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Article

A Convenient, Rapid, Conventional Heating Route to MIDA Boronates

by
Andrew McGown
1,†,
Anthony K. Edmonds
1,†,
Daniel Guest
1,
Verity L. Holmes
1,
Chris Dadswell
1,
Ramón González-Méndez
1,
Charles A. I. Goodall
2,
Mark C. Bagley
1,
Barnaby W. Greenland
1 and
John Spencer
1,*
1
Department of Chemistry, School of Life Sciences, University of Sussex, Brighton BN1 9QJ, UK
2
Faculty of Engineering & Science, University of Greenwich, Medway Campus, Central Avenue, Chatham Maritime, Chatham ME4 4TB, UK
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Molecules 2022, 27(16), 5052; https://doi.org/10.3390/molecules27165052
Submission received: 26 June 2022 / Revised: 11 July 2022 / Accepted: 4 August 2022 / Published: 9 August 2022
(This article belongs to the Special Issue Molecules in 2022)
Browse Figures
Review Reports Versions Notes

Abstract

:
A cheap, conventional, sealed heating reactor proved to be a useful alternative to a microwave reactor in the synthesis of a >20-member MIDA boronate library (MIDA = N-methyliminodiacetic acid). Reaction times were 10 min and work-ups were minimal, saving on energy and solvent usage.

1. Introduction

Performing chemical reactions in an efficient manner, in terms of reduced solvent and energy use and higher yields, is desirable [1,2]. These include reactions that involve late-stage functionalisation of key scaffolds or ones that “lose control” and produce a greater number of products for greater diversity for biological evaluation [3], e.g., in the synthesis of benzodiazepines or pyridine libraries [4,5,6,7]. Given that time is often a limiting factor, and a significant cost to factor in, processes that are “plug and play” and, can be carried out with little, or no, optimisation, are often de rigueur (Figure 1).
MIDA boronates occupy a central role in organic synthesis with many applications including, but not limited to, masked boronic acids in total synthesis [8,9,10]; catalysis [11,12,13,14,15,16,17], including iterative or telescopic couplings [17,18,19,20,21]; oxidation chemistry [22] or as C1 or C2 building blocks [23,24]. Although traditionally made by a Dean-Stark protocol, usually employing DMSO as solvent [25,26,27,28], many recent methods have shifted towards milder reaction conditions, more convenient work-up, purification and isolation techniques, notably to enable the synthesis of unstable esters such as 2-phenol [12] or 2-hetero-aryl MIDA analogues [29]. We wish now to disclose a conventional, sealed, heating reactor-based synthesis of MIDA boronates that offers a cheaper, effective alternative to our earlier disclosed microwave-mediated route [30]. Hereafter, we have focused our efforts mainly on a group of “off the shelf” boronic acids that were readily available in our laboratory at the time of the study. Indeed, the samples that were subjected to our new protocol were rather broad in scope, encompassing boronic acids based on an aryl 1, isoxazole 2, alkyl 3, benzimidazole, indole, pyrazole 4–6, respectively, or 1,2-methylenedioxybenzene 7 scaffolds (Figure 2).

2. Results and Discussion

For the current program, we made use of a Monowave-50 (Anton Paar), a relatively cheap, albeit low scale, alternative to a microwave reactor, which uses conventional rather than microwave heating (see Experimental Section). Reaction protocols were mainly un-optimised; 10 min, heated to 160 °C, and in DMF, and were subjected to a short work-up (Scheme 1). Starting with arylboronic acids with various steric and electronic properties, a small library of aryl MIDA boronate esters was formed in yields ranging from low (30%) to excellent (90%) (e.g., 8a and 8b, respectively). This protocol is tolerant of functional groups such as sulphonamide (8a, 8n), ester, nitrile and amide (8d, 8f, 8j and 8n respectively). The yield of 8q is inferior to a recent improved protocol using MIDA anhydride (21% vs. 81%) yet higher than the yield obtained using Dean Stark conditions starting from MIDA (0%) [29]. Similarly, 8r is formed in inferior yield compared to the recently reported improved protocol (11% vs. 92%, vs. 42% in our previous microwave route) [12,30]. A number of reactions were repeated using PEG-300 as solvent and, in general, gave slightly lower yields, except for 8l, which was formed in near quantitative yield. All compounds were isolated and fully characterised by 1H, 13C NMR spectroscopy, and HRMS.
We next focussed on heterocycle-containing boronic acids or an alkylboronic acid and synthesised the analogues 9–14 in poor to moderate yields. Analogue 9 was synthesised in lower yield than the state-of-the-art (57% vs. 75%) (Figure 3).

3. Materials and Methods

3.1. General Conditions

The Anton-Paar Monowave-50 was purchased directly from the manufacturer (https://www.anton-paar.com/uk-en/products/details/synthesis-reactor-monowave-50/, accessed on 1 June 2022). Reactions were performed behind a suitably ventilated, closed, fume hood, in small, bespoke, high-pressure, sealed vials (maximum volume is around 5 mL) on a small scale and needed to be performed by a trained chemist. Solvents, reagents and consumables, such as TLC plates, column material, were purchased from commercial suppliers and solvents/reagents were subsequently used without purification. 1H, 13C NMR spectroscopy was performed on Varian 500 MHz or 600 MHz spectrometers (Supplementary Materials) and chemical shifts are reported in ppm, usually referenced to TMS as an internal standard. LCMS measurements were performed on a Shimadzu LCMS-2020 equipped with a Gemini® 5 µm C18 110 Å column and percentage purity measurements were run over 30 minutes in water/acetonitrile with 0.1% formic acid (5 min at 5%, 5–95% over 20 min, 5 min at 95%) with the UV detector set at 254 nm. High-Resolution Accurate Mass Spectrometry measurements were taken using a Waters Xevo G2 Q-ToF HRMS (Wilmslow, Cheshire, UK), equipped with an ESI source and MassLynx software. Experimental parameters were: (1)—ESI source: capillary voltage 3.0 kV, sampling cone 35 au, extraction cone 4 au, source temperature 120 °C and desolvation gas 450 °C with a desolvation gas flow of 650 L/h and no cone gas; (2)—MS conditions: MS in resolution mode between 100 and 1500 Da. Additionally, a Waters (Wilmslow, Cheshire, UK) Acquity H-Class UHPLC chromatography pumping system with column oven was used, connected to a Waters Synapt G2 HDMS high-resolution mass spectrometer.

3.2. Experimental Procedures

MIDA Synthesis in DMF as Solvent

Typically, a boronic acid (1.0 mmol, 1.0 eq) and N-methyliminodiacetic acid (MIDA) (1.0 mmol, 1.0 eq) were dissolved in anhydrous DMF (1 mL) in a Monowave reaction vial containing a stirrer bar. The reaction mixture was heated to 160 °C at full power in the Monowave for 10 min (5 min temperature ramp followed by a 10-min hold time). Upon completion, the reaction mixture was cooled to room temperature and the DMF was removed using an Asynt Smart Evaporator (Isleham, Cambridgeshire, UK), https://www.asynt.com/product/smart-evaporator/, accessed on 1 June 2022. The resulting residue was suspended in water (5 mL) and sonicated for 10 min leading to the formation of a fine precipitate which was collected by filtration. The resulting solid was then suspended in diethyl ether (5 mL) and sonicated for a further 10 min leading to the formation of a colourless solid as pure MIDA protected boronic ester, which was collected and dried by filtration.

3.3. Molecules Synthesised

4-(6-Methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)benzenesulfonamide (8a)
Molecules 27 05052 i001
Yield = 93.5 mg (30%). 1H NMR (600 MHz, DMSO-d6) δ 7.78 (d, J = 8.1 Hz, 2H), 7.61 (d, J = 8.1 Hz, 2H), 7.34 (s, 2H), 4.35 (d, J = 17.2 Hz, 2H), 4.14 (d, J = 17.2 Hz, 2H), 2.50 (s, 3H). 13C NMR (151 MHz, DMSO-d6) δ 169.7, 144.9, 133.4, 125.1, 62.4, 48.1. HRMS (CI) [M + NH4} Predicted mass = 330.0931. Experimental mass = 330.0939.
2-(3-Fluoro-4-methoxyphenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione (8b)
Molecules 27 05052 i002
Yield = 252.7 mg (90%). 1H NMR (600 MHz, DMSO-d6) δ 7.17–7.11 (m, 3H), 4.29 (d, J = 17.2 Hz, 2H), 4.08 (d, J = 17.2 Hz, 2H), 3.82 (s, 3H), 2.49 (s, 3H). 13C NMR (151 MHz, DMSO-d6) δ 169.8, 152.5 (1JCF = 244.0 Hz) 148.1 (d, 2JCF = 10.4 Hz), 129.4 (d, 3JCF J = 3.3 Hz), 119.71 (d, 2JCF J = 15.3 Hz), 113.7, 62.2, 56.2, 48.0. HRMS [M + H] Predicted mass = 282.0949. Experimental mass = 282.0943.
2-(3-Ethoxyphenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione (8c)
Molecules 27 05052 i003
Yield = 196.9 mg (71%). 1H NMR (600 MHz, DMSO-d6) δ 7.24 (pt, J = 7.5 Hz, 1H), 6.95 (d, J = 8.0 Hz, 1H), 6.92 (d, J = 2.7 Hz, 1H), 6.89 (dd, J = 8.0, 2.7 Hz, 1H), 4.30 (d, J = 17.2 Hz, 2H), 4.08 (d, J = 17.2 Hz, 2H), 3.99 (q, J = 7.0 Hz, 2H), 2.50 (s, 3H), 1.30 (t, J = 7.0 Hz, 3H). 13C NMR (151 MHz, DMSO-d6) δ 169.9, 158.5, 129.4, 124.8, 118.6, 115.1, 63.1, 62.2, 47.9, 15.2. HRMS (CI) [M + H] Predicted mass = 278.1200. Experimental mass = 278.1200.
Methyl 4-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)benzoate (8d)
Molecules 27 05052 i004
Yield = 221.1 mg (76%). 1H NMR (600 MHz, DMSO-d6) δ 7.92 (d, J = 7.8 Hz, 2H), 7.58 (d, J = 7.8 Hz, 2H), 4.35 (d, J = 17.2 Hz, 2H), 4.13 (d, J = 17.2 Hz, 2H), 3.83 (s, 3H), 2.48 (s, 3H). 13C NMR (151 MHz, DMSO-d6) δ 169.8, 166.9, 133.3, 130.4, 128.7, 62.4, 52.6, 48.1. HMRS (ESI) [M + H] Predicted mass = 292.0992. Experimental mass = 292.0995.
6-Methyl-2-(2-(trifluoromethyl)phenyl)-1,3,6,2-dioxazaborocane-4,8-dione (8e)
Molecules 27 05052 i005
Yield = 114.3 mg (38%). 1H NMR (600 MHz, DMSO-d6) δ 7.74 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 4.5 Hz, 2H), 7.58 (m, J = 8.0, 4.5 Hz, 1H), 4.39 (d, J = 17.5 Hz, 2H), 4.17 (d, J = 17.5 Hz, 2H), 2.47 (s, 3H). 13C NMR (151 MHz, DMSO-d6) δ 169.7, 136.5, 132.7 (q, 2JCF = 30.7 Hz), 131.9, 129.9, 126.4 (q, 3JCF = 6.3 Hz), 124.1, 63.8, 49.3. HRMS (ESI) [M + H] Predicted mass = 302.0811. Experimental mass = 302.0811.
2-Fluoro-4-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)benzonitrile (8f)
Molecules 27 05052 i006
Yield = 198.0 mg (72%). 1H NMR (600 MHz, DMSO-d6) δ 7.89 (pt, J = 7.1 Hz, 1H), 7.48–7.44 (m, 2H), 4.37 (d, J = 17.2 Hz, 2H), 4.15 (d, J = 17.2 Hz, 2H), 2.55 (s, 3H). 13C NMR (151 MHz, DMSO-d6) δ 169.5, 163.3 (1JCF = 256.0 Hz), 133.5, 129.8 (d, 3JCF = 3.3 Hz), 120.4 (d, 2JCF = 17.0 Hz), 114.7, 100.8 (d, 2JCF = 15.0 Hz), 62.6, 48.2. HRMS (CI) [M + NH4] Predicted mass = 294.1061. Experimental mass = 294.1063.
2-(3-Ethoxy-4-fluorophenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione (8g)
Molecules 27 05052 i007
Yield = 208.2 mg (71%). 1H NMR (600 MHz, DMSO-d6) δ 7.19–7.10 (m, 3H), 4.31 (d, J = 17.2 Hz, 2H), 4.11 (d, J = 17.2 Hz, 2H), 4.09 (d, J = 6.9 Hz, 2H), 2.51 (s, 3H), 1.34 (t, J = 6.9 Hz, 3H). 13C NMR (151 MHz, DMSO-d6) δ 169.8, 152.6 (1JCF = 247.0 Hz), 147.4 (d, 2JCF = 10.5 Hz), 129.4 (d, 3JCF = 3.3 Hz), 119.8 (d, 2JCF = 15.7 Hz), 114.6, 64.5, 62.2, 48.0, 15.1 HRMS (ESI) [M + NH4] Predicted Mass = 313.1371. Experimental mass = 313.1376.
2-(2-Chloro-4-(trifluoromethyl)phenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione (8h)
Molecules 27 05052 i008
Yield = 245.7 mg (73%). 1H NMR (600 MHz, DMSO-d6) δ 7.80 (d, J = 8.0 Hz, 1H), 7.78 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 4.44 (d, J = 17.5 Hz, 2H), 4.19 (d, J = 17.5 Hz, 2H), 2.67 (s, 3H). 13C NMR (151 MHz, DMSO-d6) δ 169.6, 138.9, 137.5, 132.1 (q, 2JCF = 32.0 Hz), 126.7 (d, 3JCF = 3.3 Hz), 123.6 (3JCF = 3.3 Hz), 122.9, 64.3, 48.6. HRMS (CI) [M + NH4] Predicted mass = 353.0687. Experimental mass = 353.0685.
2-(2,4-Difluorophenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione (8i)
Molecules 27 05052 i009
Yield = 209.7 mg, (78%). 1H NMR (600 MHz, DMSO-d6) δ 7.25 (m, 1H), 7.16 (m, 2H), 4.40 (d, J = 17.3 Hz, 2H), 4.09 (d, J = 17.3 Hz, 2H), 2.63 (s, 3H). 13C NMR (151 MHz, DMSO-d6) δ 169.4, 162.6 (1JCF = 237.7 Hz) 159.4 (1JCF = 241.1 Hz), 121.0 (d, 2JCF = 10.8 Hz), 118.5 (dd, 2JCF = 10.2 Hz, 2JCF = 10.2 Hz), 117.4 (dd, 3JCF = 8.2 Hz, 3JCF = 8.2 Hz), 62.9, 48.0. HRMS (ESI) [M + H] Predicted mass = 270.0749. Experimental mass = 270.0743.
N-(tert-Butyl)-3-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)benzamide (8j)
Molecules 27 05052 i010
Yield = 129.0 mg (39%). 1H NMR (600 MHz, DMSO-d6) δ 7.79 (s, 1H), 7.75 (dt, J = 7.5, 1.5 Hz, 1H), 7.70 (s, 1H), 7.51 (dd, J = 7.5, 1.5 Hz, 1H), 7.38 (t, J = 7.5 Hz, 1H), 4.33 (d, J = 17.3 Hz, 2H), 4.13 (d, J = 17.3 Hz, 2H), 2.48 (s, 3H) 1.36 (s, 9H). 13C NMR (151 MHz, DMSO-d6) δ 169.9, 167.3, 135.7, 135.2, 131.7, 128.3, 127.7, 62.3, 51.2, 48.2, 29.1. HRMS (ESI) [M + H] Predicted mass = 333.1622. Experimental mass = 333.1633.
6-Methyl-2-(4-(pyrrolidine-1-carbonyl)phenyl)-1,3,6,2-dioxazaborocane-4,8-dione (8k)
Molecules 27 05052 i011
Yield = 83.2 mg (25%). 1H NMR (600 MHz, DMSO-d6) δ 7.46 (s, 4H), 4.33 (d, J = 17.2 Hz, 2H), 4.12 (d, J = 17.2 Hz, 2H), 3.43 (t, J = 7.0 Hz, 2H), 3.34 (t, J = 7.0 Hz, 2H), 2.49 (s, 3H), 1.84 (d, J = 7.0 Hz, 2H), 1.77 (m, J = 7.0 Hz, 2H). 13C NMR (151 MHz, DMSO-d6) δ 169.8, 168.8, 138.1, 132.7, 126.6, 62.3 (2C), 49.3, 48.1, 46.3, 26.4, 24.4. HRMS (ESI) [M + H] Predicted mass = 331.1465. Experimental mass = 331.1472.
2-([1,1′-Biphenyl]-3-yl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione (8l)
Molecules 27 05052 i012
Yield = 281.6 mg (86%). 1H NMR (600 MHz, DMSO-d6) δ 7.66 (m, 3H), 7.63 (d, J = 7.5 Hz, 1H), 7.45–7.35 (m, 4H), 7.34 (t, J = 7.5 Hz, 1H), 4.33 (d, J = 17.2 Hz, 2H), 4.14 (d, J = 17.2 Hz, 2H), 2.54 (s, 3H).13C NMR (151 MHz, DMSO-d6) δ 169.9, 141.1, 139.9, 132.0, 131.3, 129.3, 128.7, 127.8, 127.7, 127.3, 62.4, 48.2. HRMS (ESI) [M+H] Predicted mass = 310.1251. Experimental mass = 310.1242.
2-(3,5-bis(Trifluoromethyl)phenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione (8m)
Molecules 27 05052 i013
Yield = 311.6 mg (80%). 1H NMR (600 MHz, DMSO-d6) δ 8.10 (s, 3H), 4.40 (d, J = 17.2 Hz, 2H), 4.22 (d, J = 17.2 Hz, 2H), 2.62 (s, 3H). 13C NMR (151 MHz, DMSO-d6) δ 169.3, 133.3, 129.4 (q, 2JCF = 32.6 Hz), 126.4, 124.6, 122.8, 122.7 (q, 3JCF = 9.1 Hz), 62.7, 48.1. HRMS (CI) [M + NH4] Predicted mass = 387.0951. Experimental mass = 387.0947.
6-Methyl-2-(4-(pyrrolidin-1-ylsulfonyl)phenyl)-1,3,6,2-dioxazaborocane-4,8-dione (8n)
Molecules 27 05052 i014
Yield = 326.3 mg (84%). 1H NMR (600 MHz, DMSO-d6) δ 7.78 (d, J = 7.8 Hz, 2H), 7.69 (d, J = 7.8 Hz, 2H), 4.40 (d, J = 17.2 Hz, 2H), 4.18 (d, J = 17.2 Hz, 2H), 3.15 (s, 4H), 2.50 (s, 3H), 1.64–1.56 (m, 4H). 13C NMR (151 MHz, DMSO-d6) δ 169.7, 136.9, 133.8, 126.8, 62.4, 48.3, 48.1, 25.1. HRMS (ESI) [M + H] Predicted mass = 367.1135. Experimental mass = 367.1129.
2-(3-(tert-Butyl)phenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione (8o)
Molecules 27 05052 i015
Yield = 230.0 mg (75%). 1H NMR (600 MHz, DMSO-d6) δ 7.44 (s, 1H), 7.37 (dd, J = 7.5 Hz, 2.1 Hz, 1H), 7.26 (t, J = 7.5 Hz, 1H), 7.19 (d, J = 7.5 Hz, 1H), 4.30 (d, J = 17.2 Hz, 2H), 4.08 (d, J = 17.2 Hz, 2H), 2.46 (s, 3H), 1.26 (s, 9H). 13C NMR (151 MHz, DMSO-d6) δ 169.9, 150.0, 129.9, 129.3, 127.8, 126.1, 62.2, 48.0, 34.8, 31.7. HRMS (ESI) [M + H] Predicted mass = 290.1564. Experimental mass = 290.1568.
2-(3-(2-Methoxyethoxy)phenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione (8p)
Molecules 27 05052 i016
Yield = 199.2 mg (61%). 1H NMR (600 MHz, DMSO-d6) δ 7.25 (pt, J = 8.0 Hz, 1H), 6.96 (d, J = 7.3 Hz, 1H), 6.94 (d, J = 2.7 Hz, 1H), 6.91 (dd, J = 8.0 Hz, 1H), 4.30 (d, J = 17.2 Hz, 2H), 4.10 (J = 17.2 Hz, 2H), 4.08 (t, J = 9.0 Hz, 2H), 3.65 (t, J = 9.0 Hz, 2H), 3.29 (s, 3H), 2.49 (s, 3H). 13C NMR (151 MHz, DMSO-d6) δ 169.9, 158.4, 129.4, 125.0, 118.7, 115.2, 70.9, 67.0, 62.2, 58.6, 48.0. HRMS (ESI) [M + H] Predicted mass = 308.1305. Experimental mass = 308.1305.
6-Methyl-2-(perfluorophenyl)-1,3,6,2-dioxazaborocane-4,8-dione (8q)
Molecules 27 05052 i017
Yield = 68.2 mg (21%). 1H NMR (600 MHz, DMSO-d6) δ 4.22 (d, J = 17.2 Hz, 2H), 3.98 (d, J = 17.2 Hz, 2H), 2.79 (s, 3H). 13C NMR (151 MHz, DMSO-d6) δ 168.4, 62.6, 45.9. Aromatic carbons not observed [29].
2-(3,5-Dimethylisoxazol-4-yl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione 9
Molecules 27 05052 i018
Yield = 154.0 mg (57%). 1H NMR (600 MHz, DMSO-d6) δ 4.32 (d, J = 17.2 Hz, 2H), 4.12 (d, J = 17.2 Hz, 2H), 2.63 (s, 3H), 2.30 (s, 3H), 2.11 (s, 3H). 13C NMR (151 MHz, DMSO-d6) δ 173.8, 169.5, 162.8, 62.3, 47.5, 12.9, 12.2. [M+H] Predicted mass = 253.0996. Experimental mass = 253.1020.
6-Methyl-2-propyl-1,3,6,2-dioxazaborocane-4,8-dione 10
Molecules 27 05052 i019
Yield = 34.4 mg (17%). 1H NMR (600 MHz, DMSO-d6) δ 4.14 (d, J = 17.0 Hz, 2H), 3.94 (d, J = 17.0 Hz, 2H), 2.80 (s, 3H), 1.31–1.21 (m, 2H), 0.90 (t, J = 7.3 Hz, 3H), 0.51–0.45 (m, 2H). 13C NMR (151 MHz, DMSO-d6) δ 169.5, 61.9 (2C), 45.9, 17.9, 17.6. [M + H] Predicted mass = 200.1094. Experimental mass = 200.1094.
6-Methyl-2-(1-methyl-1H-benzo[d]imidazol-5-yl)-1,3,6,2-dioxazaborocane-4,8-dione 11
Molecules 27 05052 i020
Yield = 161.0 mg (56%). 1H NMR (600 MHz, DMSO-d6) δ 8.03 (s, 1H), 7.80 (s, 1H), 7.58 (d, J = 8.5 Hz, 1H), 7.43 (dt, J = 8.5, 1.2 Hz, 1H), 4.34 (d, J = 17.2 Hz, 2H), 4.11 (d, J = 17.2 Hz, 2H), 4.02 (s, 3H), 2.45 (s, 3H). 13C NMR (151 MHz, DMSO-d6) δ 169.9, 140.6, 133.0, 130.3, 125.8, 123.9, 109.3, 62.2, 48.0, 35.7. [M + H] Predicted mass = 288.1156. Experimental mass = 288.1161.
2-(1H-Indol-5-yl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione 12
Molecules 27 05052 i021
Yield = 142.2 mg (52%). 1H NMR (600 MHz, DMSO-d6) δ 11.03 (s, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.44 (s, 1H), 7.32 (pt, J = 2.8 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 6.38 (t, J = 2.8 Hz, 1H), 4.30 (d, J = 17.2 Hz, 2H), 4.08 (d, J = 17.2 Hz, 2H), 2.44 (s, 3H). 13C NMR (151 MHz, DMSO-d6) δ 170.0, 136.4, 128.6, 125.9, 123.1, 119.9, 115.9, 101.2, 62.0, 47.9. [M + H] Predicted exact mass = 273.1047. Experimental mass = 273.1051.
6-Methyl-2-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-1,3,6,2-dioxazaborocane-4,8-dione 13
Molecules 27 05052 i022
Yield = 21.0 mg (7%). 1H NMR (600 MHz, DMSO-d6) δ 6.72 (s, 1H), 4.38 (d, J = 17.2 Hz, 2H), 4.19 (d, J = 17.2 Hz, 2H), 3.93 (s, 3H), 2.66 (s, 3H). 13C NMR (151 MHz, DMSO-d6) δ 169.2, 140.1 (q, 2JCF = 37.3 Hz), 124.9 (q, 1JCF = 268.3 Hz), 112.2, 62.4 (2C), 47.8. [M + H] Predicted mass = 306.0873. Experimental mass = 306.0875.
2-(Benzo[d][1,3]dioxol-5-yl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione 14
Molecules 27 05052 i023
Yield = 199.1 mg (71%). 1H NMR (600 MHz, DMSO-d6) δ 6.90 (s, 1H), 6.89 (d, J = 7.9 Hz, 2H), 5.97 (s, 2H), 4.29 (d, J = 17.2 Hz, 2H), 4.06 (d, J = 17.2 Hz, 2H), 2.49 (s, 3H). 13C NMR (151 MHz, DMSO-d6) δ 169.8, 148.3, 147.4, 126.7, 112.3, 108.6, 100.9, 62.2, 47.9. HRMS (ESI) [M + H] Predicted mass = 278.0836. Experimental mass = 278.0833.
Boronic acid (1.0 mmol, 1.0 eq) and MIDA (1.0 mmol, 1.0 eq) were dissolved in PEG-300 (1 mL) in a Monowave reaction vial containing a stirrer bar. The reaction mixture was heated to 160 °C at full power in the Monowave for 10 min (5 min temperature ramp followed by a 10 min hold time) (Table 1).
Upon completion, the reaction mixture was cooled to room temperature the resulting reaction mixture was diluted in water (5 mL) and sonicated for 10 minutes leading to the formation of a fine, white precipitate which was collected by filtration. The resulting solid was then suspended in diethyl ether (5 mL) and sonicated for a further 10 min leading to the formation a white solid of pure MIDA protected boronic ester which was collected and dried by filtration.
The following compounds were made by this method.
2-(3-Ethoxyphenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione 8c
Molecules 27 05052 i024
Yield = 152.0 mg (55%). Spectral data as above.
Methyl 4-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)benzoate 8d
Molecules 27 05052 i025
Yield = 193.0 mg (67%). Spectral data as above.
2-([1,1′-biphenyl]-4-yl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione 8l
Molecules 27 05052 i026
Yield = 309.0 mg (99%). Spectral data as above.
2-(3-(tert-Butyl)phenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione 8o
Molecules 27 05052 i027
Yield = 299.0 mg (97 %). Spectral data as above.
6-Methyl-2-(Perfluorophenyl)-1,3,6,2-dioxazaborocane-4,8-dione 8q
Molecules 27 05052 i028
Yield = 68.2 mg (21%). Spectral data as above.
2-(2-Hydroxyphenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione 8r
Molecules 27 05052 i029
Work-up procedure differed from reported method as, upon the addition of water to the residue, no precipitate formed. The aqueous mixture was extracted into EtOAc (3 × 15 mL). The combined organics were then dried over MgSO4 and concentrated to dryness yielding a colourless solid. Yield = 26.2 mg (11%). 1H NMR (600 MHz, DMSO-d6) δ 9.58 (s, 1H), 7.38 (d, J = 7.2 Hz, 1H), 7.17 (t, J = 7.8 Hz, 1H), 6.81–6.73 (m, 2H), 4.33 (d, J = 17.2 Hz, 2H), 4.04 (d, J = 17.2 Hz, 2H), 2.63 (s, 3H). 13C NMR (151 MHz, DMSO-d6) δ 169.9, 160.5, 134.5, 130.8, 119.2, 115.0, 63.6, 47.6. [M + H] Predicted mass = 250.0887. Experimental mass = 250.0895.
2-(3,5-Dimethylisoxazol-4-yl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione 9
Molecules 27 05052 i030
Yield = 80.2 mg (32%). Spectral data as above.
2-(Benzo[d][1,3]dioxol-5-yl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione 14
Molecules 27 05052 i031
Yield = 187.0 mg (68%). Spectral data as above.

4. Conclusions

We have demonstrated that the use of a relatively cheap conventional heating manifold is capable of generating MIDA boronates in often good to excellent yields. Combined with a short work-up, these protocols should enable facile access to these synthetically useful building blocks.

Supplementary Materials

The following are available online at https://www.mdpi.com/article/10.3390/molecules27165052/s1, NMR and MS data for all compounds made in this study.

Author Contributions

Conceptualisation, A.M., A.K.E., M.C.B., B.W.G. and J.S.; methodology, A.M., A.K.E. and D.G. Data curation, spectroscopic and spectrometric characterisation: V.L.H., C.D. R.G.-M. and C.A.I.G.; writing—original draft preparation, J.S.; writing—review and editing, J.S. and B.W.G. All authors have read and agreed to the published version of the manuscript.

Funding

Financial support is gratefully acknowledged from the EDRF (Labfact: interReg V project 121) as well as HEIF-Covid-19 Emergency Funds (University of Sussex).

Institutional Review Board Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Byrne, F.P.; Jin, S.; Paggiola, G.; Petchey, T.H.M.; Clark, J.H.; Farmer, T.J.; Hunt, A.J.; Mcelroy, C.R.; Sherwood, J. Tools and techniques for solvent selection: Green solvent selection guides. Sustain. Chem. Processes 2016, 4, 7. [Google Scholar] [CrossRef] [Green Version]
  2. Coby, C.J.; Tu, W.-C.; Levers, O.; Bröhl, A.; Hallett, J.P. Green and Sustainable Solvents in Chemical Processes. Chem. Rev. 2018, 118, 747–800. [Google Scholar] [CrossRef]
  3. Guariento, S.; Biagetti1, M.; Ronchi, P. Non-regioselective functionalization: An underestimate chemical diversity generator in medicinal chemistry. Future Med. Chem. 2021, 13, 595–599. [Google Scholar] [CrossRef] [PubMed]
  4. Khan, R.; Boonseng, S.; Kemmitt, P.D.; Felix, R.; Coles, S.J.; Tizzard, G.J.; Williams, G.; Simmonds, O.; Harvey, J.-L.; Atack, J.; et al. Combining Sanford Arylations on Benzodiazepines with the Nuisance Effect. Adv. Synth. Catal. 2017, 359, 3261–3269. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  5. Spencer, J.; Rathnam, R.P.; Chowdhry, B.Z. 1,4-benzodiazepin-2-ones in medicinal chemistry. Future Med. Chem. 2010, 2, 1441–1449. [Google Scholar] [CrossRef]
  6. Spencer, J.; Rathnam, R.P.; Harvey, A.L.; Clements, C.J.; Clark, R.L.; Barrett, M.P.; Wong, P.E.; Male, L.; Coles, S.J.; MacKay, S.P. Synthesis and biological evaluation of 1,4-benzodiazepin-2-ones with antitrypanosomal activity. Bioorg. Med. Chem. 2011, 19, 1802–1815. [Google Scholar] [CrossRef] [PubMed]
  7. Khan Tareque, R.; Hassell-Hart, S.; Krojer, T.; Bradley, A.; Velupillai, S.; Talon, R.; Fairhead, M.; Day, I.J.; Bala, K.; Felix, R.; et al. Deliberately Losing Control of C−H Activation Processes in the Design of Small-Molecule-Fragment Arrays Targeting Peroxisomal Metabolism. ChemMedChem 2020, 15, 2513–2520. [Google Scholar] [CrossRef]
  8. Suk, J.L.; Gray, K.C.; Paek, J.S.; Burke, M.D. Simple, efficient, and modular syntheses of polyene natural products via iterative cross-coupling. J. Am. Chem. Soc. 2008, 130, 466–468. [Google Scholar] [CrossRef] [Green Version]
  9. Blair, D.J.; Chitti, S.; Trobe, M.; Kostyra, D.M.; Haley, H.M.S.; Hansen, R.L.; Ballmer, S.G.; Woods, T.J.; Wang, W.; Mubayi, V.; et al. Automated iterative Csp3–C bond formation. Nature 2022, 604, 92–97. [Google Scholar] [CrossRef] [PubMed]
  10. Lehman, J.W.; Blair, D.J.; Burke, M.D. Burke mIDA review nat rev.pdf. Nat. Rev. Chem. 2018, 2, 0115. [Google Scholar] [CrossRef] [Green Version]
  11. Yang, L.; Tan, D.H.; Fan, W.X.; Liu, X.G.; Wu, J.Q.; Huang, Z.S.; Li, Q.; Wang, H. Photochemical Radical C–H Halogenation of Benzyl N-Methyliminodiacetyl (MIDA) Boronates: Synthesis of α-Functionalized Alkyl Boronates. Angew. Chem. Int. Ed. 2021, 60, 3454–3458. [Google Scholar] [CrossRef] [PubMed]
  12. Ahn, S.J.; Lee, C.Y.; Cheon, C.H. General methods for synthesis of N-methyliminodiacetic acid boronates from unstable ortho-phenolboronic acids. Adv. Synth. Catal. 2014, 356, 1767–1772. [Google Scholar] [CrossRef]
  13. Khanizeman, R.N.; Barde, E.; Bates, R.W.; Guérinot, A.; Cossy, J. Modular access to triarylethylene units from arylvinyl MIDA boronates using a regioselective heck coupling. Org. Lett. 2017, 19, 5046–5049. [Google Scholar] [CrossRef] [PubMed]
  14. Seo, K.B.; Lee, I.H.; Lee, J.; Choi, I.; Choi, T.L. A Rational Design of Highly Controlled Suzuki-Miyaura Catalyst-Transfer Polycondensation for Precision Synthesis of Polythiophenes and Their Block Copolymers: Marriage of Palladacycle Precatalysts with MIDA-Boronates. J. Am. Chem. Soc. 2018, 140, 4335–4343. [Google Scholar] [CrossRef] [PubMed]
  15. St. Denis, J.D.; Scully, C.C.G.; Lee, C.F.; Yudin, A.K. Development of the direct Suzuki-Miyaura cross-coupling of primary B-alkyl MIDA-boronates and aryl bromides. Org. Lett. 2014, 16, 1338–1341. [Google Scholar] [CrossRef]
  16. Isley, N.A.; Gallou, F.; Lipshutz, B.H. Transforming Suzuki-Miyaura cross-couplings of MIDA boronates into a green technology: No organic solvents. J. Am. Chem. Soc. 2013, 135, 17707–17710. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  17. Close, A.J.; Kemmitt, P.; Mark Roe, S.; Spencer, J. Regioselective routes to orthogonally-substituted aromatic MIDA boronates. Org. Biomol. Chem. 2016, 14, 6751–6756. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  18. Hyodo, K.; Suetsugu, M.; Nishihara, Y. Diborylation of alkynyl MIDA boronates and sequential chemoselective suzuki-miyaura couplings: A formal carboborylation of alkynes. Org. Lett. 2014, 16, 440–443. [Google Scholar] [CrossRef]
  19. McLaughlin, M.G.; McAdam, C.A.; Cook, M.J. midas SM couplings.pdf. Org. Lett. 2015, 17, 10–13. [Google Scholar] [CrossRef] [PubMed]
  20. Grob, J.E.; Dechantsreiter, M.A.; Tichkule, R.B.; Connolly, M.K.; Honda, A.; Tomlinson, R.C.; Hamann, L.G. One-pot C-N/C-C cross-coupling of methyliminodiacetic acid boronyl arenes enabled by protective enolization. Org. Lett. 2012, 14, 5578–5581. [Google Scholar] [CrossRef] [PubMed]
  21. Muir, C.W.; Vantourout, J.C.; Isidro-Llobet, A.; Macdonald, S.J.F.; Watson, A.J.B. One-Pot Homologation of Boronic Acids: A Platform for Diversity-Oriented Synthesis. Org. Lett. 2015, 17, 6030–6033. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Castro-Godoy, W.D.; Schmidt, L.C.; Argüello, J.E. A Green Alternative for the Conversion of Arylboronic Acids/Esters into Phenols Promoted by a Reducing Agent, Sodium Sulfite. Eur. J. Org. Chem. 2019, 2019, 3035–3039. [Google Scholar] [CrossRef]
  23. Ivon, Y.M.; Mazurenko, I.V.; Kuchkovska, Y.O.; Voitenko, Z.V.; Grygorenko, O.O. Formyl MIDA Boronate: C1 Building Block Enables Straightforward Access to α-Functionalized Organoboron Derivatives. Angew. Chem. Int. Ed. 2020, 59, 18016–18022. [Google Scholar] [CrossRef] [PubMed]
  24. Lin, S.; Wang, L.; Aminoleslami, N.; Lao, Y.; Yagel, C.; Sharma, A. A modular and concise approach to MIDA acylboronates: Via chemoselective oxidation of unsymmetrical geminal diborylalkanes: Unlocking access to a novel class of acylborons. Chem. Sci. 2019, 10, 4684–4691. [Google Scholar] [CrossRef] [Green Version]
  25. Colgin, N.; Flinn, T.; Cobb, S.L. Synthesis and properties of MIDA boronate containing aromatic amino acids: New peptide building blocks. Org. Biomol. Chem. 2011, 9, 1864–1870. [Google Scholar] [CrossRef] [PubMed]
  26. Grob, J.E.; Nunez, J.; Dechantsreiter, M.A.; Hamann, L.G. One-pot reductive amination and Suzuki-Miyaura cross-coupling of formyl aryl and heteroaryl MIDA boronates in array format. J. Org. Chem. 2011, 76, 4930–4940. [Google Scholar] [CrossRef] [PubMed]
  27. Baldwin, A.F.; North, R.; Eisenbeis, S. Trace Level Quantification of Derivatized Boronic Acids by LC/MS/MS. Org. Process Res. Dev. 2019, 23, 88–92. [Google Scholar] [CrossRef]
  28. Boureghda, C.; Macé, A.; Berrée, F.; Roisnel, T.; Debache, A.; Carboni, B. Ene reactions of 2-borylated α-methylstyrenes: A practical route to 4-methylenechromanes and derivatives. Org. Biomol. Chem. 2019, 17, 5789–5800. [Google Scholar] [CrossRef] [PubMed]
  29. Kelly, A.M.; Chen, P.J.; Klubnick, J.; Blair, D.J.; Burke, M.D. A Mild Method for Making MIDA Boronates. Org. Lett. 2020, 22, 9408–9414. [Google Scholar] [CrossRef] [PubMed]
  30. Close, A.J.; Kemmitt, P.; Emmerson, M.K.; Spencer, J. Microwave-mediated synthesis of N-methyliminodiacetic acid (MIDA) boronates. Tetrahedron 2014, 70, 9125–9131. [Google Scholar] [CrossRef] [Green Version]
Molecules 27 05052 g001 550
Figure 1. Readily accessible diversifiable scaffolds.
Figure 1. Readily accessible diversifiable scaffolds.
Molecules 27 05052 g001
Molecules 27 05052 g002 550
Figure 2. Boronic acid starting materials in this study.
Figure 2. Boronic acid starting materials in this study.
Molecules 27 05052 g002
Molecules 27 05052 sch001 550
Scheme 1. Initial MIDA boronate library synthesis.a Alternative synthesis using PEG-300 solvent.
Scheme 1. Initial MIDA boronate library synthesis.a Alternative synthesis using PEG-300 solvent.
Molecules 27 05052 sch001
Molecules 27 05052 g003 550
Figure 3. Other MIDA Boronates Synthesised in DMF.
Figure 3. Other MIDA Boronates Synthesised in DMF.
Molecules 27 05052 g003
Table
Table 1. PEG-300 Procedure.
Table 1. PEG-300 Procedure.
CompoundMwEqMmolMgρµL
Boronic acid-1.01.0---
Methyliminodiacetic acid (MIDA)147.131.01.0---
PEG-300-----1000
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McGown, A.; Edmonds, A.K.; Guest, D.; Holmes, V.L.; Dadswell, C.; González-Méndez, R.; Goodall, C.A.I.; Bagley, M.C.; Greenland, B.W.; Spencer, J. A Convenient, Rapid, Conventional Heating Route to MIDA Boronates. Molecules 2022, 27, 5052. https://doi.org/10.3390/molecules27165052

AMA Style

McGown A, Edmonds AK, Guest D, Holmes VL, Dadswell C, González-Méndez R, Goodall CAI, Bagley MC, Greenland BW, Spencer J. A Convenient, Rapid, Conventional Heating Route to MIDA Boronates. Molecules. 2022; 27(16):5052. https://doi.org/10.3390/molecules27165052

Chicago/Turabian Style

McGown, Andrew, Anthony K. Edmonds, Daniel Guest, Verity L. Holmes, Chris Dadswell, Ramón González-Méndez, Charles A. I. Goodall, Mark C. Bagley, Barnaby W. Greenland, and John Spencer. 2022. "A Convenient, Rapid, Conventional Heating Route to MIDA Boronates" Molecules 27, no. 16: 5052. https://doi.org/10.3390/molecules27165052

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