Stereoselective Synthesis of trans-Tetrahydroindolines Promoted by a

Communication pubs.acs.org/Organometallics

Stereoselective Synthesis of trans-Tetrahydroindolines Promoted by a Tungsten π Base Brianna L. MacLeod,†,∥ Jared A. Pienkos,†,∥ Jeffery T. Myers,† Michal Sabat,‡ William H. Myers,§ and W. Dean Harman*,† †

Department of Chemistry and ‡Nanoscale Materials Characterization Facility, Department of Materials Science and Engineering, University of Virginia, Charlottesville, Virginia 22904, United States § Department of Chemistry, University of Richmond, Richmond, Virginia 23173, United States S Supporting Information *

ABSTRACT: Indoline and tetrahydroquinoline derivatives form η2-bound complexes with the dearomatization agent {TpW(NO)(PMe3)} that can be isolated as triflic acid salts. Protonation occurs selectively in the aromatic ring, either ortho or para to the nitrogen. With the tetrahydroquinoline complexes, para protonation dominates. For the indoline ligands, alkylation of the nitrogen dramatically affects the ortho/para isomer ratio present after protonation. In the case of the N-ethylindoline and N-isopropylindoline ligands, the bridgehead-protonated isomer (ortho) is formed with >10/1 selectivity. This indolinium isomer is found to undergo acid-catalyzed hydroarylation or hydroamination with various heterocycles. Oxidative decomplexation is demonstrated for the pyrazole and 2-methylfuran derivatives using 2,3-dichloro-5,6dicyano-1,4-benzoquinone (DDQ). The resulting tetrahydroindolines feature three new stereocenters determined by the configuration of the tungsten complex.

P

exploiting a bicyclic pyrrole.14−18 In contrast, few examples have been reported of a perhydroindoline or perhydroquinoline generated from a bicyclic arene (Figure 2).19,20

erhydroindole (octahydroindole) and perhydroquinoline (decahydroquinoline) cores are present in a wide variety of natural products and pharmaceutical compounds (Figure 1).1−4

Figure 2. Dearomatization of indoline and tetrahydroquinoline. Figure 1. Natural products containing perhydroindole or perhydroquinoline cores.

Previous work has shown that N,N-dimethylaniline can be coordinated by the {TpW(NO)(PMe3)} metal fragment and, in the presence of diisopropylammonium triflate (DiPAT), trapped as its ortho-protonated triflate salt.21 Various cyclohexenone derivatives have been generated from subsequent modification of this material, [TpW(NO)(PMe 3 )(2Hanilinium)]OTf.22,23 It was anticipated that, by binding an indoline or tetrahydroquinoline to this π-basic tungsten

Some of these alkaloids feature a cis-fused ring system, such as the serine protease inhibitor Dysinosin A1 or the nicotinic antagonist Pumiliotoxin C,5,6 while others contain trans-fused motifs, such as the majority of the Stemona alkaloids (e.g., (−)-Tuberostemonine7 and (−)-stenine).8−12 Owing to their prevalence in nature, a number of strategies for the synthesis of perhydroindoles and perhydroquinolines have been reported. A variety of these methodologies for perhydroindolines utilize dearomatization reactions,13 typically © XXXX American Chemical Society

Received: October 5, 2014

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methylindoline, DiPAT, and TpW(NO)(PMe3)(η2-benzene). After 1 h the ratio 2a/2b was 8/1. After 3 h, however, this ratio had degraded to 4/1. A similar experiment was performed with 1-methyl-1,2,3,4-tetrahydroquinoline, which showed that the ratio 3a/3b changed from 1/4 (30 min) to 1/8 (2.5 h). Unfortunately, we were unable to find a process for the preparation of the desired ortho isomers (2a or 3a) free of their para counterparts. With the hope of generating a higher ratio of the ortho protonation isomers, other N-alkylated indolines and tetrahydroquinolines were synthesized and combined with TpW(NO)(PMe3)(η2-benzene) (1) and DiPAT. For the indoline derivatives, it was found that larger alkyl groups on the nitrogen dramatically enhanced ortho protonation (C3a) over para protonation (C5) (Scheme 2). For both ethyl and isopropyl

complex, novel and highly substituted hydroindole and hydroquinoline systems could be obtained. When a DME solution of N-methylindoline, DiPAT, and TpW(NO)(PMe3)(η2-benzene) was prepared and stirred overnight, a salt precipitated from solution in 47% yield (Scheme 1). Unfortunately, analysis of the product mixture Scheme 1. Protonation of η2-Coordinated Indoline and Tetrahydroquinoline Complexes Leading to Ortho and Para Isomers

Scheme 2. Dearomatization of N-Substituted Heterocycles

showed that along with the desired ortho-protonation product (the 3aH-indolinium complex 2a), its para tautomer (5Hindolinium 2b) was formed in almost equal amounts (2a/2b ≈ 1.5/1). The monitoring (31P NMR) of a similar reaction with 1methyl-1,2,3,4-tetrahydroquinoline showed the formation of an analogous cationic complex (J183W−31P = 286 Hz; cf. 285 Hz for 2a); however, this compound failed to precipitate from the DME solvent. By repeating the reaction as a heterogeneous mixture of TpW(NO)(PMe3)(η2-benzene), DiPAT, and 1methyl-1,2,3,4-tetrahydroquinoline in hexanes, a quinolinederived salt could be isolated as a mixture of two isomers, 3a,b, in a ratio of ∼1/10. By layering a DCM solution of 3a,b with acetone and isooctane, a crystal of 3b was produced that was suitable for structural analysis by X-ray diffraction. A molecular structure diagram of the cation (Figure 3) confirms the assigned structure of 3b as the para isomer (a 6H-1,2,3,4tetrahydroquinolinium complex).

derivatives, salt mixtures 4a,b and 5a,b were formed in ratios of >10/1, favoring the ortho (3aH-indolinium) form. Unfortunately, this was not the case for the quinolone-derived system, where the ortho/para ratios were virtually identical for the Nmethyl and N-ethyl analogues. Preliminary reactivity studies of 4a,b and 5a,b showed that, once protonated, 4a and 5a undergo hydroamination and hydroarylation with various amines and activated aromatic compounds. Because of their similarities in reactivity, we focused only on the N-ethyl derivatives (Scheme 3). For Scheme 3. Functionalization of 4a

example, the C4−C5 double bond of 4a can be hydroaminated with pyrazole (94%), piperidine (67%), or propylamine (64%), promoted by acid. When 4a is treated with HOTf in CH3CN, the resulting allyl intermediate readily reacts with pyrazole at C5, to give the salt 6. Similar complexes are observed for the aliphatic amines and imidazole (66%). In a similar fashion, compound 4a is able to undergo hydroarylation with various aromatic heterocycles and arenes. For example, in the presence of HOTf, 2-methylfuran adds to 4a to produce the Friedel− Crafts product 7 in 90% yield.25 Complexes similar to 7 resulted from reactions with indole (61%), 2-methylthiophene (50%), and 1,3-dimethoxybenzene (63%). Because of its ease of crystallization, a solid-state analysis of the N-isopropyl derivative, 6-iPr, was carried out using X-ray diffraction, which confirms the relative stereochemistry of these addition products (Figure 4).

Figure 3. Crystal structure of compound 3b.

For both the indoline (2a,b) and tetrahydroquinoline (3a,b) salts, computational analysis suggested that the para-protonated isomers are thermodynamically favored over their ortho counterparts.24 This implied that the best chance of obtaining the desired ortho isomers 2a and 3a would be to trap them under kinetically controlled reaction conditions (i.e., irreversible protonation). Consistent with this, a homogeneous reaction mixture was monitored (31P NMR), containing NB

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Consistent with the decreased π acidity of the ligand, compounds 8 and 9 are much easier to oxidize than their iminium precursors (Ep,a ≈ 0.5 V, cf. ∼1.2 V @ 100 mV/s). This was reflected in the ability to liberate the organic ligand from the complex through metal oxidation. Although the coordinated eneiminium complexes 6 and 7 fail to oxidize in the presence of DDQ at room temperature, the allylamine ligands of 8 and 9 are readily removed from the tungsten by this method and can be isolated. 2D-NMR data for 10 and 11 confirm that the three stereocenters in these compounds are unaltered by the decomplexation process (Scheme 4). Preliminary data suggest that the process described for the preparation of 10 and 11 from N-ethylindoline is effective for a broad range of electrophiles (C4 addition) and nucleophiles (C5 addition), and the full scope of this reactivity will be reported in due course. Regarding compounds 10 and 11, similar hydroindole ring systems have been synthesized directly through palladiummediated ring closure reactions with cyclic dienes.26 However, this annulation process produces a cis-fused ring system. In an elegant study by Wipf et al., trans-perhydroindoles were directly formed through a dearomatization reaction of L-tyrosine with PhI(OAc)2, followed by intramolecular nucleophilic addition of an NH group to the resultant α,β-unsaturated enone. These scaffolds were further elaborated to the biologically active natural products (−)-tuberostemonine7 and (−)-stenine.8 To our knowledge, the hydroindole derivatives 10 and 11 are unique. Moreover, 4a and similar species should serve as valuable precursors for new hydroindole derivatives with substituents at C4−C7. Efforts continue to find a route into selective formation of tetrahydroquinolinium derivatives similar to 3a. Moreover, the chemical nature of the para isomers 2b and 3b is currently under investigation. Representative Syntheses and Characterization of New Compounds. Compound 2. Compound 1 (1.79 g, 3.08 mmol) was combined with DiPAT (0.81 g, 3.22 mmol). To this heterogeneous mixture was added a DME (6 mL) solution of N-methylindoline (4.05 g, 30.41 mmol). This dark yellow and homogeneous solution was stirred overnight (∼14 h), forming a precipitate. The reaction mixture was filtered through a 30 mL fine-porosity fritted funnel. The collected yellow solid was washed with DME (2 × 2 mL) and Et2O (2 × 50 mL), yielding a 2a,b mixture (1.14 g, 1.45 mmol, 47%). 1 H NMR (CD3CN, δ): 8.09 (d, J = 2.0, 1H, Pz3/5), 7.98 (d, J = 2.0, 1H, Pz3/5), 7.93 (d, J = 2.0, 1H, Pz3/5), 7.84 (d, J = 2.0, 1H, Pz3/5), 7.73 (d, J = 2.0, 1H, Pz3/5), 7.39 (d, J = 2.0, 1H, Pz3/5), 6.57 (m, 1H, H5), 6.44 (overlapping triplets, J = 2.0, 2H, Pz4), 6.32 (t, J = 2.0, 1H, Pz4), 4.92 (dd, J = 1.9, 9.3, 1H, H4), 4.28 (m, 1H, H2x), 3.96 (m, 2H, H6 and H3a), 3.79 (dd, J = 8.9, 10.5, 1H, H2y), 2.82 (s, 3H, NMe), 2.54 (m, 1H, H3x), 2.29 (d, J = 8.0, 1H, H7), 1.95 (m, 1H, H3y), 1.24 (d, J = 9.3, 9H, PMe3). 13C NMR (CD3CN, δ): 191.7 (C7a), 145.6 (d, J = 2.0.3, Pz3), 143.4 (Pz3), 142.5 (Pz3), 138.8 (Pz5), 138.7 (Pz5), 138.2 (Pz5), 131.5 (d, J = 3.4, C5), 116.3 (C4), 108.4 (Pz4), 108.0 (Pz4), 107.5 (Pz4), 70.8 (d, J = 12.8, C6), 59.0 (C2), 50.1 (C7), 45.1 (C3a), 35.8 (NMe), 29.2 (C3), 13.5 (d, J = 32.1, PMe3). 31P NMR (d-acetone, δ): −9.03 (JWP = 285). Compound 6. A solution of HOTf in CH3CN (22 mL, 0.125 M) was added to 4a,b (1.06 g, 1.32 mmol), resulting in a dark yellow, homogeneous solution. To this was added pyrazole (501 mg, 7.34 mmol). The resulting light yellow homogeneous solution was stirred for 5 min. The mixture was removed from the glovebox and was diluted with 75 mL of DCM. This

Figure 4. Crystal structure of compound 6-iPr.

The structure of 6-iPr and NOE data for 6 and 7 indicate that the ortho protonation occurs syn to the metal center, contrary to expectation. We attribute this to the steric interaction that the pyrrolidine ring would have with the metal complex, were protonation to occur anti to the metal. Provided that the iminium group of 6 or 7 could be reduced with the hydride adding anti to the metal, a trans-ring junction would be expected. Reduction of 6 and 7, using LiAlH4 in Et2O, forms products 8 and 9, respectively (Scheme 4), and a crystal Scheme 4. Stereoselective Reduction of the Iminium Group and Oxidative Decomplexation

structure determination of the latter (Figure 5) confirms both the predicted trans-ring junction and the addition of the furan anti to the metal. In total, three new stereocenters are selectively created relative to the initial configuration of the tungsten stereocenter.

Figure 5. Crystal structure of compound 9. C

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solution was treated with 2 × 100 mL of Na2CO3 (saturated, aqueous). The reaction mixture was extracted with DCM (1 × 200 mL, followed by 2 × 50 mL), and the combined organic layers were washed with deionized water (200 mL), dried over anhydrous MgSO4, and concentrated in vacuo. The yellow oil was redissolved in minimal DCM and then added to stirred Et2O (500 mL) to induce precipitation of a white solid. The solid was collected on a 30 mL fine-porosity fritted funnel and washed with Et2O (2 × 50 mL), yielding 6 (1.08 g, 1.24 mmol, 94%). 1 H NMR (CD3CN, δ): 8.12 (d, J = 2.0, 1H, PzB3), 7.96 (d, J = 2.0, 1H, PzC5), 7.93 (d, J = 2.0, 1H, PzB5), 7.89 (dd, J = 2.0, 0.6, 1H, H5′), 7.86 (d, J = 2.0, 1H, PzA5), 7.55 (d, J = 2.0, 1H, PzC3), 7.52 (d, J = 2.0, 1H, H3′), 7.30 (d, J = 2.0, 1H, PzA3), 6.45 (t, J = 2.0, 1H, PzB4), 6.40 (t, J = 2.0, 1H, PzC4), 6.38 (t, J = 2.0, 1H, H4′), 6.33 (d, J = 2.0, 1H, PzA4), 5.82 (m, 1H, H5), 4.10 (m, 1H, H2x), 3.92 (m, 1H, H2y), 3.83 (m, 1H, H6), 3.50 (m, 1H, H3a), 2.84 (m, 1H, N-ethyl-CH2), 2.75 (m, 1H, Nethyl-CH2), 2.50 (m, buried, 1H, H3x), 2.47 (m, 1H, H4x), 2.24 (d, J = 8.9, 1H, H7), 1.88 (m, buried, 1H, H4y), 1.83 (m, buried, 1H, H3y), 1.07 (t, J = 7, 3H, N-ethyl-CH3), 1.00 (d, J = 9.1, 9H, PMe3). 13C NMR (CD3CN, δ): 189.6 (C7a), 145.3 (d, J = 2.1, PzB3), 144.7 (PzA3), 142.3 (PzC3), 139.4 (C3′), 138.8 (PzC5 and PzB5), 138.6 (PzA5), 128.9 (C5′), 108.5 (PzB4), 108.1 (PzC4), 107.7 (PzA4), 106.9 (C4′), 70.6 (d, J = 14.3, C6), 62.8 (d, J = 2.6, C5), 54.4 (C2), 49.3 (C7), 43.0 (N-ethylCH2), 41.8 (C3a), 41.7 (C4), 28.6 (C3), 13.4 (d, J = 31.0, PMe3), 11.8 (N-ethyl-CH3). 31P NMR (CD3CN, δ): −8.8 (JWP = 281). IR: νBH 2511 cm−1, νNO and νiminium 1612 and 1577 cm −1 . CV (DMA): E p,a = 1.34 V. Anal. Calcd for C26H37BF3N10O4PSW·1/2H2O: C, 35.39; H, 4.37; N, 15.97. Found: C, 35.44; H, 4.28; N, 15.81.

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AUTHOR INFORMATION

(5) Pelss, A.; Koskinen, A. M. P. Chem. Heterocycl. Compd. 2013, 49, 226. (6) Warnick, J. E.; Jessup, P. J.; Overman, L. E.; Eldefrawi, M. E.; Nimit, Y.; Daly, J. W.; Albuquerque, E. X. Mol. Pharmacol. 1982, 22, 565. (7) Wipf, P.; Rector, S. R.; Takahashi, H. J. Am. Chem. Soc. 2002, 124, 14848. (8) Wipf, P.; Kim, Y.; Goldstein, D. M. J. Am. Chem. Soc. 1995, 117, 11106. (9) Chen, C. Y.; Hart, D. J. J. Org. Chem. 1990, 55, 6236. (10) Ginn, J. D.; Padwa, A. Org. Lett. 2002, 4, 1515. (11) Zeng, Y.; Aubé, J. J. Am. Chem. Soc. 2005, 127, 15712. (12) Aloise Pilli, R.; da Conceicao Ferreira de Oliveira, M. Nat. Prod. Rep. 2000, 17, 117. (13) Roche, S. P.; Porco, J. A. Angew. Chem., Int. Ed. 2011, 50, 4068. (14) Zhang, X.; Han, L.; You, S.-L. Chem. Sci. 2014, 5, 1059. (15) Lucarini, S.; Bartoccini, F.; Battistoni, F.; Diamantini, G.; Piersanti, G.; Righi, M.; Spadoni, G. Org. Lett. 2010, 12, 3844. (16) Han, S.; Movassaghi, M. J. Am. Chem. Soc. 2011, 133, 10768. (17) Sirasani, G.; Paul, T.; Dougherty, W.; Kassel, S.; Andrade, R. B. J. Org. Chem. 2010, 75, 3529. (18) Martin, D. B. C.; Nguyen, L. Q.; Vanderwal, C. D. J. Org. Chem. 2011, 77, 17. (19) Ç avdar, H.; Saraçoğlu, N. Tetrahedron 2005, 61, 2401. (20) Fang, M.; Machalaba, N.; Sanchez-Delgado, R. A. Dalton Trans. 2011, 40, 10621. (21) Salomon, R. J.; Todd, M. A.; Sabat, M.; Myers, W. H.; Harman, W. D. Organometallics 2010, 29, 707. (22) Pienkos, J. A.; Knisely, A. T.; Liebov, B. K.; Teran, V.; Zottig, V. E.; Sabat, M.; Myers, W. H.; Harman, W. D. Organometallics 2013, 33, 267. (23) Pienkos, J. A.; Zottig, V. E.; Iovan, D. A.; Li, M.; Harrison, D. P.; Sabat, M.; Salomon, R. J.; Strausberg, L.; Teran, V. A.; Myers, W. H.; Harman, W. D. Organometallics 2013, 32, 691. (24) Harrison, D. P.; Nichols-Nielander, A. C.; Zottig, V. E.; Strausberg, L.; Salomon, R. J.; Trindle, C. O.; Sabat, M.; Gunnoe, T. B.; Iovan, D. A.; Myers, W. H.; Harman, W. D. Organometallics 2011, 30, 2587. (25) The distinct splitting pattern (qd) of the methyl on the furan moiety was used as a spectroscopic handle to monitor subsequent reactivity. (26) Baeckvall, J. E.; Andersson, P. G.; Stone, G. B.; Gogoll, A. J. Org. Chem. 1991, 56, 2988.

S Supporting Information *

Text, figures, tables, and CIF files giving full experimental procedures for all previously unreported compounds and descriptions of their spectroscopic analysis, crystallographic data and structures of compounds 3b, 6-iPr, and 9, 1H and 13C NMR spectra of selected compounds, and Cartesian coordinates of calculated structures. This material is available free of charge via the Internet at http://pubs.acs.org. Corresponding Author

*E-mail for W.D.H.: [email protected]. Author Contributions ∥

These authors contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We acknowledge the NSF (CHE-1152803; University of Virginia). REFERENCES

(1) Hanessian, S.; Margarita, R.; Hall, A.; Johnstone, S.; Tremblay, M.; Parlanti, L. J. Am. Chem. Soc. 2002, 124, 13342. (2) Dunetz, J. R.; Danheiser, R. L. J. Am. Chem. Soc. 2005, 127, 5776. (3) Correa, A.; Tellitu, I.; Domínguez, E.; SanMartin, R. J. Org. Chem. 2006, 71, 8316. (4) Boal, B. W.; Schammel, A. W.; Garg, N. K. Org. Lett. 2009, 11, 3458. D

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