CuO/I₂-mediated intramolecular annulation for the synthesis of 2-aroyl-3-hydroxy-4-iodonaphthalenes

Abstract

A novel strategy has been developed for the direct synthesis of 2-aroyl-3-hydroxy-4-iodonaphthalenes from easily available (Z)-2-(hetero)arylidene-1-(hetero)arylbutane-1,3-diones in the presence of copper(II) oxide and iodine. This domino process involves consecutive methyl iodination/carbon–carbon double bond isomerization/6π-electrocyclization/aromatization/arene iodination sequences.

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Naphthalene derivatives are an important class of compounds that can be found in numerous natural products and broadly used in medicinal chemistry, particularly as antiviral, anticancer, antibacterial, and antihypertensive agents.¹ They also have widespread applications in optical and electronic materials as basic building blocks.² Therefore, the development of novel methods for the construction of naphthalene skeletons has always attracted much attention from chemists. To date, several excellent methods have been established,³ including Diels–Alder reactions,⁴ Dötz reactions,⁵ ring expansion reactions,⁶ rearrangement reactions,⁷ the cyclization of aromatic alkynes, enynes or enediynes,⁸ photo- or thermo-induced cyclization reactions,⁹ Lewis acid-catalyzed cyclization reactions,¹⁰ and many others.¹¹ These promising results hold the advantages of broad substrate scope, good functional group tolerance and high yields. However, the limitations are also obvious including the use of multistep-prepared materials, precious metal catalysts, multiple reaction sequences and harsh reaction conditions. In contrast to multistep reactions, one-pot processes have remarkable merits that greatly improve synthetic efficiency and generate less chemical waste. Furthermore, the use of molecular iodine and non-precious metal catalysts in cyclization reactions for the preparation of naphthalene derivatives is still an economical and fascinating theme. For example, Yamamoto and co-workers had developed the iodine-mediated electrophilic cyclization for the synthesis of naphthalenes from aryl propargyl alcohols.¹² Such kind of reaction type also includes Larock's electrophilic cyclization of 2-(phenylethynyl)benzaldehyde and ketones with iodine¹³ and Zhang's electrophilic annulation of aryl enynes with disulfides or diselenides under FeCl₃/I₂-mediated conditions.¹⁴ Besides, the utilization of non-precious metal iron or copper in benzoannulation makes it even more appealing for the construction of different types of naphthalene derivatives, which has been previously reported by several groups.¹⁵ Despite these significant results, novel methods for the synthesis of naphthalenes employing unprecedented synthons are still highly desirable. Herein, we report a new strategy for the direct access to 2-aroyl-3-hydroxy-4-iodonaphthalenes from easily available (Z)-2-arylidene-1-arylbutane-1,3-diones via a CuO/I₂-mediated intramolecular cyclization reaction with carbon–carbon bond formation in one pot.

Recently, we reported a highly efficient method for the synthesis of α-iodoketals from (Z)-2-arylidene-1-arylbutane-1,3-diones or aryl methyl ketones in the presence of copper(II) oxide and iodine in ethylene glycol (Scheme 1a).¹⁶ While studying this reaction, we unexpectedly found that the novel 2-benzoyl-3-hydroxy-4-iodonaphthalene was obtained when the reaction was conducted with ethanol as the solvent from (Z)-2-benzylidene-1-phenylbutane-1,3-dione, and the structure of this compound was unambiguously confirmed by X-ray diffraction analysis (Fig. 1a). To the best of our knowledge, this work represents the first reported example of the direct synthesis of naphthalene derivatives via the coupling of C_sp³–C_sp² under CuO/I₂-mediated conditions (Scheme 1b).

Scheme 1 The reactions using (Z)-2-(hetero)arylidene-1-(hetero)arylbutane-1,3-diones as substrates.

Fig. 1 X-ray structures of compound 2a, 2i and 2j.

Inspired by this discovery, we tried to optimize the reaction conditions using (Z)-2-benzylidene-1-phenylbutane-1,3-dione (1a) as a model substrate (Table 1). To our delight, the reaction proceeded successfully to give the desired product 2a in 42% yield when it was conducted at 60 °C in ethanol over 48 h using 1.5 equiv. of CuO and 1.2 equiv. of iodine (Table 1, entry 1). After screening several different amounts of CuO and iodine, we found that the yield could be increased to 65% using 3.0 equiv. of CuO and 2.0 equiv. of iodine (Table 1, entries 2–5). Furthermore, the yield was improved to 72% when the reaction was conducted at reflux (Table 1, entry 6). It is noteworthy that the best result (80% yield of 2a) was obtained when additional 3.0 equiv. of CuO and 2.0 equiv. of iodine were added to the reaction mixture (Table 1, entry 7). Based on this encouraging result, we evaluated a series of different copper catalysts, including Cu₂O, CuBr, CuCl, CuI, CuCl₂, CuBr₂, CuSO₄·5H₂O and Cu(OAc)₂·H₂O, but none of these had a positive impact on the outcome of the reaction (Table 1, entries 8–15). Several other solvents were also examined, including CH₃OH, DMF, CH₃CN, HOAc, CH₃Cl, DMSO, toluene and 1,4-dioxane, but none of these performed any better than EtOH (Table 1, entries 16–23).

Table 1 Optimization of the reaction conditions^a

Entry	Copper salts (equiv.)	I2 (equiv.)	Solvent	Temp (°C)	Yield^b (%)
a Unless otherwise specified, all reactions were carried out using 1a (0.5 mmol, 1.0 equiv.), copper salt (x equiv.) and I2 (x equiv.) in 2.5 mL solvent in sealed tube for 48 h.b Isolated yields.c 1a (0.5 mmol, 1.0 equiv.), CuO (3.0 equiv.) and I2 (2.0 equiv.) in 2.5 mL EtOH in sealed tube for 36 h, then filter the precipitate and add CuO (3.0 equiv.) and I2 (2.0 equiv.) to mother liquor. Continue refluxing for 12 h.d No desired products were obtained.
1	CuO (1.5)	1.2	C2H5OH	60	42
2	CuO (2.0)	2.0	C2H5OH	60	59
3	CuO (3.0)	2.0	C2H5OH	60	65
4	CuO (4.0)	2.0	C2H5OH	60	60
5	CuO (3.0)	3.0	C2H5OH	60	62
6	CuO (3.0)	2.0	C2H5OH	Reflux	72
7^c	CuO (3.0)	2.0	C2H5OH	Reflux	80
8	Cu2O (3.0)	2.0	C2H5OH	Reflux	—^d
9	CuCl (3.0)	2.0	C2H5OH	Reflux	—
10	CuBr (3.0)	2.0	C2H5OH	Reflux	—
11	CuI (3.0)	2.0	C2H5OH	Reflux	—
12	CuCl2 (3.0)	2.0	C2H5OH	Reflux	—
13	CuBr2 (3.0)	2.0	C2H5OH	Reflux	—
14	CuSO4·5H2O (3.0)	2.0	C2H5OH	Reflux	18
15	Cu(OAc)2·H2O (3.0)	2.0	C2H5OH	Reflux	22
16	CuO (3.0)	2.0	CH3OH	Reflux	37
17	CuO (3.0)	2.0	DMF	80	—
18	CuO (3.0)	2.0	CH3CN	80	—
19	CuO (3.0)	2.0	HOAc	80	—
20	CuO (3.0)	2.0	CH3Cl	80	—
21	CuO (3.0)	2.0	DMSO	80	—
22	CuO (3.0)	2.0	Toluene	80	—
23	CuO (3.0)	2.0	1,4-Dioxane	80	—

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With the optimized reaction conditions in hand, the generality of this reaction was then explored using a series of various (Z)-2-arylidene-1-arylbutane-1,3-diones (1), which were prepared according to our previously reported method.¹⁶ As shown in Table 2, the scope of the R¹ substituents was initially investigated. Much to our satisfaction, substrates with a phenyl group as the R¹ substituent bearing an electron-neutral (–H, –Me) or electron-donating (–OMe) group were converted to the corresponding products 2a–c in moderate to excellent yields (62–80%). For substrates with a sterically hindered 2-naphthyl or a heterocyclic 2-thienyl as the R¹ substituent, the reaction proceeded smoothly to provide the desired products 2d and 2e in 57 and 51% yields, respectively. The scope of this reaction was subsequently expanded to the R² group. Substrates with a phenyl group as the R² substituent bearing an electron neutral (–Me) or electron donating (–OMe) group reacted successfully under the optimized conditions to afford the corresponding products 2f and 2g in 68–72% yields. Substrates containing a sterically hindered 1-naphthyl or heterocyclic 2-thienyl group as the R² substituent also reacted smoothly to afford the corresponding products 2h and 2i in 59 and 43% yields, respectively. However, substrates with a 2-naphthyl or phenyl bearing an electron withdrawing group (–NO₂) as the R² substituent could only afford the corresponding des-iodo products 2j and 2k in 85 and 38% yields, respectively. Notably, the structures of 2a, 2i and 2j were unambiguously confirmed by X-ray diffraction analysis (Fig. 1). Unfortunately, substrates with a halogenated (–Br) phenyl as the R² substituent were not tolerated under these reaction conditions and resulted in the formation of an inseparable mixture (2l).

Table 2 The scope of substrate 1^ab

a Reaction was performed with 1a (1.0 mmol, 1.0 equiv.), CuO (3.0 equiv.) and I₂ (2.0 equiv.) in 5.0 mL EtOH in sealed tube for 36 h, then filter the precipitate and add CuO (3.0 equiv.) and I₂ (2.0 equiv.) to mother liquor. Continue refluxing for 12 h.b Isolated yields.

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To gain some insight into the mechanism, a series of control experiments were performed as shown in Scheme 2. (E)-2-Benzylidene-4-iodo-1-phenylbutane-1,3-dione B was firstly synthesized according to a known method¹⁷ (Scheme 2a), and subsequently reacted under the standard conditions to afford the corresponding product 2a in 87% yield (Scheme 2b). This result confirmed that (E)-2-benzylidene-4-iodo-1-phenylbutane-1,3-dione B was the key intermediate in the transformation. The prefabricated substrate 1m was also subjected to the reaction under the standard conditions, however, we could not obtain the corresponding product 2m (Scheme 2c), which indirectly indicated that the two carbonyl groups in substrate 1 were extremely necessary in the transformation of the hydrogen bond-assisted 6π-electrocyclization.

Scheme 2 Control experiments.

Although mechanistic details are not clear at this stage, on the basis of these experimental results and previous reports from the literature,^16,18,19 a possible reaction mechanism was proposed in Scheme 3 using (Z)-2-phenylidene-1-phenylbutane-1,3-dione (1a) as an example. The reaction would begin with the copper(II) oxide-promoted iodination of the methyl ketone group in 1a to afford intermediate B,¹⁶ which would be subsequently converted to intermediate C via iodine-catalyzed cis/trans-isomerization of its carbon–carbon double bond.¹⁸ The enol form of intermediate C would then undergo a hydrogen bond-assisted 6π-electrocyclization to give intermediate D,¹⁹ which would be converted to intermediate E through an aromatization reaction by elimination of hydrogen iodide. Finally, the desired product 2a would be obtained by the regioselective iodination of the electron-rich arene. Given that the iodination reaction would be dependent on the electron density of the aryl ring, the substrates bearing an electron-deficient R² substituent would only afford E as the final product.

Scheme 3 Possible reaction mechanism.

In conclusion, we have developed a novel strategy for the synthesis of 2-aroyl-3-hydroxy-4-iodonaphthalenes via domino reaction sequences involving the CuO-promoted iodination of a methyl ketone, iodine-catalyzed isomerization of a carbon–carbon double bond, hydrogen bond-assisted 6π-electrocyclization, aromatization via the elimination of HI and regioselective iodination of an electron-rich arene. In the whole process, iodine plays a double role. It not only acts as an iodine source during the construction of the iodonaphthalene product, but also acts as a catalyst to promote the cis/trans-isomerization of a carbon–carbon double bond. Further studies to elucidate a detailed mechanism for this protocol are currently underway in our laboratory.

Acknowledgements

We are grateful for financial support from the National Natural Science Foundation of China (Grant 21472056, 21272085).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 986777 (2a), 986778 (2i) and 986779 (2j). For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ra17651d

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