Construction of highly functionalized naphthalenes using an in situ ene–allene strategy

Abstract

Construction of highly functionalized naphthalene derivatives remains a challenging task for organic chemists because of the effect of the substituent. In this paper, we have developed a sequence of propargyl-allenyl isomerization and electrocyclization for the synthesis of polyfunctionalized naphthalenes.

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The benzenoid aromatic compounds are arguably the most common structures in nature and the laboratory and polysubstituted naphthalenes, as an important class of benzenoid aromatic compounds, have attracted considerable interest because of their unique physiological activities and functions.^1–5 Numerous famous molecules in the naphthalene family, for example, naproxen,² naftopidi,³ nafamostat,⁴ and butenafine⁵ (Fig. 1), occupy a prominent place in medicinal chemistry.

Fig. 1 Drugs containing naphthalene.

Allene-mediated cyclization reactions have attracted much attention by the organic community,⁶ and the electrocyclization of ene–allenes represents one of efficient tools for constructing a new benzene ring, in which the allene moiety could be thought as an “activated olefin”, generally enhancing the possibility of reaction compared with a normal olefin.⁷ In the last decade, sequential reactions about the in situ generated allenes have been increasingly explored,⁸ getting benefit from convenient construction of starting materials instead of unstable or reactive polyfunctionalized allene substrates. Our group also established a series of sequential reactions for the efficient synthesis of fused polycyclic skeletons, including benzothiepine sulfones, 2,3-dihydropyrroles and furans, polyfunctionalized quinolines and benzenoid aromatic compounds.⁹

Generally, performing a 6π-electrocyclic reaction requires a triene moiety (or analogue) involving a middle cis-double bond, which might be not easy to achieve for the acyclic substrates because of the steric hindrance (Scheme 1a).¹⁰ During our research on organosulfur chemistry, we found that the treatment of 3-substituted propargyl aldehydes with aqueous MeSNa stereoselectively offers thermodynamically unfavored (E)-3-(methylthio)-3-substituted acrylaldehydes (Scheme 1b), which might provide an efficient way to construct a highly substituted benzene ring, using in situ ene–allene electrocyclization strategy. Herein we wish to report a sequence of propargyl-allenyl isomerization, electrocyclization and aromatization, yielding highly functionalized naphthalene derivatives, which are difficult to obtain via direct functionalization to naphthalene because of the effect of the substituent (Scheme 1c).

Scheme 1 Proposal for the construction of naphthalenes.

As a first attempt, we chose (E)-1-phenyl-1-methylthio-3-methoxypent-1-en-4-yne (1a) as the starting material, which could be readily prepared via the treatment of (E)-(E)-3-(methylthio)-3-phenylacrylaldehyde with ethynyl magnesium bromide and iodomethane. We anticipated that the treatment of 1a by acyl chloride under Sonogashira conditions could offer ene–allene intermediate via a sequence of Sonogashira coupling and propargyl-allenyl isomerization. We initiated our study by testing the reaction of 1a with benzoyl chloride (2a) in THF at room temperature, with the assistance of Pd(PPh₃)₂Cl₂, CuI and triethylamine (TEA). To our delight, this set of conditions afforded the expected product naphthalenyl phenylethanone (3a) in 55% yield (Table 1, entry 1) and the structure of 3d was revealed by X-ray diffraction analysis of the (2,4-dinitrophenyl)hydrazone of 3d (see ESI†).¹¹ Replacing triethylamine by DIPEA (N,N-diisopropylethylamine) gave similar yields and the stronger organic bases such as DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) and DBN (1,5-diazabicyclo[4.3.0]non-5-ene) afforded sluggish results (Table 1, entries 2–4). Subsequent screening of other common solvents, such as toluene, xylene, chlorobenzene, 1,4-dioxane, acetonitrile and DMF did not improve the yield (Table 1, entries 5–10). Raising the reaction temperature to 60 °C offered a satisfactory yield of 85% (Table 1, entry 13). Thus, the optimized reaction conditions were chosen as follows: 0.5 mmol of 1a, 0.6 mmol of 2a, 0.025 mmol of Pd(PPh₃)₂Cl₂, 0.025 mmol of CuI and 1.5 mmol of triethylamine in 5 mL THF were stirred at 60 °C under nitrogen.

Table 1 Optimization of the reaction conditions^a

Entry	Base	Solvent	T (°C)	Yield of 3a (%)
a Conditions: 1a (0.5 mmol), 2a (0.6 mmol), Pd(PPh3)2Cl2 (0.025 mmol), CuI (0.025 mmol) and TEA (1.5 mmol) in 5 mL THF were stirred at 60 °C under nitrogen.
1	TEA	THF	r.t.	55
2	DIPEA	THF	r.t.	54
3	DBU	THF	r.t.	0
4	DBN	THF	r.t.	0
5	TEA	Toluene	r.t.	12
6	TEA	Xylene	r.t.	15
7	TEA	Chlorobenzene	r.t.	21
8	TEA	1,4-Dioxane	r.t.	44
9	TEA	MeCN	r.t.	37
10	TEA	DMF	r.t.	49
11	TEA	THF	40	64
12	TEA	THF	50	75
13	TEA	THF	60	85

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With this result in hand, we examined the scope of the reaction and obtained polysubstituted naphthalenes in moderate to good yields under mild conditions (Table 2). The R² and R³ can be phenyl groups optionally substituted with an electron-withdrawing or an electron donating group (3b–3f). The R¹ can be alkyl, benzyl (3g–3h) and 2-methylenefuran (3i–3j), and the yields are satisfactory.

Table 2 Synthesis of naphthalene derivatives^a

a Conditions: 1 (0.5 mmol), 2 (0.6 mmol), Pd(PPh₃)₂Cl₂ (0.025 mmol), CuI (0.025 mmol) and TEA (1.5 mmol) in 5 mL THF were stirred at 60 °C under nitrogen.

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Then our attention was diverted to the rearrangement of propargyl phosphite to allenyl phosphonate, one of most facile methods generating allenes, which requires just propargyl alcohols as the substrates.¹² We prepared propargyl alcohol (4) as the substrates and treated it with chlorodiphenylphosphine with the assistance of Ga(OTf)₃ (ref. 9c) and triethylamine. The expected (naphthalen-1-yl(phenyl)methyl)diphenylphosphine oxides (5) were obtained in good yields (Table 3).

Table 3 Synthesis of naphthalene-1-yl-methyl diphenylphosphine oxide compounds^a

a Conditions: 4 (0.5 mmol), Ph₂PCl (0.6 mmol), Ga(OTf)₃ (0.025 mmol) and TEA (1.5 mmol) in 5 mL THF were stirred at 0–60 °C under nitrogen.

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The alkylthio groups, helping construct the cis middle double bond of the substrates, are useful for numerous transformations in organic chemistry, which could be used as a convenient chemical handle for preparing other compounds.¹³ We treated 3a with NaIO₄ in aqueous methanol and 2-(2-methoxy-4-(methylsulfinyl)naphthalen-1-yl)-1-phenylethanone 6 was isolated in 90% yield (Scheme 2).

Scheme 2 The oxidation of 3a.

Through our previous studies, phosphine oxides are serviceable building blocks and applied widely in Wittig-type olefination.¹⁴ Herein we treated 5a with NaH in the presence of dry THF under oxygen atmosphere and obtained (4-(methylthio)naphthalen-1-yl)(phenyl)methanone, which contains a synthetically “omnipotent” carbonyl group, in 65% yield (Scheme 3).

Scheme 3 The transformation of 5a.

We proposed a plausible pathway as shown in Scheme 4. The substrate 1, via a Sonogashira coupling/propargyl-allenyl isomerization in the presence of triethylamine through propargyl intermediate A, gives allene intermediate B, which undergoes electrocyclization reaction to give product 3 (Scheme 4).

Scheme 4 Plausible mechanism.

In summary, we have developed a protocol for the synthesis of polyfunctionalized naphthalenes via propargyl-allenyl isomerization and electrocyclization. As a result of the readily accessible starting materials and simple operation, this reaction should be an appealing strategy in organic synthesis. Further studies on the synthetic application are currently ongoing.

Acknowledgements

This work was supported by Zhejiang Provincial Natural Science Foundation of China (No. LY14B020008).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, characterization data, crystallographic data in CIF and NMR spectra. CCDC 1491859. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra21889j

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