Olesja
Koleda‡
ac,
Tobias
Prenzel‡
a,
Johannes
Winter‡
a,
Tomoki
Hirohata
ad,
María
de Jesús Gálvez-Vázquez
a,
Dieter
Schollmeyer
a,
Shinsuke
Inagi
d,
Edgars
Suna
c and
Siegfried R.
Waldvogel
*ab
aDepartment of Chemistry, Johannes Gutenberg University Mainz, Duesbergweg 10–14, 55128 Mainz, Germany. E-mail: waldvogel@uni-mainz.de; Web: https://www.aksw.uni-mainz.de/
bInstitute of Biological and Chemical Systems –Functional Molecular Systems (IBCS-FMS) Hermann-von-Helmholtz-Platz 1 76344 Eggenstein-Leopoldshafen, Germany
cLatvian Institute of Organic Synthesis, Aizkraukles 21, LV-1006 Riga, Latvia
dDepartment of Chemical Science and Engineering, School of Materials and Chemical Technology, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8502, Japan
First published on 16th February 2023
Cathodic synthesis provides sustainable access to 1-hydroxy- and 1-oxy-quinazolin-4-ones from easily accessible nitro starting materials. Mild reaction conditions, inexpensive and reusable carbon-based electrode materials, an undivided electrochemical setup, and constant current conditions characterise this method. Sulphuric acid is used as a simple supporting electrolyte as well as a catalyst for cyclisation. The broad applicability of this protocol is demonstrated in 27 differently substituted derivatives in high yields of up to 92%. Moreover, mechanistic studies based on cyclic voltammetry measurements highlight a selective reduction of the nitro substrate to hydroxylamine as a key step. The relevance for preparative applications is demonstrated by a 100-fold scale-up for gram-scale electrolysis.
Methaqualone (1) (Chart 1), known by its brand name Quaalude, is a hypnotic sedative that increases GABAA receptor activity.4 The drug was withdrawn from the U.S. market in 1985, primarily because of its psychologically addictive potential, widespread abuse, and illicit recreational use.5 The medication idelalisib (2) (Chart 1) is used to treat certain types of blood cancer and acts as a phosphoinositide 3-kinase inhibitor.6 This drug alone amounted to a $72 million annual revenue for Gilead Sciences, Inc.7 The naturally occurring plant alkaloid tryptanthrine (3) exhibits a broad spectrum of biological and pharmaceutical activity including antimicrobial, antiviral, anticancer, and antiparasitic properties.8 In addition, the AstraZeneca anti-metabolite and cytotoxic drug raltitrexed (4) is used in chemotherapy treatments. The folic acid analogue acts as a selective inhibitor of thymidylate synthase.9 Notably, N-oxides and N-hydroxy derivatives of these pharmaceuticals were found to be metabolites of these drugs.10,11 However, the therapeutic effects of endocyclic N-hydroxy and N-oxy compounds have not been researched to the same degree. Considering their metabolic stability and the unique features of the N–O bond, this class of novel compounds are the subject of current pharmaceutical research.12
The synthesis of N-oxides and N-hydroxy derivatives of quinazolin-4-ones is scarce in the literature and the few published examples present various challenges. The synthesis of 1-oxy-2-alkylquinazolin-4-ones was described by Tennant starting from N-(1-cyano-alkyl)-2-nitro benzamides (Scheme 1, top).13 Its base-catalysed cyclisation approach does not require additional reagents, but does use harsh reaction conditions.13 The synthesis of 1-hydroxyquinazoline-2,4-diones by Yamanaka comprises a multi-step sequence from 4-methoxyquinazoles and involves two oxidizers: hazardous monoperoxyphthalate for the generation of the 1-oxide and highly toxic chromium(VI) oxide for the oxidation of the C-2 (Scheme 1, top).14 Reductive cyclisation of nitro precursors is also known, typically via hydrogenation with expensive palladium catalysts.15 In addition, Tallec described an electrochemical synthesis within polarographic studies (Scheme 1, middle). However, highly toxic mercury electrodes were required in a sophisticated potentiostatic reaction setup that was run on a small scale with a limited scope.16
Herein, a versatile, scalable, and high-yielding electrochemical reductive cyclisation of widely available, easy to prepare, and inexpensive nitro arenes17 into 1-hydroxy-quinazolin-4-ones is presented. The method uses a simple constant current setup and applies conditions that consider sustainable and environmental aspects (Scheme 1, bottom). In particular, this methodology can easily pay off for high value-added products.18 The field of electrosynthesis is experiencing a renaissance as an alternative to conventional synthesis protocols19–21 and is emerging as a key discipline for future synthetic applications.22 The use of electric current as a reagent enables inherently safe processes by precise control of the reaction. Practically, turning off the electricity immediately stops the conversion and, unlike with traditional reagents, thermal runaway reactions are not possible. The absence of toxic and hazardous reagents and the use of sustainable electricity makes these methods almost waste- and pollutant-free, especially when solvents and supporting electrolytes are reused.23,24 However, several parameters and counter reactions seem to play a crucial role for success.25,26 Carbon-based electrode materials such as graphite, glassy carbon (GC), and boron-doped diamond (BDD) are sustainable and widely available.27 In particular, these are superior in the synthesis of pharmaceuticals or APIs where trace metal impurities must be avoided.22,28
Entry | Deviation from standard conditions | Yield 6ab/% |
---|---|---|
a Concentration of sulphuric acid in the electrolyte, obtained by using methanol and 1 M aqueous sulphuric acid (1:1 (v/v)). b Yield of 6a was determined by 1H NMR spectroscopy using 2,2-dimethylmalonic acid as internal standard. c Isolated yield. d 0.5 M AcOH/AcONa was prepared with 90 mmol acetic acid and 10 mmol sodium acetate in 100 mL of distilled water and 100 mL methanol. BDD = boron-doped diamond; GC = glassy carbon. | ||
1 | None | 91% (91%)c |
2 | 2.7 mA cm−2 | 78% |
3 | 5.7 mA cm−2 | 78% |
4 | EtOH instead of MeOH | 84% |
5 | MeCN instead of MeOH | 71% |
6 | 0.5 M acetate bufferd | 66% |
7 | Pb cathode | 27% |
8 | CuSn7Pb15 cathode | 0% |
9 | Pt cathode | 0% |
10 | Graphite cathode | 84% |
11 | GC cathode | 90% |
12 | 0.06 M 5a | 85% |
13 | 0.10 M 5a | 73% |
The starting conditions used a water–methanol mixture (1:1 (v/v)) as a green solvent capable of dissolving the nitro compound 5a. A moderate concentration of sulphuric acid (0.5 M) was used as the supporting electrolyte based on previous investigations into the concentration effect of the acidic component on the electrochemical reduction.16,33 Moreover, it was envisioned that sulphuric acid may play a dual role in the reaction since acidic media should be beneficial for cyclisation after a nitro group reduction. Taking this into account, we examined constant current electrolysis (3.7 mA cm−2 current density) of benzamide 5a in an undivided cell in water–methanol media, using a glassy carbon anode and a boron-doped diamond (BDD) cathode. BDD as a carbon-based material offers unique reactivity towards electrochemical conversion of a multitude of substrates and can be manufactured in a sustainable manner by utilizing methane as carbon source.34
To our delight, the desired 1-hydroxyquinazolinone 6a was isolated in 91% yield. Furthermore, the theoretical amount of charge required for this process (4 F) was applied and the high yield obtained shows that this process has a high current efficiency (Table 1, entry 1). The molecular structure of heterocycle 6a was confirmed by X-ray analysis of a suitable single crystal.
Deviation from the starting electrolysis conditions obtained by electrosynthetic screening resulted in lower yields.20,21,24,35 Both lower or higher current densities led to a decreased yield of 1-hydroxyquinazolinone 6a to 78% (Table 1, entries 2 and 3). Replacement of methanol with other solvents such as ethanol and acetonitrile (Table 1, entries 4 and 5) afforded the desired heterocycle 6a in slightly lower yields of 84% and 71%, respectively. Acetate buffer (Table 1, entry 6) was used as a weaker and biogenic alternative to sulphuric acid; however, the yield of 6a decreased to 66%. Substitution of BDD as cathode material for lead significantly decreased the yield of 6a to 27% (Table 1, entry 7). Furthermore, cathodic corrosion was observed resulting in the precipitation of lead salts.
More stable alternatives to lead cathodes such as leaded bronzes36 (Table 1, entry 8) failed entirely in the formation of 6a. Platinum was equally unsuccessful as cathode material (Table 1, entry 9), completely avoiding the desired reaction likely due its low overpotential for the hydrogen evolution side-reaction.37
Besides BDD, other carbon-based cathode materials such as graphite and glassy carbon provided product 6a in comparable yields of 84% and 90% (Table 1, entries 10 and 11). Nevertheless, we decided to proceed with BDD due to its sustainability and chemical durability.38 Electrolysis at higher benzamide 5a concentrations resulted in lowered yields by up to nearly 20% (Table 1, entries 12 and 13). It is likely that higher concentrations of starting material result in the formation of high molecular weight side products which were observed as a brown plaque after the electrolysis was finished.
Both the 2-unsubstituted quinazolin-4-one 6e and the 2-phenyl analogue 6h were obtained in moderate to good yields (65% and 79%, respectively). Alkene as well as a benzylic moieties, usually prone to anodic oxidation, were well tolerated in the electrochemical reduction, and the desired heterocycles 6g and 6i were obtained in 67% and 81% yield. Interestingly, even the 2-chloromethyl substituted product 6f was isolated in 24% yield despite its inherent instability.
Next, various functional groups in the aromatic subunit of 1-hydroxyquinazolin-4-ones 6j–r were tested (Chart 2, middle). In all cases, the products were obtained in good to excellent yields regardless of the substituent's electronic nature. Benzamides with an electron-donating methoxy group and an electron-withdrawing ester moiety afforded the corresponding heterocycles 6q and 6r in comparable yields (77% and 85%, respectively). Likewise, the trifluoromethyl derivative 6n and methyl quinazolin-4-ones 6o and 6p were obtained in 73–92% yield.
The 6-methyl derivative 6o is an N-hydroxy analogue of a precursor to raltitrexed (4), thus its successful formation adds industrial relevance to this transformation.39 Halides are redox-active groups in electrochemical reactions. To our delight, fluoro-, chloro- and bromo-substituted quinazolin-4-ones 6j–l were obtained in 76–85% yield. Moreover, the developed electrochemical method also afforded the iodo-substituted product 6m, albeit in moderate yield (50%) likely due to its susceptibility to oxidation.
It is noteworthy that heteroaromatic amides such as those derived from pyridines and imidazoles are applicable with the developed conditions (Chart 2, middle left). The pyrido pyrimidinone 6s was obtained in 82% yield and the bromo substituent offers availability for a variety of post-functionalization reactions. Even the N-hydroxy purine 6t was obtained in a good yield of 57%.
Furthermore, N-acetyl-N-aryl benzamides were converted into the corresponding N-oxy-quinazolin-4-ones 7a and 7b in moderate yields, likely due to their tendency to rearrangement reactions (Chart 2, middle right).40 Interestingly, 7b is a reported metabolite of methaqualone (1).10 Furthermore, tertiary amides are also suitable as substrates as exemplified by the synthesis of pyrrolidone-based N-oxy-quinazolin-4-one 7c (72%).
Finally, the presented methodology has also been applied to the synthesis of 1-hydroxy-quinazoline-2,4-diones 8a–d by electrochemical reduction of methyl-(2-nitrobenzoyl)carbamates, which gave up to 77% yield (Chart 2, bottom). Here, the unsubstituted derivative 8a had the best yield of 77%. The electron-withdrawing trifluoromethyl- and chloro-substituted products 8b and 8d were isolated in 59% and 48% yield. The methyl-substituted derivative 8c was obtained in moderate yield of 66%.
Electrolysis cell | Scale/mmol | Current (electrolysis time) | Yield 6a |
---|---|---|---|
a Constant current conditions; surface areas of the electrodes: 5 mL Teflon™ cell (1.5 cm 2), 25 mL and 100 mL glass cell (6.0 cm2), 250 mL glass cell (29.7 cm2). b GC cathode. c 0.06 M 5a. | |||
0.15 | 5.6 mA (2.9 h) | 24 mg (91%) | |
0.75 | 22.2 mA (3.6 h) | 120 mg (91%) | |
0.75b | 118 mg (89%) | ||
3.00 | 22.2 mA (14.5 h) | 481 mg (91%) | |
7.50 | 109.9 mA (7.3 h) | 1.13 g (86%) | |
15.0c | 109.9 mA (14.6 h) | 2.19 g (83%) |
Footnotes |
† Electronic supplementary information (ESI) available. CCDC 2234739. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d3sc00266g |
‡ Contributed equally. |
This journal is © The Royal Society of Chemistry 2023 |