Sulfone promoted Rh(III)-catalyzed C–H activation and base assisted 1,5-H shift strategy for the construction of seven-membered rings

Abstract

A facile synthesis of thiepine sulfones is described. It relies on a sequence of Rh(III)-catalyzed C–H cleavage, 1,5-H shift, and intramolecular allene insertion. As a result of extremely readily accessible starting materials and convenient operation, this protocol should be an appealing strategy in organic synthesis.

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Introduction

Over the past few decades, directing group (DG) promoted transition-metal-catalyzed C–H activation has emerged as a versatile and efficient tool for the construction of cyclic compounds.¹ With the chelation assistance of DG/metal, numerous C(sp²)–H activation-annulations have been successfully achieved.^2,3 However, on the other hand, the chelation assistance limits the construction of cyclic compounds, because of the cyclometalated intermediate, generally with six to seven-membered sizes (Scheme 1a).⁴ Recently, Glorius's group and Zhao's group reported a rhodium catalyzed C–H activation/[4 + 3] annulation protocols, respectively, using α,β-unsaturated aldehydes (ketones) as the C3 sources (Scheme 1b).⁵ Herein we wish to report the realization of a new strategy in which the carbon–rhodium species, derived from ortho C–H activation, underwent an intramolecular insertion of the allene moiety in situ generated from a 1,5-H shift, affording thiepine sulfone derivatives (Scheme 1c).

Scheme 1 Proposal of Rh(III)-catalyzed C–H activation/intramolecular insertion of allene.

Results and discussion

Optimization of reaction conditions

On the basis of the understanding of base-assisted propargyl–allenyl isomerization,⁶ we initiated our studies by examining the reaction of 2-methyl-5-phenylpent-2-en-4-yn-1-yl phenyl sulfone (1a) in the presence of [(Cp*RhCl₂)₂] (0.025 eq.) and triethylamine (3 eq.) in toluene at 100 °C. Substrate 1a could be prepared readily via treatment of commercially available 5-bromo-4-methyl-1-phenylpent-3-en-1-yne with sodium benzenesulfinate and [Cp*Rh^III] was chosen as the catalyst because of its high efficiency, mild reaction conditions and good functional group compatibility on C–H activation. This set of conditions afforded the desired product benzothiepine sulfone (2a) in 18% yield (Table 1, entry 1) and the structure of 2a was revealed by X-ray diffraction analysis (Fig. 1).⁷ We tested different additives in this system, and observed that Cu(OAc)₂ (0.25 eq.) was the most efficient, affording 2a in 54% yield (Table 1, entry 8). Lowering the reaction temperature to 80 °C improved the yield slightly (Table 1, entry 9). Subsequent screening of solvents showed that dichloroethane was the best choice, giving 82% yield (Table 1, entry 11); and the use of other rhodium catalysts did not offer better results (Table 1, entries 15–17). Control experiments confirmed that the transformation did not occur in the absence of [(Cp*RhCl₂)₂] or triethylamine (Table 1, entries 18 and 19).

Fig. 1 ORTEP representation of 2a.

Table 1 Optimization of the reaction conditions^a

Entry	Catalyst	Additive (eq.)	Solvent	T (°C)	Yield (%)
a Conditions: 1a (0.20 mmol), catalyst (0.025 eq.), Et3N (3 eq.), additive, and solvent (2.0 mL). b 1a was recovered in 95% yield. c The reaction was conducted without triethylamine and 1a was recovered in 88% yield.
1	C1	—	PhMe	100	18
2	C1	AgOAc (0.5)	PhMe	100	25
3	C1	Ag2CO3 (0.5)	PhMe	100	22
4	C1	CuBr2 (0.5)	PhMe	100	25
5	C1	CuSO4 (0.5)	PhMe	100	19
6	C1	AgBF4 (0.5)	PhMe	100	28
7	C1	Cu(OAc)2 (0.5)	PhMe	100	48
8	C1	Cu(OAc)2 (0.25)	PhMe	100	54
9	C1	Cu(OAc)2 (0.25)	PhMe	80	61
10	C1	Cu(OAc)2 (0.25)	PhMe	60	41
11	C1	Cu(OAc) 2 (0.25)	DCE	80	82
12	C1	Cu(OAc)2 (0.25)	CH3CN	80	57
13	C1	Cu(OAc)2 (0.25)	DMF	80	28
14	C1	Cu(OAc)2 (0.25)	1,4-Dioxane	80	25
15	C2	Cu(OAc)2 (0.25)	DCE	80	15
16	C3	Cu(OAc)2 (0.25)	DCE	80	19
17	C4	Cu(OAc)2 (0.25)	DCE	80	43
18	—	Cu(OAc)2 (0.25)	DCE	80	0^b
19	C1	Cu(OAc)2 (0.25)	DCE	80	0^c

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Scope of the Rh(III)-catalyzed C–H activation

With the optimized conditions in hand, we examined the scope of this reaction and obtained polyfunctionalized benzothiepine sulfones (2) in moderate to good yields under mild conditions (Table 2). The R² can be a phenyl group optionally substituted with either an electron-withdrawing or an electron-donating group (2b–2f), a naphthalenyl group (2g and 2h), or an alkyl group (2p and 2q). The substrates containing an electron-donating or electron-withdrawing group on the phenyl ring adjacent to sulfone also reacted efficiently (2h–2l).

Table 2 Synthesis of benzothiepine sulfones^a

a Conditions: 1 (0.20 mmol), [(Cp*RhCl₂)₂] (0.005 mmol), Et₃N (0.6 mmol), Cu(OAc)₂ (0.05 mmol), and DCE (2.0 mL) at 80 °C.

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Then our attention was diverted to the synthesis of heterocycle-annulated thiepine sulfones. The substrates with furanyl and pyrrolyl sulfone moieties decomposed under the standard conditions; while stable thiophenyl sulfone substrates reacted smoothly and afforded desired products in good yields (Table 3).

Table 3 Synthesis of thieno[2,3-b]thiepine sulfones^a

a Conditions: 3 (0.20 mmol), [(Cp*RhCl₂)₂] (0.005 mmol), Et₃N (0.6 mmol), Cu(OAc)₂ (0.05 mmol), and DCE (2.0 mL) at 80 °C.

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Mechanistic discussion

The C–H activation using sulfone as a coordinating directing group has not been well documented, probably due to its weak Lewis basicity.⁸ To probe the mechanism of the C–H activation–annulation, we prepared d₅-1a for the control experiments. First, we measured the value of K_H/D = 3.17, indicating that C–H bond cleavage is the rate-determining step [Scheme 2, (1)]. The KIE value was calculated by dividing the ¹H NMR yields of the isotopic products after 6 h (approximation to initial rate ratios). Then, we conducted the reaction using d₅-1a as the substrate under similar conditions. One of the ortho deuterium atoms on the benzene ring moved to the methylene group of 2a, demonstrating that an intramolecular insertion had occurred [Scheme 2, (2)].

Scheme 2 Deuterium labeling studies.

Based on these results, a plausible mechanism is proposed in Scheme 3. Coordination of sulfone 1a to a [Cp*Rh^III] species for the C–H bond cleavage affords A, which experiences a base-assisted 1,5-H shift to form allene intermediate B.⁹ The rhodacycle moiety of intermediate B coordinates intramolecularly the allene moiety and undergoes insertion giving intermediate C.¹⁰ Subsequently, protonolysis of C delivers the product 2a.

Scheme 3 Plausible mechanism.

Conclusion

In conclusion, a sequence of Rh(III)-catalyzed C–H activation, 1,5-H shift, intramolecular allene insertion and protonolysis to afford thiepine sulfones has been realized. As a result of extremely readily accessible starting materials and the convenient operation, the protocol presented here should be an appealing strategy in organic synthesis. Further studies on the synthetic application are currently ongoing.

Acknowledgements

We are grateful to the National Natural Science Foundation of China (Project No. 20972134) and Zhejiang Provincial Natural Science Foundation of China (Project No. LY14B020008) for financial support.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1050464. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5qo00089k

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