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

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.

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

References and Notes

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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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For publications related to the catalysis of Knoevenagel reaction by supported reagents, see:

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17a

www.silicycle.com.

17b

www.sigma-aldrich.com.

For publications related to the aza-Michael reaction by supported reagents, see:

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19

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).