Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
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A Strategy To Obtain o‑Naphthoquinone Methides: Ag(I)-Catalyzed Cyclization of Enynones for the Synthesis of Benzo[h]chromanes and Naphthopyryliums Feng Wu† and Shifa Zhu*,†,‡ †
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Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, P.R. China ‡ State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, P.R. China S Supporting Information *
ABSTRACT: A new strategy to obtain o-NQM intermediates through a ring-formation strategy by Ag(I)-catalyzed cyclization of 2-alkenylphenyl alkynyl ketones and its [4 + 2] annulations with styrenes has been developed. This reaction features high efficiency, mild reaction conditions, as well as flexible substitutions and atom economy. The obtained benzo[h]chromane products were further oxidized to naphthopyryliums, which displayed tunable photophysical properties.
o-Quinone methides (o-QMs), known as highly reactive and ephemeral intermediates, are widely harnessed for the synthesis of a variety of biologically important structures.1 Traditionally, o-QMs are generated from phenol derivatives with an activated benzylic carbon atom ortho to the hydroxy group by thermal-,2a−c or acid/base-induced elimination.2d−j Other methods, such as photoinduction,3a,b benzylic oxidation,3c,d o-quinone olefination,3e aldol condensation/dehydration,3f and thermal rearrangement,3g−i were also applied to generate different o-QMs. As a subtype of o-QMs, the o-naphthoquinone methides (oNQMs) have been regarded as useful precursors for [4 + 2] annulation to synthesize benzo[h]chromanes, which are the core structure of many natural products and bioactive substances (Figure 1).4 Compared with the o-QMs, fewer
On the other hand, substituted pyrylium salts are widely used in diverse areas, such as photoelectric materials, photocatalysis, and analytical studies,6 on account of their tunable fluorescence properties. The optoelectronic properties of pyrylium salts are highly dependent on the substituents of the pyrylium cores.7 Traditionally, the main strategies for the synthesis of pyrylium salts include intramolecular condensations of 1,5-dicarbonyl compounds or oxidation from other precursors.8 However, these methods often suffer from low efficiency, a tedious separation process, and the inconvenience of synthesizing unsymmetrical pyryliums. Efforts have been devoted to circumventing these problems in recent years. In 2012, Minami and Hiyama established a facile and selective C−H activation/cycloaddition protocol to substituted 2Hchromanes9a and benzopyrylium.9b In 2017, You reported an elegant C−H activation/annulation reaction for the one-pot synthesis of fused pyrylium cations.10 Recently, Sasidhar demonstrated the synthesis of triarylpyrylium via an inverseelectron-demand Diels−Alder reaction.11 Although great progress has been achieved, the rapid assembly of pyryliums with tunable substituents still would be advantageous. As part of our continuous efforts to develop practical methods to generate reactive intermediates based on alkyne chemistry,12 we proposed a new strategy to obtain o-NQMs species by transition-metal-catalyzed cyclization of 2-alkenyl alkynyl ketones (Scheme 1). In contrast to previous protocols, this strategy features generation of a naphthalene ring in situ. To the best of our knowledge, this is the first example of the generation of o-NQMs through ring-formation strategy.
Figure 1. o-NQMs for the construction of benzo[h]chromane skeletons.
examples concerning the generation and application of oNQMs have been reported,5 largely due to the dearth of convenient routes to access the uniquely substituted onaphthol precursors. Therefore, the development of general strategies to obtain these useful o-NQM intermediates are of great importance. © XXXX American Chemical Society
Received: January 23, 2019
A
DOI: 10.1021/acs.orglett.9b00281 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters Scheme 1. New Strategy to o-NQMs (This Work)
be improved to 11:1 with a slight decrease of yield (79%) when pentane, a nonpolar solvent, was applied, although the AgOTf catalyst was almost insoluble in this system (entry 14). The yield of this cloudy AgOTf/pentane reaction mixture could be enhanced to 97% by elevating the temperature to 40 °C with the diastereoselectivity remaining unchanged (entry 15). It is worth mentioning that a silver mirror was observed on the walls of the reaction tube when DCE or THF was used as the solvent, which indicated the AgOTf was reduced during the reaction process and resulted in the deactivation of catalyst. Attempts to decrease the loading of AgOTf (5 mol %) and the amount of styrene (1.2 equiv) finally proved that the reaction can occur smoothly without loss of efficiency and selectivity (entry 16). It is of great practicability with only 1.2 equiv of styrene used, since a large excess styrene was often required to inhibit the potential side reactions, such as polymerization of styrene and dimerization of o-NQMs.5a,c,d,13 The desired product was not detected when HOTf was used as catalyst, which indicated the formation of 3aa was not a Bronsted acid catalyzed process. With the optimal conditions in hand (Table 1, entry 16), the reaction scope of different styrenes was then examined (Scheme 2). As shown in Table 2, different styrene derivatives
The readily available 2-alkenylphenyl alkynyl ketone 1a was first chosen as the o-NQM precursor (Table 1). Initially, Table 1. Optimization of the Reaction Conditionsa
entry
cat.
solution
1a/2a
temp (°C)
2ab (%)
c
IPrAuCl/AgBF4 PtCl2 AgOTf Y(OTf)3 In(OTf)3 Fe(OTf)3 AgOTf AgOTf AgOTf AgOTf AgOTf AgOTf AgOTf AgOTf AgOTf AgOTf HOTf
DCE DCE DCE DCE DCE DCE DCE DCE DCE DCM THF CH3CN toluene pentane pentane pentane pentane
1:2 1:2 1:2 1:2 1:2 1:2 1:2 1:2 1:2 1:2 1:2 1:2 1:2 1:2 1:2 1:1.2 1:1.2
25 60 25 100 80 100 40 60 25 25 25 25 25. 25 40 40 40
nd nd 35 17 nd 15 33 28 56 76 83 nd 74 79 97 96e nd
1 2c 3c 4 5 6 7c 8c 9 10 11 12 13 14 15 16c 17
drd
Scheme 2. Substrate Scope of Styrenea 7:1 10:1 4:1 6:1 5:1 6:1 6:1 7:1 8:1 11:1 11:1 11:1
a The reaction was performed under N2 for 12 h; 1a (0.1 mmol) in 1 mL solvent. bThe yield of 3aa was determined by 1H NMR spectroscopy with dimethyl terephthalate as internal standard. c5 mol % catalyst was used. ddr value was determined by 1H NMR spectroscopy of crude products. eIsolated yield.
cationic gold(I) salt and PtCl2 were examined because they are typically regarded as good catalysts for the activation of alkynes. However, only complicated mixtures were obtained with no desired product detected (entries 1 and 2). To our delight, the desired benzo[h]chromane product 3aa could be obtained in a yield of 35% (dr = 7:1) when AgOTf was used as catalyst at 25 °C (entry 3). Other Lewis acids, such as Y(OTf)3, Fe(OTf)3, and In(OTf)3, were less effective for this transformation (entries 4−6). The reaction conditions were then further optimized by varying the solvents and temperature (entries 7−14). The yields decreased when the reaction temperature was raised to 40 and 60 °C in DCE (entries 7 and 8). When the catalyst loading was increased to 10 mol %, the yield of 3aa was improved to 56% (entry 9). The solvent has a great impact on the reaction results (entries 10−14). The yield could be enhanced to 83% when THF was used as solvent (entry 11). Interestingly, the diastereoselectivity of 3aa could
a
Reaction conditions: 5 mol % of AgOTf, 1 (0.2 mmol), 2 (0.24 mmol), 2 mL of pentane; isolated yield. bTHF was used as solvent. c2 equiv of alkene was used.
bearing electron-donating or -withdrawing groups at the paraposition could be used as effective substrates, giving the desired benzo[h]chromanes 3aa−ai in 25−96% yields. The results indicated that the electron-rich styrenes delivered the products in higher yields but with relatively lower diastereoselectivity. For example, 3ai bearing −CF3 was obtained in 25% yield, but with 29:1 diastereoselectivity. 2,4-Dimethylstyrene and 2-vinylnaphthalene can serve as efficient substrates B
DOI: 10.1021/acs.orglett.9b00281 Org. Lett. XXXX, XXX, XXX−XXX
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higher than 11:1 diastereoselectivity (3ba−fa). Furthermore, this reaction can be extended to enynones with alkylalkyne and terminal alkyne, affording products 3ga and 3ia in relatively lower yields (22% and 31%). Enynone with bulkier tertiary butylalkyne resulted in no reaction (3ha). Other aryl groups (R1) bearing 3-thienyl and 1,1′-biphenyl moieties were also well tolerated, furnishing the corresponding products 3ja and 3ka in 71% and 78% yield, respectively. Thienylene- and phenanthrene-fused enynones were compatible with this reaction as well, which provided access to products 3la, 3ma, and 3na, albeit with diminished yields. Enynones with different substituents (R2, R3) at the olefinic carbons were then tested (3oa−ra). When R2, R3 = H, the desired product 3oa was obtained only in trace amounts, while the substrates with alkyl and phenyl groups at R2 afforded the corresponding products in moderate yields (3pa and 3qa). The substrate with a methyl group at the distal olefinic carbon could also participate in the reaction and furnished 3ra in 25% yield. Unfortunately, the attempt to produce and trap o-QMs by using linear enynone was unsuccessful (3sa). In order to further illustrate the utility and efficiency of this protocol, double annulation/[4 + 2] reaction products 3ar and 3te were assembled and isolated in 39% and 42% yield, respectively (Scheme 4).
to form the corresponding products 3aj and 3ak, respectively, in almost quantitative yield and excellent diastereoselectivity. It is noteworthy that estrone-derived styrene could be smoothly transferred to the desired product 3al in 95% yield. Except for styrenes, less reactive allyltrimethylsilane was also applicable and afforded the product 3am in 34% yield with 1.6:1 diastereoselectivity. Moreover, α-substituted and β-substituted styrenes were also tested and gave the corresponding products in 34−99% yields (3an−aq). α-Phenylstyrene and αmethylstyrene produced the desired products 3an and 3ao in excellent yields (95% and 99%). β-Methylstyrene and indene provided inferior results with the corresponding products 3ap and 3aq in 35% and 34% yields, which may be attributed to the steric hindrance. To further evaluate the applicability of this strategy, a variety of enynones 1 were also applied as o-NQM precursors to react with styrene 2a in the presence of 5 mol % of AgOTf (Scheme 3). As expected, different enynones bearing electron-donating or -withdrawing groups functioned well and afforded the corresponding benzo[h]chromanes in 56−91% yield with Scheme 3. Substrate Scope of Substrates 1a
Scheme 4. Double Cyclization/[4 + 2] Reactiona
a
The dr value was not determined because of poor solubility.
A plausible mechanism is proposed in Scheme 5. Initial activation of enynone 1 through a Ag(I)−π complex I gave the 6-exo-dig cyclization intermediate II. The sequential βelimination of stabilized carbocation and protonation led to Scheme 5. Proposed Mechanism
a
Reaction conditions: 1 (0.2 mmol),2a (0.24 mmol), 2 mL of pentane, 5 mol % of AgOTf; isolated yield. bDCM/pentane = 1:1 was used as solvent. C
DOI: 10.1021/acs.orglett.9b00281 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters the key o-NQM intermediate III. The major products from the [4 + 2] reactions generally have cis relative stereochemistry for the 2,4-diaryl substituents. It is believed that there is secondary orbital overlap between the aryl group of the styrenes and the π-system of the o-NQM intermediates, which provides additional stabilization of the transition state.2e,3c This speculation was strengthened by the poor diastereoselectivity of 3am derived from allyltrimethylsilane. After exploring the substrate scope of this ring-formation strategy to o-NQMs and its [4 + 2] reaction, we then moved to oxidize the obtained benzo[h]chromanes to the corresponding naphthopyryliums. The results indicated that Ag2CO3 was a good oxidant to realize this process (see the SI for details). Naphthopyryliums bearing different electron-donating or -withdrawing groups could be obtained in 27−87% yields (Scheme 6). It is noteworthy that the naphthopyrylium 4na Scheme 6. Substrate Scope of Naphthopyryliums 4
and Figure 2. These cations exhibit high stability and tunable emissions in CH2Cl2 (543−670 nm) and CH3CN (515−616
Figure 2. Emission spectra of the representative products in CH2Cl2 (c = 1.00 × 10−5 mol L−1).
a,b
nm).14 Most of these cations have good fluorescence quantum yields (up to 76%). The inspection of Scheme 6 shows the hypsochromic effects on the emission wavelengths by donor substituents at the R3 position. This effect can be apparently observed in the serials of compounds in which R3 is varied from H (4ab, λem = 567 nm) via Me (4aa, λem = 557 nm) to OMe (4ad, λem = 543 nm). A contrary trend is observed if R4 is varied from H (4aa, λem = 557 nm) to F (4da, λem = 568 nm) and Cl (4ca, λem = 567 nm). The further extension of conjugated system at R4 (4na) resulted in a strong bathochromic shift in emission wavelengths (Δλem = 103 nm), along with a sudden drop in fluorescence quantum yield (Φf = 5%). The extension to naphthyl at the R3 position (4ak) made no difference in the emission but showed a bathochromic shift on the absorption behavior (Δλabs = 36 nm) compared with compound 4ab. The 4-OMe-substituted compound 4ea has a significant bathochromic shift in emission wavelengths (Δλem = 113 nm) with the maximum emission band at 670 nm, in contrast to 4aa, whereas the emission behavior did not show a clear change when R2 was a 3-thienyl group (4ja). Changing R1 to a phenyl group resulted in a bathochromic shift in emission (4qa, Δλem = 42 nm) compared with the methyl-tethered 4aa. In summary, we have established a new strategy for the generation of o-NQM intermediates through a ring-formation strategy. A variety of benzo[h]chromanes with flexible substituents could be synthesized efficiently through Ag(I)catalyzed formation of o-NQMs and [4 + 2] annulations. Oxidation of the benzo[h]chromanes to naphthopyryliums and the substituted effects on their photophysical properties were then demonstrated, which was instructive for the design of the luminescent materials based on pyrylium structures. Future work in our laboratory will focus on potential applications of this new strategy.
a
Reaction conditions: 1 (0.2 mmol),2a (0.24 mmol), 2 mL of pentane, 5 mol % of AgOTf; isolated yield. bDCM/pentane = 1:1 was used as solvent.
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ASSOCIATED CONTENT
S Supporting Information *
with three continuous benzene rings, which were otherwise difficult to access, were obtained in a yield of 55%. By the combination of the [4 + 2] reaction of o-NQMs and oxidations, diverse naphthopyryliums with four tunable sites (R1, R2, R3, and R4) were obtained. With different naphthopyryliums in hand, their photophysical properties were measured and are shown in Scheme 6
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b00281. Typical experimental procedures and characterization for all products (PDF) D
DOI: 10.1021/acs.orglett.9b00281 Org. Lett. XXXX, XXX, XXX−XXX
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Shifa Zhu: 0000-0001-5172-7152 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We appreciate financial support from the Ministry of Science and Technology of the People’s Republic of China (2016YFA0602900), the NSFC (21871096, 21672071), Guangdong Science and Technology Department (2018B030308007, 2018A030310359, 2016A030310433), and Science and Technology Program of Guangzhou (201707010316).
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DOI: 10.1021/acs.orglett.9b00281 Org. Lett. XXXX, XXX, XXX−XXX
