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Synlett 2004(5): 0895-0897  
DOI: 10.1055/s-2004-820028
LETTER
© Georg Thieme Verlag Stuttgart · New York

Direct Synthesis of Functionalized Pyrrole Derivatives from Aldehydes, Bis(trimethylsilyl)amide and Methoxyallene

Oliver Flögel, Hans-Ulrich Reissig*
Institut für Chemie, 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 9 February 2004
Publication Date:
04 March 2004 (online)

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Abstract

In situ generation of N-trimethylsilylated imines from aldehydes and lithium bis(trimethylsilyl)amide and subsequent treatment with lithiated methoxyallene afforded after warm up of the mixture to room temperature the corresponding 3-methoxy substituted dihydropyrrole derivatives like 7. Boc-protection at the pyrrole nitrogen could smoothly be included into the reaction sequence, leading to compounds such as 8, 10, 11, and 13. This ­direct generation of functionalized and N-protected pyrrole derivatives proceeds particularly well when N-methylpyrrole-2-carbaldehyde (14) was the starting material which furnished compounds 16 to 19 in very good yields. The corresponding reaction conditions for aliphatic ­aldehydes require optimization; dihydro­pyrroles 20 and 21 were ­obtained only in low yields.

Key words

pyrroles - allenes - N-trimethylsilylated imines - [3+2] cyclization - acylation - oxidation

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7

Compound 6 was not purified since it slowly decomposes. The structural assignment is based on the NMR spectra, which show the expected signals for an allenyl amine. In addition, trimethylsilyl signals could be observed which are probably due to (Me3Si)2O.

8

Correct spectroscopic data were obtained for all new compounds. Correct elemental analyses were achieved for all stable compounds.

9

Typical Procedure, 14 → 15 → 16: N-Methylpyrrole-2-carbaldehyde (14) (0.22 mL, 222 mg, 2.04 mmol) was dissolved in THF (1 mL) and cooled to 0 °C. Lithium bis(trimethylsilyl)amide (1.06 M in THF, 2.30 mL, 2.40 mmol) was added and the reaction mixture was stirred for 0.5 h at this temperature. In a second flask to a solution of methoxyallene 1 (0.40 mL, 336 mg, 4.80 mmol) in abs. THF (10 mL) was added n-BuLi (2.5 M in n-hexane, 1.60 mL, 4.00 mmol) at -40 °C and stirred for 15 min. To this solution the freshly prepared TMS-imine was added at -40 °C via transfer syringe and the cooling bath was then removed. After stirring for 16 h the reaction mixture was quenched with NH4Cl solution (12 mL) and stirred for another 0.5 h. The aqueous phase was extracted with Et2O (3 × 20 mL), the combined organic phases were dried (MgSO4) and the solvents were removed under reduced pressure.
The crude product 15 was dissolved in CH2Cl2 (10 mL) and DMAP (24 mg, 0.20 mmol), Et3N (0.55 mL, 402 mg, 3.97 mmol) and Boc-anhydride (0.92 mL, 874 mg, 4.00 mmol) were added. After stirring for 16 h at r.t. water (20 mL) was added and the solution was extracted with CH2Cl2 (3 × 20 mL). The combined organic phases were dried with MgSO4 and the solvents were removed under reduced pressure. Product 16 was obtained as light yellow solid (455 mg, 80%, mp 74-76 °C) after column chromatography on aluminium oxide (n-hexane/EtOAc = 8:1).
Analytical data of 16:
1H NMR (250 MHz, CDCl3): d = 6.45 (mc, 1 H, Ar), 6.04-5.93 (m, 2 H, Ar), 5.41, 5.31 (2 sbr, 1 H, 2¢-H), 4.62-4.54 (m, 1 H, 4¢-H), 4.23-4.12 (m, 2 H, 5¢-H), 3.66, 3.55, 3.53 (3 s, 6 H, 2 CH3), 1.42, 1.24 [2 s, 9 H, C(CH3)3]; due to rotamers most signals showed doubling.
13C NMR (62.9 MHz, CDCl3): d = 156.1, 155.7, 153.6, 153.2 (4 s, C-3¢, CO), 130.6, 130.4 (2 s, i-Ar), 122.0, 121.6, 107.5, 106.6, 106.2 (5 d, Ar), 88.5, 88.1 (2 d, C-4¢), 78.9, 78.8 [2 s, C(CH3)3], 58.2, 57.3, 56.5 (2 d, q, C-2¢, OMe), 49.9, 49.4 (2 t, C-5¢), 33.4, 33.2 (2 q, NMe), 28.0, 27.6 [2 q, C(CH3)3]; due to rotamers most signals showed doubling.
IR (KBr): n = 3100-3005 cm-1 (=C-H), 2975-2860 (C-H), 1700 (C=O), 1665 (C=C).
C15H22N2O3 (278.4): calcd C, 64.73; H, 7.97; N, 10.06. Found: C, 64.88; H, 7.84; N, 9.86.

11

A small amount of the addition product of lithiated methoxyallene to the starting aldehyde was detected by NMR; thus, incomplete generation of the N-trimethylsilylated imines may be one of the problems when aliphatic aldehydes are employed.