tert-Butoxide mediated cascade desulfonylation/arylation/hydrolysis of cyclic sulfonyimines using diaryliodonium salts: synthesis of diaryl ether derivatives bearing a 2-aldehyde group

Abstract

Cascades of cyclic sulfonyimines mediated by ^tBuOK with diaryliodonium salts has been developed, giving the diaryl ethers in good yields. Furthermore, bulky ortho-substituted diaryl ethers with an aldehyde group can be obtained easily in comparision with metal-catalyzed protocols.

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Aryl ethers as common structural motifs can be found in various biological compounds, drug candidates and functional material molecules.¹ For example, D-phenothrin and oxyfluorfen including a diarylether skeleton are a well-known insecticide and herbicide, respectively. α-Mangostin is a natural xanthonoid which was studied for potential usage in pharmaceutical research (Fig. 1).² Therefore, construction of diaryl ethers has attracted considerable interest.³ Typical procedures in the synthesis of diaryl ethers are Ullmann-type reactions.⁴ However, the Ullmann reactions usually required stoichiometric amounts of copper catalysts and harsh reaction conditions.^4,5 Hence, the development of new methods to access aryl ethers is still in demand. Despite various powerful synthetic approaches of cross-coupling reactions mediated by copper or palladium complexes being recorded in recent decades,⁶ the use of heavy metals limits their practical application due to purification and cost. Therefore, the Ullmann ether synthesis with a metal-free method using highly activated aryl fluorides was also reported,⁷ while most cases were limited to the electron-rich or neutral phenols.

Fig. 1 Selected samples of diaryl ether structures.

Recently, Olofsson and coworkers pioneered the arylation of phenols under the mild and metal-free conditions by using diaryliodonium salts.⁸ The methodology was further extended to the O-arylation of N-hydroxyphthalimides and carboxylic acids.⁹ However, the synthesis of ortho-substituted diaryl ethers with steric hindrance still remained a challenge. In 2014, Jiang and coworkers developed a practical approach for the synthesis of ortho-CHO diaryl ethers by a three component sequential coupling of arynes, N,N-dimethylformamide and diaryliodonium salts.¹⁰ In this context, we reported N-arylations of carbazoles and hydroxylamines, O-arylation of oximes and C-arylations of tetrahydrocarbazoles, pyrazolin-5-ones, cyanoacetates and 1-acetylindolin-3-ones by using diaryliodonium salts.¹¹ With our continuous interest in arylations under metal-free conditions, we were intrigued by the possibility of arylation with cyclic imines to synthesize ortho-CHO diaryl ethers. Herein, we reported the detail results that potassium tert-butoxide mediated arylation of cyclic imines, giving an efficient access to ortho-CHO diaryl ethers.

We began our study by chosen benzo[e][1,2,3]oxathiazine-2,2-dioxide (1a) and diphenyliodonium triflate (2a) as model substrates to optimize the reaction conditions. To our delight, the reaction gave the desired product in 40% yield in presence of K₂CO₃ as the base and MeCN as solvent at 60 °C (Table 1, entry 1). After screening several bases, it was found that strong inorganic bases worked well, for example, the base of ^tBuOK gave 3a in 55% yield (Table 1, entry 2–4). When the organic bases of lutidine and DMAP were employed, the reaction cannot occur at all (Table 1, entry 5–6). Screening of solvents showed that potassium tert-butoxide in dichloroethane (DCE) delivered the desired product 3a in the most efficient manner (Table 1, entry 5–12). We also tried to increase the reaction temperature, however, the yield of 3a was slightly decreased (Table 1, entries 13). Furthermore, different counteranions of diphenyliodonium salts were also evaluated on the reactivity, only a negligible influence on the yields was observed (Table 1, entries 14–16).

Table 1 Screening of reaction conditions for arylation of benzo[e][1,2,3]oxathiazine 2,2-dioxide^a

Entry	X	Base	Solvent	% yield^b
a Unless otherwise specified, reaction conditions: 1a (0.3 mmol), iodonium salt (0.33 mmol, 1.1 equiv.), base (0.33 mmol) and solvent (2 mL); 60 °C, 30 min.b Isolated yield.c For 80 °C.
1	OTf	K2CO3	MeCN	40
2	OTf	Cs2CO3	MeCN	44
3	OTf	NaOH	MeCN	50
4	OTf	^tBuOK	MeCN	55
5	OTf	Lutidine	MeCN	—
6	OTf	DMAP	MeCN	—
7	OTf	^tBuOK	Toluene	24
8	OTf	^tBuOK	CH2Cl2	35
9	OTf	^tBuOK	DCE	62
10	OTf	^tBuOK	THF	40
11	OTf	^tBuOK	DMF	25
12	OTf	^tBuOK	MeCN	36
13^c	OTf	^tBuOK	DCE	55
14	PF6	^tBuOK	DCE	61
15	OTs	^tBuOK	DCE	55
16	BF4	^tBuOK	DCE	59

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With the optimal conditions in hand, we then investigated various diaryliodonium salts as arylation partners. Generally, the reaction condition proved to be efficient to a variety of functionalities of diaryliodonium salts, and the reactions were completed in the short time of 30 minutes as determined by thin layer chromatography. For symmetrical diaryliodonium salts, it was found that the diaryliodonium salts bearing the alkyl including the trifluoromethyl on the phenyl ring furnished 3b–f in moderate yields of 44–50% (Table 2, entry 1–5). Notably, when the substitute groups changed to halogen, the desired products were obtained in good yields of 69–80% (Table 2, entry 6–9). The electron-withdrawing groups such as ester gave a moderate yield of 62% (Table 1, entry 10). When 2l was used as reactant, no product was observed; and it was found that the reaction lead to decompose the substrate 2l to give a complicated mixtures as shown in thin layer chromatography (Table 1, entry 11). Next, unsymmetrical diaryliodonium salts were employed in the reaction, it is interesting found that electron-withdrawing groups were transferred to the desired products, for example, only 3m bearing a ester substituent was obtained when [4-CO₂EtC₄H₄I(mesityl)]OTf was employed in the reaction, the product of mesityl ether was not observed. In order to prove the steric effect of mesityl group on the selectivity, [4-MeC₆H₄I(mesityl)]OTf was used in the reaction, both products of 3e and 3c was yielded. Surprisingly the major product is 3e and the ratio of 3e/3a is more than 20/1.

Table 2 Scope of diverse iodonium salts in arylation of benzo[e][1,2,3]oxathiazine 2,2-dioxide^a

Entry	Ar^1(Ar^2)	X	Product	% yield^b
a Unless otherwise specified, reaction conditions: 1a (0.3 mmol), BuOK (0.33 mmol) iodonium salt (0.33 mmol, 1.1 equiv.), and DCE (2 mL); 60 °C, 30 min.b Isolated yield.
1	(4-^tBuC6H4)2	OTf	3b	49
2	(4-MeC6H4)2	OTf	3c	50
3	(3-MeC6H4)2	OTf	3d	48
4	(Mesityl)2	OTf	3e	44
5	(4-CF3C6H4)2	BF4	3f	50
6	(4-FC6H4)2	OTf	3g	69
7	(4-ClC6H4)2	OTf	3h	80
8	(3,4-Cl2C6H3)2	BF4	3i	74
9	(4-BrC6H4)2	OTf	3j	80
10	(3-CO2EtC6H4)2	PF6	3k	62
11	(3-NO2C6H4)2	PF6	3l	N.D.
12	4-CO2EtC6H4(mesityl)	OTf	3m	40
13	Mesityl(4-MeC6H4)	OTf	3e: 3c > 20: 1	32

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For further exploring the scope of this reaction, a wide range of benzoxathiazine derivatives were employed under standard reaction conditions. The electron-donating substituents such as alkyl, benzene, methoxy or N,N-diethyl amino groups, gave the desired products 4a–4e in 59–68% yields (Table 3, entry 1–5). When the substituents (R) were halogen atoms, the desired products were furnished in moderate yields of 41–52% (Table 3, entry 6–10). Furthermore, the reaction it is noted that benzoxathiazines carrying the electron-withdrawing substituents, can also reacted well. For example, the product 4j was achieved in 45% yield when 1j was used with the standard procedure. Additionally, naphthalene derivative 4k was obtained in 50% yield under the standard reaction conditions.

Table 3 Scope of diverse benzoxathiazine derivatives in arylation^a

Entry	1	Product	% yield^b
a Unless otherwise specified, reaction conditions: 1 (0.3 mmol), ^tBuOK (0.33 mmol) 2a (0.33 mmol, 1.1 equiv.), and DCE (2 mL); 60 °C, 30 min.b Isolated yield.
1			68
2			67
3			60
4			63
5			59
6			52
7			44
8			43
9			41
10			45
11			50

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Finally, the utility of the arylation products for conversion into useful skeleton was attempted. Xanthones are the core structures of many naturally occurred compounds exhibiting biological and pharmaceutical activities.^1c,2b Therefore, 2-phenoxybenzaldehyde was tried in a preparative scale of 50 mmol, which was obtained in 62% yield. Then, the xanthone was prepared under oxidative conditions via a dehydrogenative coupling reaction,¹² the final product of 5 was achieved in 60% yield (Scheme 1).

Scheme 1 Synthesis of xanthone.

Conclusions

In summary, we developed a new O-arylation method through a cascade reaction of benzo[e][1,2,3]oxathiazine 2,2-dioxides by using diaryliodonium salts under metal-free condition. Various diaryl ethers bearing a variety of functional groups could be obtained with this procedure. Moreover, the products of 2-phenoxybenzaldehyde were important intermediates for valuable chemicals. It was demonstrated by a further conversion of diaryl ether into an xanthone.

Experimental section

General methods

All reagents were obtained from commercial sources without further purification. The diaryliodonium salts and substrates were prepared according to the literature report.^13,14 All reactions were performed in glassware under air. ¹H NMR and ¹³C NMR spectra were respectively recorded at 400 and 100 MHz, using tetramethylsilane as an internal reference. Chemical shifts (δ) and coupling constants (J) were expressed in parts per million and hertz, respectively. High-resolution mass spectrometry (HRMS) was performed on an EI-TOF spectrometer. Mass spectra were recorded by the mass spectrometry service of Shanghai Institute of Organic Chemistry. Column chromatography was performed on silica gel (Huang-hai, 300–400 mesh).

Typical procedure for arylation of benzo[e][1,2,3]oxathiazine 2,2-dioxide and the derivatives

A Schlenk tube was charged with benzo[e][1,2,3]oxathiazine 2,2-dioxide (54.9 mg, 0.3 mmol, 1 equiv.), potassium tert-butoxide (37.0 mg, 0.33 mmol, 1.1 equiv.), diaryliodonium salts (0.33 mmol, 1.1 equiv.), then 2 mL DCE was added under air. Then the tube was sealed with a rubber under air, and the reaction was heated to 60 °C for 30 min. After cooling to room temperature, the solvent was removed in vacuo and the residue was purified by silica gel using a proper eluent to afford the desired products.

Typical procedure for synthesis of xanthone

A Schlenk tube was charged with 2-phenoxybenzaldehyde (198.2 mg, 1.0 mmol), tetrabutylammonium bromide (161.2 mg, 0.5 mmol), H₂O (5 mL), TBHP (70% solution in water, 2 mL). Then the tube was sealed with a Teflon plug, the reaction was heated to 120 °C over night. After cooling to room temperature, the solvent was removed in vacuo and the residue was purified by silica gel using a proper eluent to afford xanthone.

Acknowledgements

This work was supported by grants from the National Nature Science Foundation of China (NSFC No. 21272069, 21472213, 21202186) and the Fundamental Research Funds for the Central Universities, Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra19313g

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