A FeCl3-promoted highly atropodiastereoselective cascade reaction: synthetic utility of radical cations in indolostilbene construction

Article abstract of DOI:10.1016/j.tet.2008.11.100

The FeCl₃-promoted oxidative cyclization/coupling of acetamidostilbenes possessing 3-methoxy, 4-methoxy and 3,5-methoxy substitutions (21), (22) and (23) is described. Only 3,5-substitution gave rise to novel indolostilbenes, each possessing two stereogenic axes (axially chiral but racemic dimers (39) and (40)). The 4-methoxy substituted acetamidostilbenes, by contrast, yielded the bisindoline dimer (36).

Full text of DOI:10.1016/j.tet.2008.11.100

Tetrahedron 65 (2009) 1504–1516
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A FeCl3-promoted highly atropodiastereoselective cascade reaction: synthetic
utility of radical cations in indolostilbene construction
,
b
c
Kartini Ahmad a, Noel F. Thomas b , Mat Ropi Mukhtar , Ibrahim Noorbatcha ,
Jean-Frederic Faizal Weber d, Mohd Azlan Nafiah a, Saraswati S. Velu d, Koichi Takeya e,
Hiroshi Morita f, Chuan-Gee Lim g, A. Hamid A. Hadi b, Khalijah Awang b
*
a Department of Chemistry, Faculty of Science and Technology, University Pendidikan Sultan Idris, 35900 Tanjong Malim, Perak, Malaysia
b Department of Chemistry, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia
c Department of Biotechnology, Faculty of Science, International Islamic University, Jalan Gombak, 53100 Kuala Lumpur, Malaysia
d iKUS, Faculty of Pharmacy, University Teknologi MARA, 40450 Shah Alam, Selangor D.E., Malaysia
e Tokyo University of Pharmaceutical and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
f Faculty of Pharmaceutical Sciences, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan
g Environmental and Bioprocess Technology Centre, SIRIM Berhad, 40000 Shah Alam, Selangor, Malaysia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 July 2008
Received in revised form 5 November 2008
Accepted 20 November 2008
Available online 7 December 2008
The FeCl3-promoted oxidative cyclization/coupling of acetamidostilbenes possessing 3-methoxy, 4-
methoxy and 3,5-methoxy substitutions (21), (22) and (23) is described. Only 3,5-substitution gave rise
to novel indolostilbenes, each possessing two stereogenic axes (axially chiral but racemic dimers (39) and
(40)). The 4-methoxy substituted acetamidostilbenes, by contrast, yielded the bisindoline dimer (36).
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
Diels–Alder reaction with a pendant ethynyl moiety. This tactic
effectively installed not only the distorted biaryl system but also
Axially chiral molecules are no longer regarded as exotic curi-
osities. Such molecules, possessing one or more stereogenic axes
about which rotation is restricted, have become increasingly im-
portant since the configuration at a biaryl axis often plays a major
role in the pharmacological characteristics of the compound.1
Among the axially chiral molecules exhibiting remarkable proper-
ties are the antibiotic heptapeptide vancomycin (1)2 and knipho-
lone (2),2 from the family of 1-phenylanthraquinones, which
exhibit antimalarial and antitumour properties. Many invaluable
reagents for asymmetric synthesis have exploited axial chirality.3,4
Many approaches have been adopted for constructing the
biaryl (or biheteroaryl) motif. These include the Ullman Coupling
the azaparacyclophane ring system characteristic of (ꢀ)-haou-
amine A (3).
OH
OH
HO
H2N
HO
Me
O
Me
O
O
O
Cl
O
O
OH
Cl
HO
H
O
O
O
H
N
H
H
H
H
N
NHMe
N
H
O
O
N
N
H
H
NH
O
O
HO2C
(Cu/DMF
D
),5–7 oxidative methods (Mn(acac)3),8–10 palladium
NH2
OH
OH
assisted aryl coupling [PdCl2(PPh3)2]11 and one-pot deiodination/
aryl–aryl coupling (tBuLi/CuCN).12–14 As an alternative to transition
metal mediated approaches for direct aryl–aryl coupling, Carter15
has described a Diels–Alder cycloaddition/cycloreversion tactic
involving a disubstituted alkynyl stannane and a functionalized
cyclohexadiene. An even more spectacular [4þ2]/[reverse 4þ2]
cycloaddition was accomplished by Baran16 in which a pyrone was
appended to a benzene ring thus setting up an intramolecular
vancomycin (1)
HO
HO
O
OH
OH
HO
Me
OH
HO
H
N
O
H
HO
Me
HO
haouamine A (3)
O
OMe
knipholone (2)
* Corresponding author. Tel.: þ60 3 79674065; fax: þ60 3 79674193.
E-mail address: noelfthomas@um.edu.my (N.F. Thomas).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.11.100

K. Ahmad et al. / Tetrahedron 65 (2009) 1504–1516
1505
(1) What would be the effect of subjecting an analogue of (8)
lacking the 4-methoxy substituent (but retaining the 3-
methoxy) in ring B (9) (Scheme 2) to the FeCl3 oxidation
conditions?
(2) Would the 3-methoxy and 3,5-dimethoxy acetamidostilbene
radical cations exhibit similar behaviour, e.g., inhibition of
bisindoline formation, etc. (Scheme 3).
The above do not exhaust all creativity in this field since Jai-
sankar17 has reported a three-component route to chiral 3,30-
bipyrroles that employs diaryl acetylenes, 1,3-dicarbonyls and
ammonium acetate.
We have previously described our investigation of radical cation
mediated cascades culminating in the synthesis of dihydronaph-
thalenes18 (pericyclic) and a bisindoline19 (non-pericyclic). The
mechanistic hypotheses then and now are worth considering. The
dihydronaphthalene (6) and bisindoline (12) construction we pre-
viously described is predicated on the prior generation of stilbene
radical cations (5) and (9) (Schemes 1 and 2) where the position of
the positive charge is determined by the mesomeric stabilization
made available by a para electron donating substituent. This re-
quirement is met in the dehydronaphthalene (6) and bisindoline
(12) syntheses described below (Schemes 1 and 2).18,19 The radical
cations (5) (Scheme 1) and (9) (Scheme 2) are thus crucial
intermediates.
R1
R1
H
5
4
6
1
B 3
8
2
R2
R2
14
FeCl3
9
10
7
13
12A
11
NH
NH
O
O
(13) R1= OMe, R2= H
(14) R1= R2= OMe
(15) R1= OMe, R2= H
(16) R1= R2= OMe
In examining the bisindoline construction in Scheme 2, the
following questions need to be addressed.
R1
H
H
O
N
N
N
R2
O
H
H
OMe
OMe
OMe
FeCl3
O
(17) R1= OMe, R2= H
(18) R1= R2= OMe
B
B
8
7
8
R2
R1
(19) R1= OMe, R2= H
R2
R1
OMe
7
A
A
(4)
AcO
(5)
AcO
(20) R1= R2= OMe
Dimerization
Cyclization
(Pericyclic)
Scheme 3.
OMe
OMe
OMe
OMe
We would expect that in the absence of a para electron do-
nating substituent in ring B (Scheme 2), a different radical cation
would be generated. Under these conditions bisindoline formation
should be extremely unlikely in contrast to indoline formation
(Scheme 3).
Addressing these questions would lend further support to the
radical cation hypothesis we have employed in previous reports.
We would like to highlight the fact that cyclization of (9)
(Scheme 2) produces an indolyl radical (10) from which (11) and
(12) are generated. We have already described20 the remarkable
elevation in the yield of indoline (11) and suppression of bisin-
dolisation by the simple expedient of the addition of benzophe-
HO
+
AcO
OMe
OMe
OMe
OMe
AcO
AcO
(7)
(6)
Scheme 1.
OMe
OMe
OMe
OMe
5
6
4
none, which on
a number of occasions was quantitatively
B 3
8
1
B
2
7
14
8
recovered from the reaction mixture at the end of the reaction.
We suggested that electron transfer from the benzophenone
radical anion to the indoline radical was the key to understanding
this transformation and lends considerable weight to the
hypothesized intermediacy of radical cations (and radical cation–
radical cation or in this case radical–radical dimerization).20
In order to probe the relationship between the aryl substitution
pattern and stilbene radical cation reactivity (Scheme 3) the fol-
lowing stilbenes (21), (22) and (23) (Fig. 1) were prepared as de-
scribed in the next section.
9
FeCl3
13
7
12 A
A
10NH
11
NH
O
O
(9)
(8)
Cyclization
(non-pericyclic)
dimerization
8
7
OMe
OMe
N
OMe
OMe
N
O
(11)
O
(10)
+
OMe
OMe
H
H
OMe
O
8
N
N
7
H
O
H
OMe
NH
NH
NH
MeO
OMe
O
O
O
OMe
OMe
(22)
(23)
(21)
(12)
Figure 1.
Scheme 2.

1506
K. Ahmad et al. / Tetrahedron 65 (2009) 1504–1516
2. Results and discussion
OMe
Hβ
OMe
3
4
Hα
2
1
The styrenes (27), (28) and (29) were readily obtained by Wittig
methodology from the corresponding aldehydes (Scheme 4); the
subsequent Heck coupling proceeded smoothly according to our
usual protocol.18,19
FeCl3
CH2Cl2
8
5
8
6
7
14
A
C
B
9
13
12
7
10
11
N
H
O
NH
O
(34) 6%
(21)
CHO
Scheme 6.
CH3PPh3I, DMF
NaH
R1
R3
R1
R3
R2
R2
(24) R1 = OMe, R2, R3 = H (27) R1 = OMe, R2, R3 = H (48%)
(25) R1 = R3 = H, R2 = OMe (28) R1 = R3 = H, R2 = OMe (43%)
(26) R1 = R3 = OMe, R2 = H (29) R1 = R3 = OMe, R2 = H (44%)
OMe
FeCl3
CH2Cl2
Hβ
Hα
8
A
C 7
N
B
OMe
H
O
Scheme 4.
NH
The three styrenes (27), (28) and (29) were produced in yields of
48%, 43% and 44%, respectively. Heck reactions were performed by
heating (120 ꢁC) the corresponding styrenes with 2-iodophenyl-
N-acetamide19 (30) with Pd(OAc)2 in dry DMF for 48 h. The corre-
sponding stilbenes (21), (22) and (23) were generated in yields
exceeding 40% (Scheme 5).
(35)16%
O
(22)
+
H
H
O
8
N
N
7
O
H
H
I
O
+
OMe
OMe
(36) 24%
R3
R1
N
H
R2
(27) R1 = OMe, R2, R3 = H
(28) R1 = R3 = H, R2 = OMe
(29) R1 = R3 = OMe, R2 = H
Scheme 7.
(30)
Pd(OAc)2
(C2H5)3N
DMF
With respect to the bisindoline (36), spectroscopic agreement with
its previously described analogue (12) (Scheme 2) was observed.
R1
Thus the H-7 resonated at
d 4.66 as a singlet as did H-8 (d 3.48 and
120°C
R2
R3
R1
R2
also a singlet). These features are consistent with the symmetrical
structure and stereochemical assignments have been made by
comparison with previously published determinations, both
mechanistic19 and computational19 (AM 1).
+
NH
R3
NH
O
We must now address a quite unexpected development made as
(31) R1 = OMe, R2, R3 = H (5%)
O
(21) R1 = OMe, R2, R3 = H (48%) (32) R1 = R3 = H, R2 = OMe (4%)
(22) R1 = R3 = H, R2 = OMe (48%) (33) R1 = R3 = OMe, R2 = H (3%)
(23) R1 = R3 = OMe, R2 = H (45%)
a
result of the FeCl3 oxidation of the 3,5-dimethoxy acet-
amidostilbene (23), as fully described in the next section.
Scheme 5.
2.2. The unprecedented construction of the axially chiral
(racemic) stilbenes incorporating an indole moiety
The geminally substituted olefins (31), (32) and (33) were
obtained as minor products.
That 3,5-dimethoxy substitution should profoundly influence
stilbene radical cation reactivity compared to 3,4-dimethoxy sub-
stitution was to be expected. What was not foreseen was the radical
departure from the pattern observed for 3-methoxyacetamido-
stilbene (21) (Scheme 6).
Subjection of (23) to our oxidative protocol produced ortho-
acetamidobenzaldehyde (37), a dichlorostilbene monomer (38) and
two dimers (39) and (40), each of the latter contained a clearly
intact stilbene olefinic bond (Scheme 8). We suspect that oxidative
cleavage of (23) (for example) leading to water-soluble products
(e.g., carboxylic acids) is a major factor for the low yields in these
and previously described reactions.z
2.1. The Ferric chloride reactionsdthe moment of truth!
y
The acetamidostilbene (21) was subjected to ‘anhydrous’ FeCl3
(as opposed to the hydrated salt) oxidation (1:5 molar ratio). The
only isolable product was the indoline (34) obtained in 6% yield
(Scheme 6).
The influence of substitution pattern in the B-ring of the stil-
bene was dramatically revealed when the stilbene (22) was sub-
jected to FeCl3 oxidation. In contrast to the previously described
chemistry (Scheme 6), the 4-methoxystilbene (22) gave rise to the
bisindoline (36) in 24% yield in addition to indoline (35) in 16%
yield (Scheme 7).
z
Oxidation of (23) would produce two aldehydes, however, the 3,5-dimethoxy-
benzaldehyde undergoes faster oxidation to the water soluble carboxylic acid (50)
and (unlike (37)) is therefore not isolated. The electrochemical oxidative cleavage of
alkenes has been described by Fry.34
y
Strictly speaking ‘anhydrous’ FeCl3 does absorb small amounts of water due to
its hygroscopic character.

K. Ahmad et al. / Tetrahedron 65 (2009) 1504–1516
1507
Table 1
OMe
OMe
1H NMR [400 MHz, dH (J, Hz)] and 13C NMR [100 Hz, dC] in CDCl3
FeCl3
Cl
CH2Cl2
6
6
No.
(39)
(40)
CHO
2
2
OMe
[MþþNa]¼648.1998
[MþþH]¼625.2111
OMe
+
(calcd 648.1998)
(calcd 625.2105)
Ac
Ac Cl
N
NH
N
H
1H (J Hz)
13C
1H (J Hz)
13C
H
O
(37) 2.4%
1
2
3
4
5
6
7
8
9
10
11
12
d
138.9
116.1
157.7
98.1
d
138.2
102.0
157.5
113.3
157.7
102.6
133.1
123.9
130.3
134.7
124.2
128.5
125.6
127.1
134.7
118.9
155.3
97.7
158.3
115.6
135.7
111.4
129.1
137.0
117.0
124.7
123.2
127.1
56.6
(38) 8%
(23)
d
6.48 (s)
d
Cl
OMe
d
Cl
OMe
14'
6'
1'
5'
4'
8'
C
6.08 (s)
d
d
13'
9'
10' N
12'A
14'
B
6'
5'
3
8'
7'
13'
9'
160.2
102.5
131.1
128.0
130.4
135.6
124.9
128.5
125.0
127.3
134.4
120.6
156.4
97.5
155.5
115.7
136.4
112.6
129.0
136.5
115.8
124.8
123.6
120.4
55.4
d
1'
1
2'
3'
12'A
4'
11'
2B'
C7'
10' N
3'
11'
6.48 (s)
6.65 (d, 16.0)
6.82 (d, 16.0)
d
6.48 (s)
6.77 (d, 16.0)
6.96 (d, 16.0)
d
OMe
OMe
O
MeO
OMe
OMe
O
4
O
5
+
3
2
D 6
N
H
1
2
D
6
d
d
7
4
1121E10
7
16
15
5
7.85 (d, 8.2)
7.26 (t, 8.2)
7.08 (t, 8.2)
7.85 (d, 8.2)
d
7.76 (d, 7.8)
7.25 (t, 7.8)
7.13 (t, 7.8)
7.37 (d, 7.8)
d
O
9
8
8
14
13
OMe
HN
13
9
E
14
13
10
11
14
12
10
20
d
d
(40) 10%
(39) 14%
30
d
d
Scheme 8.
40
6.72 (s)
d
6.72 (s)
d
50
In examining (39) and (40), two stereogenic axes (biaryl link-
ages) have been installed. This is a unique structural feature (when
set in the context of an arrangement incorporating biphenyl,
stilbene and indole moieties in the same molecule) although
other oxidative methods for constructing the biaryl linkage are
known.8–10,21
60
d
d
70
d
d
80
6.42 (s)
d
6.36 (s)
d
90
100
d
d
110
8.03 (d, 8.2)
7.21 (t, 8.2)
7.16 (t, 8.2)
7.39 (d, 8.2)
3.59 (s)
3.67 (s)
3.85 (s)
3.99 (s)
8.86 (s)
d
8.34 (d, 8.2)
7.22 (t, 8.2)
7.19 (t, 8.2)
7.39 (d, 8.2)
3.78 (s)
3.61 (s)
4.00 (s)
3.74 (s)
120
130
140
8'
7'
1'
4'
OMe
3-OMe
5-OMe
30-OMe
50-OMe
NH
NHC]O
NHCO–CH3
NC]O
NCO–CH3
N
55.3
56.4
56.6
55.3
56.5
55.8
Boc
Indole (69)
22
169.7
24.2
172.3
26.3
d
168.8
24.5
171.4
25.2
2.36 (s)
d
2.30 (s)
d
1.88 (s)
2.14 (s)
2.3. Spectroscopic features
The comparison of the spectroscopic features of these two
unprecedented structures with previously published indole
(69)22 is instructive. The H-2, H-6 doublets (see 23, Scheme 8 and
indole (69)) are clearly absent in (39) and (40). The corresponding
must be borne in mind that sp2 carbons have higher s character and
are more electronegative than sp3 carbons. The C-4 carbon that is
now located at a stereogenic axis (C-44C-20 in (40)) is now more
deshielded than the corresponding C-4 in (39) because of increased
steric hindrance (barriers to rotation), which results in reduced sp2
(increased sp3 or lower % of s character) on the carbon and con-
comitant greater deshielding.
carbons (C-20 and C-60) in (39), at
erably more deshielded than the corresponding carbons of
starting acetamidostilbene (23) ( 105.0). The disruption of
d 120.6 and 115.7, are consid-
d
symmetry in ring B of (39) when compared to (38) should be duly
noted along with the C-20 13C chemical shift. Replacement of
a chlorine in (38) with an aromatic ring (D) in (39) has resulted in
We see this phenomenon in relation to the C-2 carbon in (40)
(d 102.0) (ring D). Note that the C-2 and C-6 carbons are close to
a greater deshielding of the C-20 (
d
120.6) in (39) compared to
114.0 in (38).
being but not quite equivalent (Table 1). Once the C-2 carbon (ring
It should also be noticed that the carbons connected by the
stereogenic axis between indole ring C and ring B (C-70 and
C-10) (Scheme 8) are significantly more deshielded in (39)
compared to the indole (69)22 probably reflecting the radical
departure from coplanarity with respect to these rings (39) and
the reduced sp2 character (increased sp3 character) of these
D) is bound to C-20 of ring B as in (39) its chemical shift changes to
d
116.0. These observations confirm the location of the stereogenic
axes C-704C-10–C-204C-2 (39) and C-704C-10–C-204C-4 (40).
These connectivities are confirmed by HSQC and HMBC correla-
tions. Stereochemical relationship in (39) and (40) were estab-
lished by computational calculations (PM623/MOPAC200724) and
NOESY correlations (Figs. 2 and 3). One critical observation is NH
carbons. The C-20 (
d 120.6) in (39) is noticeably more deshielded
than the C-2 of the acetamidodichlorostilbene (38) in spite of
the presence of an electron withdrawing chlorine. This is an-
other indication of the profound effect of two new stereogenic
axes in (39).
Analogous arguments could be made regarding dimer (40)
where the point of attachment of ring D to ring B is different. The
signal in (39) at d 8.86. The 3-dimensional arrangement corre-
sponding to conformational isomer (39) incorporating H-bonding
(missing in 40) has been determined. This data have enabled us to
confirm the structures of both atropodiastereoisomers (39) and
(40) demonstrating the remarkable atropodiastereoselective na-
ture of this stilbene radical cation mediated transformation.
The 14-membered pseudo-macrocyclic structure (39), made
possible by intramolecular H bonding, is unique (in the stilbenoid-
indole field).
H-4 doublet (
4 in (39) (ring D) (
observe a phenomenon to which we have previously referred. It
d
6.08) in (39) (ring D) is clearly absent in (40). The C-
d
98.1) is found in (40) at 113.3. Once again we
d

1508
K. Ahmad et al. / Tetrahedron 65 (2009) 1504–1516
whose site-specificity is explainable based on frontier orbital
considerations.25
The remarkable regiospecificity of our FeCl3, 3,4-dimethoxy-
12-acetoxystilbene dimerizations seem to us to require a radical
cation–radical cation union.18
The classic synthesis of usnic acid by Barton26 exploited the one-
electron oxidant [K3Fe(CN)6] and was rationalized as proceeding
via the generation and coupling of delocalized phenoxy radicals
(the heterodimerization of resonance contributors).27 A more re-
cent demonstration of single electron transfer was described by
Baran27 in his direct indole and pyrrole coupling using copper(II) 2-
ethylhexanoate. Mechanistically, Baran favours a radical–radical (or
radical anion–radical) dimerization assisted by chelation to the
copper reagent.27 Chelation could play a vital role in our FeCl3 ox-
idative couplings.
Steckhan28 in 1978 described extensive spectroelectro-
chemical studies in the stilbene field. The anodic oxidation of
4,40-dimethoxystilbene26 gave rise to tetrahydronapthalene and
tetrahydrofuran dimers. His detailed experiments (including ki-
netic evaluations) pointed to two pathways: radical cation–rad-
ical cation and radical cation–neutral molecule, with the former
predominating in the absence of methanol.28 Further examples of
stilbene radical dimerization may be seen in the work of Niwa29
and Lin.30–32 Nelson’s31 comprehensive discussion on the possi-
ble resonance forms for 4-methoxytriphenylaminium33 cation
radicals and the subsequent dimerization is worthy of careful
study.
Figure 2. Selected NOESY correlations chloroindolostilbene (39).
OMe
FeCl3
OMe
5
B
4
3
6
1
8
2
14
A
9
10
7
13
12
11
NH
NH
O
O
(22)
(41)
OMe
OMe
N
N
O
O
(35)
(42)
+
H
H
O
N
N
O
H
H
Figure 3. Selected NOESY correlations chloroindolostilbene (40).
OMe
OMe
(36)
2.4. Mechanistic considerations
Scheme 9.
The cyclization and dimerization pathways of the stilbene (22),
incorporating the 4-methoxysubstituent, must followa mechanistic
pathway similar to that we previously reported19 for the 3,4-dime-
thoxyacetamido stilbene (8).
This study like its predecessors (the construction of catechol
substituted bisindolines19 and the benzophenone radical anion
phenomenon20), fully vindicates radical cation–radical cation
dimerization as a reasonable mechanistic interpretation. Al-
though it is often said that radical coupling20 (or for that
matter radical cation coupling) is not a common reaction25
because of the low concentration of the reactive intermediate,
the phenomenon is not unknown.25 Radical–radical coupling
It is noteworthy that the bisindoline (36) (Scheme 9) is now the
major product in contrast to our experience with the dimerization
of 3,4-dimethoxystilbene (8) (Scheme 2).19
With 3-methoxyacetamidostilbene (21), the pathway to the
indoline is as shown in Scheme 10.
As previously described (Scheme 8), the 3,5-dimethoxy de-
rivative produced the aldehyde (37), dichlorostilbene (38) and
the unprecedented indolostilbene dimers (39) and (40). The
low yield of the ortho-acetamidobenzaldehyde (37) suggested
to us the minor pathway for its formation as described in
Scheme 11.34
has been observed for the benzyl and
a-nitromethyl radicals

K. Ahmad et al. / Tetrahedron 65 (2009) 1504–1516
1509
-H
OMe
OMe
FeCl3
H
O
NH
N
O
7
(21)
(43)
N
OMe
O
(44)
Fe2+
Fe3+
H
H
N
OMe
O
(34)
Scheme 10.
OMe
In the anodic chlorination of aromatics (30% CH2Cl2–MeCN
OMe
containing 0.1 M Et4NClO4 and 2,6-lutidine), CH2Cl2 is thought to
be the source of chlorine.36 This possibility cannot be ruled out
although given the number of potential sites for chlorination in
our molecules as opposed to those studied by Kam36 it would
appear to be less likely. For alternative chlorination pathways see
Schemes 13–15.
FeCl3
OMe
OMe
OMe
NH
NH
H
O
O
H
By contrast, Tanemura37 has described halogenation of aro-
matics by means of FeCl3 (10 mmol %) in CH3CN at 100 ꢁC. On
balance, an electrophilic chlorination pathway is to be preferred all
be it slightly favour electrophilic over free radical chlorination or
some combination of the two e.g.x (and Scheme 15). The regio-
specificity of our chlorinations would appear to favour an electro-
philic pathway.
O
(23)
(45)
Cl
Cl
O
OMe
Fe
O
NH
OMe
O
(46)
NH
OMe
OMe
O
H
O
(48)
2.5. Pathways leading to indolostilbene dimers (39) and
(40)dstereochemical considerations
OMe
O
NH
H
[O]
In accordance with our previous discussion, oxidation of stil-
bene (23) generates the radical cation (45) from which the indole
(58) is obtained (Scheme 16). We note at this point (to which we
will return, see Scheme 16) that in contrast to our experience with
the 3-methoxyacetamidostilbene (21) (Scheme 10), the 3,5-
O
(47)
O
O
H
COOH
notes‡34
H
+
NH
OMe
MeO
MeO
OMe
O
x
By analogy with N-chlorosuccinimide promoted electrophilic chlorination, N–H
(50)
(49)
(37)
to N–Cl conversion (free radical) would produce the N-chloroacetamidostilbene.
The electrophilic N–Cl would then be attacked by a second stilbene molecule.
Scheme 11.
OMe
OMe
Cl-Cl
An alternative pathway that involves the oxygen diradical
leading to the dioxetane (52) is shown in Scheme 12.35
The dichlorostilbene monomer (38) could be explained as the
product of an electrophilic substitution either via an in-
termolecular pathway (Scheme 13) or the intramolecular alter-
native (the azaquinodimethyde (55) intermediate) (Scheme 14).
Alternatively a radical cation pathway (Scheme 15) may be pro-
posed. Chlorination at C-4 in (23) appears to be prohibited for
steric reasons.
Schemes 13 and 14 depict an electrophilic chlorination mecha-
nism. An alternative mechanism that depends on prior generation
of the radical cation (45) and clearly implies the presence of chloro
radicals (ꢂCl) is shown in Scheme 15.
OMe
FeCl3
OMe
CH2Cl2
N
Cl
N
H
O
O
OMe
(23)
OMe
N
H
O
(38)
(39) and (40)

1510
K. Ahmad et al. / Tetrahedron 65 (2009) 1504–1516
OMe
OMe
O2
OMe
( O O )
OMe
NH
NH
O
O
OMe
O
O
(45)
(23)
OMe
O
NH
O
O
OMe
OMe
(51)
MeO
O O
NH
OMe
O
NH
OMe
OMe
O
via
NH
O
MeO
O
O
H
OMe
H
+
NH
NH
O
O
(52)
O
OMe
(See Scheme 11 above)
MeO
O
(49)
(37)
Scheme 12.
OMe
dimethoxy analogue appears to undergo the deprotonation nec-
essary for indole (58) formation, as opposed to the indoline. This
allows us to suggest another way of visualizing the chlorination
step. In this alternative, electrophilic chlorination proceeds in
contrast to the reactions in Schemes 13–15, via the indolenium
species (59), Scheme 16. Compound (61) is of course a racemate
(assuming restricted rotation).
The next scheme (Scheme 17) describes the pathway leading
from (61) to the indolostilbene. The alignment of the acet-
amidostilbene (23) with the chlorophenylindole (61) is guided, it
would seem, by hydrogen bonding. Removal of an electron from the
olefinic bond of (23) produces the radical cation (62), which attacks
the chlorophenylindole (61) as shown. Removal of an electron from
the methoxy lone pair sets up the para–para (or ortho–ortho)
OMe
FeCl3
OMe
OMe
Cl
Cl
NH
NH
O
(55)
OMe
O
(23)
OMe
Cl
OMe
OMe
Cl
H
NH
OMe
NH
O
(54)
Cl
O
(53)
OMe
Cl
OMe
NH
OMe
O
5
6
(38)
FeCl3
8
3
1
OMe
OMe
OMe
Scheme 14. Indirect pathway (intramolecular).
7
H
Cl
NH
Cl
NH
O
O
(53)
(23)
oxidative coupling. This accounts for the installation of the ster-
eogenic axes between rings B and D.
OMe
Cl
Cl
The H-bonded conformational isomer (one of the most stable ar-
rangements but see Fig. 5) (heat of formation of ꢃ134.29 kcal molꢃ1
)
OMe
OMe
with a 2.02 Å hydrogen bond length (Fig. 4) is in effect a pseudo-
macrocycle.
Cl
NH
NH
An alternative arrangement that has a different stilbene double
bond orientation and a H-bond length of 2.20 Å is the conforma-
O
O
(54)
(38)
tional isomer (Fig. 5) that has
a lower heat of formation
(ꢃ139.28 kcal molꢃ1). 3D-representation of these conformations
Scheme 13.

K. Ahmad et al. / Tetrahedron 65 (2009) 1504–1516
1511
OMe
CH3
O
OMe
H3C
O
CH3
O
[O]
OMe
H3C
D
OMe
O
A
C
N
H
O
D
Cl
NH
NH
CH3
A
B
C
N
Cl
H
O
O
O
H3C
O
H3C
H
(45)
O
CH3
(23)
B
H
Fe3+
H3C
Cl
H3C
N
OMe
Cl
O
H3C
H
OMe
O
E
(61)
H
N
O
E
-Fe2+
(62)
H3C
OMe
OMe
CH3
O
O
H
(23)
H3C
Cl
NH
NH
OCH3
O
H3CO
D
O
O
H
H
D
(54)
(56)
A
A
-H+
-H
C
N
H
O
C
N
H
O
OMe
Cl
CH3
B
CH3
Cl
B
Cl
H C
H
H3C
Cl
H
O
3
H3C
O
N
O
H
H3CO
H
OMe
N
O
E
H3C
H3C
E
NH
OCH3
O
(63)
O
H3CO
(64)
D
A
C
N
Scheme 15. The chloro-radical alternative.
O
CH3
H
B
Cl
H3C
O
was obtained by PM623/MOPAC200724 determinations and is pro-
vided in Figures 4 and 5.
H3CO
H
H
N
The formation of the second dimer (40) is the result of an anal-
ogous radical cation mediated ortho–para coupling (Scheme 18).
H3C
E
O
(64)
(39) scheme 8
OMe
14-membered pseudo-macrocycle
OMe
Scheme 17.
Fe3+
OMe
OMe
H
O
N
NH
Intramolecular hydrogen bonding is clearly impossible in this case.
The PM623/MOPAC200724 determined heat of formation (the low-
est) is ꢃ123.41 kcal molꢃ1 (Fig. 6). PM623/MOPAC200724 calcula-
tions indicate the most stable conformational isomers.
O
(45)
(23)
Cl+
OMe
OMe
OCH3
N
H
N
O
OCH3
(57)
O
(58)
Cl
OCH3
OCH3
OCH3
6
N
2
N
2
Cl
O
H
OCH3
OCH3
O
(60)
(59)
6
N
2
Cl
O
OCH3
(61)
Figure 4.
Scheme 16.

1512
K. Ahmad et al. / Tetrahedron 65 (2009) 1504–1516
By contrast, 3,5-substitution produces the indole (61).
OMe
OMe
8
2
OMe
7
OMe
Cl
NH
NH
O
O
(23)
(54)
OMe
OMe
6
4
2
N
indolostilbene dimers (39) and (40)
Cl
Figure 5.
O
(61)
This difference in behaviour may be explained by a ‘charge-
radical inversion’. In this process electrophilic chlorinationproduces
stilbene (54) and cyclization proceeds to produce chlorodimeth-
oxystilbene (61). The 2-chloro substituent in (54) (Scheme 19)
provides some degree of stabilization for the C-7 carbenium ion
through delocalization of Cl lone pairs. This is an alternative inter-
pretationdsee our previous hypothesis in Scheme 16.
CH3
O
O
CH
O
Cl
3 Fe3+
O
Cl
B
A
C
N
B
C
A
CH3
CH3
O
N
O
H3C
CH3
O
CH3
O
CH3
O
O
(61)
D
H3C
CH3
D
H
H
H
H
N
H3C
H
H
E
N
H3C
O
E
(23)
(65)
O
CH3
O
CH3
O
O
Cl
Cl
-H+
-H
B
A
C
B
C
N
A
CH3
N
O
CH3
O
O
H3C
CH3
H
CH3
O
H3C
O
H
O
CH3
O
D
CH3
D
H
H
H
H
H
H
N
H3C
E
N
H3C
E
O
O
(40)
(66)
Scheme 18.
Figure 6.
We can now return to the problem of indole formation. We
observed that the 3-methoxyacetamidostilbene (21) did not pro-
duce indole but indoline (34) on FeCl3 oxidation (see Scheme 6).
The indolyl radical (68) unlike its analogue (42) (Schemes 7 and
9) undergoes rapid loss of Hꢂ en route to indole formation. The
orientation of the chlorophenyl ring and the substitution pattern
sufficiently modifies indolyl radical (68) behaviour given, we pre-
sume, a more product-like transition state (early indole double
bond formation) between C-7 and C-8. The chlorophenyl ring’s
orientation and the electron withdrawing Cl substituent may also
contribute to inhibition of the bisindoline formation we observed in
Scheme 9. With regard to the failure of dichloro derivatives of (54)
to cyclize (see (38), Scheme 14), effective delocalization and hence
8
OMe
7
N
FeCl3"anh"
NH
OMe
O
O
(21)
(34)
stabilization of the
d
þ (p-orbital) with respect to a planar dichlor-
OMe
via
ophenyl ring is rendered difficult because of steric inhibition in-
volving the Cl group. In addition, the inductive withdrawal of
electrons by the two chlorines may render oxidative radical cation
formation more difficult.
NH
O
(43)

K. Ahmad et al. / Tetrahedron 65 (2009) 1504–1516
1513
Developing δ+ charge
4.2. Phase II: preparation of protected styrenes
4.2.1. Preparation of 3-methoxystyrene 27
H
Cl
Ar
Cl
Cl
Ar
8
OMe
OMe
OMe
OMe
8
H
+
Methyltriphenylphosphonium iodide (9.72 g, 0.0240 mol) was
stirred in dry DMF (20 mL) at 0 ꢁC for 0.5 h in a two-necked round
bottomed flask. Sodium hydride (3.30 g, 0.1375 mol) and
3-methoxybenzaldehyde 24 (3.0 mL, 0.025 mol) were then added.
The temperature was maintained between 0 and 4 ꢁC under ni-
trogen for 4 h. The mixture was allowed to stir at room temperature
overnight. When the product was obtained (based on the TLC), an
aqueous solution of NH4Cl (25 mL) was added. The mixture was
transferred to a separating funnel and extracted with ethyl acetate
(3ꢄ25 mL). The organic layer was then washed with distilled water
and dried over anhydrous sodium sulfate. The crude extract was
purified by column chromatography (hexane/ethyl acetate, 99.6:
0.4) to yield 3-methoxystyrene 2738 as a light yellowish oil
(1.4405 g, 43% yield).
H
H
Cl
OMe
OMe
8
2
OMe
7
OMe
Cl
NH
NH
O
(54)
O
(23)
OMe
Cl
4.2.1.1. 3-Methoxystyrene 2738. MS m/z: 134 [Mþ]; UV (MeOH) lmax
nm: 266, 221; IR nmax cmꢃ1: 1603, 1517. 1H NMR (400 MHz, CDCl3)
OMe
H
7
8
Cyclization
d
ppm: 7.23 (t, J¼8.0 Hz, H-5,1H), 6.99 (d, J¼8.0 Hz, H-6, 1H), 6.93 (t,
N
Cl
OMe
OMe
J¼2.0 Hz, H-2, 1H), 6.79 (dd, J¼2.4, 8.0 Hz, H-4, 1H), 6.67 (dd, J¼11.0,
17.6 Hz, H-7, 1H), 5.73 (d, J¼17.6 Hz, H-8a, 1H), 5.24 (d, J¼11.0 Hz, H-
O
NH
(68)
8b, 1H), 3.81 (s, OCH3, 3H). 13C NMR (100 MHz, CDCl3)
d ppm: 159.7
O
(67)
(C-3), 139.0 (C-1), 136.8 (C-7), 129.5 (C-5), 118.9 (C-6), 114.1 (C-8),
113.4 (C-4), 111.5 (C-2), 55.2 (OCH3).
OMe
OMe
8
7
N
Cl
4.2.2. Preparation of 4-methoxystyrene 28
Methyltriphenylphosphonium iodide (8.8409 g, 0.02186 mol)
was stirred in dry DMF (20 mL) at 0 ꢁC for 0.5 h in a two-necked
round bottomed flask. Sodium hydride (3.3349 g, 0.14 mol) and 4-
methoxybenzaldehyde 25 (2.75 mL, 0.02263 mol) were then
added. The temperature was maintained between 0 and 4 ꢁC under
nitrogen for 4 h. The mixture was allowed to stir at room temper-
ature overnight. When starting material was consumed (based on
the TLC), an aqueous solution of NH4Cl (25 mL) was added. The
mixture was transferred to a separating funnel and extracted with
ethyl acetate (3ꢄ25 mL). The organic layer was then washed with
distilled water and dried over anhydrous sodium sulfate. The crude
extract was purified by column chromatography (hexane/ethyl
acetate, 99:1) to yield 4-methoxystyrene 2838,39 (1.456 g, 48% yield)
in the form of a light yellowish oil.
O
(61)
Scheme 19.
3. Conclusions
This study culminates in the syntheses of a new class of axially
chiral (racemic) indolostilbenes by a FeCl3-promoted radical cation
mediated cascade reaction. Further developments in this field will
be reported in due course.
4. Experimental
4.1. Phase I: preparation of 2-iodophenyl-N-acetamide
4.2.2.1. 4-Methoxystyrene 2838,39. MS m/z: 134 [Mþ]; UV (MeOH)
lmax nm: 266, 221; IR nmax cmꢃ1: 1603, 1516. 1H NMR (400 MHz,
Iodoaniline (2.5014 g, 0.0114 mol) was dissolved in 20 mL dry
dimethylformamide (DMF) and reacted with 0.550 g (0.01375 mol)
sodium hydride (NaH) and acetic anhydride (5.435 mL). The mix-
ture was stirred overnight at room temperature under nitrogen.
After 24 h, saturated ammonium chloride (aqueous) was added to
the reaction mixture followed by extraction with ethyl acetate
(3ꢄ50 mL). The combined ethyl acetate extracts were then washed
six times with distilled water to remove DMF. The mixture was then
dried over anhydrous sodium sulfate. The crude product, obtained
after concentration under reduced pressure, was purified by col-
umn chromatography (hexane/ethyl acetate, 4:6) to give 70% yield
(2.083 g) of 2-iodophenyl-N-acetamide 30 (CAS No. 19591-17-4) as
light brown crystals.19
CDCl3)
d
ppm: 7.34 (d, J¼8.8 Hz, H-2, H-6,1H), 6.86 (d, J¼8.8 Hz, H-3,
H-5, 1H), 6.66 (dd, J¼10.7, 17.6 Hz, H-7, 1H), 5.61 (dd, J¼1.0, 17.6 Hz,
H-8a, 1H), 5.12 (dd, J¼1.0, 10.7 Hz, H-8b, 1H), 3.82 (s, OCH3, 3H). 13
C
NMR (100 MHz, CDCl3)
d ppm: 159.3 (C-4), 136.2 (C-7), 130.4 (C-1),
127.4 (C-2, C-6), 113.9 (C-8), 111.5 (C-3, C-5), 55.2 (OCH3).
4.2.3. Preparation of 3,5-dimethoxystyrene 29
Methyltriphenylphosphonium iodide (2.4264 g, 0.006 mol) was
stirred in dry DMF (20 mL) at 0 ꢁC for 0.5 h in a two-necked round
bottomed flask. Potassium tert-butoxide (0.6917 g, 0.006 mol) and
3,5-dimethoxybenzaldehyde 26 (1.000 g, 0.006 mol) were then
added. The temperature was maintained between 0 and 4 ꢁC under
nitrogen for 4 h. Then the mixture was allowed to stir at room
temperature overnight. When starting material was consumed
(based on the TLC), an aqueous solution of NH4Cl (25 mL) was
added. The mixture was transferred to a separating funnel and
extracted with ethyl acetate (3ꢄ25 mL). The organic layer was then
washed with distilled water and dried over anhydrous sodium
sulfate. The crude extract was purified by column chromatography
(hexane/ethyl acetate, 90:10), which afforded 2940 (0.443 g, 44%
yield) in the form of a light yellowish oil.
4.1.1. 2-Iodophenyl-N-acetamide 3019
MS m/z: 261 [Mþ]; UV (MeOH) lmax nm: 223; IR nmax cmꢃ1: 3270,
1660. 1H NMR (400 MHz, CDCl3)
d
ppm: 8.18 (d, J¼8.0 Hz, H-14, 1H),
7.75 (d, J¼8.0 Hz, H-11,1H), 7.39 (br s, NH,1H), 7.32 (d, J¼7.3 Hz, H-13,
1H), 6.82 (d, J¼7.3 Hz, H-12, 1H), 2.22 (s, CH3, 3H). 13C NMR
(100 MHz, CDCl3)
d ppm: 168.2 (C-15), 138.7 (C-14), 138.1 (C-10),
129.1 (C-12), 126.0 (C-13), 122.2 (C-11), 90.2 (C-9), 24.7 (C-16).

1514
K. Ahmad et al. / Tetrahedron 65 (2009) 1504–1516
4.2.3.1. 3,5-Dimethoxystyrene 2940. MS m/z: 164 [Mþ]; UV (MeOH)
lmax nm: 266, 221; IR nmax cmꢃ1: 1603, 1516. 1H NMR (400 MHz,
a 48% yield of 3-methoxystilbene 22 (0.3649 g) as amorphous
white solid and 4% of its isomer 32 (30 mg) as brownish oil.
CDCl3)
d
ppm: 6.68 (dd, J¼10.8, 17.6 Hz, H-7, 1H), 6.61 (d, J¼2.0 Hz,
H-2, H-6, 2H), 6.43 (d, J¼2.0 Hz, H-4, 1H), 5.77 (d, J¼17.6 Hz, H-8a,
4.3.2.1. 4-Methoxystilbene (22). HRESIMS m/z: 268.1335 ([MþH]þ;
calcd for C17H18NO2, 268.1338); UV (MeOH) lmax nm: 306, 220, 200;
IR nmax cmꢃ1: 3007,1737,1662, 1034, 770. 1H NMR (400 MHz, CDCl3)
1H), 5.28 (d, J¼10.8 Hz, H-8b, 1H), 3.82 (s, 2ꢄOCH3, 6H). 13C NMR
(100 MHz, CDCl3)
d ppm: 160.8 (C-3, C-5), 139.4 (C-1), 136.7 (C-7),
114.0 (C-8), 104.1 (C-2, C-6), 99.8 (C-4), 55.0 (2ꢄOCH3).
d
ppm: 7.72 (d, J¼8.0 Hz, H-11, 1H), 7.49 (d, J¼8.0 Hz, H-14, 1H), 7.48
(br s, NH, 1H), 7.42 (d, J¼9.0 Hz, H-2, H-6, 2H), 7.22 (t, J¼8.0 Hz, H-
12, 1H), 7.14 (t, J¼8.0 Hz, H-13, 1H), 6.98 (d, J¼16.1 Hz, H-7, 1H), 6.91
(d, J¼16.1 Hz, H-8, 1H), 6.89 (d, J¼9.0 Hz, H-3, H-5, 2H), 3.82 (s,
4.3. Phase III: synthesis of stilbenes
OCH3, 3H), 2.16 (s, CH3, 3H). 13C NMR (100 MHz, CDCl3)
d ppm:
4.3.1. Synthesis of 3-methoxystilbene (21)
168.8 (C-15), 159.5 (C-4), 134.4 (C-10), 131.6 (C-7), 130.7 (C-9), 129.8
(C-1), 127.9 (C-2, C-6), 127.8 (C-12), 126.4 (C-14), 125.5 (C-13), 124.4
(C-11), 121.2 (C-8), 114.1 (C-3, C-5), 55.3 (OCH3), 24.1 (C-16).
2-Iodophenyl-N-acetamide 30 (1.2046 g, 4.62 mmol) was dis-
solved in 10 mL dry DMF in a clean dry two-necked round bot-
tomed flask. The solution was heated to 120 ꢁC and stirred under
nitrogen. Palladium(II) acetate (0.023 g, 0.1025 mmol) was added to
the solution followed by triethylamine (2.6 mL, 0.187 mmol) and 3-
methoxystyrene 27 (0.6216 g, 4.64 mmol). The mixture was
refluxed under nitrogen for 48 h. After this period, the reaction
mixture was filtered and saturated aqueous sodium chloride
(25 mL) added. The mixture was then extracted with ethyl acetate
(3ꢄ25 mL) and the combined extracts were dried over anhydrous
sodium sulfate. Finally the crude extract was purified by column
chromatography (hexane/ethyl acetate, 50:50) to give 3-methoxy-
stilbene 21 (0.5923 g, 48%) as amorphous white solid and its isomer
31 (62 mg, 5%) as a brownish oil.
4.3.2.2. N-{2-[1-(4-Methoxyphenyl)vinyl]phenyl}acetamide
(32).
HRESIMS m/z: 268.1324 ([MþH]þ; calcd for C17H18NO2, 268.1338);
UV (MeOH) lmax nm: 302, 270, 202; IR nmax cmꢃ1: 3300, 2841, 1737,
1673, 1032, 753. 1H NMR (400 MHz, CDCl3)
d ppm: 8.17 (d,
J¼8.0 Hz, H-11, 1H), 7.36 (t, J¼8.0 Hz, H-12, 1H), 7.27 (d, J¼8.0 Hz,
H-14, 1H), 7.26 (d, J¼9.0 Hz, H-2, H-6, 2H), 7.15 (t, J¼8.0 Hz, H-13,
1H), 7.09 (br s, NH, 1H), 6.86 (d, J¼9.0 Hz, H-3, H-5, 2H), 5.78 (s, H-
8a, 1H), 5.25 (s, H-8b, 1H), 3.80 (s, OCH3, 3H), 1.84 (s, CH3, 3H). 13
C
NMR (100 MHz, CDCl3)
d ppm: 168.3 (C-15), 160.0 (C-4), 145.6 (C-
7), 135.3 (C-10), 132.1 (C-9), 131.8 (C-1), 130.3 (C-14), 128.7 (C-12),
127.9 (C-2, C-6), 124.3 (C-13), 124.3 (C-13), 121.7 (C-11), 115.4 (C-8),
114.2 (C-3, C-5), 55.4 (OCH3), 24.5 (C-16).
4.3.1.1. 3-Methoxystilbene (21). HRESIMS m/z: 268.1334 ([MþH]þ;
calcd for C17H18NO2, 268.1338); UV (MeOH) lmax nm: 300, 240, 203;
IR nmax cmꢃ1: 3040, 1650, 1219, 773. 1H NMR (400 MHz, CDCl3)
4.3.3. Synthesis of 3,5-dimethoxystilbene (23)
2-Iodophenyl-N-acetamide 30 (1.02511 g, 3.93 mmol) was dis-
solved in 10 mL dry DMF in a clean dry two-necked round bot-
tomed flask. The solution was heated to 120 ꢁC and allowed to stir
under nitrogen. Palladium acetate (16.5 mg, 0.0735 mmol) was
added to the solution followed by triethylamine (1.938 mL,
0.139 mmol) and 3,5-dimethoxystyrene 29 (0.7817 g, 4.77 mmol).
The mixture was refluxed under nitrogen for 48 h. After this period,
the reaction mixture was then filtered and an aqueous solution of
sodium chloride (25 mL) was added. The mixture was then
extracted with ethyl acetate (3ꢄ25 mL) and the combined extracts
were dried over anhydrous sodium sulfate. Finally the crude extract
was purified by column chromatography (hexane/ethyl acetate,
40:60) to give 45% yield of 3,5-dimethoxystilbene 23 (0.52 g) as
amorphous white solid and 3% of its isomer 33 (35 mg) as
a brownish oil.
d
ppm: 7.76 (d, J¼8.0 Hz, H-11, 1H), 7.50 (d, J¼8.0 Hz, H-14, 1H), 7.27
(t, J¼8.0 Hz, H-12, 1H), 7.25 (t, J¼8.0 Hz, H-5, 1H), 7.16 (t, J¼8.0 Hz,
H-13, 1H), 7.10 (d, J¼16.1 Hz, H-8, 1H), 7.07 (d, J¼4.0 Hz, H-6, 1H),
7.01 (t, J¼4.0 Hz, H-2, 1H), 6.93 (d, J¼16.1 Hz, H-7, 1H), 6.83 (dd,
J¼2.4, 8.0 Hz, H-4, 1H), 3.82 (s, OCH3, 3H), 2.18 (s, CH3, 3H). 13C NMR
(100 MHz, CDCl3) d ppm: 168.6 (C-15),159.9 (C-3),138.4 (C-1),134.6
(C-10), 132.4 (C-7), 130.2 (C-9), 129.7 (C-5), 128.4 (C-12), 126.9 (C-
14), 125.6 (C-13), 124.3 (C-11), 123.8 (C-8), 119.3 (C-6), 113.4 (C-4),
112.3 (C-2), 55.3 (OCH3), 24.3 (C-16).
4.3.1.2. N-{2-[1-(3-Methoxyphenyl)vinyl]phenyl}acetamide
(31).
HRESIMS m/z: 268.1324 ([MþH]þ; calcd for C17H18NO2, 268.1338);
UV (MeOH) lmax nm: 290, 250, 210; IR nmax cmꢃ1: 3291, 1673, 1041,
752. 1H NMR (400 MHz, CDCl3)
d
ppm: 8.09 (d, J¼8.0 Hz, H-11, 1H),
7.33 (t, J¼8.0 Hz, H-12, 1H), 7.25 (d, J¼8.0 Hz, H-14, 1H), 7.23 (t,
J¼8.0 Hz, H-5, 1H), 7.13 (t, J¼8.0 Hz, H-13, 1H), 6.88 (d, J¼8.0 Hz, H-
6, 1H), 6.84 (d, J¼8.0 Hz, H-4, 1H), 6.81 (br s, H-2, 1H), 5.83 (s, H-8a,
1H), 5.34 (s, H-8b, 1H), 3.73 (s, OCH3, 3H), 1.78 (s, CH3, 3H). 13C
4.3.3.1. 3,5-Dimethoxystilbene (23). HRESIMS m/z: 298.1430
([MþH]þ; calcd for C18H20NO3, 298.1443); UV (MeOH) lmax nm:
305, 215; IR nmax cmꢃ1: 3262, 1654, 1153, 773. 1H NMR (400 MHz,
NMR (100 MHz, CDCl3)
d
ppm: 168.2 (C-15), 159.9 (C-3), 146.2 (C-
CDCl3)
d
ppm: 7.77 (d, J¼8.0 Hz, H-11, 1H), 7.49 (d, J¼8.0 Hz, H-14,
7), 140.9 (C-1), 135.1 (C-10), 132.0 (C-9), 130.3 (C-14), 129.9 (C-5),
128.8 (C-12), 124.4 (C-13), 122.0 (C-11), 119.0 (C-6), 117.6 (C-8),
113.9 (C-4), 112.2 (C-2), 55.3 (OCH3), 24.3 (C-16).
1H), 7.27 (t, J¼8.0 Hz, H-12, 1H), 7.20 (br s, NH, 1H), 7.15 (t, J¼8.0 Hz,
H-13, 1H), 7.08 (d, J¼16.1 Hz, H-8, 1H), 6.88 (d, J¼16.1 Hz, H-7, 1H),
6.63 (d, J¼2.2 Hz, H-2, H-6, 2H), 6.41 (t, J¼2.2 Hz, H4, 1H), 3.82 (s,
2ꢄOCH3, 6H), 2.19 (s, CH3, 3H). 13C NMR (100 MHz, CDCl3)
d ppm:
4.3.2. Synthesis of 4-methoxystilbene (22)
168.8 (C-15), 161.1 (C-3, C-5), 139.1 (C-1), 134.7 (C-10), 132.4 (C-7),
130.3 (C-9), 128.4 (C-12), 126.9 (C-14), 125.7 (C-13), 124.4 (C-11),
124.2 (C-8), 105.0 (C-2, C-6), 100.1 (C-4), 55.4 (C-3, C-5), 24.3 (C-16).
2-Iodophenyl-N-acetamide 30 (0.747 g, 2.86 mmol) was dis-
solved in 10 mL dry DMF in a clean dry two-necked round bot-
tomed flask. The solution was heated to 120 ꢁC and allowed to stir
under nitrogen. Palladium(II) acetate (0.0138 g, 0.06147 mmol) was
added to the solution followed by triethylamine (1.7 mL,
0.122 mmol) and 4-methoxystyrene 28 (0.4015 g, 3.00 mmol). The
mixture was refluxed under nitrogen for 48 h. After this period, the
reaction mixture was then filtered and an aqueous sodium chloride
solution (25 mL) was added. The mixture was then extracted with
ethyl acetate (3ꢄ25 mL) and the combined extracts were dried over
anhydrous sodium sulfate. Finally the crude extract was purified by
column chromatography (hexane/ethyl acetate, 50:50) to give
4.3.3.2. N-{2-[1-(3,5-Dimethoxyphenyl)vinyl]phenyl}acetamide (33).
HRESIMS m/z: 298.1426 ([MþH]þ; calcd for C18H20NO3, 298.1443);
UV (MeOH) lmax nm: 303, 210; IR nmax cmꢃ1: 3009, 1677, 1156, 752.
1H NMR (400 MHz, CDCl3)
d
ppm: 8.08 (d, J¼8.0 Hz, H-11, 1H), 7.33
(t, J¼8.0 Hz, H-12, 1H), 7.32 (d, J¼8.0 Hz, H-14, 1H), 7.12 (t, J¼8.0 Hz,
H-13, 1H), 6.99 (br, s, NH, 1H), 6.41 (d, J¼2.4 Hz, H-2, H-4, H-6, 3H),
5.81 (s, H-8a, 1H), 5.33 (s, H-8b, 1H), 3.71 (s, 2ꢄOCH3, 6H), 1.82 (s,
CH3, 3H). 13C NMR (100 MHz, CDCl3)
d ppm: 168.1 (C-15), 161.0 (C-3,
C-5), 146.3 (C-7), 141.6 (C-1), 135.1 (C-10), 131.8 (C-9), 130.1 (C-14),

K. Ahmad et al. / Tetrahedron 65 (2009) 1504–1516
1515
128.7 (C-12), 124.3 (C-13), 122.0 (C-11), 117.6 (C-8), 104.7 (C-2, C-6),
100.2 (C-4), 55.3 (2ꢄOCH3), 24.2 (C-16).
H-6, H-60, 4H), 4.66 (s, H-7, H-70, 2H), 3.69 (s, 2ꢄOCH3, 6H), 3.48 (s,
H-8, H-80, 2H), 1.87 (s, 2ꢄCH3, 6H). 13C NMR (100 MHz, CDCl3)
d
ppm: 169.8 (C-15, C-150), 159.1 (C-4, C-40), 143.9 (C-10, C-100),
4.4. Phase IV: ferric chloride oxidative coupling and
cyclization
133.9 (C-1, C-10), 130.1 (C-9, C-90), 129.4 (C-12, C-120), 125.7 (C-2,
C-20, C-6, C-60), 125.3 (C-14, C-140), 125.0 (C-13, C-130), 117.7 (C-11,
C-110), 114.5 (C-3, C-30, C-5, C-50), 64.2 (C-7, C-70), 56.8 (C-8, C-80),
55.3 (OCH3), 23.7 (C-16, C-160).
Acetamidostilbene 23 (0.2775 g, 0.9343 mmol) was dissolved in
10 mL dichloromethane. ‘Anhydrous’ FeCl3 (0.7578 g, 4.672 mmol)
was then added to the mixture under nitrogen. The mixture was
stirred for 7 h at room temperature and monitored by TLC. After the
consumption of the starting material, the reaction mixture was
diluted with an aqueous ammonium chloride solution and extrac-
ted with ethyl acetate (3ꢄ25 mL). The combined ethyl acetate ex-
tracts were dried over anhydrous sodium sulfate. The crude
product was finally purified by column chromatography (hexane/
ethyl acetate; 80:20, 70:40; toluene/ethyl acetate; 80:20 and
70:30), which afforded four compounds, 37,41 38, 39 and 40 in 2.4%
(12 mg), 8% (18 mg), 14% (18 mg) and 10% (13 mg) yields,
respectively.
The reaction described above was repeated on stilbenes 21
(0.0978 g, 36.629 mmol) and 22 (0.1089 g, 40.787 mmol). To each of
these stilbenes in 10 mL dichloromethane, anhydrous FeCl3
(0.2348 g, 1.4475 mmol and 0.3116 g, 1.921 mmol) was added, re-
spectively, which resulted in the formation of indoline 34 (6 mg, 6%,
hexane/ethyl acetate, 80:20), indoline 35 (18 mg, 16%, hexane/ethyl
acetate, 85:15) and bisindoline 36 (13 mg, 24%, hexane/ethyl
acetate, 80:20), respectively.
4.4.4. N-(2-Formylphenyl)acetamide (37)41
MS m/z: 163 [Mþ]; UV (MeOH) lmax nm: 223; IR nmax cmꢃ1
:
3270, 1660. 1H NMR (400 MHz, CDCl3)
d ppm: 11.11 (s, N-H, 1H),
9.90 (s, H-17, 1H), 8.71 (d, J¼8.7 Hz, H-11, 1H), 7.65 (dd, J¼1.8, 7.8 Hz,
H-14, 1H), 7.60 (t, J¼8.7 Hz, H-12, 1H), 7.21 (t, J¼7.8 Hz, H-13, 1H),
2.24 (s, CH3, 3H). 13C NMR (100 MHz, CDCl3)
d ppm: 195.7 (C-17),
169.8 (C-15), 141.0 (C-10), 136.3 (C-12), 136.2 (C-14), 123.0 (C-13),
121.6 (C-9), 119.9 (C-11), 25.5 (C-16).
4.4.5. N-{2-[(E)-2-(2,6-Dichloro-3,5-dimethoxyphenyl)-
ethenyl]phenyl}acetamide (38)
HRESIMS m/z: 388.0463 ([MþNa]þ; calcd for C18H17NO3NaCl2,
388.0483); UV (MeOH) lmax nm: 223; IR nmax cmꢃ1: 3475, 1738,
1213, 802, 747. 1H NMR (400 MHz, CDCl3)
d
ppm: 7.97 (d, J¼8.0 Hz,
H-11, 1H), 7.52 (d, J¼8.0 Hz, H-14, 1H), 7.31 (t, J¼8.0 Hz, H-12, 1H),
7.17 (t, J¼8.0 Hz, H-13, 1H), 7.09 (d, J¼17.0 Hz, H-8, 1H), 6.87 (d,
J¼17.0 Hz, H-7, 1H), 6.52 (s, H-4, 1H), 3.92 (s, 2ꢄOCH3, 6H), 2.18 (s,
CH3, 3H). 13C NMR (100 MHz, CDCl3)
d ppm: 168.6 (C-15), 154.7
(C-3, C-5), 136.1 (C-1), 135.2 (C-10), 132.9 (C-8), 129.2 (C-9), 129.0
(C-12), 127.4 (C-7, C-14), 125.2 (C-13), 123.1 (C-11), 114.0 (C-2, C-6),
96.4 (C-4), 56.7 (2ꢄOCH3), 24.3 (C-16).
4.4.1. 1-[2-(3-Methoxyphenyl)-2,3-dihydro-1H-indol-1-yl]-1-
ethanone (34)
HRESIMS m/z: 268.1325 ([MþH]þ; calcd for C17H18NO2,
4.4.6. N-(2-{(E)-2-[20-(1-Acetyl-1H-indol-2-yl)-30chloro-4,40,6,60-
tetramethoxy[1,10-biphenyl]-2-yl]ethenyl}phenyl)acetamide (39)
HRESIMS m/z: 648.1998 ([MþNa]þ; calcd for C36H33ClN2NaO6,
648.1998); UV (MeOH) lmax nm: 302, 270, 202; IR nmax cmꢃ1: 3378,
268.1338); UV (MeOH) lmax nm: 280, 252, 239, 213; IR nmax cmꢃ1
:
3001, 1662, 1049, 752. 1H NMR (400 MHz, CDCl3)
d ppm: 8.30 (d,
J¼8.0 Hz, H-11, 1H), 7.25 (t, J¼8.0 Hz, H-12, 1H), 7.22 (d, J¼8.0 Hz, H-
4, 1H), 7.12 (d, J¼8.0 Hz, H-14, 1H), 7.04 (t, J¼8.0 Hz, H-13, 1H), 6.78
(d, J¼8.0 Hz, H-6, 1H), 6.75 (t, J¼8.0 Hz, H-5, 1H), 6.70 (s, H-2, 1H),
2969,1738, 1218, 775. 1H NMR (400 MHz, CDCl3)
d ppm: 8.86 (s, NH,
1H), 8.03 (d, J¼8.2 Hz, H-110, 1H), 7.85 (d, J¼8.2 Hz, H-11, H-14, 2H),
7.39 (d, J¼8.2 Hz, H-140, 1H), 7.26 (t, J¼8.2 Hz, H-12, 1H), 7.21 (t,
J¼8.2 Hz, H-120, 1H), 7.16 (t, J¼8.2 Hz, H-130, 1H), 7.08 (t, J¼8.2 Hz,
H-13, 1H), 6.82 (d, J¼16.0 Hz, H-8, 1H), 6.72 (s, H-40, 1H), 6.65 (d,
J¼16.0 Hz, H-7, 1H), 6.48 (s, H-6, 1H), 6.42 (s, H-80, 1H), 6.08 (s, H-4,
1H), 3.99 (s, 50-OCH3, 3H), 3.85 (s, 30-OCH3, 3H), 3.67 (s, 5-OCH3,
3H), 3.59 (s, 3-OCH3, 3H), 2.36 (s, CH3, 3H), 1.88 (s, CH3, 3H). 13C
5.34 (d, J¼9.0 Hz, H-7, 1H), 3.80 (dd, J¼16.0, 9.0 Hz, H-8
b
, 1H), 3.67
, 1H), 2.05 (s, CH3, 3H).
ppm: 169.7 (C-15), 160.2 (C-3), 144.8
(s, OCH3, 3H), 2.98 (dd, J¼16.0, 2.0 Hz, H-8
a
13C NMR (100 MHz, CDCl3)
d
(C-10), 143.3 (C-1), 130.4 (C-4), 129.2 (C-9), 127.8 (C-12), 124.9 (C-
14), 124.1 (C-13), 117.3 (C-5), 117.0 (C-11), 112.7 (C-6), 111.0 (C-2),
63.5 (C-7), 55.2 (OCH3), 38.9 (C-8), 24.2 (C-16).
NMR (100 MHz, CDCl3) d
ppm: 172.3 (C-150), 169.7 (C-15), 160.2 (C-
4.4.2. 1-[2-(4-Methoxyphenyl)-2,3-dihydro-1H-indol-1-yl]-1-
ethanone (35)
5), 157.7 (C-3), 156.4 (C-30), 155.5 (C-50), 138.9 (C-1), 136.5 (C-100),
136.4 (C-70), 135.6 (C-10), 134.4 (C-10), 131.1 (C-7), 130.4 (C-9), 129.0
(C-90), 128.5 (C-12), 128.0 (C-8), 127.3 (C-14), 125.0 (C-13), 124.9 (C-
11), 124.8 (C-120), 123.6 (C-130), 120.6 (C-20), 120.4 (C-140), 116.1 (C-
2),115.8 (C-110), 115.7 (C-60),112.6 (C-80),102.5 (C-6), 98.1 (C-4), 97.5
(C-40), 56.6 (50-OCH3), 56.4 (30-OCH3), 55.4 (3-OCH3), 55.3 (5-
OCH3), 26.3 (C-160), 24.2 (C-16).
HRESIMS m/z: 268.1330 ([MþH]þ; calcd for C17H18NO2,
268.1338); UV (MeOH) lmax nm: 281, 252, 238, 213; IR nmax cmꢃ1
:
3002, 1663, 1049, 752. 1H NMR (400 MHz, CDCl3)
d ppm: 8.28 (d,
J¼8.0 Hz, H-11, 1H), 7.25 (t, J¼8.0 Hz, H-12, 1H), 7.10 (d, J¼8.0 Hz,
H-14, 1H), 7.05 (d, J¼8.0 Hz, H-2, H-6, 2H), 7.03 (t, J¼8.0 Hz, H-13,
1H), 6.80 (d, J¼8.0 Hz, H-3, H-5, 2H), 5.30 (d, J¼10.0 Hz, H-7, 1H),
3.75 (dd, J¼16.0, 10.0 Hz, H-8
J¼16.0, 2.0 Hz, H-8
CDCl3) ppm: 169.7 (C-15), 159.2 (C-4), 143.4 (C-10), 135.3 (C-1),
b
, 1H), 3.74 (s, OCH3, 3H), 2.92 (dd,
4.4.7. N-(2-{(E)-2-[20-(1-Acetyl-1H-indol-2-yl)-30chloro-2,40,6,60-
tetramethoxy[1,10-biphenyl]-4-yl]ethenyl}phenyl)acetamide (40)
HRESIMS m/z: 625.2111 ([MþH]þ; calcd for C36H34ClN2O6,
625.2105); UV (MeOH) lmax nm: 298, 240, 202; IR nmax cmꢃ1: 3675,
a
, 1H), 2.02 (s, CH3, 3H). 13C NMR (100 MHz,
d
129.3 (C-9), 127.8 (C-12), 126.2 (C-2, C-6), 125.0 (C-14), 124.1 (C-13),
117.1 (C-11), 114.5 (C-3, C-5), 63.2 (C-7), 55.4 (OCH3), 39.1 (C-8),
24.2 (C-16).
3016, 2970, 1738, 1217, 772. 1H NMR (400 MHz, CDCl3)
d ppm: 8.34
(d, J¼8.2 Hz, H-110, 1H), 7.76 (d, J¼7.8 Hz, H-11, 1H), 7.39 (d,
J¼8.2 Hz, H-140,1H), 7.37 (d, J¼7.8 Hz, H-14,1H), 7.25 (t, J¼7.8 Hz, H-
12,1H), 7.22 (t, J¼8.2 Hz, H-120, 1H), 7.19 (t, J¼8.2 Hz, H-130, 1H), 7.13
(t, J¼7.8 Hz, H-13, 1H), 6.96 (d, J¼16.0 Hz, H-8, 1H), 6.77 (d,
J¼16.0 Hz, H-7, 1H), 6.72 (s, H-40, 1H), 6.48 (s, H-2, H-6, 2H), 6.36 (s,
H-80, 1H), 4.00 (s, 30-OCH3, 3H), 3.78 (s, 3-OCH3, 3H), 3.74 (s, 50-
OCH3, 3H), 3.61 (s, 5-OCH3, 3H), 2.30 (s, CH3, 3H), 2.14 (s, CH3, 3H).
4.4.3. Bis-1-[2-(4-methoxyphenyl)-2,3-dihydro-1H-indol-1-yl]-1-
ethanone (36)
HRESIMS m/z: 533.2430 ([MþH]þ; calcd for C34H33N2O4,
533.2440); UV (MeOH) lmax nm: 282, 252, 239, 214; IR nmax cmꢃ1
:
1668, 1049, 752. 1H NMR (400 MHz, CDCl3)
d ppm: 8.45 (d,
J¼8.0 Hz, H-11, H-110, 2H), 7.46 (t, J¼8.0 Hz, H-12, H-120, 2H), 7.27 (d,
J¼8.0 Hz, H-14, H-140, 2H), 7.25 (t, J¼8.0 Hz, H-13, H-130, 2H), 6.66
(d, J¼9.0 Hz, H-3, H-30, H-5, H-50, 4H), 6.43 (d, J¼9.0 Hz, H-2, H-20,
13C NMR (100 MHz, CDCl3) ppm: 171.4 (C-150), 168.8 (C-15), 158.3
d
(C-50), 157.7 (C-5), 157.5 (C-3), 155.3 (C-30), 138.2 (C-1), 137.0 (C-100),
135.7 (C-70), 134.7 (C-10), 134.7 (C-10), 133.1 (C-7), 130.3 (C-9), 129.1

1516
K. Ahmad et al. / Tetrahedron 65 (2009) 1504–1516
(C-90), 128.5 (C-12), 127.1 (C-14), 125.6 (C-13), 124.7 (C-120), 124.2
(C-11), 123.9 (C-8), 123.2 (C-130), 120.2 (C-140), 118.9 (C-20), 117.0
(C-110), 115.6 (C-60), 113.3 (C-4), 111.4 (C-80), 102.6 (C-6), 102.0 (C-2),
97.7 (C-40), 56.6 (3-OCH3), 56.5 (30-OCH3), 55.8 (50-OCH3), 55.3 (5-
OCH3), 25.2 (C-160), 24.5 (C-16).
15. Perkins, J. R.; Carter, R. G. J. Am. Chem. Soc. 2007.
16. Baran, P. S.; Noah, Z. B. J. Am. Chem. Soc. 2006, 128, 3908–3909.
17. Dey, S.; Pal, C.; Nandi, D.; Giri, V. S.; Zaidlewicz, M.; Krzeminski, M.; Smentek, L.;
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Lett. 2008, 10, 1373–1376.
18. Thomas, N. F.; Lee, K. C.; Paraidathathu, T.; Weber, J. F. F.; Awang, K.; Rondeau,
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19. Thomas, N. F.; Velu, S. S.; Weber, J. F. F.; Lee, K. C.; Hadi, A. H. A.; Richomme, P.;
Rondeau, D.; Noorbatcha, I.; Awang, K. Tetrahedron 2004, 60, 11733–11742.
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Mukhtar, M. R.; Hadi, A. H. A. Heterocycles 2008, 75, 1097–1108.
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Acknowledgements
We gratefully acknowledge the financial support provided by
University of Malaya (Vote: P0188/2006A and PS142/2007B),
Academy of Sciences Malaysia for the SAGA Fund: 66-02-03-0036
and 06-02-03-0038 and finally the Ministry of Higher Education.
25. Fleming, I. Frontier Orbitals and Organic Chemical Reactions; John Wiley & Sons:
West Sussex, England, 1976.
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