Single cobalt atom catalysis for the construction of quinazolines and quinazolinones via the aerobic dehydrocyclization of ethanol

Abstract

The synthesis of N-heterocycles through the aerobic dehydrocyclization of ethanol is still significant and challenging since ethanol is the largest renewable small molecule feedstock but with high dehydrogenation activation energy. Herein, a single Co catalyst (Co₁@NC-50) with oxidase-like active sites (CoN₄) has been fabricated for the construction of quinazolines and quinazolinones using ethanol as the C₂-synthon. The merits of this approach include the use of air as the oxidant and abundant metal recyclable catalyst, free of additives, high step and atom economy, and broad substrate scope, showing great potential for application in drug synthesis. The mechanistic insights are also gained: (1) ethanol dehydrogenation is the rate-determining step of this reaction, which is mainly implemented by ˙O₂⁻; (2) the CoN₄ site exhibits a strong ability for adsorption of O₂ and ethanol, and it has the lowest ethanol dehydrogenation energy barrier than CuN₄ and FeN₄. To the best of our knowledge, this is the first example of single atom catalysis for the synthesis of N-heterocycles using ethanol as the C₂-synthon.

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Introduction

Ethanol is widely used in industry, medicine and daily life and is mainly produced through biomass fermentation.¹ At present, the annual production of ethanol worldwide is about 100 million tons, making it the largest renewable small molecule feedstock.² Most ethanol is used as fuel, and it can also be used as a C₂-synthon to synthesize high-value N-heterocycles since it has both electrophilic and nucleophilic sites,³ which is undoubtedly more in line with the principles of green chemistry. The construction of N-heterocyclic compounds has always been a central topic in organic synthesis.⁴ As important representatives of these compounds, quinazolines and quinazolinones have been widely used in dyes,⁵ fluorescent materials,⁶ and drugs (Fig. 1).⁷ In view of this, it is meaningful and sustainable to develop novel strategies for the construction of quinazoline and quinazolinone skeletons using ethanol as the C₂-synthon.

Fig. 1 Representative examples of quinazoline and quinazolinone drugs.

Nevertheless, most studies have focused on the dehydrogenation coupling of aromatic alcohols (benzyl alcohols, heterocyclic methanols, aryl ethanols) for the synthesis of N-heterocycles.⁸ Ethanol has much higher dehydrogenation activation energy than aromatic alcohols. For example, the bond dissociation energy of the methylene C–H bond of ethanol (403 kJ mol⁻¹) is much higher than that of benzyl alcohol (332 kJ mol⁻¹), so the construction of N-heterocycles via ethanol as a C₂-synthon is still in its infancy.

In 2015, Singh's group⁹ reported KOH-promoted synthesis of quinolines from ethanol and 2-aminobenzyl alcohols/2-aminobenzophenones. Several homogeneous transition metal catalysts, such as Co, Ir, Ru complexes¹⁰ and CuI¹¹ have also been developed for the fabrication of quinazolinones through dehydrogenative coupling strategies. However, these homogeneous catalytic systems suffer from separation difficulties and the use of stoichiometric oxidants and bases. In terms of heterogeneous catalysis, several studies have disclosed the generation of benzimidazoles,¹² but the reaction temperature is up to 180 °C. Two heterogeneous catalysts including oxygen lattice modified MoS₂ ¹³ and Ni-NiAl-LDO¹⁴ have been developed for the synthesis of methyl substituted quinolines and 1,2,3,4-tetrahydroquinolines via dehydrocyclization of ethanol (Fig. 2a). In view of the importance of quinazoline and quinazolinone frameworks and the scarcity of ethanol as a C₂-synthon for the construction of these two frameworks, it is meaningful to develop an effective and abundant transition metal heterogeneous catalyst to realize this strategy.

Fig. 2 Synthesis strategies for the construction of N-heterocycles from ethanol.

Single-atom catalysts (SACs) narrow the gap between homogeneous and heterogeneous catalyses because of their 100% metal atom utilization, uniformly adjustable active sites and the characteristics of heterogeneous catalysts.¹⁵ Among them, the single metal sites anchored on the N-doped carbon structure (M–N–C) have a MN_x coordination structure similar to active sites of many natural oxidases, which can effectively activate oxygen to form reactive oxygen species.¹⁶ More recently, cobalt catalysis has received widespread attention due to its inexpensiveness, easy availability and excellent redox properties.¹⁷ Co single atoms confined in N-doped carbon display excellent performance in many aerobic oxidations and their induced tandem reactions.¹⁸

Based on the above results, we have developed a Co single-atom anchored N-doped carbon catalyst (Co₁@NC-50) with CoN₄ sites for the coupling–annulation reaction for quinazolines and quinazolinones trigged by the aerobic oxidation of ethanol (Fig. 2b). This approach has the characteristics of high step and atom economy, a wide range of substrates, free of organic solvent and additives. To the best of our knowledge, this is the first example of single Co atom catalysis for dehydrogenation coupling of ethanol to construct N-heterocycles, providing an opportunity to study the facilitating role of Co species in the aerobic oxidation of alkyl alcohols.

Experimental

Catalyst preparation

The synthesis of Co@NC-10, Co@NC-20, Co₁@NC-50, Co@NC-50-1 and Zn@NC. Typically, 24 mmol 2-methylimidazole (2-MeIm) and 24 mmol benzylamine were dissolved in 80 mL deionized water to obtain solution A. Meanwhile, 6 mmol Zn(NO₃)₂·6H₂O and 0.12 mmol Co(NO₃)₂·6H₂O were dissolved in 80 mL deionized water to obtain solution B. Solution B was added to the above solution A, and then the resulting mixture was vigorously stirred at room temperature for 4 h. The obtained sample was centrifuged and washed with deionized water and methanol, and the collected solid sample was dried in a vacuum at 80 °C for 12 h to obtain the precursor CoZn@BZIF-50.

Other precursors including CoZn@BZIF-10, CoZn@BZIF-20 and ZIF-8 were prepared by changing the amount of Co(NO₃)₂·6H₂O (the numbers represent the molar ratios of Zn(NO₃)₂·6H₂O and Co(NO₃)₂·6H₂O). CoZn@BZIF-50-1 precursors were prepared without adding benzylamine.

Subsequently, the prepared precursors were calcined under a N₂ atmosphere at 900 °C for 2 h to obtain an N-doped carbon-based catalyst. CoZn@BZIF-10, CoZn@BZIF-20, CoZn@BZIF-50, CoZn@BZIF-50-1 and ZIF-8 were converted into Co@NC-10, Co@NC-20, Co₁@NC-50, Co@NC-50-1 and Zn@NC, respectively.

The synthesis of Fe@NC-50, Cu@NC-50 and Mo@NC-50. The synthetic procedures of Fe@NC-50, Cu@NC-50 and Mo@NC-50 were the same as that of Co₁@NC-50, except that Fe(NO₃)₃·9H₂O, Cu(NO₃)₂·3H₂O and Na₂MoO₄·2H₂O were used instead of Co(NO₃)₂·6H₂O. The naming conventions for ZIFs and Co@NC are shown in Table 1.

Table 1 The naming conventions of ZIFs and Co@NC

Entry	ZIFs	M@NC^a	Note^b
a NC means N-doped carbon. b 10, 20 and 50 are the molar ratios of Zn/M.
1	CoZn@BZIF-10	Co@NC-10	Zn/Co = 10
2	CoZn@BZIF-20	Co@NC-20	Zn/Co = 20
3	CoZn@BZIF-50	Co1@NC-50	Zn/Co = 50
4	CoZn@BZIF-50-1	Co@NC-50-1	Zn/Co = 50, no use of benzylamine
5	ZIF-8	Zn@NC	No use of Co(NO3)2·6H2O
6	FeZn@BZIF-50	Fe@NC-50	Zn/Fe = 50
7	CuZn@BZIF-50	Cu@NC-50	Zn/Cu = 50
8	MoZn@BZIF-50	Mo@NC-50	Zn/Mo = 50

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The synthesis of Co@C. 200 mg of graphite and 19.8 mg of Co(NO₃)₂·6H₂O were taken in a mortar, and the mixture was ground evenly with a small amount of ethanol as the medium. The mixture was dried in a vacuum drying oven to obtain a precursor. Subsequently, the precursor was calcined under a N₂ atmosphere at 900 °C for 2 h to obtain Co@C.

The synthesis of NC. 200 mg of graphite and 200 mg of melamine were finely ground in a mortar to obtain the precursor. Subsequently, the precursor was calcined under a N₂ atmosphere at 900 °C for 2 h to obtain NC.

Catalytic reaction

Typically, 0.2 mmol o-aminobenzyl alcohol, 2 mL ethanol, 1 mL NH₃·H₂O and 20 mg Co₁@NC-50 (2.5 mol% Co) were added to a 25 mL sealed tube. The sealed tube was placed in an oil bath preheated to 100 °C, and the reaction was stirred for 6 h. After the reaction was complete, ethyl acetate was added to dilute the reaction mixture. The diluted mixture was filtered through a bed of silica gel layered over Celite, and concentrated under reduced pressure to obtain a crude product. The crude product was purified through silica gel column chromatography using petroleum ether/ethyl acetate as the eluent with the polarity gradually increasing from 20% (ethyl acetate/petroleum ether, v/v = 2 : 8) to 70% (ethyl acetate/petroleum ether, v/v = 7 : 3).

Catalyst characterization

An N-doped carbon supported Co single atom catalyst (Co₁@NC-50) was obtained by the pyrolysis of CoZn@BZIF-50, which was derived from a one-pot self-assembly of Co(NO₃)₂·6H₂O, Zn(NO₃)₂·6H₂O, 2-MeIm and benzylamine (Fig. 3).¹⁹ The Co content of Co₁@NC-50 is about 1.48 wt% as determined by ICP-MS (Table S1†). The scanning electron microscopy (SEM) image exhibits that CoZn@BZIF-50 is in regular dodecahedral morphology (Fig. 4a). After pyrolysis at 900 °C for 2 h, Co₁@NC-50 retains the morphology of the precursor, but with partial shrinkage and shape defects (Fig. 4b). For a comparison, NC, Co@NC-10, Co@NC-20 and M@NC-50 (M = Fe, Cu and Mo) were also synthesized using a similar procedure.

Fig. 3 The strategy for the synthesis of Co₁@NC-50.

Fig. 4 SEM images of (a) CoZn@BZIF-50 and (b) Co₁@NC-50. (c) TEM image of Co₁@NC-50. (d) HAADF-STEM image of Co₁@NC-50. (e) The EDX elemental mapping images of C, N and Co of Co₁@NC-50.

The two wide peaks at 24° and 43° in the XRD pattern of Co₁@NC-50 are attributed to the (002) and (101) crystal faces of graphite-carbon materials, respectively,²⁰ and no Co characteristic diffraction peaks can be detected (Fig. S1†). There are obvious metal Co diffraction peaks at 44°, 51° and 76° (JCPDS 15-0806) in the XRD pattern of Co@NC-10 (Fig. S1†). According to the transmission electron microscopy (TEM) images, no cobalt nanoparticles are observed in Co₁@NC-50 (Fig. 4c). Co@NC-10 exhibits an irregular nanotube morphology, in which obvious cobalt nanoparticles were observed (Fig. S2†).

The porous nature of Co₁@NC-50 and Co@NC-10 was also studied by N₂ adsorption–desorption isotherm testing. Co₁@NC-50 is a type I isotherm with a BJH adsorption average pore diameter of 2.6 nm and a Brunauer–Emmett–Teller surface area (S_BET) of 1115.8 m² g⁻¹. Co@NC-10 is a type IV isotherm with a S_BET of 614.6 m² g⁻¹, and its pore diameter is 3.8 nm (Fig. S3 and Table S2†). It can be concluded that the cobalt content is inversely proportional to the dispersion of cobalt sites and the specific surface area of the catalyst. It is universally acknowledged that atomic dispersed metal sites and high S_BET are essential to improve the metal utilization rate and catalytic activity of catalysts.²¹

The surface electronic structure and chemical state of Co₁@NC-50 were analyzed by X-ray photoelectron spectroscopy (XPS). In the survey spectrum, elements including C, N, O, Co and Zn can be identified (Fig. S4a†). In the Co 2p spectrum of Co₁@NC-50, no peaks of metallic cobalt were resolved. The binding energies of 779.9 eV and 781.5 eV are assigned to Co³⁺ and Co²⁺, respectively (Fig. S4b†), manifesting its ionic Co^δ+ (2 < δ < 3).²² In the N 1s spectrum, oxidized-N (403.1 eV), graphitic-N (401.2 eV), pyrrolic-N (399.2 eV) and pyridinic-N (398.5 eV) can be detected.²³ Notably, a signal of CoN_x can be observed at 400.6 eV (Fig. S4c†), which verifies the existence of a Co–N coordination structure in the material.^23c

The Co configurations in Co₁@NC-50 is further analyzed at the atomic level by high angle annular dark-field STEM (HAADF-STEM), where a large number of bright spots marked in yellow represent a single isolated Co atom (Fig. 4d). The elements C, N and Co are uniformly distributed in Co₁@NC-50 according to the EDX elemental mapping images (Fig. 4e).²⁴

The Co site coordination structure of Co₁@NC-50 was revealed at the atomic level by the Co K-edge X-ray absorption near-edge structure (XANES) and extended X-ray absorption fine structure (EXAFS). The XANES spectrum of Co₁@NC-50 exhibits a signal distinct from that of Co foil, Co₂O₃ and CoPc (Fig. 5a). The absorption edge or the K-edge of the sample is between Co₂O₃ and CoPc, indicating that the valence state of Co in the sample is between +2 and +3. In the EXAFS spectrum, Co₁@NC-50 shows an obvious strong peak at 1.41 Å, which can be attributed to the Co–N scattering path, and there is no Co–Co coordination peak at 2.18 Å (Fig. 5b). These results demonstrate that Co species of Co₁@NC-50 mainly exists in the form of single atoms, which is consistent with HAADF-STEM and XRD results. The EXAFS spectrum of Co₁@NC-50 was analyzed using IFEFFIT fitting. The peak at 1.41 Å originates from the first-shell coordination of CoN₄, and the error of the best fitting results was within a reasonable range (Fig. 5c and Table S3†).²⁵

Fig. 5 (a) Co K-edge XANES spectra. (b) FT EXAFS spectra. (c) EXAFS curve fitting of Co₁@NC-50 in R space.

Catalytic performance

The catalytic performance of the catalyst was investigated using the annulation reaction of o-aminobenzyl alcohol, ethanol and ammonia as the model reaction (Table 2). After screening of different M@NC-50 catalysts (M = Fe, Cu, Mo), Co₁@NC-50 exhibited the best catalytic activity (entries 1–4). Other M@NC-50 displayed poor catalytic capacity for this C–N bond coupling cyclization (Table S4†). Only 9% yield of 4a was observed using Co@C as the catalyst, indicating that N-doping can effectively enhance the catalytic activity of cobalt sites (entry 5).²⁶

Table 2 Optimization of the reaction conditions^a,b

Entry	Catalyst	Atmosphere	Conv. (%)	Yield of 4a
a Reaction conditions: 1a (0.2 mmol), 2a (2 mL), 3 (1 mL), catalyst (2.5 mol% of metal), air, 100 °C, 6 h. b Yields were determined by GC using mesitylene as the internal standard. c 20 mg. d 60 °C. e 80 °C.
1	Fe@NC-50	Air	95	48
2	Cu@NC-50	Air	95	30
3	Mo@NC-50	Air	67	22
4	Co 1 @NC-50	Air	97	97
5	Co@C	Air	23	9
6	—	Air	4	—
7	NC	Air	59	20
8	Zn@NC^c	Air	64	24
9	Co@NC-50-1	Air	76	30
10	Co@NC-20	Air	96	86
11	Co@NC-10	Air	95	48
12	Co(NO3)2·6H2O	Air	96	61
13	Co(OAc)2·4H2O	Air	96	52
14	CoPc	Air	84	61
15	Co(acac)2	Air	41	15
16	Co2O3	Air	6	—
17^d	Co1@NC-50	Air	97	15
18^e	Co1@NC-50	Air	96	85
19	Co1@NC-50	N2	77	44
20	Co1@NC-50	O2	98	98

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No reaction took place in the absence of catalysts (entry 6). Poor yields of 4a were afforded in the cases of NC and Zn@NC, suggesting that Co is the main active center of this catalyst (entries 7 and 8). Compared with other Co catalysts, Co₁@NC-50 provided the best results (entries 4 and 7–16). Among them, the cobalt phthalocyanine complex (CoPc) with a CoN₄ coordination structure could not achieve the same catalytic activity as the Co₁@NC-50 catalyst. This may be related to the large specific surface area, suitable pore structure, and unique electronegativity of Co in Co₁@NC-50. Lowering the temperature is not conducive to the reaction (entries 17 and 18). The control experiments imply that molecular oxygen is necessary for the reaction (entries 19 and 20). To demonstrate the practicability of the developed synthesis methodology, compound 4a was synthesized on a gram scale using 9 mmol o-aminobenzyl alcohol (Scheme S1†), yielding a good product yield of 79%.

In order to further test the general applicability of Co₁@NC-50, a series of 2-aminoaryl alcohols and aliphatic alcohols were applied in the protocol (Scheme 1). This approach is suitable for a wider range of aliphatic alcohols including methanol, ethanol, 1-propanol, 1-butanol, 1-pentanol, 1-hexanol, 1-heptanol, 1-octanol, isoheptanol and isopropanol, all of which can covert to corresponding 2-substituted quinazolines in 31–92% isolated yields (4a–4k). Both 2-aminoaryl alcohols with electron-donating (–Me, –OMe) and weak electron-withdrawing (–F, –Cl) groups afford the desired products in medium to excellent yields (4l–4o). Generally, electron-rich 2-aminoaryl alcohols are more likely to be oxidized and coupled to trigger the reaction.²⁷ In addition, both 2-amino-3-hydroxypyridine and 1-(2-aminophenyl) ethanol could be converted to the corresponding quinazolines (4p–4r). The yield of the reaction between benzyl alcohol and o-aminobenzyl alcohol was 67% (4s).

Scheme 1 Substrate range of o-aminoalcohols 1 and alkyl alcohols 2.^a,b (a) Reaction conditions: 1 (0.2 mmol), 2 (2 mL), 3 (1 mL), Co₁@NC-50 (2.5 mol% of Co, 20 mg), 100 °C, 6 h, air. (b) Isolated yields. (c) 2 (3 eq.), 3 (6 eq.), H₂O (1 mL), 120 °C, 10 h.

2-Aminobenzophenone derivatives were also explored to obtain the quinazoline products 6 (Scheme 2). 2-Aminobenzophenones with weak electron-withdrawing (–F, –Cl, –Br) groups provide the corresponding quinazolines with high yields (6b–6e), while the strong electron withdrawing (–NO₂) group inhibits the reaction (6f).

Scheme 2 Substrate range of 2-aminobenzophenone derivatives 5.^a,b (a) Reaction conditions: 5 (0.2 mmol), 2 (2 mL), 3 (1 mL), Co₁@NC-50 (2.5 mol% of Co, 20 mg), 100 °C, 6 h, air. (b) Isolated yields.

In order to further expand the scope of this transformation, direct synthesis of quinazolinone from isatoic anhydrides was also attempted (Scheme 3). This transformation could be achieved by increasing the reaction temperature and prolonging the reaction time. A series of alkyl alcohols could react with isatoic anhydride to form corresponding coupling products (8a–8d). In addition, the electronic effect of the substituents has little effect on this reaction (8e–8j).

Scheme 3 Substrate range of isatoic anhydrides 7 and alkyl alcohols 2.^a,b (a) Reaction conditions: 1 (0.2 mmol), 2 (2 mL), 3 (1 mL), Co₁@NC-50 (2.5 mol% Co), 120 °C, 24 h, air. (b) Isolated yields.

It should be noted that the synthesis of 2-methyl-substituted quinazolines and quinazolinones have significant implications in the field of medicinal chemistry (Fig. 1). As shown in Scheme 4a, a 84% yield of 6g was produced by the annulation of (2-aminophenyl)(2-chlorophenyl)methanone, ethanol and ammonia, which can be used as an intermediate for the synthesis of ER176 (positron emission tomography (PET) radioactive ligand).²⁸8a, 8e, and 8g can serve as intermediates for the synthesis of Methaqualone (sedative-hypnotic drug),²⁹Raltitrexed (thymidylate synthase inhibitor)³⁰ and CHEMBL5087955 (epithelial growth factor receptor),³¹ respectively (Scheme 4b). Furthermore, a microtubule blocker, Verubulin8ab, was synthesized by the chlorination and amination reactions using 8a as the raw material.³²

Scheme 4 Synthesis of pharmaceutical intermediates and their isolated yields.

Catalytic mechanism

According to control experiments (Scheme S2†), compounds I–III should be the intermediates of this tandem reaction. This assumption was also verified by reaction tracking experiments (Fig. 6a). All the possible intermediates I–III can be detected by GC-MS at the initial stage of the reaction (Fig. S6†), and these compounds will gradually be consumed as the reaction continues.

Fig. 6 (a) Tracking experiments. (b) The relationship between ethanol (2–5 mmol) and ln(TOF). Reaction conditions: ammonia (1 mL), Co₁@NC-50 (2.5 mol% Co), 100 °C, 0.5 h, air. (c) The relationship between oxygen concentration (0–100%) and ln(TOF). Reaction conditions: ethanol (2 mL), ammonia (1 mL), Co₁@NC-50 (2.5 mol% Co), 100 °C, 0.5 h.

According to kinetic studies, it can be observed that (1) the ethanol concentration was positively correlated with the initial reaction rate (Fig. 6b); (2) O₂ concentration was not related to the initial reaction rate (Fig. 6c); (3) 2-aminobenzyl alcohol and ammonia were negatively correlated with the initial reaction rate (Fig. S5†). These results indicate that the activation of ethanol may be included in the rate-determining step (RDS) of the reaction.³³

To further elucidate the reaction mechanism, we conducted free radical capture (Fig. 7) and H/D kinetic isotope effect (KIE) experiments (Fig. 8a). The addition of TEMPO and t-butanol (˙OH scavenger) to the model reaction has little effects on the reaction (Fig. 7a and b). β-Carotene and p-benzoquinone (BQ) were also applied to the reaction to trap ¹O₂ ˙O₂⁻, respectively.³⁴ β-Carotene has a moderate inhibitory effect on the reaction, and only a trace amount of 4a is afforded in the presence of BQ (Fig. 7c and d). Furthermore, β-Carotene and BQ as radical scavengers were added to the reactions of III with 2, and I with 2, respectively (Fig. S7 and S8†). The inhibition of BQ on both reactions mentioned above is greater than that of β-Carotene. It can be concluded that (1) ˙O₂⁻ plays the main role in the dehydrogenation of alcohols; (2) ¹O₂ should generate ˙O₂⁻ through a single electron transfer process to achieve alcohol dehydrogenation;³⁵ (3) ˙OH is not generated during the reaction process, or it has little effect on the reaction.

Fig. 7 (a) Inhibition experiments of all free radicals, (b) ˙OH, (c) ¹O₂˙ and (d) O₂⁻. Reaction conditions: 1a (0.2 mmol), 2a (2 mL), 3 (1 mL), Co₁@NC-50 (2.5 mol% Co), 100 °C, 6 h, air, free radical scavengers (3 eq.).

Fig. 8 (a) The H/D KIE experiments. Reaction conditions: 1a (0.2 mmol), ethanol or deuterated ethanol (2 mL), NH₃·H₂O (1 mL), Co₁@NC-50 (2.5 mol% Co), 100 °C, air. (b) Energy profiles of ethanol aerobic dehydrogenation on MN₄ sites (M = Cu, Fe and Co). (c) Proposed reaction pathways.

In view of the Electron Paramagnetic Resonance (EPR) results (Fig. S9†), Cu@NC-50 produces more ¹O₂ and ˙O₂⁻ than Co₁@NC-50, while the catalytic activity of Co₁@NC-50 was better than Cu@NC-50 (Table 2, entries 2 and 4), further confirming that the O₂ activation step is not the RDS. The H/D KIE experiments were also performed to further explore the RDS of the reaction. The value of k_H/k_D is 2.71, which was calculated by parallel experiments using ethanol/deuterated ethanol as substrates (Fig. 8a), so the RDS may be the dehydrogenation of ethanol.^15b

In addition, the energy barriers of the RDS (the aerobic dehydrogenation of ethanol) on different MN₄ sites were calculated using Density Functional Theory (DFT) (Fig. 8b and S10–S12†). The order of the energy barrier is CoN₄ (2.83 eV) < FeN₄ (3.42 eV) < CuN₄ (3.44 eV), which is consistent with the experimental results (Table 2, entries 1, 2 and 4). Based on the DFT calculation results, CoN₄ has stronger adsorption for O₂ and ethanol than CuN₄ and FeN₄, which may be the main reason for the lowest energy barrier of CoN₄-catalyzed ethanol aerobic dehydrogenation.

Based on experiments and previous studies,³⁶ two possible reaction pathways are proposed for the Co-catalyzed C–N bond coupling cyclization (Fig. 8c). Initially, the CoN₄ sites activate O₂ to generate ¹O₂ and ˙O₂⁻, among which ˙O₂⁻ plays a major role in the oxidation of ethanol, while ¹O₂ generates ˙O₂⁻ through a single electron transfer process to achieve alcohol dehydrogenation.³⁵ The Co-catalyzed aerobic oxidation of 1a to afford the corresponding aldehyde I. There are two pathways for the generation of 4a from I. Path A: 2-Aminobenzonitrile (III) is formed by the ammoxidation of I. Then, III is condensed with acetaldehyde to produce the target product 4a. Path B: Intermediate II is obtained by the condensation of acetaldehyde with I. Finally, II undergoes cyclization with ammonia to yield the product 4a.

Catalyst recyclability and stability

The recyclability and reusability of Co₁@NC-50 were investigated by the model reaction. The reaction time was shortened to 3 h in order to better detect the loss of catalytic activity of the catalyst during recycling. In each catalytic cycle, the catalyst was simply separated by centrifugation, washed with ethyl acetate and reused in the next reaction after drying. Co₁@NC-50 maintained high catalytic activity (62%–69%) after 6 runs (Fig. S13†). The results of ICP-MS, TEM and XRD suggest that there is almost no loss of Co content and no aggregation of Co sites in the recovered catalyst (Table S1 and Fig. S14, S15†).

Conclusions

In conclusion, we have disclosed for the first time C–N coupling cyclization using ethanol as a C₂-synthon catalyzed by an N-doped carbon supported cobalt single atom catalyst with oxidase-like CoN₄ for the preparation of quinazolines and quinazolinones. This transformation provides several advantages including the use of air as the oxidant and abundant metal recyclability catalyst, free of additives, high step and atom economy, and a wide range of substrates (38 examples), thereby exhibiting high potential in drug synthesis. Kinetic studies suggest that the dehydrogenation of ethanol is the RDS for the reaction, and further coupling cyclization is carried out through two pathways.

Co₁@NC-50 can effectively activate O₂ to generate ¹O₂ and ˙O₂⁻, and ˙O₂⁻ plays a major role in the oxidation of ethanol. CoN₄ more easily adsorbs O₂ and ethanol and has a lower dehydrogenation energy barrier than other MN₄ (M = Cu and Fe) sites, so Co₁@NC-50 exhibits the best catalytic performance in this reaction. Furthermore, Co₁@NC-50 has good stability and recyclability, which can be recycled at least six times. This chemistry not only provides a new and sustainable access for the synthesis of N-heterocycles from ethanol, but also offers mechanistic insights into the aerobic oxidation of alkyl alcohols.

Data availability

Data are available on request from the authors.

The data that support the findings of this study are available from the corresponding author, upon reasonable request.

Conflicts of interest

There are no conflicts to declare.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d4gc04928d

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