Inverse electron demand hetero-Diels-Alder reaction in preparing 1,4-benzodioxin from o-quinone and enamine

Article abstract of DOI:10.1016/j.tetlet.2013.09.013

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.

Full text of DOI:10.1016/j.tetlet.2013.09.013

Tetrahedron Letters 54 (2013) 6298–6302
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Tetrahedron Letters
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Inverse electron demand hetero-Diels–Alder reaction in preparing
1,4-benzodioxin from o-quinone and enamine
a
a
a
a,b
Jinsong Zhang a, , Chris Taylor , Erich Bowman , Leo Savage-Low , Michael W. Lodewyk
⇑
Larry Hanne c, Guang Wu d
a Department of Chemistry and Biochemistry, California State University, Chico, CA 95929, United States
b Department of Chemistry, University of California, Davis, CA 95616, United States
c 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
a r t i c l e i n f o
a b s t r a c t
Article history:
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.
Received 9 August 2013
Revised 2 September 2013
Accepted 4 September 2013
Available online 11 September 2013
Published by Elsevier Ltd.
Keywords:
o-Quinones
Enamines
1,4-Benzodioxins
Diels–Alder reaction
Introduction
formation) and silybin/isosilybin (4:3 mixture, 76% total yield for
benzodioxin formation).8 Stermitz and co-worker synthesized
Natural products containing a 1,4-benzodioxin group have
demonstrated various biological activities. For instance, silybin
has anti-inflammatory, cytoprotective, hepatoprotective and anti-
carcinogenic acitivity,1 and americanins possess antibacterial
activity 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 clinopodic
acids have been isolated from Clinopodium chinense var. parviflorum
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-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 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 path-
way utilizing a metal–ion oxidizing agent. Merlini et al. utilized
Ag2O to synthesize ( )-eusiderin (40% yield for the benzodioxin
hydnocarpin-type flavonolignans by treating luteolin (a catechol)
and coniferyl alcohol with Ag2CO3.9 Pan’s group has successfully
synthesized a series of benzodioxin-based natural products utiliz-
ing silver (I) and iron (III) reagents.10 Even though the biomimetic
approach is very efficient in making the benzodioxin ring, control
of the stereochemistry in this free radical reaction is an obvious
challenge.
Herein we report a hetero-Diels–Alder cycloaddition between o-
quinones and enamines to synthesize the 1,4-benzodioxin moiety.
As a highly reactive 8
display two 4 components as potential sites for a Diels–Alder
reaction. The selectivity between these sites is determined by the
polarizability of the complementary 2 component, the specific
p-electron system, o-quinones (1, Scheme 1)
p
p
mechanistic details and reaction conditions, including catalyst
selection, temperature and solvent polarity.11 The hetero-Diels–Al-
der approach to generate the key benzodioxin scaffold has the
advantages 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 metal
oxidizing 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 a
wide variety of 1,4-benzodioxin-derived natural products.
⇑
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

J. Zhang et al. / Tetrahedron Letters 54 (2013) 6298–6302
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
1
o-Quinone
Enamine
Productsa
Yield (%)
80
47
2
3
1a
1a
73
(continued on next page)

6300
J. Zhang et al. / Tetrahedron Letters 54 (2013) 6298–6302
Table 1 (continued)
Entry
o-Quinone
Enamine
Productsa
Yield (%)
42
4
5
1a
1a
1a
71
48
6
7
1a
1a
73
46
8
a
All the products are mixtures of a pair of regioisomers.
Table 2
Formation of 1,4-benzodioxins starting with various o-quinone
Entry
1
o-Quinone
Enamine
Productsa
Yield (%)
2a
25
30
2
3
2a
2a
28 for 3k_i
19 for 3k_ii
4
5
6
1d
2b
2a
2a
22
26
77
a
All the products are mixtures of a pair of regioisomers except 3i.

J. Zhang et al. / Tetrahedron Letters 54 (2013) 6298–6302
6301
Table 3
Comparison of experimental and computed chemical shifts for 3k_i
13C Chemical shifts (ppm) 1H Chemical shifts (ppm)
Expt.
Computeda
Expt.
Computeda
144.82
143.34
137.12
131.10
128.91
128.67
127.61
120.40
117.02
115.45
103.70
93.01
142.99
142.02
138.33
133.84
127.10
127.09
126.82
117.68
114.55
113.14
102.08
91.85
7.41
7.40
7.40
7.10
7.04
6.97
5.74
4.98
4.67
4.12
3.57
2.88
7.36
7.32
7.28
6.98
6.89
6.84
6.02
4.80
4.55
3.73
3.28
2.74
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.
76.03
67.05
75.18
65.44
65.45
64.03
48.24
47.42
Results and discussion
CMADb
Largest
1.64
CMADb
Largest
outlier
0.17
Dd = 0.39
D
d = 2.74
Our reaction scheme involves IBX oxidation of substituted
phenols 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 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 stereo-
chemistry of the enamine in the Diels–Alder adducts was
confirmed via 1H NMR coupling constants of the Diels–Alder 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 identified 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 identified 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 feasibil-
ity 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
1H shifts for each structure. However, it is also clear from the data
that the chemical shift profiles 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 specific
assignment 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 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 sufficiently resolved in the spectra.
In order to study the regioselectivity of these reactions, the
outcome of reacting various o-quinones (1a–1f) with enamines
(2a–2h) 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
outlier
a
See Supplementary data complete for assignment details and additional
comparisons.
n
ꢀ
ꢀ
ꢀ
ꢀ
P
b
1
n
CMAD = corrected mean absolute deviation and is computed as
where dcomp refers to the scaled computed chemical shifts.
dcomp À dexp
i
Table 4
Comparison of experimental and computed chemical shifts for 3k_ii
13C Chemical shifts (ppm) 1H Chemical shifts (ppm)
Expt. Expt.
Computeda Computeda
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
142.59
142.41
137.78
134.80
127.44
127.14
126.54
116.51
114.73
112.85
102.08
91.70
7.13
7.42
7.41
7.40
6.98
6.94
5.76
4.99
4.67
4.09
3.56
2.87
7.00
7.35
7.34
7.31
6.84
6.78
6.03
4.83
4.43
3.75
3.29
2.73
75.23
65.43
64.07
47.41
1.66
CMADb
Largest outlier
0.17
Dd = 0.34
D
d = 3.11
a
See Supplementary data for complete assignment details and additional
comparisons.
b
CMAD = corrected mean absolute deviation and is computed as
dcomp À dexp where dcomp refers to the scaled computed chemical shifts.
n
ꢀ
ꢀ
ꢀ
P
1
n
ꢀ
i
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 reac-
tions) 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 Diels–Al-
der reaction.17 With the electron donating groups lowering the

6302
J. Zhang et al. / Tetrahedron Letters 54 (2013) 6298–6302
Scheme 2. Preparation and Diels–Alder reaction of 1e.
transition states to the regioisomers, it was hoped that one regio-
isomer 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 mix-
ture of compound 3j and its regioisomer demonstrated weak anti-
microbial activity towards Staphylococcus epidermidis.
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To summarize, an inverse electron demand hetero-Diels–Alder
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Acknowledgments
This work was supported in part by a Research Corporation
Cottrell 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: 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-field 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 dur-
ing 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.
´
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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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