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Synlett 2006(4): 0547-0550  
DOI: 10.1055/s-2006-926246
LETTER
© Georg Thieme Verlag Stuttgart · New York

A Straightforward Approach towards Piperidines via Stille Coupling and Subsequent 1,4-Addition of Amines

Sandra Dörrenbächera, Uli Kazmaier*a, Sven Rufb
a Institut für Organische Chemie, Universitaet des Saarlandes, 66123 Saarbruecken, Germany
b Chemical Sciences, Sanofi-Aventis, Industriepark Höchst, G838, 65926 Frankfurt am Main, Germany
Fax: +49(681)3022409; e-Mail: u.kazmaier@mx.uni-saarland.de;
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Publication History

Received 7 December 2005
Publication Date:
20 February 2006 (online)

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Abstract

Substituted 4-piperidones are easily obtained from alkynes via molybdenum-catalyzed regioselective hydrostannation and subsequent Stille-coupling of the vinyl stannanes obtained with α,β-unsaturated acyl chlorides. The resulting divinylketones can undergo a double 1,4-addition of amines giving rise to the required 4-piperidones. The best results are obtained if the Stille couplings and the 1,4-additions are combined in a one-pot procedure.

Key words

heterocycles - hydrostannations - piperidines - Stille couplings

19

One-Pot Stille Couplings and 1,4-Additions; General Procedure
A mixture of [allylPdCl]2 (1.8 mg, 0.005 mmol) and PPh3 (2.6 mg, 0.01 mmol) was dissolved in anhyd THF (1 mL) and stirred for at least 15 min at r.t. The freshly prepared, pale-yellow catalyst solution was added to a solution of β-stannylated allylic substrate (1 mmol) and acyl chloride (1.5 mmol) in anhyd THF (2 mL) at 60 °C. After complete cross-coupling (ca. 30-60 min) the reaction mixture was stirred for an additional 2 h at 60 °C, then amine (2 mmol) was added. After the reaction was complete (2-3 h), the solvent was evaporated, the residue was dissolved in EtOAc, and then stirred vigorously with a sat. solution of KF (2 mL) for at least 12 h. After extraction of the aqueous layer, the organic layer was washed with H2O (× 2) and dried over Na2SO4. The crude product was purified by chromatography over silica gel (hexanes-EtOAc).
10b: Diastereomer A: 1H NMR (500 MHz, CDCl3): δ = 7.78-7.80 (dd, 3 J = 5.4, 5.8 Hz, 4 J = 3.2 Hz, 5 J = 2.8 Hz, 2 H), 7.67-7.69 (dd, 3 J = 5.4 Hz, 4 J = 3.2 Hz, 2 H), 7.31 (d, 3 J = 7.3 Hz, 2 H), 7.23-7.28 (dd, 3 J = 7.3 Hz, 2 H), 7.16-7.21 (t, 3 J = 7.3 Hz, 1 H), 4.25 (dd, 2 J = 14.2 Hz, 3 J = 7.3 Hz, 1 H), 3.91 (d, 2 J = 13.6 Hz, 1 H), 3.61 (dd, 2 J = 14.2 Hz, 3 J = 7.9 Hz, 1 H), 3.44 (d, 2 J = 13.2 Hz, 1 H), 3.06-3.12 (m, 1 H), 2.96-3.02 (q, 3 J = 7.3 Hz, 1 H), 2.85 (dd, 2 J = 12.3 Hz, 3 J = 7.9 Hz, 1 H), 2.68 (dd, 2 J = 12.3 Hz, 3 J = 5.7 Hz, 1 H), 2.63 (dd, 2 J = 14.0 Hz, 3 J = 4.9 Hz, 1 H), 2.45 (dd, 2 J = 13.9 Hz, 3 J = 5.7 Hz, 1 H), 1.12 (d, 3 J = 6.7 Hz, 3 H). 13C NMR (125 MHz, CDCl3): δ = 15.8, 37.1, 47.0, 47.9, 51.9, 55.5, 57.5, 123.3, 127.1, 128.4, 128.5, 131.9, 133.9, 138.8, 168.2, 209.2. HRMS (EI): m/z calcd for C22H22N2O3: 362.4322; found: 362.1602. Diastereomer B: 1H NMR (500 MHz, CDCl3): δ = 7.75-7.78 (dd, 3 J = 3.9 Hz, 4 J = 7.2 Hz, 2 H), 7.66-7.68 (dd, 3 J = 3.9 Hz, 4 J = 6.6 Hz, 2 H), 7.24-7.29 (m, 2 H), 7.13-7.21 (m, 2 H), 7.06-7.10 (m, 1 H), 4.15 (dd, 2 J = 14.2 Hz, 3 J = 6.6 Hz, 1 H), 3.86 (d, 2 J = 13.6 Hz, 1 H), 3.58 (dd, 2 J = 14.2 Hz, 3 J = 8.4 Hz, 1 H), 3.46 (d, 2 J = 13.3 Hz, 1 H), 2.90-2.99 (m, 3 H), 2.59 (dd, 2 J = 14.2 Hz, 3 J = 4.1 Hz, 1 H), 2.29-2.35 (m, 2 H), 1.19 (d, 3 J = 6.3 Hz, 3 H). 13C NMR (125 MHz, CDCl3): δ = 18.4, 36.6, 47.9, 48.2, 53.6, 56.1, 57.3, 123.3, 127.0, 128.2, 128.7, 131.8, 134.0, 138.5, 168.1, 208.7. HRMS (EI): m/z calcd for C22H22N2O3: 362.4322; found: 362.1640.
11a: Mixture of diastereomers. 1H NMR (500 MHz, CDCl3): δ = 7.80 (d, 3 J = 5.7 Hz, 0.5 H), 7.44 (d, 3 J = 7.9 Hz, 2 H), 7.22-7.38 (m, 8.5 H), 4.43-4.46 (m, 0.5 H), 4.23-4.28 (m, 0.5 H), 3.82 (d, 2 J = 13.7 Hz, 0.5 H), 3.80 (d, 2 J = 13.7 Hz, 0.5 H), 3.54 (t, 3 J = 3.2 Hz, 0.5 H), 2.52 (t, 3 J = 3.2 Hz, 0.5 H), 3.24 (dd, 2 J = 11.3 Hz, 3 J = 6.0 Hz, 0.5 H), 3.12 (dd, 2 J = 11.4 Hz, 3 J = 6.0 Hz, 0.5 H), 2.89 (d, 2 J = 13.9 Hz, 0.5 H), 2.86 (d, 2 J = 13.6 Hz, 0.5 H), 2.70-2.83 (m, 2 H), 2.58 (dd, 2 J = 6.4 Hz, 3 J = 3.4 Hz, 0.5 H), 2.55 (dd, 2 J = 6.3 Hz, 3 J = 3.5 Hz, 0.5 H), 2.20-2.27 (m, 1 H), 2.07-2.13 (m, 1 H), 1.53-1.59 (m, 1 H), 1.38-1.47 (m, 9 H). 13C NMR (125 MHz, CDCl3): δ = 27.82/27.85/27.94, 28.16/28.60, 46.67/47.89, 50.44/50.49, 51.79/53.11, 57.65/57.84, 58.13, 69.13/69.18, 83.07/83.10, 115.75 (q, 3 J = 288 Hz), 127.16/127.20, 127.21, 128.02/128.04, 128.33/128.37, 128.52/128.45, 129.06, 138.34/138.50, 141.91/141.95, 157.08 (q, 3 J = 38 Hz), 168.98/169.23, 209.69/210.00. HRMS (EI): m/z calcd for C27H31N2O4F3: 504.5543; found: 504.2259.