Taming Silylium Ions for Synthesis: N-Heterocycle Synthesis via Stereoselective C–C Bond FormationThis work was financially supported by the DOE (Basic Energy Sciences, DE-FG02-05ER15630)
Received: 08 May 2017
Accepted after revision: 28 June 2017
16 August 2017 (eFirst)
Published as part of the Cluster Silicon in Synthesis and Catalysis
Silylium ions (formally [R3Si]+) have long been the subject of investigations and significant debate in both theoretical and experimental chemistry, but few catalytic, synthetic applications have been reported due to the exceptionally high reactivity and Lewis acidity of these elusive species. Results to be discussed include the application of easily accessible silylium ion catalysts to the stereoselective synthesis of various N-heterocyclic pyrrolidine and piperidine scaffolds. The tested substrates are derived from the chiral pool and can be obtained in three high-yielding steps from amino alcohols; subsequent stereoselective silylium ion catalyzed Prins cyclization and trapping with R3Si–Nu nucleophiles (e.g., Nu = H, allyl, azide, and enol ethers) results in novel nitrogen-containing polycyclic scaffolds with potential medicinal chemistry applications.
Key wordssilylium ion - silylium catalysis - Lewis acid - Prins cyclization - Hosomi–Sakurai allylation - Si–X reagent - N-heterocycle - polycyclic scaffold
References and Notes
- 1a Reed CA. Xie Z. Bau R. Benesi A. Science 1993; 262: 402
- 1b Lambert JB. Zhao Y. Angew. Chem., Int. Ed. Engl. 1997; 36: 400
- 1c Gaspar PP. Science 2002; 297: 785
- 1d Kim K.-C. Reed CA. Elliott DW. Mueller LJ. Tham F. Lin L. Lambert JB. Science 2002; 297: 825
- 2a Corriu RJ. P. Henner M. Organomet. Chem. 1974; 74: 1
- 2b Lambert JB. Kania L. Zhang S. Chem. Rev. 1995; 95: 1191
- 2c Reed C. Acc. Chem. Res. 1998; 31: 325
- 2d Lambert JB. Zhao Y. Zhang SM. J. Phys. Org. Chem. 2001; 14: 370
- 2e Müller T. Adv. Organomet. Chem. 2005; 53: 155
- 2f Klare HF. T. Oestreich M. Dalton Trans. 2010; 39: 9176
- 2g Schulz A. Villinger A. Angew. Chem. Int. Ed. 2012; 51: 4526
- 3 Großekappenberg H. Reißmann M. Schmidtmann M. Müller T. Organometallics 2015; 34: 4952
- 4a Strauss SH. Chem. Rev. 1993; 93: 927
- 4b Krossing I. Raabe I. Angew. Chem. Int. Ed. 2004; 43: 2066
- 4c Reed CA. Acc. Chem. Res. 2010; 43: 121
- 5a Corey JY. J. Am. Chem. Soc. 1975; 97: 3237
- 5b Lambert JB. Zhang S. J. Chem. Soc., Chem. Commun. 1993; 383
- 5c Lambert JB. Zhang S. Ciro SM. Organometallics 1994; 13: 2430
- 5d Lambert JB. Zhang S. Stern CL. Huffman JC. Science 1993; 260: 1917
- 5e Nava M. Reed CA. Organometallics 2011; 30: 4798
- 6a Lambert JB. Zhao Y. J. Am. Chem. Soc. 1996; 118: 7867
- 6b Lambert JB. Zhao Y. Wu H. J. Org. Chem. 1999; 64: 2729
- 7a Kira M. Hino T. Sakurai H. Chem. Lett. 1992; 555
- 7b Parks DJ. Blackwell JM. Piers WE. J. Org. Chem. 2000; 65: 3090
- 7c Müther K. Oestreich M. Chem. Commun. 2011; 47: 334
- 8 Müther K. Mohr J. Oestreich M. Organometallics 2013; 32: 6643
- 9a Scott VJ. Çelenligil-Çetin R. Ozerov OV. J. Am. Chem. Soc. 2005; 127: 2852
- 9b Panisch R. Bolte M. Müller T. J. Am. Chem. Soc. 2006; 128: 9676
- 9c Douvris C. Ozerov OV. Science 2008; 321: 1188
- 9d Perutz RN. Science 2008; 321: 1168
- 9e Douvris C. Nagaraja CM. Chen C.-H. Foxman BM. Ozerov OV. J. Am. Chem. Soc. 2010; 132: 4946
- 9f Stahl T. Klare HF. T. Oestreich M. ACS Catal. 2013; 3: 1578
- 10a Hara K. Akiyama R. Sawamura M. Org. Lett. 2005; 7: 5621
- 10b Klare HF. T. Bergander K. Oestreich M. Angew. Chem. Int. Ed. 2009; 48: 9077
- 10c Nödling AR. Müther K. Rohde VH. G. Hilt G. Oestreich M. Organometallics 2014; 33: 302
- 10d Rohde VH. G. Pommerening P. Klare HF. T. Oestreich M. Organometallics 2014; 33: 3618
- 10e Rohde VH. G. Müller MF. Oestreich M. Organometallics 2015; 34: 3358
- 10f Shaykhutdinova P. Oestreich M. Organometallics 2016; 35: 2768
- 10g Schmidt RK. Klare HF. T. Fröhlich R. Oestreich M. Chem. Eur. J. 2016; 22: 5376
- 11a Lühmann H. Panisch R. Müller T. Appl. Organomet. Chem. 2010; 24: 533
- 11b Duttwyler S. Douvris C. Nathanael CD. Fackler LP. Tham FS. Reed CA. Baldridge KK. Siegel JS. Angew. Chem. Int. Ed. 2010; 49: 7519
- 11c Allemann O. Duttwyler S. Romanato P. Baldridge KK. Siegel JS. Science 2011; 332: 574
- 11d Allemann O. Baldridge KK. Siegel JS. Org. Chem. Front. 2015; 2: 1018
- 12a Bähr S. Oestreich M. Angew. Chem. Int. Ed. 2017; 56: 52
- 12b Furukawa S. Kobayashi J. Kawashima T. J. Am. Chem. Soc. 2009; 131: 14192
- 12c Chen Q.-A. Klare HF. T. Oestreich M. J. Am. Chem. Soc. 2016; 138: 7868
- 13 The choice of arylsulfonyl protecting group was based on yield and general ease of substrate synthesis. Other N-protecting groups (e.g., Boc, Ac, Bz, TFA, and p-Ns) were found to be difficult to install in satisfactory yields and so were not investigated for compatibility in the Prins cyclization.
- 14 Other R3Si–Nu sources, including TMS–I, TMS–CN, and TMS–OAc, provided complex mixtures of products by 1H NMR and 13C NMR analyses.
- 15a Hosomi A. Acc. Chem. Res. 1988; 21: 200
- 15b Mahlau M. García-García P. List B. Chem. Eur. J. 2012; 18: 16283
- 15c Sai M. Yamamoto H. J. Am. Chem. Soc. 2015; 137: 7091
- 15d Kaib PS. J. Schreyer L. Lee S. Properzi R. List B. Angew. Chem. Int. Ed. 2016; 55: 13200
- 16 The substrate is consumed; in the absence of a suitable trapping nucleophile, catalytic [Et3Si][B(C6F5)4] leads to a 54% NMR yield of eliminated products 22 and 23 in 78:22 cis/trans d.r.
- 17 Analysis of crude pre- and post-annulation 13C NMR suggests the reason for exclusively high d.r. but low yield is most likely due to double diastereo-differentiation during annulation of intermediate I; diastereomers with a trans-configuration of the C–O and C–Nu bonds decompose and/or are easily separated away from the cis-bridged products. We have not attempted to isolate or characterize the intermediate ketone diastereomers I.
- 18 Reaction with the corresponding acyclic acetophenone-derived silyl enol ether yielded only trace cyclized product (see Supporting Information).
- 19 Wuts PG. M. Greene TW. N-Sulfonyl Derivatives: R2NSO2R′ . In Greene’s Protective Groups in Organic Synthesis . John Wiley and Sons; Hoboken, NJ; 2007. 4th ed. 851-868
- 20a Nyasse B. Grehn L. Maia HL. S. Monteiro LS. Ragnarsson U. J. Org. Chem. 1999; 64: 7135
- 20b Grehn L. Ragnarsson U. J. Org. Chem. 2002; 67: 6557
- 21 CCDC 1548662 contains the supplementary crystallographic data for this structure. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
- 22 DFT calculations (ωB97X-D//6-311+G**//CPCM:CH2Cl2) on 2-methyl-1-(phenylsulfonyl)piperidine show the lowest energy axial conformer to be 3.3 kcal/mol more stable than the lowest energy equatorial conformer. We speculate that this is paralleled in TS and TS′.
- 23 Interestingly, 10 mol% HBArF24 ([H(OEt2)2][B(C6H3(CF3)2)4], Brookhart’s acid) as catalyst provided hydride-trapped 6 in an inferior 47% NMR yield but 45:36:19 d.r. favoring the same diastereomers as those resulting from the putative silylium ion catalysis (cf. Table 1, entry 2; see Supporting Information). This suggests that the reaction can be catalyzed by Brønsted acid and that co-catalysis could be operative via adventitious water. See: Schmidt RK. Muether K. Mueck-Lichtenfeld C. Grimme S. Oestreich M. J. Am. Chem. Soc. 2012; 134: 4421
- 24 The relative stereochemistry of cis- and trans-tetrahydropyridine products was determined via X-ray crystallography and comparison of 1H NMR and 13C NMR data (see S19 in the Supporting Information).
- 25a Attempts to intercept the carbocation with R3Si–Nu using BCF have been unsuccessful; Et3Si–H hydrosilylates the aldehyde in 32% NMR yield, along with 44% of 23, and 7% and 12%, respectively, of minor isomers B and C of 6.
- 25b Aldehyde hydrosilylation has been well documented, see: Oestreich M. Hermeke J. Mohr J. Chem. Soc. Rev. 2015; 44: 2202
- 26 Representative Procedure for the Synthesis of Piperidine 20 In a dry, N2-filled glove box, aldehyde S16 (0.150 mmol, 68.3 mg, 1.00 equiv) and trityl BArF20 (0.0150 mmol, 13.8 mg, 0.10 equiv) were weighed into a screw-cap 1 dram vial equipped with a stir bar and sealed with a septum cap. In a separate vial, Et3SiH (0.0180 mmol, 2.9 μL, 0.12 equiv) and cyclohexanone-derived silyl enol ether (0.375 mmol, 72 μL, 2.50 equiv) were dissolved in 3.00 mL of CH2Cl2 and the vial sealed with a septum cap. Both vials were removed from the glove box, and the vial containing the aldehyde and trityl BArF20 was cooled to –78 °C in an acetone/CO(s) bath. The room-temperature solution in CH2Cl2 was syringed dropwise and slowly down the side of the vial into the vigorously stirring solution over 5–10 min. The reaction was stirred for an additional 2 h at –78 °C, quenched with 50 μL Et3N, and warmed to r.t. The solution was repeatedly washed with CH2Cl2 (3×; to remove excess base) and dried in vacuo. The resulting residue was taken up in 2 mL of 1:1 CH2Cl2/MeOH, approximately 10–20 beads of Dowex resin (50W-X8) were added, and the reaction was stirred at 22 °C for 3 h. The mixture was then filtered through a cotton/sand plug, rinsed with 1 mL CH2Cl2 (2×), and concentrated in vacuo. The crude residue was purified by silica gel chromatography (Rf = 0.5, n-pentane/EtOAc = 5:1), providing heterocycle 20 as a crystalline white solid in 55% yield (44.3 mg). 1H NMR (600 MHz, CDCl3): δ = 8.50 (d, 1 H J = 1.9 Hz), 8.01 (d, 1 H, J = 8.7 Hz), 7.99 (d, 1 H, J = 8.2 Hz), 7.95 (d, 1 H, J = 8.0 Hz), 7.90 (dd, 1 H, J = 8.7, 1.9 Hz), 7.67 (ddd, 1 H, J = 8.2, 6.9, 1.4 Hz), 7.63 (ddd, 1 H, J = 8.2, 6.8, 1.4 Hz), 7.37 (t, 2 H, J = 7.7 Hz), 7.29 (dd, 2 H, J = 8.2, 1.3 Hz), 7.27–7.22 (m, 3 H), 7.18 (d, 1 H, J = 7.4 Hz), 7.16 (dd, 2 H, J = 7.1, 1.6 Hz), 4.69 (dd, 1 H, J = 11.4, 2.7 Hz), 3.89 (dt, 1 H, J = 4.0, 1.9 Hz), 3.57 (dd, 1 H, J = 12.7, 3.5 Hz), 3.40 (d, 1 H, J = 11.5 Hz), 3.30 (ddd, 1 H, J = 11.6, 3.6, 1.8 Hz), 2.85 (t, 1 H, J = 12.8, 11.6 Hz), 2.39–2.32 (m, 2 H), 2.24–2.19 (m, 1 H), 1.94–1.90 (m, 1 H), 1.72–1.53 (m, 6 H). 13C NMR (151 MHz, CDCl3): δ = 150.1, 143.5, 139.6, 138.2, 134.8, 132.4, 129.8, 129.4, 129.3, 128.9, 128.6, 128.6, 128.1, 127.8, 127.7, 126.7, 126.6, 126.4, 122.5, 106.3, 67.4, 65.5, 54.1, 39.1, 39.0, 35.8, 27.8, 24.8, 23.4, 23.1. HRMS (ESI+): m/z calcd for C34H34NO3S+ [M + H]+: 536.2260; found: 536.2259. [α]D 26 +11.7 (c 1.70, CH2Cl2, l = 100 mm).
For authoritative reviews, see:
See (a) and (b) for Kira–Piers mechanism:
For an ACS Catalysis Perspective, see:
For a recent review, see:
For selected examples, see:
For a review, see:
For selected modern asymmetric examples, see: