Consecutive reactions between methyl 3-dehydroshikimiate, amines and 1,2-dichloroalkanes under microwave conditions: a practical, one-pot construction of N-substituted dihydrobenzoxazines

Abstract

A biomass-involved, one-pot, two-step protocol for the synthesis of N-substituted 3,4-dihydro-2H-1,4-benzoxazines has been developed. A wide range of new compounds have been efficiently synthesized in moderate to excellent yields via the three-component consecutive reactions between methyl 3-dehydroshikimiate (3-MDHS), amines and 1,2-dichloroalkanes in short reaction times under microwave conditions.

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Introduction

N-substituted 3,4-dihydro-1,4-benzoxazines are an attractive class of nitrogen-containing compounds prevalent in pharmaceuticals, agrochemicals and bioactive molecules.¹ Their usefulness can be reflected in the great value of the antibiotic levofloxacin² and the herbicide safener benoxacor.³ Recent studies also showed that the N-substituted 3,4-dihydro-1,4-benzoxazines have emerged as intriguing building blocks for biologically interesting molecules such as human URAT-1 inhibitor,⁴ a tumor-driven angiogenesis inhibitor,⁵ and PPAR α/γ agonist⁴ (Fig. 1). The N-substituted 3,4-dihydro-1,4-benzoxazines are generally constructed by reactions of o-aminophenol,⁶ o-nitrophenol,⁷ o-halogenated phenol⁸ or o-halogenated aniline⁹ with bifunctional components such as chloroacetone, chloroacetyl chloride or chloroethanol, followed by stepwise annulations and N-substitutions using Pd- or Ni-containing catalyst and phosphine or bidentate nitrogen ligands.¹⁰ Although much progress has been made, these approaches still suffer from multistep procedures, preformed substrates and relatively low yields in some cases. To the best of our knowledge, the synthesis of N-substituted 3,4-dihydro-1,4-benzoxazines using an aliphatic to aromatic protocol in a metal-free, one-pot manner has not yet been reported. In addition, from sustainable chemistry perspective, the unremitting excavation and utilization of biofeedstocks to replace limited fossil oil as resources for chemical and pharmaceutical industries represents one of the most fundamental tasks for chemists.¹¹

Fig. 1 Examples of biologically active 3,4-dihydro-2H-1,4-benzoxazine derivatives.

Over recent years, findings from Belotti,¹² Yoshikai,¹³ Deng,¹⁴ Rodrigues,¹⁵ Saito,¹⁶ and Jiang¹⁷ groups have shown that the aromatization of cyclohexenones induced by amines through enamine intermediates in presence of palladium, iodine or even p-TsOH constitutes an effective tool for constructing N-arylanilines or N-alkylanilines. Our group has also recently disclosed the effectiveness of a special type of biomass-derived cyclohexenone, the methyl 3-dehydroshikimiate (3-MDHS, 1), in the facile and metal-free synthesis of polyfunctionalized diarylamines and arylalkylamines via the tandem cross-coupling and aromatization reactions.¹⁸ In the course of our study, we envisioned that this aliphatic to aromatic methodology could further be extended for the assembly of N-substituted 3,4-dihydro-1,4-benzoxazines through a cascade process by using the readily accessible 3-MDHS, primary amines and a bifunctional substrate like 1,2-dichloroethane or 1,2-dichloropropane as the reactant. In continuation of our work on biomass conversion and utilization,¹⁸ we describe herein a 3-MDHS-based, metal- and ligand-free, one-pot method for access to N-substituted 3,4-dihydro-1,4-benzoxazines, providing a practical and efficient alternative to traditional stepwise approaches.

Results and discussion

In recent years, (−)-shikimic acid has become abundantly available and cost-effective either through biomass extraction from fruits of Chinese star anise (Illicium verum Hook. f.) or through bioengineering production starting from glucose mediated by E. coli.¹⁹ (−)-shikimic acid could then be readily transformed to 3-MDHS (1) based on our previous findings^18a and the recent improved procedures (see the ESI† for detail). Therefore, 3-MDHS has become an easily accessible platform compound deserve further transformation studies.

Our research was initiated by investigating the three-component reaction between 3-MDHS (1, 1.1 mmol), aniline (2a, 1.0 mmol), and 1,2-dichloroethane (3a, 1.5 ml) in a one-pot, two-step manner. p-TsOH was used as the catalyst for step-one and a base was used as additive for step-two, both under microwave conditions (Table 1). Although the intermediate A was detected in the reaction mixture, no desired product 4a could be found when using ethanol as the solvent, 5 mol% p-TsOH as the catalyst, and Cs₂CO₃ (3 mmol) as the base (Table 1, entry 1). This might be due to the relatively high reaction temperature needed for initiating step-two cannot be reached with ethanol in an open vessel. Accordingly, solvents with higher boiling-points such as DMF, NMP, DMAC, 1,4-dioxane, DMSO, PEG-200, PEG-400 and glycol were tested. We were pleased to find that the expected product 4a could substantially be obtained in most of these solvents, whereas DMSO proved to be the most optimal (92% isolated yield, Table 1, compare entry 9 to entries 2–8). A survey of different bases showed that Cs₂CO₃ was superior to other bases such as K₂CO₃, Na₂CO₃, Et₃N, pyridine, NaOH, KOH, CH₃ONa, DBU and DMAP (Table 1, entries 9–18). Moreover, no desired product 4a but only intermediate A could be obtained in absence of a base (Table 1, entry 19). In addition, temperature studies indicated that a 110/120 °C combination of step-one and step-two, respectively, was more favourable for the formation of 4a, whereas lower or higher temperature modes gave lower yields (Table 1, entries 9, 20 and 21). Also, it could be found that the reaction time was greatly shortened under microwave conditions comparing with conventional heating, for this two-step reaction took only 13 min (t₁ + t₂) to go to completion under microwave irradiation, whereas 600 min (t₁ + t₂) was needed to gave a 78% yield in an oil bath (Table 1, entry 9 vs. 22). Thus, the optimized reaction conditions were: 3-MDHS (1, 1.10 mmol), aniline (2a, 1.0 mmol), 1,2-dichloroethane (3a, 1.5 ml), p-TsOH (0.05 mmol) in DMSO at 110 °C for step one, followed by the addition of Cs₂CO₃ (3 mmol) and reacted at 120 °C for step two, both under microwave conditions (Table 1, entry 9).

Table 1 Optimization of reaction conditions^a

Entry	Solvent	Base	T1/T2 (°C)	t1/t2 (min)	Yield^b (%)
a Reaction conditions: 1 (1.1 mmol), 2a (1.0 mmol), solvent (5 ml), DCE (1.5 ml), p-TsOH (0.05 mmol) at T1 °C (240 W) for t1 min, then base (3 mmol) was added and reacted at T2 °C (240 W) for t2 min. All reactions were carried out in a flask connected with a condenser.b Isolated yields based on aniline.c ND: no desired product.d Only intermediate A was obtained.e Reaction was carried out in an oil bath for a total of 600 min (t1 + t2).
1	Ethanol	Cs2CO3	78/78	30/30	ND^c^,^d
2	DMF	Cs2CO3	110/120	8/6	72
3	NMP	Cs2CO3	110/120	7/5	84
4	DMAC	Cs2CO3	110/120	7/7	74
5	1,4-Dioxane	Cs2CO3	90/90	15/16	Trace
6	PEG-200	Cs2CO3	110/120	8/7	40
7	PEG-400	Cs2CO3	110/120	8/7	40
8	Glycol	Cs2CO3	110/120	8/7	55
9	DMSO	Cs2CO3	110/120	8/5	92
10	DMSO	K2CO3	110/120	8/12	85
11	DMSO	Na2CO3	110/120	8/12	Trace
12	DMSO	Et3N	110/120	8/12	Trace
13	DMSO	Pyridine	110/120	8/12	Trace
14	DMSO	NaOH	110/120	8/12	62
15	DMSO	KOH	110/120	8/12	60
16	DMSO	CH3ONa	110/120	8/12	65
17	DMSO	DBU	110/120	8/12	Trace
18	DMSO	DMAP	110/120	8/12	Trace
19	DMSO	—	110/120	8/30	ND^c^,^d
20	DMSO	Cs2CO3	90/110	15/15	82
21	DMSO	Cs2CO3	150/180	5/3	80
22^e	DMSO	Cs2CO3	110/120	240/360	78

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With the optimized conditions in hand, we next examined the scope for this three-component consecutive reaction using various arylamines. As shown in Table 2, a variety of N-aryl-3,4-dihydro-2H-1,4-benzoxazines were readily obtained in good to excellent yields. In general, arylamines containing an electron-donating group are more reactive than those bearing an electron-withdrawing group. For example, substituted arylamines with a Me or OMe group provided high yields (Table 2, entries 2 and 3), whereas substrates with an electron-withdrawing group such as Ac, NO₂ or CF₃ gave moderate yields (Table 2, entries 8, 9, 18 and 20). We were disappointed to note that no desired product was detected when 2,4-dinitroaniline was used as the substrate, probably due to the insufficient nucleophilicity of the amino group (Table 2, entry 17). A comparison of the reaction yields indicated that the reactivity of halo-substituted arylamines decreased in the order I > Br > Cl > F (Table 2, entries 4–7). Results also showed that arylamines with substituents on the 2,6-positions gave relative lower yields, which might be due to the steric hindrance of the substrates (Table 2, entries 15 and 16). It is gratifying to mention that mutisubstituted or polycyclic (pseudo)arylamines such as benzidine (2v, molar ratio: 1/2v = 2/1), 1-naphthylamine (2w) and benzophenone hydrazone (2x) proceeded smoothly in this cascade coupling reaction to afford the corresponding N-aryl-3,4-dihydro-2H-1,4-benzoxazines 4v–4x in satisfactory yields (Scheme 1).

Table 2 Scope of the one-pot synthesis of N-aryl-3,4-dihydro-2H-1,4-benzoxazines^a

Entry	Arylamine	t1/t2 (min)	Products	Yield^b (%)
a Reaction conditions: 1 (1.1 mmol), 2 (1.0 mmol), p-TsOH (0.05 mmol) in DMSO (5 ml) and 3a (1.5 ml) stirred for t1 min at 110 °C (240 W), then Cs2CO3 (3 mmol) was added and stirred for t2 min at 120 °C (240 W). All reactions were carried out in a flask connected with a condenser.b Isolated yields.c ND: not detected.
1		8/5		92
2		8/5		96
3		8/5		95
4		8/5		88
5		8/6		85
6		8/6		83
7		8/7		78
8		8/6		82
9		8/10		84
10		8/8		85
11		8/9		80
12		8/10		82
13		8/8		87
14		8/12		75
15		8/12		65
16		8/10		61
17		20/20		ND^c
18		10/10		72
19		10/8		92
20		10/8		78
21		10/8		82

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Scheme 1 Cascade reactions of 3-MDHS, 1,2-dichloroethane with benzidine, 1-naphthylamine and benzophenone hydrazone.

To further investigate the synthetic utility of our protocol, a range of alkylamines were subjected to the typical reaction conditions (Table 3). Inspiringly, all of these substrates reacted smoothly to afford the N-alkyl-3,4-dihydro-2H-1,4-benzoxazines in acceptable to good yields. For example, benzylamine (5a) reacted with 3-MDHS (1) and DCE (3a) to afford the corresponding product 6a in 82% yield within 13 min (Table 3, entry 1). Other alkylamines such as cyclohexylamine, n-butylamine and ethylamine were all successfully converted into the desired products 6b–6d in moderate yields (Table 3, entries 2–4).

Table 3 Scope for the one-pot synthesis of N-alkyl-3,4-dihydro-2H-1,4-benzoxazines^a

Entry	Alkylamine	t1/t2 (min)	Product	Yield^b (%)
a Typical reaction procedure: 1 (1.1 mmol), 5 (1.0 mmol), p-TsOH (0.05 mmol) in DMSO (5 ml) and 3a (1.5 ml) stirred for t1 min at 110 °C (240 W), then Cs2CO3 (3 mmol) was added and stirred for t2 min at 120 °C (240 W).b Isolated yields.
1		8/5		82
2		8/5		60
3		8/6		62
4		8/6		65

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The diversity of our protocol was further explored by using 1,2-dichloropropane 3b to react with 3-MDHS (1) and anilines (Table 4, entries 1–7). As expected, these consecutive reactions proceeded smoothly and gave the N-aryl-dihydrobenzoxazines (7/8) as a regioisomeric mixture in good yields (Table 4). Both the electron-rich (entries 2 and 3) and the electron-poor (entries 5–7) arylamines were applicable to this tandem reactions and the molar ratios of 7/8 were ranging from 0.9–1.5, which showed somewhat selectivity for generating 7 over 8 (entries 1–7). Interestingly and unexpectedly, we have found that the use of other bifunctional substrates like 1,3-dichloropropane (3c), epichlorohydrin (3d) and propargyl chloride (3e) could afford the corresponding O-alkylated products (9c–9e) in excellent yields, whereas no N-alkylated products or N-phenyl dihydrobenzoxazines were obtained (Scheme 2). This and the above-mentioned results indicated that the O-alkylation process might be more preferential than the N-alkylation process under these reaction conditions.

Table 4 Expanding of substrate scope using 1,2-dichloropropane as the bifunctional substrate^a

Entry	Arylamine	t1/t2 (min)	Ratio of products^b (7/8)	Yield^c (%)
a Typical reaction procedure: 1 (1.1 mmol), 2 (1.0 mmol), p-TsOH (0.05 mmol) in DMSO (5 ml) and 1,2-dichloropropane (2.0 ml) stirred for t1 min at 110 °C (240 W), then Cs2CO3 (3 mmol) was added and stirred for t2 min at 120 °C (240 W).b The ratio of products (7/8) were detected by ^1H NMR.c Isolated yields.
1		8/25	7a/8a = 1.5	85
2		8/25	7b/8b = 1.0	86
3		8/25	7c/8c = 0.9	86
4		8/30	7d/8d = 1.0	74
5		8/30	7g/8g = 1.0	70
6		8/35	7i/8i = 1.3	68
7		8/35	7n/8n = 1.4	61

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Scheme 2 Cascade reactions of methyl 3-dehydroshikimiate, aniline with other bifunctional substrates.

With the important intermediate II (R² = benzyl) being isolated from the reaction mixture of 3-MDHS (1), benzylamine (5a) and DCE (3a), and as an overview of the experimental results, a plausible mechanism was postulated (Scheme 3). 3-MDHS (1) reacted with a primary amine through the tandem condensation/isomerization/dehydration process to afford the N-substituted o-aminophenol (I), which could then be O-alkylated by 1,2-dichloroethane to afford the intermediate II through nucleophilic substitution (Path A, whereas Path B can be excluded because the N-alkylated intermediate III was not observed).²⁰ The intermediate II can then undergo an intramolecular S_N2 cyclization to give the desired N-substituted 3,4-dihydro-2H-1,4-benzoxazines (IV).

Scheme 3 Plausible reaction pathway.

Conclusions

In conclusion, a facile and efficient methodology for access to N-substituted 3,4-dihydro-2H-1,4-benzoxazines starting from 3-MDHS (1), primary amines and 1,2-dichloroalkanes via an aliphatic to aromatic, cascade process has been established. The notable features include the use of the biomass-derived platform compound 3-MDHS, metal- and ligand-free reaction conditions, short reaction times, and operational simplicity that make it an interesting paradigm for biomass conversion and a practical strategy for the library synthesis of newer N-substituted dihydrobenzoxazines with biological importance.

Acknowledgements

This work was supported by the National Science Foundation of China (no. 21272280, 81201716, 81301890), Science & Technology Program of Guangdong Province (S2013010014278, 2011A081401002, 2012B091100241), Zhejiang Province (LY1 3H160010, 2012ZQ017) and Guangzhou City (2012J4300097). The authors are thankful to Prof. Ming Yan at Sun Yat-sen University for helpful discussion and are also grateful to Guangxi Wanshan Spice Co. Ltd. for giving high quality (−)-shikimic acid as a gift.

References

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20. Intermediate II was confirmed by IR, MS, HRMS, ¹H NMR spectrum and chemical methods. The ferric chloride test demonstrated the absence of a phenolic hydroxyl group and the Hinsberg reaction proved the existence of a secondary amino group in the structure of the compound. For more detail information about intermediate II, see the ESI.†.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c3ra47221c

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