Radical-Triggered Tandem Cyclization of 1,6-Enynes with H2O: A Way

Letter Cite This: Org. Lett. 2018, 20, 7053−7056

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Radical-Triggered Tandem Cyclization of 1,6-Enynes with H2O: A Way to Access Strained 1H‑Cyclopropa[b]naph thalene-2,7-diones Limeng Zheng,† Bingwei Zhou,† Hongwei Jin,† Ting Li,*,‡ and Yunkui Liu*,† †

State Key Laboratory Breeding Base of Green Chemistry-Synthesis Technology, Zhejiang University of Technology, Hangzhou, 310014, P. R. China ‡ College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nangyang, Henan 473061, P. R. China

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S Supporting Information *

ABSTRACT: A radical-triggered tandem cyclization of 1,6enynes has been developed herein. Strained 1H-cyclopropa[b]naphthalene-2,7-diones are successfully obtained in moderate to good yields with excellent stereoselectivity. Mechanistic studies reveal a key role of water in generating a hydroxyl radical that initiates a sequential Michael addition/ring closure pathway. Importantly, the formed hydroxyl is proposed to be a good leaving group during the cyclopropane ring formation.

C

Scheme 1. Construction of the Cyclopropane Ring via an Anionic/Cationic Pathway

yclopropanes are known as biologically and medicinally active structures that are widely found in natural products, medicines, and agrochemicals.1 Synthetically, they are versatile building blocks enabling a ring-opening reaction to access functionalized acyclic compounds due to the unique structure of the three-membered ring.2 Additionally, cyclopropanes have practical utilities in mechanistic studies of various organic transformations associating with a radical pathway.3 Consequently, the construction of the cyclopropane subunit is of synthetic interest, and various methodologies have been developed over the past several decades.4 Among them, the sequential Michael addition-ring closure pathway has gained considerable attention since the pioneering work by Corey in 1958.5 A variety of heteroatom-derived ylides and electron-withdrawing group (EWG)-stabilized carbanions are proven to be versatile methylene precursors (Scheme 1a). Other anionic cyclizations of 1,2-electrophiles such as epichlorohydrins, epoxyolefins, and cyclic 1,2-sulfates are also demonstrated (Scheme 1b).6 Relatively, the cationic cyclizations of O-protected allylic alcohols are less reported (Scheme 1c).7 It should be mentioned that a good leaving group such as sulfide, OTf, or bromide is indispensable to facilitate the formation of the cyclopropane ring in those reactions, whereas the free hydroxyl has never been disclosed as a leaving group in the ring closure step. Thus, the development of facile cyclopropane ring formation by using small leaving groups (such as a hydroxyl group) in a more atom-economic manner is highly desirable. Transition metal-catalyzed or radical-mediated cascade cyclization of 1,n-enynes has emerged as a powerful strategy to achieve cyclic compounds with operational simplicity and high efficiency.8,9 Specifically, (E)-3-phenyl-1-(2-(2-phenylethynyl) phenyl)prop-2-en-1-one represents one of the typical 1,6-enynes and has been explored in several reactions independently by Li,10 Hu,11 and others.12 Recently, our © 2018 American Chemical Society

group has also reported a Cu(0)/Selectfluor system-catalyzed annulation of 1,6-enynes affording benzo[b]fluorenones under mild conditions.13 To further extend the reaction scope of 1,6enynes, we herein disclose a radical-triggered tandem Received: September 19, 2018 Published: October 25, 2018 7053

DOI: 10.1021/acs.orglett.8b03007 Org. Lett. 2018, 20, 7053−7056

Letter

Organic Letters

With the optimized reaction conditions in hand, we set out to investigate the scope of 1,6-enynes (Scheme 2). The

cyclization for the synthesis of strained 1H-cyclopropa[b]naphthalene-2,7-diones with an exclusive cis stereoselectivity (Scheme 1d). The strained cyclopropane ring can be constructed with an in situ-generated hydroxyl as a suitable leaving group, thus featuring an excellent step and atom economy. Initially, we chose (E)-3-phenyl-1-(2-(phenylethynyl) phenyl) prop-2-en-1-one 1a as a model substrate to optimize the reaction conditions. The reaction was performed in the presence of I 2 O 5 and water in dioxane at 100 °C. Unexpectedly, 1H-cyclopropa[b]naphthalene-2,7-dione 2a was obtained in 50% LC yield (Table 1, entry 1). We then

Scheme 2. Substrate Scope for 1,6-Enynes

Table 1. Optimization of the Reaction Conditionsa

entry

I2O5 (equiv)

additive (mol %)

solvent

temp (°C)

yield (%)b

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 3.0 1.5 1.0 d 2.0 2.0 2.0 2.0 2.0 2.0 2.0

c FeCl3/20 CuSO4·5H2O/20 Cu/20 CuCl/20 Cu(OAc)2/20 FeCl3·6H2O/20 AgNO3/20 AlCl3/20 BF3·Et2O/20 FeCl3·6H2O/20 FeCl3·6H2O/20 FeCl3·6H2O/20 FeCl3·6H2O/20 FeCl3·6H2O/20 FeCl3·6H2O/20 FeCl3·6H2O/20 FeCl3·6H2O/20 FeCl3·6H2O/20 FeCl3·6H2O/20 FeCl3·6H2O/20 FeCl3·6H2O/20 FeCl3·6H2O/10 FeCl3·6H2O/30 FeCl3·6H2O/40

dioxane dioxane dioxane dioxane dioxane dioxane dioxane dioxane dioxane dioxane PhCF3 MeCN DMSO toluene dioxane dioxane dioxane dioxane dioxane dioxane dioxane dioxane dioxane dioxane dioxane

100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 110 90 80 70 80 80 80

50 59 62 57 61 50 72 36 35 21 trace trace 0 0 66 65 69 0 69 70 77 70 50 87 (83e) 78

substitutes R1 on phenyl ring A were first examined. It was found that electron-donating groups had a positive effect on the outcome of the reaction, whereas electron-withdrawing groups had a negative effect (2a, 2b vs 2c−e). A substrate with fluorine at the 2- or 5-position of phenyl ring A provided a comparable yield (2d, 2e). Next, the R2 group on the chalcone moiety of 1 was screened. When R2 equals an aryl group, it was found that a range of electron-varied functional groups such as halogen, cyano, or free hydroxyl on the phenyl ring were all tolerated in this reaction (2f−n). Of note, the structure of 2j and the cis configuration of the two aryl rings on the cyclopropane were unambiguously confirmed by the X-ray crystallographic analysis (see Supporting Information). In addition, substrates with R2 as 1-naphthalenyl and 2thiophenyl were also workable for the reaction, and the desired products were obtained in 51 and 81% yields, respectively (2o, 2p). Substrate 1y with R2 as an n-propyl group failed to give the desired product. Surprisingly, 1z with R2 as a cyclopropyl group delivered diketonized product 2z′ in 67% yield instead of the formation of 2z. Furthermore, we evaluated the scope of the R3 group connecting to the alkyne moiety. Again, the reaction could proceed very well when R3 equals an aryl ring (either electron-rich or -deficient) as well as a heteroaromatic ring (2q−x). When 1aa with R3 as a tert-butyl group was used, the reaction failed to give desired product 2aa, whereas carbon−carbon bond-cleaved product 2aa′ was obtained in 55% yield. Finally, a gram-scale (5 mmol of 1a used) synthesis of 2a was also carried out, and 2a could be obtained in 67% yield (see Supporting Information).

a Reaction conditions: 1a (0.2 mmol), H2O (0.4 mmol), oxidant, additive in dry solvent (4 mL) under air for 0.5 h. bYields determined by LC analysis. cNo additive. dNo oxidant. eIsolated yield shown in parentheses.

screened a series of Lewis acids where FeCl3·6H2O promoted this transformation efficiently (entries 2−10). Different solvents were examined, and dioxane was proven to be the best one (entries 11−14). Two equivalents of I2O5 were enough to obtain a satisfactory yield of 2a, as either increasing or decreasing the amount of I2O5 could not improve the yield of 2a (entry 7 vs 15−18). Finally, the optimal reaction conditions were obtained by tuning the reaction temperature to 80 °C and using 30 mol % of FeCl3·6H2O (entry 24). 7054

DOI: 10.1021/acs.orglett.8b03007 Org. Lett. 2018, 20, 7053−7056

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under thermal conditions might generate a hydroxyl radical and I2.14,16 The sequential Michael addition of the hydroxyl radical to 1a followed by an intramolecular cyclization produced intermediate B. Active B was then captured by I2 to form intermediate C.14a An oxidation of C by HIO3 provided an vinyl-λ3-iodane intermediate D that underwent substitution by H2O to deliver intermediate E.14a The cyclopropane moiety was constructed via a ring closure process where the hydroxyl acted as a leaving group under the assistance of a proton (or FeCl3·6H2O if added).17 Eventually, the deprotonation of resulting intermediate F released desired product 2a. In addition, mechanism II involved in a high-valent iron(IV or V)18 species-triggered water addition to chalcone10,19 followed by the formation of intermediate E under oxidative conditions16,20 is also possible. In summary, we have developed a tandem cyclization of 1,6enynes via a cascade Michael addition/ring closure pathway. During the cyclopropane ring formation, the hydroxyl is viewed as a good leaving group under the assistance of a Lewis acid. Various substituted 1H-cyclopropa[b]naphthalene-2,7diones were obtained in moderate to good yields with excellent cis stereoselectivity. The characteristic features of this reaction are as follows: (1) low toxicity and inexpensive iron catalyst, (2) water as a source for C=O bond formation, and (3) the reaction exhibiting step and atom economy due to the in situgenerated hydroxyl group as the leaving group. Further studies on cyclizations of other 1,n-enynes via a radical process are underway in our laboratory.

To ascertain the possible reaction mechanism, we conducted several mechanistic experiments (Scheme 3). At the beginning, Scheme 3. Mechanistic Studies Based on 1a

TEMPO was used as a radical scavenger and subjected to the standard conditions. We found that the reaction was almost suppressed, which indicated that a radical pathway might be involved in this reaction. Next, we performed an isotope labeling experiment by utilizing H218O to clarify the oxygen source and possible radical species. The result shows that 18O was incorporated into product 2a and the oxygen in air was excluded to be an oxygen precursor. Thus, a hydroxyl radical was proposed to be generated from the reaction of H2O and I2O5.14 Furthermore, we performed a control experiment by removing the H2O and using anhydrous FeCl3. As expected, no product was detected, and this result further supported our previous hypothesis. At last, an attempt to run the reaction under dark conditions was also investigated, and 2a could still be obtained in 85% yield. On the basis of our preliminary results and previous literature,14−20 we proposed two possible mechanisms of this reaction, as depicted in Scheme 4. Mechanism I involves a radical process: First, the hydrolysis of I2O5 by water gave HIO3.15 Then, the oxidation reaction between HIO3 and water

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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.8b03007. Experimental details, full characterization data, mechanistic experiments, X-ray crystallographic structure of 2j, and copies of NMR spectra for compound 2 (PDF) Accession Codes

CCDC 1856715 contains 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 [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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Scheme 4. Proposed Mechanism

AUTHOR INFORMATION

Corresponding Authors

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

Ting Li: 0000-0002-2186-6992 Yunkui Liu: 0000-0001-8614-458X Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful to the Natural Science Foundation of China (Nos. 21772176 and 21372201) for financial support. 7055

DOI: 10.1021/acs.orglett.8b03007 Org. Lett. 2018, 20, 7053−7056

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Organic Letters

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DOI: 10.1021/acs.orglett.8b03007 Org. Lett. 2018, 20, 7053−7056