Protecting-Group-Free Route to Hydroxylated Pyrrolidine and Piperidine Derivatives through Cu(I)-Catalyzed Intramolecular Hydroamination of Alkenes

Abstract

An efficient approach to hydroxylated pyrrolidine and piperidine derivatives through the intramolecular hydroamination catalyzed by a Cu(I)-Xantphos system is described. The transformation allows for the short synthesis of N-alkylated aza-sugars without a protection-deprotection event of the hydroxy groups.

Key words

pyrrolidines - piperidines - protecting-group-free synthesis - hydroamination - copper

References and Notes

• For reviews:
• 1a Iminosugars as Glycosidase Inhibitors - Nojirimycin and Beyond   Stütz AE. Wiley-VCH; Weinheim: 1999. 
• 1b Asano N. Nash RJ. Molyneux RJ. Fleet GW. Tetrahedron: Asymmetry  2000,  11:  1645 
• 1c Lillelund VH. Jensen HH. Liang X. Bols M. Chem. Rev.  2002,  102:  515 
• 1d Pearson MSM. Mathe-Allainmat M. Fargeas V. Lebreton J. Eur. J. Org. Chem.  2005,  2159 
• For reviews on the hydroamination of alkenes and alkynes, see:
• 2a Müller TE. Beller M. Chem. Rev.  1998,  98:  675 
• 2b Müller TE. Hultzsch KC. Yus M. Foubelo F. Tada M. Chem. Rev.  2008,  108:  3795 
• For late transition-metal-catalyzed intramolecular hydroaminations of amino alkenes bearing a protecting-group-free hydroxy group, see: Rh:
• 3a Liu Z. Hartwig JF. J. Am. Chem. Soc.  2008,  130:  1570 
• Pt:
• 3b Han X. Widenhoefer RA. Angew. Chem Int. Ed.  2006,  45:  1747 
• Pd:
• 3c Michael FE. Cochran BM. J. Am. Chem. Soc.  2006,  128:  4246 
• For intramolecular amidomercurations of amidoalkenes bearing a protecting-group-free free hydroxy group, see:
• 4a Singh S. Chikkanna D. Singh OV. Han H. Synlett  2003,  1279 
• 4b Chikkanna D. Han H. Synlett  2004,  2311 ; see also ref. 2
• 5 Ohmiya H. Moriya T. Sawamura M. Org. Lett.  2009,  11:  2145 
• For reviews on the protecting-group-free synthesis, see:
• 6a Hoffmann RW. Synthesis  2006,  3531 
• 6b Young IS. Baran PS. Nature Chem.  2009,  1:  193 
• 7 For a synthesis of hydroxypyrrolidines without protecting groups, see: Dangerfield EM. Timmer MSM. Stocker BL. Org. Lett.  2009,  11:  535 
• 9 The relative stereochemistry of 2bb was assigned according to the literature. See: Andrés JM. Pedrosa R. Pérez-Encabo A. Eur. J. Org. Chem.  2007,  1803 
• 10 The ee of (2R,3S)-4 (95% ee) was determined by chiral HPLC analysis of the p-nitrobenzoate derivative. See: Jäger V. Hümmer W. Stahl U. Gracza T. Synthesis  1991,  769 
• 11 The ee value of (2S,3R)-6 (99% ee) was determined by the Mosher’s NMR spectroscopic method. See: Crimmins MT. Powell MT. J. Am. Chem. Soc.  2003,  125:  7592 
• 12 The epoxides 8 were prepared according to the reported procedure. The ee of 8 has not been determined in our hand. See: Takano S. Iwabuchi Y. Ogasawara K. J. Am. Chem. Soc.  1991,  113:  2786 

8

General Procedure for the Cu(I)-Catalyzed Hydroamination of Amino Alkene [Procedure A with CuO t -Bu-Xantphos (Scheme 1, Tables 1 and 2)] In a glove box, CuOt-Bu (0.06 mmol, 8.2 mg or 0.08 mmol, 10.9 mg) and Xantphos (0.06 mmol, 34.7 mg or 0.08 mmol, 46.3 mg) were placed in a screw vial. Anhydrous, degassed mixed solvent, MeOH-p-xylene (1:1, 0.4 mL) was added and stirred at r.t. for 10 min to give a pale yellow solution.
A solution of a hydroxylated amino alkene (0.4 mmol) in MeOH-p-xylene (1:1, 0.4 mL) was added. The vial was sealed with a screw cap and was removed from the glove box. The mixture was stirred and heated at 140 ˚C for 72 h. The reaction mixture was cooled to r.t. and concentrated. An internal standard (1,1,2,2-tetrachloroethane) was added to the residue. The yield of the product was determined by ^¹H NMR. Purification by Kugelrohr distillation or preparative TLC (silica gel, MeOH) gave the desired product in a practically pure form.
General Procedure for the Cu(I)-Catalyzed Hydroamination of Amino Alkene [Procedure B with CuOAc-KO t -Bu-Xantphos (Tables 1 and 2)] In a glove box, CuOAc (0.06 mmol, 7.4 mg or 0.08 mmol, 9.8 mg), Xantphos (0.06 mmol, 34.7 mg or 0.08 mmol, 46.3 mg), and KOt-Bu (0.09 mmol, 12.3 mg or 0.12 mmol, 16.4 mg) were placed in a screw vial. Anhydrous, degassed mixed solvent, MeOH-p-xylene (1:1, 0.4 mL) was added and stirred at r.t. for 10 min to give a pale yellow solution. The following procedure is identical to that described above.

13

The isolated 2e was contaminated with unidentified materials. See experimental procedure in note 17.

14

1-Benzyl-3-hydroxy-2-methylpyrrolidine (2ac, 69:31 mixture of diastereomers) Viscous oil. ^¹H NMR (300 MHz, CDCl₃): δ (major isomer) = 1.22 (d, J = 6.3 Hz, 3 H), 1.66 (m, 1 H), 1.97-2.16 (m, 2 H), 2.30 (m, 1 H), 2.93 (ddd, J = 11.1, 8.4, 2.1 Hz, 1 H), 3.10 (d, J = 12.9 Hz, 1 H), 4.02 (d, J = 12.9 Hz, 1 H), 4.03 (m, 1 H), 7.23-7.35 (m, 5 H); δ (minor isomer) = 1.18 (d, J = 6.3 Hz, 3 H), 1.53 (m, 1 H), 1.97-2.16 (m, 2 H), 2.41 (m, 1 H), 2.79 (ddd, J = 11.4, 8.7, 2.4 Hz, 1 H), 3.29 (d, J = 12.9 Hz, 1 H), 3.89 (m, 1 H), 3.94 (d, J = 12.9 Hz, 1 H), 7.23-7.35 (m, 5 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 12.84 16.25, 32.22, 32.84, 50.89, 51.24, 57.51, 57.77, 63.85, 67.26, 74.31, 78.22, 126.98, 127.01, 128.27 (2×), 128.98, 129.03, 138.99, 139.04. ESI-HRMS: m/z [M + H]⁺ calcd for C₁₂H₁₈ON: 192.1382; found: 192.1381.

15

(3 S ,4 R )-3,4-Dihydroxy-1,2-dimethylpyrrolidine (2ca, >20:1 mixture of diastereomers) Viscous oil. ^¹H NMR (300 MHz, CDCl₃): δ = 1.15 (d, J = 6.6 Hz, 3 H), 2.26 (s, 3 H), 2.31 (m, 1 H), 2.42 (dd, J = 11.0, 6.9 Hz, 1 H), 2.97 (dd, J = 11.0, 2.7 Hz, 1 H), 4.00 (dd, J = 6.3, 5.2 Hz, 1 H), 4.22 (ddd, J = 6.9, 6.3, 2.7 Hz, 1 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 12.27, 39.84, 63.42, 65.02, 69.53, 73.37. HRMS-FAB: m/z [M + H]⁺ calcd for C₆H₁₃O₂N: 131.0946; found: 132.1032. [α]_D ^²7 +37.0 (c 0.6, MeOH).

16

(4 R ,5 S )-4,5-Dihydroxy-1,2-dimethylpiperidine (2d, 62:38 mixture of diastereomers) Viscous oil. ^¹H NMR (300 MHz, CD₃OD): δ (major isomer) = 1.10 (d, J = 6.3 Hz, 3 H), 1.54-1.67 (m, 2 H), 2.18-2.41 (m, 2 H), 2.19 (s, 3 H), 2.91 (dd, J = 12.6, 3.3 Hz, 1 H), 3.55 (m, 1 H), 3.77 (m, 1 H); δ (minor isomer) = 1.04 (d, J = 6.3 Hz, 3 H), 1.44 (ddd, J = 14.7, 11.8, 2.7 Hz, 1 H), 1.77 (dt, J = 14.7, 3.6 Hz, 1 H), 2.18-2.41 (m, 2 H), 2.27 (s, 3 H), 2.62 (dd, J = 10.8, 4.8 Hz, 1 H), 3.65 (m, 1 H), 3.90 (m, 1 H). ^¹³C NMR (75 MHz, CD₃OD): δ = 19.38, 20.25, 37.71, 40.50, 42.57, 43.15, 53.45, 57.39, 58.89, 61.80, 68.61, 69.61, 69.70, 70.95. ESI-HRMS: m/z [M + H]⁺ calcd for C₇H₁₅O₂N: 145.1103; found: 146.1179. [α]_D ^²7 +19.8 (c 1.0, MeOH).

17

Procedure for the Synthesis of Trihydroxylated Piperidine 2e (Procedure C, Scheme 5)
In a glove box, CuOAc (0.04 mmol, 4.9 mg), Xantphos (0.04 mmol, 23.1 mg), and KOt-Bu (0.06 mmol, 8.2 mg) were placed in a screw vial. Anhydrous, degassed mixed solvent, MeOH-p-xylene (1:1, 0.2 mL) was added and stirred at r.t. for 10 min to give a pale yellow solution. A solution of 1e (0.2 mmol) in MeOH-p-xylene (1:1, 0.2 mL) was added. The vial was sealed with a screw cap, and was removed from the glove box. The mixture was stirred and heated at 140 ˚C for 72 h. The reaction mixture was cooled to r.t. and concentrated. The residue was dissolved in EtOAc (5 mL) and H₂O (5 mL). The mixture was extracted with H₂O (3 × 5 mL). The combined aqueous layers were evaporated under reduced pressure to give a pale yellow oil (25.5 mg). ^¹H NMR analysis of the material using t-BuOH as an internal standard indicated that the yield and purity of 2e were 53% (17.7 mg) and 67%, respectively.

18

(3 R ,4 S ,5 S )-3,4,5-Trihydroxy-1,2-dimethylpiperidine (2e, 61:39 mixture of diastereomers) Oil. ^¹H NMR (600 MHz, D₂O): δ (major isomer) = 1.14 (d, J = 6.6 Hz, 3 H), 2.25 (m, 1 H), 2.28 (s, 3 H), 2.41 (m, 1 H), 2.66 (dd, J = 11.4, 4.8 Hz, 1 H), 3.26 (m, 1 H), 3.72 (m, 1 H), 4.02 (m, 1 H); δ (minor isomer) = 1.17 (d, J = 6.6 Hz, 3 H), 2.19 (s, 3 H), 2.25 (m, 1 H), 2.35 (d, J = 12.6 Hz, 1 H), 2.41 (m, 1 H), 2.96 (m, 1 H), 3.72 (m, 1 H), 3.97 (m, 1 H). ESI-HRMS: m/z [M + H]⁺ calcd for C₇H₁₆O₃N: 162.11247; found: 162.11242.