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Synlett 2008(8): 1250-1254  
DOI: 10.1055/s-2008-1072728
LETTER
© Georg Thieme Verlag Stuttgart · New York

Palladium-Catalyzed Amino-Heck Reaction of γ,δ-Unsaturated Ketone O-Diethylphosphinyloximes: A New Synthesis of Substituted Pyrroles and Indoles

Jia-Liang Zhu*, Yu-Hui Chan
Department of Chemistry, National Dong-Hwa University, Hualien 974, Taiwan
Fax: +886(38)633570; e-Mail: jlzhu@mail.ndhu.edu.tw;
Further Information

Publication History

Received 4 January 2008
Publication Date:
16 April 2008 (online)

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Abstract

γ,δ-Unsaturated ketone O-diethylphosphinyloximes, readily prepared from the corresponding ketones, were used as starting materials for the intramolecular amino-Heck reactions. In the presence of a catalytic amount of Pd(PPh3)4 in DBU, cyclization reactions occurred preferentially via a 5-exo fashion to afford a variety of 2-substituted 5-methyl-1H-pyrroles and several indole derivatives in moderate to high yields.

Key words

amino-Heck reaction - oximes - pyrroles - heterocycles - palladium

10

The configurations the E,Z-isomers were tentatively assigned based on the chemical shifts of the α-methylene protons on the 1H NMR spectrum.

11

General Procedure for the Preparation of Diethylphosphinyloximes from the Corresponding Ketones
To a solution of 1-phenylpent-4-en-1-one (8, 317 mg, 1.98 mmol) in MeOH (8 mL), NaOAc (179 mg, 2.18 mmol) and NH2OH·HCl (152 mg, 2.18 mmol) were successively added. The reaction mixture was stirred at 20 °C for 6 h, then diluted with CH2Cl2 (30 mL) and washed sequentially with H2O (2 × 10 mL) and sat. NaCl aq soln (10 mL). After dried over anhyd Na2SO4 and concentrated at ambient temperature, the crude hydroxyoxime was dissolved in anhyd THF (13 mL). The solution was cooled to 0 °C and added with NaH (60%, 95 mg, 2.38 mmol). Stirring was continued at 0 °C for another 20 min under N2, before (EtO)2POCl (0.61 mL, 3.96 mmol) was added dropwise in 3 min. The reaction mixture was allowed to warm to r.t. and continued to stir for 12 h. After concentration, the crude residue was subjected to chromatographic purification on silica gel (hexane-EtOAc = 5:1 and 1:1) to afford 1a as a mixture of two isomers
(E/Z = 87:13, 513 mg, 83%).
1-Phenyl-4-penten-1-one O-diethylphosphinyloxime (1a): IR (neat): 2983, 1276, 1034, 919 cm-1. 1H NMR (400 MHz, CDCl3): δ (Z-isomer) = 1.30 (td, J 1 = 7.1 Hz, J 2 = 0.7 Hz, 6 H), 2.24 (td, J 1 = 7.2 Hz, J 2 = 6.9 Hz, 2 H), 2.74 (br t, J = 7.6 Hz, 2H), 4.10-4.19 (m, 4 H), 4.96-5.09 (m, 2 H), 5.70-5.83 (m, 1 H), 7.31-7.37 (m, 2 H), 7.37-7.48 (m, 3 H); δ (E-isomer) = 1.38 (td, J 1 = 7.1 Hz, J 2 = 0.7 Hz, 6 H), 2.32 (td, J 1 = 7.8 Hz, J 2 = 6.4 Hz, 2 H), 2.95 (br t, J = 7.9 Hz, 2 H), 4.21-4.34 (m, 4 H), 5.00 (br d, J = 11.5 Hz, 1 H), 5.04 (br d, J = 17.1 Hz, 1 H), 5.82 (dm, J = 17.1 Hz, 1 H), 7.37-7.45 (m, 3 H), 7.65 (br d, J = 7.8 Hz, 2 H). 13C NMR (100 MHz, CDCl3): δ (Z-isomer) = 16.1 (d, J = 6.1 Hz), 30.2, 34.7, 64.5 (d, J = 5.5 Hz), 115.8, 127.5, 128.3, 129.6, 132.1, 136.5, 166.9 (d, J = 13.0 Hz); δ (E-isomer) = 16.2 (d, J = 6.3 Hz), 27.0, 30.5, 64.6 (d, J = 6.0 Hz), 115.8, 127.1, 128.7, 130.5, 133.6, 136.6, 166.7 (d, J = 13.4 Hz). HRMS-FAB: m/z calcd for C15H23O4NP [M + H]+: 312.1365; found: 312.1357.

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Typical Procedure of the Amino-Heck Reaction for 1a
Under a nitrogen atmosphere, Pd(PPh3)4 (89 mg, 0.08 mmol) and DBU (356 mg, 2.34 mmol) were sequentially added to a solution of 1a (120 mg, 0.39 mmol) in anhyd MeCN (19.3ml) at r.t. The resulting yellow suspension was quickly warmed to 80 °C and continued to stir for 3 h. The mixture was then filtrated through a Celite pad, washed with EtOAc and concentrated. The chromatographic purification of the crude products on aluminum oxide (hexane-EtOAc = 30:1, 10:1, and 5:1) provided 2a in 90% yield (55 mg) and 9 in 10% yield (6 mg).
5-Methyl-2-phenyl-1H-pyrrole (2a): IR (neat): 3399, 774, 751 cm-1. 1H NMR (400 MHz, CDCl3): δ = 2.36 (s, 3 H), 5.99 (m, 1 H), 6.44 (t, J = 3.0 Hz, 1 H), 7.19 (t, J = 7.3 Hz, 1 H), 7.36 (t, J = 7.8 Hz, 2 H), 7.45 (br d, J = 8.2 Hz, 2 H), 8.13 (br s, 1 H). 13C NMR (100 MHz, CDCl3): δ = 13.2, 106.2, 108.0, 123.4, 125.7, 128.9, 129.1, 130.8, 133.0. LRMS (MALDI): m/z calcd for C11H11N [M]+: 157.1; found: 157.0.
2-Phenylpyridine (9): IR (neat): 1735, 1266, 739 cm-1. 1H NMR (400 MHz, CDCl3): δ = 7.19-7.26 (m, 1 H), 7.40-7.52 (m, 3 H), 7.70-7.79 (m, 2 H), 8.00 (d, J = 7.3 Hz, 2 H), 8.70 (d, J = 4.7 Hz, 1 H). 13C NMR (100 MHz, CDCl3): δ = 120.6, 122.1, 126.9, 128.8, 129.0, 136.7, 139.4, 149.7, 157.5. LRMS (MALDI): m/z calcd. for C11H10N [M + H]+: 156.1; found: 156.1.

13

The reactions were performed similarly as indicated in ref. 12 except for adding 4 Å MS (90 mg/1 mmol) to the solution of oxime before Pd(PPh3)4 and DBU were introduced.

14

The E/Z ratios were tentatively assigned based on 1H NMR spectra.

19

As an unknown compound, the spectral data of 2-(1-heptyl)-5-methyl-1H-pyrrole (2g) are as follows: IR (neat): 3373, 2925, 2854, 765 cm-1. 1H NMR (400 MHz, CDCl3): δ = 0.89 (t, J = 6.9 Hz, 3 H), 1.22-1.39 (m, 8 H), 1.54-1.66 (m, 2 H), 2.25 (s, 3 H), 2.55 (t, J = 7.7 Hz, 2 H), 5.76 (br s, 1 H), 5.77 (br s, 1 H), 7.56 (br s, 1 H). 13C NMR (100 MHz, CDCl3):
δ = 13.0, 14.1, 22.6, 27.8, 29.1, 29.4, 29.8, 31.8, 104.8, 105.6, 125.8, 131.6. HRMS-FAB: m/z calcd for C12H20N
[M - H]+: 178.1596; found: 178.1600.