A new route to naphthyl ketones via copper-mediated intramolecular aerobic oxidative cyclization of alkynes and sulfonylcrotonates

Abstract

Herein we report a copper-mediated intramolecular aerobic oxidative cyclization of alkynes and sulfonylcrotonates. This method provides simple, efficient and easy to operate access to a variety of highly functionalized naphthyl ketones with excellent functional group tolerance.

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Naphthalene derivatives are useful frameworks due to their frequent presence in pharmaceuticals, natural products and structural motifs with widespread use in materials science, chiral catalysis and as synthetic intermediates.¹ Efficient routes toward naphthalene skeletons has attracted the continued interest of the synthetic organic chemistry community.² Therefore, recent years have witnessed a rapid growth in the development of annulation reactions to construct naphthalene derivatives.^3–5 For example, the [4 + 2] benzannulations of alkynes with carbonyl groups have proved as powerful approaches to construct naphthalene derivatives. However, cyclization reactions of alkynes with sp³ carbons, which was an fascinating strategies for functionalization of sp³ carbons,⁶ leading to naphthalene derivatives are rarely reported.⁷ In this regard, cyclization reactions of alkynes with sp³ carbons would enrich the access to naphthalene derivatives.

Organosulfones serve as versatile synthetic building blocks in organic synthesis.^3h,8 Recently, Menon reported an oxidative [3 + 3] benzannulation reaction of 4-sulfonylcrotonates (or 1,3-bissulfonylpropene) with α,β-unsaturated aldehydes and ketones to assemble substituted arenes via allylic carbanion intermediate (Scheme 1, eqn (1)).⁹ Since allylic carbanion is feature of nucleophilicity, we conceived that annulation reaction of sulfonylcrotonates with alkynes might be realized via the intramolecular nucleophilic attack of allylic carbanion intermediate to alkyne,¹⁰ with the aid of base and transition metals, leading to aryl sulfones (Scheme 1, eqn (2)). Therefore, we started to explore this proposed synthetic route. We herein report our efforts to develop a new copper mediated annulation reaction of alkynes with sulfonylcrotonates to construct unexpected naphthyl ketones under aerobic conditions in an open flask procedure (Scheme 1, eqn (3)).

Scheme 1 Proposed synthetic routes of organosulfones.

Our study began to examine the feasibility of the proposed annulation reaction of ethyl 3-(2-(phenylethynyl)phenyl)-2-((phenylsulfonyl)methyl)acrylate (1a) in the presence of a series of copper catalysts and bases (Table 1). However, we did not observe the formation of the desired ethyl 4-benzyl-3-(phenylsulfonyl)-2-naphthoate. Instead, ethyl 4-benzoyl-2-naphthoate 2a was produced in 12% yield, using 20 mol% Cu(OAc)₂ as catalyst and Cs₂CO₃ as base (Table 1, entry 3). The other copper salts, such as CuI, CuCl₂, Cu(OOCCF₃)₂, Cu(OTf)₂, Cu(acac)₂ gave none or a trace amount of 2a (Table 1, entries 1, 2 and 4–6). To our delight, the yield of 2a was increased to 87% when using 100 mol% Cu(OAc)₂ (Table 1, entry 7). Notably, the reaction did not take place in the absence of either the Cu catalysts or bases (Table 1, entries 8 and 9). These results encouraged us to evaluate other bases, such as K₂CO₃, t-BuOK, DBU and Et₃N (Table 1, entries 10–13). However, no better results were obtained. Other solvents were examined subsequently and the results were inferior when the reaction took place in other solvents (Table 1, entries 14–16). For examples, DMF and DMSO could deliver 2a in 51% and 67% yields respectively, toluene suppressed the reaction greatly.

Table 1 Screening optimal conditions^a

Entry	[Cu]	Base	Solvent	Yield^b
a Reaction conditions: 1a (0.15 mmol), [Cu] (20 mol%), base (2 equiv.) and solvent (2 mL) in air at 100 °C for 48 h.b Isolated yield.c [Cu] (100 mol%).
1	CuI	Cs2CO3	MeCN	Trace
2	CuCl2	Cs2CO3	MeCN	5
3	Cu(OAc)2	Cs2CO3	MeCN	12
4	Cu(OOCCF3)2	Cs2CO3	MeCN	9
5	Cu(OTf)2	Cs2CO3	MeCN	Trace
6	Cu(acac)2	Cs2CO3	MeCN	Trace
7^c	Cu(OAc)2	Cs2CO3	MeCN	87
8	—	Cs2CO3	MeCN	NR
9^c	Cu(OAc)2	—	MeCN	NR
10^c	Cu(OAc)2	K2CO3	MeCN	Trace
11^c	Cu(OAc)2	KOtBu	MeCN	28
12^c	Cu(OAc)2	DBU	MeCN	72
13^c	Cu(OAc)2	Et3N	MeCN	NR
14^c	Cu(OAc)2	Cs2CO3	DMF	51
15^c	Cu(OAc)2	Cs2CO3	DMSO	67
16^c	Cu(OAc)2	Cs2CO3	Toluene	20

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We next explored the scope of this Cu(II)-mediated cyclization reaction under the optimized conditions: 100 mol% of Cu(OAc)₂, 2.0 equiv. of Cs₂CO₃, MeCN, 100 °C. The results are summarized in Table 2. Screening revealed that a series of aryl substitutions on the R position at the terminal alkynes were all tolerated, including 4-MeC₆H₄, 4-MeOC₆H₄, 4-FC₆H₄, 4-ClC₆H₄, 4-CF₃C₆H₄, 3-MeC₆H₄, 2-MeC₆H₄ (2b–2h). Gratifyingly, some heterocyclic substitutions on the R position were also compatible with this reaction and gave the target products in moderate to good yields, which makes this methodology more useful (2i–2k). For example, ethyl 4-(thiophene-2-carbonyl)-2-naphthoate (2i) and ethyl 4-(benzofuran-2-carbonyl)-2-naphthoate (2j) could be afforded in 70% and 62% yields respectively. To our disappointment, when the R position was changed to enynes and aliphatic alkynes, an inseparable complex mixture was obtained from the reaction (2l–2n). Next, substitutions on the aromatic ring (R¹) were investigated. It was found that substrates 1 with electron withdrawing and electron-donating groups and heterocyclic rings on the aromatic ring were all workable in the reactions (2o–2t). To our delight, the current reaction could be used to construct a heterocycle-containing cyclic system: the reaction of ethyl 3-(3-(phenylethynyl)thiophen-2-yl)-2-((phenylsulfonyl)methyl) acrylate gave product 2u in 61% yield, thus making this method applicable for the preparation of heterocycle-containing pharmaceuticals and materials. Lastly, it is noteworthy that the ester group at the R² position is necessary for the reaction: when the CO₂Et group replaced by CO₂Me, corresponding product 2v was obtained in moderate yield; however, products 4-benzoyl-2-naphthonitrile (2w) and naphthalen-1-yl(phenyl)methanone (2x) could not be obtained from substrate with a CN or H atom at the R² position.

Table 2 Cu(II)-mediated synthesis of naphthyl ketones^ab

a Reaction conditions: 1a (0.15 mmol), [Cu] (0.15 mmol), Cs₂CO₃ (2 equiv.) and MeCN (2 mL) in air at 100 °C for 48 h.b Isolated yield.c 36 h.

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Some control experiments were performed to understand the mechanism (Scheme 2).¹¹ Firstly, the yield of product 2a was reduced to 12% (48% deuteration) when treatment of 1a with 20 equiv. D₂O, and 60% of 1a (73% deuteration) was recovered [eqn (1)]. These results indicated that 1a could be deprotonated by base under the reaction condition. In addition, product 2a could not be formed when treatment of 1a in N₂ atmosphere and greater than 90% of 1a was recovered [eqn (2)]. Subsequently, an ¹⁸O-labeled experiment by using H₂¹⁸O was investigated [eqn (3)]. In the presence of H₂¹⁸O, treatment of 1a in air, only ¹⁶O-containing product 2a was isolated in 19% yield. These results confirmed that oxygen was essential for this reaction and the oxygen atom was really incorporated from atmospheric molecular oxygen. It was found that the cyclization reaction of 1a was completely suppressed when stoichiometric amounts of radical inhibitors (TEMPO) were added and greater than 90% of 1a was recovered together with a trace of target product 2a [eqn (4)]. These results suggest that this annulation proceeds via a radical process.

Scheme 2 Control experiments.

The mechanism for the cyclization reaction is proposed on the basis of the present results and previous reports (Scheme 3). Initially, allylic carbanion intermediate A is generated by deprotonation of the C(sp³)–H bond adjacent to the sulfonyl group by Cs₂CO₃,⁹ and the triple bond is activated by Cu(II). Next, nucleophilic cyclization with alkyne in intermediate A takes place to form intermediate B, followed by oxidation of intermediate B with O₂ (ref. 12) to form a Cu(III) peroxo species C. Reductive elimination of intermediate C furnishes a peroxide intermediate D. Finally, the peroxide intermediate D undergoes sequentially the O–O bond cleavage, reductive elimination and desulfonative aromatization^3h,8c to furnish 2a and the Cu(I) species.

Scheme 3 Possible mechanism.

Conclusions

In conclusion, we have described a new Cu(II)-mediated carbocyclization reaction of alkynes with C(sp³)–H bond adjacent to the sulfonyl group. This present protocol provides an alternative to naphthyl ketones by employing an oxygen atom from molecular oxygen.

Acknowledgements

We are grateful to the Ministry of Science and Technology of the People's Republic of China (973 Project No. 2014CB660804), Natural Science Foundation of China (21302105, U1504208, 21404061) and the financial support from Nanyang Normal University (ZX2014049).

Notes and references

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11. Please see the ESI† for more details.
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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra23244b

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