Letter pubs.acs.org/OrgLett
Palladium(0)-Catalyzed Dearomative [3 + 2] Cycloaddition of 3‑Nitroindoles with Vinylcyclopropanes: An Entry to Stereodefined 2,3-Fused Cyclopentannulated Indoline Derivatives Maxime Laugeois, Johanne Ling, Charlène Férard, Véronique Michelet, Virginie Ratovelomanana-Vidal, and Maxime R. Vitale* PSL Research University, Chimie ParisTech, CNRS, Institut de Recherche de Chimie Paris, Paris 75005, France S Supporting Information *
ABSTRACT: The palladium(0)-catalyzed diastereoselective dearomative cyclopentannulation of 3-nitroindoles with vinylcyclopropanes is described. This straightforward and highly atomeconomical method leads to a wide range of functionalized indolines in good yields and diastereoselectivities and represents an unprecedented entry toward the valuable 2,3-fused cyclopentannulated indoline scaffold.
T
evidenced once by Trost et al. in a study dedicated to the palladium(0)-catalyzed cycloaddition of trimethylenemethane with nitroarenes [Scheme 1, eq (a)].9 Therefore, we questioned
he indoline motif is prevalent in nature and can be found in a wide variety of synthetic or natural products encompassing a broad range of biological activities.1 In this family, a great deal of interest has long been devoted to the 2,3fused pyrrolo derivatives (pyrroloindolines), for which abundant synthetic methods have been developed.2 In sharp contrast, despite also being important structural cores of various natural products (Figure 1),3 the construction of 2,3fused cyclopentannulated analogues has been comparatively less investigated.4−6
Scheme 1. Dearomative Cyclopentannulation of 3Nitroindoles
Figure 1. Relevant natural products containing a 2,3-fused cyclopentannulated indoline core.
whether vinylcyclopropanes (VCPs), which we and others have previously exploited as sources of all-carbon 1,3-dipoles,10 could promote the dearomatization of 3-nitroindole acceptors [Scheme 1, eq (b)]. We wish to report herein that this original dearomative [3 + 2] cycloaddition strategy gives access to a wide variety of valuable 2,3-fused cyclopentannulated indolines in a diastereoselective manner. At the onset of our study, the validity of our approach was evaluated by submitting N-benzoyl-3-nitroindole 1a and dicyano vinylcyclopropane 2 to catalytic quantities of Pd2(dba)3·CHCl3 in various reaction conditions (Table 1).
Following Kerr’s seminal studies,4 the main strategy allowing the access to such skeletons has so far capitalized on the nucleophilic character of indole substrates in 1,3-dipolar cycloaddition reactions.5 However, this synthetic manifold is still inadequate for the use of electron-deficient indole partners, for which novel approaches remain highly desirable. Recently, 3-nitroindoles, a particular class of electron-poor indole derivatives, have demonstrated their interesting synthetic potential in a variety of dearomative [3 + 2] heteroannulation processes.7,8 Although successfully coupled with heteroatombased dipolar intermediates including azomethine ylides and azomethine imines,7 their use in cycloaddition reactions employing all-carbon 1,3-dipoles remains scarce. Actually, to the best of our knowledge, this reactivity profile has only been © 2017 American Chemical Society
Received: March 16, 2017 Published: April 18, 2017 2266
DOI: 10.1021/acs.orglett.7b00784 Org. Lett. 2017, 19, 2266−2269
Letter
Organic Letters Table 1. Optimization Studiesa
entry 1 2 3 4 5 6d 7d 8d 9d 10d 11d
ligand (%) L1 L1 L1 L1 L1 L1
(10) (10) (10) (10) (10) (5)
L2 L3 L4 L5
(10) (10) (5) (5)
Scheme 2. Influence of the Indole N-Substitution Patterna
solvent
drb
yield (%)c
THF toluene DMF EtOAc MeCN MeCN MeCN MeCN MeCN MeCN MeCN
6:1 11:1 11:1 10:1 9:1 10:1
52 46 82 95 99 95 (95)e f 86 85 39 f
2:1 5:1 13:1
Reaction conditions: 1a (0.2 mmol), 2 (0.2 mmol), Pd2(dba)3·CHCl3 (5 mol %), ligand (x mol %) in 1 mL of solvent (0.2 M) at room temperature for 45 min. bDiastereoisomeric ratio was determined by 1 H NMR analysis of the crude material. c1H NMR yields determined using ethylene carbonate as internal standard. dReaction run with 2.5 mol % Pd2(dba)3·CHCl3. eIsolated yield. fNo reaction. a
a Reaction conditions: 1a−i (0.2 mmol), 2 (0.2 mmol), Pd2(dba)3· CHCl3 (2.5 mol %), dppe (5 mol %) in 1 mL of MeCN (0.2 M) at room temperature. Diastereoisomeric ratios were determined by 1H NMR analysis of the crude material.
When the reaction was initially realized in THF in the presence of 10 mol % dppe (L1) at room temperature, the desired cycloaddition took place and the diastereoisomeric 2,3fused cyclopentannulated indolines 3a/3a′ (6:1 dr) were obtained in encouraging 52% yield (Table 1, entry 1).11 Switching to toluene improved the diastereoselectivity of the cycloaddition process, although at the expense of the reaction yield (Table 1, entry 2). After a wider solvent screening,12 dimethylformamide, ethyl acetate, and acetonitrile showed their superiority (Table 1, entries 3−5) with the best compromise between yield and diastereoselectivity being obtained with the latter (Table 1, entry 5). Interestingly, without substantial detrimental effect, the catalyst loading could be reduced to 2.5 mol % of Pd2(dba)3·CHCl3 and 5 mol % of L1 (Table 1, entry 6). Although this reaction did not proceed in the absence of dppe (Table 1, entry 7), other mono- or bidentate ligands L2− L5 led to a drop in either diastereoselectivity or yield (Table 1, entry 8−11). With these optimized reaction conditions in hand, we then investigated the influence of the indole N-substitution pattern on the efficiency of this diastereoselective [3 + 2] cycloaddition reaction (Scheme 2). Increasing the steric bulk on the benzoyl aromatic ring did not severely impact the reaction such that the 2,3-fused cyclopentannulated indoline 3b could be obtained in 89% yield and 10:1 dr. When employing substrates 1c−1e possessing acetyl, ethoxycarbonyl, and tert-butyloxycarbonyl groups, the cycloaddition was equally operative, although a diminution of the diastereoselectivity was typically observed. In the same vein, a lower diastereocontrol was observed with both the N-tosyl- and N-(2-nosyl)- substrates 1f and 1g. Nevertheless, switching to more sterically demanding 2,4,6trisubstituted arylsulfonyl moieties allowed a return to satisfactory levels of stereocontrol (dr > 10:1) while retaining
good reaction efficiency (3h and 3i). However, N-benzyl and N-methyl 3-nitroindoles 1j and 1k did not undergo the desired cycloaddition process, the polymerization of the starting VCP 2 being predominant in each of these cases.13,14 Next, a wider variety of N-benzoyl 3-nitroindoles was prepared and evaluated (Scheme 3). Apart from 4g, which proved to be inert in our reaction conditions,14 this palladiumcatalyzed cycloaddition operated efficiently with a nice range of 5-substituted substrates. Accordingly, the 5-methyl cyclopentannulated indoline 5a was obtained in 84% yield and 13:1 dr and the 5-F, 5-Cl, 5-Br, and 5-I nitroindoles 4b−e straightforwardly afforded the desired cycloadducts 5b−e. Interestingly, in the latter case, the potential competitive oxidative addition of the carbon−iodine bond to the palladium(0) complex did not hamper the reaction, showing that the [3 + 2] cycloaddition pathway is kinetically preferred. On its side, the 5-CN indoline 5f was obtained in 65% yield and lower 5:1 dr. Gratifyingly, this palladium-catalyzed reaction was also amenable to the use of 6- and 7-functionalized 3nitroindoles without noticeable setbacks (5h−l), but the steric hindrance in position 4 typically induced a slower cycloaddition process encouraging the competitive polymerization of the starting VCP. Nonetheless, performing the reaction in DMF with 2.0 equiv of 2 allowed access to the cyclopentannulation products 5m and 5n with good yields and remarkable diastereocontrols (>50:1 dr). Probing the scope of this [3 + 2] cycloaddition reaction further, we demonstrated that other VCPs such as diesters 6 and 7 could be employed, although in these cases poorer diastereoselectivities were observed [Scheme 4, eq (a)]. 2267
DOI: 10.1021/acs.orglett.7b00784 Org. Lett. 2017, 19, 2266−2269
Letter
Organic Letters Scheme 5. Scale-up Experimentsa and PostFunctionalization Reactionsb
Scheme 3. Scope of Variously Functionalized 3Nitroindolesa
a Experiments run on a 3 mmol scale (1a, in MeCN) or 2 mmol scale (5e, in DMF). bReaction conditions: (a) 5e (1.0 equiv), PhB(OH)2 (1.5 equiv), Pd(PPh3)4 (5 mol %), NaHCO3 (2.2 equiv), toluene/ water (20/1), reflux, 16 h; (b) 5e (1.0 equiv), phenylacetylene (2.0 equiv), PdCl2(PPh3)2 (1 mol %), CuI (2 mol %), THF/Et3N (1/1), rt, 2 h.
From a mechanistic point of view (Scheme 6), we propose that, upon oxidative addition of the starting VCP to the
Reaction conditions: 4a−n (0.2 mmol), 2 (0.2 mmol), Pd2(dba)3· CHCl3 (2.5 mol %), dppe (5 mol %) in 1 mL of MeCN at room temperature (isolated yields; diastereoisomeric ratios were determined by 1H NMR of the crude material). bDMF instead of MeCN. c1.5 equiv of 2. d2.0 equiv of 2. a
Scheme 6. Mechanistic Proposal
Scheme 4. Evaluation of other VCPs and 2-Nitroindolea
palladium(0) complex, the zwitterionic 1,3-dipole A would initially be engaged in a Michael addition process with the electrophilic 3-nitroindole partner. The irreversible intramolecular attack of the nitronate anion onto the π-allyl palladium(II) moiety would then follow according to chairlike transition states B or C.16,17 Although both would compete, B would be favored because it allows the minimization of 1,3diaxial interactions with the pseudoequatorial π-allylpalladium residue. Thus, diastereromer 3a would preferentially be formed. However, transition state C, which notably entails steric interactions between the pseudoaxial π-allylpalladium moiety and the indole core, would lead to 3a′, a competitive cyclization pathway, which could be suppressed when using more sterically demanding 3-nitroindoles possessing a substituent in position 4. In conclusion, we have developed a palladium-catalyzed dearomative [3 + 2] cycloaddition of 3-nitroindoles and vinylcyclopropanes. This efficient and atom-economical method generates highly substituted 2,3-fused cyclopentannulated indoline derivatives in a diastereoselective fashion. The study of other 2-nitroindole derivatives, the use of a larger range of alkenyl cyclopropanes, and the development of an enantioselective version of this reaction are currently underway and will be reported in due course.
a
Reaction conditions: 1a or 10 (0.2 mmol), 2, 6, or 7 (0.2 mmol), Pd2(dba)3·CHCl3 (2.5 mol %), dppe (5 mol %) in 1 mL of MeCN at room temperature (isolated yields; diastereoisomeric ratios were determined by 1H NMR of the crude material). bDMF instead of MeCN.
Interestingly, when using the N-benzoyl-2-nitroindole 10, the preparation of the isomeric cyclopentannulated indoline 11 was also achievable, in quantitative yield and with perfect diastereocontrol [Scheme 4, eq (b)].15 The usefulness of this method could be also established by performing scale-up experiments and post-functionalization reactions (Scheme 5). When starting from 1a (3.0 mmol), the gram-scale preparation of 3a could be performed without major impact on either reaction yield or diastereoselectivity. Alternatively, starting from 4e (2.0 mmol) and after careful column chromatography, the 5-iodo cycloadduct 5e was isolated in diastereomerically pure form in 54% yield. Interestingly, we could demonstrate that 5e may serve as a valuable platform for the preparation of other 5-substituted cyclopentannulated indolines through palladium-catalyzed cross-coupling reactions. Indeed, the corresponding Suzuki− Miyaura and Sonogashira cross-coupling products 12 and 13 were obtained in 92% yields. 2268
DOI: 10.1021/acs.orglett.7b00784 Org. Lett. 2017, 19, 2266−2269
Letter
Organic Letters
■
6900−6903. (f) Li, H.; Hughes, R. P.; Wu, J. J. Am. Chem. Soc. 2014, 136, 6288−6296. (6) (a) Trost, B. M.; Quancard, J. J. Am. Chem. Soc. 2006, 128, 6314− 6315. (b) Wang, X.; Wang, S. Y.; Ji, S. J. Org. Lett. 2013, 15, 1954− 1957. (c) Iqbal, N.; Sperger, C. A.; Fiksdahl, A. Eur. J. Org. Chem. 2013, 5, 907−914. (d) Zhao, X.; Liu, X.; Mei, H.; Guo, J.; Lin, L.; Feng, X. Angew. Chem., Int. Ed. 2015, 54, 4032−4035. (e) Zhang, X.; Liu, W.-B.; Tu, H.-F.; You, S.-L. Chem. Sci. 2015, 6, 4525−4529. (7) (a) Lee, S.; Diab, S.; Queval, P.; Sebban, M.; Chataigner, I.; Piettre, S. R. Chem. - Eur. J. 2013, 19, 7181−7192. (b) Awata, A.; Arai, T. Angew. Chem., Int. Ed. 2014, 53, 10462−10465. (c) Rivinoja, D. J.; Gee, Y. S.; Gardiner, M. G.; Ryan, J. H.; Hyland, C. J. T. ACS Catal. 2017, 7, 1053−1056. (d) Liu, X.; Yang, D.; Wang, K.; Zhang, J.; Wang, R. Green Chem. 2017, 19, 82−87. (8) For [4 + 2] processes, see: (a) Victoria Gómez, M.; Aranda, A. I.; Moreno, A.; Cossío, F. P.; de Cózar, A.; Díaz-Ortiz, Á .; de la Hoz, A.; Prieto, P. Tetrahedron 2009, 65, 5328−5336. (b) Andreini, M.; De Paolis, M.; Chataigner, I. Catal. Commun. 2015, 63, 15−20. (c) Li, Y.; Tur, F.; Nielsen, R. P.; Jiang, H.; Jensen, F.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2016, 55, 1020−1024. (9) Trost, B. M.; Ehmke, V.; Michael O’Keefe, B.; Bringley, D. A. J. Am. Chem. Soc. 2014, 136, 8213−8216. (10) For recent reviews, see: (a) Meazza, M.; Guo, H.; Rios, R. Org. Biomol. Chem. 2017, 15, 2479−2490. (b) Ganesh, V.; Chandrasekaran, S. Synthesis 2016, 48, 4347−4380. For selected examples, see: (c) Shimizu, I.; Ohashi, Y.; Tsuji, J. Tetrahedron Lett. 1985, 26, 3825− 3828. (d) Goldberg, A. F. G.; Stoltz, B. M. Org. Lett. 2011, 13, 4474− 4476. (e) Trost, B. M.; Morris, P. J. Angew. Chem., Int. Ed. 2011, 50, 6167−6170. (f) Trost, B. M.; Morris, P. J.; Sprague, S. J. J. Am. Chem. Soc. 2012, 134, 17823−17831. (g) Wei, F.; Ren, C.-L.; Wang, D.; Liu, L. Chem. - Eur. J. 2015, 21, 2335−2338. (h) Yuan, Z.; Wei, W.; Lin, A.; Yao, H. Org. Lett. 2016, 18, 3370−3373. (i) Laugeois, M.; Ponra, S.; Ratovelomanana-Vidal, V.; Michelet, V.; Vitale, M. R. Chem. Commun. 2016, 52, 5332−5335. (11) The major diastereoisomer 3a was isolated by crystallization and its relative stereochemistry was determined by X-ray analysis [CCDC 1536416]. (12) See the Supporting Information for more details. (13) (a) Suzuki, M.; Sawada, S.; Saegusa, T. Macromolecules 1989, 22, 1505−1507. (b) Suzuki, M.; Sawada, S.; Yoshida, S.; Eberhardt, A.; Saegusa, T. Macromolecules 1993, 26, 4748−4750. (14) Compounds 1j, 1k, and 4g did not allow the desired cycloaddition to take place as a probable consequence of an increase of the electron density at C2 hampering the Michael addition step. (15) The relative stereochemistry of 11 was established by X-ray analysis after recrystallization [CCDC 1535863]. (16) The diastereomerically pure 3a, when resubmitted to the palladium-catalyzed cycloaddition conditions, did not form any isomer 3a′ such that the allylic alkylation step is most likely irreversible. (17) In the case of VCPs 6 and 7, the steric interactions between the ester and the indole moieties may favor other transition states leading to less clear-cut diastereocontrols.
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b00784. Experimental procedures, analytical data, and NMR spectra for all compounds (PDF) X-ray data for compound 3a (CIF) X-ray data for compound 11 (CIF)
■
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected] ORCID
Maxime R. Vitale: 0000-0002-6740-2472 Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS This work was supported by the Ministère de l’Education Nationale, de l’Enseignement Supérieur et de la Recherche, and the Centre National de la Recherche Scientifique. The authors warmly thank L.-M. Chamoreau and G. Gontard (IPCM, Université Pierre et Marie Curie, Paris) for X-ray analyses.
■
REFERENCES
(1) (a) Medicinal Natural Products: A Biosynthetic Approach; Dewick, P. M., Ed.; Wiley-VCH: New York, 2002. (b) Modern Alkaloids: Structure, Isolation, Synthesis, and Biology; Fattorusso, E., TaglietelaScafati, O., Eds.; Wiley-VCH: Weinheim, 2007. (2) For a review, see: (a) Repka, L. M.; Reisman, S. E. J. Org. Chem. 2013, 78, 12314−12320. For selected examples, see: (b) Austin, J. F.; Kim, S.-G.; Sinz, C. J.; Xiao, W.-J.; MacMillan, D. W. C. Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 5482−5487. (c) Newhouse, T.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 10886−10887. (d) Repka, L. M.; Ni, J.; Reisman, S. E. J. Am. Chem. Soc. 2010, 132, 14418−14420. (e) Lucarini, S.; Bartoccini, F.; Battistoni, F.; Diamantini, G.; Piersanti, G.; Righi, M.; Spadoni, G. Org. Lett. 2010, 12, 3844−3847. (f) Ni, J.; Wang, H.; Reisman, S. E. Tetrahedron 2013, 69, 5622−5633. (g) Kieffer, M. E.; Chuang, K. V.; Reisman, S. E. J. Am. Chem. Soc. 2013, 135, 5557− 5560. (h) Spangler, J. E.; Davies, H. M. L. J. Am. Chem. Soc. 2013, 135, 6802−6805. (i) Acharya, A.; Anumandla, D.; Jeffrey, C. S. J. Am. Chem. Soc. 2015, 137, 14858−14860. (j) DiPoto, M. C.; Hughes, R. P.; Wu, J. J. Am. Chem. Soc. 2015, 137, 14861−14864. (k) Chai, Z.; Zhu, Y. M.; Yang, P. J.; Wang, S.; Wang, S.; Liu, Z.; Yang, G. J. Am. Chem. Soc. 2015, 137, 10088−10091. (l) Liu, C.; Yi, J. C.; Zheng, Z. B.; Tang, Y.; Dai, L. X.; You, S. L. Angew. Chem., Int. Ed. 2016, 55, 751−754. (3) (a) Djerassi, C.; Flores, S. E.; Budzikiewicz, H.; Wilson, J. M.; Durham, L. J.; Le Men, J.; Janot, M.-M.; Plat, M.; Gorman, M.; Neuss, N. Proc. Natl. Acad. Sci. U. S. A. 1962, 48, 113−120. (b) Baldé, A. M.; Pieters, L. A.; Gergely, A.; Wray, V.; Claeys, M.; Vlietinck, A. J. Phytochemistry 1991, 30, 997−1000. (c) Lim, S.; Sim, K.; Abdullah, Z.; Hiraku, O.; Hayashi, M.; Komiyama, K.; Lam, T.-S. J. Nat. Prod. 2007, 70, 1380−1383. (4) (a) Kerr, M. A.; Keddy, R. G. Tetrahedron Lett. 1999, 40, 5671− 5675. (b) England, D. B.; Kuss, T. D. O.; Keddy, R. G.; Kerr, M. A. J. Org. Chem. 2001, 66, 4704−4709. (5) For selected examples, see: (a) Venkatesh, C.; Singh, P. P.; Ila, H.; Junjappa, H. Eur. J. Org. Chem. 2006, 23, 5378−5386. (b) Bajtos, B.; Yu, M.; Zhao, H.; Pagenkopf, B. L. J. Am. Chem. Soc. 2007, 129, 9631−9634. (c) Lian, Y.; Davies, H. M. L. J. Am. Chem. Soc. 2010, 132, 440−441. (d) Xiong, H.; Xu, H.; Liao, S.; Xie, Z.; Tang, Y. J. Am. Chem. Soc. 2013, 135, 7851−7854. (e) Zhu, J.; Liang, Y.; Wang, L.; Zheng, Z. B.; Houk, K. N.; Tang, Y. J. Am. Chem. Soc. 2014, 136, 2269
DOI: 10.1021/acs.orglett.7b00784 Org. Lett. 2017, 19, 2266−2269
