Tetrahedron Letters 54 (2013) 6298–6302

Contents lists available at ScienceDirect

Tetrahedron Letters

journal homepage: www.elsevier .com/ locate / tet let

Inverse electron demand hetero-Diels–Alder reaction in preparing1,4-benzodioxin from o-quinone and enamine

0040-4039/$ - see front matter Published by Elsevier Ltd.http://dx.doi.org/10.1016/j.tetlet.2013.09.013

⇑ Corresponding author. Tel.: +1 530 898 5622; fax: +1 530 898 5234.E-mail address: jzhang2@csuchico.edu (J. Zhang).

Jinsong Zhang a,⇑, Chris Taylor a, Erich Bowman a, Leo Savage-Low a, Michael W. Lodewyk a,b

Larry Hanne c, Guang Wu d

a Department of Chemistry and Biochemistry, California State University, Chico, CA 95929, United Statesb Department of Chemistry, University of California, Davis, CA 95616, United Statesc Department of Biological Sciences, California State University, Chico, CA 95929, United Statesd Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA 93106, United States

a r t i c l e i n f o a b s t r a c t

Article history:Received 9 August 2013Revised 2 September 2013Accepted 4 September 2013Available online 11 September 2013

Keywords:o-QuinonesEnamines1,4-BenzodioxinsDiels–Alder reaction

A process for synthesizing 1,4-benzodioxin, through oxidation of a phenol to an o-quinone followed bytreatment with an enamine, has been developed. Adduct stereochemistry is found to be retained via thisone-pot reaction. The method uses hypervalent iodine reagent under mild conditions and is compatiblewith a wide scope of phenols and enamines.

Published by Elsevier Ltd.

Introduction

Natural products containing a 1,4-benzodioxin group havedemonstrated various biological activities. For instance, silybinhas anti-inflammatory, cytoprotective, hepatoprotective and anti-carcinogenic acitivity,1 and americanins possess antibacterialactivity as well as neurotrophic activity.2 In addition, six neolign-ans have been isolated from Rodgersia podophylla (Saxifragaceae),the rhizomes of which have been used for the treatment of enter-itis and bacillary dysentery and have been reported to exhibit anti-pyretic, analgesic and hepatoprotective effects.3 Nine clinopodicacids have been isolated from Clinopodium chinense var. parviflorumand have shown matrix metalloproteinase-2 inhibition activities.4

A group of six junipercomnosides have demonstrated antioxidantproperties.5 In addition, two acetamide derived 1,4-benzodioxinshave shown antioxidant and anti-inflammatory activities (Fig. 1).6

The 1,4-benzodioxin moiety can serve as a scaffold for the syn-thesis of a large number of natural products. The biosyntheticpathway to a benzodioxin substructure is believed to follow a freeradical mechanism, starting from a catechol derivative.7 Previoussynthetic efforts have been made to mimic the biosynthetic path-way utilizing a metal–ion oxidizing agent. Merlini et al. utilizedAg2O to synthesize (±)-eusiderin (40% yield for the benzodioxin

formation) and silybin/isosilybin (4:3 mixture, 76% total yield forbenzodioxin formation).8 Stermitz and co-worker synthesizedhydnocarpin-type flavonolignans by treating luteolin (a catechol)and coniferyl alcohol with Ag2CO3.9 Pan’s group has successfullysynthesized a series of benzodioxin-based natural products utiliz-ing silver (I) and iron (III) reagents.10 Even though the biomimeticapproach is very efficient in making the benzodioxin ring, controlof the stereochemistry in this free radical reaction is an obviouschallenge.

Herein we report a hetero-Diels–Alder cycloaddition between o-quinones and enamines to synthesize the 1,4-benzodioxin moiety.As a highly reactive 8p-electron system, o-quinones (1, Scheme 1)display two 4p components as potential sites for a Diels–Alderreaction. The selectivity between these sites is determined by thepolarizability of the complementary 2p component, the specificmechanistic details and reaction conditions, including catalystselection, temperature and solvent polarity.11 The hetero-Diels–Al-der approach to generate the key benzodioxin scaffold has theadvantages of (1) using readily accessible phenols as starting mate-rials instead of catechols; (2) utilizing environmentally friendly 2-iodoxybenzoic acid (IBX) as an oxidizing agent instead of a metaloxidizing agent; (3) using an electron-rich enamine as the dieno-phile to ensure the desired dione–enamine cycloaddition(LUMO–HOMO interaction) and (4) greater stereochemical control.This approach provides a novel methodology for synthesizing awide variety of 1,4-benzodioxin-derived natural products.

Figure 1. Natural products contain 1,4-benzodioxin core structure.

Scheme 1. 1,4-Benzodioxin preparation.

Table 1Formation of 1,4-benzodioxins starting with 4-t-butyl-1,2-quinone

Entry o-Quinone Enamine Productsa Yield (%)

1 80

2 1a 47

3 1a 73

(continued on next page)

J. Zhang et al. / Tetrahedron Letters 54 (2013) 6298–6302 6299

Table 1 (continued)

Entry o-Quinone Enamine Productsa Yield (%)

4 1a 42

5 1a 71

6 1a 48

7 1a 73

8 1a 46

a All the products are mixtures of a pair of regioisomers.

Table 2Formation of 1,4-benzodioxins starting with various o-quinone

Entry o-Quinone Enamine Productsa Yield (%)

1 2a 25

2 2a 30

3 2a28 for 3k_i19 for 3k_ii

4 1d 2b 22

5 2a 26

6 2a 77

a All the products are mixtures of a pair of regioisomers except 3i.

6300 J. Zhang et al. / Tetrahedron Letters 54 (2013) 6298–6302

Figure 2. X-ray Chrystallography of 4-(7-(1,3-dioxolan-2-yl)-3-phenyl-2,3-dihy-drobenzo[b][1,4]dioxin-2-yl)morpholine 3k_ii.

Table 3Comparison of experimental and computed chemical shifts for 3k_i

13C Chemical shifts (ppm) 1H Chemical shifts (ppm)

Expt. Computeda Expt. Computeda

144.82 142.99 7.41 7.36143.34 142.02 7.40 7.32137.12 138.33 7.40 7.28131.10 133.84 7.10 6.98128.91 127.10 7.04 6.89128.67 127.09 6.97 6.84127.61 126.82 5.74 6.02120.40 117.68 4.98 4.80117.02 114.55 4.67 4.55115.45 113.14 4.12 3.73103.70 102.08 3.57 3.28

93.01 91.85 2.88 2.7476.03 75.1867.05 65.4465.45 64.0348.24 47.42

CMADb 1.64 CMADb 0.17Largest

outlierDd = 2.74 Largest

outlierDd = 0.39

aSee Supplementary data complete for assignment details and additional

comparisons.b

CMAD = corrected mean absolute deviation and is computed as 1n

Pn

idcomp � dexp��

��

where dcomp refers to the scaled computed chemical shifts.

Table 4Comparison of experimental and computed chemical shifts for 3k_ii

13C Chemical shifts (ppm) 1H Chemical shifts (ppm)

Expt. Computeda Expt. Computeda

144.32 142.59 7.13 7.00143.91 142.41 7.42 7.35137.08 137.78 7.41 7.34132.00 134.80 7.40 7.31128.94 127.44 6.98 6.84128.69 127.14 6.94 6.78127.65 126.54 5.76 6.03119.62 116.51 4.99 4.83117.01 114.73 4.67 4.43115.35 112.85 4.09 3.75103.73 102.08 3.56 3.29

92.93 91.70 2.87 2.7376.18 75.2367.07 65.4365.49 64.0748.27 47.41

CMADb 1.66 CMADb 0.17Largest outlier Dd = 3.11 Largest outlier Dd = 0.34

a See Supplementary data for complete assignment details and additionalcomparisons.

b CMAD = corrected mean absolute deviation and is computed as1n

Pn

idcomp � dexp��

�� where dcomp refers to the scaled computed chemical shifts.

J. Zhang et al. / Tetrahedron Letters 54 (2013) 6298–6302 6301

Results and discussion

Our reaction scheme involves IBX oxidation of substitutedphenols to generate o-quinones 1, which undergo in situ cycloaddi-tion with enamines 2 to produce the 1,4-benzodioxin scaffold 3(Scheme 1, Tables 1 and 2 entry 1). Enamines 2 were generallyprepared by direct nucleophilic addition of secondary amines toaldehydes and subsequent elimination to produce predominantlytrans products (Scheme 1, entry 2). Retention of the trans stereo-chemistry of the enamine in the Diels–Alder adducts wasconfirmed via 1H NMR coupling constants of the Diels–Alder adducts.

1,4-Benzodioxins were obtained from a variety of startingphenols (Tables 1 and 2) in yields ranging from 22% to 80%. Currentreaction conditions typically produced nearly equal mixtures ofregioisomers (ranging from 62:38 to 57:43), as identified via 1HNMR (see Table 2, entry 3 as an example). Regioisomers 3k_i and3k_ii were separated using HPLC on a semi-preparative normalphase column. The structure of 3k_ii was identified using X-raydiffraction crystallography (XRD, Fig. 2).12 In addition, densityfunctional theory calculations were performed to compute NMRchemical shifts of these regioisomers in order to assess the feasibil-ity of assigning 1,4-benzodioxin regioisomeric mixtures withoutthe need for chromatography.13,14 As shown in Tables 3 and 4,computed 1H and 13C chemical shifts were found to be in excellentagreement with experimental data for both regioisomers, withaverage deviations of �1.7 ppm for 13C shifts and �0.17 ppm for1H shifts for each structure. However, it is also clear from the datathat the chemical shift profiles for the two structures are toosimilar to assign them based on CMAD (corrected mean absolutedeviations) comparisons between experiment and theory alone.Therefore, we employed the CP3 statistical analysis developed bySmith and Goodman for the purpose of assigning closely relatedstructures based on experimental and computed chemical shiftswhen both sets of data are available for both isomers.15 Whenthe data in Tables 3 and 4 were used as input without specificassignment restrictions, the CP3 analysis matched the experimen-tal data sets to the correct 3k_i and 3k_ii regioisomeric structures(100% probability based on 13C data, 99.7% probability based on 1Hdata and 100% probability overall). Thus it appears, at least for thisexample, that such NMR calculations, in conjunction with the CP3analysis, can reliably identify the components of these mixtures,provided that each set is sufficiently resolved in the spectra.

In order to study the regioselectivity of these reactions, theoutcome of reacting various o-quinones (1a–1f) with enamines(2a–2h) was examined. o-Quinones 1e (prepared in six stepsfrom 4-hydroxy-3,5-dimethoxybenzaldehyde, Scheme 2)16 and 1fwere examined to determine if a strong electron donating group(–OMe, –OBn) would show regioselectivity, but no improvement of

regioselectivity was indicated by 1H NMR (Table 2, entries 5 and6). Compound 1c was chosen to explore how a bulky group (t-butyl)ortho to the dione would affect the reaction (Table 2, entry 2). Thereaction took a longer time (over 48 h vs less than 24 h for most reac-tions) and the crude product contained a large quantity of unreactedenamine, which contributed to the low yield of that reaction.

Enamines 2b and 2h were prepared in order to explore howelectron donating groups in the enamine affect regioselectivitycompared to their parent compounds 2a and 2g (Table 1, entries1, 2, 7 and 8). In general, electron donating groups on the aromaticrings make the enamine electron rich and increase the energy ofthe HOMO of the dienophile, enabling a more appropriate overlapof the molecular orbitals for the inverse electron demand Diels–Al-der reaction.17 With the electron donating groups lowering the

Scheme 2. Preparation and Diels–Alder reaction of 1e.

6302 J. Zhang et al. / Tetrahedron Letters 54 (2013) 6298–6302

transition states to the regioisomers, it was hoped that one regio-isomer might be preferred over the other, affording a majority ofthe kinetic control product. Unfortunately 1H NMR did not showimprovement of regioselectivity in the presence of electrondonating groups.

Antimicrobial screening of some of the 1,4-benzodioxins hasbeen performed by the Kirby Bauer disc diffusion assay.18 A mix-ture of compound 3j and its regioisomer demonstrated weak anti-microbial activity towards Staphylococcus epidermidis.

Conclusion

To summarize, an inverse electron demand hetero-Diels–Alderreaction between o-quinones and enamines has been developedto prepare 1,4-benzodioxin derivatives. The regioisomers producedcan be separated with flash chromatography and HPLC. The calcu-lated chemical shifts correlate to the X-ray diffraction crystallogra-phy and NMR data. One 1,4-benzodioxin has demonstratedantimicrobial activities. Currently, further work to develop a regio-selective hetero-Diels–Alder reaction is in progress.

Acknowledgments

This work was supported in part by a Research CorporationCottrell College Science Award (#7720), a California State Uni-versity Program for Education and Research in Biotechnology(CSUPERB) Faculty-Student Collaborative Research Seed Grant,CSUPERB Faculty-Student Collaborative Research: DevelopmentGrant, and start-up funds provided by the College of NaturalSciences of California State University, Chico. Thanks are alsogiven to Professor David B. Ball for obtaining the departmentalhigh-field NMR spectrometer through a CCLI grant (#99-50413)from NSF. Thanks are given to Professors David B. Ball andChristopher J. Nichols in providing thoughtful suggestions dur-ing the development of the project. We are grateful to Prof.Dean Tantillo (UC Davis) for the use of computational resourcesand to Prof. Thomas T. T. Pettus (UC Santa Barbara) for theHRMS analysis.

Supplementary data

Supplementary data associated with this article can be found,in the online version, athttp://dx.doi.org/10.1016/j.tetlet.2013.09.013.

References and notes

1. Li, L.; Wu, L.; Tashiro, S.; Onodera, S.; Uchiumi, F.; Ikejima, T. Biol. Pharm. Bull.2006, 29(6), 1096–1101.

2. Takahasi, H.; Yanagi, K.; Ueda, M.; Nakade, K.; Fukuyama, Y. Chem. Pharm. Bull.2003, 51(12), 1377–1381.

3. (a) Kim, Y. L.; Chin, Y.; Kim, J. Chem. Pharm. Bull. 2005, 53(1), 103–104; (b) Chin,Y.; Kim, J. Tetrahedron Lett. 2004, 45, 339–341; (c) Kim, C. M.; Kang, S. S. KoreanJ. Pharmacogn. 1986, 17, 195–198.

4. Murata, T.; Sasaki, K.; Sato, K.; Yoshizaki, F.; Yamada, H.; Mutoh, H.; Umebara,K.; Miyase, T.; Warashina, T.; Aoshima, H.; Tabata, H.; Matsubara, K. J. Nat. Prod.2009, 72, 1379–1384.

5. Nakanishi, T.; Ida, N.; Inatomi, Yl.; Murata, H.; Inada, A.; Murata, J.; Lang, F. A.;Linuma, M.; Tanaka, T. Heterocycles 2005, 63, 2573–2580.

6. Xu, M.; Lee, W. S.; Han, J.; Oh, H.; Park, D.; Tian, G.; Jeong, T.; Park, H. Bioorg.Med. Chem. 2006, 14, 7826–7834.

7. (a) Freudenberg, K.; Neish, A. C. Constitution and Biosynthesis of Lignins; SpringerVerlag: New York, 1968; (b) Becker, H.; Schrall, R. Planta Med. 1977, 31, 185–192; (c) Schrall, R.; Becker, H. Planta Med. 1977, 32, 297–307.

8. (a) Merlini, L.; Zanarotti, A.; Pelter, A.; Rochefort, M. P.; Hansel, R. J. Chem. Soc.,Perkin Trans. 1 1980, 775–778; (b) Arnoldi, A.; Merlini, L. J. Chem. Soc., PerkinTrans. 1 1985, 2555–2557.

9. Guz, N. R.; Stermitz, F. R. J. Nat. Prod. 2000, 63(8), 1140–1145.10. (a) She, X.; Gu, W.; Wu, T.; Pan, X. J. Chem. Res. 1999, 100–101; (b) Wang, X.; Feng,

J.; Xie, X.; Cao, X.; Pan, X. Chin. Chem. Lett. 2004, 15(9), 1036–1038; (c) She, X.; Jing,X.; Pan, X.; Chan, A. S. C.; Yang, T. Tetrahedron Lett. 1999, 40, 4567–4570.

11. (a) Nair, V.; Mailiakal, D.; Treesa, P. M.; Rath, N. P.; Eigendorf, G. K. Synthesis2000, 6, 850–856; (b) Nair, V.; Kumar, S. Synlett 1996, 1143–1147.

12. (a) Crystallographic data (excluding structure factors) for the structure havebeen deposited with the Cambridge Crystallographic Data Centre assupplementary publication nos. CCDC 954474. Copies of the data can beobtained, free of charge, on application to CCDC, 12 Union Road, CambridgeCB2 1EZ, UK, (fax: +44 (0)1223 336033 or e-mail: deposit@ccdc.cam.ac.Uk).(b) Sheldrick, G. M. SHELXTL PC, Version 6.12; Bruker Analytical X-ray Systems,Inc.: Madison, WI, 2006.

13. For reviews on NMR chemical shift calculations, see: (a) Helgaker, T.; Jaszunski,M.; Ruud, K. Chem. Rev. 1999, 99, 293–352; (b) Bifulco, G.; Dambruoso, P.;Gomez-Paloma, L.; Riccio, R. Chem. Rev. 2007, 107, 3744–3779; (c) Lodewyk, M.W.; Siebert, M. R.; Tantillo, D. J. Chem. Rev. 2012, 112, 1839–1862.

14. For recent examples of our work using chemical shift calculations to assist innatural product structure revision and synthetic efforts, see: (a) Lodewyk, M.W.; Tantillo, D. J. J. Nat. Prod. 2011, 74, 1339–1343; (b) Quasdorf, K. W.; Huters,A. D.; Lodewyk, M. W.; Tantillo, D. J.; Garg, N. K. J. Am. Chem. Soc. 2012, 134,1396–1399; (c) Lodewyk, M. W.; Soldi, C.; Jones, P. B.; Olmstead, M. M.;Larrucea, J. R.; Shaw, J. T.; Tantillo, D. J. J. Am. Chem. Soc. 2012, 134, 18550–18553; (d) Lebold, T. P.; Wood, J. L.; Deitch, J.; Lodewyk, M. W.; Tantillo, D. J.;Sarpong, R. Nat. Chem. 2013, 5, 126–131.

15. (a) Smith, S. G.; Goodman, J. M. J. Org. Chem. 2009, 74, 4597–4607; The CP3analysis is available through a web-based Java Applet. See http://www-jmg.ch.cam.ac.uk/tools/nmr/.

16. (a) Kuboki, A.; Yamamoto, T.; Taira, M.; Arishige, T.; Ohira, S. Tetrahedron Lett.2007, 771–774; (b) Kuboki, A.; Yamamoto, T.; Ohira, S. Chem. Lett. 2003, 32(5),420–421.

17. (a) Woodward, R. B. Hoffmann; Academic Press: R. The Conservation of OrbitalSymmetry, 1969; (b) Woodward, R. B.; Hoffmann, R. J. Am. Chem. Soc. 1969,87(2), 395–397.

18. Andrews, J. M. J. Antimicrob. Chemother. 2001, 48, 5–16 (Supplement S1).