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Green synthesis of benzo[b]thiophenes via iron(III) mediated 5-endo-dig iodocyclization of 2-alkynylthioanisoles
Tetrahedron Letters 57 (2016) 411–414
Contents lists available at ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Green synthesis of benzo[b]thiophenes via iron(III) mediated 5-endo-dig iodocyclization of 2-alkynylthioanisoles Tanay Kesharwani ⇑, Cory T. Kornman, Amanda L. Tonnaer, Andrew D. Royappa Department of Chemistry, University of West Florida, Pensacola, FL 32514-5750, United States
a r t i c l e
i n f o
Article history: Received 12 November 2015 Accepted 8 December 2015 Available online 9 December 2015 Keywords: Green chemistry Electrophilic cyclization Iodocyclization Benzo[b]thiophene Iron(III) mediated
a b s t r a c t A reaction of iron(III) chloride with sodium iodide was used to generate iodine for an innovative take on electrophilic cyclization. With ethanol as solvent, the reaction was observed to provide ideal conditions for iodocyclization of 2-alkynylthioanisoles. The fundamental step allows formation of iodine which becomes free to undergo reaction with the starting alkyne to yield the cyclized product. Implementing environmentally benign and simple chemistry, 2-iodosubstituted benzo[b]thiophenes were synthesized in high yields to produce an interesting display of useful molecules. Ó 2015 Elsevier Ltd. All rights reserved.
Electrophilic cyclization is a reaction sequence which involves cyclization of an unsaturated C–C bond onto an internal nucleophilic carbon or heteroatom in the presence of an external electrophile.1 In the past decade reactions involving alkynes having a variety of nucleophilic attachments such as carbon,2 oxygen,3 nitrogen,4 sulfur,5 selenium6 and tellurium6e have been extensively investigated. A variety of electrophilic agents may be employed to synthesize a diverse library of biologically active molecules. In such processes the most commonly used electrophiles are I2, ICl, Br2, NBS and PhSeBr.1–6 Examples of other electrophiles such as TCCA,7 NIS,8 p-NO2C6H4SCl,2d,3b,4c,d CuCl29 and CuBr29b,c are also known. In a competitive study Larock and co-workers have demonstrated that more nucleophilic atoms, such as S or Se, work better in electrophilic cyclization reactions when compared with C, O and N nucleophiles.10 Benzo[b]thiophenes are naturally occurring11 sulfur containing heterocycles that provide the core structure for many biologically active molecules12 and commercially available drugs (Fig. 1). Therefore they are of great interest to both synthetic and medicinal chemists. Recently reported syntheses of benzo[b]thiophenes via electrophilic 5-endo-dig iodocyclization have been known to use less-friendly solvents such as acetonitrile and dichloromethane, and employ electrophilic reagents such as iodine, bromine and phenyl selenium bromide. While synthetically useful, electrophilic reagents such as iodine and bromine are volatile, corrosive and
⇑ Corresponding author. Tel.: +1 850 474 2743. E-mail address: [email protected] (T. Kesharwani). http://dx.doi.org/10.1016/j.tetlet.2015.12.037 0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
toxic and thus pose unnecessary risks to the chemist and to the environment. Iron salts are not only environmentally friendly but abundantly available. Furthermore, many iron salts and related complexes are inexpensive and easily obtainable from commercial sources. Despite the above-mentioned advantages, iron mediated reactions have been underrepresented for a long time until recent work involving several interesting iron mediated processes was introduced.13 With this in mind, we report a more benign process for the synthesis of various 3-iodobenzo[b]thiophenes via iron(III) mediated 5-endo-dig electrophilic iodocyclization of 2-alkynylthioanisoles in ethanol (Scheme 1). It was determined that substituted 2-alkynylthioanisoles in the presence of iron(III) chloride hexahydrate and sodium iodide underwent electrophilic iodocyclization to form 2,3-disubstituted benzo[b]thiophene derivatives in high yields of up to 97%. This room temperature, single-step methodology eliminates the need for harsh solvents or direct contact with halogen cyclizing agents thus allowing for a greener electrophilic synthesis. The desired starting alkynes (1–12) were synthesized using procedures reported in recent literature.5e,14 The Sonogashira coupling of 2-iodothioanisole with terminal alkyne in presence of copper iodide and palladium catalyst proceeded at room temperature and furnished excellent yields. Alkyne 13 was synthesized by deprotection of TMS group in compound 7.15 To determine the scope of this method, a variety of functionalized 2-alkynylthioanisoles were cyclized via our standard reaction procedure as described in Scheme 1. Substituted 2-alkynylthioanisoles (1 equiv) were reacted in the presence of iron(III)
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T. Kesharwani et al. / Tetrahedron Letters 57 (2016) 411–414
N
O H CH3
O
N
NH2 S
N HO
OMe O
Zileuton
Benocyclidine
Arzoxifene Cl
N N
O O
S
S
HO
O
N HN
Cl OH
S
S
HO
S
N
O
Cl
Cl
Encenicline
Raloxifene
Sertaconazole
Figure 1. Drug molecules containing benzo[b]thiophene core structure.
SMe
NaI, FeCl3•6H2O
chloride hexahydrate (1.2 equiv) and sodium iodide (2.4 equiv) in 95% ethanol at room temperature for twelve hours. Reaction mixtures were monitored to completion via TLC before purification via column chromatography.16 A molecular library of 2-iodo substituted benzo[b]thiophene derivatives were prepared using our methodology (Table 1). Starting with simple aromatic phenyl and p-tolyl substituents (entries 1 and 2) on the alkyne, this reaction proceeded with respective yields of 93% and 97%. However, electron rich p-methoxy phenyl substituted alkyne 3 resulted in 16 in a slightly lower yield of
S R
r.t., EtOH I
R 1-13
14-25 Yield 48-97%
R = alkyl, aryl, vinyl
Scheme 1. Iron(III) mediated electrophilic iodocyclization.
Table 1 5-endo-Dig cyclization/etherification of 2-alkynlythioanisoles to corresponding 3-iodosubstituted benzo[b]thiophenesa Entry
Substrate
% Yieldb
Product
S
SMe 1
1
SMe
I
14
93
15
97
16
89
17
93
18
93
19
92
S Me 2
2
I
Me SMe
S OMe 3
3
I
OMe
SMe
S 4
4
I
S
SMe
n-Bu 5
5
I
n-Bu
SMe
S t-Bu 6
6
t-Bu
I
413
T. Kesharwani et al. / Tetrahedron Letters 57 (2016) 411–414 Table 1 (continued) Entry
Substrate
% Yieldb
Product
S
SMe 7
SiMe 3
7
SMe
92
21
86
22
48
17
83
23
97
24
96
25
56
OH
S 8
8
OH
I
SMe
OH
S OH
9
20
I
SiMe3
9
I
S
SMe 10
10
OH
SMe
I
OMe
S 11
11
OMe
I S
SMe
(CH 2)3CN
12
12
I
(CH 2)3CN SMe
S H
13
13
I
H a
Reaction condition A: All reactions were performed on a 0.3 mmol scale using 1.0 equiv of alkyne, 1.2 equiv of FeCl36H2O, and 2.4 equiv of NaI in 4 mL of ethanol at room temperature for 24 h. b Isolated yields.
SMe
NaX, FeCl3 •6H 2O
S
FeCl3 + NaI
Me S
r.t., EtOH
I2
X 1
14 X = I 26 X = Br 27 X = Cl
Me S
90% 0% 0%
Ph
1
+ I 28
I
Ph
I Scheme 2. Effect of various sodium halides on electrophilic cyclization.
Me S Ph
89% (entry 3). Iodocyclization of vinyl substituted alkyne 4 furnished the desired cyclized product 17 in a very high yield of 93%. Simple n-butyl and bulky tert-butyl substituted alkynes 5 and 6 resulted in desired cyclized products 18 and 19 in almost identical yield (entries 5 and 6) suggesting that the bulky group had no or minimal effect on the incoming electrophile during the cyclization reactions. The sterically demanding TMS group worked well and provided benzo[b]thiophene 20 in 92% yield, once again supporting our previous observation (entry 7). Primary propargylic alcohol 8 worked well and resulted in 86% yield of the cyclized product 21. However, secondary propargylic alcohol 9 resulted in lower yield of the product 22. Propargylic alcohol 10 underwent iodocyclization with an elimination mechanism to yield cyclized benzo[b]thiophene 17 in 83% yield. This novel method of dehydration makes an interesting candidate for future research possibilities. Our reaction conditions also seem to tolerate ether and nitrile functionalities (entries 11 and 12). We
29
I
S
- MeI
Ph 14
I
Scheme 3. Proposed mechanism of iodocyclization involving FeCl3 and NaI.
also accomplished the cyclization of a terminal alkyne (13) with our conditions, which was not reported in earlier iodocyclization methodologies (entry 13). Recently we have reported an environmentally friendly method for the synthesis of 3-halosubstituted benzo[b]thiophenes using CuSO45H2O in ethanol at ambient temperature.14a Upon consideration, however, the use of the relatively toxic metal copper in lieu of less toxic iron salts may limit the large-scale applications of this method. However, the former methodology supports bromo- and chlorocyclizing agents whereas the latter only supports iodocyclization methods (Scheme 2). Even though
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the present iron(III) chloride methodology is more limited than the wider tolerance shown by the copper sulfate method, it is compensated for by more benign reaction conditions and comparatively higher yields. While understanding of FeCl3/NaI mediated cyclization requires additional studies, a reasonable mechanism is proposed in Scheme 3. We believe elemental iodine is generated within the reaction mixture via reaction of iron(III) chloride and sodium iodide. As shown in Scheme 3, an in situ-generated iodine cation coordinates with the unsaturated carbon–carbon triple bond forming an iodonium cation (28). The tethered sulfur atom acts as a nucleophile to attack and open the three-membered ring containing the iodonium cation, resulting in 5-endo-dig ring-closure, forming the charged intermediate 29. Lastly, the iodide anion attacks the methyl group through an SN2 mechanism, to lose the desired benzo[b]thiophene derivative 14 as a leaving group. In summary, we have developed an environmentally friendly alternative for the electrophilic cyclization reaction sequence. 5-endo-Dig cyclization of 2-alkynylthioanisoles proceeded in high yields to form an interesting library of potentially useful benzo [b]thiophene derivatives. In addition to reducing harmful waste and byproducts, this green process proceeds at room temperature, demonstrates functional group tolerance and results in excellent yields of the desired product. Our process provides a clean and simple method for the synthesis of many benzo[b]thiophene derivatives. Acknowledgments We are grateful to Research Corporation for Science Advancement for a Cottrell College Science Award, and the University of West Florida (UWF) and UWF’s Office of Research and Sponsored Programs for supporting this research. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.12. 037. References and notes 1. (a) Godoi, B.; Schumacher, R. F.; Zeni, G. Chem. Rev. 2011, 111, 2937–2980; (b) Sakakura, A.; Ishihara, K. Chem. Rec. 2015, 15, 728–742; (c) Mendoza, A.; Fananas, F. J.; Rodriguez, F. Curr. Org. Synth. 2013, 10, 384–393; (d) Singh, S.; Chimni, S. S. Synthesis 2015, 47, 1961–1989; (e) Gilmore, K.; Alabugin, I. V. Chem. Rev. 2011, 111, 6513–6556; (f) Rousseau, G.; Homsi, F. Chem. Soc. Rev. 1997, 26, 453–461. 2. (a) Worlikar, S. A.; Kesharwani, T.; Yao, T.; Larock, R. C. J. Org. Chem. 2007, 72, 1347–1353; (b) Zhang, X.; Sarkar, S.; Larock, R. C. J. Org. Chem. 2006, 71, 236– 243; (c) Zhang, X.; Campo, M. A.; Yao, T.; Larock, R. C. Org. Lett. 2005, 7, 763– 766; (d) Yao, T.; Campo, M. A.; Larock, R. C. J. Org. Chem. 2005, 70, 3511–3517. 3. (a) FláviaManarin, F.; Roehrs, J. A.; Gay, R. M.; Brandão, R.; Menezes, P. H.; Nogueira, C. W.; Zeni, G. J. Org. Chem. 2009, 74, 2153–2162; (b) Zhou, C.; Dubrovskiy, A. V.; Larock, R. C. J. Org. Chem. 2006, 71, 1626–1632; (c) Yue, D.; Yao, T.; Larock, R. C. J. Org. Chem. 2005, 70, 10292–10296; (d) Yao, T.; Zhang, X.; Larock, R. C. J. Org. Chem. 2005, 70, 7679–7685; (e) Liu, Y.; Zhou, S. Org. Lett. 2005, 7, 4609–4611.
4. (a) Barluenga, J.; Trincado, M.; Rubio, E.; González, J. M. Angew. Chem., Int. Ed. 2003, 42, 2406–2409; (b) Yue, D.; Yao, T.; Larock, R. C. J. Org. Chem. 2006, 71, 62–69; (c) Huang, Q.; Hunter, J. A.; Larock, R. C. J. Org. Chem. 2002, 67, 3437– 3444; (d) Chen, Y.; Cho, C.-H.; Larock, R. C. Org. Lett. 2009, 11, 173–176; (e) Fischer, D.; Tomeba, H.; Pahadi, N. K.; Patil, N. T.; Yamamoto, Y. Angew. Chem., Int. Ed. 2007, 46, 4764–4766; (f) Metin Zora, M.; Kivrak, A.; Yazici, C. J. Org. Chem. 2011, 76, 6726–6742. 5. (a) Larock, R. C.; Yue, D. Tetrahedron Lett. 2001, 42, 6011–6222; (b) Yue, D.; Larock, R. C. J. Org. Chem. 2002, 67, 1905–1909; (c) Hessian, K. O.; Flynn, B. L. Org. Lett. 2003, 5, 4377–4380; (d) Flynn, B. L.; Flynn, G. P.; Hamel, E.; Jung, M. K. Bioorg. Med. Chem. Lett. 2001, 11, 2341–2343; (e) Kesharwani, T.; Craig, J.; Del Rosario, C.; Shavnore, R.; Kornman, C. Tetrahedron Lett. 2014, 55, 6812–6816. 6. (a) Kesharwani, T.; Worlikar, S. A.; Larock, R. C. J. Org. Chem. 2006, 71, 2307– 2312; (b) Bui, C. T.; Flynn, B. L. J. Comb. Chem. 2006, 8, 163–167; (c) Alves, D.; Luchese, C.; Nogueira, C. W.; Zeni, G. J. Org. Chem. 2007, 72, 6726–6734; (d) Garud, D. R.; Koketsu, M. Org. Lett. 2008, 10, 3319–3322; (e) Cristiano, R. B. R.; Zeni, G. Org. Biomol. Chem. 2011, 9, 1301–1313. 7. (a) Sniady, A.; Morreale, M. S.; Wheeler, K. A.; Dembinski, R. Eur. J. Org. Chem. 2008, 3449–3452; (b) Ashtekar, K. D.; Marzijarani, N. S.; Jaganathan, A.; Holmes, D.; Jackson, J. E.; Borhan, B. J. Am. Chem. Soc. 2014, 136, 13355–13362. 8. (a) Huber, F.; Kirsch, S. F. J. Org. Chem. 2013, 78, 2780–2785; (b) Sniady, A.; Wheeler, K. A.; Dembinski, R. Org. Lett. 2005, 7, 1769–1772; (c) Huo, Z.; Tomeba, H.; Yamamoto, Y. Tetrahedron Lett. 2008, 49, 5531–5533; (d) Huo, Z.; Gridnev, I. D.; Yamamoto, Y. J. Org. Chem. 2010, 75, 1266–1270. 9. (a) Lu, W.-D.; Wu, M.-J. Tetrahedron 2007, 63, 356–362; (b) Fei, N.; Yin, H.; Wang, S.; Wang, H.; Yao, Z.-J. Org. Lett. 2011, 13, 4208–4211; (c) Tang, S.; Xie, Y.-X.; Li, J.-H.; Wang, N.-X. Synthesis 2007, 400–406. 10. Mehta, S.; Waldo, J. P.; Larock, R. C. J. Org. Chem. 2009, 74, 1141–1147. 11. (a) Koike, K.; Jia, Z.; Nikaido, T.; Liu, Y.; Zhao, Y.; Guo, D. Org. Lett. 1999, 1, 197– 198; (b) Jeong, S.-J.; Higuchi, R.; Miyamoto, T.; Ono, M.; Kuwano, M.; Mawatari, S. F. J. Nat. Prod. 2002, 65, 1344–1345. 12. (a) Berrade, L.; Aisa, B.; Ramirez, M. J.; Galiano, S.; Guccione, S.; Moltzau, L. R.; Levy, F. O.; Nicoletti, F.; Battaglia, G.; Molinaro, G.; Aldana, I.; Monge, A.; PerezSilanes, S. J. Med. Chem. 2011, 54, 3086–3090; (b) Han, Z.; Pinker, J. S.; Ford, B.; Obermann, R.; Nolan, W.; Wildman, S. A.; Hobbs, D.; Ellenberger, T.; Cusumano, C. K.; Hultgren, S. J.; Janetka, J. W. J. Med. Chem. 2010, 53, 4779–4792; (c) Valderrama, J. A.; Espinoza, O.; Rodriguez, J.; Theoduloz, C. Lett. Org. Chem. 2009, 6, 278–281; (d) Romagnoli, R.; Baraldi, P. G.; Salvador, M. K.; Preti, D.; Tabrizi, M. A.; Bassetto, M.; Brancale, A.; Hamel, E.; Castagliuolo, I.; Bortolozzi, R.; Basso, G.; Viola, G. J. Med. Chem. 2013, 56, 2606–2618. 13. (a) Cao, Y.; Zhang, Y.; Zhang, L.; Zhang, D.; Leng, X.; Huang, Z. Org. Chem. Front. 2014, 1, 1101–1106; (b) Paul, K.; Bera, K.; Jalal, S.; Sarker, S.; Jana, U. Org. Lett. 2014, 16, 2166–2169; (c) Zheng, J.; Wang, D.; Cui, S. Org. Lett. 2015, 17, 4572– 4575; (d) Lai, J.; Du, W.; Tian, L.; Zhao, C.; She, X.; Tang, S. Org. Lett. 2014, 16, 4396–4399; (e) Yang, K.; Song, Q. Org. Lett. 2015, 17, 548; (f) Hoyt, J. M.; Schmidt, V. A.; Tondreau, A. M.; Chirik, P. J. Science 2015, 349, 960–963; (g) Wang, L.; Zhu, H.; Che, J.; Yang, Y.; Zhu, G. Tetrahedron Lett. 2014, 55, 1011– 1014; (h) Belger, C.; Plietker, B. Chem. Commun. 2012, 5419–5421; (i) Holzwarth, M. S.; Frey, W.; Plietker, B. Chem. Commun. 2011, 11113–11115; (j) Guisan-Ceinos, M.; Tato, F.; Bunuel, E.; Calle, P.; Cardenas, D. J. Chem. Sci. 2013, 4, 1098–1104; (k) Dieskau, A. P.; Plietker, B. Org. Lett. 2011, 13, 5544– 5547. 14. (a) Kim, S.; Dahal, N.; Kesharwani, T. Tetrahedron Lett. 2013, 54, 4373–4376; (b) Chen, Q.-H.; Rao, P. N.; Praveen, K.; Edward, E. Bioorg. Med. Chem. 2005, 13, 6425–6434. 15. Tréguier, B.; Lawson, M.; Bernadat, G.; Bignon, J.; Dubois, J.; Brion, J.-D.; Alami, M.; Hamze, A. ACS Comb. Sci. 2014, 16, 702–710. 16. General procedure for the synthesis of compounds 14–25. To a 6-dram vial containing starting alkyne (0.30 mmol), 5 mL 95% ethanol was added. To the mixture, FeCl36H2O (100 mg, 0.37 mmol) and sodium iodide (111 mg, 0.74 mmol) were added. The reaction mixture was allowed to stir at room temperature for 24 h. The reaction mixture was concentrated, absorbed in silica gel and purified via column chromatography using hexanes to ethyl acetate mixture as eluent. 3-Iodo-2-phenylbenzo[b]thiophene (14). Product was isolated as a pale yellow oil; 1H NMR (400 MHz, Chloroform-d) d 7.40 (t, J = 7.6 Hz, 1H) 7.44–7.53 (m, 4H) 7.70 (d, J = 7.2 Hz, 2H) 7.80 (d, J = 8.0 Hz, 1H) 7.85 (d, J = 8.0 Hz, 1H); 13 C NMR (100 MHz, Chloroform-d) d 79.6, 122.3, 125.6, 125.7, 126.5, 128.7, 129.0, 130.2, 134.8, 139.1, 142.1, 142.4. HRMS (EI+, m/z) calcd for (C14H9IS)+ 335.9470, found 335.9473.
Contents lists available at ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Green synthesis of benzo[b]thiophenes via iron(III) mediated 5-endo-dig iodocyclization of 2-alkynylthioanisoles Tanay Kesharwani ⇑, Cory T. Kornman, Amanda L. Tonnaer, Andrew D. Royappa Department of Chemistry, University of West Florida, Pensacola, FL 32514-5750, United States
a r t i c l e
i n f o
Article history: Received 12 November 2015 Accepted 8 December 2015 Available online 9 December 2015 Keywords: Green chemistry Electrophilic cyclization Iodocyclization Benzo[b]thiophene Iron(III) mediated
a b s t r a c t A reaction of iron(III) chloride with sodium iodide was used to generate iodine for an innovative take on electrophilic cyclization. With ethanol as solvent, the reaction was observed to provide ideal conditions for iodocyclization of 2-alkynylthioanisoles. The fundamental step allows formation of iodine which becomes free to undergo reaction with the starting alkyne to yield the cyclized product. Implementing environmentally benign and simple chemistry, 2-iodosubstituted benzo[b]thiophenes were synthesized in high yields to produce an interesting display of useful molecules. Ó 2015 Elsevier Ltd. All rights reserved.
Electrophilic cyclization is a reaction sequence which involves cyclization of an unsaturated C–C bond onto an internal nucleophilic carbon or heteroatom in the presence of an external electrophile.1 In the past decade reactions involving alkynes having a variety of nucleophilic attachments such as carbon,2 oxygen,3 nitrogen,4 sulfur,5 selenium6 and tellurium6e have been extensively investigated. A variety of electrophilic agents may be employed to synthesize a diverse library of biologically active molecules. In such processes the most commonly used electrophiles are I2, ICl, Br2, NBS and PhSeBr.1–6 Examples of other electrophiles such as TCCA,7 NIS,8 p-NO2C6H4SCl,2d,3b,4c,d CuCl29 and CuBr29b,c are also known. In a competitive study Larock and co-workers have demonstrated that more nucleophilic atoms, such as S or Se, work better in electrophilic cyclization reactions when compared with C, O and N nucleophiles.10 Benzo[b]thiophenes are naturally occurring11 sulfur containing heterocycles that provide the core structure for many biologically active molecules12 and commercially available drugs (Fig. 1). Therefore they are of great interest to both synthetic and medicinal chemists. Recently reported syntheses of benzo[b]thiophenes via electrophilic 5-endo-dig iodocyclization have been known to use less-friendly solvents such as acetonitrile and dichloromethane, and employ electrophilic reagents such as iodine, bromine and phenyl selenium bromide. While synthetically useful, electrophilic reagents such as iodine and bromine are volatile, corrosive and
⇑ Corresponding author. Tel.: +1 850 474 2743. E-mail address: [email protected] (T. Kesharwani). http://dx.doi.org/10.1016/j.tetlet.2015.12.037 0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
toxic and thus pose unnecessary risks to the chemist and to the environment. Iron salts are not only environmentally friendly but abundantly available. Furthermore, many iron salts and related complexes are inexpensive and easily obtainable from commercial sources. Despite the above-mentioned advantages, iron mediated reactions have been underrepresented for a long time until recent work involving several interesting iron mediated processes was introduced.13 With this in mind, we report a more benign process for the synthesis of various 3-iodobenzo[b]thiophenes via iron(III) mediated 5-endo-dig electrophilic iodocyclization of 2-alkynylthioanisoles in ethanol (Scheme 1). It was determined that substituted 2-alkynylthioanisoles in the presence of iron(III) chloride hexahydrate and sodium iodide underwent electrophilic iodocyclization to form 2,3-disubstituted benzo[b]thiophene derivatives in high yields of up to 97%. This room temperature, single-step methodology eliminates the need for harsh solvents or direct contact with halogen cyclizing agents thus allowing for a greener electrophilic synthesis. The desired starting alkynes (1–12) were synthesized using procedures reported in recent literature.5e,14 The Sonogashira coupling of 2-iodothioanisole with terminal alkyne in presence of copper iodide and palladium catalyst proceeded at room temperature and furnished excellent yields. Alkyne 13 was synthesized by deprotection of TMS group in compound 7.15 To determine the scope of this method, a variety of functionalized 2-alkynylthioanisoles were cyclized via our standard reaction procedure as described in Scheme 1. Substituted 2-alkynylthioanisoles (1 equiv) were reacted in the presence of iron(III)
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T. Kesharwani et al. / Tetrahedron Letters 57 (2016) 411–414
N
O H CH3
O
N
NH2 S
N HO
OMe O
Zileuton
Benocyclidine
Arzoxifene Cl
N N
O O
S
S
HO
O
N HN
Cl OH
S
S
HO
S
N
O
Cl
Cl
Encenicline
Raloxifene
Sertaconazole
Figure 1. Drug molecules containing benzo[b]thiophene core structure.
SMe
NaI, FeCl3•6H2O
chloride hexahydrate (1.2 equiv) and sodium iodide (2.4 equiv) in 95% ethanol at room temperature for twelve hours. Reaction mixtures were monitored to completion via TLC before purification via column chromatography.16 A molecular library of 2-iodo substituted benzo[b]thiophene derivatives were prepared using our methodology (Table 1). Starting with simple aromatic phenyl and p-tolyl substituents (entries 1 and 2) on the alkyne, this reaction proceeded with respective yields of 93% and 97%. However, electron rich p-methoxy phenyl substituted alkyne 3 resulted in 16 in a slightly lower yield of
S R
r.t., EtOH I
R 1-13
14-25 Yield 48-97%
R = alkyl, aryl, vinyl
Scheme 1. Iron(III) mediated electrophilic iodocyclization.
Table 1 5-endo-Dig cyclization/etherification of 2-alkynlythioanisoles to corresponding 3-iodosubstituted benzo[b]thiophenesa Entry
Substrate
% Yieldb
Product
S
SMe 1
1
SMe
I
14
93
15
97
16
89
17
93
18
93
19
92
S Me 2
2
I
Me SMe
S OMe 3
3
I
OMe
SMe
S 4
4
I
S
SMe
n-Bu 5
5
I
n-Bu
SMe
S t-Bu 6
6
t-Bu
I
413
T. Kesharwani et al. / Tetrahedron Letters 57 (2016) 411–414 Table 1 (continued) Entry
Substrate
% Yieldb
Product
S
SMe 7
SiMe 3
7
SMe
92
21
86
22
48
17
83
23
97
24
96
25
56
OH
S 8
8
OH
I
SMe
OH
S OH
9
20
I
SiMe3
9
I
S
SMe 10
10
OH
SMe
I
OMe
S 11
11
OMe
I S
SMe
(CH 2)3CN
12
12
I
(CH 2)3CN SMe
S H
13
13
I
H a
Reaction condition A: All reactions were performed on a 0.3 mmol scale using 1.0 equiv of alkyne, 1.2 equiv of FeCl36H2O, and 2.4 equiv of NaI in 4 mL of ethanol at room temperature for 24 h. b Isolated yields.
SMe
NaX, FeCl3 •6H 2O
S
FeCl3 + NaI
Me S
r.t., EtOH
I2
X 1
14 X = I 26 X = Br 27 X = Cl
Me S
90% 0% 0%
Ph
1
+ I 28
I
Ph
I Scheme 2. Effect of various sodium halides on electrophilic cyclization.
Me S Ph
89% (entry 3). Iodocyclization of vinyl substituted alkyne 4 furnished the desired cyclized product 17 in a very high yield of 93%. Simple n-butyl and bulky tert-butyl substituted alkynes 5 and 6 resulted in desired cyclized products 18 and 19 in almost identical yield (entries 5 and 6) suggesting that the bulky group had no or minimal effect on the incoming electrophile during the cyclization reactions. The sterically demanding TMS group worked well and provided benzo[b]thiophene 20 in 92% yield, once again supporting our previous observation (entry 7). Primary propargylic alcohol 8 worked well and resulted in 86% yield of the cyclized product 21. However, secondary propargylic alcohol 9 resulted in lower yield of the product 22. Propargylic alcohol 10 underwent iodocyclization with an elimination mechanism to yield cyclized benzo[b]thiophene 17 in 83% yield. This novel method of dehydration makes an interesting candidate for future research possibilities. Our reaction conditions also seem to tolerate ether and nitrile functionalities (entries 11 and 12). We
29
I
S
- MeI
Ph 14
I
Scheme 3. Proposed mechanism of iodocyclization involving FeCl3 and NaI.
also accomplished the cyclization of a terminal alkyne (13) with our conditions, which was not reported in earlier iodocyclization methodologies (entry 13). Recently we have reported an environmentally friendly method for the synthesis of 3-halosubstituted benzo[b]thiophenes using CuSO45H2O in ethanol at ambient temperature.14a Upon consideration, however, the use of the relatively toxic metal copper in lieu of less toxic iron salts may limit the large-scale applications of this method. However, the former methodology supports bromo- and chlorocyclizing agents whereas the latter only supports iodocyclization methods (Scheme 2). Even though
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the present iron(III) chloride methodology is more limited than the wider tolerance shown by the copper sulfate method, it is compensated for by more benign reaction conditions and comparatively higher yields. While understanding of FeCl3/NaI mediated cyclization requires additional studies, a reasonable mechanism is proposed in Scheme 3. We believe elemental iodine is generated within the reaction mixture via reaction of iron(III) chloride and sodium iodide. As shown in Scheme 3, an in situ-generated iodine cation coordinates with the unsaturated carbon–carbon triple bond forming an iodonium cation (28). The tethered sulfur atom acts as a nucleophile to attack and open the three-membered ring containing the iodonium cation, resulting in 5-endo-dig ring-closure, forming the charged intermediate 29. Lastly, the iodide anion attacks the methyl group through an SN2 mechanism, to lose the desired benzo[b]thiophene derivative 14 as a leaving group. In summary, we have developed an environmentally friendly alternative for the electrophilic cyclization reaction sequence. 5-endo-Dig cyclization of 2-alkynylthioanisoles proceeded in high yields to form an interesting library of potentially useful benzo [b]thiophene derivatives. In addition to reducing harmful waste and byproducts, this green process proceeds at room temperature, demonstrates functional group tolerance and results in excellent yields of the desired product. Our process provides a clean and simple method for the synthesis of many benzo[b]thiophene derivatives. Acknowledgments We are grateful to Research Corporation for Science Advancement for a Cottrell College Science Award, and the University of West Florida (UWF) and UWF’s Office of Research and Sponsored Programs for supporting this research. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.12. 037. References and notes 1. (a) Godoi, B.; Schumacher, R. F.; Zeni, G. Chem. Rev. 2011, 111, 2937–2980; (b) Sakakura, A.; Ishihara, K. Chem. Rec. 2015, 15, 728–742; (c) Mendoza, A.; Fananas, F. J.; Rodriguez, F. Curr. Org. Synth. 2013, 10, 384–393; (d) Singh, S.; Chimni, S. S. Synthesis 2015, 47, 1961–1989; (e) Gilmore, K.; Alabugin, I. V. Chem. Rev. 2011, 111, 6513–6556; (f) Rousseau, G.; Homsi, F. Chem. Soc. Rev. 1997, 26, 453–461. 2. (a) Worlikar, S. A.; Kesharwani, T.; Yao, T.; Larock, R. C. J. Org. Chem. 2007, 72, 1347–1353; (b) Zhang, X.; Sarkar, S.; Larock, R. C. J. Org. Chem. 2006, 71, 236– 243; (c) Zhang, X.; Campo, M. A.; Yao, T.; Larock, R. C. Org. Lett. 2005, 7, 763– 766; (d) Yao, T.; Campo, M. A.; Larock, R. C. J. Org. Chem. 2005, 70, 3511–3517. 3. (a) FláviaManarin, F.; Roehrs, J. A.; Gay, R. M.; Brandão, R.; Menezes, P. H.; Nogueira, C. W.; Zeni, G. J. Org. Chem. 2009, 74, 2153–2162; (b) Zhou, C.; Dubrovskiy, A. V.; Larock, R. C. J. Org. Chem. 2006, 71, 1626–1632; (c) Yue, D.; Yao, T.; Larock, R. C. J. Org. Chem. 2005, 70, 10292–10296; (d) Yao, T.; Zhang, X.; Larock, R. C. J. Org. Chem. 2005, 70, 7679–7685; (e) Liu, Y.; Zhou, S. Org. Lett. 2005, 7, 4609–4611.
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Lett. 2011, 13, 5544– 5547. 14. (a) Kim, S.; Dahal, N.; Kesharwani, T. Tetrahedron Lett. 2013, 54, 4373–4376; (b) Chen, Q.-H.; Rao, P. N.; Praveen, K.; Edward, E. Bioorg. Med. Chem. 2005, 13, 6425–6434. 15. Tréguier, B.; Lawson, M.; Bernadat, G.; Bignon, J.; Dubois, J.; Brion, J.-D.; Alami, M.; Hamze, A. ACS Comb. Sci. 2014, 16, 702–710. 16. General procedure for the synthesis of compounds 14–25. To a 6-dram vial containing starting alkyne (0.30 mmol), 5 mL 95% ethanol was added. To the mixture, FeCl36H2O (100 mg, 0.37 mmol) and sodium iodide (111 mg, 0.74 mmol) were added. The reaction mixture was allowed to stir at room temperature for 24 h. The reaction mixture was concentrated, absorbed in silica gel and purified via column chromatography using hexanes to ethyl acetate mixture as eluent. 3-Iodo-2-phenylbenzo[b]thiophene (14). Product was isolated as a pale yellow oil; 1H NMR (400 MHz, Chloroform-d) d 7.40 (t, J = 7.6 Hz, 1H) 7.44–7.53 (m, 4H) 7.70 (d, J = 7.2 Hz, 2H) 7.80 (d, J = 8.0 Hz, 1H) 7.85 (d, J = 8.0 Hz, 1H); 13 C NMR (100 MHz, Chloroform-d) d 79.6, 122.3, 125.6, 125.7, 126.5, 128.7, 129.0, 130.2, 134.8, 139.1, 142.1, 142.4. HRMS (EI+, m/z) calcd for (C14H9IS)+ 335.9470, found 335.9473.