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Synlett 2024; 35(20): 2496-2502
DOI: 10.1055/a-2388-9487
letter
Special Issue to Celebrate the 75th Birthday of Prof. B. C. Ranu

Acceptorless Dehydrogenation under Neat Reaction Conditions: Synthesis of 2-Aryl/Alkyl Quinazolinones Using Supported Ni NPs as Catalyst

Vageesh M.‡
,
Omkar Patil‡
,
Hima P.
,
Raju Dey∗

R.D. acknowledges the Science and Engineering Research Board (SRG/2020/002161) for funding. V.M. and H.P. are thankful to the National Institute of Technology (NIT) Calicut for their fellowship. O.P. thanks the National Institute of Technology (NIT) Calicut for the Student Innovative Project (SIP) research grant. The authors are grateful to the Department of Science and Technology, Ministry of Science and Technology, India (DST-FIST) for providing HRMS facility at the Department of Chemistry, National Institute of Technology (NIT) Calicut.
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Abstract

We report here a Ni-NPs-catalyzed one-pot synthesis of 2-alkyl/aryl quinazolinone motifs via acceptorless dehydrogenation of alcohol, condensation of an aldehyde intermediate with 2-aminobenzamide, followed by a second dehydrogenation of the cyclized intermediate. The protocol is atom-economical and require earth-abundant Ni as the catalyst. The present report involves the annulation of 2-aminobenzamide with various types of primary alcohols, including aryl/heteroaryl methanol, and aliphatic alcohols, and produces high yields of the desired products under neat conditions. The catalyst was synthesized via a high-temperature pyrolysis strategy, using ZIF-8 as the sacrificial template. The Ni NPs@N-C catalyst was characterized by XPS, HR-TEM, HAADF-STEM, XRD, and ICP-MS. The catalyst is stable even in air at room temperature and displayed excellent activity in the acceptorless dehydrogenative coupling synthesis of quinazolinones and could be recycled five times without appreciable loss of its activity.


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Key words

acceptorless dehydrogenation - alkyl/aryl quinazolinone - nitrogen-doped carbon - Ni nanoparticles - solvent-free protocol

Heterocyclic compounds are extremely important building blocks that are often used as life-saving medicines.[1] In particular, N-containing heterocycles have received considerable attention as they are present in numerous natural products and biologically active compounds.[2] Among others, quinazolinone derivatives are one of the predominant structural motifs that exhibit a broad range of biological spectra.[3] Several synthetic quinazolinone derivatives are employed as anti-HIV,[4] antifungal,[5] anti-inflammatory,[6] anticancer,[7] antimutagenic,[8] and anti insect agents.[9] On the other hand, due to high thermal stability and exceptional electronic properties, several substituted quinazolinones are used as functional materials and dyes.[10]

Over the years, many strategies like cyclooxidation[11`] [b] [c] and cascade aerobic oxidative synthesis,[11] electrochemical[12] and photochemical oxidative synthesis,[12] transition-metal-catalyzed coupling between 2-aminobenzamide and alcohols,[13] and multicomponent synthesis[14] have been extensively employed for the synthesis of the wide variety of quinazolinone moieties. However, these protocols suffer drawbacks such as the use of stoichiometric oxidizing agents,[11a] [b] sophisticated ligands,[13a] and the requirement of rare-earth transition metals as catalyst.[11a] [d]

Acceptorless dehydrogenative coupling of alcohols provides an easy and direct access to a large library of heterocycles under benign pathways, as water and H2 are the only by-products.[15] [16] Apart from atom-economy this strategy uses inexpensive and abundant alcohol as feedstock, emphasizing its importance in the current era of organic synthesis. Thus, owing to its great importance, several methods for the synthesis of quinazolinones via acceptorless dehydrogenative coupling utilizing various homogeneous catalytic systems involving transition metals, e.g. Ni,[17] Mn,[18] Co,[19] Ru,[20] Ir,[21] Pd[22], and Pt,[23] are reported in the literature. Despite several efficient homogeneous catalysts that have been reported in the synthesis of 2-alkyl/aryl-quinazolinones, homogeneous catalysts exhibit several drawbacks such as low thermal stability, poor recyclability, difficulties in separation from the products,[24] and the use of sophisticated ligands and volatile organic solvents as media.

On the other hand, metal catalysts decorated on inorganic supports often show excellent performances in terms of product selectivity, catalyst stability, and reusability in a variety of catalytic transformations.[25] However, reports on the synthesis of 2-alkyl/aryl-quinazolinones using alcohol dehydrogenation employing heterogeneous catalysts are scarce in the literature.[26] [27] Siddiki et al. developed HBEA zeolite-supported Pt metal nanoclusters for the synthesis of quinazolinone derivatives,[26] whereas Srimani and coworkers utilized Ru nanoparticles on hydrotalcite to accomplish the same (Scheme [1]).[27]

Zoom Image
Scheme 1 State of art for the synthesis of 2-aryl/alkyl quinazolinones via acceptorless dehydrogenation catalyzed by a heterogeneous catalyst

Very recently, Cai et al. reported supported Co nanoparticles as catalysts for the synthesis of 2-aryl quinazolinones starting from 2-nitrobenzonitrile as a coupling partner via tandem transfer hydrogenation in toluene media.[28] Further, the organic solvents are highly volatile, it leads to the exposure of solvents to air rapidly. Therefore, solventless synthesis gained much popularity because it directly eliminates the use of harmful and expensive volatile organic solvents.[29] We didn’t come across any reports on the synthesis of 2-aryl/alkyl quinazolinones via acceptorless dehydrogenation under solvent-free reaction conditions using an earth-abundant inexpensive Ni-based heterogeneous catalytic system. Thus, in continuation of our research interest in acceptorless dehydrogenation and borrowing hydrogenation strategies,[30] we report here the synthesis of 2-aryl/alkyl quinazolinones catalyzed by Ni nanoparticles supported on nitrogen-doped carbon (Ni NPs@N-C) under solvent-free reaction conditions. The catalyst Ni NPs@N-C was synthesized via high-temperature pyrolysis following a sacrificial template strategy.[31a] It involves the pyrolysis of Ni@ZIF-8 at 900 °C leading to the reduction of Zn+2 present in the Ni@ZIF-8 to metallic Zn.

Zoom Image
Figure 1 a) HR-TEM image of Ni NPs@N-C, b) magnified HR-TEM image of Ni NPs@N-C with an interplanar distance of 0.203 nm corresponding to the (111) plane of Ni nanoparticles, c) HAADF-STEM images of elemental mapping of Ni NPs@N-C and XPS spectra of Ni NPs@N-C catalyst, d) elemental survey, e) Ni, and f) N.

At 900 °C the evaporation of metallic Zn creates small vacancies[31] and helps Ni atoms to aggregate around it. The catalyst Ni NPs@N-C was characterized by XPS, HR-TEM, XRD, ICP-MS, HAADF-STEM and could be recycled five times without any appreciable loss of its activity (see Figure S8 in the SI). The XRD patterns of the catalyst Ni NPs@N-C (see Figure S4 in the SI) displayed major peaks at 20–30° (002) and 40–50° (101) which are characteristic peaks for graphitic carbon.[32b]

Table 1 Optimization of Reaction Conditionsa

Entry

Catalyst

Temp ( °C)

Time (h)

Yield (%)b

1

Ni NPs@N-C

110

24

12

2

Ni NPs@N-C

130

24

33

3

Ni NPs@N-C

150

24

89

4

Ni NPs@N-C

150

12

53

5

Ni NPs@N-C

150

20

76

6

N-C

150

12

33

7

Ni@ZIF-8

150

24

28

8

Ni(NO3)2 c

150

24

11

9

Ni NPs@N-C

150

24

31d

a Reaction conditions: 4-methoxybenzyl alcohol (1.5 mmol), 2-aminobenzamide (0.5 mmol), catalyst (10 mg), and Cs2CO3 (0.1 mmol, 20 mol%) were stirred under argon atmosphere for the required time using a preheated heating block.

b Yield was calculated from 1H NMR analysis using 4,4′-dimethylbiphenyl as the internal standard.

c Amount equivalent to 0.5 wt% of Ni was used.

d 4-Methoxybenzyl alcohol (0.5 mmol) and 2-aminobenzamide (0.5 mmol) were used.

Zoom Image
Scheme 2 Plausible reaction mechanism for the synthesis of 2-aryl/alkyl quinazolinones

The presence of nanoparticles with an average size of 12–15 nm and an interplanar distance of 0.203 nm which corresponds to Ni nanoparticles (Figure [1a] and 1b) was validated by HR-TEM.[32a] [33] The HAADF elemental mapping provided the distribution of the elemental ‘C’, ‘N’, and ‘Ni’ in Ni NPs@N-C (Figure [1c]). The XPS analysis was carried out to obtain insights regarding the electronic properties and oxidation state of the surface species present in the catalyst. The XPS spectra of Ni NPs@N-C in Ni region (Figure [1e]) showed two major peaks corresponding to 852.7 eV and 869.8 eV binding energy, indicating the presence of metallic Ni species.[32a] [34]. Furthermore, the XPS spectrum (Figure [1f]) at the nitrogen region indicated the presence of pyridinic N (398.4 eV), pyrrolic N (399.1 eV), graphitic N (400.9 eV), and oxidized nitrogen species which is in good agreement with the literature reports.[31] [32]

To optimize the reaction conditions, we selected 2-aminobenzamide and 4-methoxybenzyl alcohol as model substrates and varied the reaction parameters like temperature, reaction time, solvent, and catalyst support to achieve the maximum conversion as summarized in Table [1] (see also Table S1 in the SI). A complete conversion into the product with 89% of isolated yield was obtained when 0.5 mmol of 2-aminobenzamide and 4-methoxybenzyl alcohol (1.5 mmol) were stirred under neat reaction conditions for 24 h with 10 mg of Ni NPs@N-C as a catalyst (Ni loading 0.252 wt%) and 20 mol% of Cs2CO3 as base on a heating block at 150 °C (Table [1], entry 3). Lowering the reaction temperature, the amount of alcohol, or shortening the reaction time from the optimal conditions led to a decrease in the conversion and the yield of the product. Solvent screening has been performed using 1,4-dioxane, DMF, and toluene. Surprisingly, in DMF and 1,4-dioxane, the reaction failed to proceed (see Table S1, entries 9 and 10 in the SI). Additionally, in a controlled experiment with only the catalyst precursors, e.g. unpyrolyzed Ni@ZIF-8, nitrogen-doped carbon (N-C) and Ni(NO3)2 didn’t provide the significant conversion of starting material into the desired product (Table [1], entries 6–8). Thus, the aforementioned results clearly indicated that the Ni NPs play a crucial role in the catalysis. However, the role of the base is not very clear to us, and we noticed that the reaction stopped at the intermediate aldehyde step in the absence of a base (see Table S1, entry 14 in the SI). This indicates the condensation step was facilitated in the presence of the base.

Table 2 Substrate Scopea,b

3a (92%)

3b (95%)

3c (80%)

3d (91%)

3e (87%)

3f (93%)

3g (70%)

3h (73%)

3i (65%)

3j (65%)

3k (77%)

3l (80%)

3m (93%)

3n (68%)

3o (80%)

3p (83%)

a Reaction conditions: alcohol (1.5 mmol), 2-aminobenzamide (0.5 mmol), Ni NPs@N-C (10 mg, Ni loading 0.252 wt%), and Cs2CO3 (0.1 mmol, 20 mol%) were stirred under an argon atmosphere for 24 h using a heating block maintained at 150 °C (heating block temperature).

b Yield in the brackets refers to the isolated yield of compounds characterized by 1H NMR and 13C NMR spectroscopy.

The scope of the protocol was extended further with structurally different arylmethanols, heteroaryl methanols, and aliphatic alcohols which underwent acceptorless dehydrogenative coupling with 2-aminobenzamide under the standard reaction conditions to the corresponding 2-aryl/alkyl quinazolinones (Table [2]). Benzyl alcohols bearing an electron-donating group at the para, meta, and ortho positions gave the desired products in good to excellent yields (Table [2, 3b– f ]). Notably, the substrate containing halogen substituents at the ortho position also underwent clean transformation without affecting the halogen functionality (Table [2, 3g ] and 3h). Similarly, the heteroaryl methyl alcohols like furfural alcohol and thiophenyl methanol also gave the desired products in moderate yields (Table [2, 3i ] and 3j).

The strategy was further extrapolated with aliphatic alcohols which gave the desired compounds in moderate to good yields (Table [2, 3k ] and 3l). Furthermore, moderate to good yields of the corresponding quinazolinones are also obtained when substituted 2-aminobenzamides (Table [2, 3m–p ]) were used in the reaction.

To investigate the mechanistic pathway of the reaction, a series of control experiments were carried out (Table S2, NMR spectra, and Figures S9 and S10 in the SI). It was observed from control experiments that the alcohol underwent a dehydrogenation to aldehyde by the liberation of H2 gas which was detected qualitatively using gas chromatography (Figure S6 in the SI). Based on the evidence from control experiments (Table S2 in the SI) a plausible reaction mechanism is proposed in Scheme [2], where at the beginning alcohol undergoes an acceptorless dehydrogenation in the presence of Ni NPs@N-C to give the corresponding aldehyde. The aldehyde intermediate then undergoes condensation with 2-aminobenzamide followed by a second dehydrogenation to give the desired 2-aryl/alkyl quinazolinone as the product.

In conclusion, we synthesized nickel nanoparticles on nitrogen-doped carbon using high-temperature pyrolysis via a sacrificial template strategy using readily available and inexpensive precursors.[35] The catalyst Ni NPs@N-C was precisely characterized by various analytical and spectroscopic techniques, which verified the presence of Ni nanoparticles as metallic species with low metal loading. The catalyst displayed good activity in the synthesis of 2-aryl/alkyl quinazolinones via an acceptorless dehydrogenative coupling strategy using inexpensive and readily available alcohols as one of the starting materials under neat reaction conditions and could be recycled 5 times without appreciable loss in its activity. The present protocol is versatile and a wide variety of functional groups are well tolerated and provide the desired 2-aryl/alkyl quinazolinone products in good to excellent yields. To the best of our knowledge, this is the first report on the synthesis of quinazolinone derivatives via acceptorless dehydrogenative coupling using earth-abundant Ni as a heterogeneous transition-metal catalyst.


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Conflict of Interest

The authors declare no conflict of interest.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-2388-9487.
  • Supporting Information

Corresponding Author

Raju Dey
Department of Chemistry
National Institute of Technology Calicut, Kozhikode, 673601
India   

Publication History

Received: 22 June 2024

Accepted after revision: 15 August 2024

Accepted Manuscript online:
15 August 2024

Article published online:
18 September 2024

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   Permissions and Reprints All articles of this category
Zoom Image
Scheme 1 State of art for the synthesis of 2-aryl/alkyl quinazolinones via acceptorless dehydrogenation catalyzed by a heterogeneous catalyst
Zoom Image
Figure 1 a) HR-TEM image of Ni NPs@N-C, b) magnified HR-TEM image of Ni NPs@N-C with an interplanar distance of 0.203 nm corresponding to the (111) plane of Ni nanoparticles, c) HAADF-STEM images of elemental mapping of Ni NPs@N-C and XPS spectra of Ni NPs@N-C catalyst, d) elemental survey, e) Ni, and f) N.
Zoom Image
Scheme 2 Plausible reaction mechanism for the synthesis of 2-aryl/alkyl quinazolinones