Synthesis of 3,3′-disubstituted-2,2′-biindolyls through sequential palladium-catalysed reactions of 2,2,2-trifluoro-N-(2-(4-[2,2,2- trifluoro-acetylamino)-phenyl]-buta-1,3-diynyl)-phenyl)-acetamide with organic halides/triflates

Article abstract of DOI:10.1016/j.tet.2006.01.041

Palladium-catalysed reactions of aryl iodides/vinyl triflates with 2,2,2-trifluoro-N-(2-(4-[2,2,2-trifluoro-acetylamino)-phenyl]-buta-1,3-diynyl) -phenyl)-acetamide provide a straightforward entry into 3,3′- disubstituted-2,2′-biindolyls. Subsequent appli

Full text of DOI:10.1016/j.tet.2006.01.041

Tetrahedron 62 (2006) 3033–3039
Synthesis of 3,30-disubstituted-2,20-biindolyls through sequential
palladium-catalysed reactions of 2,2,2-trifluoro-N-(2-(4-[2,2,2-
trifluoro-acetylamino)-phenyl]-buta-1,3-diynyl)-phenyl)-
acetamide with organic halides/triflates
a
b
Giorgio Abbiati,a Antonio Arcadi,b, Egle Beccalli, Gabriele Bianchi,
*
Fabio Marinellib and Elisabetta Rossia
a
` `
Istituto di Chimica Organica ‘Alessandro Marchesini’, Facolta di Farmacia, Universita degli
Studi di Milano, Via Venezian 21, 20133 Milano, Italy
b
`
Dipartimento di Chimica, Ingegneria Chimica e Materiali, Universita degli Studi dell’Aquila, Via Vetoio, 67010 Coppito (AQ), Italy
Received 31 October 2005; revised 13 December 2005; accepted 12 January 2006
Available online 3 February 2006
Dedicated to the memory of Prof. Bianca Rosa Pietroni
Abstract—Palladium-catalysed reactions of aryl iodides/vinyl triflates with02,2,2-trifluoro-N-(2-(4-[2,2,2-trifluoro-acetylamino)-phenyl]-
buta-1,3-diynyl)-phenyl)-acetamide provide a straightforward entry into 3,3 -disubstituted-2,20-biindolyls. Subsequent application of the
procedure to homochiral aryl iodides affords the corresponding chiral 3,30-disubstituted-2,20-biindolyls. The methodology can also be
applied to the synthesis of benzo[c]indolo[2,3-a]carbazoles.
q 2006 Elsevier Ltd. All rights reserved.
1. Introduction
This chemistry has been employed in the preparation of
biologically active compounds.5 It has also been adapted to
a solid-supported synthesis for the preparation of combi-
natorial libraries of indoles with three variable
components.6
Palladium-catalysed routes to heterocyclic compounds
represent well-exploited synthetic approaches.1 In particular,
palladium-catalysed annulations involving both formation of
carbon–carbon and carbon–nitrogen bonds, have proven to
be very useful in the synthesis of a variety of heterocyclic
systems.2
However, while a variety of indole derivatives could be
prepared in good to excellent yield by using aryl/vinyl
halides/triflates as s-donors,7 the extension0of the procedure
to the synthesis of 3,30-disubstituted-2,2 -biindolyl deri-
vatives was limited to the synthesis of indolo[2,3-
a]carbazole alkaloids5c by using N-benzyl-3,4-dibromoma-
leimide as the s-donor. Products containing the biindolyl
unit are of considerable interest, not only for their chemical
architecture, but also due to their diverse pharmacological
profiles.8 Biindolyl-based red fluorescent materials have
been prepared and used as non-doping red emitters.9 The
juxtaposition of the two nitrogens in 2,20-biindolyls has also
been exploited in the construction of various ligand
systems.10
The aminopalladation/reductive elimination domino
reaction of alkynes containing proximate nitrogen nucleo-
philes is a versatile synthetic methodology to build up
complex indole and polycyclic indole derivatives.3 The
trifluoroacetamido group was shown to act as the proximate
nitrogen nucleophile of choice for favouring palladium-
catalysed cyclisations of o-alkynylaniline derivatives invol-
ving h2-alkyne organopalladium intermediates. In addition,
it allows the formation of free N–H indoles (the amide bond
is broken during the reaction or/and the work-up), avoiding
troublesome and time-consuming deprotection steps.4
In connection with our current research interests in this area
and in order to widen the scope and generality of the
methodology, we decided to develop a procedure for the
preparation of 3,30-disubstituted-2,20-biindolyl derivatives 3
through the palladium-catalysed reaction of readily
Keywords: Biindolyls; Palladium; Cyclisation; Aminopalladation/reductive
elimination.
*
Corresponding author. Tel.: C39 0862 433774; fax: C39 0862 433753;
e-mail: arcadi@univaq.it
0040–4020/$ - see front matter q 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.01.041

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G. Abbiati et al. / Tetrahedron 62 (2006) 3033–3039
available 2,2,2-trifluoro-N-(2-(4-[2,2,2-trifluoro-acetyla-
mino)-phenyl]-buta-1,3-diynyl)-phenyl)-acetamide5c
with organic halides/triflates (Scheme 1). Despite its
importance, synthetic methodologies for the construction
of 3,30-disubstituted-2,20-biindolyl derivatives are scarce.11
The cyclisation of 2,2,2-trifluoro-N-(2-(4-[2,2,2-trifluoro-
acetylamino)-phenyl]-buta-1,3-diynyl)-phenyl)-acetamide
1 to give the 2,20-biindolyl 4 involves a palladium-catalysed
process rather than a base-promoted process. Thus, when 1
was reacted in CH3CN at reflux for 24 h under the presence
of Pd(PPh3)4 and K2CO3 the corresponding 2,20-biindolyl
4 was isolated in 75% yield (the starting alkyne 1 was
recovered in 21% yield). The involvement of a base-
promoted cyclisation14 of 1 to 4 could be ruled out since the
starting reagent 1 was recovered (90% yield) when the same
reaction was carried out omitting the palladium catalyst.
1
R1
H
N
Pd(0)
R1X
N
H
R1
NH
HN
F3COC
COCF3
A plausible rationale, which accounts for the obtained
results may involve two competing mechanisms. The
sequential aminopalladation/reductive elimination reaction
leading to the target derivatives 3 most probably proceeds
through a mechanism most frequently found in the
literature.2d,e,3 Oxidative addition of palladium(0) in the
aryl/vinyl halide/triflate bond affords a s-organopalla-
dium(II) intermediate, which can coordinate to the triple
bond to give the h2-alkyne-organopalladium intermediate 6.
The acetylene is then sufficiently electrophilic to undergo
nucleophilic attack by the tethered nitrogen to give the
s-indolylpalladium complex 7 (5 endo-dig process). As far
as the aniline moiety is concerned, no 3,30-disubstituted-
2,20-biindolyl derivatives were obtained using the 2-[4-(2-
aminophenyl)buta-1,3-diynyl]aniline containing free amino
groups. Presumably, when carbon–carbon triple bonds are
activated via coordination to organopalladiums, anionic
nitrogen nucleophiles, or nitrogen atoms whose nucleophi-
lic attack can be assisted by proton removal in the transition
state leading to the aminopalladation adduct, are required
to produce the desired cyclisation products.12b Reductive
elimination of palladium(0) from the intermediate 7
regenerates the catalyst and affords product 3 after an
iterative aminopalladation/reductive elimination reaction
and protective group cleavage (Scheme 2).
1
3
Scheme 1.
Herein, we report the results of this study. The methodology
was also applied to the synthesis of benzo[c]indolo[2,3-
a]carbazole.
2. Results and discussion
Initial palladium-catalysed polyannulation attempts were
focused on finding a general set of reaction conditions that
could be used with a variety of aryl/vinyl halides/triflates.
Based on the results obtained in the palladium-catalysed
synthesis of 2,3-disubstituted indoles,12 we initially
examined the reaction of 1 (1 equiv) with aryl iodides
(2.2 equiv) in the presence of Pd(PPh3)4 (0.05 equiv) and
K2CO3 (5 equiv) in acetonitrile at 8008C. Under these
conditions, target 3,30-disubstituted-2,2 -biindolyls 3a–e
can be prepared in satisfactory yields from aryl iodides
2a–e, (Table 1, entries 1–5). As shown in Table 1, the
reaction tolerates both electron-withdrawing or electron-
donating substituents in the Csp2 donors. In a few cases, the
3-substituted biindolyls 5a–c (Fig. 1) were also isolated in
significant yields (Table 1, entries 6–9), and a tendency
towards the production of 2,20-biindolyl 4 (Fig. 1) was also
observed (Table 1, entries 9 and 10).
Alternatively, a competitive oxidative addition of Pd(0) into
the N–H bond of 1 to form a Pd–H species can take place
under the reaction conditions. Then, intramolecular inser-
tion of the triple bond can result in a 3-indolylpalladium
derivative 8. Sequential reductive elimination of the Pd–H
intermediates/oxidative addition into N–H will provide 2,20-
biindolyl 4 (Scheme 3).
Moreover, the 2,20-biindol 4 was isolated as the main reaction
product, when we extended the same procedure to include aryl
bromides and aryl triflates (Table 1, entries 12 and 13). It was
previously reported7 that the reaction of o-alkynyltrifluoro-
acetanilides with aryl bromides and triflates preferably afford
2-substituted 3-arylindoles rather than 2-substituted-indoles
by increasing the temperature to 100 8C. However, when we
tried to perform the reactionof1 with2jand2kunderthe same
reaction conditions we failed to obtain the corresponding
derivatives 3b,f in satisfactory yields and the cyclisation of 1
to 4 was a significant side reaction or even the main reaction
path. Presumably, this different reactivity could be a
consequence of higher acidity of 1 compared to that of
o-alkynyltrifluoroacetanilides [calculations at the HF/
4-31GCPCM show that DpKa (H2O) at 300 K between 1
and the o-ethynyltrifluoroacetanilide is ZK1.5].13
The activation of Pd(0) via oxidative addition into NH bond
has been previously reported to take place with more acidic
amides.15 A similar mechanism has been suggested for the
palladium-catalysed cyclisations of acetylene-containing
N-protected a-aminoesters.16 The formation of amido
complexes directly from amines has also been observed.17
Nevertheless, as demonstrated by the results obtained in the
experiments performed in the presence either of Pd(II)18 and
Au(III),19 a mechanism that leads to the 2,20-biindolyl 4
involving a palladium catalyst that acts simultaneously20
both as transition metal in the Pd(0) oxidation state and as
Lewis acid in the Pd(II) oxidation state can not be ruled
out.21
Finally, when vinyl triflates were used as s-donors, best
results in the synthesis of the title derivatives 3 could be
achieved by decreasing the reaction temperature at 45 8C
(Table 1, entries 16 and 17).
It is possible that the two different reaction paths afford
the formation of derivative 5 when operating together.

G. Abbiati et al. / Tetrahedron 62 (2006) 3033–3039
3035
Table 1. Synthesis of 2,20-biindolyls 3
Entry
1
s-Donor 2
Time (h)
24
3 (%)a,b
3a 82
4 (%)a,b
5 (%)a,b
—
—
I
2a
2b
2
3
3.5
4
3b 77
3c 63
—
—
—
—
O
I
OCH3
O
OCH3
I
2c
4
24
3d 73
—
—
O
I
CH
3
2d
2e
5
6
1.5
16
3e 82
3f 50
—
—
—
I
Cl
5a 47
I
CH
3
2f
2f
7
8
4
3f 79c
3g 23
—
—
5a 14c
5b 67
4.5
I
CH
3
H C
3
2g
9
24
17
3h 38
3i 75
23
15
5c 30
OCH
3
I
2h
10
—
I
OCH
O
3
2i
2i
11
12
2
3i 90c
3b 15d
—
65d
—
—
24
Br
CH
3
2j
13
16
3f 15e
33e
—
TfO
CH3
2k
2k
14
15
16
24
3f 34f
3j 51g
—
—
—
—
OTf
2l
2m
2n
16
17
4
5
3k 45g
3l 61g
—
—
—
—
OTf
OTf
a Yields refer to single runs and are given for isolated products.
b Unless otherwise stated, reactions were carried out under a nitrogen atmosphere according to the following procedure: 1/2/K2CO3/Pd(PPh3)4Z1:2.2:5:0.07 in
CH3CN at 80 8C (0.12–0.35 mmol scale).
c Reaction was carried out at 80 8C in CH3CN under a nitrogen atmosphere using the following molar ratios: 1/2/K2CO3/Pd(PPh3)4Z1:4.4:5:0.07.
d The reaction was carried out in CH3CN at 100 8C under a nitrogen atmosphere using the following molar ratios: 1/2c/Cs2CO3/Pd(PPh3)4Z1:3:3:0.07.
e The reaction was carried out in CH3CN at 100 8C under a nitrogen atmosphere using the following molar ratios: 1/2g/Cs2CO3/Pd(PPh3)4Z1:2.2:3:0.07.
f
The reaction was carried out in CH3CN at 100 8C under a nitrogen atmosphere using the following molar ratios: 1/2g/Cs2CO3/Pd(PPh3)4Z1:3:3:0.07.
g The reaction was carried out in CH3CN at 45 8C under a nitrogen atmosphere using the following molar ratios: 1/2/K2CO3/Pd(PPh3)4Z1:2.2:3:0.07.
The feature of the s-donor 2, the reaction temperature and
the 1:s-donor ratio were found to play a pivotal role in
controlling the balance of the reaction paths. The
preferential formation of 2,20-biindolyl 4 is observed when
aryl bromides/triflates are used as s-donor precursors.
Apparently, at the temperature of 80 8C the oxidative
addition of aryl bromides/triflates is relatively slow and the
cyclisation of 1 to 4 is the main reaction. According to that

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G. Abbiati et al. / Tetrahedron 62 (2006) 3033–3039
Interestingly, application of the procedure to (K)-menthyl
H
N
H
N
p-iodobenzoate 2o (Scheme 4) and (C)-menthyl p-iodo-
benzoate 2o0 led to the formation in good yields of
corresponding chiral 3,30-disubstituted-biindolyls 3m
(67% yield) and 3m0 (61% yield) derivatives, respectively.
The absolute stereochemistry of 3m and 3m0 can be
assigned on the assumption that the stereogenic centres in
the starting aryl iodide are not affected during this
transformation.
N
H
N
H
R1
5
4
Figure 1.
R1
X
Pd
Pd(0)
K2CO3
1
R1X
R1
Pd
X
R
NH
HN
COCF3
R
S
F3COC
O
S
R
O
O
6
O
R
R1
Pd
L
H
2o
L
N
I
1
3
N
Pd(0), K2CO3
N
H
COCF3
HN
COCF3
3m (67%)
7
O
Scheme 2.
O
S
R
R
Pd(0)
K2CO3
H
1
Scheme 4.
N
Pd
L
HN
L
F3COC
H
COCF3
Moreover, treating 1 with 1,2-diiodobenzene provides an
easy entry into the benzo[c]indolo[2,3-a]carbazole 9
(Scheme 5).
L
Pd
L
4
N
COCF3
HN
COCF3
I
I
CH3CN, K2CO3
8
1
+
Pd(PPh3)4, 80 °C
N
H
N
H
Scheme 3.
9 (51%)
the reaction of 1 with the 5-bromopyrimidine under the
same reaction conditions used for aryl iodides led only to
the formation of 4 (75% yield). However, under the
conditions previously reported to successfully give 2-sub-
stituted 3-aryl- and 3-heteroarylindoles by the palladium-
catalysed reaction of o-alkynyltrifluoroacetanilides with
aryl bromides and triflates7 the formation of 3 was
disappointing from a synthetic point of view (Table 1,
entries 12 and 13). Very likely, at 100 8C the oxidative
addition of Pd(0) into the N–H bond is the fastest process.
According to that the formation of the 2,20-biindolyl 4 was
the main reaction product (88% yield) when 1 was reacted
with the more reactive vinyl triflate 2m in CH3CN at 100 8C
in the presence of Pd(PPh3)4 and K2CO3. Consequently, we
failed to shift the reaction towards the aminopalladation/
reductive elimination mechanism when aryl/heteroaryl
bromides were used as s-donors, even if the formation of
the target derivatives 3 can be achieved in moderate yield by
increasing the 1:2 molar ratio (Table 1, entry 14).
Scheme 5.
To the best of our knowledge, the synthesis of this
heterocyclic system has not been reported previously.
Intermediates 10–13 are suggested to be involved in a
palladium(0)/palladium(II) catalytic cycle (Scheme 6).
In conclusion, because of the simple experimental
procedure, easy availability of starting materials, and
ability to incorporate a variety of functional groups, the
present methods represents a valuable tool for the
synthesis of 3,30-disubstituted-2,20-biindolys through the
palladium-catalysed reaction of 2,2,2-trifluoro-N-(2-(4-
[2,2,2-trifluoro-acetylamino)-phenyl]-buta-1,3-diynyl)-phe-
nyl)-acetamide with aryl iodides/vinyl triflates. Sub-
sequent application of the procedure to homochiral aryl
iodides affords the corresponding chiral 3,30-disubsti-
tuted-2,20-biindolys. It is worth noting that the here
reported protocol could allow a versatile access to
indolobenzocarbazole fused derivatives from 1,2-
diiodoarenes.
The increasing of the 1:2 molar ratio also limited the
formation of the derivates 5 (Table 1, entries 7 and 11).

G. Abbiati et al. / Tetrahedron 62 (2006) 3033–3039
3037
containing water and ethyl acetate. The organic layer was
separated and the aqueous layer was extracted twice with
ethyl acetate. The combined organic layers were dried
(Na2SO4) and evaporated under vacuum. The residue was
purified by flash chromatography on silica gel eluting with a
80:20 n-hexane/EtOAc mixture to give 0.117 g (77%) of 3b:
I
Pd
I
-Pd(0)
+Pd(0)
N
Y
N
Y
Yellow solid; IR (KBr) 3340, 1720, 1610, 770, 740 cmK1
;
YHN
YHN
10
11
1H NMR (DMSO) d 3.74 (s, 6H), 7.05–7.20 (m, 8H), 7.45–
7.56 (m, 8H), 11.83 (s, 2H); 13C NMR d 57.9, 117.9, 121.0,
124.4, 126.1, 128.5, 132.1, 132.6, 133.0, 134.3, 135.4,
135.5, 139.3, 141.2, 142.6, 172.1; ESI-MS: m/z (% relative
intensity) 499.3 (93) (MKH)K; ESI-HRMS calcd for
C32H23N2O4 499.544, Found 499.541.
I
Pd
Pd
-Pd(0)
9
N
Y
N
Y
N
YHN
Y
3.1.2. 3,30-Bis-(3-benzoic acid methyl ester)-1H,10H-
[2,20]biindolyl 3c. Yield: 144.0 mg, 63%; Yellow solid;
IR (KBr) 3320, 1710, 860 cmK1; 1H NMR (DMSO) d 3.74
(s, 6H), 7.06–7.20 (m, 8H), 7.45–7.56 (m, 8H), 11.83 (br s,
2H); 13C NMR (DMSO) d 57.9, 117.9, 121.0, 124.4, 126.1,
128.5, 132.1, 132.6, 133.0, 134.4, 135.4, 135.5, 139.3,
141.2, 142.6, 172.0. Anal. Calcd for C32H24N2O4 C, 76.78;
H, 4.83; N, 5.60; Found C, 76.63; H, 4.86; N, 5.55.
13
12
Y= COCF3
Scheme 6.
3. Experimental
3.1. General
3.1.3. 1-{4-[30-(4-Acetyl-phenyl)-1H,10H-[2,20]biindolyl-
3-yl]-phenyl}-ethanone 3d. Yield: 166.0 mg, 73%; Yellow
solid; IR (KBr) 3320, 1740, 730 cmK1; 1H NMR (DMSO) d
2.50 (s, 6H), 7.06–7.21 (m, 6H), 7.19 (d, JZ8.3 Hz, 4H),
7.48 (d, JZ7.7 Hz, 2H), 7.64 (d, JZ8.3 Hz, 4H), d 11.64 (br
s, 2H); 13C NMR d 26.4, 111.8, 115.3, 118.8, 120.2, 122.5,
126.5, 127.4, 127.9, 128.5, 133.7, 136.7, 140.2, 196.8; ESI-
MS: m/z (% relative intensity) 467.4 (100) (MKH)K; ESI-
HRMS calcd for C32H23N2O2 467.551, Found 467.553.
Temperatures are reported as bath temperature. Solvents
used in extraction and purification were distilled prior to
use. Compounds were visualised on analytical thin-layer
chromatograms (TLC) by UV light (254 nm). The products,
after usual work-up, were purified by flash chromatography
on silica gel (230–400 mesh) eluting with n-hexane/ethyl
1
acetate mixtures. H and 13C NMR spectra were recorded
with a Varian-Gemini at 200 MHz and a Bruker AC 200 E
spectrometers. ESI mass spectra were recorded with a
ThermoFinnigan LCQ Deca XP Plus equipped with an
orthogonal ESI source and ESI accurate mass measurements
were recorded with a Mass spectrometer Finnigan TSQ
Quantum Ultra with accurate mass options instrument. IR
were recorded with Perkin-Elmer 683 and 16 PC spectro-
meters. Only the most significant IR absorptions are given.
Optical rotations were measured on a Perkin Elmer 343 plus
polarimeter. CHN analyses were recorded with an Eager
200 analyser. All starting materials, catalysts, and solvents
if not otherwise stated, are commercially available and were
used as purchased, without further purification. The 2,2,2-
trifluoro-N-(2-(4-[2,2,2-trifluoro-acetylamino)-phenyl]-
buta-1,3-diynyl)-phenyl)-acetamide5c 1, triflates22 2f, l–n,
(K)-menthyl p-iodobenzoate23 2o and (C)-menthyl p-iodo-
benzoate were prepared according to described methods.
The following products were identified by comparison of
their physical and spectral data with those given in the cited
references: 2,20biindolyl14b 4 and 3,30-diphenyl-1H,10H-
[2,20]biindolyl11a 3a.
3.1.4. 3,30-Bis-(4-chloro-phenyl)-1H,10H-[2,20]biindolyl
3e. Yield: 172.0 mg, 82%; Yellow solid; IR (KBr) 3425,
1
1620, 1020, 810 cmK1; H NMR (CDCl3) d 6.95–7.26 (m,
12H), 7.36–7.46 (m, 2H), 7.54–7.61 (m, 2H), 11.69 (br s,
2H); 13C NMR (CDCl3) d 111.8, 114.6, 118.6, 120.0, 122.4,
126.4, 126.8, 127.6, 130.1, 133.6, 136.5; ESI-MS: m/z (%
relative intensity) 453.4 (65) (MKH)K, 451.4 (100)
(MKH)K. Anal. Calcd for C28H18Cl2N2 C, 74.18; H,
4.00; N, 6.18; Found C, 74.05; H, 4.16; N, 6.25.
3.1.5. 3,30-Di-p-tolyl-1H,10H-[2,20]biindolyl 3f. Yield:
148.0 mg, 79%; Yellow solid; IR (KBr) 3300, 1520,
1
810 cmK1; H NMR (CDCl3) d 2.43 (s, 6H), 7.08–7.28
(m, 6H), 7.26 (d, JZ7.9 Hz, 4H), 7.48 (d, JZ7.9 Hz, 4H),
7.60 (d, JZ7.3 Hz, 2H), 8.05 (br s, 2H); 13C NMR (CDCl3)
d 21.3, 110.8, 115.6, 119.4, 120.2, 122.9, 125.9, 127.9,
129.7, 130.1, 131.3, 135.8, 136.8. Anal. Calcd for C30H24N2
C, 87.35; H, 5.86; N, 6.79; Found C, 87.40; H, 5.68; N, 6.89.
3.1.1. General procedure for the preparation of 3,30-
disubstituted-2,20-biindolys 3. A typical procedure is as
follows: to a stirred solution of 2,2,2-trifluoro-N-(2-(4-
[2,2,2-trifluoro-acetylamino)-phenyl]-buta-1,3-diynyl)-
phenyl)-acetamide 1 (0.150 g, 0.35 mmol) in boiling
acetonitrile (7 mL) were added methyl 4-iodobenzoate 2b
(0.195 g, 0.78 mmol), K2CO3 (0.244 g, 1.77 mmol) and
Pd(PPh3)4 (0.029 g, 0.025 mmol). The reaction mixture was
stirred at 80 8C (bath temperature) under a nitrogen
atmosphere for 3.5 h and poured in a separatory funnel
3.1.6. 3,30-Bis-(2,4-dimethyl-phenyl)-1H,10H-[2,20]biin-
dolyl 3g. Yield: 100.0 mg, 23%; Dark brown solid; IR
1
(KBr) 3480, 750 cmK1; H NMR (DMSO) d 2.21 (s, 6H),
2.22 (s, 6H), 6.46 (d, JZ7.7 Hz, 1H), 6.58–6.68 (m, 3H),
6.79 (s, 2H), 6.091–7.16 (m, 6H), 7.44 (d, JZ8.0 Hz, 2H),
11.48 (br s, 1H), 11.55 (br s, 1H); 13C NMR (DMSO) d 19.8,
20.8, 111.4, 115.6, 116.1, 119.0, 121.6, 125.5, 125.6, 127.7,
130.0, 130.2, 130.4, 136.0, 136.1, 136.7; ESI-MS: m/z (%
relative intensity) 439.6 (94) (MKH)K, ESI-HRMS calcd
for C32H27N2 439.579, Found 439.577.

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G. Abbiati et al. / Tetrahedron 62 (2006) 3033–3039
3.1.7. 3,30-Bis-(2-methoxy-phenyl)-1H,10H-[2,20]biindo-
lyl 3h. Yield: 84.0 mg, 38%; Dark brown solid; IR (KBr)
115.7, 119.4, 120.9, 123.5, 126.3, 127.2, 128.6, 129.5,
130.0, 136.3, 139.1, 166.1; ESI-MS: m/z (% relative
intensity) 749.2 (100) (MCH)C. Anal. Calcd for
C50H56N2O4 C, 80.18; H, 7.54; N, 3.74; Found C, 80.15;
H, 7.48; N, 7.60.
1
3490, 750 cmK1; H NMR (DMSO) d 3.40 (s, 6H), 6.65–
6.70 (m, 2H), 6.80–6.82 (m, 2H), 6.98–7.186 (m, 8H), 7.39
(d, JZ8.0 Hz, 4H), 11.30 (br s, 2H); 13C NMR (DMSO) d
55.1, 100.3, 111.2, 116.4, 126.9, 127.7, 128.1, 128.8, 131.1,
136.0, 156.7, 157.6. Anal. Calcd for C30H24N2O2 C, 81.06;
H, 5.44; N, 6.30; Found C, 81.04; H, 5.71; N, 6.27.
3.1.13. (D)-3,30-Bis[benzoic(1S,2R,5S)-2-isopropyl-5-
methyl-cyclohexyl ester]-1H,10H-[2,20]biindolyl 3m0.
Yield: 468.0 mg, 61%; Yellow solid; [a]D C20.5
(5.24 mg/mL, CHCl3).
3.1.8.
3,30-Bis-(4-methoxy-phenyl)-1H,10H-[2,20]-
biindolyl 3i. Yield: 108.0 mg, 75%; Brown solid; IR
1
(KBr) 3300, 1730, 820 cmK1; H NMR (DMSO) d 3.60
3.1.14. 3-p-Tolyl-1H,10H-[2,20]biindolyl 5a. Yield:
(s, 6H), 6.69 (d, JZ8.3 Hz, 4H), 6.93–7.12 (m, 8H), 7.32 (d,
JZ7.6 Hz, 2H), 7.54 (d, JZ7.6 Hz, 2H), 11.37 (br s, 2H);
13C NMR (DMSO) d 54.9, 111.6, 113.8, 115.8, 118.9,
119.5, 122.0, 126.5, 126.7, 127.2, 129.5, 136.2, 157.3; ESI-
MS: m/z (% relative intensity) 445.3 (100) (MCH)C, 339.3
(84); ESI-HRMS calcd for C30H25N2O2 445.540, Found
445.535.
20.0 mg, 14%; Brown solid; IR (KBr) 3400, 820 cmK1
;
1H NMR (DMSO) d 2.37 (s, 3H), 6.48 (s, 1H), 6.98–7.49
(m, 12H), 11.06 (br s, 1H), 11.48 (br s, 1H); mass spectrum
(EI): m/z (% relative intensity) 323 (100) (MCH)C, Anal.
Calcd for C23H18N2 C, 85.68; H, 5.63; N, 8.69; Found C,
85.70; H, 5.82; N, 8.57.
3.1.9. 3,30-Di-naphthalen-1-yl-1H,10H-[2,20]biindolyl 3j.
Yield: 120.0 mg, 51%; Dark brown solid; IR (KBr) 3200,
3.1.15. 3-(2,4-Dimethyl-phenyl)-1H,10H-[2,20]biindolyl5b.
Yield: 222.0 mg, 67%; Dark yellow solid; IR (KBr) 3490,
750 cmK1; 1H NMR (DMSO) d 1.97 (s, 3H), 2.38(s, 3H), 6.10
(s, 1H), 6.94–7.19 (m, 9H), 7.37–7.50 (m, 6H), 10.99 (br s,
1H), 11.38 (br s, 1H); 13C NMR (DMSO) d 19.6, 20.8, 100.0,
111.2, 113.5, 118.6, 119.4, 119.6, 119.8, 121.5, 121.9, 126.7,
127.2, 128.1, 128.7, 130.7, 130.9, 131.1, 131.3, 135.7, 136.1,
136.3, 136.9; (EI): m/z (% relative intensity) 337 (100) (MC
H)C, 322 (34). Anal. Calcd for C24H20N2 C, 85.68; H, 5.99; N,
8.33; Found C, 85.59; H, 5.84; N, 8.41.
1
740 cmK1; H NMR (DMSO) d 6.51–7.63 (m, 22H), 7.86
(d, JZ8.6 Hz, 2H), 11.64 (br s, 2H); 13C NMR d 101.4,
111.8, 113.9, 118.7, 119.4, 119.9, 120.0, 121.7, 122.4,
125.1, 126.1, 126.7, 127.3, 127.6, 127.8, 128.1, 128.5,
131.3, 132.5, 136.5; ESI-MS: m/z (% relative intensity)
483.4 (100) (MKH)K, ESI-HRMS calcd for C36H23N2
483.592, Found 483.589.
3.1.10. 3,30-Bis-(4-phenyl-cyclohex-1-enyl)-1H,10H-
[2,20]biindolyl 3k. Yield: 86.0 mg, 45%; Brown solid; IR
1
(KBr) 3180, 1480, 740 cmK1; H NMR (DMSO) d 1.85–
3.1.16. 3-(2-Methoxy-phenyl)-1H,10H-[2,20]biindolyl 5c.
Yield: 36.0 mg, 30%; Yellow solid; H NMR (DMSO) d
1.95 (m, 4H), 2.03–2.07 (m, 4H), 2.53–2.59 (m, 6H), 6.15
(br s, 2H), 7.05–7.49 (m, 16H), 7.76 (d, JZ7.6 Hz, 2H),
10.35 (br s, 2H); 13C NMR (DMSO) d 28.9, 30.0, 34.2,
111.4, 117.8, 119.5, 121.8, 125.9, 126.6, 126.7, 126.9,
128.4, 131.5, 136.0, 136.3, 147.0; ESI-MS: m/z (% relative
intensity) 543.4 (100) (MKH)K, ESI-HRMS calcd for
C40H35N2 543.731, Found 543.730.
1
3.60 (s, 3H), 6.60–7.41 (m, 13H), 10.95 (br s, 11.35H); EI-
MS: m/z (% relative intensity) 339.2 (100) (MCH)C; ESI-
HRMS calcd for C23H19N2O 339.409, Found 339.405.
3.1.17. Experimental procedure for the preparation of
benzo[c]indolo[2,3-a]carbazole 9. To a stirred solution
of 2,2,2-trifluoro-N-(2-(4-[2,2,2-trifluoro-acetylamino)-
phenyl]-buta-1,3-diynyl)-phenyl)-acetamide 1 (0.100 g,
0.24 mmol) in acetonitrile/DMSO (7 mL/1 mL) were
added 1,2-diiodobenzene (0.093 g, 0.28 mmol), K2CO3
(0.099 g, 0.72 mmol) and Pd(PPh3)4 (0.019 g,
0.017 mmol). The reaction mixture was stirred at 80 8C
(bath temperature) under a nitrogen atmosphere for 20 h and
poured in a separatory funnel containing water and ethyl
acetate. The organic layer was separated and the aqueous
layer was extracted twice with ethyl acetate. The combined
organic layers were dried (Na2SO4) and evaporated under
vacuum. The residue was purified by flash chromatography
on silica gel eluting with a 75:25 n-hexane/EtOAc mixture
to give 0.037 g (51%) of 9: Dark solid; IR (KBr) 3450, 820,
3.1.11. 3,30-Bis-(4-tert-butyl-cyclohex-1-enyl)-1H,10H-
[2,20]biindolyl 3l. Yield: 150.0 mg, 61%; Yellow solid; IR
1
(KBr) 3415, 1614, 736 cmK1; H NMR (CDCl3) d 0.97 (s,
18H), 1.01–1.55 (m, 6H), 1.93–2.05 (m, 4H), 2.35 (br s, 4H),
6.10(m, 2H), 7.08–7.25(m, 4H), 7.33(d, JZ7.3 Hz, 2H), 7.59
(d, JZ7.7 Hz, 2H), 8.71 (br s, 2H); 13C NMR (CDCl3) d 25.1,
27.5, 27.8, 31.7, 32.6, 44.4, 110.9, 117.6, 119.8, 120.0, 122.8,
126.3, 128.3, 129.6, 132.9, 135.9; ESI-MS: m/z (% relative
intensity) 505.5 (43) (MCH)C, 504.4 (100) (M)C, 503.3 (73)
(MKH)C, 367 (21). Anal. Calcd for C36H44N2 C, 85.66; H,
8.79; N, 5.55; Found C, 85.49; H, 8.73; N, 5.58.
3.1.12. (L)-3,30-Bis[benzoic(1R,2S,5R)-2-isopropyl-5-
methyl-cyclohexyl ester]-1H,10H-[2,20]biindolyl 3m.
Yield: 216.0 mg, 67%; Yellow solid; [a]D K20.8
(5.45 mg/mL, CHCl3); IR (KBr) 3350, 1720, 1600, 1270,
1
750 cmK1; H NMR (DMSO) d 6.81–6.84 (m, 4H), 7.06–
1
740 cmK1; H NMR (DMSO) d 0.83 (d, JZ5.8 Hz, 6H),
7.10 (m, 2H), 7.24–7.28 (d, JZ8.0 Hz, 2H), 8.04–8.08 (d,
JZ8.0 Hz, 2H), 8.32–8.36 (m, 2H), 11.01 (s, 2H); 13C NMR
d 112.1, 113.2, 119.0, 120.1, 121.2, 121.6, 123.6, 123.8,
125.8, 126.3, 138.4; ESI-MS m/z (% relative intensity)
329.2 (100) (MCNa)C ESI-HRMS calcd for C22H14N2Na
329.357, Found 329.353.
0.89 (d, JZ3.6 Hz, 6H), 0.93 (d, JZ4.1 Hz, 6H), 1.02–2.13
(m, 18H), 4.85–5.04 (m, 2H), 7.13–7.24 (m, 6H), 7.52 (d,
JZ8.3 Hz, 4H), 7.72 (d, JZ8.0 Hz, 2H), 7.98 (d, JZ
8.3 Hz, 4H), 8.46 (br s, 2H); 13C NMR (DMSO) d 16.5,
20.8, 22.0, 23.6, 26.5, 31.4, 34.3, 40.9, 42.2, 74.9, 111.4,

G. Abbiati et al. / Tetrahedron 62 (2006) 3033–3039
3039
Engler, T. A.; Sullivan, K. A.; Grutsch, J. L.; Clayton, M. T.;
Martinelli, M. J.; Pawlak, J. M.; LeTourneau, M.; Coffey,
D. S.; Pedersen, S. W.; Kolis, P.; Furness, K.; Malhotra, S.;
Al-awar, R. M.; Ray, J. E. J. Org. Chem. 2004, 69, 2967–2975.
(g) Kuethe, J. T.; Wong, A.; Davies, I. W. Org. Lett. 2003, 5,
3721–3723. (h) Wood, J. L.; Stoltz, B. M.; Dietrich, H.-J.;
Pflum, D. A.; Petsch, D. T. J. Am. Chem. Soc. 1997, 119,
9641–9651.
Acknowledgements
`
Support from FIRB 2001 (RBAU01FEPP), and the Universita
degli studi dell’Aquila are gratefully acknowledged
References and notes
9. Fang, Q.; Xu, B.; Jiang, B.; Fu, H.; Chen, X.; Cao, A. J. Chem.
Soc. 2005, 1468–1470.
10. Black, D. St. C. Synlett 1993, 246–252.
1. (a) Zeni, G.; Larock, R. C. Chem. Rev. 2004, 104, 2285–2309.
(b) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104,
2127–2198. (c) Handbook of Organopalladium Chemistry for
Organic Synthesis; Negishi, E., Ed.; Wiley Interscience: New
York, 2002. (d) Lee, J. J.; Gribble, G. W. In Palladium in
Heterocyclic Chemistry; Baldwin, J. E., Williams, R. M., Eds.;
Elsevier Science: Oxford, UK, 2000.
11. (a) Fu¨rster, A.; Ptock, A.; Weintritt, H.; Goddard, R.;
Kru¨ger, C. Angew. Chem., Int. Ed. Engl. 1995, 34, 678–681.
(b) Bergman, J.; Kock, E.; Pelcman, B. Tetrahedron 1995, 51,
5631–5642 and references therein.
12. (a) Arcadi, A.; Cacchi, S.; Marinelli, F. Tetrahedron Lett.
1992, 33, 3915–3918. (b) Arcadi, A.; Cacchi, S.; Carnicelli,
V.; Marinelli, F. Tetrahedron 1994, 50, 437–452.
13. Aschi, M., Unplubished results.
2. (a) Kirsch, G.; Hesse, S.; Comel, A. Curr. Org. Synth. 2004, 1,
47–63. (b) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Parisi, L. M.
Tetrahedron Lett. 2004, 45, 2431–2434. (c) Bacchi, A.; Costa,
14. (a) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F.; Parisi,
L. M. Heterocycles 2004, 475–482. (b) Koradin, C.; Dohle,
W.; Rodriguez, A. L.; Schmid, B.; Knochel, P. Tetrahedron
2003, 59, 1571–1587. (c) Suzuki, N.; Yasaki, S.; Yasuhara, A.;
Sakamoto, T. Chem. Pharm. Bull. 2003, 51, 1170–1173.
(d) Dai, W.-M.; Sun, L.-P.; Guo, D.-S. Tetrahedron Lett. 2002,
42, 7699–7702. (e) Dai, W.-M.; Guo, D.-S.; Sun, L.-P.
Tetrahedron Lett. 2001, 41, 5275–5278. (f) Yasuhara, A.;
Kanamori, Y.; Kaneko, M.; Numata, A.; Kondo, Y.;
Sakamoto, T. J. Chem. Soc., Perkin Trans. 1 1999, 529–534.
(g) Kondo, Y.; Kojima, S.; Sakamoto, T. J. Org. Chem. 1997,
62, 6507–6511.
`
M.; Della Ca, N.; Fabbricatore, M.; Fazio, A.; Gabriele, B.;
Nasi, C.; Salerno, G. Eur. J. Org. Chem. 2004, 574–585. (d)
Balme, G.; Bossharth, E.; Monteiro, N. Eur. J. Org. Chem.
2003, 4101–4111. (e) Balme, G.; Bouyssi, D.; Lomberget, T.;
Monteiro, N. Synthesis 2003, 2115–2134. (f) Dai, G.; Larock,
R. C. J. Org. Chem. 2003, 68, 920–928. (g) Rossi, E.; Abbiati,
G. In Attanasi, O. A., Spinelli, D., Eds.; Targets in
Heterocyclic Systems; Italian Society of Chemistry: Rome,
2003; Vol. 7, pp 87–107.
3. (a) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873–2920.
(b) Cacchi, S.; Fabrizi, G.; Battistuzzi, G. Eur. J. Org. Chem.
2002, 2671–2681. (c) Cacchi, S.; Marinelli, F. In Negishi, E.,
Ed.; Handbook of Organopalladium Chemistry for Organic
Synthesis; Wiley: New York, 2002; Vol. 2, pp 2227–2244.
4. Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F.; Parisi, L. M.
J. Org. Chem. 2005, 70, 6213–6227 and references therein.
5. (a) Flynn, B. L.; Hamel, E.; Jung, M. K. J. Med. Chem. 2002,
45, 2670–2673. (b) McGuinan, C.; Brancale, A.; Barucki, H.;
Srinivasan, S.; Jones, G.; Pathirana, R.; Carangio, A.;
Blewett, S.; Luoni, G.; Bidet, O.; Andrei, G.; Snoek, R.; De
Clercq, E.; Balzarini, J. Antiviral Chem. Chemother. 2001, 12,
77–89. (c) Saulnier, M. G.; Frennesson, D. B.; Deshpande, M.;
Vyas, D. M. Tetrahedron Lett. 1995, 35, 7841–7844.
15. Kinderman, S. S.; de Gelder, R.; van Maarseveen, J. H.;
Schoemaker, H. E.; Hiemstra, H.; Rutjes, F. P. J. T. J. Am.
Chem. Soc. 2004, 126, 4100–4101.
16. Wolf, L. B.; Tjen, K. C. M. F.; Brink, H. T.; Blaauw, R. H.;
Hiemstra, H.; Schoemaker, H. E.; Rutjes, F. P. J. T. Adv.
Synth. Catal. 2002, 344, 70–83.
17. (a) Abbiati, G.; Beccalli, E. M.; Broggini, G.; Zoni, C. J. Org.
Chem. 2003, 68, 7625–7628. (b) Driver, M. S.; Hartwig, J. F.
J. Am. Chem. Soc. 1996, 118, 4206–4207. (c) Casalnuovo,
A. L.; Calabres, J. C.; Milstein, D. Inorg. Chem. 1987, 26,
971–972. (d) Fryzuk, M. D.; Montgomery, C. D. Coord. Chem.
Rev. 1989, 95, 1–40.
6. Collini, M. D.; Ellingboe, J. W. Tetrahedron Lett. 1997, 38,
7963–7966.
18. (a) Arcadi, A.; Anacardio, R.; D’Anniballe, G.; Gentile, M.
Synlett 1997, 1315–1317. (b) Arcadi, A. Synlett 1997,
941–943.
7. (a) Cacchi, S.; Fabrizi, G.; Parisi, L. M. Synthesis 2004,
1889–1894. (b) Cacchi, S.; Fabrizi, G.; Lamba, D.;
Marinelli, F.; Parisi, L. M. Synthesis 2003, 728–734.
19. Arcadi, A.; Bianchi, G.; Marinelli, F. Synthesis 2004, 610–618.
20. (a) Abbiati, G.; Arcadi, A.; Canevari, V.; Capezzuto, A.;
Rossi, E. J. Org. Chem. 2005, 70, 6454–6460. (b) Asao, N.;
Nogami, T.; Takanashi, K.; Yamamoto, Y. J. Am. Chem. Soc.
2002, 124, 764–765.
8. (a) Saulnier, M. G.; Langley, D. R.; Frennesson, D. B.;
Long, B. H.; Huang, S.; Gao, Q.; Wu, D.; Fairchild, C. R.;
Ruediger, E.; Zimmermann, K.; St. Laurent, D. R.;
Balasubramanian, B. N.; Vyiaa, D. M. Org. Lett. 2005, 7,
1271–1274. (b) Aubry, C.; Patel, A.; Mahale, S.; Chaudhuri,
21. (a) Bouyssi, D.; Cavicchioli, M.; Balme, G. Synlett 1997,
944–946. (b) Monteiro, N.; Gore, J.; Balme, G. Tetrahedron
1992, 48, 10103–10114.
´
B.; Marechal, J.-D.; Sutcliffe, M. J.; Jenkins, P. R. Tetrahedron
Lett. 2005, 46, 1423–1425. (c) Garg, N.; Stoltz, B. M.
Tetrahedron Lett. 2005, 46, 1997–2000. (d) Kam, T.-O.; Choo,
Y.-M.; Komiyama, K. Tetrahedron 2004, 60, 3957–3966. (e)
Santos, M. M. M.; Lobo, A. M.; Prabhakar, S.; Marques,
M. M. B. Tetrahedron Lett. 2004, 45, 2347–2349. (f) Faul, M.;
22. Arcadi, A.; Cacchi, S.; Marinelli, M. Tetrahedron 1993, 49,
4955–4964.
23. Kamigata, N.; Matsuhisa, A.; Taka, H.; Shimizu, T. J. Chem.
Soc., Perkin Trans. 1 1995, 821–827.