Cyclization of para-Quinone Methides

Letter pubs.acs.org/OrgLett

Cite This: Org. Lett. 2018, 20, 1974−1977

Cascade Radical 1,6-Addition/Cyclization of para-Quinone Methides: Leading to Spiro[4.5]deca-6,9-dien-8-ones Rui Pan, Lingyin Hu, Chunhua Han, Aijun Lin,* and Hequan Yao* State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, P. R. China S Supporting Information *

ABSTRACT: A cascade three-component iodoazidation of paraquinone methides to construct spiro[4.5]deca-6,9-dien-8-ones under mild conditions has been developed. The chemoselective 1,6-addition of azide radical triggered a regioselective 5-exo-dig cyclization/radical coupling sequence, enabling C−N, C−C, and C−I bond formations in a one-pot procedure with high efficiency.

S

Scheme 1. Strategies for the Synthesis of Spirocyclohexadienones from p-QMs

piro[4.5]cyclohexadienones are not only incorporated in a large number of naturally occurring and/or biologically active molecules with important biological activities such as cytotoxicity, hepatoprotective activity, and antimicrobial activity (Figure 1)1 but also employed as key intermediates in organic

Figure 1. Natural products containing spiro[4.5]cyclohexadienone.

synthesis.2,6 Due to the high synthetic value of such targets, considerable efforts have been devoted to construct these skeletons, including dearomative spirocyclization of phenol derivatives3−5 and cycloisomerization of 1,6-enynes.6 These initial explorations prompted chemists to develop more efficient and simple synthetic methods to broaden the synthetic scope and scalability without the need for well-designed starting materials or harsh conditions. As such, our group and others have realized nucleophilic 1,6-addition-mediated [2 + 1],7 [3 + 2],8 and [4 + 2]9 annulation of para-quinone methides (pQMs) to achieve spiro[2.5]octa-4,7-dien-6-ones, spiro[4.5]deca-6,9-dien-8-ones, and 2-oxaspiro[5.5]undeca-7,10-dien-9ones with high efficiency (Scheme 1a). Additionally, nucleophilic 1,6-addition/vinylcyclopropane (VCP) rearrangement reactions of vinyl para-quinone methides (p-VQMs) provided another pathway to construct spiro[4.5]deca-6,9-dien8-ones (Scheme 1b).10 It is well-known that the cascade radical reactions represent valuable tools to access densely functionalized structures, as multiple C−C/C−X bond-forming reactions could be orchestrated in highly controlled and functional-group-compatible manners.11 As part of our ongoing project, we attempted to © 2018 American Chemical Society

incorporate an alkyne moiety, a privileged building block in a radical reaction, at the ortho position relative to the paraquinone methides. We hypothesized that the cyclohexadienone radical intermediates, which were generated in situ via a radical 1,6-addition,12 could be engaged in additional bond-forming events in the presence of an adequate alkyne moiety, delivering spiro[4.5]cyclohexadienones through an unprecedented radical 1,6-addition/cyclization/radical coupling reaction (Scheme 1c). Received: February 12, 2018 Published: March 26, 2018 1974

DOI: 10.1021/acs.orglett.8b00518 Org. Lett. 2018, 20, 1974−1977

Letter

Organic Letters

Decreasing the dosage of NIS to 2.0 equiv resulted in an 81% yield of 4a (Table 1, entry 16). With the optimized reaction conditions in hand, we then set out to investigate the substrate scope of this cascade threecomponent radical cyclization reaction, and the results are shown in Scheme 2. Substrates (1b−i) bearing electron-

To test the possibility of our envisioned protocol, we chose 2,6-di-tert-butyl-4-(2-(phenylethynyl)benzylidene)cyclo-hexa2,5-dienone 1a, TMSN3, and N-iodosuccinimide (NIS) as the model substrates. The desired iodoazidation spiro[4.5]deca-6,9dien-8-one 4a was achieved in 41% yield at 60 °C (Table 1, Table 1. Optimization of Reaction Conditionsa,b

Scheme 2. Substrate Scopea,b

entry

oxidant

I-source

solvent

t (°C)

yield (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

− PIDA H2O2 DTBP TBPB TBPB TBPB TBPB TBPB TBPB TBPB TBPB TBPB TBPB TBPB TBPB

NIS NIS NIS NIS NIS I2 TBAI KI NIS NIS NIS NIS NIS NIS NIS NIS

DCE DCE DCE DCE DCE DCE DCE DCE CH3CN toluene DMF 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane

60 60 60 60 60 60 60 60 60 60 60 60 rt 40 80 60

41 trace 18 33 50 10 NDc NDc 63 76 74 88 74 80 63 81d

a

Reaction conditions: 1a (0.2 mmol), 2 (0.4 mmol), 3 (0.6 mmol), and oxidants (0.4 mmol) in solvent (2.0 mL) for 6 h. bIsolated yield. c ND = Not detected. d3 (0.4 mmol). PIDA = phenyliodine diacetate. DTBP = di-tert-butyl peroxide. TBPB = tert-butyl peroxybenzoate.

entry 1), and the relative configuration of 4a was determined by X-ray crystal structure analysis (see the Supporting Information for details) (Figure 2). Motivated by this encouraging result, we a

Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), 3 (0.6 mmol), TBPB (0.4 mmol) in 1,4-dioxane (2.0 mL) at 60 °C for 6 h. bIsolated yields. c1.0 mmol scale.

withdrawing or -donating groups at the para-position of the aromatic ring bound to the alkynyl terminal produced the corresponding iodoazidation spiro[4.5]deca-6,9-dien-8-ones 4b−i in good to excellent yields. Products 4j−l with metasubstituents were obtained in 71−75% yields. Steric hindrance resulted in the reaction affording slightly low yields, delivering 4m and 4m′ (relative configurations of 4m and 4m′ were determined by X-ray diffraction; see the SI for details). 2Naphthalenyl (2-Np) and 2-thienyl (2-Th) counterparts were adaptable substrates, allowing 4n and 4o in 70% and 61% yields. An alkyl substituent at the terminal position of the triple bond offered 4p in 27% yield, which may be ascribed to the relative instability of the vinyl radical intermediate. Compounds 1q−u with various groups (R2) in the aromatic rings, which are directly connected to para-quinone methides, were well compatible with the reaction conditions, delivering 4q−u in 70−86% yields. Substrate 1v with 2,6-phenylethynyl groups afforded 4v in a moderate yield, which could be ascribed to the

Figure 2. X-ray structure of 4a.

continued to optimize the reaction conditions with a series of oxidants to enhance the yield (Table 1, entries 2−5). When tert-butyl peroxybenzoate (TBPB) was used, 4a could be obtained in 50% yield. It was found that iodine sources imposed an important impact on the reaction efficiency and NIS proved to be the most suitable iodine source (Table 1, entries 5−8). Screening of solvents revealed that 1,4-dioxane performed best, delivering 4a in 88% yield (Table 1, entries 9− 12). Lowering or raising the temperature had a deleterious effect on the reaction result (Table 1, entries 13−15). 1975

DOI: 10.1021/acs.orglett.8b00518 Org. Lett. 2018, 20, 1974−1977

Letter

Organic Letters increased steric effects. Polycyclic spiro-compound 4w could be obtained in 68% yield. When 1x bearing two different substituents in the cyclohexadienone moiety was tested, 4x and 4x′ were produced in 71% yield (relative configuration of 4x was determined by X-ray diffraction; see the SI for details). The synthetic value of this three-component iodoazidation cyclization protocol was demonstrated by investigating the follow-up chemistry with 4a as the starting material (Scheme 3). Exocyclic 1,3-diene functionalized spirocyclic compound 5

Scheme 4. Control Experiments and Plausible Reaction Mechanism

Scheme 3. Further Studies on 4a

by the presence of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) or 2,6-di-tert-butyl-4-methylphenol (BHT). Among them, a BHT coupling adduct was detected on MS (see the SI for details), which pointed toward a radical mechanism. On the basis of the above experiments and previous works,12,14 a plausible mechanism is depicted in Scheme 4b. Initially, the azide radical is generated from TMSN3 under the oxidative conditions. Then the in situ generated azide radical chemoselectively interacts with the activated alkene through 1,6-addition to give a cyclohexadienone radical intermediate I, which could isomerize reversibly to the phenol radical intermediate II on account of its aromatic zwitterionic resonances. The alkynyl motif in intermediate I captures the cyclohexadienone radical to generate spirocyclic vinyl intermediates III and III′ through 5-exo-dig cyclization. Due to the steric hindrance of the substituted spiro-cyclohexadienones moiety, the bulky iodine radical favors coupling with intermediate III via path a, yielding the iodoazidation spiro[4.5]deca-6,9-dien-8-one 4a, while path b is not favored to deliver the compound 9. In conclusion, we have established a novel three-component iodoazidation cyclization of ortho-alkynephenyl-substituted pQMs under mild reaction conditions, leading to biologically interesting spiro[4.5]deca-6,9-dien-8-ones with high efficiency. This reaction underwent a cascade radical 1,6-addition/5-exodig cyclization/radical coupling process, with successive formation of C−N, C−C, and C−I bonds in one pot. Further exploration of the chemistry of ortho-alkynephenyl-substituted p-QMs in organic synthesis is underway in our laboratory.

was synthesized in 71% yield through a Heck coupling reaction with styrene (Scheme 3a). Furthermore, Sonogashira coupling and Suzuki coupling reactions of 4a provided the alkynylation product 6 in 94% yield and arylation product 7 in 91% yield (Scheme 3b and 3c). Additionally, 4a could also be transformed into another functionalized skeleton under simple conditions. Indenone derivative 8 was obtained in 88% yield (Scheme 3d) in a two-step transformation, and the structure was determined by X-ray diffraction (see the SI for details) (Figure 3). According to the previous literature,13 a plausible procedure for the formation of 8 was postulated in the SI. To gain insight into the mechanism, control experiments were conducted in Scheme 4a. The efficiency of the reactions of 1a, 2, and 3 under the standard conditions was strongly affected

Figure 3. X-ray structure of 8. 1976

DOI: 10.1021/acs.orglett.8b00518 Org. Lett. 2018, 20, 1974−1977

Letter

Organic Letters

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b00518. 1 H and 13C NMR spectra for all new compounds (PDF) Accession Codes

CCDC 1821786−1821787, 1828844, and 1828847−1828848 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_request@ccdc. cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]; [email protected]. ORCID

Aijun Lin: 0000-0001-5786-4537 Hequan Yao: 0000-0003-4865-820X Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Generous financial support from the National Natural Science Foundation of China (NSFC21502232 and NSFC21572272) is gratefully acknowledged.

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REFERENCES

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DOI: 10.1021/acs.orglett.8b00518 Org. Lett. 2018, 20, 1974−1977