Organic &Biomolecular Chemistry

COMMUNICATION

Cite this: Org. Biomol. Chem., 2013, 11,7088

Received 5th August 2013,Accepted 2nd September 2013

DOI: 10.1039/c3ob41600c

www.rsc.org/obc

Visible light photoredox atom transfer Ueno–Storkreaction†

Xiangyong Gu, Ping Lu, Weigang Fan, Pixu Li* and Yingming Yao*

A visible light-promoted atom transfer Ueno–Stork reaction

was developed using Ir(ppy)2(dtb-bpy)PF6 as the sensitizer.

2-Iodoethyl propargyl ethers or 2-iodoethyl allyl ethers were used

as the radical precursors to construct tetrahydrofuran-containing

fused [6,5] and [5,5] bicyclic frameworks.

Oxabicyclic frameworks exist in many biologically interestingnatural products, such as Alboatrin,1 Aflatoxins,2 Gracilin B,3

and Xyloketals.4 Radical cyclization of α-haloacetals (Ueno–Stork reaction)5 has proven to be an extremely efficient methodto construct oxabicyclic compounds.6 Atom transfer Ueno–Stork reaction is particularly interesting because it is highlyatom economic and the C–X bond in the product may be usedas a handle for further chemical transformations.7 However,atom transfer radical addition/cyclization (ATRA/ATRC),including Ueno–Stork reaction, often employs stoichiometrictoxic organotin compounds, pyrophoric alkylborane/O2 combi-nations, or explosive peroxides. These drawbacks limit theutility and applications of radical cyclization in organic syn-thesis. Therefore, it is important to develop environmentally-benign and practical radical initiators.

One of the advantages of visible light-mediated photoredoxradical reaction is that it avoids the use of classical hazardousradical initiators. Visible light photoredox chemistry is emer-ging as a powerful synthetic methodology.8,9 Many visible-lightpromoted intramolecular8b,10 and intermolecular11–14 cycliza-tion reactions have recently been developed. However, visible-light-promoted ATRC is still a challenge. Reductive products,in which the halogen functionalities were lost in the reductivequenching step, were preferentially formed.10c,e,k,j,l,15 A photo-sensitized phenyl selenide group transfer radical additioncyclization was reported by Pandey’s group.16 More recently,

Stephenson and coworkers reported visible-light promotedATRA reactions of α-halocarbonyls and polyhalogenatedalkanes to alkenes.17 The reaction conditions worked nicely toform acyclic halogen-containing products. However, it washardly applicable to ATRC. The authors pointed out that thereactions were very substrate dependent and preferentiallyafforded reductive cyclization product with terminal alkenesand alkynes. Herein, we report a visible light-mediated intra-molecular atom transfer Ueno–Stork reaction of 2-iodoethylallyl/propargyl ethers. Oxabicyclic frameworks were formedwith the retention of halogen functionality (Fig. 1).

Our investigation of a visible light photoredox Ueno–Storkreaction used propargyl α-iodoacetal 1a as the starting materialfor the initial study. Solutions of 1a, photoredox catalysts(1 mol%), and bases (2 eq.) in dichloromethane were placedunder the irradiation of a 14 W compact fluorescent light for6 h. The results are summarized in Table 1. The desired oxa-bicyclic compound 2a was formed with all the visible lightphotoredox catalysts screened. The yields varied from 55% to78% (entries 1–5). Ir(ppy)2(dtb-bpy)PF6 was selected for furtherstudy as it afforded the highest yield. Among the solventstested, acetonitrile gave the best result (86%, entries 5–7). Thereaction was further optimized using different amine bases(entries 7–10). It was found that a sub-stoichiometric amountof tertiary amine base was sufficient to afford a clean reaction.Product 2a was formed in 90% yield with 0.5 equivalent ofDIEA (entry 10). Control reactions carried out without a base,without a catalyst, or in the dark gave little desired product

Fig. 1 Visible light-mediated radical cyclizations.

†Electronic supplementary information (ESI) available: Experimental pro-cedures, characterization data, and 1H and 13C NMR spectra for all products,X-ray crystallography data for compound 6c. CCDC 953992. For ESI and crystallo-graphic data in CIF or other electronic format see DOI: 10.1039/c3ob41600c

Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry,

Chemical Engineering, and Materials Science, Soochow University, 199 RenAi Road,

Suzhou, Jiangsu 215123, China. E-mail: lipixu@suda.edu.cn, yaoym@suda.edu.cn

7088 | Org. Biomol. Chem., 2013, 11, 7088–7091 This journal is © The Royal Society of Chemistry 2013

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(entries 11–13), confirming that both light and sensitizer wereessential to the reaction.

A variety of substrates were examined under the optimizedconditions. The results in Table 2 showed that the reactionwas quite general. Both terminal and internal alkynes under-went cyclizations to provide vinyl iodide products (entries 1–3).Substituting the tetrahydropyran ring of the substrates with atetrahydrofuran ring resulted in smooth formation of the [5,5]bicyclic framework (72%, entry 4). The cyclization was notlimited to cyclic acetal substrates. Acyclic butyl acetal 1e gavetetrahydrofuran derivative 2e in 79% yield (entry 5). While the5-exo ring closing transformation provided satisfactory yields(entries 1–5), 6-exo cyclization of 1f gave the product 2f in mod-erate yield (22%, entry 6). This result is consistent with typicalradical cyclizations in which formation of five-membered ringis more facile than that of six-membered ring.18 The visiblelight promoted Ueno–Stork reaction not only worked withalkynes but also with alkenes. Monosubstituted, 1,1-disubsti-tuted, and 1,2-disubstituted alkenes afforded the corres-ponding ring-closing products under the same conditions in74%, 70%, 66%, and 58%, respectively (entries 7–10).

Replacing the oxygen atoms in the tetrahydrofuran or tetra-hydropyran motifs with heteroatoms or carbon-based groupswould greatly diversify the types of ring structures formed inthe reaction. Therefore, it was decided to investigate the for-mation of other bicyclic systems using the newly developedvisible light Ueno–Stork reaction. The results showed that thevisible light promoted atom transfer radical cyclization wasnot limited to acetals (Table 3). During our study, it was foundthat the addition of water improves the robustness of the reac-tion. Therefore, a mixture of MeCN–H2O (4 : 1) was used as thesolvent system for all the reactions in Table 3. Propargylaminals 3a–b provided the corresponding products 4a–b in

good yields (82–85%, entries 1–2). The ring-closing addition of3c to CvC double bond afforded 4c in excellent yield (92%,entry 3). More importantly, propargyl β-iodoethers underwentsimilar transformation. Although the C–I bond of β-iodoetherwas expected to be much less activated than that of α-iodo-acetal, similar levels of reactivity were observed (entries 4–7).Ring systems 6a–d containing cyclohexane or cyclopentanefused to a tetrahydrofuran ring were successfully formed. Acrystal of one of the isomers of 6c was obtained. The X-ray

Table 1 Optimization of propargyl α-iodoacetal cyclizationa

Entry Catalyst Base Solvent Yieldb

1 Ru(bpy)3Cl2·6H2O DIEA CH2Cl2 55%2 Ru(bpy)3(PF6)2 DIEA CH2Cl2 67%3 Ir(ppy)3 DIEA CH2Cl2 77%4 [Ir(dF(CF3)ppy)2(dtb-bpy)PF6 DIEA CH2Cl2 64%5 Ir(ppy)2(dtb-bpy)PF6 DIEA CH2Cl2 78%6 Ir(ppy)2(dtb-bpy)PF6 DIEA DMSO 75%7 Ir(ppy)2(dtb-bpy)PF6 DIEA MeCN 86%8 Ir(ppy)2(dtb-bpy)PF6 Et3N MeCN 80%9 Ir(ppy)2(dtb-bpy)PF6 TMEDA MeCN 82%10 Ir(ppy)2(dtb-bpy)PF6 DIEAc MeCN 90%11 Ir(ppy)2(dtb-bpy)PF6 — MeCN —12 Ir(ppy)2(dtb-bpy)PF6 DIEA MeCN 8%d,e

13 — DIEA MeCN 7%e

a Reaction conditions: 1a (1.0 mmol), catalyst (1 mol%), base (2 eq.),solvent (4 mL), 14 W fluorescence lamp irradiation for 6 h. bGC yield.c 0.5 eq. DIEA was used. d The reaction was carried out in the dark.e Reacted for 12 h.

Table 2 Substrate scope study of visible light promoted radical cyclization ofα-iodoacetala

Entry Substrate Product Yieldb Ratioc

1 80% 10/1

2 67% ND

3 87% 2.2/1

4 72% 1.3/1

5 79% 1.4/1

6 22% 5.6/1

7 74% 8.4/1

8 70% 1.4/1

9 66% >20/1

10 58% 1.1/1

a Reaction conditions: substrate 1 (1.0 mmol), Ir(ppy)2(dtb-bpy)PF6(1 mol%), DIEA (0.5 eq.), MeCN (4 mL), 14 W fluorescence lampirradiation for 9 h. b Isolated yield. c Ratios were determined by GC;ND: not determined.

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crystallography showed a cis-[5,5] fused ring structure wasformed in the radical reaction (Fig. 2).

The proposed mechanism is illustrated in Fig. 3, α-halo-acetal 1a (Ered = −0.55 V vs. SCE, see ESI†) was reduced byvisible light activated Ir(III)* (Ered = −0.88 V vs. SCE) to formradical 7. A typical 5-exo intramolecular radical addition to thetriple bond affords vinyl radical 8. At this stage, either chain

propagation or radical/ionic crossover pathway could lead tothe formation of final product. Because oxidation of a vinylradical to its corresponding vinyl cation is unfavored, radicalpropagation pathway is more likely to happen. Radical 8abstracts an iodine atom of 1a to complete the ATRC reaction.Oxabicyclic product 2a was formed and radical 7 was regener-ated. A light switched on/off experiment showed that almostno reaction occurred during the light off period, indicating thechain propagation might be very short-lived. However, theradical/ionic crossover pathway, oxidation of radical 8 to itscorresponding alkenyl cation followed by reaction with iodineanion to give final product 2a, could not be ruled out. In thecases where products are alkyl iodides (Table 2, entries 7–10),the reductive potential of compound 2g was measured (Ered =−0.89 V vs. SCE, see ESI†). It is higher than that of α-haloacetal1a and is not reduced by activated Ir(III)*. Therefore, the pro-ducts did not participate in the reaction.

In conclusion, a visible light promoted atom transfer Ueno–Stork reaction was successfully developed. Iodoalkanes actedas the radical precursors in the photoredox process. Tetra-hydrofuran-containing oxabicycles were successfully con-structed. The ring structures were expanded to fused [6,5] and[5,5] systems of piperidine, pyridine, cyclohexane, or cyclo-pentane with tetrahydrofuran. The ability to build a variety offused ring structures suggests great potential of the visiblelight promoted atom transfer radical cyclization reaction inthe synthesis of complex molecules.

Acknowledgements

Financial support was provided by NSFC (21102097), theSpecialized Research Fund for the Doctoral Program of HigherEducation (20103201120006), Beijing National Laboratoryfor Molecular Sciences (BNLMS), and the Qing Lan Project(Dr. Y. M. Yao).

Notes and references

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3 L. Mayol, V. Piccialli and D. Sica, Tetrahedron Lett., 1985,26, 1357.

Table 3 Visible light promoted radical cyclization of aminals and β-iodoethersa

Entry Substrate Product Yieldb Ratioc

1 85% ND

2 82% ND

3 94% ND

4 80% 2.5/1

5 74% 1.4/1

6 69% 1.2/1

7 78% 1.2/1

a Reaction conditions: substrate 3 or 5 (1.0 mmol), Ir(ppy)2(dtb-bpy)]-(PF6) (1 mol%), DIEA (0.5 eq.), MeCN (4 mL), H2O (1 mL), 14 Wfluorescence lamp irradiation for 9 h. b Isolated yield. c Ratios weredetermined by GC; ND: not determined.

Fig. 2 X-ray structure of compound 6c.

Fig. 3 Proposed mechanism.

Communication Organic & Biomolecular Chemistry

7090 | Org. Biomol. Chem., 2013, 11, 7088–7091 This journal is © The Royal Society of Chemistry 2013

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12 Selected visible light [3 + 2] cyclization: (a) Y.-Q. Zou,L.-Q. Lu, L. Fu, N.-J. Chang, J. Rong, J.-R. Chen andW.-J. Xiao, Angew. Chem., Int. Ed., 2011, 50, 7171; (b) Z. Lu,M. H. Shen and T. P. Yoon, J. Am. Chem. Soc., 2011, 133,1162; (c) M. Rueping, D. Leonori and T. Poisson, Chem.Commun., 2011, 47, 9615; (d) G. Zhao, C. Yang, L. Guo,H. Sun, R. Lin and W. Xia, J. Org. Chem., 2012, 77, 6302;(e) S. Maity, M. Zhu, R. S. Shinabery and N. Zheng, Angew.Chem., Int. Ed., 2012, 51, 222.

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