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Synlett 2006(19): 3324-3328  
DOI: 10.1055/s-2006-951559
LETTER
© Georg Thieme Verlag Stuttgart · New York

Efficient Consecutive Alkylation-Knoevenagel Functionalisations in Formyl Aza-Heterocycles Using Supported Organic Bases

Alberto Coelhoa, Abdelaziz El-Maatouguib, Enrique Raviñab, José A. S. Cavaleiroa, Artur M. S. Silva*a
a Departamento de Química, Universidade de Aveiro, 3810-193 Aveiro, Portugal
Fax: +351(234)370084; e-Mail: arturs@dq.ua.pt;
b Departamento de Química Orgánica, Laboratorio de Química Farmacéutica, Facultad de Farmacia, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain
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Publication History

Received 8 August 2006
Publication Date:
23 November 2006 (online)

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Abstract

An efficient solution-phase parallel procedure to perform the structural diversification of some formyl aza-heterocycles employing supported organic bases (PS-BEMP, PS-TBD or Si-TBD) is described. The library synthesis is based on a consecutive alkylation-Knoevenagel functionalisation that employs alkyl halides, Michael acceptors, and malonic acid derivatives as diversity elements.

Key words

supported bases - catalysis - consecutive functionalisations - Knoevenagel condensation - Michael addition

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Relative base strength of supported bases used in this study; the pKa values reported for the conjugated acids of their corresponding non-supported analogues are: TBD: 25.44 (MeCN, 25 °C), BEMP: 27.63 (MeCN, 25 °C); see ref. 6a. Supported reagents employed in this work were purchased from Fluka (PS-BEMP), Argonaut (PS-TBD) and Silicycle (Si-TBD).

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Representative Procedure for the Alkylation-Knoevenagel (Method A) or Aza-Michael-Knoevenagel (Method B) Sequences: In a coated Kimble vial was charged a mixture of the scaffold A1-A3 (0.60 mmol) in the appropriate solvent [THF (3 mL) for A1 or A3, toluene for A2]. The supported organic base (1.5 mmol of PS-TBD 2 for method A, 0.12 mmol for method B) and the alkyl halide (0.66 mmol; method A) or the Michael acceptor (0.72 mmol; method B) were added at the appropriate temperature (40 °C for A1 and A3, r.t. for A2 in method A, 60 °C for all scaffolds in method B). The sample was vortexed for 30 min to give the corresponding N-blocked adduct. Addition of the appropriate malonic acid derivative (1.1 equiv, stirring for 4-14 h; see Figure [4] ) to the adduct at the appropriate temperature (40 °C for A1, 60 °C for A2, r.t. for A3 in method A; 50 °C, 60 °C and r.t. for A1, A2 and A3, respectively in method B) in the corresponding solvent, led to the Knoevenagel product after simple filtration of the supported reagents by a fritted syringe. Evaporation of the solvent and purification by a parallel short chromatographic filtration (on silica gel) employing a vacuum manifold (Visiprep®) to remove the small excess of malonic acid derivative afforded pure samples that were characterised by spectroscopic and analytical data.

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Complete details of the synthesis and spectral characteristics of the compounds obtained will be published elsewhere in a full paper. All compounds gave satisfactory spectral data (1H NMR, 13C NMR, FTIR, MS). Yields given correspond to the isolated pure compounds. Chromatographic filtration for all compounds was carried out using EtOAc-hexane (1:4) as eluent mixture. Selected physical and spectral data for some compounds are as follows: A1B4D3: mp 218-219 °C (i-PrOH); yield: 70%. IR (KBr): 2233 (CN), 1709 (CO), 1665 (CO), 1599 (Ar) cm-1. 1H NMR (300 MHz, CDCl3): δ = 9.12 (s, 1 H, CH), 8.88 (s, 1 H, CH), 8.47 (d, J = 8.2 Hz, 1 H, Ar), 7.50-7.64 (m, 1 H, Ar), 7.33-7.43 (m, 4 H, Ar), 7.19-7.23 (m, 3 H, Ar), 5.42 (s, 2 H, CH2), 4.34 (q, J = 7.2 Hz, 2 H, CH2), 1.35 (t, J = 7.2 Hz, 3 H, CH3). MS (70 eV): m/z (%) = 358 (11) [M+], 285 (100), 91 (16). HRMS: m/z [M+] calcd for C22H18N2O3: 358.1317; found: 358.1316. A2B4D3: mp 130-131 °C (i-PrOH); yield: 67%. IR (KBr): 2209 (CN), 1747 (CO), 1578 (Ar), 1094 (COC) cm-1. 1H NMR (300 MHz, CDCl3): δ = 8.61 (s, 1 H, CH), 8.60 (s, 1 H, CH), 7.83-7.86 (m, 1 H, Ar), 7.27-7.35 (m, 6 H, Ar), 7.15-7.18 (m, 2 H, Ar), 5.41 (s, 2 H, CH2), 4.37 (q, J = 7.1 Hz, 2 H, CH2), 1.39 (t, J = 7.1 Hz, 3 H, CH3). MS (70 eV): m/z (%) = 330 (75) [M+], 183 (1), 139 (2), 91 (100). A3B1D2: mp 220-221 °C (i-PrOH); yield: 79%. IR (KBr): 2229 (CN), 1727 (CO), 1659 (CO), 1580 (Ar), 1083 (COC) cm-1. 1H NMR (300 MHz, CDCl3): δ = 7.92 (s, 1 H, CH), 7.44-7.53 (m, 4 H, Ar + CH), 7.35-7.39 (m, 2 H, Ar), 3.92 (s, 3 H, CH3), 3.89 (s, 3 H, CH3). MS (70 eV): m/z (%) = 295 (100) [M+], 236 (100), 208 (35), 164 (30). HRMS: m/z [M+] calcd for C16H13N3O3: 295.0957; found: 295.0955. A1C4D2: mp 186-187 °C (i-PrOH); yield: 70%. IR (KBr): 2220 (CN), 1717 (CO), 1624 (CO), 1584 (Ar), 1093 (COC) cm-1. 1H NMR (300 MHz, CDCl3): δ = 9.10 (s, 1 H, CH), 8.81 (s, 1 H, CH), 8.47 (d, J = 8.2 Hz, 1 H, Ar), 7.70-7.74 (m, 1 H, Ar), 7.45-7.48 (m, 2 H, Ar), 4.54 (t, J = 6.7 Hz, 2 H, CH2), 4.15 (q, J = 7.2 Hz, 2 H, CH2), 3.86 (s, 3 H, CH3), 2.91 (t, J = 6.7 Hz, 2 H, CH2), 1.20 (t, J = 7.2 Hz, 3 H, CH3). MS (70 eV): m/z (%) = 354 (16) [M+], 323 (4), 295 (100), 267 (16). A2C1D3: mp 153-154 °C (i-PrOH); yield: 80%. IR (KBr): 2215 (CN), 1721 (CO), 1589 (Ar), 1039 (COC) cm-1. 1H NMR (300 MHz, CDCl3): δ = 8.55 (s, 1 H, CH), 8.54 (s, 1 H, CH), 7.86 (dd, J = 1.6, 5.1 Hz, 1 H, Ar), 7.35-7.45 (m, 3 H, Ar), 4.57 (t, J = 6.9 Hz, 2 H, CH2), 4.37 (q, J = 7.1 Hz, 2 H, CH2), 2.94 (t, J = 6.9 Hz, 2 H, CH2), 1.35 (t, J = 7.1 Hz, 3 H, CH3). MS (70 eV): m/z (%) = 293 (100) [M+], 253 (64), 225 (26), 179 (9). A3C2D1: mp 127-128 °C (i-PrOH); yield: 65%. IR (KBr): 2235 (CN), 1736 (COO), 1670 (CO), 1588 (Ar), 1092 (COC) cm-1. 1H NMR (300 MHz, CDCl3): δ = 7.51-7.55 (m, 5 H, Ar), 7.47 (s, 1 H, CH), 7.34 (s, 1 H, CH), 4.38 (t, J = 6.9 Hz, 2 H, CH2), 3.67 (s, 3 H, CH3), 2.90 (t, J = 6.9 Hz, 2 H, CH2). MS (70 eV): m/z (%) = 334 (22) [M+], 303 (16), 275 (26), 247 (50), 234 (100), 222 (25), 191 (23).