Cu(II)-catalyzed domino construction of spironaphthalenones by dearomatization of β-naphthols and using N,N-dimethylaminoethanol as a C1 synthon

Abstract

Herein, a Cu(II)-catalyzed facile construction of synthetically valuable spiro compounds from β-naphthols in air is reported, in which N,N-dimethylaminoethanol (DMEA) serves as an efficient and unique C1 synthon. This transformation proceeds through an ortho-quinone methide (o-QM) formation/Michael addition/dearomatization sequence, affording various spiro(naphthalenenaphtho)furan-2-ones in moderate to excellent yields.

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Introduction

Spirocyclic scaffolds are valuable structural motifs in pharmaceuticals,¹ functional materials,² and many privileged chiral ligands.³ Transition-metal-catalyzed dearomatization of arenes has demonstrated to be efficient for accessing various challenging but appealing spirocyclic compounds;⁴ however, existing limitations such as tedious preparation of specified substrates, high cost of transition-metal catalysts and sophisticated ligands, and harsh reaction conditions have somehow hindered its application.

Phenols are readily available chemical starting materials and have found widespread applications in organic synthesis.⁵ Oxidative dearomatization of phenols has been paid a lot of attention due to its ability to construct spiro-cyclohexadienones, which are widely found in various natural products and artificial chemicals that exhibit appealing bioactivities⁶ and excellent photoelectric performance.⁷ Usually α-substituted β-naphthols are required as the substrates to inhibit the undesired rearomatization process. The dearomatization of α-unsubstituted β-naphthols is more challenging and less explored.

The groups of Kita and Ishihara have realized chiral hypervalent iodine catalyzed intramolecular spirolactonizations with m-CPBA as the terminal oxidant (Scheme 1a).⁸ Feringa et al. developed a sequential asymmetric conjugate addition/oxidative cyclization for the synthesis of highly functionalized spironaphthalenones using stoichiometric copper(II) as the oxidant (Scheme 1b).⁹ The Wu group developed a method for the selective synthesis of six-membered and five-membered spironaphthalenones from α-unsubstituted β-naphthols by controlling the molar ratio of ternary gallium/indium/copper (Ga/In/Cu) catalysts (Scheme 1c).¹⁰ The Katsuki group established an iron-salen-catalyzed method for the asymmetric synthesis of spirocyclic (2H)-dihydrobenzofurans from 1-methyl-2-naphthols and phenols (Scheme 1d).¹¹ These reports are elegant and inspiring; however, limitations still exist, such as a limited substrate scope and requirement of high loadings of catalysts and other metal reagents. In view of these, novel methods for the synthesis of spironaphthalenone molecules from readily available starting materials and inexpensive catalytic systems are still highly desirable.

Scheme 1 Synthesis of spiro-cyclohexadienones from naphthols.

Recently, N,N-dimethylethanolamine (DMEA) has been developed as a novel C1 synthon by our group.¹² It has been successfully applied to several types of transformations and has shown some unique activities, compared to conventional C1 synthons such as DMF, DMSO, formaldehyde and methanol. Herein, we present the development of a Cu(II)-catalyzed facile construction of spironaphthalenones from β-naphthols and DMEA in air.

Results and discussion

We initiated our investigation with 2-naphthol (1a) as the model substrate. Under the catalysis of Cu(OAc)₂ (30 mol%) at 120 °C, 2-naphthol reacted with DMEA smoothly, affording the spirocyclization product 2a in 50% yield (Table 1, entry 1). PPh₃ was found to be an ineffective ligand in this transformation (Table 1, entry 2). We then turned our attention to the effect of N-ligand (Table 1, entries 3–7). Screening of several N-ligands revealed that 4,7-diphenyl-1,10-phenanthroline (L5) was the best ligand, increasing the yield of 2a to 59% (Table 1, entry 7). With the addition of NaHCO₃ as a base additive, the yield of 2a was improved to 72% (Table 1, entry 8). Decreasing the loading of Cu(OAc)₂ and ligand L5 to 15 mol% and 18 mol% respectively afforded 2a in a comparable 70% yield, while further decreasing their loadings led to only 57% yield (Table 1, entries 9 and 10). A lower temperature was found to be disadvantageous to obtain 2a (Table 1, entries 11 vs. 9). Investigation of bases other than NaHCO₃, either organic bases or inorganic bases, failed to find a better choice of base (Table S1, entries 1–6†). Generally, weak bases gave better performance than relatively strong bases. To our delight, the yield of 2a was further increased to 75% when the reaction was conducted at a higher concentration (Table 1, entry 12).

Table 1 Optimization of the reaction conditions^a

Entry	NaHCO3 (equiv.)	Ligand (mol%)	Yield^b (%)
a Unless otherwise stated, the reaction was carried out with 1a (1.0 mmol), NaHCO3, Cu(OAc)2 (30 mol%), and a ligand in DMEA (5 mL) at 120 °C in air for 3–5 h. b Isolated yield of 2a. c Cu(OAc)2 (15 mol%) was used. d Cu(OAc)2 (10 mol%) was used. e The reaction was carried out at 110 °C. f 3 mL of DMEA was used.
1	—	—	50
2	—	PPh3 (40)	Trace
3	—	L1 (40)	40
4	—	L2 (40)	46
5	—	L3 (40)	55
6	—	L4 (40)	20
7	—	L5 (40)	59
8	0.5	L5 (40)	72
9^c	0.5	L5 (18)	70
10^d	0.5	L5 (12)	57
11^c^,^e	0.5	L5 (18)	60
12 ^c^,^f	0.5	L5 (18)	75

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With the optimal conditions in hand, the substrate scope of this transformation was assessed. As illustrated in Table 2, electron-donating group substituted 2-naphthols such as 6-methyl-2-naphthol 1b, 6-ethyl-2-naphthol 1c, 6-methoxy-2-naphthol 1d, 7-methyl-2-naphthol 1g, 7-methoxy-2-naphthol 1h, 7-ethoxy-2-naphthol 1i, 7-acetamido-2-naphthol 1j, 3-methyl-2-naphthol 1k, and 3-methoxy-2-naphthol 1l reacted smoothly with DMEA, affording the corresponding five-membered spironaphthalenones 2b–2d, 2g–2j, and 2k–2l in 64–93% isolated yields. However, when 2-naphthols bearing an electron-withdrawing group such as 6-Br (1e), 6-CN (1f), 7-Br (1k), and 3-Br (1n) were applied as substrates, the spiro compounds (2e, 2f, 2k, and 2n) were produced in much lower yields (12–50%). To our surprise, when (6-hydroxynaphthalen-2-yl)boronic acid was applied in the transformation, deboration occurred, affording product 2a in 57% yield. In addition, phenanthren-9-ol was employed in the reaction and a good yield of the desired product (2o) was afforded. Quinolin-7-ol and quinolin-6-ol were also tested in the reaction, both failing to produce the desired spiro-product while 8,8′-methylenebis(quinolin-7-ol) 3 was obtained in 80% yield in the former case. 5,6,7,8-Tetrahydronaphthalen-2-ol also failed to give the desired spiro-product. The structure of 2a was unambiguously confirmed by single-crystal X-ray crystallography.

Table 2 Substrate scope of 2-naphthols for the construction of spirocompounds 2 ^a

a Standard conditions: 1a (1 mmol), NaHCO₃ (0.5 mmol), Cu(OAc)₂ (15 mol%), and BPhen (L5) (18 mol%) in DMEA (3 mL) were stirred at 120 °C for 3–5 h in a reaction tube in air. b Product 2a can also be prepared from (6-hydroxynaphthalen-2-yl)boronic acid (57% isolated yield).

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Several control experiments were carried out to obtain preliminary insight into the reaction mechanism (Scheme 2). The reaction of 2-naphthol (1a) with DMEA performed in the presence of the radical scavenger TEMPO (2 equiv.) or BHT (2 equiv.) failed to yield the desired spiro compound 2a (Scheme 2, eqn (1)), indicating that the formation of 2a might proceed through a radical pathway. When DMEA was replaced with N,N-Diethylethanolamine (DEEA), DMF, or DMSO, no product 2a was detected (Scheme 2, eqn (2)), demonstrating the unique activity of DMEA as a C1 synthon in this transformation.

Scheme 2 Control experiments.

Based on the control experiments aforementioned and previous literature reports,^11–13 a plausible mechanism of the Cu-catalyzed spirocyclization is proposed, as depicted in Scheme 3. The reaction initiates from the formation of cationic copper complex A, which proceeds through Fenton-like reactions¹⁴ to form a reactive iminium C. Complex D is then generated through the Mannich reaction of 2-naphthol with iminium C. Complex D then undergoes a 1,5-hydride transfer to yield a key intermediate ortho-quinone methide E, as well as complex F, which then regenerates Cu²⁺ and releases 2-(methylamino)ethanol G as a byproduct. Intermediate E, which is a strong Michael acceptor, undergoes Michael addition of 2-naphthol to afford compound H. Compound H would then tautomerize to its enol form I rapidly. Spiro-product 2a is finally produced through SET oxidation by O₂ and sequential nucleophilic dearomatization of compound I.

Scheme 3 Proposed mechanism.

Conclusions

In summary, we have demonstrated a Cu(II)-catalyzed novel and facile access for the domino construction of spironaphthalenones through an ortho-quinone methide (o-QM) formation/Michael addition/dearomatization sequence. Using Cu(OAc)₂ as the catalyst, a formal [3 + 1 + 1] spirocyclization reaction between α-unsubstituted β-naphthols and N,N-dimethylethanolamine (DMEA) was developed in air. This reaction provides an effective and convenient method for obtaining synthetically valuable spironaphthalenones. DMEA acts as a distinctive C1 synthon and a reaction solvent in the transformation.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work is financially supported by the Natural Science Foundation of Zhejiang Province of China (Grant No. LQ20B020008) and the Leading Innovative and Entrepreneur Team Introduction Program of Zhejiang (No. 2019R01005).

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Footnote

† Electronic supplementary information (ESI) available. CCDC 2208411. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d3ob00296a

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