Electrochemically Mediated Oxidative Transformations of Substituted 4-Methoxystilbenes: Effect of Ortho-Substituted Nucleophilic Groups

Article abstract of DOI:10.1021/acs.joc.7b00753

A systematic study was undertaken to determine the influence of ortho′-substituted nucleophilic groups (OH, NH₂, or NHR) on the reactivity of anodically generated 4-methoxy- and 3,4-dimethoxystilbene cation radicals. The results showed that when ortho-substituted nucleophilic groups such as OH and NHR are present in the other ring, both direct and crossover intramolecular cation-nucleophile reactions occur to give bisbenzofurans/bisindoles or fused bisbenzopyrans/bisquinolines, respectively. Where an additional 3-methoxy substituent is present, bridged oxocine/azocine products are formed in addition to the bisbenzopyrans/bisquinolines and bisbenzofurans/bisindoles. Mechanistic rationalization of the observed behavior is presented based on a generalized pathway involving fast cation radical dimerization following electron transfer, followed by direct and crossover trapping of the benzylic cations by the ortho-substituted oxygen and nitrogen nucleophilic groups. In the instances where an additional 3-methoxy group is present, the bridged oxocine/azocine products are also formed as a result of competing aromatic substitution (Friedel-Crafts reaction). The results have shed further light and provided additional clarification on the reactivity of anodically generated stilbene cation radicals.

Full text of DOI:10.1021/acs.joc.7b00753

Article
Electrochemically-mediated oxidative transformations of substituted 4-
methoxystilbenes – the effect of ortho-substituted nucleophilic groups
Kam-Weng Chong, Fong-Jiao Hong, Noel Francis Thomas, Yun-Yee Low, and Toh-Seok Kam
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 29 May 2017
Downloaded from http://pubs.acs.org on May 29, 2017
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Electrochemically-mediated oxidative transformations
of substituted 4-methoxystilbenes – the effect of ortho-
substituted nucleophilic groups
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Kam-Weng Chong, Fong-Jiao Hong, Noel F. Thomas, Yun-Yee Low, and Toh-Seok
Kam*
Department of Chemistry, Faculty of Science, University of Malaya, 50603 Kuala
Lumpur, Malaysia
Corresponding author’s e-mail address: tskam@um.edu.my
HX
Ar1
X
Ar1
Ar1'
Ar2
X
−
e
MeO
MeO
X
X
anode
Ar1
X
Ar1'
O
Ar1
Ar1'
O
Ar1'
(3 stereoisomers)
(2 stereoisomers)
1
Ar = 4-MeO−C H − or
6
4
3,4-(MeO)
2
−C
6
H
3
−;
1
2
Ar = 4-MeO−C H − or 3,4-(MeO) −C H −; Ar = 2-X−C H −; X = O or NR
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4
2
6
3
6
4
2
Ar = 2-X−C H −;
6
4
X = OH or NHR
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Abstract
A systematic study was undertaken to determine the influence of ortho'-substituted
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nucleophilic groups (OH, NH or NHR) on the reactivity of anodically-generated 4-
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methoxy- and 3,4-dimethoxystilbene cation radicals. The results showed that when ortho-
substituted nucleophilic groups such as OH or NHR are present in the other ring, both
direct and crossover intramolecular cation-nucleophile reactions occur to give
bisbenzofurans/bisindoles or fused bisbenzopyrans/bisquinolines, respectively. Where an
additional 3-methoxy substituent is present, bridged oxocine/azocine products are formed
in addition to the bisbenzopyrans/bisquinolines and bisbenzofurans/bisindoles.
Mechanistic rationalization of the observed behavior is presented based on a generalized
pathway involving fast cation radical dimerization following electron transfer, followed
by direct and crossover trapping of the benzylic cations by the ortho-substituted oxygen
and nitrogen nucleophilic groups. In the instances where an additional 3-methoxy group
is present, the bridged oxocine/azocine products are also formed as a result of competing
aromatic substitution (Friedel Crafts reaction). The results have shed further light and
provided additional clarification on the reactivity of anodically-generated stilbene cation
radicals.
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Introduction
Although relatively underexploited as a tool in organic synthesis, electrochemically-
mediated processes nevertheless remain an attractive and complimentary alternative in the
organic chemists’ armory of methods for functional group manipulation and C-C bond
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1
-5
formation. This is in large part due to certain inherent advantages associated with the
electrochemical technique which includes inter alia, high chemoselectivity, umpolung
reactivity, the use of comparatively mild reaction conditions and environmentally friendly
1
-5
procedures, and in some instances the amenability to scale up. As part of our interest in
6
electrochemically-mediated transformations in organic chemistry, we recently carried out
a reinvestigation of the anodic oxidation of 4,4'-dimethoxystilbene followed by a
systematic study of the effect of aromatic substitution on the nature and distribution of the
7
products as well as the reaction pathways, in the oxidation of substituted stilbenes. The
motivation for these studies was to explore access to natural polyphenol skeletons via
anodic oxidation, as well as to gain a better understanding of the behavior of the first-
formed intermediate, viz., the cation radical, a species endowed with high reactivity and
8
an inherent ambident or dualistic character. The results showed that the aromatic
substituents fall into three categories: those that resulted in the formation of
tetrahydrofurans and dehydrotetralins, those that gave rise to a mixture of indanyl (or
tetralinyl) acetamides and dehydrotetralins (or pallidols), and those where strategic
placement of donor groups resulted in products incorporating pallidol and ampelopsin F
carbon skeletons (Figure 1). The results from this study have provided valuable insight
into how subtle changes in the nature and position of the aromatic substituents can affect
the course of the electrochemical oxidation of substituted stilbenes, in addition to
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clarifying the reactivity and fate of the cation radical intermediate, subsequent to the
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initial electron transfer step.
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Ar1'
Ar1'
R2'
H
Ar1'
R1
Ar2'
Ar2'
Ar2
H
Ar1
H
Ar2
Ar1
−
e
−e
Ar2
R1
H
H
H
Ar1
Ar1'
R2
Ar2'
Ar2
Ar2'
Ar1'
R2'
Ar2
H
H
R2
−
e
Ar1
Ar1'
Ar1
O
O
R2'
Ar1
Ar1'
Ar1'
H
H
R2'
H
R1
Ar2'
R1
Ar2'
Ar2
Ar1
H
Ar2
H
H
H
Ar
NHAc
2
Ar1'
1'
Ar
NHAc
H
R2
Figure 1. Reactivity of anodically generated stilbene cation radicals: effect of aromatic
substitution.
In continuation of our studies of stilbene cation radicals generated by anodic oxidation,
we next investigated what would be the effect of placing nucleophilic groups (such as OH
and NH ) at the ortho position of one ring in 4-methoxy and 3,4-dimethoxy substituted
2
stilbenes, and herein report the results.
RESULTS AND DISCUSSION
The required stilbenes were synthesized by Heck coupling of the appropriate
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styrene and aryl halide precursors. It has been previously noted that anodic oxidation of
-methoxystilbene substituted by an ortho-methoxy group in the other ring gave a
4
mixture comprising the stereoisomeric tetraaryltetrahydrofurans accompanied by the
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methoxy-migrated dehydrotetralin. In the present study, similar results were also
obtained on oxidation of 4-methoxy-2'-acetoxystilbene, which gave the corresponding
tetraaryltetrahydrofurans and the unrearranged dehydrotetralin (Figure 2).
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RO
OR
RO
OR
O
O
MeO
OMe
OMe MeO
R = Me, Ac
OR
Controlled potential
electrolysis (CPE)
ACN, 0.2 M LiClO4
OMe
OMe
OMe
R = Me, Ac
MeO
OAc
OMe
MeO
AcO
MeO
Figure 2. Products from the anodic oxidation of 4,2'-dimethoxystilbene and 4-methoxy-
'-acetoxystilbene
2
Arising from these observations, the next stilbene chosen for investigation was 4-
methoxy-2'-hydroxystilbene 1, which has an ortho-hydroxy group present in one ring and
a para-methoxy group in the other ring. Anodic oxidation of 1 (Pt anode, MeCN/0.2 M
LiClO ) showed the presence of one irreversible wave at +0.87 V versus Ag/AgNO in
4
3
the potential range investigated as revealed by cyclic voltammetry. Controlled potential
electrolysis (Pt gauze anode, Pt cathode; MeCN/0.2 M LiClO ) at the anodic wave (+0.97
4
V) was allowed to proceed until about 1 F of charge had been transferred. A mixture of
dimeric products (as indicated by their MS data) was obtained in total yield of about
8
0%, comprising the stereoisomeric fused bisbenzopyrans (as the major products in
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Scheme 1. Products from the anodic oxidation of stilbenes 1 and 2
1
2a
12b
MeO 4a
MeO
MeO 4a
4b OMe
9
a
9b
H
H
OR
O 10b
O
H
10a
10b
1a
12b
1a
1b
H
H
7
a
8a 8b
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H
O 7a
O
7b
CPE at +0.97 V, 1 F/mol
7b
8b
8
a
9
a
H
9a
9b
H H
12a
8
b
1a
1b
9b
ACN, 0.2 M LiClO4
H
O
H
O
8a
7a
7b
1
2a
1b
H
10a
10a
12b
O
O 10b
H
H
4a
4b
H
4b
OMe
OMe
OMe
MeO
OMe
1
a
1b
1c
1e
1 R = H
R = SiMe3
R = H, Total = 80%
25%
27%
14%
15%
19%
20%
22%
20%
2
R = SiMe , Total = 82%
3
Scheme 2. Products from the anodic oxidation of stilbenes 3 and 4
1
2a
10a
HO
H
MeO
MeO
9
a
8a
H
H
OR
O
H
H
H
H
H
MeO 3a
7a
O 10b
1a
O
O
O
O
12b
CPE at +0.95 V, 1 F/mol
ACN, 0.2 M LiClO4
H H
H H
4a
6a 7b
9b
H
O
MeO
OMe
OMe
8b
1b
H
H
H
OMe
MeO
OMe
MeO
OMe
4
b
3b
OMe
MeO
OMe
MeO
OMe
MeO
OMe
3a
3c
3d
3f
3
R = H
R = H, Total = 88%
21%
19%
17%
18%
18%
32%
30%
R = SiMe , Total = 85%
18%
4 R = SiMe3
3
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combined yield of ca. 40% (1a, 25%; 1b, 14%), the bisbenzofuran 1c (19%), and the
fused benzofurano-benzopyran 1e (22%) (Scheme 1). The product mixture was separated
by a combination of preparative radial chromatography on SiO (Chromatotron), RP-
2
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HPLC, and Sephadex LH20, and the products were characterized by their spectroscopic
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1
data (HRESIMS, H and C{ H} NMR), as well as X-ray analysis.
Compound 1a had molecular formula C H O from HRESIMS measurements.
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However, the H and C{ H} NMR data showed only resonances due to one half of the
molecule, indicating the presence of an element of symmetry. Aside from the readily
1
recognizable aromatic and methoxy resonances, the H NMR spectrum showed two
mutually coupled methine hydrogens at δ 5.28 (H-7a) and 3.33 (H-8a) with a coupling
constant of ca. 10 Hz. The former resonance corresponds to an oxymethine while the
latter is likely a benzylic methine. Analysis of the 2-D NMR data (COSY, HSQC,
HMBC) led to two possible structures, one a fused bisbenzopyran and the other a
bisbenzofuran (Figure 3). Differentiation between the two structures was made possible
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3
1
by comparison of the C{ H} shifts of the α and β methine carbons with model
1
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benzopyran and benzofuran compounds from the literature (Figure 3) which allowed
1
a to be assigned the fused bisbenzopyran structure (and compound 1c, the bisbenzofuran
structure, vide infra). Assignment of the stereochemistry was based on the observed H-
1
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a/H-8a coupling of ca. 10 Hz in the H NMR spectrum of 1a, indicating that these
hydrogens are trans-diaxially oriented in the six-membered pyran ring, leading to a fused
bisbenzopyran with a C axis. In the event these conclusions were confirmed by X-ray
2
analysis, which also revealed the cis-fusion of the pyran rings (Figure 3).
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Figure 3. COSY and selected HMBCs of 1a and 1c, C{ H} shifts of the α and β
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methine carbons of model benzopyran and benzofuran, and X-ray structures of 1a and
c.
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Unlike the previous compound (1a), the H and C{ H} NMR data of compound
1b (C H O , isomeric with 1a) indicated a dimerization product devoid of any
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symmetry, and, based on comparison of the observed C{ H} shifts of the α and β
carbons as before, indicated that 1b possesses a similar fused bisbenzopyran structure. In
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the H NMR spectrum, H-8a was observed as a triplet with a coupling constant of 10.8
Hz, indicating that both the adjacent hydrogens (H-7a and H-8b) were in a trans
relationship with H-8a (a trans-fused bisbenzopyran). H-8b on the other hand was
observed as a doublet of doublets with coupling constants of 10.8 and 3.9 Hz, indicating
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that H-7b and H-8b were cis to each other. These conclusions were also confirmed by X-
ray analysis (Figure 4).
Compound 1c (C H O ) was deduced to be a bisbenzofuran possessing an
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element of symmetry, based on the H and C{ H} NMR data (vide supra). In this
instance (five-membered furan rings), the observed H-7a/H-8a coupling of 3.6 Hz was
insufficient for definitive assignment of the relative configurations at C-7a and C-8a.
Fortunately suitable crystals were obtained, and X-ray analysis revealed a trans
arrangement between H-7a and H-8a, resulting in the presence of a C axis (Figure 3).
2
4a
5
a
3a
5a
MeO 4a
6
a
11b
0b
2
a
6a
1
1
a
11b
12b
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3a
O
10b
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a
1a
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a
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1
4a
8a
8a
9b
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1
3a
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b
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13a
9a
8b
8b
1
4b
5b
4b
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b
7
b
2b
7b 1b
12a
1b
3b
1
0a
O
3b
11a
12a
2
b
10a
6b
11a
4
b
OMe
5b
COSY
HMBC
NOE
Figure 4. COSY, selected HMBCs, selected NOEs and X-ray crystal structure of 1b
1
The H NMR data of compound 1e (C H O ) showed the presence of 16
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aromatic resonances, four methine protons and two methoxy groups. The resonance at δH
6.36 (δ 104.2) was assigned to a methine (H-7a) linked to two oxygen atoms while the
C
resonance at δ 4.04 (δ 44.8) which was coupled to H-7a, was attributed to the adjacent
H
C
benzylic methine (H-8a). The COSY spectrum revealed in addition to the OCH(O)−CH
partial structure, the presence of another fragment, CH−CH, which was assigned to H-8b
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(
δ 3.74, δ 45.7) and H-7b (δ 4.23, δ 53.6). The observed H-8a to C-7b three-bond
H
C
H
C
correlation in the HMBC spectrum (Figure 5) indicated that H-8b was linked to H-8a
resulting in the partial structure, C-7a−C-8a−C-8b−C-7b. The rest of the molecule can be
assembled based on the HMBC data (Figure 5), which revealed a fused benzofurano-
benzopyran as shown in 1e. Cis-fusion of the furan and pyran rings was based on the
observed J7a-8a vicinal coupling of 7.8 Hz, as well as the reciprocal NOEs observed
between H-7a and H-8a (Figure 5). The resonance for H-8b was observed as a doublet
with J = 11.8 Hz, as a result of H-8a and H-8b being orthogonal to each other, which was
also consistent with the cis-fused geometry. The α-orientation of H-8b was also
consistent with the NOEs observed for H-8b/H-14a, H-8b/H-14b, and H-8b/H-2a, H-6a.
The structure and relative configuration were also confirmed by X-ray diffraction (Figure
5).
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8
9
0
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7
8
9
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3
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9
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8
9
0
1
2
3
4
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7
8
9
0
4
a
5
a
3a
5
b
MeO 4a
4b OMe
4b
2
a
6b
6
a
1a
1b
3
b
7
b
1
a
1b
2b
7
b
14a
8b
12a
8b
13a
12a
8a
7a
14b
9
a
9
b
9b
9
a 8a
1
3b
10a
12b
10a
10b
11b
1
1a
12b
O
7a
10b
O
COSY
HMBC
NOE
Figure 5. COSY, selected HMBCs, selected NOEs, and X-ray crystal structure of 1e
We next investigated the anodic oxidation of the TMS protected 4-methoxy-2'-
hydroxystilbene 2. The results showed that the same four products (1a, 1b, 1c, 1d) were
1
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obtained and although there were minor variations in the product distribution, the overall
yield was essentially unchanged (Scheme 1).
The next compound investigated was 3,4-dimethoxy-2'-hydroxystilbene 3, which
has an additional methoxy substituent at the meta position in the p-methoxysubstituted
10
11
12
13
14
15
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ring. In this case, anodic oxidation gave 4 isomeric products, the C symmetric fused
2
bisbenzopyran 3a (analogous to 1a), the C symmetric bisbenzofuran 3c (analogous to
2
1
c), another symmetric bisbenzofuran 3d, and the bridged oxocine 3f (Scheme 2). The
1
13
1
structures of 3a and 3c were readily assigned based on their H and C{ H} NMR data
and by analogy to 1a and 1c, respectively (which have been thoroughly characterized by
MS, NMR, and X-ray diffraction analysis, vide supra; structure of 3a was also confirmed
by X-ray analysis).
Compound 3d (C H O ) was a symmetric bisbenzofuran as indicated by the MS
3
2
30
6
and NMR data. For the bisbenzofurans, there are a total of eight possible diastereomers
after discounting enantiomeric partners). Of these, there are four symmetric and four
(
non-symmetric stereoisomers. Of the symmetric arrangements, two have C axis and two
2
are meso structures characterized by the presence of a mirror plane σ. Compound 3c (C2)
showed the presence of two enantiomers on chiral phase HPLC analysis. Compound 3d
on the other hand showed only one peak on chiral phase HPLC analysis (tested on two
different chiral stationary phases). Compound 3d must therefore correspond to either one
of two meso bisbenzofurans (3d and 3d', Figure 6). Examination of models showed that
3d' with an all cis configuration of the methine hydrogens should suffer from appreciable
steric congestion (hence less stable) compared to 3d (3d is estimated to be more stable
-1
than 3d' by ca. 14.74 kcal mol , see supporting information). The structure of this
1
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1
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5
5
5
5
6
compound is probably 3d, which received further confirmation by analogy to the
corresponding nitrogen analogue (6d, vide infra) whose structure was verified by X-ray
1
2
analysis (Figure 6).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 6. Structures of 3d, 3d′, and X-ray crystal structure of 6d
HRMS measurements of compound 3f established the molecular formula as
1
C H O , indicating that it is isomeric with compounds 3a, 3c and 3d. The H NMR
32
30
6
spectrum showed the presence of 13 aromatic resonances, four methoxy groups, four
methine protons (δ 5.60, 4.48, 3.81, 3.35) and an OH group (δ 5.40, exchanged with
D O). The low field resonance at δ 5.60 (δ 73.5) was due to an oxymethine (H-7a),
2
C
while the resonance at δ 4.48 (δ 56.1) can be attributed the doubly benzylic H-7b by
C
analogy to H-7b in compound 1e. The COSY spectrum (Figure 7) showed the presence of
an OCH−CH−CH−CH fragment, corresponding to C-7a−C-8a−C-8b−C-7b, based on the
observed three bond correlations from H-7b to C-8a and from H-8b to C-7a in the HMBC
1
spectrum (Figure 7). In addition, the H NMR spectrum of 3f showed two of the aromatic
hydrogens of one ring as singlets (H-2a, δ 6.99; H-5a, δ 6.43), indicating that one
3
aromatic moiety was 1,2,4,5-tetrasubstituted. The observed three-bond correlations ( J)
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for H-7a/C-2a, C-6a and H-7b/C-1a, C-5a, in the HMBC spectrum indicated the
attachment of C-7a to the aromatic C-1a, and C-7b to C-6a. This accounted for the 1,2-
substitution of a 4,5-dimethoxyaryl moiety by the four-carbon CHCHCHCH unit. The
HMBC data (Figure 7) also showed that the oxygen linked to C-7a is attached to the
10
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3
aromatic C-10b ( J for H-7a/ C-10b), while the adjacent aromatic C-9b is linked to the
3
methine C-8b ( J for H-8b/C-10b, H-14b/ C-8b), thus forging the bridged oxocine core.
3
Attachment of the remaining aryl units at C-7b ( J for H-7b/C-6b, H-2b/C-7b) and C-8a
3
( J for H-14a/C-8a) completed the assembly of the structure of 3f, which was also
consistent with the NOE data. In addition, the IR spectrum of 3f showed a sharp band due
−
1
to an OH function at 3441 cm indicating the presence of a free OH that remained intact
throughout the reaction.
10a
HO
9a
8
a
MeO 3a
1a 7a
O 10b
4a
6a
7
9b
MeO
b
8
b
1
b
4b
3b
MeO
OMe
3f
COSY
HMBC
13f
Figure 7. COSY, selected HMBCs, and selected NOEs of 3f, and X-ray crystal structure
of 13f
Of the four stereogenic centers in 3f, the relative configurations of two, C-7a and
C-8b, are fixed by the geometry of their attachment to the methine bridge (C-8a). The
NOEs observed for H-6b/H-8a required H-8a to be directed towards ring A, while the
substitution of ring A' at C-7b is deduced to be β from the observed H-6b/H-8a and H-
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1
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2
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2
2
2
3
3
3
3
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5
6
7
b/H-14b NOEs. Attempts to obtain suitable crystals of 3f and its derivatives (tosylate,
acetate, p-bromobenzoate; see Supporting Information) were singularly unsuccessful.
However, the nitrogen analogue of 3f (13f) furnished suitable crystals, which allowed X-
ray analysis to be carried out (Figure 7), providing verification of the structure of 13f and
support for the structure proposed for 3f.
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9
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5
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7
8
9
0
We next investigated the effect of an ortho-substituted amino group. Anodic
oxidation of 4-methoxy-2'-aminostilbene 5 was unsuccessful due to significant electrode
6
,7
fouling which was not unanticipated in the light of our previous experience. Anodic
oxidation of the N-acetylated derivative 6 gave two dimeric products in total yield of ca.
4
0%: the C symmetric bisindole 6c (35%) and the meso bisindole 6d (6%) (Scheme 3).
2
The structure of 6c can be assigned based on their MS and NMR data and by analogy to
c and 9c (X-ray structures available for both), while the structure of 6d was confirmed
1
1
2
by X-ray analysis (Figure 6). A bisindole was previously reported in an FeCl mediated
3
13a
oxidation of the o-acetamidostilbene 6, which was assigned the structure 6d. Based on
the present results however, the previous assignment requires amendment as the bisindole
reported does not correspond to 6d but to 6c.
Scheme 3. Products from the anodic oxidation of stilbenes 6−8
MeO
R
H
NHR
N
H
H
H
H
H
7
a
N
N
N
N
CPE
8a
R
R
R
R
H
H
H H
8b
ACN, 0.2 M LiClO
4
H
7
b
N
R
H
4
b
OMe
OMe
R = Ac
MeO
OMe
MeO
OMe
6
R = Ac
6c
6d
6%
Total = 41%
35%
7 R = Boc
R = H
7c
7g
Total = 35%
23%
12%
8
R = CO
2
Me
R = CO
Total = 79%
2
Me
8c
57%
8g
22%
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Since only a moderate yield was obtained for the acetylated derivative, it was of
interest to investigate the dependence of both the product distribution and the yields on
the nature of the protecting group. Anodic oxidation of the N-Boc derivative 7 gave two
10
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13
14
15
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53
54
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56
57
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60
products in combined yield of only 35%, viz., the C symmetric bisindole 7c (23%) and
2
the symmetric fused bisquinoline 7g (12%) (Scheme 3). In this instance both products
have lost their respective protecting groups during electrolysis and a substantial quantity
(ca. 40%) of deprotected starting material was also recovered. The fused bisquinoline
structure of 7g was indicated by the characteristic carbon shifts of the non-aromatic
carbons (C-7a, C-8a), which were different from those of the bisindoles, corresponding to
1
quinoline as opposed to indoline units (Figure 8). The H NMR spectrum showed
resonances due to only one half of the molecule, including a pair of doublet of doublets at
δ 4.60 (H-7a) and 3.39 (H-8a) with J = 6.9, 2.8 Hz (attributed to a pair of mutually
coupled methine hydrogens), in addition to the aromatic and methoxy resonances. The
NMR data other than indicating the presence of an element of symmetry was insufficient
for complete stereochemical assignment of the structure of this bisquinolinic compound.
In view of this finding, as well as the poor yields obtained for the N-Boc
derivative, we next investigated the oxidation of the carbamate 8. Anodic oxidation
proceeded smoothly in this case and gave a mixture of products comprising the bisindole
8
c (57%) and the fused bisquinoline 8g (22%) in combined yield of ca. 80% (Scheme 3).
In this case, the bisquinoline 8g provided suitable crystals for X-ray analysis (Figure 8),
which confirmed its structure as well as that for the previous amide analog 7g. The X-ray
structure also showed that the element of symmetry present in 7g and 8g was a center of
inversion (i).
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3
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3
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6
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7
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9
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8
9
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8
9
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3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
1
Figure 8. COSY, selected HMBCs of 7c and 7g, comparison of the C{ H} shifts of the
13b
14
α and β methine carbons with model bisindole and quinoline and X-ray crystal
structures of 9c and 8g
Anodic oxidation of the N-tosyl aminostilbene 9 gave a mixture comprising the
bisindole 9c (52%) and the fused bisquinoline 9g (25%). In addition, the rearranged
monomeric indole 9h was also isolated as a minor product (6%) (Scheme 4). X-ray
structures were available for both 9c (Figure 8) and 9g. In the case of the N-nosyl
protected stilbene, anodic oxidation gave the symmetric bisindoles 10c (C , 49%) and
2
1
0d (σ, 21%), the symmetric fused bisquinoline 10g (i, 13%), and a trace of the
monomer, 10h (Scheme 4). X-ray structure was available for 10g.
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Scheme 4. Products from the anodic oxidation of stilbenes 9 and 10
MeO
R
N
H
OMe
4
H
NHR
H
H
H
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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32
33
34
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43
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45
46
47
48
49
N
N
N
N
CPE
1
R
R
R
R
9
H H
H H
8
ACN, 0.2 M LiClO4
H
N
R
1
2
7
1
0
N
R
H
OMe
OMe
9 R = Ts
MeO
OMe
MeO
OMe
R = Ts
9c
9d
trace
9g
25%
9h
6%
Total = 83%
52%
1
0 R = Ns
R = Ns
10c
10d
21%
10g
13%
10h
trace
Total = 83%
49%
Scheme 5. Products from the anodic oxidation of stilbenes 11 and 12
MeO
MeO
R
OMe
OMe
H
NHR
N
H
9
8
H
H
N
N
CPE
R
R
12
1
7
3
OMe
OMe
10
H H
N
ACN, 0.2 M LiClO4
H
N
R
R
OMe
4
N
H
OMe
MeO
OMe
R
OMe
OMe
MeO
OMe
11 R = Ac
R = Ac
11c
11i
12%
Total = 39%
27%
1
2 R = CO Me
R = CO
Me
2
12c
12g
5%
12h
1%
2
Total = 73%
67%
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1
1
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2
2
2
2
2
2
2
2
2
3
3
3
3
3
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3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 6. Products from the anodic oxidation of stilbenes 13 and 14
RHN
H
H R
N
NHR
H
H
MeO
N
N
CPE
R
R
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
H H
ACN, 0.2 M LiClO4
MeO
H
H
OMe
MeO
OMe
OMe
MeO
OMe
MeO
OMe
13f
13 R = Ts
R = Ts
13c
Total = 70%
54%
16%
14 R = Ns
R = Ns
14c
14f
9%
Total = 70%
61%
In the case of the 3,4-dimethoxsubstituted aminostilbenes, some variation in the
product type and distribution were noted. The acetylated derivative 11 gave only the
bisindole 11c and the monomeric indole 11i in a total yield of only 39% (Scheme 5). In
an earlier study of FeCl -promoted oxidation of o-amidostilbenes, bisindole 11c and
3
1
3b,c
dihydroindole 11i were also obtained for the reaction of the o-acetamidostilbene 11.
As before, in view of the poor yields for the acetylated derivative, anodic oxidation of the
carbamate derivative 12 was next attempted which gave the bisindole 12c as the major
product in 67% yield, the bisquinoline 12g (5%), and the rearranged monomeric indole
1
2h as a very minor product (1%) (Scheme 5). The tosyl and nosyl derivatives 13 and 14,
respectively, gave only two products, the bisindoles 13c and 14c, and the bridged
azocines 13f and 14f (Scheme 6). The structures of 12c, 12g (Figure 8), 13c, and 13f
(Figure 7) were also confirmed by X-ray analysis. The X-ray structure of the azocine 13f
provides additional support for the structure proposed for the oxocine analogue, 3f (vide
supra). The products for the oxidation of stilbenes 1-14 are summarized in Table 1.
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a
Table 1. Products from the anodic oxidation of stilbenes (1−14)
% Yield
Entry Stilbene
a (threo) b (meso) g (meso) c (threo) d (meso) e (meso) f (meso)
h
i
Total
80
1a
1b
14
1b
15
1c
19
1c
20
3c
17
3c
18
6c
1e
22
1e
20
1
2
3
4
5
6
7
8
9
1
2
3
4
2
5
1
a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
27
82
3
2
3
1
a
1
a
9
3d
18
3d
18
6d
6
3f
32
3f
88
30
85
b
6
7
3
5
41
7
g
7c
23
8c
57
9c
52
10c
49
c
12
35
8g
22
9g
25
8
79
83
83
39
73
70
70
9h
6
d
9
10g
10d
21
b
10
11
12
13
14
1
3
1
2
1c
7
11i
12
10
1
2g
12c
67
12h
1
11
5
1
5
3c
4
13f
16
14f
9
12
14c
1
13
6
a
b
c
Pt anode, Pt cathode, versus Ag/AgNO in MeCN/0.2 M LiClO , Traces of monomer (6i and 10h) observed in NMR spectra of product mixtures. Yield based on stilbene
3
4
d
reacted, reaction accompanied by recovery of ca. 35% of the deprotected stilbene 7. Traces of meso bisindole 9d observed in NMR spectra of product mixtures.
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2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
Scheme 7. Proposed mechanism for the formation of products in the anodic oxidation of stilbenes (1, 6−10) in MeCN/LiClO4
B
B
B'
B
B'
XHR
XHR
RHX
XHR
XHR
R
X
−H+
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
−2e
2
2
(a)
A
A
A'
OMe
A
A'
OMe
OMe
OMe
MeO
MeO
1
5
16
1
6
: X = O ; R = nil
: X = N ; R = Ac
7: X = N ; R = Boc
H+
(a)
−
−
H+
(b)
8
9
: X = N ; R = CO Me
: X = N ; R = Ts
2
MeO
R
X
H
H
10: X = N ; R = Ns
A
B
X
R
X
R
H
H
B'
A'
X
R
H
MeO
OMe
OMe
−H
1c: X = O ; R = nil
6
7
8
9
c: X = N ; R = Ac
c: X = N ; R = H
c: X = N ; R = CO
c: X = N ; R = Ts
H+
+
−
(b)
(b)
2
Me
10c: X = N ; R = Ns
MeO
MeO
MeO
R
X
H
R
R
X
H
H
H
H
X
H
+
H
H
H
X
H
X
R
H
X
R
X
X
R
R
H
H
H
H
H
R
OMe
OMe
OMe
1
a: X = O ; R = nil
1b: X = O ; R = nil
7g: X = N ; R = H
8g: X = N ; R = CO Me
MeO
OMe
2
9g: X = N ; R = Ts
6d: X = N ; R = Ac
1
0d: X = N ; R = Ns
1
0g: X = N ; R = Ns
2
0
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The current investigation was carried out to address several questions regarding
stilbene cation radical reactivity. First, will the proximate ortho-substituted nucleophilic
groups (OH, NH ) engage the cation radical in an intramolecular reaction? Second, if
2
10
11
12
13
14
15
16
17
18
19
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21
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intramolecular cation trapping occurs, does it precede bimolecular dimerization of the
first formed cation radical, or does trapping by the internal nucleophile take place
subsequent to cation radical dimerization? Additionally, can ‘crossover trapping’ occur to
provide six-membered ring products (pyrans/quinolines) in addition to five-membered
ring products (furans/indoles) from direct trapping? The formation of the fused
bisbenzopyrans/ bisquinolines (a result of crossover trapping), in addition to the
bisbenzofurans/bisindoles clearly showed that the ortho-substituted OH (and NHR)
groups do react with cationic groups, and that such engagements occur subsequent to
cation radical dimerization. We propose the following mechanism to rationalize the
formation of the products in the oxidation of the 4-methoxy-2'-hydroxy(or 2'-
amino)stilbenes, 1, 2, 6−10.
One-electron oxidation of the starting stilbene gave the cation radical 15, which
under the conditions of preparative electrolysis undergoes facile cation radical
dimerization to give the dicationic intermediate 16 as the dominant step, as demonstrated
7
by previous studies. Formation of the fused bisbenzopyrans (1a, 1b) or bisquinolines
(7g−10g) is a result of “crossover trapping” by the ortho-substituted nucleophiles, i.e., o-
OH (or o-NHR) in ring B of one stilbene half attacks the benzylic cation associated with
ring A' of the other stilbene half, while, o-OH (or o-NHR) in ring B' attacks the benzylic
cation of ring A (Scheme 7, path b). On the other hand, the formation of the
bisbenzofuran (1c) or bisindoles (6c−10c, 6d, 10d) is a consequence of the respective
2
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
direct trapping of the cation by the ortho-substituted nucleophiles belonging to the same
stilbene half, i.e., o-OH (or o-NHR) belonging to ring B of one stilbene half reacts with
the benzylic cation of ring A of the same stilbene half, while, o-OH (or o-NHR) in ring B'
reacts with the benzylic cation of ring A', as shown in Scheme 7, path a. The occurrence
of crossover trapping represents firm evidence for intramolecular cation trapping by the
internal nucleophile taking place subsequent to cation radical dimerization.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
B
O
Ar2'
H
H
O
O
H
H
−H
+
H+
H
H
−
(
a)
Ar2
(a)
HO
B
B'
HO
Ar2'
MeO
OMe
H
H
1
c
HO Ar2
MeO
B'
B
H
H+
O
O
H
−
Ar2'
Ar2
−
H+
1
6a
H
H
(b)
threo, C2
(b)
H
O
HO
H
B'
OMe
1a
MeO
B
B
H
OH
O
H
O
−H+
H
H+
H
−
Ar2'
Ar2'
Ar2
Ar2
H
H
H
O
(b)
(b)
HO
HO
H
B'
B'
OMe
16b
1b
meso
Figure 9. Origin of the fused benzopyrans 1a, 1b, and bisbenzofuran 1c from the threo
and meso dications
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There are two possible modes for the initial cation radical coupling to give the
7
dication 16, from which all the products are derived. The two regioisomers 1a and 1c
formed in the oxidation of 1 originate from the threo-dication 16a, which is characterized
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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34
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
by the presence of a C axis. On the other hand, the fused benzopyran 1b originates from
2
the meso-dication 16b, as shown in Figure 9. The origin of the various products from the
corresponding threo- or meso-dications is also given in Table 1.
The fused benzofurano-benzopyran 1e formed in the anodic oxidation of stilbene
1, appeared at first sight to be an unusual product. It possesses an acetal function shared
between two rings and in addition showed evidence of aryl migration, features which had
7
been noted previously. Interception of the dicationic intermediate 16 by water gives
cation 17 which then forms the spirocyclic carbocation intermediate 18, as shown in
Scheme 8, path c. The formation of such spirocationic intermediates has been postulated
7
previously by Hong in the anodic oxidation of substituted stilbenes, and is assisted by
the p-OMe substituent in ring A. Subsequent ring opening, leads to the aldehyde 19
which upon intramolecular acetalization via attack by the ortho-OH groups in rings B and
B' furnishes the cyclic acetal 1e, as shown in Scheme 8. The formation of this acetal
product (1e) and its purported origin suggest that not all of the dicationic intermediate in
this case is trapped by the internal nucleophile. A portion is diverted by intermolecular
capture leading eventually to the acetal product 1e.
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8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 8. Proposed mechanism for the formation of 1e in the anodic oxidation of 1 in
MeCN/LiClO4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
B
B
B'
OH
OH
HO
OH
B
B'
−2e
2
H O
2
2
HO
A
OH
A'
−
H+
A
A
A'
OMe
MeO
OH
OMe
OMe
OMe
MeO
1
15
16
17
MeO
OMe
B'
MeO
OMe
A'
B'
HO
A'
−
H+
O
HO
H
OH
B
(c)
A
H
B
A
MeO
O
O
O
HO
H
H
OMe
18
1e
1
9
Anodic oxidation of the 3,4-dimethoxysubstituted 2'-hydroxystilbene 3 (and the
corresponding aminostilbenes 11−14) were also investigated, since it has been shown in
the previous study that the presence of a m-methoxy group in addition to a p-methoxy
substituent, enhances the nucleophilicity of the aromatic carbon para to the m-OMe
7
group (C-6), and this had an effect on the product distribution. Indeed, oxidation of 3 (as
a representative example) gave in addition to the expected bisbenzopyran 3a,
bisbenzofurans 3c and 3d, the unexpected bridged oxocine 3f. The latter product was
formed as a result of 3,4-dimethoxy substitution in the starting 2'-hydroxystilbene and
was also obtained in the oxidation of the corresponding 3,4-dimethoxy-, tosyl- and nosyl-
protected 2'-amino analogues, 13 and 14, respectively. We propose the following
mechanism (Scheme 9) to rationalize the formation of these products. Direct trapping of
2
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the dication 20 from the initial cation radical dimerization leads to the isomeric fused
bisbenzofurans 3c and 3d. Two successive crossover trapping reactions lead to the
formation of one of the expected bisbenzopyrans, 3a. The other bisbenzopyran 3b
however was not formed, instead the bridged oxocine was isolated in 32% yield. The
cationic intermediate 21 formed after the first crossover trapping instead of undergoing a
second crossover trapping to 3b, undergoes electrophilic substitution (Friedel-Crafts
alkylation) via attack of the benzylic cation (associated with ring A') on the activated C-6
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13
14
15
16
17
18
19
20
21
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59
60
7
,15
of ring A. This aromatic substitution is facilitated by the activation of ring A due to the
appropriately placed m-OMe group, and as a result is able to compete favorably with the
second crossover trapping by o-OH.
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
Scheme 9. Proposed mechanism for the formation of products in the anodic oxidation of stilbenes (3, 11−14) in MeCN/LiClO4
B
B
B'
B
B'
XHR
XHR
RHX
XHR
XHR
R
X
H
H
−H+
a)
−H+
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
−2e
X
X
2
2
R
R
H
H
(
(a)
A
A
A'
A
A'
OMe
OMe
MeO
OMe
MeO
OMe
MeO
OMe
OMe
OMe
MeO
OMe
MeO
OMe
MeO
OMe
3
: X = O ; R = nil
20
3c: X = O ; R = nil
11: X = N ; R = NAc
11c: X = N ; R = NAc
1
2: X = N ; R = CO Me
12c: X = N ; R = CO Me
13c: X = N ; R = Ts
14c: X = N ; R = Ns
2
2
−
H+ (b)
13: X = N ; R = Ts
1
4: X = N ; R = Ns
RHX
B
MeO
MeO
MeO
MeO
R
R
X
H
R
X
X
H
A
B
MeO
H+
OR
A
B'
−
B'
A'
MeO
(
c)
H
X
R
H
H
OMe
OMe
OMe
OMe
X
X
X
R
A'
R
R
H
H
H H
MeO
−H
OMe
(d)
2
1
MeO
OMe
3
a: X = O ; R = nil
−H
+
+
MeO
OMe
(
c)
−
H+
(c)
3
d: X = O ; R = nil
RHX
MeO
MeO
MeO
MeO
R
R
H
H
X
H
H
R
H
X
H
X
H
MeO
MeO
H
X
R
H
X
OMe
OMe
OMe
OMe
H
H
R
MeO
OMe
1
2
2g: X = N ; R = CO Me
3b: X = O ; R = nil (not formed)
3
f: X = O ; R = nil
13f: X = N ; R = Ts
4f: X = N ; R = Ns
1
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Arising from the above, a pertinent question is why 3a was formed while 3b was
not, instead the oxocine 3f was formed in its place, and not vice versa (i.e., formation of
3
b and the corresponding oxocine in place of 3a). The bisbenzopyrans 3a and 3b
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21
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originate from different dications arising from the initial cation radical coupling.
Bisbenzopyran 3a results from two successive crossover trapping reactions from the
threo-dication. Bisbenzopyran 3b on the other hand is a result of two successive
crossover trapping reactions from the meso-dication (Scheme 10). Examination of models
showed that while the second crossover reaction from the cationic intermediate 21b (from
the meso-dication) to give 3b is feasible, the alternative electrophilic substitution reaction
was able to compete effectively, resulting instead in the formation of the bridged oxocine
product at the expense of 3b. In the case of the cation 21a (from the threo-dication),
examination of models showed that while a second cyclization from 21a to 3a is feasible,
the alternative aromatic substitution to the bridged oxocine product is highly unlikely for
geometric reasons, as it will result in formation of a trans-bridged oxocine. A similar
explanation applies in the case of the ortho-NHR-substituted dimethoxystilbenes (e.g., 13
1
6
and 14 in Scheme 10).
Another difference in the oxidation of 1 versus 3 was the absence of the acetal
product (analogous to 1e) in the reaction of the 3,4-dimethoxy-substituted stilbene 3. A
possible explanation for this is that activation of the aromatic ring A (at C-6) towards
aromatic substitution by the 3-OMe group has resulted in intramolecular pathways being
overwhelmingly favored over competing intermolecular reactions. The same difference
was noted when comparing the results for the reactions of the o-aminostilbenes (6−10)
versus the reaction of the o-hydroxystilbene 1, where the amino acetal (or aminal)
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1
1
1
1
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1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
analogue of 1e was not detected among the products in the reactions of 6−10, which may
be attributed to the greater nucleophilicity of nitrogen versus oxygen, resulting in the
predominance of the more facile intramolecular reactions over competing intermolecular
pathways.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 10. Pathway showing the formation of 3a and 3f (or 13f) instead of 3b (or 13g)
and the trans-bridged oxocine/azocine
B
H
B'
H
B
H
B'
H
XHR
XHR
RHX
XHR
RHX
XHR
−
2e
2
2
A
A'
OMe
A
A'
OMe
OMe
OMe
MeO
OMe
MeO
OMe
OMe
OMe
MeO
MeO
20a
threo-dication
20b
3
: X = O ; R = nil
or
3: X = N ; R = Ts
meso-dication
−H+ (b)
1
−
H+ (b)
MeO
MeO
MeO
MeO
R
X
H
R
X
H
H+
−H
+
−
3
b or 13g
3a
(
not formed)
(
c)
H
X
R
H
(c)
OMe
OMe
OMe
OMe
X
H
H
R
21a
(d)
trans-bridged oxocine/azocine
21b
H+
−H+ (d)
3f or 13f
−
Another difference when comparing the products of the ortho'-OH- versus those
of the ortho'-NHR-substituted 4-methoxystilbenes (for which we were unable to
formulate a convincing explanation), was the formation of the crossover trapping derived
bisquinolines of the g series (from the meso-dication, and characterized by presence of a
center of inversion, i) for the ortho'-NHR-substituted stilbenes, whereas this type of
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product was absent for the reaction of the ortho'-OH-substituted stilbenes, where meso-
1
7
dication derived crossover bisbenzopyran products of the b type were formed instead.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
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36
37
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 11. Proposed mechanism for the formation of the rearranged monomeric indoles
9h, 12h and dihydroindole 11i
NHR2
NHR2
−H+
−
e
N
H
N
8
R2
8
R2
7
7
(a)
(a)
R1
R1
R1
R1
OMe
OMe
22
OMe
23
OMe
9: R1 = H ; R2 = Ts
1: R1 = OMe ; R2 = Ac
2: R1 = OMe ; R2 = NCO Me
1i: R1 = OMe ; R2 = Ac
1
1
1
−e (b)
2
N
−H+
N
8
R2
R2
7
R1
R1
R2
N
R2
N
(
c)
OMe
24
OMe
7
8
7
+
8
−H
H
(not formed)
(d)
R1
R1
OMe
OMe
9h: R1 = H ; R2 = Ts
2h: R1 = OMe ; R2 = NCO Me
R2
N
1
2
8
7
R1
OMe
25
The monomeric indoles (9h, 12h) and dihydroindole (11i) were minor products
and were detected only in the oxidation of the ortho-amino substrates (9, 11, 12). Their
2
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