Letter Cite This: Org. Lett. 2018, 20, 5190−5193
pubs.acs.org/OrgLett
F− Nucleophilic-Addition-Induced [3 + 2] Annulation: Direct Access to CF3‑Substituted Indenes Hai-Jun Tang, Yu-Feng Zhang, Yi-Wen Jiang, and Chao Feng* Institute of Advanced Synthesis (IAS), College of Chemistry and Molecular Engineering, Jiangsu National Synergetic Innovation Center for Advanced Materials (SICAM), Nanjing Tech University, 30 South Puzhu Road, Nanjing 211816, People’s Republic of China
Org. Lett. 2018.20:5190-5193. Downloaded from pubs.acs.org by UNIV OF SOUTH DAKOTA on 09/08/18. For personal use only.
S Supporting Information *
ABSTRACT: An efficient [3 + 2] annulation of (2,2-difluorovinyl)-2iodoarenes and internal alkynes was developed for the synthesis of 1(trifluoromethyl)-1H-indenes. The success of this strategy hinges upon a well-balanced process for the generation of two transient reactive species, specifically trifluoroethylsilver and alkenylpalladium intermediates, in the same molecule, as well as a smooth transmetalation step, which delicately joins together these two different metallic intermediates.
T
advances, the frameworks constructed are relatively restricted, thus prompting us to further explore the synthetic potential of the strategy of fluoride nucleophilic-addition-induced transformations. Indene represents a molecular structure of considerable interest in many research fields, including pharmaceuticals,7 materials,8 and organometallics.9 Therefore, many elegant strategies for their construction were formulated,10 such as intramolecular electrophilic substitution reactions,11 nucleophilic-attack-induced cyclizations,12 ring contraction and expansion,13 and transition-metal-catalyzed cyclizations.14 Nevertheless, there is still a lack of general synthetic approaches that permit the rapid assembly of 1-trifluoromethyl-1H-indenes. The introduction of the CF3 unit into indene skeletons not only brings forth intriguing electronic perturbation to the parent molecules but also exerts a positive influence on the exploitation of specific architecture with desirable bioactivities.15 While 1-trifluoromethyl-1H-indenes can be accessed by nucleophilic trifluoromethylation of indenones16 or intramolecular cyclization with CF3-containing molecules,17 these strategies suffer from either the utilization of exquisitely elaborated precursors or narrow scope with restricted substitution patterns. Under these circumstances, we envisioned an appealing strategy that engages the in-situ-generated α-CF3-carboanion with an internal electrophilic vinylpalladium species, thereby enabling an expedient synthetic protocol for the construction of trifluoromethylated indenes. Herein, we describe a palladium-catalyzed [3 + 2] annulation of (2,2difluorovinyl)-2-iodoarenes and internal alkynes (see Scheme 1b). This reaction provides a versatile and simple platform for the construction of densely substituted 1-(trifluoromethyl)1H-indene derivatives that could not be easily accessed by the reported methods. Since multisubstituted indenes are known to be potent bioactive molecules and synthetically useful
he trifluoromethyl group is widely present in pharmaceuticals, agrochemicals, and functional materials, mainly because of its profound influence on the biological, chemical, and physical properties of related structural motifs.1 As such, diverse strategies aiming at its efficient incorporation have been thoroughly investigated with the ever-increasing amount of reports on nucleophilic, electrophilic, and radical trifluoromethylation being nicely devised.2 Although impressive, most of the reported methods intrinsically rely on the elaborated trifluomethylation reagents, thus suffering from problems such as low atom economy,3 utilization of stoichiometric amounts of transition-metal catalysts,4 or high cost of the CF3containing reagents. Recently, our group reported a conceptually novel protocol for the expedient synthesis of homoallyltrifluoromethane derivatives triggered by fluoride nucleophilic addition to gem-difluorolakenes. In the presence of Pd-catalyst, the otherwise intractable α-CF3-carboanion, generated in situ, underwent an allylation to afford homoallyltrifluoromethanes in an efficient manner (see Scheme 1a).5 Further expanding this strategy to arylation led to a successful development of an intriguing synthetic protocol for the construction of trifluoromethyl-diarylmethane motifs (Scheme 1a).6 Note that, by taking advantage of easily available gem-difluoroalkenes as reliable α-CF3-carboanion precursors, the dilemma that conventional protocols may experience can be elegantly ameliorated. Despite these Scheme 1. Methods for the Formation of Indene Derivatives
Received: July 7, 2018 Published: August 20, 2018 © 2018 American Chemical Society
5190
DOI: 10.1021/acs.orglett.8b02128 Org. Lett. 2018, 20, 5190−5193
Letter
Organic Letters Scheme 2. Reaction Scope of Alkynesa
ligands, the development of this novel protocol will further expand the potential application of these prominent molecular structures. Our investigation was initiated with the reaction between 1(2,2-difluorovinyl)-2-iodobenzene 1a and diphenylacetylene 2a, using [allylPdCl]2 as the precatalyst and XPhos as the ligand (see Table 1). We were delighted to find that the Table 1. Optimization of Reaction Conditionsa
entry
catalyst
ligand
yield (%)
1 2 3 4 5 6 7
[allylPdCl]2 Pd2(dba)3 Pd(COD)Cl2 Pd(COD)Cl2 Pd(COD)Cl2 Pd(COD)Cl2 Pd(COD)Cl2
XPhos XPhos XPhos BrettPhos tBuBrettPhos tBuXPhos BrettPhos
22b,c NRc 58b 85,b 77d 57b 81,b 75d trace,e tracef
a Reactions performed with 1a (0.15 mmol), 2a (0.30 mmol), catalyst (5.0 mol %), ligand (10 mol %), and AgF (1.2 equiv) in dioxane (1.0 mL) at 80 °C for 12 h. bNMR yield. c2.5 mol % catalyst was used. d Isolated yield. e1.2 equiv of KF was used instead of AgF. f1.2 equiv of CsF was used instead of AgF.
desired product 3aa was obtained in 22% yield at 80 °C with AgF as the fluoride donor (Table 1, entry 1). An improved result was achieved by changing the palladium catalyst to Pd(COD)Cl2 (Table 1, entry 3). Further screening of phosphine ligands demonstrated that BrettPhos was the optimal choice, by which the product 3aa was obtained in 85% yield (Table 1, entries 3−6). After judiciously tuning the reaction parameter, the combination of Pd(COD)Cl2, BrettPhos, AgF, and dioxane was identified to be optimal. Notably, replacing AgF with other alkali-metal-derived fluorides, such as KF and CsF, had a deleterious effect on the annulation reaction (Table 1, entry 7). Not surprisingly, without either palladium catalyst or the phosphine ligand, no desired product was observed (see the Supporting Information for details). With the optimized reaction conditions in hand, the reaction generality, with respect to alkynes, were surveyed (see Scheme 2). Diverse symmetrical diarylacetylenes are viable substrates to form 1-trifluoromethylindenes 3db−3dk. Different substituents on the aryl group were well-tolerated; for example, Me- and OMe-bearing substrates provided the desired products in good to excellent yields (70%−90%). Moreover, halogen substituents, including F, Cl, and Br, were compatible to the reaction conditions, giving rise to the desired products in moderate to good yields. In addition, diarylacetylenes with electron-withdrawing groups, such as CF3, CN, and COMe were examined, and they afforded the corresponding 1trifluoromethylindenes in 38%−76% yields. The internal alkynes substituted with two aliphatic groups were also efficiently transformed to the desired products in moderate yields by changing the ligand to tBuXPhos (3dl−3dn). As expected, unsymmetrical internal alkynes participated in the annulation successfully and the two regioisomeric products could be isolated separately (3do/3do′ and 3dp/3dp′). In these cases, the main reason for the major isomers formation was attributed to the electronic perturbation of alkynyl
a
Reactions performed with 1d (0.15 mmol), 2 (0.225 mol), Pd(COD)Cl2 (5.0 mol %), BrettPhos (10 mol %), and AgF (1.2 equiv) in dioxane (1.0 mL). b1.5 equiv of AgF was used. ctBuXPhos was used instead of BrettPhos. d2.0 equiv of 2 was used. eNMR yield was indicated. f Major isomer was shown.
moieties, thus favoring the mode of triple-bond migration insertion by generating C(aryl)−C(alkenyl) bonds at electronically more-positive carbon atoms. It is noteworthy that activated alkyne substrates such as alkynyl ketone and acetylenic acid derivatives were also amenable to this reaction and delivered the products as a single regioisomer, which was ascribed to the same reason for electronic polarization that caused a highly selective alkyne migratory insertion (3dq− 3ds). The scope of the reaction was further explored with various (2,2-difluorovinyl)-2-iodoarenes (see Scheme 3). The substrates bearing a range of functional groups, such as methyl, methoxy, fluoride, chloride, bromide, or trifluoromethyl, were well-tolerated. Electron-donating groups, such as Me and OMe, on the phenyl ring had little influence on the reaction efficiency, providing the corresponding products in 71%−91% yields (3aa−3fa). To our pleasure, electron-deficient substrates were also amenable in the reaction (3ga−3na), albeit with somewhat diminished reaction efficiency. Remarkably, halogen-containing substrates, especially those with Br, could survive in this Pd-catalyzed reaction, thus providing the opportunity for further synthetic elaboration of these structure motifs (3ga−3la). Note that compound 1 was invariably consumed completely, even in cases wherein the products were obtained in low yields. To evaluate the scalability of this 5191
DOI: 10.1021/acs.orglett.8b02128 Org. Lett. 2018, 20, 5190−5193
Letter
Organic Letters Scheme 3. Reaction Scope of o-iodo-difluorolefinsa
intermediate IV affords the six-membered palladacycle V,19 which further undergoes reductive elimination to release the desired product 3, along with the regeneration of active catalyst. Path b represents an alternative reaction sequence, by which the α,α,α-trifluoroethylsilver intermediate is performed before the alkyne insertion. Analogously, vinylpalladium intermediate IV is generated in the following step and furnishes the product through the successive intramolecular transmetalation and reductive elimination. In summary, we have presented a Pd-catalyzed [3 + 2] annulation of (2,2-difluorovinyl)-2-iodoarenes and internal alkynes triggered by a fluoride nucleophilic addition. This reaction is characterized by its operational simplicity and mild reaction conditions, as well as wide functionality tolerance. By leveraging on a smooth intramolecular transmetalation between organosilver and palladium intermediates, the strategy of fluoride nucleophilic-addition-induced transformations are successfully expanded, thus providing a practical and efficient synthetic route for the construction of highly functionalized 1trifluoromethyl-1H-indenes.
a Reactions performed with 1 (0.15 mmol), 2a (0.225 mol), Pd(COD)Cl2 (5.0 mol %), BrettPhos (10 mol %), and AgF (1.5 equiv) in dioxane (1.0 mL). b1.2 equiv of AgF was used. c3.0 mmol scale reaction. dNMR yield was indicated.
■
ASSOCIATED CONTENT
S Supporting Information *
annulation reaction, a 3.0 mmol scale reaction between 1d and 2a was carried out, which gave rise to product 3da in 80% yield. Elegant works from Sanford and Hu’s groups suggested that homolysis of organosilver intermediates could generate radical species;18 however, such intermediates were not detected in our previous fluoroallylation/arylation protocols. In order to gain more insight into the reaction mechanism of the present [3 + 2] annulation, control experiments with radical scavengers, such as TEMPO, BHT, and 1,1-diphenylethylene were performed. It was found that none of these additives showed any impediment in the reaction efficiency, indicating that a radical intermediate is not involved in the catalytic cycle (see the Supporting Information for details). Therefore, we proposed two plausible ionic reaction pathways, as shown in Scheme 4. For path a, the reaction starts from oxidative
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b02128. Detailed experimental procedures, and full spectroscopic data for all new compounds (PDF)
■
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Chao Feng: 0000-0003-4494-6845 Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS We gratefully acknowledge the financial support of the “Thousand Talents Plan” Youth Program, the “Jiangsu Specially-Appointed Professor Plan”, the Natural Science Foundation of Jiangsu Province (No. BK20170984), and SICAM Fellowship by the Jiangsu National Synergetic Innovation Center for Advanced Materials.
Scheme 4. Proposed Mechanism
■
REFERENCES
(1) (a) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320−330. (b) Smits, R.; Cadicamo, C. D.; Burger, K.; Koksch, B. Chem. Soc. Rev. 2008, 37, 1727−1739. (c) Hagmann, W. K. J. Med. Chem. 2008, 51, 4359−4369. (d) O’Hagan, D. J. Fluorine Chem. 2010, 131, 1071−1081. (e) Wang, J.; Sánchez-Roselló, M.; Aceña, J. L.; del Pozo, C.; Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.; Liu, H. Chem. Rev. 2014, 114, 2432−2506. (2) For reviews, see: (a) Liu, X.; Xu, C.; Wang, M.; Liu, Q. Chem. Rev. 2015, 115, 683−730. (b) Egami, H.; Sodeoka, M. Angew. Chem., Int. Ed. 2014, 53, 8294−8308. (c) Merino, E.; Nevado, C. Chem. Soc. Rev. 2014, 43, 6598−6608. (d) Studer, A. Angew. Chem., Int. Ed. 2012, 51, 8950−8958. (e) Barata-Vallejo, S.; Postigo, A. Coord. Chem. Rev. 2013, 257, 3051−3069. (3) For innovation of trifluoromethylation reagents, see: (a) Teruo, U.; Sumi, I. Tetrahedron Lett. 1990, 31, 3579−3582. (b) Eisenberger, P.; Gischig, S.; Togni, A. Chem. - Eur. J. 2006, 12, 2579−2586.
addition of (2,2-difluorovinyl)-2-iodoarene to the palladium catalyst to afford the arylpalladium intermediate I. Subsequently, the coordination of internal alkynes to complex I would lead to the generation of intermediate II, which undergoes migratory insertion of the aryl−Pd bond to alkyne to provide vinylpalladium intermediate III. Then, fluoride nucleophilic addition leads to the formation of benzylsilver intermediate IV, and the ensuing transmetalation within 5192
DOI: 10.1021/acs.orglett.8b02128 Org. Lett. 2018, 20, 5190−5193
Letter
Organic Letters (c) Matsnev, A.; Noritake, S.; Nomura, Y.; Tokunaga, E.; Nakamura, S.; Shibata, N. Angew. Chem., Int. Ed. 2010, 49, 572−576. (d) Morimoto, H.; Tsubogo, T.; Litvinas, N. D.; Hartwig, J. F. Angew. Chem., Int. Ed. 2011, 50, 3793−3798. (e) Urban, C.; Cadoret, F.; Blazejewski, J.-C.; Magnier, E. Eur. J. Org. Chem. 2011, 4862− 4867. (4) (a) Urata, H.; Fuchikami, T. Tetrahedron Lett. 1991, 32, 91−94. (b) Chu, L.; Qing, F.-L. Org. Lett. 2010, 12, 5060−5063. (c) Senecal, T. D.; Parsons, A. T.; Buchwald, S. L. J. Org. Chem. 2011, 76, 1174− 1176. (d) Liu, T.; Shen, Q. Eur. J. Org. Chem. 2012, 2012, 6679− 6687. (e) Khan, B. A.; Buba, A. E.; Gooβen, L. J. Chem. - Eur. J. 2012, 18, 1577−1581. (f) Ilchenko, N. O.; Janson, P. G.; Szabó, K. J. Chem. Commun. 2013, 49, 6614−6616. (5) Tian, P.; Wang, C.-Q.; Cai, S.-H.; Song, S.; Ye, L.; Feng, C.; Loh, T.-P. J. Am. Chem. Soc. 2016, 138, 15869−15872. (6) Tang, H.-J.; Lin, L.-Z.; Feng, C.; Loh, T.-P. Angew. Chem., Int. Ed. 2017, 56, 9872−9876. (7) (a) Huffman, J. W.; Padgett, L. W. Curr. Med. Chem. 2005, 12, 1395−1411. (b) Chanda, D.; Saikia, D.; Kumar, J. K.; Thakur, J. P.; Agarwal, J.; Chanotiya, C. S.; Shanker, K.; Negi, A. S. Bioorg. Med. Chem. Lett. 2011, 21, 3966−3969. (c) El-Sheshtawy, H. S.; Abou Baker, A. M. J. Mol. Struct. 2014, 1067, 225−232. (8) (a) Grimsdale, A. C.; Müllen, K. Angew. Chem., Int. Ed. 2005, 44, 5592−5629. (b) Diesendruck, C. E.; Steinberg, B. D.; Sugai, N.; Silberstein, M. N.; Sottos, N. R.; White, S. R.; Braun, P. V.; Moore, J. S. J. Am. Chem. Soc. 2012, 134, 12446−12449. (c) Hu, P.; Lee, S.; Herng, T. S.; Aratani, N.; Goncalves, T. P.; Qi, Q.; Shi, X.; Yamada, H.; Huang, K.-W.; Ding, J.; Kim, D.; Wu, J. J. Am. Chem. Soc. 2016, 138, 1065−1077. (9) (a) O’Connor, J. M.; Casey, C. P. Chem. Rev. 1987, 87, 307− 318. (b) Zargarian, D. Coord. Chem. Rev. 2002, 233-234, 157−176. (c) Leino, R.; Lehmus, P.; Lehtonen, A. Eur. J. Inorg. Chem. 2004, 2004, 3201−3222. (d) Ren, S.; Igarashi, E.; Nakajima, K.; Kanno, K.; Takahashi, T. J. Am. Chem. Soc. 2009, 131, 7492−7493. (10) For reviews, see: (a) Enders, M.; Baker, R. W. Curr. Org. Chem. 2006, 10, 937−953. (b) Gabriele, B.; Mancuso, R.; Veltri, L. Chem. Eur. J. 2016, 22, 5056−5094. (11) (a) Guo, S.; Liu, Y. Org. Biomol. Chem. 2008, 6, 2064−2070. (b) Eom, D.; Park, S.; Park, Y.; Ryu, T.; Lee, P. H. Org. Lett. 2012, 14, 5392−5395. (c) Dethe, D. H.; Murhade, G. Org. Lett. 2013, 15, 429− 431. (d) Zhang, X.; Teo, W. T.; Rao, W.; Ma, D.-L.; Leung, C.-H.; Chan, P. W. H. Tetrahedron Lett. 2014, 55, 3881−3884. (e) Egi, M.; Shimizu, K.; Kamiya, M.; Ota, Y.; Akai, S. Chem. Commun. 2015, 51, 380−383. (12) (a) Duan, X.-H.; Guo, L.-N.; Bi, H.-P.; Liu, X.-Y.; Liang, Y.-M. Org. Lett. 2006, 8, 5777−5780. (b) Guo, L.-N.; Duan, X.-H.; Bi, H.P.; Liu, X.-Y.; Liang, Y. M. J. Org. Chem. 2006, 71, 3325−3327. (c) Zhang, D.; Liu, Z.; Yum, E. K.; Larock, R. C. J. Org. Chem. 2007, 72, 251−262. (13) (a) Xi, Z.; Song, Q.; Chen, J.; Guan, H.; Li, P. Angew. Chem., Int. Ed. 2001, 40, 1913−1916. (b) Shao, L.-X.; Xu, B.; Huang, J.-W.; Shi, M. Chem. - Eur. J. 2006, 12, 510−517. (c) Wang, S.; Zhu, Y.; Wang, Y.; Lu, P. Org. Lett. 2009, 11, 2615−2618. (d) Wang, Y.; McGonigal, P. R.; Herlé, B.; Besora, M.; Echavarren, A. M. J. Am. Chem. Soc. 2014, 136, 801−809. (14) (a) Kuninobu, Y.; Tokunaga, Y.; Kawata, A.; Takai, K. J. Am. Chem. Soc. 2006, 128, 202−209. (b) Zhou, F.; Yang, M.; Lu, X. Org. Lett. 2009, 11, 1405−1408. (c) Bucher, J.; Stöβer, T.; Rudolph, M.; Rominger, F.; Hashmi, A. S. K. Angew. Chem., Int. Ed. 2015, 54, 1666−1670. (d) Das, B. G.; Chirila, A.; Tromp, M.; Reek, J. N. H.; Bruin, B. J. Am. Chem. Soc. 2016, 138, 8968−8975. (e) Xu, S.; Chen, R.; Fu, Z.; Zhou, Q.; Zhang, Y.; Wang, J. ACS Catal. 2017, 7, 1993− 1997. (15) (a) Aurelio, L.; Valant, C.; Flynn, B. L.; Sexton, P. M.; White, J. M.; Christopoulos, A.; Scammells, P. J. J. Med. Chem. 2010, 53, 6550− 6559. (b) Kiriazis, A.; Aumüller, I. B.; Arnaudova, R.; Brito, V.; Rüffer, T.; Lang, H.; Silvestre, S. M.; Koskinen, P. J.; Yli-Kauhaluoma, J. Org. Lett. 2017, 19, 2030−2033. (c) Khudina, O. G.; Shchegol’kov, E. V.;
Burgart, Y. V.; Boltneva, N. P.; Rudakova, E. V.; Makhaeva, G. F.; Saloutin, V. I. J. Fluorine Chem. 2018, 210, 117−125. (16) (a) Gassman, P. G.; Ray, J. A.; Wenthold, P. G.; Mickelson, J. W. J. Org. Chem. 1991, 56, 5143−5146. (b) Allen, A. D.; Fujio, M.; Mohammed, N.; Tidwell, T. T.; Tsuji, Y. J. Org. Chem. 1997, 62, 246−252. (c) Billard, T.; Bruns, S.; Langlois, B. R. Org. Lett. 2000, 2, 2101−2103. (d) Large, S.; Roques, N.; Langlois, B. R. J. Org. Chem. 2000, 65, 8848−8856. (e) Cherkupally, P.; Beier, P. Tetrahedron Lett. 2010, 51, 252−255. (f) Riofski, M. V.; Hart, A. D.; Colby, D. A. Org. Lett. 2013, 15, 208−211. (17) (a) Ghavtadze, N.; Fröhlich, R.; Würthwein, E.-U. J. Org. Chem. 2009, 74, 4584−4591. (b) Boreux, A.; Lonca, G. H.; Riant, O.; Gagosz, F. Org. Lett. 2016, 18, 5162−5165. (c) Martynov, M. Y.; Iakovenko, R. O.; Kazakova, A. N.; Boyarskaya, I. A.; Vasilyev, A. V. Org. Biomol. Chem. 2017, 15, 2541−2550. (d) Iakovenko, R. O.; Kazakova, A. N.; Boyarskaya, I. A.; Gurzhiy, V. V.; Avdontceva, M. S.; Panikorovsky, T. L.; Muzalevskiy, V. M.; Nenajdenko, V. G.; Vasilyev, A. V. Eur. J. Org. Chem. 2017, 2017, 5632−5643. (18) (a) Ye, Y.; Lee, S. H.; Sanford, M. S. Org. Lett. 2011, 13, 5464− 5467. (b) Gao, B.; Zhao, Y.; Ni, C.; Hu, J. Org. Lett. 2014, 16, 102− 105. (c) Gao, B.; Zhao, Y.; Hu, J. Angew. Chem., Int. Ed. 2015, 54, 638−642. (19) (a) Lee, S. Y.; Hartwig, J. F. J. Am. Chem. Soc. 2016, 138, 15278. (b) Whitaker, D.; Bures, J.; Larrosa, I. J. Am. Chem. Soc. 2016, 138, 8384.
5193
DOI: 10.1021/acs.orglett.8b02128 Org. Lett. 2018, 20, 5190−5193
