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Synlett 2008(7): 991-994  
DOI: 10.1055/s-2008-1072512
LETTER
© Georg Thieme Verlag Stuttgart · New York

Modular and Stereoselective Synthesis of Hydroxylated Angularly Fused Tricyclic Piperidine Derivatives via Samarium Diiodide Mediated Cyclization

Rajendran Senthil Kumaran, Irene Brüdgam, Hans-Ulrich Reissig*
Institut für Chemie und Biochemie, Freie Universität Berlin, Takustr. 3, 14195 Berlin, Germany
Fax: +49(30)83855367; e-Mail: hans.reissig@chemie.fu-berlin.de;
Further Information

Publication History

Received 16 January 2008
Publication Date:
28 March 2008 (online)

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Abstract

Proline-promoted Mannich reactions of a series of cycloalkanones with formalin and aniline followed by N-acetylation provided precursors 9-12 for samarium diiodide mediated cyclizations. The ketyl-aryl coupling of these compounds furnished angularly fused piperidine derivatives such as 13 in good yields. Highly stereoselective dihydroxylation gave compounds of type 14 with five contiguous stereogenic centers. Our modular approach to this type of compounds involves just four simple steps and is fairly general. For the conversion of 10 into 15 we could demonstrate that the toxic and carcinogenic additive HMPA can be successfully replaced by lithium bromide and 1,3-dimethyl-2-imidazolidinone (DMI).

Key words

samarium diiodide - ketyl - Mannich reaction - piperidines - dihydroxylation - HMPA replacement

1

Responsible for X-ray analysis.

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Typical Procedure for a Mannich Reaction, Conversion of 1 into 5
To a solution of aniline (2.3 mL, 25.0 mmol) in DMSO (25 mL) was added cyclopentanone (1, 3.3 mL, 37.5 mmol) and 36% formalin solution (0.85 mL, 30 mmol) along with (S)-proline (860 mg, 7.46 mmol), and the reaction mixture was allowed to stir at r.t. for 4 d. The reaction was quenched with aq NH4Cl solution (20 mL) and extracted twice with EtOAc (100 mL). The combined organic layers were washed with H2O (15 mL) and brine (20 mL). The extract was dried with MgSO4 and concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography on silica gel (hexane-EtOAc, 4:1) to furnish 2.32 g (49%) of Mannich product 5 as a colourless solid.
Analytical Data for (2 R* )-2-(Anilinomethyl)cyclo-pentanone (5)
Mp 71-73 °C; [α]D -0.2 (c 1, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 1.66-1.73, 1.79-1.88, 2.02-2.08 (3 m, 1 H each, CH2), 2.14-2.21 (m, 1 H, CH2CO), 2.23-2.29 (m, 1 H, CH2), 2.32-2.38 (m, 1 H, CH2CO), 2.42-2.48 (m, 1 H, CHCO), 3.27 (dd, J = 12.9, 6.5 Hz, 1 H, CH2NH), 3.36 (dd, J = 12.9, 6.9 Hz, 1 H, CH2NH), 4.16 (br s, 1 H, NH), 6.65 (d, J = 7.3 Hz, 2 H, Ar), 6.73 (t, J = 7.3 Hz, 1 H, Ar), 7.18 (t, J = 7.3 Hz, 2 H, Ar). 13C NMR (126 MHz, CDCl3): δ = 20.8, 28.2 (2 t, CH2), 38.5 (t, CH2CO), 44.0 (t, CH2NH), 48.3 (d, CHCO), 113.2 (d, Ar), 117.8 (d, Ar), 129.3 (d, Ar), 148.0 (s, Ar), 220.8 (s, CO). IR (neat): νmax = 3390 (NH), 2970-2875 (=CH, CH), 1720 (CO) cm-1. Anal. Calcd for C12H15NO (189.1): C, 76.16; H, 7.99; N, 7.40. Found: C, 75.87; H, 7.89; N, 7.36. ESI-HRMS: m/z calcd for C12H16NO [M+ + H]: 190.1232; found: 190.1239.

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Typical Procedure for SmI 2 -Mediated Cyclizations, Conversion of 9 into 13
Samarium granules (360 mg, 2.40 mmol) and diiodoethane (650 mg, 2.31 mmol) were taken in a flask and kept under an argon atmosphere. The solvent THF (23 mL) was introduced into the flask and allowed to stir at r.t. for 2.5 h. To the deep-blue-colored solution of SmI2 was added HMPA (1.75 mL, 10.0 mmol) and the color of the mixture immediately turns from blue to purple. The mixture was allowed to stir for
0.5 h, and then it was cooled to 0 °C. Compound 9 (231 mg, 1.00 mmol) and t-BuOH (0.24 mL, 2.5 mmol) in THF solution (3 mL) were introduced to the ice-cooled reaction mixture and the stirring was continued for another 1.5 h. The reaction was quenched with aq NH4Cl solution (2 mL) and THF was evaporated under reduced pressure. The mixture was diluted with EtOAc (30 mL) and washed successively with H2O (4 mL), brine (4 mL), and dried with MgSO4. The crude product was purified by column chromatography on silica gel (hexane-EtOAc, 2:8) to obtain product 13 (158 mg, 68%) as a crystalline solid.
Analytical Data for (3a R* ,9a S* ,9b S* )-5-Acetyl-1,2,3,3a,4,5,7,9a-octahydro-9b H -cyclopenta[ c ]quinolin-9b-ol (13)
Mp 141-142 °C. 1H NMR (500 MHz, CDCl3): δ = 1.31-1.36 (m, 1 H, CH2), 1.43-1.48 (m, 1 H, CH2), 1.66-1.76 (m, 2 H, CH2), 1.78-1.86 (m, 1 H), 1.90-1.95 (m, 1 H), 2.02-2.06 (m, 1 H), 2.08 (s, 3 H, CH3CO), 2.09 (s, 1 H, OH), 2.18 (t, J = 13.2 Hz, 1 H, CH2N), 2.82-2.85 (m, 2 H), 2.92-2.95 (m, 1 H), 4.53 (dd, J = 13.2, 6.6 Hz, 1 H, CH2N), 5.60 (s, 1 H), 5.73-5.77 (m, 1 H), 5.93 (dd, J = 10.2, 2.8 Hz, 1 H). 13C NMR (126 MHz, CDCl3): δ = 20.4 (t, CH2), 21.4 (q, CH3CO), 26.7, 27.0, 31.2 (3 t, CH2), 45.4 (d, CH), 45.5 (t, CH2N), 46.8 (d, CH), 84.7 (s, COH), 121.5 (d, CH), 123.7 (d, CH), 124.1 (d, CH), 136.4 (s, C), 168.9 (s, NCO). IR (neat): νmax = 3405 (OH), 2960-2870 (=CH, CH), 1630 (CO) cm-1. Anal. Calcd for C14H19NO2 (233.1): C, 72.07; H, 8.21; N, 6.00. Found: C, 71.50; H, 8.07; N, 6.05. ESI-HRMS: m/z calcd for C14H20NO2 [M+ + H]: 234.1494; found: 234.1491.

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X-ray Data
C14H21NO4, M r = 267.3; T = 173 (2) K; crystal size: 0.07 × 0.25 × 0.25 mm; monoclinic, space group P2(1)/c, a = 11.7907(20), b = 9.0598(15), c = 12.7815(23) Å; Z = 4; D c = 1.348 mg/m3; F(000) = 576; µ(MoK) = 0.098 mm-1. Θ Range for data collection: 1.79-30.57°, index ranges: -15 ≤ h ≤ 16, -12 ≤ k ≤ 11, -18 ≤ l ≤ 18; reflections collected/unique: 16539/4018 (R int = 0.0501); final R [I > 2σ(I)]: R1 = 0.0469, wR2 = 0.1208. For the structure and refinement, the programs SHELXS97 and SHELXL97 were used. Atomic coordinates and further crystallographic details have been deposited at the Cambridge Crystallographic Data Centre, deposition number CCDC 676671, and copies of this data can be obtained in application to CCDC, University Chemical Laboratory, Lensfield Road, Cambridge CB2 1EW, UK [fax:
+44 (1223)336033; email: deposit@ccdc.cam.ac.uk].

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Procedure for SmI 2 -Mediated Cyclization of 10 to 15 in the Presence of LiBr and DMI
Lithium bromide (610 mg, 7.00 mmol) was dissolved in dry THF (6 mL) and DMI (1.0 mL, 9.0 mmol) was introduced into the solution. The resulting solution was bubbled with argon for 20 min and then added to 0.1 M solution of SmI2 in THF (12 mL) at r.t. and stirred for 30 min. To the resulting purple solution, compound 10 (122 mg, 0.50 mmol, in 2 mL THF) and t-BuOH (0.12 mL, 1.3 mmol) were added at 0 °C. The reaction mixture was stirred for 1.5 h and then quenched with sat. aq NH4Cl solution (2 mL). Tetrahydrofuran was evaporated under reduced pressure, the residue was diluted with EtOAc (20 mL), washed with H2O (2 mL), brine (2 mL), and dried with MgSO4. The crude material was purified by column chromatography on silica gel (hexane-EtOAc, 2:8) to deliver 92 mg (75%) of product 15.