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

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.

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

References

Reviews:

<A NAME="RG04004ST-1A">1a</A> Zimmer R. Synthesis  1993,  165 

<A NAME="RG04004ST-1B">1b</A> Reissig H.-U. Hormuth S. Schade W. Okala Amombo GM. Watanabe T. Pulz R. Hausherr A. Zimmer R. J. Heterocycl. Chem.  2000,  37:  597 

<A NAME="RG04004ST-1C">1c</A> Reissig H.-U. Schade W. Okala Amombo GM. Pulz R. Hausherr A. Pure Appl. Chem.  2002,  74:  175 

<A NAME="RG04004ST-2A">2a</A> Hoff S. Brandsma L. Arens JF. Recl. Trav. Chim. Pays-Bas  1968,  87:  916 

<A NAME="RG04004ST-2B">2b</A> Hoff S. Brandsma L. Arens JF. Recl. Trav. Chim. Pays-Bas  1968,  87:  1179 

<A NAME="RG04004ST-2C">2c</A> Hoff S. Brandsma L. Arens JF. Recl. Trav. Chim. Pays-Bas  1969,  88:  609 

<A NAME="RG04004ST-2D">2d</A> Hormuth S. Reissig H.-U. J. Org. Chem.  1994,  59:  67 

<A NAME="RG04004ST-3A">3a</A> Schade W. Reissig H.-U. Synlett  1999,  632 

<A NAME="RG04004ST-3B">3b</A> Pulz R. Cicchi S. Brandi A. Reissig H.-U. Eur. J. Org. Chem.  2003,  1153 

<A NAME="RG04004ST-4A">4a</A> Okala Amombo GM. Hausherr A. Reissig H.-U. Synlett  1999,  1871 

<A NAME="RG04004ST-4B">4b</A> In their seminal report about the addition of lithiated methoxyallene to SAMP-hydrazones leading to enantiopure 3-pyrrolines, Goré et al. state that they did not receive satisfactory results with silyl imines. No further details about the problems are discussed in this publication: Breuil-Desvergnes V. Compain P. Vatéle J.-M. Goré J. Tetrahedron Lett.  1999,  40:  5009 

<A NAME="RG04004ST-5">5</A> Flögel O. Okala Amombo GM. Reissig H.-U. Zahn G. Brüdgam I. Hartl H. Chem.-Eur. J.  2003,  9:  1405 

<A NAME="RG04004ST-6A">6a</A> Krüger C. Rochow EG. Wannagat U. Chem. Ber.  1963,  96:  2132 

<A NAME="RG04004ST-6B">6b</A> Hart DJ. Kanai K. Thomas DG. Yang T.-K. J. Org. Chem.  1983,  48:  289 

<A NAME="RG04004ST-6C">6c</A> Cainelli G. Giacomini D. Panunzio M. Martelli G. Spunta G. Tetrahedron Lett.  1987,  28:  5369 

<A NAME="RG04004ST-7">7</A>

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.

<A NAME="RG04004ST-8">8</A>

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

<A NAME="RG04004ST-9">9</A>

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 (m_c, 1 H, Ar), 6.04-5.93 (m, 2 H, Ar), 5.41, 5.31 (2 s_br, 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.

<A NAME="RG04004ST-10">10</A> For an interesting review also regarding natural products incorporating bispyrrole substructures: Fürstner A. Angew. Chem. Int. Ed.  2003,  42:  3582 ; Angew. Chem. 2003, 115, 3706

<A NAME="RG04004ST-11">11</A>

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.

Reviews:

<A NAME="RG04004ST-12">12</A> (a) Gossauer A. Methoden der Organischen Chemie (Houben-Weyl)  1994,  4th ed., Vol. E6a/1:  556-798  

(b) Comprehensive Heterocyclic Chemistry   Vol. 2:  Katritzky A. Rees CW. Scriven EFV. Pergamon Press; Oxford: 1996.  p.1-257  

(c) For selected examples of recent pyrrole syntheses see: von der Saal W. Reinhardt R. Stawitz J. Quast H. Eur. J. Org. Chem.  1998,  1645 

(d) Merz A. Meyer T. Synthesis  1999,  94 

(e) Dieter RK. Yu H. Org. Lett.  2000,  2:  2283 

(f) Grigg R. Savic V. Chem. Commun.  2000,  873 

(g) Ghosez L. Franc C. Denonne F. Cuisinier C. Touillaux R. Can. J. Chem.  2001,  79:  1827 

(h) Marcotte F.-A. Lubell WD. Org. Lett.  2002,  4:  2601 

(i) Friedrich M. Wächtler A. de Meijere A. Synlett  2002,  619