Cyclization vs. cyclization/dimerization in o-amidostilbene radical cation cascade reactions: The amide question

Article abstract of DOI:10.3390/molecules16097267

The n-butyramido, isobutyramido, benzamido, and furancarboxamido functions profoundly modulate the electronics of the stilbene olefinic and NH groups and the corresponding radical cations in ways that influence the efficiency of the cyclization due presum

Full text of DOI:10.3390/molecules16097267

Molecules 2011, 16, 7267-7287; doi:10.3390/molecules16097267
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Cyclization vs. Cyclization/Dimerization in o-Amidostilbene
Radical Cation Cascade Reactions: The Amide Question
Chin Hui Kee 1, Azhar Ariffin 1, Khalijah Awang 1, Ibrahim Noorbatcha 2, Koichi Takeya 3,
Hiroshi Morita 4, Chuan Gee Lim 5 and Noel Francis Thomas 1,*
1
Department of Chemistry, Faculty of Science, University of Malaya, 50603 Kuala Lumpur,
Malaysia
2
Department of Biotechnology Engineering, Faculty of Engineering, International Islamic University
Malaysia, 53100 Kuala Lumpur, Malaysia
3
Department of Pharmacognosy, Tokyo University of Pharmaceutical and Life Science,
1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
4
Faculty of Pharmaceutical Sciences, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan
5
Environmental and Bioprocess Technology Centre, SIRIM Berhad, 40000 Shah Alam, Malaysia
* Author to whom correspondence should be addressed; E-Mail: noelfthomas@um.edu.my;
Tel.: +603-79674065; Fax: +603-79674193.
Received: 5 August 2011; in revised form: 16 August 2011/ Accepted: 17 August 2011 /
Published: 25 August 2011
Abstract: The n-butyramido, isobutyramido, benzamido, and furancarboxamido functions
profoundly modulate the electronics of the stilbene olefinic and NH groups and the
corresponding radical cations in ways that influence the efficiency of the cyclization due
presumably to conformational and stereoelectronic factors. For example, isobutyramido-
stilbene undergoes FeCl3 promoted cyclization to produce only indoline, while
n-butyramidostilbene, under the same conditions, produces both indoline and bisindoline.
Keywords: stilbene; indoline; bisindoline; FeCl3
1. Introduction
A large number of biologically active compounds incorporate indole and indoline moieties,
particularly those that possess C-2 phenyl or heteroaryl moieties [1]. A vast array of creative
approaches to the indoline ring system have been reported recently, for example the 1,6-H transfer

Molecules 2011, 16
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followed by the 5-exo-trigonal ring closure tactic that exploits o-nitrobenzaldehyde [2]; the 5-endo-
trigonal ring closure of N-(o-bromophenyl)ene carbamates [3]; intramolecular carbolithiation [4];
reduction of indoles [5] and the thermal reaction of N-allylaniline and various alkoxyamines [6].
Creative bisindoline construction is also increasing in importance as recent developments clearly
indicate. For example, the highly efficient successive amide transfer approach leading to C2 symmetric
bisindolines [7]; diaza-Cope rearrangement resulting in C3-C3’ bisisoindolines [8] and the
[CoCl(PPh3)3] mediated indolyl bromide homolyisis/dimerisation [9].
In 2004, we described the then unprecedented FeCl3-promoted acetamidostilbene radical cation 1*
cascade culminating in the indoline 3 and bisindoline 4a [10]. A subsequent X-ray analysis of the
bisindoline has shown that the correct structure should be the C2 symmetric dimer 4b (Scheme 1) [11].
Four years later, we published the unexpected discovery that benzophenone (2) was capable of
producing ca. a doubling of the yield of the indoline with concomittant suppression of bisindoline 4
formation (Scheme 1) [12]. The benzophenone was almost recovered always quantitatively. We
proposed a Fe3+ benzophenone ketyl radical/stilbene radical cation catalytic cycle in that paper.
Enhancement of indoline formation by an “internal agent” or via structural modification of the stilbene
starting material was not envisaged.
Scheme 1. Oxidative coupling of 3,4-dimethoxy-acetamido stilbene (1).
The transformation shown in Scheme 1 proceeds via the radical cation (1*) followed by cyclization
through the amidic NH to yield the indolyl radical and hence the products 3 and 4. One question
that we have not addressed is the relationship between the amide structure and the efficiency of
the cyclization.

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An n-butyramide (in place of the acetamide in Scheme 1) would be expected, on steric grounds, to
engage the C(7) benzylic cation with greater difficulty than stilbene 1. Cyclization (via FeCl3) in the
case of the isobutyramidostilbene would constitute an even greater steric impediment to indoline
formation. Would the furan carboxamido and benzamido moieties undergo cyclization with
comparable efficiency or are there delicate conformational factors at work here?
We reported last year full spectroscopic details of several novel stilbenes that were prepared by the
Heck procedure [13]. The amido NH in stilbene 6 is more shielded than 5 (Table 1), which suggests
that the amide in 6 should be somewhat more nucleophilic (under neutral or slightly acidic conditions).
On the other hand, the NMR spectra also reveal that the furancarboxamido stilbene 11 and the
benzamidostilbene 7 possess even more deshielded NHs compared to stilbenes 6 and 5. It could be
argued, all other things being equal, that this significant withdrawal of electron density away from the
amide NH could reduce the nucleophilicity of the amide group and thus adversely affect cyclization of
the radical cation, in contrast to the cyclization of 5 or 6. It is significant that Crich’s heterocyclization
of a non-oxidatively derived non-stilbene radical cation fails in the case of A but is successful in the
case of B (see Scheme 2). The different cyclization outcomes for A and B appear to be due to the
severely reduced nucleophilicity of the benzylaniline in A compared to B.
Scheme 2. Examples of Crich’s alkene radical cation cyclizations [14].
O
PhO P
PhO
NO2
O
Bu3SnH
AIBN,
Benzene
NHBn
50%
NHBn
NHBn
N
Bn
Example A
O
PhO P
PhO
NO2
O
Bu3SnH
H
AIBN,
Benzene
N
Bn
43%
NHBn
NHBn
Example B
Another interesting observation relates to the olefinic multiplets. For the furancarboxamido
stilbenes 9-12, the C(8)-H proton is more deshielded than the C(7)-H proton, the one noticeable
exception being stilbene 9, where the C(7)-H is significantly more deshielded. This might mean that
exposure of stilbene 9 to FeCl3 could produce a radical cation in which the positive charge was now at
C(8) rather than C(7) (in contrast to the usual pattern). The chemical shifts discussed above may be
depicted as shown in Table 1.

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Table 1. 1H-NMR [400MHz, δH (J, Hz)] of stilbenes 5-12 in CDCl3.
C(7)-H (J, Hz)
C(8)-H (J, Hz)
N-H (J, Hz)
Entry
1
Stilbene
OCH3
OCH3
7
6.85
6.95
7.56
8
O
N
H
5
6
2
3
6.90
6.93
6.97
7.04
7.31
8.03
7
4
5
6
6.91
7.40
7.02
6.97
7.29
7.22
7.21
8.25
8.17
8
H3CO
7
O
8
O
N
H
9
10
11
7
6.96
7.07
8.19

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Table 1. Cont.
8
7.00
7.09
8.17
12
In order to unveil structural (electronic) and possible conformational influences on our radical
cation cascade cyclization/dimerization, experiments were performed as described in the next section.
We included stilbene 9 in our study to investigate the possibility of mesomeric stabilization by the
ortho-methoxy substituent of the C(7) carbenium ion with the unpaired electron at C(8). Stilbene 10
was included to confirm an observation first reported in 2009 [15] where a meta-methoxy substituent
directs radical cation formation in a way that is opposite to that observed with a para-methoxy
substituent. We included stilbene 12 to examine the implications of having 4-methoxy substituent
(rather than 3,4-dimethoxy substitution) on the formation of the radical cation.
2. Results and Discussion
2.1. FeCl3 Promoted Syntheses of Indolines
Eight carboxamidostilbenes were constructed by the Heck protocol [13]. These stilbenes were then
subjected to our FeCl3 reaction conditions as shown below (Table 2). The resulting observations
demand a more complex explanation than we had anticipated based on previous experience [10].
Table 2. FeCl3 promoted syntheses of indolines and bisindolines.
Entry
1
Stilbene
Indoline (Yield)
Bisindoline (Yield)
OCH3
OCH3
7
8
O
N
H
5
6
14a (63%)
14b (6%)
OCH3
OCH3
N
O
2
-
15 (29%)

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Table 2. Cont.
3
-
-
7
16 (40%)
4
8
9
17 (21%)
18 (11%)
5
6
-
-
10
11
12
19 (38%)
20a (46%)
21a (21%)
7
8
20b (10%)
21b (12%)
Oxidation of the stilbene 5 with FeCl3 gave rise to indoline 14a (63%) and bisindoline 14b (6%) (in
the absence of benzophenone) via radical cation 13a (in contrast to the transformation in Scheme 1) an
unexpected result. We had previously reported that the 10-acetamido-4-methoxystilbene on exposure
to FeCl3 produced the bisindoline in 24% yield and the indoline in 16% yield [15]. This “4-methoxy
effect” is also seen in stilbene 12 (Entry 8, Table 2) where the proportion of bisindoline is significantly

Molecules 2011, 16
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increased. In the present study, replacement of butyramide (5) with isobutyrylamide (6) resulted in a
lowering of the yield of indoline 15 to 29%. Bisindoline formation was not observed, a result that is all
the more remarkable when compared to stilbene 12 (Entry 8, Table 2).
2.2. Effect of Amide Structure on the Radical Cyclization Leading to Indoline Formation
The very different behaviour of 5 and 6 on exposure to FeCl3 is readily explained by the early
transition state pictures I and II (Scheme 3) where the increase steric bulk of the isobutyrylamide
renders cyclization more difficult, hence the lower yield of 15 (29%). A similar explanation would
account for the low yield of indoline 17 from stilbene 8.
Scheme 3. Early transition state pictures for radical cyclization leading to indoline formation.
With respect to stilbenes 7 and 11, cyclization proceeding via radical cation 13a leading to 16 and
20a respectively, is slightly more favoured for stilbene 11 (furancarboxamide) than for stilbene 7
(benzamide) on stereoelectronic grounds [16], as the transition state pictures III and IV demonstrate
(Scheme 3). We believe that the coplanar orientation of furan and carbonyl groups means that
cyclization experiences less resistance in the case of 11. This coplanarity seems less likely for stilbene
7 (see III and IV, Scheme 3). The stereoelectronic factor also helps to explain the fact that bisindoline
formation (20b and 21b) is observed with stilbenes 11 and 12 but not with stilbene 7 (see discussion in

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Section 2.3 and Scheme 10). In the case of stilbene 9, cyclization is made more difficult (and hence the
significantly reduced yield) because it must proceed via radical cation 13b. It is noteworthy that the
C(8) carbon of 9, in this special case, is more shielded than the C(7) (compared to the other
furancarboxamidostilbenes) because of the directional nature and electron withdrawing tendency of the
2-methoxy lone electron pairs [13]. In the case of stilbene 10, radical cation 13b is again the crucial
intermediate (see Ref. [10] for the similar case of 10-acetamido-3-methoxystilbene) [15]. It may be
worth emphasising that the FeCl3 oxidation of stilbenes 9 and 10 proceed via a different radical cations
(analogous to 13b) whereas stilbene 12 proceeds via radical cation 13a (see Table 2). This is because
stilbene 12 on oxidation produces a radical cation in which the positive charge is at C(7) as a result of
mesomeric stabilization from a para-methoxy substituent. By contrast in stilbene 10 where the
methoxy group is meta, the position of the positive charge changes to C(8) because of superior
mesomeric stabilization which comes from the amide nitrogen lone pair in the ortho position (i.e., a
C-10 amido group). In the case of stilbene 9 where mesomeric stabilization of a C(7) carbocation (in
the radical cation) might have been expected, we observed a unique ortho-methoxy lone pair effect
which dramatically reverses the position of radical and positive charge. The positive charge is now at
C(8) rather than at C(7). This electronic factor is seen even in the NMR of the stilbenes (see Table 1).
Notice that remarkably in stilbene 9 the C(7) proton is substantially more deshielded than C(8). The
phenomena described above underpin the mechanistic interpretation discussed in Schemes 11 to 13. It
is significant that in contrast to our first report (Scheme 1) where the bisindoline 4A was presented in
the meso arrangement, in this report all bisindolines are designated as racemic. The reason for this is
explained in Section 2.3.
2.3. Dimerization Pathways and PM6 Calculations for the Minor Products
The basis for the observed stereoselectivity for each of the bisindoline minor products (14b, 20b
and 21b) is explained below. There are four diastereomeric possibilities. The PM6 calculations
(MOPAC2009) are provided in Tables 3-5.
Table 3. PM6 calculation for 14b.
Symmetry Heat of Formation
Stereoisomer
H2-H3 H2*-H3* H3-H3*
element
(kcal/mol)
C2 axis
−154.22
19.15
346.41
250.79
156.58
171.63
14b-A
14b-B
C2 axis
−162.78
250.79

Molecules 2011, 16
7275
Table 3. Cont.
−163.46
Plane
(Meso)
240.71
310.52
111.62
324.60
298.43
24.01
14b-C
Plane
(Meso)
−133.96
14b-D
Table 4. PM6 calculation for 20b.
Symmetry Heat of Formation
Stereoisomer
H2-H3 H2*-H3* H3-H3*
element
(kcal/mol)
C2 axis
−116.85
348.44
241.19
−111.73
352.90
348.44
241.17
119.11
26.21
155.06
120.43
61.86
20b-A
20b-B
20b-C
20b-D
C2 axis
−123.76
−126.41
−115.76
Plane
(Meso)
Plane
(Meso)
65.36

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Table 5. PM6 calculation for 21b.
Symmetry Heat of Formation
Stereoisomer
H2-H3
H2*-H3*
H3-H3*
element
(kcal/mol)
C2 axis
−48.59
340.27
340.27
115.07
172.63
298.43
69.76
21b-A
21b-B
21b-C
21b-D
C2 axis
−55.04
−56.28
−43.83
247.75
240.70
12.48
247.23
111.61
26.33
Plane
(Meso)
Plane
(Meso)
Scheme 4. Dimerization pathways leading the stereoisomers (±)14b-A, (±)20b-A and (±)21b-A.

Molecules 2011, 16
Scheme 5. Dimerization pathways leading the stereoisomers (±)14b-B, (±)20b-B and (±)21b-B.
7277
Scheme 6. Dimerization pathways leading the stereoisomers 14b-C, 20b-C and 21b-C.
H
OMe
N
H
R1
R2
H
O
H
2
H
R1
H
OMe
R2
N
N
R1
O
O
OMe
H
R2
2
H
N
H
H
H
R1
O
OMe
R2
Indolyl radical
23 : R1=n-propyl, R2=OMe
25 : R1=2-furanyl, R2=OMe
26 : R1=2-furanyl, R2=H
N
N
H
O
OMe MeO
R1
O
R1
R2
R2
Symmetry plane
Meso
14b-C : R1=n-propyl, R2=OMe
20b-C : R1=2-furanyl, R2=OMe
21b-C : R1=2-furanyl, R2=H
Scheme 7. Dimerization pathways leading the stereoisomers 14b-D, 20b-D and 21b-D.

Molecules 2011, 16
7278
These calculations (the thermodynamic argument) lead to the same conclusions as the mechanistic
analysis of dimerization pathways for the various indolyl radicals (the kinetic argument) see Scheme 4
to Scheme 7.
Scheme 8. Another perspective on dimerization pathways leading to the stereoisomer
14b-C, 20b-C and 21b-C.
The arguments that distinguish (±)14b-B and meso 14b-C (Table 3) are more finely balanced as
these two diastereoisomers are closer in energy (-162.78 and -163.46 kcal/mol). This closeness is also
reflected in the fact that in examining dimerization pathways for the indolyl radicals (Schemes 5 and
6), dimerization appears to be equally feasible in both cases. In comparing the early transition state
pictures in Schemes 8 and 9, the approach of indolyl radicals in Scheme 9 would have the effect of
keeping the “phenyl” region of the indoline rings as far apart as posible, as well as possibly
minimizing interactions between the amide moieties (see Scheme 8). This would appear to lead to the
conclusion that the correct stereostructures are (±)14b-B, (±)20b-B and (±)21b-B respectively (see
Scheme 9 and Table 2).
Scheme 9. Another perspective on dimerization pathways leading to the stereoisomer
(±)14b-B, (±)20b-B and (±)21b-B.
MeO
R2
H
H
N
H
O
H
R1
N
N
H
O
H
O
H
R1
O
OMe MeO
Racemic
R1
R1
R2
R2
N
H
(±)14b-B : R1=n-propyl, R2=OMe
(±)20b-B : R1=2-furanyl, R2=OMe
(±)21b-B : R1=2-furanyl, R2=H
R2
OMe
Indolyl radical
23 : R1=n-propyl, R2=OMe
25 : R1=2-furanyl, R2=OMe
26 : R1=2-furanyl, R2=H

Molecules 2011, 16
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One additional point of some importance relates to the PM6 calculations. Although (±)14b-B is
slightly higher in energy, the dihedral angles in this case are consistent with the symmetrical nature of
the molecule (Table 3) and is therefore to be preferred over the meso form 14b-C (Scheme 8). These
arguments fully justify the exploitation of PM6 calculations for the elucidation of stereochemical
problems inherent in reactions of this type.
Exactly analogous arguments can be used to justify the presentation of bisindolines 20b and 21b
which carry furancarboxamide moieties, as their racemic modifications (Tables 2, 4 and 5). For 20b-A,
20b-D, 21b-A and 21b-D are readily ruled out on energetic grounds and this thermodynamic argument
is again amply vindicated by the dimerization pathways for the indolyl radicals. Consideration of
indolyl radical dimerization pathways and thermodynamic arguments favour formation of (±)20b-B
and 20b-C (Schemes 5 and 6) and (±)21b-B and 21b-C (Schemes 5 and 6).
Scheme 10. Effect of amide structure on the dimerization of indolyl radical 22-26 leading
to bisindoline formation.

Molecules 2011, 16
7280
However careful scrutiny of the dimerization pathways as previously described (Schemes 9 and 10)
inevitably leads to the conclusion that the correct stereostructures are (±)20b-B and (±)21b-B. These
conclusion are supported by the X-ray data for the bisindoline depicted in Scheme 1 and confirm that
the bisindoline has the structure (±)4b (and not 4a as originally reported by us).
With respect to bisindoline formation, it would seem that in the presumably early transition states
involving the corresponding indolyl radicals 22 and 23 (Scheme 10), the methyl group of the isobutryl
moiety in 22 is able to block dimerization so that no bisindoline is obtained. By contrast indolyl radical
23 by virtue of possessing an n-butyrylamido group has only the much smaller H in that position and
dimerization is not impeded.
Scheme 11. The ortho-methoxy effect.
In the case of the 9 (Scheme 11), the attempted dimerization fails in spite of the fact that one would
have expected a radical cation intermediate analogous to 13a (Table 2). The reduced nucleophilicity of
this NH and the reduced electron density in the olefinic bond may well account for the low yield of the
indoline 18 (Scheme 10) (see our previous discussion on NMR spectroscopic characteristics for the
eight stilbenes) [13].
Scheme 12. Mechanistic interpretation I.
OCH3
OCH3
OCH3
8
1
7
N H
FeCl2
FeCl3
Cl
2
+
/
2
N H
N H
Cl Cl
O
O
O
O
O
O
10
1
FeCl2
FeCl3
2Cl2
+
/
OCH3
OCH3
N Cl
N
O
O
O
O
19
H
OCH3
Fe3+
N
Fe2+
OCH3
O
N
O
O
O
X
No dimerization

Molecules 2011, 16
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It is interesting to note that in 9 the C7-H (δ 7.40) is more deshielded than the C8-H (δ 7.29) in
contrast to the other furan carboxamidostilbenes 10, 11 and 12. This would have the effect of reversing
the position of the radical and cation (formed after oxidation) where the removal of an electron from
C8 would be preferred.
The failure of dimerization in the case of 10 is due to the formation of the radical cation analogous
to 13b (Table 2) and Scheme 12. The formation of this radical cation is related to the absence of a
paramethoxy group (in 10) that could stabilize a C7 cation and as a result the cation is formed
preferentially at C8. Ring closure proceeds possibly via homolysis of an N-Cl bond leading to the
nitrogen centred radical as shown in Scheme 12 or alternatively, via the Fe3+ azaenolate (27).
Reduction of the indolyl cation (whose formation renders dimerization impossible) to the indolyl
radical cation and H• uptake leads to the indoline. This pathway is shown in Scheme 13.
Scheme 13. Mechanistic interpretation II.
OCH3
OCH3
H
H
N
8
H
Fe3+
FeCl3
CH2Cl2
7
Fe2+
OCH3
+H
OCH3
O Fe3+
N
N H
O
N
O
O
O
19
O
O
O
10
27
3. Experimental
3.1. General
Unless otherwise noted, materials were purchased from commercial suppliers and used without
purification. THF was freshly distilled from calcium hydride. DMF was dried over 4Å molecular
sieves (Sigma-Aldrich) prior to use. Column chromatography was performed using Merck silica gel
(0.040–0.063 mm). For thin layer chromatography, Merck TLC aluminum sheets (silica gel 60 F254)
were used; centrifugal chromatography, Merck silica gel 60 PF254 containing gypsum were used.
Infrared spectra were recorded on a Perkin Elmer FTIR Spectrum RX-1 spectrometer at wavenumbers
from 4000–400 cm−1. Nuclear magnetic resonance (NMR) spectra were obtained on a JEOL JNM-LA
400 and JEOL ECA-400 instrument. Spectra are reported in units of ppm on the scale, relative to
chloroform and the coupling constants are given in Hz. Ultraviolet (UV) spectra were recorded from
190–400 nm, in methanol, on a Shimadzu UV-Visible Spectrophotometer 1650. Mass spectra were
measured using an Agilent 6530 Accurate-Mass Q-TOF LC/MS system. Detailed experimental
procedures for the synthesis of stilbenes 7-14 and starting materials have been reported elsewhere [13].
3.2. General Procedure for the FeCl3 Oxidative Coupling
Stilbene (1 equiv) was dissolved in CH2Cl2 (25 mL). ‘Anhydrous’ FeCl3 (2-3 equiv) was added to
the mixture under nitrogen. The mixture was stirred at room temperature and monitored by TLC. After
the consumption of the stilbene, the mixture was diluted with aqueous ammonium chloride solution
and extracted with ethyl acetate (3 × 25 mL). The combined organic fractions were dried over

Molecules 2011, 16
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anhydrous sodium sulphate. Purification of the crude product by column chromatography afforded the
desired products. Semi-empirical molecular orbital calculations were performed to optimise the
geometry of the molecules using the PM6 method [17] included in MOPAC2009 [18].
3.2.1. 1-(2-(3,4-Dimethoxyphenyl)indolin-1-yl)butan-1-one (14a)
Yield 0.30 g (63%); νmax/cm−1 (NaCl): 2961, 1659, 1516, 1480, 1463, 1401, 1262, 1139, 1027, 754;
1
λmax (MeOH)/nm: 237, 253, 281; H-NMR (400 MHz; CDCl3) δH 8.33 (d, J = 7.6 Hz, H-8, 1H), 7.24
(t, J = 7.8 Hz, H-7, 1H), 7.12 (d, J = 6.4 Hz, H-5, 1H), 7.03 (t, J = 7.6 Hz, H-6, 1H) , 6.76 (d, J = 8.2
Hz, H-5', 1H), 6.68 (d, J = 8.2 Hz, H-6', 1H), 6.64 (s, H-2', 1H), 5.36 (d, J = 7.3 Hz, H-2, 1H), 3.83 (s,
OCH3, 3H), 3.77 (s, OCH3, 3α, 4H), 2.94 (d, J = 16.5 Hz, H-3β, 1H), 2.09-2.36 (m, H-2", CH2, 2H),
1.67 (s, H-3", CH2, 2H), 0.84 (s, H-4", CH3, 3H); 13C-NMR (100 MHz; CDCl3) δC 172.0 (C-1"),
149.5 (C-3'), 148.5 (C-4'), 143.5 (C-9), 136.0 (C-1'), 129.3 (C-4), 127.8 (C-7), 125.1 (C-5), 124.0 (C-
6), 117.2 (C-6'), 117.0 (C-8), 111.4 (C-5'), 108.0 (C-2'), 62.6 (C-2), 56.0 (OCH3), 55.9 (OCH3), 39.2
(CH2, C-3), 37.5 (CH2, C-2"), 18.2 (CH2, C-3"), 13.9 (CH3, C-4"); HRMS (+ESI) [M+H]+: 326.1754,
C20H24NO3 requires 326.1756.
3.2.2. 1,1'-2,2'- bis(3,4-Dimethoxyphenyl)- 3,3'- biindoline-1,1'-diyl dibutan-1-one ((±)14b)
Yield 0.06 g (6%); νmax/cm−1 (NaCl): 2961, 1666, 1516, 1462, 1398, 1255, 1140, 1027, 755 ; λmax
(MeOH)/nm: 237, 249, 281; 1H-NMR (400 MHz; CDCl3) δH 8.53 (d, J = 8.2 Hz, H-8, H-8*, 2H), 7.46
(t, J = 8.0 Hz, H-7, H-7*, 2H), 7.30 (d, J = 7.3 Hz, H-5, H-5*, 2H), 7.21 (t, J = 7.3 Hz, H-6, H-6*, 2H),
6.61 (d, J = 8.7 Hz, H-5', H-5'*, 2H), 6.21 (d, J = 7.8 Hz, H-6', H-6'*, 2H), 5.81 (s, H-2', H-2'*, 2H),
4.70 (s, H-2, H-2*, CH, 2H), 3.77 (s, 2 X OCH3, 6H), 3.61 (s, 2 X OCH3, 6H), 3.52 (s, H-3, H-3*, CH,
2H), 1.83-2.12 (m, H-2", H-2"*, CH2, 4H), 1.45-1.56 (m, H-3", H-3"*, CH2, 4H), 0.76 (t, J = 7.6 Hz,
H-4", H-4"*, CH3, 6H); 13C-NMR (100 MHz; CDCl3) δC 172.4 (C-1", C-1"*), 149.4 (C-3', C-3'*),
148.3 (C-4', C-4'*), 144.3 (C-9, C-9*), 134.7 (C-1', C-1'*), 130.0 (C-4, C-4*), 129.4 (C-7, C-7*), 125.3
(C-5, C-5*), 124.5 (C-6, C-6*), 117.7 (C-8, C-8*), 115.9 (C-6', C-6'*), 111.3 (C-5', C-5'*), 107.5 (C-2',
C-2'*), 63.4 (C-2, C-2*), 56.9 (C-3, C-3*), 55.9 (2 X OCH3), 55.8 (2 X OCH3), 37.1 (CH2, C-2",
C-2"*), 17.7 (CH2, C-3", C-3"*), 13.8 (CH3, C-4", C-4"*); HRMS (+ESI) [M+H]+: 649.3276,
C40H44N2O6 requires 649.3278.
3.2.3. 1-(2-(3,4-dimethoxyphenyl)indolin-1-yl)-2-methylpropan-1-one (15)
Yield 0.13 g (29%); νmax/cm−1 (NaCl): 2964, 1653, 1516, 1479, 1263, 1138, 1026, 755; λmax
1
(MeOH)/nm: 210, 238, 253, 281; H-NMR (400 MHz; CDCl3) δH 8.36 (d, J = 5.5 Hz, H-8, 1H), 7.24
(t, J = 7.8 Hz, H-7, 1H), 7.11 (d, J = 7.3 Hz, H-5, 1H), 7.02 (t, J = 7.8 Hz, H-6, 1H) , 6.75 (d, J = 8.2
Hz, H-5', 1H), 6.68 (dd, J = 8.2 Hz, 1.8 Hz, H-6', 1H), 6.64 (s, H-2', 1H), 5.43 (d, J = 8.7 Hz, H-2, 1H),
3.82 (s, OCH3, 3H), 3.77 (s, OCH3, H-3α, 4H), 2.96 (d, J = 16.0, H-3β, 1H), 2.61 (s, H-2", 1H), 1.20
(d, J = 6.9 Hz, H-4", 3H), 0.87 (s, H-3", 1H); 13C-NMR (100 MHz; CDCl3) δC 177.0 (C-1"),
149.5 (C-3'), 148.5 (C-4'), 143.5 (C-9), 136.3 (C-1'), 129.4 (C-4), 127.8 (C-7), 125.0 (C-5), 124.1 (C-6),
117.3 (C-8), 117.1 (C-6'), 111.4 (C-5'), 108.0 (C-2'), 62.4 (C-2), 56.0 (2 x OCH3), 39.1 (CH2, C-3),

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33.4 (CH, C-2"), 20.3 (CH3, C-4"), 19.1 (CH3, C-3"); HRMS (+ESI) [M+H]+: 326.1760, C20H24NO3
requires 326.1751.
3.2.4. (2-(3,4-Dimethoxyphenyl)indolin-1-yl)(phenyl)methanone (16)
Yield 0.21 g (40%); νmax/cm−1 (NaCl): 2956, 1646, 1516, 1480, 1386, 1259, 1139, 1026, 755; λmax
1
(MeOH)/nm: 216, 267; H-NMR (400 MHz; CDCl3) δH 7.38 (t, J = 6.8 Hz, H-5", 1H), 7.17-7.31 (m,
H-5, H-7, H-8, H-3", H-4", H-6", H-7", 7H), 7.06 (t, J = 7.3 Hz, H-6, 1H), 6.68 (d, J = 8.2 Hz, H-5',
1H) , 6.55 (d, J = 5.0 Hz, H-6', 1H), 6.42 (s, H-2', 1H), 5.37 (s, H-2, 1H), 3.81 (s, OCH3, 3H),
3.67-3.74 (m, OCH3, H-3α, 4H), 2.98 (dd, J = 16.2 Hz, 1.8 Hz, H-3β, 1H); 13C-NMR (100 MHz;
CDCl3) δC 169.9 (C-1"), 149.0 (C-3'), 148.3 (C-4'), 143.2 (C-9), 137.1 (C-2"), 136.2 (C-1'),
130.7 (C-4), 130.0 (C-5"), 128.3 (C-4", C-6"), 127.6 (C-7), 127.0 (C-3", C-7"), 125.3 (C-5, C-8), 124.4
(C-6), 117.5 (C-6'), 111.3 (C-5'), 108.9 (C-2'), 64.3 (C-2), 55.9 (OCH3), 55.8 (OCH3), 38.5 (C-3);
HRMS (+ESI) [M+Na]+: 382.1416, C23H21NNaO3 requires 382.1414.
3.2.5. Cyclohexyl(2-(3,4-dimethoxyphenyl)indolin-1-yl)methanone (17)
Yield 0.13 g (12%); νmax/cm−1 (NaCl): 2930, 1655, 1516, 1479, 1403, 1265, 1138, 1027, 754; λmax
1
(MeOH)/nm: 216, 237, 254, 282; H-NMR (400 MHz; CDCl3) δH 8.35 (d, J = 6.4 Hz, H-8, 1H), 7.24
(t, J = 8.1 Hz, H-7, 1H), 7.11 (d, J = 6.6 Hz, H-5, 1H), 7.03 (t, J = 7.4 Hz, H-6, 1H) , 6.76 (d, J = 8.3
Hz, H-5', 1H), 6.70 (dd, J = 8.2 Hz, 1.7 Hz, H-6', 1H), 6.65 (s, H-2', 1H), 5.42 (d, J = 7.6 Hz, H-2, 1H),
3.83 (s, OCH3, 3H), 3.77 (s, OCH3, H-3α, 4H), 2.97 (d, J = 15.8, H-3β, 1H), 2.34 (s, H-2", 1H),
1.20-1.89 (m, 5 x CH2, 10H); 13C-NMR (100 MHz; CDCl3) δC 175.9 (C-1"), 149.3 (C-3'), 148.4 (C-4'),
143.5 (C-9), 136.5 (C-1'), 129.4 (C-4), 127.7 (C-7), 124.8 (C-5), 123.7 (C-6), 117.1 (C-8, C-5'), 111.4
(C-6'), 108.0 (C-2'), 62.3 (C-2), 55.8 (2 x OCH3), 43.8 (CH, C-2"), 38.9 (CH2, C-3), 30.0, 28.7, 26.0,
25.6, 25.4 (5 x CH2); HRMS (+ESI) [M+H]+: 366.2065, C23H27NO3 requires 366.2064.
3.2.6. Furan-2-yl(2-(2-methoxyphenyl)indolin-1-yl)methanone (18)
Yield 0.07 g (11%); νmax/cm−1 (NaCl): 3007, 1634, 1479, 1397, 1243, 1025, 832, 753; λmax
1
(MeOH)/nm: 280, 297; H-NMR (400 MHz; CDCl3) δH 8.33 (s, H-8, 1H), 7.36 (d, J = 1.8 Hz, H-5",
1H), 7.28 (t, J = 7.8 Hz, H-7, 1H), 7.17 (td, J = 7.8 Hz, 1.8Hz, H-4', 1H), 7.12 (d, J = 7.3 Hz, H-5, 1H),
7.06 (td, J = 7.6 Hz, 0.9 Hz, H-6, 1H), 6.98 (dd, J = 7.6 Hz, 1.8 Hz, H-6', 1H), 6.89 (d, J = 8.2 Hz,
H-3', 1H), 6.80 (d, J = 3.2 Hz, H-3", 1H), 6.75 (t, J = 7.5 Hz, H-5', 1H), 6.33 (dd, J = 3.7Hz, 1.8 Hz,
H-4", 1H), 6.31 (dd, J = 9.8 Hz, 1.4 Hz, H-2, 1H), 3.92 (s, OCH3, 3H), 3.76 (dd, J = 16.2 Hz, 10.1 Hz,
13
H-3α, 1H), 2.90 (dd, J = 16.5 Hz, 1.4 Hz, H-3β, 1H); C-NMR (100 MHz; CDCl3) δC 158.2 (C-1"),
155.5 (C-2'), 147.8 (C-2"), 144.5 (C-5"), 143.7 (C-9), 131.6 (C-1'), 130.7 (C-4), 128.4 (C-4'), 127.6
(C-7), 125.2 (C-5), 125.0 (C-6'), 124.7 (C-6), 120.8 (C-5'), 118.1 (C-8), 116.5 (C-3"), 111.5 (C-4"),
110.5 (C-3'), 58.9 (C-2), 55.6 (OCH3), 38.2 (C-3); HRMS (+ESI) [M+Na]+: 342.1106, C20H17NNaO3
requires 342.1101.

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3.2.7. Furan-2-yl(2-(3-methoxyphenyl)indolin-1-yl)methanone (19)
Yield 0.04 g (38%); νmax/cm−1 (NaCl): 3006, 1634, 1479, 1397, 1286, 1048, 755; λmax (MeOH)/nm:
1
281, 296; H-NMR (400 MHz; CDCl3) δH 8.24 (s, H-8, 1H), 7.39 (s, H-5", 1H), 7.27 (t, J = 8.2 Hz,
H-7, 1H), 7.12-7.16 (m, H-5, H-5', 2H), 7.07 (t, J = 7.6 Hz, H-6, 1H), 6.91 (d, J = 3.7 Hz, H-3", 1H),
6.69-6.75 (m, H-2', H-4', H-6', 3H), 6.36 (dd, J = 3.4Hz, 1.8 Hz, H-4", 1H), 6.05 (dd, J = 9.6 Hz,
1.4 Hz, H-2, 1H), 3.78 (dd, J = 15.8 Hz, 9.6 Hz, H-3α, CH2, 1H), 3.69 (s,OCH3, 3H), 3.01 (d, J = 15.6 Hz,
H-3β, CH2, 1H); 13C-NMR (100 MHz; CDCl3) δC 159.9 (C-3'), 158.3 (C-1"), 148.0 (C-2"),
145.5 (C-1'), 144.3 (C-5"), 143.6 (C-9), 130.0 (C-4, C-5'), 127.8 (C-7), 125.1 (C-5), 124.8 (C-6), 117.9
(C-8), 117.3 (C-4'), 117.1 (C-3"), 112.4 (C-6'), 111.7 (C-4"), 111.0 (C-2'), 63.3 (C-2), 55.2 (OCH3),
39.3 (C-3) ; HRMS (+ESI) [M+H]+: 320.1286, C20H18NO3 requires 320.1281.
3.2.8. (2-(3,4-Dimethoxyphenyl)indolin-1-yl)(furan-2-yl)methanone (20a)
Yield 0.15 g (46%); νmax/cm−1 (NaCl): 3008, 1634, 1479, 1397, 1257, 1140, 1026, 754; λmax
1
(MeOH)/nm: 207, 283, 296; H-NMR (400 MHz; CDCl3) δH 8.21 (d, J = 5.5 Hz, H-8, 1H), 7.41 (dd,
J = 1.8 Hz, 0.92 Hz, H-5", 1H), 7.26 (t, J = 7.8 Hz, H-7, 1H), 7.16 (d, J = 7.8 Hz, H-5, 1H), 7.07 (td,
J = 7.6 Hz, 0.92Hz, H-6, 1H), 6.89 (d, J = 3.6 Hz, H-3", 1H), 6.63-6.68 (m, H-2', H-5', H-6', 3H), 6.36
(dd, J = 3.4Hz, 1.4 Hz, H-4", 1H), 6.02 (dd, J = 9.6 Hz, 1.8 Hz, H-2, CH, 1H), 3.76-3.82 (m, H-3α,
OCH3, 4H), 3.73 (s,OCH3, 3H), 3.01 (dd, J = 16.0 Hz, 1.84Hz, H-3β, CH2, 1H); 13C-NMR (100 MHz;
CDCl3) δC 158.5 (C-1"), 149.1 (C-3'), 148.3 (C-4'), 148.1 (C-2"), 144.1 (C-5"), 143.5 (C-9),
136.4 (C-1'), 130.1 (C-4), 127.7 (C-7), 125.1 (C-5), 124.7 (C-6), 117.7 (C-8), 117.1 (C-5'),
117.0 (C-3"), 111.7 (C-4"), 111.3 (C-6'), 108.2 (C-2'), 63.1 (C-2), 55.9 (2 x OCH3), 39.4 (C-3); HRMS
(+ESI) [M+H]+: 350.1404, C21H20NO4 requires 350.1387; [M+Na]+: 372.1215, C21H19NNaO4 requires
372.1206.
3.2.9. (2,2'- bis(3,4-Dimethoxyphenyl)-3,3'-biindoline-1,1'-diyl)-bis(furan-2-ylmethanone) ((±)20b)
Yield 0.07 g (10%); νmax/cm−1 (NaCl): 2934, 1636, 1516, 1476, 1394, 1254, 1141, 1025, 754; λmax
(MeOH)/nm: 207, 283; 1H-NMR (400 MHz; CDCl3) δH 8.59 (d, J = 7.8 Hz, H-8, H-8*, 2H), 7.48 (td,
J = 7.8 Hz, 1.4 Hz, H-7, H-7*, 2H), 7.36 (d, J = 7.3 Hz, H-5, H-5*, 2H), 7.23-7.27 (m, H-6, H-6*,
H-5", H-5"*, 4H), 6.67 (d, J = 3.6 Hz, H-3", H-3"*, 2H), 6.54 (d, J = 8.2 Hz, H-5', H-5'*, 2H), 6.28 (d,
J = 1.8 Hz, H-6', H-6'*, 2H), 6.21 (dd, J = 3.4 Hz, 1.8 Hz, H-4", H-4"*, 2H), 5.83 (d, J = 1.8 Hz, H-2',
H-2'*, 2H), 5.78 (s, H-2, H-2*, CH, 2H), 3.70 (s, 2 x OCH3, 6H), 3.60 (s, H-3, H-3*, 2H), 3.57 (s,
2 x OCH3, 6H); 13C-NMR (100 MHz; CDCl3) δC 158.4 (C-1", C-1"*), 149.1 (C-3', C-3'*), 148.1 (C-4',
C-4'*), 147.4 (C-2", C-2"*), 144.9 (C-9, C-9*), 144.6 (C-5", C-5"*), 135.6 (C-1', C-1'*), 130.8 (C-4,
C-4*), 129.2 (C-7, C-7*), 125.4 (C-5, C-5*), 125.0 (C-6, C-6*), 118.2 (C-8, C-8*), 117.3 (C-3",
C-3"*), 115.9 (C-6', C-6'*), 111.5 (C-4", C-4"*), 111.1 (C-5', C-5'*), 107.6 (C-2', C-2'*), 63.6 (C-2,
C-2*), 57.3 (C-3, C-3*), 55.81 (2 x OCH3), 55.76 (2 x OCH3); HRMS (+ESI) [M+H]+: 697.2542,
C42H37N2O8 requires 697.2544.

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3.2.10. Furan-2-yl(2-(4-methoxyphenyl)indolin-1-yl)methanone (21a)
Yield 0.10 g (21%); νmax/cm−1 (NaCl): 3005, 1635, 1513, 1478, 1397, 1249, 1179, 1034, 834, 755;
1
λmax (MeOH)/nm: 203, 226, 283, 297; H-NMR (400 MHz; CDCl3) δH 8.25 (d, J = 4.6 Hz, H-8, 1H),
7.40 (dd, J = 1.8 Hz, 0.92 Hz, H-5", 1H), 7.27 (t, J = 7.8 Hz, H-7, 1H), 7.16 (d, J = 7.8 Hz, H-5, 1H),
7.04-7.09 (m, H-6, H-2', H-6', 3H), 6.90 (d, J = 4.1 Hz, H-3", 1H), 6.72-6.75 (m, H-3', H-5', 2H), 6.35
(dd, J = 3.7Hz, 1.8 Hz, H-4", 1H), 6.05 (dd, J = 9.6 Hz, 1.8 Hz, H-2, CH, 1H), 3.76 (dd, J = 16.0 Hz,
10.1Hz, H-3α, CH2, 1H), 3.70 (s, OCH3, 3H), 2.98 (dd, J = 16.0 Hz, 1.4Hz, H-3β, CH2, 1H);
13C-NMR (100 MHz; CDCl3) δC 158.8 (C-4'), 158.4 (C-1"), 148.1 (C-2"), 144.2 (C-5"), 143.6 (C-9),
136.0 (C-1'), 130.1 (C-4), 127.7 (C-7), 126.1 (C-2', C-6'), 125.1 (C-5), 124.7 (C-6), 117.8 (C-8), 117.0
(C-3"), 114.2 (C-3', C-5'), 111.7 (C-4"), 62.8 (C-2), 55.3 (OCH3), 39.4 (C-3); HRMS (+ESI) [M+H]+:
320.1294, C20H18NO3 requires 320.1281; [M+Na]+: 342.1105, C20H17NNaO3 requires 342.1101.
3.2.11. (2,2'- bis(4-methoxyphenyl)- 3,3'- biindoline-1,1'-diyl) bis(furan-2-ylmethanone) ((±)21b)
Yield 0.11 g (12%); νmax/cm−1 (NaCl): 3008, 1636, 1512, 1477, 1395, 1249, 1177, 1034, 755; λmax
(MeOH)/nm: 205, 226, 284; 1H-NMR (400 MHz; CDCl3) δH 8.59 (d, J = 8.2 Hz, H-8, H-8*, 2H), 7.49
(td, J = 7.8 Hz, 1.4 Hz, H-7, H-7*, 2H), 7.31 (d, J = 6.4 Hz, H-5, H-5*, 2H), 7.24-7.27 (m, H-6, H-6*,
H-5", H-5"*, 4H), 6.69 (d, J = 3.6 Hz, H-3", H-3"*, 2H), 6.55-6.60 (m, H-3', H-3'*, H-5', H-5'*, 4H),
6.44-6.47 (m, H-2', H-2'*, H-6', H-6'*, 4H), 6.20 (dd, J = 3.4 Hz, 1.8 Hz, H-4", H-4"*, 2H), 5.81 (s,
H-2, H-2*, CH, 2H), 3.63 (s, 2 x OCH3, 6H), 3.55 (s, H-3, H-3*, 2H); 13C-NMR (100 MHz; CDCl3) δC
158.7 (C-4', C-4'*), 158.3 (C-1", C-1"*), 147.5 (C-2", C-2"*), 144.8 (C-9, C-9*), 144.6 (C-5", C-5"*),
135.3 (C-1', C-1'*), 130.7 (C-4, C-4*), 129.3 (C-7, C-7*), 125.6 (C-2', C-2'*, C-6', C-6'*), 125.4 (C-5,
C-5*), 125.1 (C-6, C-6*), 118.1 (C-8, C-8*), 117.3 (C-3", C-3"*), 114.2 (C-3', C-3'*, C-5', C-5'*),
111.4 (C-4", C-4"*), 63.5 (C-2, C-2*), 57.2 (C-3, C-3*), 55.2 (2 x OCH3); HRMS (+ESI) [M+H]+:
637.2341, C40H33N2O6 requires 637.2333.
4. Conclusions
Although previous studies by our group have demonstrated the synthetic utility of benzophenone
(an organocatalyst) as an effective additive for dramatically improving the yield of indolines (and
suppressing bisindoline formation), the present study demonstrated that even in the absence of
benzophenone, the amide structure can also under certain conditions discriminate between the indoline
and bisindoline forms (enhancing the former and suppressing the latter). Stilbene 5 (with an n-
butyramide moiety) will, on exposure to FeCl3, give the corresponding indoline 14a in 63% yield,
compared to stilbene 6 (with an isobutyramide moiety) which yields indoline 15 in 29%. Previously
undiscovered steric, conformational and stereoelectronic effects have been considered in this study
involving eight stilbenes.
We would like to draw the reader’s attention to some intriguing electronic effects. For example,
stilbene 9 with an ortho-methoxy substituent dramatically shifts the electron density in the olefinic
bond (see Table 1). The C(7) olefinic proton is now more deshielded than the C(8) proton. This in turn
changes the position of the positive charge and unpaired electron (in the radical cation) compared to

Molecules 2011, 16
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stilbenes 11 and 12 with predictable consequences for the cyclization/dimerization. These
transformations exploit FeCl3 (an environmentally friendly oxidant) as the single electron transfer
reagent [19-21]. Further developments will be reported in due course.
Acknowledgments
The authors (NFT, AA, KA) thank MOSTI (eScienceFund: 14-02-03-4013) and University of
Malaya (UMRG: RG023/09AFR, FRGS: FP018/2009). CHK thanks University of Malaya (Vote:
P0263/2007A and PS195/2008A), Malaysia Toray Science Foundation (08/G21) and MOSTI for a
NSF scholarship.
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