Synthesis of Squaric Acid Monoamides as Building Blocks for Drug Discovery

The Wren Group would like to dedicate this article to Tory May Wren who sadly passed away on the 28^th October 2022. She is a constant source of inspiration for her dad (Stephen P. Wren).

Abstract

Herein, we present a synthetic compound library comprising of 28 anilino and benzylamino monosquarate-amide derivatives. Members of this library were designed as bioisosteric replacements for groups such as the ubiquitous carboxylic acid moiety. Further to their synthesis, we have shown the potential of these chemical building blocks for the generation of additional novel compounds. This work forms part of our efforts aimed at the assembly of 96-well plates loaded with bioisosteric analogues that may be used to enrich drug discovery programs. The research presented in this work focuses on the chemistry of 3,4-dihydroxycyclobut-3-ene-1,2-dione, a known carboxylic acid bioisostere.

Key words

squaric acid - squaramide - bioisostere - carboxylic acid - compound library

Publication History

Received: 03 July 2023

Accepted after revision: 03 August 2023

Accepted Manuscript online:
04 August 2023

Article published online:
29 August 2023

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• 31 Experimental procedures are detailed in the Supporting Information. Two example syntheses are given here.Compound 26To 3,4-diethoxycyclobut-3-ene-1,2-dione (500 mg, 0.43 mL, 2.94 mmol, 1 equiv) dissolved in EtOH (15 mL) at 0 °C was added 4-hydroxyaniline (321 mg, 2.94 mmol, 1 equiv) in EtOH (10 mL). The reaction was allowed to warm to r.t. and stirred for 12 h before being concentrated under reduced pressure and purified via column chromatography (5% MeOH in DCM). The desired compound was obtained as a tan solid (311 mg, 45%); mp 208–213 °C. FTIR: ν_max = 3695 (NH), 3212 (OH stretch), 2982 (CH aromatic), 1807 (CH alkyl), 1728 (C=O) cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 10.56 (s, 1 H), 9.42 (s, 1 H), 7.14 (s, 2 H), 6.75–6.69 (m, 2 H), 4.72 (q, J = 7.1 Hz, 2 H), 1.44–1.32 (m, 3 H). ¹³C NMR (101 MHz, acetone-d ₆): δ = 155.6, 131.2, 122.5, 116.5, 70.3, 16.1. HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₂H₁₁NO₄Na: 256.0580; found: 256.0603.Compound 41To 3,4-diethoxycyclobut-3-ene-1,2-dione (500 mg, 0.43 mL, 2.94 mmol, 1 equiv) dissolved in EtOH (7 mL) was added 1-(4-bromophenyl)-N-methylmethanamine (588 mg, 0.59 mL, 2.94 mmol, 1 equiv) dropwise. The reaction was then stirred at r.t. for 24 h before being concentrated under reduced pressure and purified via column chromatography (55% EtOAc–hexane). The product was obtained as a white solid (870 mg, 91%); mp 110–114 °C. FTIR: ν_max = 2988 (NH), 2928 (CH aromatic), 1802 (CH alkyl), 1703 (C=O), 1591 (CO) cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 7.59 (d, J = 8.4 Hz, 2 H), 7.28 (d, J = 8.4 Hz, 2 H), 4.75 (s, 1 H), 4.67 (p, J = 6.8 Hz, 2 H), 4.52 (s, 1 H), 3.05 (d, J = 63.5 Hz, 3 H), 1.35 (q, J = 7.3 Hz, 3 H). ¹³C NMR (151 MHz, DMSO-d ₆): δ = 188.8, 181.6, 176.5, 171.4, 134.9, 131.7, 130.3, 130.2, 121.2, 69.2, 53.0, 36.0, 15.5. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₄H₁₅ ⁸¹BrNO₃: 326.02298; found: 326.0203.