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

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).

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

References and Notes

1

Responsible for X-ray analysis.

2a Girard P. Namy JL. Kagan HB. Nouv. J. Chim.  1977,  1:  5 

2b Girard P. Namy JL. Kagan HB. J. Am. Chem. Soc.  1980,  102:  2693 

2c Kagan HB. Namy JL. Top. Organomet. Chem.  1999,  2:  155 

Selected reviews on samarium diiodide promoted chemistry:

3a Kagan HB. Namy JL. Tetrahedron  1986,  42:  6573 

3b Molander GA. Harris CR. Chem. Rev.  1996,  96:  307 

3c Molander GA. Harris CR. Tetrahedron  1998,  54:  3321 

3d Krief A. Laval A.-M. Chem. Rev.  1999,  99:  745 

3e Steel PG. J. Chem. Soc., Perkin Trans. 1  2001,  2727 

3f Hölemann A. Synlett  2001,  1497 

3g Berndt M. Gross S. Hölemann A. Reissig H.-U. Synlett  2004,  422 

3h Edmonds DJ. Procter DJ. Chem. Rev.  2004,  104:  3371 

3i Concellón JM. Rodriguez-Solla H. Chem. Soc. Rev.  2004,  33:  599 

4a Dinesh CU. Reissig H.-U. Angew. Chem. Int. Ed.  1999,  38:  789 ; Angew. Chem. 1999, 111, 874

4b Nandanan E. Dinesh CU. Reissig H.-U. Tetrahedron  2000,  56:  4267 

4c Berndt M. Reissig H.-U. Synlett  2001,  1290 

4d Gross S. Reissig H.-U. Synlett  2002,  2027 

4e Gross S. Reissig H.-U. Org. Lett.  2003,  5:  4305 

4f Berndt M. Hlobilová I. Reissig H.-U. Org. Lett.  2004,  6:  957 

4g Hölemann A. Reissig H.-U. Synlett  2004,  2732 

4h Blot V. Reissig H.-U. Synlett  2006,  2763 

4i Blot V. Reissig H.-U. Eur. J. Org. Chem.  2006,  4989 

4j Reissig H.-U. Khan FA. Czerwonka R. Dinesh CU. Shaikh AL. Zimmer R. Eur. J. Org. Chem.  2006,  4419 

4k Aulenta F. Berndt M. Brüdgam I. Hartl H. Sörgel S. Reissig H.-U. Chem. Eur. J.  2007,  13:  6047 

4l Wefelscheid UK. Reissig H.-U. Adv. Synth. Catal.  2008,  350:  65 

4m

Aulenta, F.; Wefelscheid, U. K.; Reissig, H.-U. Eur. J. Org. Chem. 2008, in press.

For related phenyl-carbonyl coupling reactions, see:

5a Schmalz HG. Siegel S. Bats JW. Angew. Chem., Int. Ed. Engl.  1995,  34:  2383 ; Angew. Chem. 1995, 107, 2597

5b Shiue J.-S. Lin M.-H. Fang J.-M. J. Org. Chem.  1997,  62:  46 

5c Kuo CH.-W. Fang J.-M. Synth. Commun.  2001,  31:  877 

5d Schmalz H.-G. Kiehl O. Gotov B. Synlett  2002,  1253 

5e Ohno H. Maeda S.-i. Okumura M. Wakayama R. Tanaka T. Chem. Commun.  2002,  316 

5f Ohno H. Okumura M. Maeda S.-i. Iwasaki H. Wakayama R. Tanaka T. J. Org. Chem.  2003,  68:  7722 

5g Ohno H. Wakayama R. Maeda S.-i. Iwasaki H. Okumura M. Iwata C. Mikamiyama H. Tanaka T.
J. Org. Chem.  2003,  68:  5909 

The addition of HMPA as an additive strongly raises the reduction potential of samarium diiodide and is generally required for ketyl coupling reactions. See:

6a Inanaga J. Ishikawa M. Yamaguchi M. Chem. Lett.  1987,  1485 

6b Prasard E. Flowers RA. J. Am. Chem. Soc.  2002,  124:  6895 

6c Flowers RA. Xu X. Timmons C. Li G. Eur. J. Org. Chem.  2004,  2988 

6d Dahlén A. Hilmersson G. Eur. J. Inorg. Chem.  2004,  3393 

7

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): ν_max = 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.

For reviews on organocatalysis, see:

8a List B. Synlett  2001,  1675 

8b List B. Tetrahedron  2002,  58:  5573 

8c Alcaide B. Almendros P. Angew. Chem. Int. Ed.  2003,  42:  858 

8d List, B. Acc. Chem. Res. 2004, 37, 548

8e For literature in proline-catalyzed Mannich reactions, see: Notz W. Tanaka F. Barbas CF. Acc. Chem. Res.  2004,  37:  580 

8f Ibrahem I. Casas J. Córdova A. Angew. Chem. Int. Ed.  2004,  43:  6528 

8g Ibrahem I. Zou W. Casas J. Sundén H. Córdova A. Tetrahedron  2006,  62:  357 

8h Rodríguez B. Bolm C. J. Org. Chem.  2006,  71:  2888 

8i Ting A. Schaus SE. Eur. J. Org. Chem.  2007,  5797 

9

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): ν_max = 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.

10 For a recent example of stereoselective dihydroxylation, see ref. 4l; for a review dealing with directed dihydroxylation reactions, see: Donohoe TJ. Synlett  2002,  1223 

11

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:
[phone]; email: [e-mail]].

12 Wei H.-L. Yan Z.-Y. Niu Y.-N. Li G.-Q. Liang Y.-M. J. Org. Chem.  2007,  72:  8600 

For the use of DMPU, see:

13a Curran DP. Wolin RL. Synlett  1991,  317 

13b For the use of DMI, see: Inokuchi T. J. Org. Chem.  2005,  70:  1497 

14

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.

Reviews:

15a Laschat S. Dickner T. Synthesis  2000,  1781 

15b Buffat MGP. Tetrahedron  2004,  60:  1701 

15c Hsung RP. Kurdyumov AV. Sydorenko N. Eur. J. Org. Chem.  2005,  23