Pd(0)-Catalyzed intramolecular arylative dearomatization of β-naphthols

Abstract

An efficient Pd(0)-catalyzed intramolecular arylative dearomatization of β-naphthols is described. Using Q-Phos as a ligand, the arylative dearomatization reaction proceeded smoothly affording excellent yields and chemoselectivity even when the catalyst loading was reduced to 0.1 mol%. This method offers an efficient access to a series of structurally diverse spirocarbocycles. Preliminary investigation indicates that an enantioselective reaction is feasible in the presence of a chiral phosphoramidite ligand.

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Spirocarbocycles often exist in diverse natural products, biologically active molecules¹ and useful chemical structures² (Fig. 1). Therefore, it has attracted the intense attention of organic chemists to synthesize the unique structure of spirocarbocycles. Due to the congested quaternary carbon centers existed in spirocarbocycles, it has been a long-standing challenge to develop convenient synthetic methodologies. The recent progress in organometallic catalysis provides new solutions for the synthesis.³ However, highly efficient synthetic routes to obtain structurally diverse spirocarbocycles from readily available starting materials are still in great demand.

Fig. 1 Biologically active spirocarbocycle-based compounds and ligands.

Phenol and its derivatives are important chemical starting materials and are widely used in organic synthesis.⁴ The recent development on the dearomatization of phenol and derivatives provides a novel route for the construction of spirocarbocycles.^5,6 Of particular note, Pd-catalyzed cross-coupling type dearomatization reactions of anilines,⁷ phenols,⁸ indoles,⁹ pyrroles,¹⁰ pyridines¹¹ and furans¹² have been reported to construct interesting and useful structures. We envisaged that through an intramolecular design, spirocarbocycles can be easily obtained via the Pd-catalyzed arylative dearomatization of phenol derivatives. However, the chemoselectivity between the O-arylation and C-arylation reaction pathways is of great challenge in Pd-catalyzed dearomatization reactions especially when a quaternary carbon center is needed to be formed at the ortho-position of the phenolic hydroxyl group. For instance, the group of Buchwald reported that only the O-arylation product is obtained when an ortho-substituted phenol is subjected to Pd(0) catalysis (Scheme 1, eqn (1)).^8b Recently, Luan and co-workers^8e reported an elegant microwave-assisted Pd(0)-catalyzed alkyne migratory insertion and β-naphthol dearomatization cascade process, in which excellent chemoselectivity was achieved (Scheme 1, eqn (2)). However, to our knowledge, Pd(0)-catalyzed intramolecular direct arylative dearomatization of β-naphthols has not been reported. Herein, we describe an efficient Pd(0)-catalyzed intramolecular arylative dearomatization of β-naphthols affording all-carbon spirocarbocycle structures in excellent yields and chemoselectivity (Scheme 1, eqn (3)).

Scheme 1 Pd-catalyzed arylation of phenols and naphthols.

Initially, 1-(2-bromophenethyl)-2-naphthol (1aa) was chosen as a model substrate to examine different ligands under palladium catalysis. The results are summarized in Table 1. No desired dearomatized product was obtained when the diphosphine ligand dppf (L1) was used (Table 1, entry 1), while the utilization of PPh₃ led to the formation of the desired dearomatized product (2a) in 24% NMR yield (Table 1, entry 2). With the Buchwald-type ligand RuPhos (L2), 2a was isolated in 11% yield together with the isolation of the O-arylation product in 9% yield (Table 1, entry 3). When the sterically bulky (di-^tBu)XPhos (L3) was used as a ligand, only the O-arylation product was obtained (Table 1, entry 4). The utilization of the rac-Feringa ligand (L4) or SIPr·HBF₄ (L5) led to the exclusive formation of 2a (56% yield, Table 1, entries 5 and 6). With Q-Phos (L6) as a ligand, 2a could be obtained in 68% yield with 3a isolated in 17% yield. Subsequently, several bases were examined (Table 1, entries 8–11). To our delight, the stronger inorganic base Cs₂CO₃ almost exclusively gave the desired dearomatized product (2a) in 91% yield within 1 hour. Lowering the catalyst loading to 0.5 mol% and 0.1 mol% led to slightly higher yields in both cases but a longer reaction time was needed (Table 1, entries 12 and 13). Notably, the reaction underwent smoothly even at 40 °C (Table 1, entry 14). The reaction in varied solvents, such as DCM, dioxane and THF, all gave satisfactory yields at 40 °C (92–95% yields, Table 1, entries 15–18). Considering the efficiency and convenience of the experiments, the optimized conditions were obtained as the following: 0.5 mol% [Pd(C₃H₅)Cl]₂, 1.5 mol% Q-Phos (L6), and 1.5 equiv. of Cs₂CO₃ in toluene at 120 °C (Table 1, entry 12).

Table 1 Optimization of the reaction conditions^a

Entry	Ligand	Base	Solvent	T (°C)	Time (h)	2a yield^b (%)	2a : 3a^c
a Reaction conditions: 1aa (0.2 mmol), [Pd(C3H5)Cl]2 (0.005 mmol), ligand (0.015 mmol), base (0.3 mmol) in solvent (1.0 mL), T °C. b Determined by ^1H NMR using CH2Br2 (0.2 mmol) as an internal standard. c Determined by ^1H NMR of the crude products. d Isolated yield. e [Pd(C3H5)Cl]2 (0.5 mol%) and L6 (1.5 mol%) were used. f [Pd(C3H5)Cl]2 (0.1 mol%) and L6 (0.3 mol%) were used.
1	L1	K2CO3	Toluene	120	8	0	ND
2	PPh3	K2CO3	Toluene	120	8	24	>20 : 1
3	L2	K2CO3	Toluene	120	8	11^d	55 : 45
4	L3	K2CO3	Toluene	120	8	0	<20 : 1
5	L4	K2CO3	Toluene	120	8	56^d	>20 : 1
6	L5	K2CO3	Toluene	120	8	56^d	>20 : 1
7	L6	K2CO3	Toluene	120	8	68^d	4 : 1
8	L6	Na2CO3	Toluene	120	8	Trace	ND
9	L6	K3PO4	Toluene	120	8	64	19 : 1
10	L6	DBU	Toluene	120	10	13	ND
11	L6	Cs2CO3	Toluene	120	1	91^d	19 : 1
12^e	L6	Cs2CO3	Toluene	120	5	95^d	>20 : 1
13^f	L6	Cs2CO3	Toluene	120	31	95^d	>20 : 1
14	L6	Cs2CO3	Toluene	40	7	92^d	>20 : 1
15	L6	Cs2CO3	DCM	40	7	93^d	>20 : 1
16	L6	Cs2CO3	THF	40	7	92	>20 : 1
17	L6	Cs2CO3	CH3CN	40	7	20	ND
18	L6	Cs2CO3	Dioxane	40	7	95	>20 : 1

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Next, we turned our attention to examine the substrate scope of this reaction. As shown in Scheme 2, substrates by cleaving different C–X bonds all gave their corresponding products in excellent yields and chemoselectivity (X = Cl, 92% yield, 2a : 3a = 14 : 1; X = Br, 95% yield, 2a : 3a > 20 : 1; X = I, 94% yield, 2a : 3a = 20 : 1). Then, a wide range of substituted aryl bromides bearing either electron-donating or electron-withdrawing groups was tested. In all cases, the intramolecular dearomatization reaction proceeded smoothly to afford their corresponding products (2b–2g) in excellent yields (92–95%) and chemoselectivity. The structure of 2c was confirmed by X-ray crystallographic analysis. The reaction of the CF₃-substituted substrate gave the desired product (2h) in good yield with slightly decreased chemoselectivity (86% yield, 2h : 3h = 12 : 1). Then the influence of the substituent group on the β-naphthol moiety was investigated. 3-Substituted (Me, CO₂Me) naphthols were transformed into dearomatized products (2i and 2j) in good yields and chemoselectivity (80% yield, 2i : 3i = 10 : 1; 82% yield, 2j : 3j = 8 : 1). Fortunately, the substituents on the other positions (6-Ph and 7-Ph) of the β-naphthol moiety did not influence the chemoselectivity to give 2k and 2l in excellent yields and chemoselectivity (95% yield, 2k : 3k = 19 : 1; 95% yield, 2l : 3l = 18 : 1). Apart from substrates bearing an all-carbon tether, the substrate with an N-linked tether (1m) was also compatible, affording the desired product (2m) in 74% yield and excellent chemoselectivity (2m : 3m > 20 : 1) under relatively milder conditions (at 60 °C). For substrate 1n with an extended carbon chain, the desired dearomatized product with a 6-membered ring formation (2n) was obtained smoothly in 96% yield and excellent chemoselectivity (2n : 3n > 20 : 1). Interestingly, the reaction of the α-naphthol substrate gave the dearomatized product (2o) in 88% yield with a 2o : 3o ratio of 20 : 1.

Scheme 2 The reaction substrate scope. ^a Reaction conditions: 1 (0.8 mmol), [Pd(C₃H₅)Cl]₂ (0.004 mmol), L6 (0.012 mmol), Cs₂CO₃ (1.2 mmol) in toluene (4.0 mL), 120 °C. Isolated yield. ^b Determined by ¹H NMR of the crude products. ^c 1 (0.4 mmol), Cs₂CO₃ (0.6 mmol) in toluene (2.0 mL). ^d 1 (0.2 mmol), Cs₂CO₃ (0.3 mmol) in toluene (1.0 mL), 60 °C. ^e 1 (0.2 mmol), [Pd(C₃H₅)Cl]₂ (0.005 mmol), L6 (0.015 mmol), Cs₂CO₃ (0.3 mmol) in toluene (1.0 mL).

The asymmetric reaction was also explored. Several commercially available chiral phosphine ligands were screened. TADDOL-derived phosphoramidite (L7) was found to be the optimal ligand. In the presence of 2.5 mol% [Pd(C₃H₅)Cl]₂ and 3.75 mol% L7, the reaction of 1aa could give 2a in 60% yield and 72% ee with excellent chemoselectivity (2a : 3a > 20 : 1, Scheme 3, see the ESI† for details).

Scheme 3 Pd(0)-Catalyzed asymmetric intramolecular arylative dearomatization of β-naphthols.

To further demonstrate the utility of this method, a gram-scale reaction and several transformations of the 2-naphthalenone product have been carried out. The intramolecular dearomatization of 1aa on a 5.0 mmol scale gave the desired product 2a in 95% yield and excellent chemoselectivity (2a : 3a = 21 : 1) while the catalyst loading could be further reduced to 0.1 mol% (Scheme 4). In addition, the ketone group of the product (2a) could be selectively reduced by LiAlH₄ to afford the alcohol 4a in 93% yield (dr = 5 : 1), while the carbon–carbon double bond could be reduced by Pd/C catalyzed hydrogenation to afford 5a in 83% yield (Scheme 5).

Scheme 4 Gram-scale reaction.

Scheme 5 Transformations of the 2-naphthalenone product.

In summary, we have developed a Pd-catalyzed intramolecular dearomatization of β-naphthols to construct an all-carbon quaternary stereocenter at the ortho-position of the hydroxyl group with excellent yields and chemoselectivity. A series of structurally diverse spirocarbocycles were obtained efficiently and conveniently. Further studies on the application of the current method and development of more efficient catalytic asymmetric reactions are currently underway in our laboratory.

We thank the National Key Research and Development Program of China (2016YFA0202900), the National Basic Research Program of China (2015CB856600), the NSFC (21332009, 21361140373, and 21421091), the Program of Shanghai Subject Chief Scientist (16XD1404300), and the Chinese Academy of Sciences (XDB20000000, QYZDY-SSW-SLH012) for generous financial support.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1534422. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c7cc04022a

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