 equiv of xanthate provided 42% of 2t. Thus, the reaction was conducted with an initial addition of 2 equiv of xanthate. As expected, the reaction yield of 2t was increased to 62% in 1 h. Remarkably, aliphatic ketone derived chalcones were effectively converted into the cyclized products 2w and 2x in commendable yield. It is worth mentioning that compound 2w is synthetically important and can be used for anti-osteoporosis, which is directly accessed using this methodology.17 The optimized conditions were then employed for substitution on both phenyl rings of the chalcone to produce 56% of 2y. The methodology was examined for less reactive bromo substrates such as 2-bromochalcone 3. Under the optimized reaction conditions (100 °C), the 2-bromochalcone failed to yield the expected product. However, 78% of 2a was obtained when the reaction temperature was increased to 120 °C (Scheme 3). Then several 2-bromochalcones were successfully converted

Scheme 5. Controlled Reactions

Scheme 3. Synthesis of 2-Acylbenzo[b]thiophenes from 2Bromochalconea

solvent like ethyl acetate with 10 mol % of Cu(OAc)2 and 2 equiv of xanthate at 80 °C. This reaction produced 23% of 2a in 21 h along with 7% of 7a, which was not observed in DMSO and DMF solvents (Scheme 5a). The compound 7a was confirmed by single-crystal XRD analysis (CCDC no. 1525719). The mechanism for the formation of 7a was hypothesized to proceed via coupling of 2-iodochalcone with xanthate sulfur in the presence of Cu catalyst followed by inter- and intramolecular Michael addition and ene reaction with loss of acetophenone.19 This observation shows that compound 2a is competing with 7a where intermolecular Michael addition takes place after xanthate coupling. When 1o was subjected to the initial reaction conditions (entry 1, Table 1), this reaction furnished 32% of 2o and 17% of 8o (Scheme 5b). We speculated that compound 7o20 is the intermediate in the formation of 8o through intramolecular Michael addition after coupling with xanthate. Compound 8o was confirmed by X-ray diffraction analysis (CCDC no. 1525721). From these experiments, we found that xanthate activates the Michael addition when 2 equiv of xanthate is added at one time. Formation of 7a can be controlled either by reducing the quantity of xanthate or by the slow addition of xanthate. This might be the reason for the increase in yield when xanthate is added portionwise (entry 9 vs 13, Table 1). The plausible mechanism of the cyclization reaction is proposed as shown in Scheme 6. According to the previous report1c,13d it is assumed that 2-iodochalcone 1 with copper acetate may give oxidative addition intermediate A, which gives intermediate B in the presence of xanthate. Then intermediate B may provide intermediate C via reductive elimination. Finally, the intermediate C in the presence of excess xanthate will yield product 2. The second equivalent of xanthate is expected to cleave the S−C bond to give thiolate, which will cyclize via reaction with olefin activated by Cu.21 However, in-depth mechanistic studies and further application of the newly developed reaction are underway. In conclusion, the synthesis of 2-acylbenzo[b]thiophene derivatives from easily accessible 2-iodo or 2-bromo chalcones has been developed using copper catalyst and odorless xanthate

a

Reaction conditions: 3 (0.5 mmol), xanthate (0.5 + 0.5 mmol), Cu catalyst (10 mol %) in DMSO (2 mL) at 120 °C.

to the corresponding cyclized products 2j, 2g, 2i, and 2n in moderate to excellent yield. It is important to mention that only the 2-bromophenyl ring attached to the alkene part selectively underwent cyclization by keeping the 4-bromophenyl ring tethered to the ketone part unaffected. This might be due to olefin coordination with the metal, which could cause direct selectivity. 2-Benzoylbenzothiophene 2a was further functionalized into useful moieties like benzo[b]thiophene-2-yl(phenyl)methanol (see the SI, compound 4) by reduction with NaBH4 and subsequent reduction of the resulting secondary alcohol with sodium borohydride and trifluoroacetic acid to yield 5, which is a precursor molecule for the treatment of insulin resistance and hyperglycemia18a and inactivators of protein tyrosine phosphatase 1B (PTP 1B)18b (Scheme 4). To showcase the application of this synthetic method, 2a was converted to a pre-mRNA Scheme 4. Synthetic Application of 2-Acylbenzothiophenes

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DOI: 10.1021/acs.orglett.7b00462 Org. Lett. XXXX, XXX, XXX−XXX

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(4) Bhambra, A. S.; Edgar, M.; Elsegood, M. R. J.; Li, Y.; Weaver, G. W.; Arroo, R. R. J.; Yardley, V.; Burrell-Saward, H.; Krystof, V. Eur. J. Med. Chem. 2016, 108, 347. (5) Romagnoli, R.; Baraldi, P. G.; Cara, C. L.; Hamel, E.; Basso, G.; Bortolozzi, R.; Viola, G. Eur. J. Med. Chem. 2010, 45, 5781. (6) (a) Stroba, A.; Schaeffer, F.; Hindie, V.; Lopez-Garcia, L.; Adrian, I.; Froehner, W.; Hartmann, R. W.; Biondi, R. M.; Engel, M. J. Med. Chem. 2009, 52, 4683. (b) Lindenschmidt, C.; Krane, D.; Vortherms, S.; Hilbig, L.; Prinz, H.; Mueller, K. Eur. J. Med. Chem. 2016, 110, 280. (7) (a) Kantam, M. L.; Ranganath, K. V. S.; Sateesh, M.; Kumar, K. B. S.; Choudary, B. M. J. Mol. Catal. A: Chem. 2005, 225, 15. (b) Morizur, V.; Hector, D.; Olivero, S.; Desmurs, J. R.; Dunach, E. Eur. J. Org. Chem. 2016, 2016, 3126. (c) Pal, S.; Khan, M. A.; Bindu, P.; Dubey, P. K. Beilstein J. Org. Chem. 2007, 3, 35. (8) (a) Ushijima, S.; Dohi, S.; Moriyama, K.; Togo, H. Tetrahedron 2012, 68, 1436. (b) Pouzet, P.; Erdelmeier, I.; Dansette, P. M.; Mansuy, D. Tetrahedron 1998, 54, 14811. (9) (a) Chan, S. L.-F.; Low, K.-H.; Yang, C.; Cheung, S. H.-F.; Che, C.M. Chem. - Eur. J. 2011, 17, 4709. (b) Debray, J.; Lemaire, M.; Popowycz, F. Synlett 2013, 24, 37. (10) (a) Yasuike, S.; Nakata, K.; Qin, W.; Matsumura, M.; Kakusawa, N.; Kurita, J. J. Organomet. Chem. 2015, 788, 9. (b) Kuriyama, M.; Hamaguchi, N.; Sakata, K.; Onomura, O. Eur. J. Org. Chem. 2013, 2013, 3378. (c) Meng, G.; Szostak, M. Org. Biomol. Chem. 2016, 14, 5690. (11) Cheng, W.-M.; Shang, R.; Yu, H.-Z.; Fu, Y. Chem. - Eur. J. 2015, 21, 13191. (12) Selected references: (a) Liwosz, T. W.; Chemler, S. R. Org. Lett. 2013, 15, 3034. (b) Faulkner, A.; Race, N. J.; Scott, J. S.; Bower, J. F. Chem. Sci. 2014, 5, 2416. (13) (a) Prasad, D. J. C.; Naidu, A. N.; Sekar, G. Tetrahedron Lett. 2009, 50, 1411. (b) Prasad, D. J. C.; Sekar, G. Org. Lett. 2011, 13, 1008. (c) Prasad, D. J. C.; Sekar, G. Org. Biomol. Chem. 2013, 11, 1659. (d) Sangeetha, S.; Muthupandi, P.; Sekar, G. Org. Lett. 2015, 17, 6006. (14) Knochel et al. reported functionalized benzothiophene synthesis using copper catalyst. However, 2-acylbenzothiophene has been synthesized in five steps starting from commercially available 1,2dihalobenzene with acyl chloride as acyl source: Kunz, T.; Knochel, P. Angew. Chem., Int. Ed. 2012, 51, 1958. (15) 12% of compound 8a with its trace isomer (Scheme 5b) was isolated along with 2a. (16) This product might have formed by an SNAr mechanism. When the ketone analogue of 1a was used (3-(2-iodophenyl)-1-phenylpropane-1-one) under the optimized reaction conditions, it did not give product 2a, which supports formation of a trace amount of 2a with 1a by an SNAr mechanism in the absence of Cu catalyst. (17) Liu, Z.-y.; He, X.-b.; Yang, Z.-y.; Shao, H.-y.; Li, X.; Guo, H.-f.; Zhang, Y.-q.; Si, S.-y.; Li, Z.-r. Bioorg. Med. Chem. Lett. 2009, 19, 4167. (18) (a) Wrobel, J. E.; Dietrich, A. J.; Li, Z. US6110962A, 2000. (b) Shrestha, S.; Hwang, S. Y.; Lee, K.-H.; Cho, H. Bull. Korean Chem. Soc. 2005, 26, 1138. (c) Schmitt, C.; Miralinaghi, P.; Mariano, M.; Hartmann, R. W.; Engel, M. ACS Med. Chem. Lett. 2014, 5, 963. (19) 5% yield for acetophenone was obtained (calculated by 1H NMR). (20) The expected structure of 7o is

Scheme 6. Proposed Mechanism

as a sulfur surrogate. The methodology proceeds via in situ sulfur incorporation followed by cyclization to generate 2-acylbenzothiophenes without external acyl source. Compounds with various substituents including halogen derivatives of 2acylbenzothiophene can be synthesized, which shows the robustness of the method. The synthetic application of this method was also showcased by synthesizing 1-(5-hydroxybenzothiophene-2-yl)ethanone, which is known as a pre-mRNA splicing modulator.

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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.7b00462. Detailed experimental procedures, characterization data, and NMR spectra (PDF)

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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 We thank the DST New Delhi (Project No. SB/S1/OC-72/ 2013) for financial support. S.S. thanks IIT Madras for a fellowship.

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REFERENCES

(1) (a) Scrowston, R. M. Adv. Heterocycl. Chem. 1981, 29, 171. (b) Hari, D. P.; Hering, T.; Koenig, B. Org. Lett. 2012, 14, 5334. (c) Sun, L.-L.; Deng, C.-L.; Tang, R.-Y.; Zhang, X.-G. J. Org. Chem. 2011, 76, 7546. (2) Romagnoli, R.; Baraldi, P. G.; Lopez-Cara, C.; Preti, D.; Aghazadeh Tabrizi, M.; Balzarini, J.; Bassetto, M.; Brancale, A.; Fu, X.-H.; Gao, Y.; Li, J.; Zhang, S.-Z.; Hamel, E.; Bortolozzi, R.; Basso, G.; Viola, G. J. Med. Chem. 2013, 56, 9296. (3) Miralinaghi, P.; Schmitt, C.; Hartmann, R. W.; Frotscher, M.; Engel, M. ChemMedChem 2014, 9, 2294.

(21) The controlled reactions were carried out using TEMPO (2,2,6,6tetramethylpiperidin-1-yl)oxidanyl and BHT (2,6-di-tert-butyl-4-methylphenol) under the optimized reaction conditions. However, no change in the yield was found in either case.

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DOI: 10.1021/acs.orglett.7b00462 Org. Lett. XXXX, XXX, XXX−XXX