Advanced Catalytic Approaches for Synthesizing 1,2-dihydro-1-aryl-3H-naphtho[1,2-e]-[1,3]oxazin-3-one Derivatives through Electrophilic Substitution Reactions using Mono- and Bimetallic Phosphate Catalysts: A Study of Co₃(PO₄)₂ and CoCa₃(HPO₄)(PO₄)₂(OH)

doi:10.21203/rs.3.rs-4730851/v1

This research introduces a novel catalytic approach for the synthesis of 1,3-oxazinone derivatives through a multicomponent reaction that relies on an electrophilic substitution mechanism, employing two cobalt-based phosphate catalysts. This approach, allowed us to synthesize oxazine derivatives, known for their significant biological activities, achieving impressive yields of up to 97% in a remarkably short time of only 7 minutes, all under conditions environmentally friendly according to the principles of green chemistry using the ethanol/water mixture as a green solvent. In our study, we utilized two catalysts derived from cobalt-modified phosphate, which were synthesized in our laboratory using simple methods. The first support consists of a monometallic catalyst, denoted as Co₃(PO₄)₂, whereas the second is a bimetallic phosphate catalyst modified with cobalt and calcium CoCa₃(HPO₄)(PO₄)₂(OH). Our developed methods had various advantages including simplicity of the process, rapid reaction time, simple clean-up, ability to recover and reuse the catalyst and overall simplicity. All these advantages render this developed approach effective and viable for synthesizing oxazine derivatives suitable for large-scale applications.

Phosphate catalyst

naphthoxazine

cobalt orthophosphate (Co3(PO4)2)

CoCa3(HPO4)(PO4)2(OH)

heterogeneous catalyst

One-pot condensation

Over the past decade, oxazines have garnered considerable attention within the scientific community, yet their comprehensive exploration remains relatively limited. Oxazines represent a class of heterocyclic compounds characterized by a molecular framework composed of one nitrogen atom and one oxygen atom. Their structural versatility, coupled with straightforward chemical architectures and abundant accessibility, imbue oxazines with considerable potential as reservoirs of bioactive agents, particularly molecules with acknowledged cytotoxic properties [1, 2]. In this context, several anti-cancer drugs are prepared based on oxazine derivatives [3]. In addition, these molecules have demonstrated suitable pharmacological effects, including antibacterial, antiepileptic [4], Analgesic [5], Anti-anginal [6], Anti-hypertensive, anti-osteoclastic [7], Anti-coagulant, Protein kinases [8], HIV inhibitors [9], antiviral agents, Antimicrobial agents [10], Antimalarial agents [11], Antihypertensive agents [1], and antiarrhythmic agents [12] are some of the notable categories of biologically active compounds. Additionally, molecules containing 1,3-amino oxygen functions exhibit a wide range of biological and pharmacological activities. These include nucleoside antibiotics [13] and HIV protease inhibitors [14]. Anticonvulsant, and antiparkinsonian effects [15, 16, 17]. Moreover, 1,3-oxazines derivatives can be used as intermediates in the preparation of N-substituted amino alcohols or enantioselective syntheses of chiral amines [18]. The tautomeric character of 1,3-O,N-heterocycles suggests a large number of synthetic potentials.

Due to their diverse and extensive biological activities, oxazine derivatives have garnered significant attention in the field of organic synthesis. Recently, many efforts have been made to create efficient methods for synthesizing oxazine using diverse catalytic methodologies anchored upon catalysts including phenylboronic acid [19], N,N-disulfo-1,1,3,3-tetramethylguanidinium [DSTMG]n[X] [20], graphene oxide [21], [bmim]Br [22], 4-hydroxypyridinium tetrachloride/silica gel [23], tetramethyl ammonium hydroxide [24], ZnO [25], Propylphosphonic Anhydride [26], silica-bonded S-sulfonic acid, p-TsOH [27], Cu, GO-Fe3O4–Ti^(IV) [28], and TiCl₄ [29]. However, the methods mentioned in the literature have disadvantages such as difficult reaction conditions, toxic and expensive catalysts and difficulties in processing the reactions.

Continuing our pursuit of innovative synthetic methods for creating heterocyclic compounds with potential therapeutic applications for chronic diseases such as cancer, Parkinson's disease, HIV, and Alzheimer's disease, we have turned our attention to naphthoxazinone derivatives. In this study, we aim to develop two novel synthesis methods for naphthoxazinone derivatives utilizing two newly designed catalysts [30]. These catalysts are phosphate compounds modified with cobalt and calcium, representing a new generation of heterogeneous catalysts in organic chemistry.The choice of this support is due to the effectiveness of cobalt catalysts in organic reactions [31],[32] and to enhance Moroccan phosphate in the field of catalysis.

In this section, we embark on an in-depth review of the results derived from our investigation of the catalytic prowess of two innovative heterogeneous catalysts based on cobalt-modified phosphate matrices. we delve into an in-depth discussion regarding the catalytic effectiveness of these materials in targeted chemical transformations, elucidating their potential implications for advancing green and sustainable catalytic methodologies. The catalysts used in this study were prepared in our laboratory by the coprecipitation method and they showed significant efficiency in organic synthesis [33],[34].

The choice of cobalt-modified phosphate catalysts is motivated by the exceptional catalytic properties of cobalt, which is particularly effective in organic chemistry. Indeed, cobalt presents great versatility and high catalytic activity, which makes it an element of choice for many chemical reactions. Cobalt complexes are often used because of their ability to facilitate various types of organic transformations, such as hydrogenation, oxidation, and coupling reactions[35],[36]. Additionally, cobalt-modified phosphate can provide better stability and increased selectivity in catalytic reactions, contributing to higher yields and more sustainable processes [37]. This unique combination of properties makes phosphate-modified cobalt catalysts particularly suitable for advanced applications in organic chemistry.

In pursuit of this goal, we investigated diverse reaction conditions to identify the optimal parameters for the efficient synthesis of 1,2-dihydro-1-phenyl-3H-naphtho[1,2-e]-[1, 3]oxazin-3-one (4a) from β-naphthol (1a), benzaldehyde (2a), and urea (3). First of all, the study began with a catalytic test of the two Co₃(PO₄)₂, CoCa₃(HPO₄)(PO₄)₂(OH) supports using acetonitrile as solvent at reflux temperature which indicated that the addition of one of the two supports in the reaction medium significantly improves both the kinetics and the yield of the chemical reaction, leading to the synthesis of the final product 4a with a remarkable yield of 72% using Co₃(PO₄)₂ (Table 1, entry 2) while that the use of CoCa₃(HPO₄)(PO₄)₂(OH) gives a yield of product 4a of 86% (Table 1, entry 3). The results show the catalytic efficiency of the supports used in synthesizing 1,3-oxazine derivatives. The efficiency of these catalysts is due to increased resulting catalytic properties inherent to phosphates and cobalt. However, combining calcium, cobalt, and phosphate in the bimetallic catalyst further enhances the support's effectiveness through the synergistic effect between the atoms. This synergy ensures a perfect distribution of active sites and reagents on the catalytic surface, resulting in even more efficient catalytic performance. The presence of calcium stabilizes the structure and contributes to the overall catalytic activity by facilitating better interaction between the cobalt and phosphate components. This optimized distribution and interaction improve the overall efficiency and effectiveness of the catalyst, making it a powerful tool for advancing organic synthesis. In addition, the excitation of Brønsted acid sites on the surface of the bimetallic catalyst increases its effectiveness. These acid sites play a crucial role in catalysis, as their activation enhances the catalyst's ability to facilitate proton transfer reactions, thereby improving the overall efficiency and performance of the catalytic system. This combination of synergistic atomic interactions and activated acid sites makes the bimetallic catalyst an exceptionally powerful tool in advancing organic synthesis.

Table 1

Catalytic and heterogeneity test of the catalyst
Entry	Condition^a	Time (min)	Yield (%)
1	Free-catalyst reaction	180	10
2	Co₃(PO₄)₂	20	72
3	CoCa₃(HPO₄)(PO₄)₂(OH)	20	86

^aReaction conditions

β-naphthol (1 mmol), benzaldehyde (1 mmol), and urea (1.5 mmol), 0,1 g of catalyst, acetonitrile as solvent, at reflux.

The investigation into solvent effects revealed a significant enhancement in reaction performance. Conducting the reaction in a mixture of Ethanol/Water (80%), using Co₃(PO₄)₂ as a catalyst, yielded 89%. However, employing the bimetallic catalyst (CoCa₃(HPO₄)(PO₄)₂(OH)) in the same solvent mixture improved the yield to an impressive 96%. This improvement can be attributed to the increased polarity and solubility of the reagents in the Ethanol/Water mixture. Both catalysts facilitated the synthesis of 1,3-oxazine derivatives under green, ecological conditions in minimal time.Table 2. Solvent Effect on the reaction^a kinetics and yield

Entry	Solvent	Time (min)		Temperature(°C)		Yield^b (%)
Entry	Solvent	Co₃(PO4)₂	CoCa₃(HPO₄) (PO₄)₂(OH)	Co₃(PO4)₂	CoCa₃(HPO₄) (PO₄)₂(OH)	Co₃(PO4)₂	CoCa₃(HPO₄) (PO₄)₂(OH)
1	Solvent-free conditions	90	15	110	110	40	83
2	Chloroform	30	30	reflux	reflux	78	86
3	Acetonitrile	30	20	reflux	reflux	72	80
4	DMF	70	70	reflux	reflux	62	83
5	THF	70	40	reflux	reflux	58	70
6	Dichloromethane	60	30	reflux	reflux	68	93
7	Ethanol	40	20	reflux	reflux	80	92
8	Methanol	70	20	reflux	reflux	53	82
9	Cyclohexane	120	60	reflux	reflux	17	43
10	Water	120	120	reflux	reflux	Trace	trace
11	Ethanol/water (80%)	30	15	reflux	reflux	86	95
12	Ethanol/water (80%)	30	40	t.a	t.a	Trace	29

^aReaction conditions

β-naphthol (1 mmol), benzaldehyde (1 mmol), and urea (1.5 mmol), 0,1 g of catalyst, Solvent, reflux.

We then explored the impact of different amounts of catalyst, recognizing the crucial role of catalyst active sites in triggering chemical reactions. Importantly, the success of the catalyst depends on how its active sites interact with the reactants involved in the process, thereby shedding light on key factors influencing catalyst performance [38, 39]. The results show that the reaction yield increases by increasing the mass of the catalytic support of the two catalysts used and a mass of 10 mg of Co₃(PO₄)₂ is sufficient to achieve a yield of 92% in a minimum time of 30 min, while 7 mg of CoCa₃(HPO₄)(PO₄)₂(OH) is adequate for a 97% yield in only 10 min. This means that these masses have a sufficient number of active sites to activate a large quantity of reagents and lead to the final product with excellent yield. these masses were chosen as optimal to continue this study.

The long durability of a catalyst is one of the most important properties that prove its catalytic efficiency. The experimental results show that the catalytic activity of the two catalysts was not greatly affected in terms of yields even after multiple cycles for the model reaction while the Co₃(PO₄)₂ retained its catalytic activity after 7 cycles, and the bimetallic catalyst after 8 cycles. These results are explained by the structural stability of our catalysts which was confirmed by the XRD and IR spectra of the catalysts (Fig. 3, 4) which shown that its structure remains unchanged during the study of its recovery and its reuse.

Figure 4. Comparison of FTIR spectra of the catalyst after reuse. a: FTIR spectrum of Co₃(PO₄)₂, b: FTIR spectrum of CoCa₃(HPO₄)(PO₄)₂(OH).

After optimization of the reaction conditions, we have extended our study to prepare naphthoxazine derivatives using various aryl aldehydes with electron-donating or electron-withdrawing groups to study the efficacy of this protocol (Table 3). As expected, all naphthoxazine derivatives were easily synthesized with good to excellent yields which confirms the great catalytic capacity of our support and makes this method useful for the synthesis of 1,2-dihydro-l-phenyl-3H-naphth [1,2-e]-[1, 3] oxazin-3-one derivatives. This efficiency is due to the effective interactions of the reactants with the catalysts and with each other. To explain the intervention of the catalyst in the formation of the final product, a mechanism has been proposed based on the fundamental basis of organic chemistry and bibliographic studies [40, 41]. Concerning the Co₃(PO₄)₂ catalyst (Fig. 4), the first step was activating the carbonyl group of aryl aldehyde through the Van Der Wall interactions with the catalyst, facilitating the formation of the acylimine intermediate (Intermediate I). The latter is reacted with phenol by an electrophilic substitution which was activated by the catalyst to form a second intermediate (II). due to the tautomeric form of intermediate 2 and the closeness of the groups we have seen an intramolecular cyclization that makes it possible to obtain the final product. For the bimetallic catalyst, it demonstrated higher efficiency compared to the Co₃(PO₄)₂ catalyst. This superior performance is attributed to the presence of two types of active sites: Brønsted acid sites and Lewis acid sites, which guarantee dual activation of the reagents, as illustrated in Fig. 5,

To confirm the significant catalytic role of our prepared catalysts, we compared our results with those obtained using other catalysts documented in the literature. Our study revealed that our catalyst demonstrates a higher catalytic capacity than most previously reported catalysts, particularly in preparing oxazine derivatives under green and ecological conditions and in minimal time. This superior performance highlights our catalyst as an excellent alternative to existing catalytic methods.

Table 4

Comparative study of Co₃(PO₄)₂ catalytic activity with that of other supports cited in the literature.
Entry	Catalyst	Conditions	Time (min)	Yield (%)
1	[SiO₂–VO(OH)₂]	Solvent free conditions /130°C	60	79–82 [47]
2	Silica-bonded S-sulfonic acid	Solvent free conditions /150°C	60	83–87 [48]
3	Tetrachloride-Functionalized Silica Gel-Nps	MeOH/reflux	180	82–96 [23]
4	K₂CO₃	DMF/r.t	20–45	84–98[49]
5	Alum(KAl(SO₄)₂.12H₂O)	Solvent free conditions /170°C	180	72–81[50]
6	OMPGC₃N₄/SO₃H	Solvent free conditions /100°C	5–10	81–97[51]
7	Co₃(PO₄)₂	Ethanol/water (80%)/reflux	30–40	90–94
8	CoCa₃(HPO₄)(PO₄)₂(OH)	Ethanol/water (80%)/reflux	10–15	93–98

In conclusion, this study introduces a highly effective and environmentally friendly synthetic protocol for the preparation of pharmacologically significant 1,2-dihydro-1-arylnaphtho[1,2-e][1, 3]-oxazin-3-one derivatives. Utilizing two novel phosphate-based catalysts—cobalt orthophosphate (Co₃(PO₄)₂) and a bimetallic catalyst (CoCa₃(HPO₄)(PO₄)₂(OH)), we demonstrate their exceptional catalytic activity under green and mild reaction conditions. These findings not only advance the field of green chemistry but also provide a sustainable approach to synthesizing complex organic compounds with potential therapeutic applications. The two catalytic methods developed enabled the preparation of oxazine derivatives with excellent yields-up to 98% within 10 to 15 minutes using the CoCa₃(HPO₄)(PO₄)₂(OH) catalyst, and up to 94% yield using Co₃(PO₄)₂. These methods ensure that organic synthesis is carried out under green and ecological conditions, using a mixture of ethanol and water as solvents. This demonstrates a sustainable and efficient approach with significant potential for pharmacological applications. The efficacy of phosphate catalysts is highlighted, and the fields of application for Moroccan phosphate in catalysis are expanded. Additionally, both catalysts demonstrated remarkable stability and reusability, maintaining their catalytic activity for up to seven cycles without significant loss, making them highly applicable in the industrial field.

General procedure

The synthesis of naphthoxazine derivatives was achieved through a mixture of β-naphthol (1 mmol), aryl aldehyde (1 mmol), and urea (1.5 mmol) in the presence of ethanol/water (80%) as solvent using the catalyst cobalt orthophosphate Co₃(PO₄)₂. The mixture was rapidly stirred and heated at a reflux temperature for the appropriate time. After checking the completion of the reaction by thin-layer chromatography (TLC), the mixture was extracted with ethyl acetate, to recover the solid catalyst by filtration for subsequent reuse. Finally, the mixture was evaporated in a vacuum to give the crude product, purified by recrystallization from ethanol to obtain the desired product.

General information:

All reactions were carried out in dried glassware at a temperature of 150°C. All reagents obtained from commercial sources (SigmaAldrich, Ried-de-haen and fluka) and they were used without purification. The commercial grade purity of aldehydes, acetophenone derivatives and ammonium acetate is ≥ 97% ≥ 98% and 99% respectively. Thin-layer chromatography (TLC) was performed on pre-coated glass plates of Silica Gel 60 F254 (0.25 mm, Merck), and UV light for TLC analysis was a UVGL-25 compact UV lamp (4 W/254 nm). Melting points were determined with a Kofler bench (MP-2D melting apparatus melting apparatus with a temperature range (0-260°C)). ¹H NMR, ¹³C NMR, were recorded by Bruker AC-400 F (300 MHz for ¹H and 75 MHz for ¹³C). Chemical shifts are in ppm from Me₄Si, generated from the CDCl₃ lock signal at δ 7.24 and 77.16 ppm for ¹H and ¹³C NMR, respectively. Multiplicities are reports by using the following abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, m = multiplet, dd = doublet of doublets; J = coupling constant values in Hertz.

The Spectral (¹H NMR, ¹³C NMR) and Analytical Data

1,2-dihydro-1-phenyl-3H-naphtho[1,2-e]-[1, 3]oxazin-3-one (4a): ¹H NMR (300 MHz, DMSO-d₆): 𝛿ppm 6.2 (d, 1H, CH), 7.2–8.2 (m, 11H, ArH), 8.9 (d, 1H, NH),

¹³C NMR (75 MHz, (DMSO-d₆) δ ppm: 54.24, 114.91, 117.33, 123.56, 125.54, 127.19, 127.53, 128.48, 129.35, 133.5, 141.3, 151.8, 157.8.

1-(4-chlorophenyl)-3H-naphtho[1,2-e]- [1, 3]oxazin-3-one (4b):

¹H NMR (300 MHz, DMSO-d₆) δ ppm 6.72 (d, 1H, CH), 7.16–7.99 (m, 10H, ArH), 8.64 (d, 1H, NH). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm: 162.11, 153.88, 138.24, 133.61, 131.34, 130.35, 129.58, 129.46, 129.21, 128.98, 127.18, 126.36, 123.74, 117.33, 114.61, 52.68.

1,2-dihydro-1-(4-bromophenyl)-3H-naphtho[1,2- e]-[1, 3]oxazin-3-one (4c):

¹H NMR (300 MHz, DMSO-d₆): 𝛿ppm 6.22 (d, 1H, CH), 7.1-8 (m, 10H, ArH), 8.9 (d, 1H, NH). 13C ¹³C NMR (75 MHz, DMSO-d₆) δppm: 52.9, 115.4, 118.9, 121, 123.8, 128.3, 128.8, 132.1, 133.5, 140, 151.8, 157.8.

1,2-dihydro-1-(4-methoxyphenyl)-3H−naphtho[1,2-e]-[1, 3]oxazin-3-one (4d):

¹H NMR (300 MHz, DMSO-d₆): δppm: 6.12 (d, 1H, CH), 6.75-8 (m, 10H, ArH), 8.8 (d, 1H, NH). 13C ¹³C NMR (75 MHz, DMSO-d₆) δppm: 53.65, 55.53, 114.66, 117.30, 123.29, 125.47, 127.73, 128.65, 129.05, 129.35, 135.48, 147.76, 149.79, 159.29.

1,2-dihydro-1-(p-tolyl)-3H-naphtho[1,2-e]- [1, 3]oxazine-3-one (4e):

¹H NMR (300 MHz, DMSO-d₆): δppm: 6.13 (d, 1H, CH), 7.04–7.95 (m, 10H, ArH), 8.82 (d, 1H, NH). ¹³C NMR (75 MHz, DMSO-d₆): δppm: 149.84, 147.87, 143.29, 130.87, 130.71, 129.42, 129.33, 129.09, 128.50, 127.84, 127.41, 125.56, 123.51, 117.31, 114.48.

1,2-dihydro-1-(4-nitrophenyl)-3H-naphtho[1,2-e]-[1, 3]oxazin-3-one (4f):

¹H NMR (300 MHz, DMSO-d₆): δppm: 6.35 (d, 1H, CH), 7.04–8.08 (m, 10H, ArH), 8.1 (d, 1H, NH). ¹³C NMR (75 MHz, DMSO-d₆): δppm: 109.22, 119.08, 119.78, 124.35, 124.89, 127.04, 127.87, 128.46, 128.46, 128.67, 129.59, 129.86, 130.74, 137.57, 147.78, 148.80, 149.53, 154.30.

1,2-dihydro-1-(2-chlorophenyl)-3H-naphtho[1,2- e]-[1, 3]oxazin-3-one (4g):

¹H NMR (300 MHz, DMSO-d₆): δppm: 6.43 (d, 1H, CH), 7.01–8.12 (m, 10H, ArH), 8.31(d, 1H, NH).

¹³C NMR (75 MHz, DMSO-d₆): δppm: 109.22, 119.08, 119.78, 124.35, 124.89, 127.04, 127.87, 128.46, 128.46, 128.67, 129.59, 129.86, 130.74, 137.57, 147.78, 148.80, 149.53, 154.30.

1-(4-fluorophenyl)-3H-naphtho[1,2-e]-[1, 3]oxazin3-one (4h):

¹H NMR (300 MHz, DMSO-d₆): δppm 6.12 (d, 1H, CH), 7.26–7.89 (m, 10H, ArH), 8.60 (d, 1H, NH). ¹³C NMR (75 MHz, DMSO-d₆): δppm: 161, 154.28, 148.20, 131.11, 140.34, 127.05, 129.18, 129.13, 129.01, 128.98, 127.14, 126.52, 123.86, 117.11, 114.75, 52.08.

1-(4-aminophenyl)-3H-naphtho[1,2-e]- [1, 3]oxazin-3-one (4i):

¹H NMR (300 MHz, DMSO-d₆): δppm 5.01 (s, 2H, NH2), 6.34 (d, 1H, CH), 7.01–7.77 (m, 10H, ArH), 8.15 (d, 1H, NH).

¹³C NMR (75 MHz, DMSO-d₆): δppm: 157.8, 154.28, 152.11, 151.8, 145.30, 133.5, 131.05, 129, 128.3, 126.3, 123.6, 123.2, 118.4, 115.70, 52.9.

Author Contribution

Dr. Achraf EL hallaoui is the corresponding author and the responsible for processing the results and writing.Dr Nouhaila Ferraa is responsible for preparing the catalyst with Dr Merroun Youssef.Prof Chehab Soukaina and Prof Ghailane Rachida are responsible for revising and correcting the article.Professor Hassoune Hicham and Mr. Boukhriss are responsible for the characterization and processing of product analysis.Professor Souizi is the head of the laboratory and is responsible for revising the article.

Funding Declaration

No funding source: The study was conducted without a dedicated funding source.

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Table 3 is available in the Supplementary Files section.

No competing interests reported.

Advanced Catalytic Approaches for Synthesizing 1,2-dihydro-1-aryl-3H-naphtho[1,2-e]-[1,3]oxazin-3-one Derivatives through Electrophilic Substitution Reactions using Mono- and Bimetallic Phosphate Catalysts: A Study of Co₃(PO₄)₂ and CoCa₃(HPO₄)(PO₄)₂(OH)

Status:

Version 1

Abstract

Figures

Introduction

Results and discussion

Conclusion

General procedure

Experimental Section

General information:

The Spectral (¹H NMR, ¹³C NMR) and Analytical Data

Declarations

Author Contribution

References

Table 3

Additional Declarations

Supplementary Files

Status:

Version 1

Advanced Catalytic Approaches for Synthesizing 1,2-dihydro-1-aryl-3H-naphtho[1,2-e]-[1,3]oxazin-3-one Derivatives through Electrophilic Substitution Reactions using Mono- and Bimetallic Phosphate Catalysts: A Study of Co₃(PO₄)₂ and CoCa₃(HPO₄)(PO₄)₂(OH)

Status:

Version 1

Abstract

Figures

Introduction

Results and discussion

Conclusion

General procedure

Experimental Section

General information:

The Spectral (1H NMR, 13C NMR) and Analytical Data

Declarations

Author Contribution

References

Table 3

Additional Declarations

Supplementary Files

Status:

Version 1

The Spectral (¹H NMR, ¹³C NMR) and Analytical Data