Tetrahedron Letters 54 (2013) 62986302

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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet

Inverse electron demand hetero-DielsAlder reaction in preparing 1,4-benzodioxin from o-quinone and enamine
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 States Department of Chemistry, University of California, Davis, CA 95616, United States Department of Biological Sciences, California State University, Chico, CA 95929, United States d Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA 93106, United States
b c

a r t i c l e

i n f o

a b s t r a c t
A process for synthesizing 1,4-benzodioxin, through oxidation of a phenol to an o-quinone followed by treatment with an enamine, has been developed. Adduct stereochemistry is found to be retained via this one-pot reaction. The method uses hypervalent iodine reagent under mild conditions and is compatible with a wide scope of phenols and enamines. Published by Elsevier Ltd.

Article history: Received 9 August 2013 Revised 2 September 2013 Accepted 4 September 2013 Available online 11 September 2013 Keywords: o-Quinones Enamines 1,4-Benzodioxins DielsAlder reaction

Introduction Natural products containing a 1,4-benzodioxin group have demonstrated various biological activities. For instance, silybin has anti-inammatory, cytoprotective, hepatoprotective and anticarcinogenic acitivity,1 and americanins possess antibacterial activity as well as neurotrophic activity.2 In addition, six neolignans have been isolated from Rodgersia podophylla (Saxifragaceae), the rhizomes of which have been used for the treatment of enteritis and bacillary dysentery and have been reported to exhibit antipyretic, analgesic and hepatoprotective effects.3 Nine clinopodic acids have been isolated from Clinopodium chinense var. parviorum and have shown matrix metalloproteinase-2 inhibition activities.4 A group of six junipercomnosides have demonstrated antioxidant properties.5 In addition, two acetamide derived 1,4-benzodioxins have shown antioxidant and anti-inammatory activities (Fig. 1).6 The 1,4-benzodioxin moiety can serve as a scaffold for the synthesis of a large number of natural products. The biosynthetic pathway to a benzodioxin substructure is believed to follow a free radical mechanism, starting from a catechol derivative.7 Previous synthetic efforts have been made to mimic the biosynthetic pathway utilizing a metalion oxidizing agent. Merlini et al. utilized Ag2O to synthesize ()-eusiderin (40% yield for the benzodioxin
Corresponding author. Tel.: +1 530 898 5622; fax: +1 530 898 5234.
E-mail address: jzhang2@csuchico.edu (J. Zhang). 0040-4039/$ - see front matter Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.tetlet.2013.09.013

formation) and silybin/isosilybin (4:3 mixture, 76% total yield for benzodioxin formation).8 Stermitz and co-worker synthesized hydnocarpin-type avonolignans by treating luteolin (a catechol) and coniferyl alcohol with Ag2CO3.9 Pans group has successfully synthesized a series of benzodioxin-based natural products utilizing silver (I) and iron (III) reagents.10 Even though the biomimetic approach is very efcient in making the benzodioxin ring, control of the stereochemistry in this free radical reaction is an obvious challenge. Herein we report a hetero-DielsAlder cycloaddition between oquinones 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 DielsAlder reaction. The selectivity between these sites is determined by the polarizability of the complementary 2p component, the specic mechanistic details and reaction conditions, including catalyst selection, temperature and solvent polarity.11 The hetero-DielsAlder approach to generate the key benzodioxin scaffold has the advantages of (1) using readily accessible phenols as starting materials instead of catechols; (2) utilizing environmentally friendly 2iodoxybenzoic acid (IBX) as an oxidizing agent instead of a metal oxidizing agent; (3) using an electron-rich enamine as the dienophile to ensure the desired dioneenamine cycloaddition (LUMOHOMO interaction) and (4) greater stereochemical control. This approach provides a novel methodology for synthesizing a wide variety of 1,4-benzodioxin-derived natural products.

J. Zhang et al. / Tetrahedron Letters 54 (2013) 62986302

6299

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

Scheme 1. 1,4-Benzodioxin preparation.

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

Entry

o-Quinone

Enamine

Productsa

Yield (%)

80

1a

47

1a

73

(continued on next page)

6300 Table 1 (continued) Entry o-Quinone

J. Zhang et al. / Tetrahedron Letters 54 (2013) 62986302

Enamine

Productsa

Yield (%)

1a

42

1a

71

1a

48

1a

73

1a

46

All the products are mixtures of a pair of regioisomers.

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

Entry

o-Quinone

Enamine

Productsa

Yield (%)

2a

25

2a

30

2a

28 for 3k_i 19 for 3k_ii

1d

2b

22

2a

26

2a

77

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

J. Zhang et al. / Tetrahedron Letters 54 (2013) 62986302 Table 3 Comparison of experimental and computed chemical shifts for 3k_i
13

6301

C Chemical shifts (ppm) Computed 142.99 142.02 138.33 133.84 127.10 127.09 126.82 117.68 114.55 113.14 102.08 91.85 75.18 65.44 64.03 47.42 1.64 Dd = 2.74
a

H Chemical shifts (ppm) Computeda 7.36 7.32 7.28 6.98 6.89 6.84 6.02 4.80 4.55 3.73 3.28 2.74

Expt. 144.82 143.34 137.12 131.10 128.91 128.67 127.61 120.40 117.02 115.45 103.70 93.01 76.03 67.05 65.45 48.24 CMADb Largest outlier
a

Expt. 7.41 7.40 7.40 7.10 7.04 6.97 5.74 4.98 4.67 4.12 3.57 2.88

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

Results and discussion Our reaction scheme involves IBX oxidation of substituted phenols to generate o-quinones 1, which undergo in situ cycloaddition with enamines 2 to produce the 1,4-benzodioxin scaffold 3 (Scheme 1, Tables 1 and 2 entry 1). Enamines 2 were generally prepared by direct nucleophilic addition of secondary amines to aldehydes and subsequent elimination to produce predominantly trans products (Scheme 1, entry 2). Retention of the trans stereochemistry of the enamine in the DielsAlder adducts was conrmed via 1H NMR coupling constants of the DielsAlder adducts. 1,4-Benzodioxins were obtained from a variety of starting phenols (Tables 1 and 2) in yields ranging from 22% to 80%. Current reaction conditions typically produced nearly equal mixtures of regioisomers (ranging from 62:38 to 57:43), as identied via 1H NMR (see Table 2, entry 3 as an example). Regioisomers 3k_i and 3k_ii were separated using HPLC on a semi-preparative normal phase column. The structure of 3k_ii was identied using X-ray diffraction crystallography (XRD, Fig. 2).12 In addition, density functional theory calculations were performed to compute NMR chemical shifts of these regioisomers in order to assess the feasibility of assigning 1,4-benzodioxin regioisomeric mixtures without the need for chromatography.13,14 As shown in Tables 3 and 4, computed 1H and 13C chemical shifts were found to be in excellent agreement with experimental data for both regioisomers, with average deviations of $1.7 ppm for 13C shifts and $0.17 ppm for 1 H shifts for each structure. However, it is also clear from the data that the chemical shift proles for the two structures are too similar to assign them based on CMAD (corrected mean absolute deviations) comparisons between experiment and theory alone. Therefore, we employed the CP3 statistical analysis developed by Smith and Goodman for the purpose of assigning closely related structures based on experimental and computed chemical shifts when both sets of data are available for both isomers.15 When the data in Tables 3 and 4 were used as input without specic assignment restrictions, the CP3 analysis matched the experimental data sets to the correct 3k_i and 3k_ii regioisomeric structures (100% probability based on 13C data, 99.7% probability based on 1H data and 100% probability overall). Thus it appears, at least for this example, that such NMR calculations, in conjunction with the CP3 analysis, can reliably identify the components of these mixtures, provided that each set is sufciently resolved in the spectra. In order to study the regioselectivity of these reactions, the outcome of reacting various o-quinones (1a1f) with enamines (2a2h) was examined. o-Quinones 1e (prepared in six steps from 4-hydroxy-3,5-dimethoxybenzaldehyde, Scheme 2)16 and 1f were examined to determine if a strong electron donating group (OMe, OBn) would show regioselectivity, but no improvement of

CMADb Largest outlier

0.17 Dd = 0.39

See Supplementary data complete for assignment details and additional comparisons. n   P b dcomp dexp  CMAD = corrected mean absolute deviation and is computed as 1 n i where dcomp refers to the scaled computed chemical shifts.

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

13

C Chemical shifts (ppm) Computeda 142.59 142.41 137.78 134.80 127.44 127.14 126.54 116.51 114.73 112.85 102.08 91.70 75.23 65.43 64.07 47.41 1.66 Dd = 3.11

H Chemical shifts (ppm) Computeda 7.00 7.35 7.34 7.31 6.84 6.78 6.03 4.83 4.43 3.75 3.29 2.73

Expt. 144.32 143.91 137.08 132.00 128.94 128.69 127.65 119.62 117.01 115.35 103.73 92.93 76.18 67.07 65.49 48.27 CMADb Largest outlier

Expt. 7.13 7.42 7.41 7.40 6.98 6.94 5.76 4.99 4.67 4.09 3.56 2.87

CMADb Largest outlier

0.17 Dd = 0.34

a See Supplementary data for complete assignment details and additional comparisons. b CMAD = corrected mean absolute deviation and is computed as n   P 1 dcomp dexp  where dcomp refers to the scaled computed chemical shifts. n

regioselectivity was indicated by 1H NMR (Table 2, entries 5 and 6). Compound 1c was chosen to explore how a bulky group (t-butyl) ortho to the dione would affect the reaction (Table 2, entry 2). The reaction took a longer time (over 48 h vs less than 24 h for most reactions) and the crude product contained a large quantity of unreacted enamine, which contributed to the low yield of that reaction. Enamines 2b and 2h were prepared in order to explore how electron donating groups in the enamine affect regioselectivity compared to their parent compounds 2a and 2g (Table 1, entries 1, 2, 7 and 8). In general, electron donating groups on the aromatic rings make the enamine electron rich and increase the energy of the HOMO of the dienophile, enabling a more appropriate overlap of the molecular orbitals for the inverse electron demand DielsAlder reaction.17 With the electron donating groups lowering the

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J. Zhang et al. / Tetrahedron Letters 54 (2013) 62986302

Scheme 2. Preparation and DielsAlder reaction of 1e.

transition states to the regioisomers, it was hoped that one regioisomer might be preferred over the other, affording a majority of the kinetic control product. Unfortunately 1H NMR did not show improvement of regioselectivity in the presence of electron donating groups. Antimicrobial screening of some of the 1,4-benzodioxins has been performed by the Kirby Bauer disc diffusion assay.18 A mixture of compound 3j and its regioisomer demonstrated weak antimicrobial activity towards Staphylococcus epidermidis. Conclusion To summarize, an inverse electron demand hetero-DielsAlder reaction between o-quinones and enamines has been developed to prepare 1,4-benzodioxin derivatives. The regioisomers produced can be separated with ash chromatography and HPLC. The calculated chemical shifts correlate to the X-ray diffraction crystallography and NMR data. One 1,4-benzodioxin has demonstrated antimicrobial activities. Currently, further work to develop a regioselective hetero-DielsAlder reaction is in progress. Acknowledgments This work was supported in part by a Research Corporation Cottrell College Science Award (#7720), a California State University Program for Education and Research in Biotechnology (CSUPERB) Faculty-Student Collaborative Research Seed Grant, CSUPERB Faculty-Student Collaborative Research: Development Grant, and start-up funds provided by the College of Natural Sciences of California State University, Chico. Thanks are also given to Professor David B. Ball for obtaining the departmental high-eld NMR spectrometer through a CCLI grant (#99-50413) from NSF. Thanks are given to Professors David B. Ball and Christopher J. Nichols in providing thoughtful suggestions during the development of the project. We are grateful to Prof. Dean Tantillo (UC Davis) for the use of computational resources and to Prof. Thomas T. T. Pettus (UC Santa Barbara) for the HRMS 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.

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