Intramolecular C–O/C–S bond insertion of α-diazoesters for the synthesis of 2-aryl-4H-benzo[d][1,3]oxazine and 2-aryl-4H-benzo[d][1,3]thiazine derivatives

Abstract

An intramolecular C–O insertion of 2-(2-arylamidophenyl)-2-diazoacetate has been achieved using a catalytic amount of copper triflate under mild conditions to produce 2-aryl-4H-benzo[d][1,3]oxazine-4-carboxylate in good yields. In addition, 2-diazo-2-(2-arylthioamidophenyl)acetate affords the corresponding 2-aryl-4H-benzo[d][1,3]thiazine derivatives under similar conditions. This is the first example of the synthesis of benzoxazines and benzothiazines from ortho-amidophenyl diazoacetate and ortho-thioamidophenyl diazoacetate, respectively.

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The benzo[d][1,3]oxazine and benzothiazine ring systems are the core structures of many biologically active molecules.¹ They are used as fungicidal, anti-inflammatory,² anticonvulsant,³ DNA-binding agents,⁴ HSV-1 protease inhibitors (III)⁵ and inhibitors of human leukocyte elastase (IV).⁶ In particular, 2-substituted-4H-3,1-benzoxazin-4-one (II) has the ability to lower the level of plasma cholesterol and triglyceride.⁷ Furthermore, 2,4-substituted- 4H-3,1-benzoxazines are often found in various natural products and drugs. For example, etifoxine (I), a non-benzodiazepine anticonvulsant drug, is used for the treatment of psychiatric illnesses with great therapeutic efficiency and less toxicity.⁸ On the other hand, 2-substituted benzothiazines are used for the preparation of photographic materials.⁹ As a result, numerous methods have been developed for the synthesis of benzo[d][1,3]oxazines and benzothiazines.¹⁰ Among them, thermolysis of benzo[d][1,2,3]triazin-4(3H)-one or isatoic anhydride,¹¹ electrochemical cyclization of o-trichloroacetylanilide,¹² palladium-catalyzed cyclization of azidoalkyne,¹³ cycloaddition of ketenimine with thione¹⁴ and sulfurization of aryl substituted benzoxazine with P₂S₅.¹⁵ However, many of these methods suffer from several drawbacks such as the use of hazardous materials, expensive metal catalysts and harsh reaction conditions and also the yields are far from satisfactory. Therefore, the development of simple and expedient approaches still remains scarce for the synthesis of this class of N-heterocycles (Fig. 1).

Fig. 1 Biologically active natural products.

The relative stability and facile decomposition of α-diazocarbonyl compounds under thermal, photochemical, Lewis acidic and transition metal catalysis conditions makes them useful intermediates in organic synthesis.¹⁶ Recently, we explored the synthetic potential of α-diazoketones and esters for the synthesis of biologically active heterocycles such as imidazo[1,2-a]pyridines, 2-aminothiozoles, quinoxalines and trisubstituted pyrroles and indoles.¹⁷

Following our research on α-diazocarbonyl compounds, we herein report a novel approach for the synthesis of biologically active 2,4-substituted benzoxazines and benzothiazines through a copper-catalyzed intramolecular C–O insertion of α-diazocarbonyl compounds.

The starting material, 2-(2-arylamidophenyl)-2-diazoacetate (2) was prepared by the reaction of 2-arylamidophenyl acetate (1) with p-methylbenzenesulfonylazide (PMBSA) in the presence of base. Further the amide derivative (1) was prepared from methyl o-aminophenyl acetate and acid chloride (Scheme 1). Similarly, methyl 2-arylthioamidophenyl-2-diazoacetate (4) was prepared from the corresponding 2-arylthioamidophenylacetate (3) which was prepared by the reaction of 2-arylamidophenyl acetate (1) with equimolar amount of Lawesson's reagent,¹⁸ as shown in Scheme 1.

Scheme 1 Synthesis of 2-(2-arylamidophenyl)-2-diazoacetate.

As a model reaction, we first attempted the intramolecular cyclization of methyl 2-(2-benzamidophenyl)-2-diazoacetate (2a) in the presence of 10 mol% Cu(OTf)₂ in dichloroethane. The reaction proceeded smoothly at room temperature to furnish the respective 4H-benzo[d][1,3]oxazine 5a as a sole product in 90% yield.

To optimize the reaction conditions, several Lewis acids such as Cu(OTf)₂, CuOTf, Sc(OTf)₃, In(OTf)₃, Bi(OTf)₃, Cu(hfacac)₂, Cu(OAc)₂, and Cu(acac)₂ were screened. Among them, Cu(OTf)₂ gave the best results in terms of reaction time and conversion (entry a, Table 1). Other copper salts such as Cu(hfacac)₂, Cu(OAc)₂, Cu(acac)₂, CuSO₄ and CuI were found be less effective. Similarly, Lewis acids like Sc(OTf)₃, In(OTf)₃, Bi(OTf)₃ were also not effective for this conversion. Indeed, 5 mol% Rh₂(OAc)₄ was found to be more effective (entry d, Table 1). However, no cyclization was observed in the absence of catalyst. Next, we examined the effect of solvents such as dichloroethane, toluene, and tetrahydrofuran. Of these, dichloroethane gave the best results in terms of conversion.

Table 1 Screening of various catalysts in the formation of 5a

Entry	Lewis acid	Mol%	Solvent^a	Time (min)	Yield^b (%) (5a)
a Reaction was performed at 0.5 mmolscale.b Isolated yield.
a	Cu(OTf)2	10	ClCH2CH2Cl	20	90
b	Cu(hfacac)2	10		30	70
c	Cu(acac)2	10		30	65
d	Rh2(OAc)4	5	ClCH2CH2Cl	25	93
e	CuOTf	10		40	75
f	Cu(OAc)2	10		50	40
g	Cul	10		50	45
h	CuSO4	10		40	40
i	Sc(OTf)3	10		30	65
j	In(OTf)3	10		40	70
k	Bi(OTf)3	10		50	45
l	Cu(OTf)2	10	THF	40	70
m	Cu(OTf)2	10	Toluene	40	75

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The scope of this process is further illustrated with respect to various amides and the results are summarized in Table 2. In the presence of either electron-rich (entries c and g, Table 2) or electron-deficient substituents (entry d, Table 2) on aromatic ring, the amides gave the desired products in good yields. Similarly, halogen substituted amides also afforded the respective benzo[d][1,3]oxazine derivatives in good yields (entries b, f and h, Table 2). In all cases, the reactions proceeded efficiently in the presence of 10 mol% of Cu(OTf)₂ in dichloroethane. All products were characterized by IR, ¹H and ¹³C NMR and mass spectrometry. It is entirely a new approach for the direct conversion of methyl 2-(2-arylamidophenyl)-2-diazoacetates (2) into benzoxazine derivatives. The structure and stereochemistry of 5c were confirmed by X-ray crystallography (Fig. 2).¹⁹

Table 2 Synthesis of benzo[d][1,3]oxazine derivatives from (arylamidophenyl)diazoacetate

Entry	Phenyldiazoacetate (2)	Product (5)^a	Time (min)	Yield^b (%)
a All the products were characterized by NMR, IR and mass spectroscopy.b Yield refers to pure products after chromatography.
a			20	90
b			35	87
c			30	80
d			25	85
e			30	85
f			40	80
g			35	70
h			30	75

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Fig. 2 ORTEP diagram of 5c.

Encouraged by the results obtained with methyl 2-(2-arylamidophenyl)-2-diazoacetate (2), we extended this method to the synthesis of 2,4-disubstituted benzothiazines. Accordingly, the 2-(2-phenylthioamidophenyl)-2-diazoacetate (4a) was treated with Cu(OTf)₂ (10 mol%) in dichloroethane (5 mL) at room temperature to afford the respective benzothiazine 6a as a sole product in 85% yield (Table 3). Similarly, halogen substituted aromatic thioamides gave the corresponding benzothiazines in good yields (Table 3).

Table 3 Synthesis of benzo[d][1,3]thiazines via an intramolecular C–S bond insertion

Entry	Phenyldiazoacetate (4)	Product (6)^a	Time (min)	Yield^b (%)
a All the products were characterized by NMR, IR and mass spectroscopy.b Yield refers to pure products after chromatography.
a			30	80
b			40	76
c			45	75
d			35	78

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Mechanistically, we assume that the metal is expected to activate the diazo functionality to generate the metal carbenoid which facilitates the intramolecular O/S atom insertion leading to the formation of 1,3-benzofused heterocycles (5 & 6) (Scheme 2).

Scheme 2 A plausible reaction pathway.

In summary, we have developed a novel method for the synthesis of benzoxazine derivatives from easily accessible 2-(2-arylamidophenyl)-2-diazoacetate. It also provides a direct access to produce a new series of benzothiazine derivatives in a single-step process.

Experimental

General

All reactions were carried out under nitrogen atmosphere. Commercial reagents were used as received, unless otherwise stated. ¹H NMR spectra were recorded on 300 MHz or 500 MHz spectrometer using CDCl₃ as a solvent. ¹³C NMR were recorded on 75 MHz and 125 MHz spectrometer using CDCl₃. TMS was used as an internal reference for ¹H NMR analysis. All the compounds were purified by column chromatography on silica gel (60–120 mesh) using hexane–ethyl acetate mixture as eluent. Mass analysis was carried out using APCI mass spectrometer.

General procedure for the synthesis of 2-(2-aryl thioamidophenyl)acetate (3)

A solution of methyl 2-(2-arylamidophenyl)acetate (1) (1 mmol) and Lawesson's reagent (1 mmol) in toluene (10 mL) was heated at reflux conditions under argon atmosphere for 15 min. After removal of the solvent, the residue was purified by column chromatography on silica gel using hexane–ethyl acetate as eluent to give the thioamidophenyl acetate (3).

General procedure for the synthesis of diazoesters (2 & 4)

To a stirred solution of 1 or 3 (1 mmol) and p-methylbenzenesulfonylazide (PMBSA) (1.5 mmol) in acetonitrile (5 mL) was added 1,8-diazabicycloundec-7-ene (DBU) (1.5 mmol) at 0 °C. The mixture was then allowed to warm to room temperature. After stirring for 1 h, the mixture was quenched with aqueous NH₄Cl, extracted with diethyl ether, and dried over anhydrous Na₂SO₄. The solvent was removed under reduced pressure and purified by flash column chromatography on silica gel to give the corresponding diazo compound 2 or 4.

General procedure for the synthesis of benzo[d][1,3]oxazine and benzo[d][1,3]thiazine (5 & 6)

To a stirred solution of 2 or 4 (1 mmol) in dichloroethane (5 mL) was added Cu(OTf)₂ (10 mol%). The resulting mixture was stirred at 25 °C under nitrogen atmosphere. The yellow colour mixture was allowed to stir until it turns pale red colour (10–30 min). The mixture was quenched with sat. NaHCO₃ solution (1.0 mL) and extracted with dichloromethane (2–5 mL). The combined organic layers were washed with brine solution (3–5 mL), dried over anhydrous Na₂SO₄, and concentrated in vacuo. The resulting crude product was purified by silica gel column chromatography (100–200 mesh) using ethyl acetate–hexane as eluent to afford the pure product.

Acknowledgements

B. V. S thanks CSIR, New Delhi for the financial support as a part of XII five year plan program under title ORIGIN (CSC-0108).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Copies of ¹H and ¹³C NMR spectrum of products. Detailed procedures and spectroscopic data for novel compounds, copies of ¹H NMR, ¹³C NMR of novel compounds prepared are available. CCDC 994907. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ra08208g

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