Solvent-assisted one-pot green and diastereoselective synthesis of 1,4-oxazines and 1,4-thioxazines under metal-free conditions

Abstract

A novel and efficient three-component, one-pot green and diastereoselective synthesis of 1,4-oxazines and 1,4-thioxazines using formyl-chromone-based enamines under mild reaction conditions is presented. The desired products are afforded in anti-conformation and high yields (up to 95%). This method offers a significant improvement over traditional approaches, which often require harsh conditions, multiple steps, and expensive reagents. The broad substrate scope and high functional group tolerance make this protocol a powerful tool for highly diastereoselective synthesis of diverse classes of 1,4-oxazine and 1,4-thioxazine compounds, known for their wide range of biological activities. The synthetic route is environmentally friendly, aligning with the principles of green chemistry, as it avoids the use of toxic solvents and heavy metal catalysts.

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Introduction

Heterocyclic compounds constitute a significant and diverse category of natural products, biologically and pharmaceutically active molecules and other synthetic compounds.¹ Commonly, heteroatoms such as nitrogen (N), oxygen (O), and sulfur (S) are present in heterocyclic compounds, although other elements are also present in heterocyclic rings.^2,3 The incorporation of nitrogen and oxygen atoms into cyclic structures imparts unique physico-chemical properties, which are crucial for their various functions, particularly of biological and pharmaceutical importance.^4,5 For example, 1,4-oxazines and their saturated counterparts, morpholines, play key roles in medicinal chemistry (Fig. 1).⁶ N,O-Heterocycles are recognized for their stability and operational efficacy within the human body.⁷ In fact, approximately 60% of all FDA-approved small-molecule drugs contain at least one nitrogen-containing heterocyclic ring.^8,9

Fig. 1 Bio-active molecules containing a 1,4-oxazine moiety.

The development of reliable synthetic methods for the synthesis of 1,4-oxazine derivatives continues to be challenging owing to their broad applications.¹⁰ These heterocycles have been synthesised using traditional methods such as hydroamination or hydroalkoxylation of alkenes and alkynes, cyclisation of β-amino alcohols, and annulation of imine intermediates.^11–13 Despite the above developments, these approaches often demand extreme conditions, operate over a restricted range of substrates, or provide poor regio- and stereoselectivity.

Significant advancements have been made in recent years due to the development of novel catalytic approaches. Under moderate circumstances, functionalised 1,4-oxazines might be obtained via tandem N–H insertion of α-arylamino ketones with diazo pyruvates, using ruthenium catalysts.¹⁴ Asymmetric transfer hydrogenation of alkynones using Ru- and Au-metal relay catalysts gave 3,4-dihydro-2H-1,4-oxazines in high yields, exhibiting high enantioselectivity.¹⁵ Through regio- and stereoselective tandem ring-opening and cyclisation of spiro-aziridines, spiro-fused frameworks, including spiro[3,4-dihydrobenzo[b][1,4]oxazine-2,3′-oxindole], have been obtained stereoselectively, yielding enantiopure scaffolds that have considerable synthetic and biological significance.¹⁶ Silver triflate-catalysed oxidation of N-propargyl N-sulfonyl amino alcohols has emerged as an effective method for obtaining 3,4-dihydro-2H-1,4-oxazines, thus broadening the synthetic scope. Crucially, solid-phase peptide synthesis (SPPS) has effectively used this technology, allowing for the late-stage integration of oxazine moieties into peptides at threonine and serine ends.¹⁷

Furthermore, expanding the synthetic scope,¹⁸ metal-free [5 + 1] cycloaddition reactions,^18d transition metal catalysts,¹⁹ metal carbenes,²⁰ and catalyst-free reactions²¹ as well as microwave irradiation²² have been widely used for synthesising substituted 1,4-oxazines. Recently, enol was used as an O-nucleophile source for an intramolecular substitution reaction on the allylic site using an iridium catalyst to afford chiral 2H-1,4-oxazine derivatives (Scheme 1a)²³ and a one-pot three-component synthesis of 1,4-benzothiazines was reported via cyclisation using copper(I) thiophene-2-carboxylate (Scheme 1b).²⁴

Scheme 1 Previous reports and this work.

Our group has consistently focused on designing and synthesising biologically active heterocyclic compounds,²⁵ such as 4-hydroxycoumarins, imidazo[1,2-a]pyridines, pyrroles, 1,4-dihydroquinolines and tetrazoles. Dual formyl-chromone and 1,4-oxazine scaffolds represent a new class of molecules with promising applications in medicinal chemistry, as both formyl-chromones and 1,4-oxazines are privileged structures in drug discovery. Chromone-based enamines were previously reported²⁶via condensation of chromone derivatives with amines. We adopted a modified procedure to prepare these intermediates efficiently; herein, we report a novel and operationally simple method that enables the one-pot synthesis of 1,4-oxazine and 1,4-thioxazine derivatives under mild basic conditions, using a green and eco-friendly solvent system, with high atom economy and minimal waste generation (Scheme 1c).

Results and discussion

To optimize the reaction conditions, we initially screened various alcohols (ROH) at room temperature, of which primary alcohols such as methanol (MeOH), ethanol (EtOH), and isopropanol (ⁱPrOH) provided high yields of the desired product (Table 1, entries 1–3). tert-Butanol (^tBuOH), a sterically hindered alcohol, also gave an excellent yield of 95% (Table 1, entry 4), demonstrating the tolerance of the reaction to bulky solvents. In contrast, polyhydroxy alcohols such as propane-1,2-diol, ethylene glycol, and glycerol led to significantly reduced yields (Table 1, entries 5, 6 and 9). Phenol and benzyl alcohol (Table 1, entries 7 and 8) were found to be ineffective and failed to give the desired product. This might be due to their poor nucleophilicity and acidic nature. Similarly, propargyl alcohol, allylic alcohol and H₂O gave lower yields of the desired product (Table 1, entries 10–12). The optimised reaction time for obtaining maximum product yield was 2 hours (Table 1, entries 13–15) when using EtOH, ⁱPrOH, or ^tBuOH, confirming that the reaction proceeds efficiently and rapidly in these solvents. Isopropanol remained the optimal solvent, delivering 98% yield in just 2 hours (Table 1, entry 14). Other non-polar and aprotic solvents like toluene, xylene, dimethylsulfoxide, and dichloromethane gave intermediate-1′, which failed to undergo cyclization to give the desired product.

Table 1 Optimisation of reaction conditions^a

Entry	ROH	Time (h)	% Yield^b
a Reaction conditions: (i) 1 (0.5 mmol), 2 (0.5 mmol), ROH (3.0 ml) at room temperature. b Isolated yield. c No result.
1	MeOH	12	89
2	EtOH	12	94
3	^iPrOH	12	98
4	^tBuOH	12	95
5	Propane-1,2-diol	24	71
6	(CH2OH)2	24	64
7	Phenol	48	NR^c
8	Benzyl alcohol	48	27
9	Glycerol	24	32
10	Propargyl alcohol	24	48
11	Allylic alcohol	24	41
12	H2O	24	78
13	EtOH	2	94
14	^i PrOH	2	98
15	^tBuOH	2	95

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We also used different amines as solvents such as aniline, dimethylamine, trimethylamine, and dipropylamine. However, they failed to yield any product. Following solvent optimisation, various bases were also screened in EtOH, ⁱPrOH, and ^tBuOH solvents to determine their influence on reaction efficiency (Table 2). Strong bases such as NaOH, KO^tBu, KOH, and NaH (Table 2, entries 1–4) gave lower yields as compared to carbonates such as K₂CO₃, Cs₂CO₃, NaHCO₃ and Na₂CO₃ (Table 2, entries 5–8), while organic bases such as DBU, NEt₃, and NHEt₂ gave poor yields (Table 2, entries 12–14) as compared to the carbonates. The use of Na₂CO₃ (1.5 equiv.) gave the highest yield in all three solvents, with 92% yield in ⁱPrOH (Table 2, entry 9). Increasing the loading to 2.0 or 2.5 equivalents did not lead to any significant improvement, indicating 1.5 equivalents to be optimal. Furthermore, the reaction time study (Table 2, entries 16–18) confirmed that 1 hour is sufficient to achieve maximum yield, with no appreciable improvement beyond this time. Organic bases such as pyridine, DABCO, and piperidine were also tested but resulted in poor to low yields (10–20%), possibly due to weak basicity or steric hindrance. Overall, the combination of ⁱPrOH as solvent and Na₂CO₃ (1.5 equiv.) as a base at room temperature provided the best outcome, delivering the product in excellent yield (92%) within 1 hour reaction time (Table 2, entry 17). These mild, metal-free, and efficient conditions underscore the practical and sustainable potential of the developed protocol.

Table 2 Optimisation of reaction conditions^a

Entry	Base (equiv.)	Time (h)	% Yield^b
			EtOH	^iPrOH	^tBuOH
a Reaction conditions: (i) 3 (0.5 mmol) and base at room temperature. b Isolated yield. Organic bases such as pyridine, pyrrolidine, DABCO, morpholine, and piperidine gave poor to low yields (10–20%).
1	NaOH (2.0)	6	48	57	51
2	KO^tBu (2.0)	6	32	34	29
3	KOH (2.0)	6	45	58	50
4	NaH (2.0)	6	18	24	21
5	K2CO3 (2.0)	6	78	87	81
6	CsCO3 (2.0)	6	74	87	79
7	NaHCO3 (2.0)	12	68	72	70
8	Na2CO3 (1.0)	6	47	56	53
9	Na2CO3 (1.5)	6	85	92	88
10	Na2CO3 (2.0)	6	83	90	85
11	Na2CO3 (2.5)	6	81	85	82
12	DBU (2.0)	6	37	52	48
13	NEt3 (2.0)	6	29	41	37
14	NHEt2 (2.0)	6	21	28	26
15	Na2CO3 (1.0)	6	41	49	42
16	Na2CO3 (1.5)	0.5	57	62	59
17	Na 2 CO 3 (1.5)	1	85	92	88
18	Na2CO3 (1.5)	2	85	92	88

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Using the optimised reaction conditions, a variety of electron-donating and electron-withdrawing groups were investigated on formyl-chromone, 2-aminophenol, 2-aminothiophenol and 2-bromoacetophenone, which showcased minor yield differences. The nitro group on 2-aminophenol gave lower yields of compounds 4d and 4h, 84% and 81%, respectively, and the chloro-substituent gave compounds 4g, 4i, and 4j in yields of 89%, 83% and 88%, respectively. Electron donating groups such as the methoxy-group gave compounds 4c, 4d, 4g, 4m, 4s, 4u and 4v in good to excellent yields (83–94%), and the methyl group compounds 4e, 4f, 4j, 4q and 4r were obtained in excellent yields (88–90%). Varying substituents on all three moieties gave compounds 4n, 4o, 4p, and 4t in 84%, 80%, 83% and 85% yields, respectively (Table 3).

Table 3 Substrate scope

Entry	R1	R2	R3	Product	Yield (%)
1	H	H	H	4a	92
2	H	H	p-Br	4b	89
3	H	H	p-OMe	4c	93
4	H	p-NO2	p-OMe	4d	84
5	H	m-Me	p-Cl	4e	90
6	H	H	p-Me	4f	90
7	H	m-Cl	p-OMe	4g	89
8	H	p-NO2	p-Br	4h	81
9	H	m-Cl	p-Cl	4i	83
10	H	m-Cl	p-Me	4j	88
11	p-Br	H	p-Br	4k	85
12	p-Br	H	p-Cl	4l	84
13	p-Br	H	p-OMe	4m	87
14	p-Br	p-NO2	p-OMe	4n	84
15	p-Br	p-NO2	p-Br	4o	80
16	p-Br	m-Me	p-Cl	4p	83
17	p-Me	H	p-Cl	4q	88
18	p-Me	H	p-Br	4r	88
19	p-Me	H	p-OMe	4s	94
20	p-Me	p-NO2	p-OMe	4t	85
21	p-OMe	H	p-Br	4u	83
22	p-OMe	H	p-OMe	4v	93
23	p-OH	H	p-Br	4w	80

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Similarly, the reaction of 2-aminothiophenols (Table 4) with chromones also afforded excellent product yields. The methyl and methoxy variants gave compounds 5d, 5e, 5f and 5j in higher yields of 95%, 88%, 90% and 95%, respectively. When 2-bromoacetophenone was replaced with ortho-phenyldiamine, propargyl bromide, allylic bromide and benzylic bromide, they all failed to give the desired products.

Table 4 Substrate scope

Entry	R1	R2	R3	Product	Yield (%)
1	H	H	H	5a	94
2	H	H	p-Br	5b	85
3	H	H	p-Me	5c	94
4	H	H	p-OMe	5d	95
5	p-Br	H	p-OMe	5e	88
6	p-Br	m-Me	p-OMe	5f	90
7	p-Br	H	p-Cl	5g	86
8	p-Br	H	p-Me	5h	87
9	p-Me	H	p-Me	5i	94
10	p-Me	H	p-OMe	5j	95
11	p-Me	H	p-Cl	5k	90
12	p-Me	H	p-Br	5l	89

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The synthesis of 4a (0.176 g, 92%) was evaluated using green chemistry criteria to assess the environmental friendliness and greenness of the method. Specifically, it was determined that the reaction atom economy was 79.49%, the atom efficiency was 73.13%, and the excellent E-factor was 0.69 (Fig. 2). i-PrOH, (isopropanol) which exhibits low-to-moderate toxicity, is readily biodegradable, and is flammable (flash point ≈12 °C), was used as the solvent, which improved the green profile of this solvent.

Fig. 2 Green chemistry metrics.

We also performed a scale up reaction and the desired products 4p (2.06 g) and 5f (2.18 g) were obtained in good yields of 81% and 84% respectively (Scheme 2).

Scheme 2 Scale-up synthesis.

Plausible mechanism

The plausible reaction mechanism began with the formation of an imine. Subsequent imine–enamine tautomerization by the attack of solvent afforded an α,β-unsaturated carbonyl moiety (TS-2). The proton shift gave a stable intermediate 1 (Int-1) due to H-bonding, which further reacted with base Na₂CO₃ to generate a phenoxide ion (TS-3). The reaction of TS-3 with 2-bromoacetopheneone (3) afforded intermediate 2 (Int-2). Then, intermediate 2 reacted with Na₂CO₃ to give the carbanion TS-4 and subsequent selective attack on the β-carbon from above the plane (Michael addition) resulted in a diastereoselective product. Subsequent elimination of propanol solvent afforded the desired product (4b) (Scheme 3). To confirm the reaction mechanism, intermediate-1 (Int-1) was isolated and analysed by ¹H-NMR, ¹³C-NMR and HRMS, while intermediate-2 (Int-2) was observed in the HRMS spectrum as a peak at (M + H)⁺ = 522.0910. In the ¹H-NMR spectrum for example, compound 4a gave two doublets at δ 5.24 (d, 1H) and δ 4.23 (d, 1H) with J-values of 5.0 Hz and 5.1 Hz, respectively, indicating its anti-geometry. Similarly, the NOESY experiment of 4a failed to show cross-peaks at δ 5.24 and δ 4.23 ppm, indicating that the diastereomeric protons are anti to each other (Fig. S4). The same was confirmed by single X-ray crystallography (Fig. 3). Crude ¹H and ¹³C-NMR spectra of compound 4a were recorded, which showed only one set of signals, suggesting the formation of a single diastereomer (Fig. S3).

Scheme 3 Plausible reaction mechanism.

Fig. 3 SC-XRD image of 4a.

Single-crystal X-ray structural analysis

A small amount of compound 4a was dissolved in acetonitrile and left to slowly evaporate at room temperature, affording single crystals of the molecule. A Bruker APEX-V CCD diffractometer with graphite-monochromated Mo Kα radiation (λ = 0.71073 Å) at 300 K was used to collect crystallographic data. The monoclinic space group and bonding characteristics of 3-((2R,3R)-2-benzoyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)-4H-chromen-4-one (4a) were determined using single X-ray crystallography (CCDC 2484494) and the lattice parameters as follows: A = 20.836(4) Å, B = 7.1335(13) Å, and C = 21.837(5) Å and α = 90°, β = 146.592(5)°, and γ = 90° (Fig. 3).

Conclusions

In conclusion, we have developed a highly efficient, green and diastereoselective method for the synthesis of formyl-chromone-based 1,4-oxazine and 1,4-thioxazine derivatives as anti-conformers, via a one-pot, three-component reaction. It is a practical route to access biologically active heterocyclic compounds. The ease of purification, high product yields, and a wide substrate scope of this method highlight its potential for large-scale synthesis.

Experimental

General procedure

3.0 ml of isopropanol was added to a round-bottom flask containing 0.5 mmol of formylchromone (1) and 0.5 mmol of 2-aminophenol (2) or 2-aminothiophenol (2′), and the resulting mixture was stirred for 2 hours at room temperature, followed by the addition of 0.5 mmol of 2-bromoacetophenone (3) and 1.5 mmol of Na₂CO₃, and stirred at the same temperature for 1 hour. After completion of the reaction, 20.0 ml of ice-cold water was added to the reaction mixture to afford precipitates, which were filtered and recrystallised to get the desired product.

Author contributions

Farukh Ahmad: experiments, original writing. Rajeev Singh: experiments, original writing. Naseem Ahmed: conceptualisation, editing and writing.

Conflicts of interest

There are no conflicts to declare.

Data availability

All data are available in the article and its supplementary information (SI). Supplementary information is available. See DOI: https://doi.org/10.1039/d5ob01466b.

CCDC 2484494 contains the supplementary crystallographic data for this paper.²⁷

Acknowledgements

This research was supported by IIT Roorkee and DST-FIST [SR/FST/CS-II/2018/72(C)] (funding to the Chemistry Department, IIT Roorkee, for the provision of 500 MHz NMR and XRD facilities). Farukh Ahmad is grateful to the MHRD, IIT Roorkee, for providing a Junior Research Fellowship (JRF). We are also thankful to Md Azimuddin SK for the single-crystal X-ray structural analysis. The editor and reviewers are highly appreciated for their valuable suggestions.

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