Synthesis of polycyclic sultams via a palladium-catalyzed reaction of 1-bromo-2-(cyclopropylidenemethyl)benzenes with 2-alkynylbenzenesulfonamides

Abstract

Polycyclic sultams are efficiently synthesized through a palladium-catalyzed tandem reaction of 1-bromo-2-(cyclopropylidenemethyl)benzenes with 2-alkynylbenzenesulfonamides. The transformation proceeds through double carbometallation with excellent chemoselectivity and regioselectivity, leading to a range of 7,7a-dihydro-6H-benzo[f]indeno[1,2-d][1,2]thiazepine 5,5-dioxides in moderate to good yields. During the reaction process, three new bonds and two rings including the seven-membered sultam ring are formed.

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Introduction

Cyclic sulfonamides are widely present in both natural products and therapeutic agents, and their applications in organic synthesis and pharmaceutical research have been demonstrated.¹ Tianeptine as a typical example is a drug, which is used for the treatment of major depressive episodes.² Consistent with our continuing interest in the libraries’ construction and biological evaluation of natural product-like compounds,³ we are interested in the preparation of bioactive compounds with a core of cyclic sulfonamide.⁴ Recently, we identified that a cyclic sulfonamide has great potential in inducing apoptosis of hepatic stellate cells (HSCs) in vitro, and the activation of caspase-3 might be involved in this process.⁵ This promising result prompted us to look for more active hits. Therefore, the construction of diverse cyclic sulfonamides with complexity for further biological evaluations is in high demand.

Recently, we have developed the strategy of double carbometallation for the generation of complex molecules.^3b,e This approach is attractive, since excellent chemoselectivity and regioselectivity can be observed during the reaction process with the formation of multi-bonds and the competitive pathways are minimized.⁶ Usually, substrates with multi-active sites are involved in a tandem process.⁷ For example, the strategy was initially discovered for the reaction of 2-alkynylbenzenebromides with amines, which provided 5H-cyclopenta[c]quinolines in good yields with the formation of four new bonds via double carbometallation.^6g Based on the alkynyl moiety and aryl bromide in 2-alkynylbenzenebromide, a range of polycycles was then produced when 2-alkynylbenzenebromides reacted with various coupling partners.⁶ Further studies revealed that the approach could be extended to 1-bromo-2-(cyclopropylidenemethyl)benzenes 1,⁸ which was used as a replacement of 2-alkynylbenzenebromide. The reactivity of alkylidenecyclopropanes has been demonstrated.⁹ We conceived that the cyclopropylidenemethyl group could be considered as an equivalence of an alkynyl moiety during the reaction process. For instance, we developed a facile route for the assembly of indeno[1,2-c]chromenes via a palladium-catalyzed tandem reaction of 1-bromo-2-(cyclopropylidenemethyl)benzenes 1 with 2-alkynylphenols (Scheme 1).^8a This reaction worked well, and we did not observe the formation of benzofurans via direct cyclization of 2-alkynylphenol. As mentioned above, the excellent chemoselectivity and regioselectivity under the conditions produced the final outcome. Encouraged by this result, we envisioned that 2-alkynylbenzenesulfonamides 2 ¹⁰ would be the choice for the reaction of 1 as well. As expected, cyclic sulfonamides 3A would be prepared if the reaction proceeded through a similar transformation.^8a As described in Scheme 1, we postulated that an oxidative addition of compound 1 to palladium(0) would occur to produce Pd(II) A. Although the competitive reaction pathways including intramolecular 6-endo cyclization¹⁰ and direct C–N bond formation¹¹ would happen, we believed that the presence of sulfonamide would direct the regioselective coordination and insertion of Pd(II) A to the triple bond of 2 to generate intermediate B. Subsequently, intermediate C would be formed via an intramolecular insertion of the double bond of alkylidenecyclopropane into the carbon–Pd(II) bond. Further C–N bond formation in the presence of a base would provide compound 3. After intramolecular rearrangement as similar as the reaction of 1-bromo-2-(cyclopropylidenemethyl)benzene with 2-alkynylphenol, compound 3A would be generated. To identify the practicability of this proposed route shown in Scheme 1, we therefore started to explore the palladium-catalyzed tandem reaction of 1 with 2.

Scheme 1 A proposed palladium-catalyzed reaction of 1-bromo-2-(cyclopropylidenemethyl)benzenes 1 with 2-alkynylbenzenesulfonamides 2.

Results and discussion

Initially, the reaction of 1-bromo-2-(cyclopropylidenemethyl)benzene 1a and N-methyl-2-(phenylethynyl)benzenesulfonamide 2a was selected for reaction development (Table 1). At the beginning, the reaction was performed in the presence of palladium acetate (2.5 mol%), 1,1′-bis(diphenylphosphino)propane (DPPP, 5 mol%) and potassium carbonate in 1,4-dioxane under reflux (Table 1, entry 1). However, no reaction occurred under the conditions. Only a trace amount of the product was detected when the phosphine ligand was changed to XPhos (Table 1, entry 2). To our delight, a product was isolated in 16% yield when 1,1′-bis(diphenylphosphino)ferrocene (DPPF) was used as the ligand (Table 1, entry 3). Interestingly, the structure of this product was identified as compound 3a after X-ray crystallography analysis (see ESI†). We did not observe the formation of compound 3Aa, as illustrated above.^8a In our previous report, the driving force for the ring-opening rearrangement of cyclopropane came from the electron pair of oxygen in 2-alkynylphenol.^8a We reasoned that the weaker force from nitrogen in 2-alkynylbenzenesulfonamides provided less thrust to promote the ring-opening transformation. We further evaluated other phosphine ligands. Gratifyingly, the corresponding product 3a could be obtained in 40% yield when 1,1′-bis(dicyclohexylphosphino)ferrocene (L1) was employed as the ligand (Table 1, entry 6).

Table 1 Initial studies for the palladium-catalyzed reaction of 1-bromo-2-(cyclopropylidenemethyl)benzene 1a with 2-alkynylbenzenesulfonamide 2a ^a

Entry	[Pd]	Ligand	Base	Solvent	Yield^b (%)
a Reaction conditions: 1-bromo-2-(cyclopropylidenemethyl)benzene 1a (0.40 mmol), N-methyl-2-(phenylethynyl)benzenesulfonamide 2a (0.2 mmol), palladium catalyst (2.5 mol%), ligand (5 mol%), base (0.4 mmol), solvent (2.0 mL), reflux, N2, overnight. b Isolated yield based on N-methyl-2-(phenylethynyl)benzenesulfonamide 2a. c The reaction was performed at 80 °C.
1	Pd(OAc)2	DPPP	K2CO3	Dioxane	NR
2	Pd(OAc)2	XPhos	K2CO3	Dioxane	Trace
3	Pd(OAc)2	DPPF	K2CO3	Dioxane	16
4	Pd(OAc)2	PCy3	K2CO3	Dioxane	23
5	Pd(OAc)2	SPhos	K2CO3	Dioxane	36
6	Pd(OAc)2	L1	K2CO3	Dioxane	40
7	Pd(OAc)2	L1	K3PO4	Dioxane	NR
8	Pd(OAc)2	L1	DABCO	Dioxane	Trace
9	Pd(OAc)2	L1	KHCO3	Dioxane	10
10	Pd(OAc)2	L1	Cs2CO3	Dioxane	24
11	Pd(OAc)2	L1	KOAc	Dioxane	25
12	Pd2dba3	L1	K2CO3	Dioxane	Trace
13	PdCl2	L1	K2CO3	Dioxane	33
14	PdCl2(PPh3)2	L1	K2CO3	Dioxane	11
15	PdCl2(dppf)	L1	K2CO3	Dioxane	60
16	Pd(TFA)2	L1	K2CO3	Dioxane	40
17	PdCl2(dppf)	L1	K2CO3	DMF	NR
18	PdCl2(dppf)	L1	K2CO3	DMSO	NR
19	PdCl2(dppf)	L1	K2CO3	Toluene	22
20	PdCl2(dppf)	L1	K2CO3	AmylOH	Trace
21	PdCl2(dppf)	L1	K2CO3	Diglyme	13
22^c	PdCl2(dppf)	L1	K2CO3	Dioxane	35

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With this promising result in hand, we then explored the reaction in the presence of different bases (Table 1, entries 7–11) and no better yields were obtained. We also examined the reaction catalyzed by other palladium salts. It was found that the reaction worked efficiently when PdCl₂(dppf) was employed (Table 1, entry 15), leading to the desired product 3a in 60% yield. Other solvents including DMF, DMSO, toluene, diglyme (diethylene glycol dimethyl ether), or AmylOH (2-methyl-2-butanol) were utilized in this transformation. However, the results were inferior. The yield of the corresponding product 3a was lower when the reaction was performed at 80 °C (Table 1, entry 22). The reaction was retarded when the amount of palladium catalyst was reduced (data not shown in Table 1).

Under the above optimized conditions, the reaction scope was then investigated. Examples are presented in Table 2. Usually, the reactions went to completion in 4 hours. It was found that the palladium-catalyzed tandem reaction of 1-bromo-2-(cyclopropylidenemethyl)benzenes 1 with 2-alkynylbenzenesulfonamides 2 worked well, producing the corresponding 7,7a-dihydro-6H-benzo[f]indeno[1,2-d][1,2]thiazepine 5,5-dioxides in moderate to good yields. The polycyclic sultams could be constructed efficiently through double carbometallation with excellent chemoselectivity and regioselectivity. Different functional groups could be compatible under the standard conditions. For instance, the thiophenyl-substituted product 3n could be generated as expected. A range of compounds 2 with different substituents appended to the triple bond or the aromatic ring were good partners in the transformation as well. The electronic effects of R¹ on the aromatic ring of compounds 1 were also explored, which demonstrated that both the electron-donating group and electron-withdrawing group were tolerated under the standard reaction conditions. Additionally, the substrates with the methyl or phenyl group changed from the cyclopropyl group were synthesized and examined under the reaction conditions. However, the reactions were complex and no desired products were generated. We reasoned that the cyclopropyl group might have an influence on controlling the coordination of Pd(II) in this transformation, which would promote the intramolecular insertion of a palladium intermediate into the double bond. In the meantime, we explored the reaction of N-methyl-1-(2-(phenylethynyl)phenyl)methanamine with 1-bromo-2-(cyclopropylidenemethyl)benzene 1a. No desired product through double carbometallation was observed.

Table 2 Scope exploration of the palladium-catalyzed reaction of 1-bromo-2-(cyclopropylidenemethyl)benzenes 1 with 2-alkynylbenzenesulfonamides 2^a

a Isolated yield based on 2-alkynylbenzenesulfonamide 2.

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Conclusions

In conclusion, we have developed an efficient route to polycyclic sultams through a palladium-catalyzed tandem reaction of 1-bromo-2-(cyclopropylidenemethyl)benzenes with 2-alkynylbenzenesulfonamides. The transformation proceeds through double carbometallation with excellent chemoselectivity and regioselectivity, leading to a range of 7,7a-dihydro-6H-benzo[f]indeno[1,2-d][1,2]thiazepine 5,5-dioxides in moderate to good yields. During the reaction process, three new bonds and two rings including the seven-membered sultam ring are formed.

Acknowledgements

Financial support from the National Natural Science Foundation of China (no. 21372046 and 21532001) and the Opening Project of Gannan Medical University Collaborative Innovation Center for Gannan Oil-tea Camellia Industrial Development is gratefully acknowledged.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedure and related data. CCDC 1491815. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6qo00480f

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