Palladium-catalyzed selective N-(hetero)arylation or N,N′-di(hetero) arylation of 1-aminoindoles

Article abstract of DOI:10.1016/j.tetlet.2011.03.068

The selective synthesis of N-(hetero)aryl-1-aminoindoles 3 from the corresponding N-aminoindoles and (hetero)aryl halides using a catalyst combination of Pd₂(dba)₃ associated to Josiphos is described. By switching to Xantphos as the

Full text of DOI:10.1016/j.tetlet.2011.03.068

Tetrahedron Letters 52 (2011) 2687–2691
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Palladium-catalyzed selective N-(hetero)arylation or N,N0-di(hetero)arylation
of 1-aminoindoles
⇑
⇑
Samir Messaoudi , Jean-Daniel Brion, Mouâd Alami
CNRS, BioCIS UMR 8076, Univ Paris-Sud, BioCIS UMR 8076, Laboratoire de Chimie Thérapeutique, Faculté de Pharmacie, rue J.B. Clément, F-92296 Châtenay-Malabry, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The selective synthesis of N-(hetero)aryl-1-aminoindoles 3 from the corresponding N-aminoindoles and
(hetero)aryl halides using a catalyst combination of Pd2(dba)3 associated to Josiphos is described. By
switching to Xantphos as the ligand, the alternate catalytic system allows the coupling to proceed effi-
ciently for the preparation of symmetrical and unsymmetrical N,N0-diaryl-1-aminoindole derivatives in
good yields.
Received 30 November 2010
Revised 14 March 2011
Accepted 15 March 2011
Available online 22 March 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Palladium
Amination
Cross-coupling
N-Substituted 1-aminoindoles
Homogeneous catalysis
1-Aminoindoles represent an important class of heteroaromatic
compounds, which have attracted much attention because of their
pharmacological properties.1 For example, some of them exhibit
psychotropic,1c anticonvulsant,1d analgesic,1e and antioxidant1f,g
effects. Various N-substituted-1-aminoindoles and related
N-aminoazoles act as antidepressant,2 tyrosine hydroxylase induc-
tors,3 acetylcholinesterase,4 and aromatase5 inhibitors. In addition,
these N-substituted-1-aminoindoles are highly valuable interme-
diates in the synthesis of a number of important nitrogen-contain-
ing heterocyclic frameworks.6
pling partners for such processes, combined with our interest in
discovering new hsp90 inhibitors,12 we decided to explore the abil-
ity of the 1-aminoindoles to participate as nucleophiles in a palla-
dium-catalyzed CꢀN cross-coupling reaction with various
(hetero)aryl halides. To the best of our knowledge, there is no re-
port describing the formation of N-(hetero)aryl-1-aminoindoles
from (hetero)aryl halides and 1-aminoindoles.
N-Aminoindoles present a number of potential problems in pal-
ladium-catalyzed-cross coupling reactions. First, 1-aminoindole as
well as the reaction product N-(hetero)aryl-1-aminoindole can un-
dergo metal-mediated NꢀN bond cleavage,13 thus resulting in the
formation of undesired indole by-products. Secondly, and most
importantly, the N-(hetero)aryl-1-aminoindole still possesses
another reactive NꢀH bond that can undergo further CꢀN cross
coupling, thus leading to diarylated product. Therefore, the devel-
opment of a selective, simple, and general method for the direct
amination of unprotected 1-aminoindoles is strongly desirable
and presents an interesting challenge. Herein, we report on a pal-
ladium catalyst system and reaction conditions that allow, for
the first time, the cross-coupling of (hetero)aryl halides with
1-aminoindoles. The reaction proceeds rapidly under relatively
mild conditions with excellent monoarylation selectivity, thus pro-
viding direct access to various N-(hetero)aryl-1-aminoindole
derivatives.
Although N-substituted-1-aminoindoles exhibit a wide range of
biological activities, to date there has been a limited number of
methods for their preparation. They have been synthesized by
electrolysis,1b or Pd-catalyzed cyclization of N,N0-disubstituted
o-chloroacetaldehyde hydrazones.7 An alternative route consists
in a copper(I)-catalyzed intramolecular cyclization of a suitable
Boc-protected enehydrazine and subsequent deprotection.8
A
recent work concerning the synthesis of substituted 1-aminoin-
doles via a palladium-catalyzed N-arylation of phenylhydrazines
followed by an intramolecular cyclization process9 prompted us
to report the results of our study.
In an ongoing medicinal chemistry program,3 we have
described the metal-catalyzed CꢀN bond coupling reaction of
3-bromoquinolinones and 3-bromocoumarins10 with various
nitrogen nucleophiles,11 including amines, amides, sulfonamides,
carbamates, ureas, and azide anion. During our search for new cou-
To optimize conditions for the preparation of N-aryl-1-aminoin-
dole 3a, the coupling of 1-aminoindole 1a with 4-bromoanisole 2a
was initially selected as a model reaction for investigating the
effects of various ligands, palladium sources, and bases. Represen-
tative results from this study are summarized in Table 1. Reaction
of 1a (1 equiv) with 2a (1 equiv) under our previously reported
⇑
Corresponding authors. Tel.: +33 1 46 83 58 87; fax: +33 1 46 83 58 28 (M.A.).
E-mail addresses: samir.messaoudi@u-psud.fr (S. Messaoudi), mouad.alami@
u-psud.fr (M. Alami).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.068

2688
S. Messaoudi et al. / Tetrahedron Letters 52 (2011) 2687–2691
procedure11 [Pd(OAc)2, Xantphos, Cs2CO3, 1,4-dioxane, 100 °C]
failed to produce the desired N-arylated product 3a (Table 1, entry
1). We quickly turned our attention to the results obtained by Cac-
chi et al.14 wherein it was shown that the addition of LiCl has a
beneficial effect on the palladium-catalyzed N-arylation of dial-
kylhydrazines. Thus, when equimolar amounts of 1a and 2a were
reacted under the Cacchi’s conditions (Pd2(dba)3/Xantphos, NaOt-
Bu, LiCl toluene at 80 °C), the N-arylation reaction occurred
smoothly. However, this coupling was inefficient (conv ꢁ50%)
and resulted in a concomitant formation of the desired compound
3a and disubstitued by-product 4a (Table 1, entry 2). After a te-
dious separation, 3a and 4a were isolated in low 30% and 5% yields,
respectively. Upon adjusting the ratio of N-aminoindole 1a to 4-
bromoanisole 2a to 1:2, a complete conversion of 1a was observed
producing exclusively the N,N-diaryl coupling product 4a in 60%
isolated yield (entry 3). When increasing the temperature to
120 °C, a complete conversion of 1a was observed within 1 h, how-
ever, the reaction was not selective and provided a mixture of the
desired compound 3a (30%) and by-product 4a (51%) (entry 4). To
circumvent the formation of 4a, we proceeded to optimize the
reaction by screening various phosphine ligands (Xphos, DPEphos,
BINAP, PPh3, Josiphos, etc.). Complete conversion was observed
only in the reaction employing Xphos as the ligand, again leading
to a mixture of 3a and 4a in 49% and 42% yields, respectively (entry
5). All other ligands were ineffective (entries 6–8) except for the
electron rich bisphosphine ligand Josiphos, which provided a
breakthrough in selectivity. The reaction formed exclusively the
monoarylated product 3a in 38% yield, despite a 50% conversion
(entry 9). A further increase of the temperature (130 °C) and reac-
tion time (3 h) gave a slightly better result of 3a (56%, entry 10).
Optimization with respect to the base was next performed. LiOtBu
afforded poor results in comparison with NaOtBu (entries 10 and
11), whereas no reaction occurred with Cs2CO3 and AcONa (entries
12 and 13). However, we were pleased to find that KOtBu seems to
be the base of choice for this reaction and to exceed the threshold
of 90% of the desired product 3a. Under these conditions, pure 3a
was obtained in a 94% isolated yield (entry 14). It should be noted
that decreasing the amount of Pd2(dba)3/Josiphos ratio from 2.5:5
to 1:2 mol % resulted in diminished conversion and yields (entry
15).
Prompted by these results, we subsequently investigated the
substrate scope for the mono(hetero)arylation of 1-aminoindoles.
Results summarized in Table 2, show that the optimized conditions
described above proved to be general for the coupling with a large
variety of functionalized aryl halides. The N-arylation reaction
worked well with electron rich aryl iodides, bromides as well as
the less reactive aryl chlorides (entries 1–9). In addition, there is
little effect of the substituent pattern of the aryl halide with re-
spect to yield and selectivity. Substrate 3,4,5-trimethoxybromo-
benzene reacted reasonably well giving 3g in acceptable yield
(entry 9). One can note that compound 3g may be regarded as an
analogue of isocombretastatin A-4 (isoCA-4), a highly promising
Table 1
Optimization coupling reaction of 1-aminoindole 1a with 4-bromoanisole under various conditionsa
Br
[Pd] / L / base
N
N
N
+
+
N
NH
LiCl, Toluene
T °C
OMe
NH2
MeO
MeO
OMe
1a
2a
3a
4a
PPh2
PPh2
PPh2
PPh2
O
PCy2
i-Pr
O
PPh2
PPh2
i-Pr
P
Fe
P
i-Pr
Josiphos
Xantphos
Xphos
DPEphos
Time (h)
BINAP
Entry
[Pd]
Ligand
Base
T (°C)
Convb (%)
Yieldc (%)
3a
4a
1d
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Pd(OAc)2
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Xantphos
Xantphos
Xantphos
Xantphos
Xphos
DPEphos
BINAP
PPh3
Josiphos
Josiphos
Josiphos
Josiphos
Josiphos
Josiphos
Josiphos
Cs2CO3
12
12
6
1
1
1
1
1
1
3
3
3
3
3
6
110
80
80
0
50
100
100
100
0
0
0
50
100
90
0
—
—
5
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
LiOtBu
30e
0
60
51
42
—
—
—
0
0
0
—
—
0
120
120
120
120
120
120
130
130
130
130
130
130
30
49
—
—
—
38
56
25
—
Cs2CO3
AcONa
KOtBu
KOtBu
0
100
90
—
94f,g
74g
0
a
Reactions of 1a (1.0 mmol) with 4-bromoanisole 2a (2.0 mmol) were performed in a sealed Schlenk tube in toluene (5 mL) by using [Pd] (2.5 mol %), ligand (5 mol %), LiCl
(2.0 mmol) and base (1.4 mmol).
b
Conversion was determined by 1H NMR in the crude reaction mixture and was based on remaining 1a.
Isolated yields.
1,4-Dioxane was used as the solvent.
A 1:1 ratio of 1a/2a was used.
No reaction occurred without palladium catalyst.
Average of three runs.
A 1:2 mol % ratio Pd2(dba)3/Josiphos was used.
c
d
e
f
g
h

S. Messaoudi et al. / Tetrahedron Letters 52 (2011) 2687–2691
2689
Table 2
Palladium-catalyzed mono-(hetero)arylation of 1-aminoindoles 1 with aryl halides 2a
R1
R2
Pd2dba3 / Josiphos
X
+
N
R1
R2
NH
KOtBu, LiCl
Toluene,130 °C, 3 h
N
1
2
3
NH2
Entry
1
ArX
Product 3
Yieldb (%)
91
Entry
9
ArX
Product 3
Yieldb (%)
X
Br
OMe
OMe
51
N
N
OMe
NH
MeO
MeO
NH
X = I
X = Br
X = Cl
OMe
3a
3g
3h
2
3
94
72
MeO
MeO
OMe
Br
Br
N
N
OMe
4
3b
81
10
53
HN
NH
MeO
I
I
N
N
F
5
6
7
8
3c
3d
3e
3f
90
77
60
61
11
12
13
14
3i
3j
63
58
NH
NH
F
Br
OMe
Br
Br
Br
N
N
CN
NH
MeO
NH
NC
OMe
SMe
N
Br
Br
N
N
3k
3l
40c
NH
NH
N
OMe
N
N
N
60
NH
HN
SMe
N
a
Reactions of 1a (1.0 mmol) with 4-bromoanisole 2a (2.0 mmol) were performed in a sealed Schlenk tube in toluene (5 mL) by using Pd2(dba)3 (2.5 mol %), Josiphos
(5 mol %), LiCl (2.0 mmol) and KOtBu (1.4 mmol).
b
Isolated yields. For a general procedure; see Ref. 15.
32% of bis-coupling by-product 4d were isolated.
c
cytotoxic and antitubulin agent, developed in our group.16 Steri-
cally demanding ortho substitution pattern was tolerant toward
the arylation of 1-aminoindole 1a and led to monoarylated com-
pounds 3e, 3f, and 3h in yields ranging from 53% to 61% (entries
7, 8 and 10). Substrates bearing an electron-withdrawing group
such as 4-fluoroiodobenzene as well as 4-cyanobromobenzene
were also successfully engaged in N-arylation of 1-aminoindole
1a affording the corresponding monoarylated compounds 3i and
3j in 63% and 58% yields, respectively (entries 11 and 12). As
depicted in entries 13 and 14, heteroaromatic bromides could be
employed in this N-arylation reaction as well. Thus, 2-bromopyri-
dine and 3-bromoquinoline gave rise to the monoheteroarylated
1-aminoindoles 3k and 3l in 40% and 60% yields, respectively.
Having successfully generated monoarylated 1-aminoindoles 3
from aryl halides, the scope of this method was further expanded
to form N,N-diaryl-1-aminoindoles 4 by employing the catalytic
system based on Pd2(dba)3/Xantphos. Thus, when the reaction of
1a with appropriate (hetero)aryl halides in 1:2 ratio was con-
Pd2dba3 /Xantphos
NaOtBu, LiCl
X
Br
+
N
N
R
X
X
Toluene
90 °C, 6 h
N
R
R
NH2
1a
4
R = 4-OMe, X = CH
R = H, X = CH
R = 4-F, X = CH
R = H, X = N
4a (60%)
4b (61%)
4c (59%)
4d (83%)
Scheme 1. Palladium-catalyzed di(hetero)arylation of 1-aminoindole 1a with aryl
halides. For a general procedure; see Ref. 17.
ducted in the presence of NaOtBu (2.4 equiv) and LiCl (2.0 equiv),
only bis-coupled products 4 were formed (Scheme 1). Under these
conditions, aryl halides containing either electron-withdrawing or

2690
S. Messaoudi et al. / Tetrahedron Letters 52 (2011) 2687–2691
10. Audisio, D.; Messaoudi, S.; Brion, J.-B.; Alami, M. Eur. J. Org. Chem. 2010, 1046–
Pd2dba3 /Xantphos
N
Br
+
1051.
NaOtBu
11. (a) Audisio, D.; Messaoudi, S.; Peyrat, J.-F.; Brion, J.-D.; Alami, A. Tetrahedron
Lett. 2007, 48, 6928–6932; (b) Messaoudi, S.; Audisio, D.; Brion, J.-D.; Alami, A.
Tetrahedron 2007, 63, 10202–10210; (c) Messaoudi, S.; Brion, J.-D.; Alami, M.
Adv. Synth. Catal. 2010, 352, 1677–1687.
N
N
N
Toluene
90 °C, 12 h
N
NH
49%
12. For
a review, see: (a) Messaoudi, S.; Peyrat, J.-F.; Brion, J.-D.; Alami, M.
3a
MeO
MeO
Anticancer Agents Med. Chem. 2008, 8, 761–782; (b) Le Bras, G.; Radanyi, C.;
Peyrat, J.-F.; Brion, J.-D.; Alami, M.; Marsaud, V.; Stella, B.; Renoir, J.-M. J. Med.
Chem. 2007, 50, 6189–6200; (c) Radanyi, C.; Le Bras, G.; Messaoudi, S.; Bouclier,
C.; Peyrat, J.-F.; Brion, J.-D.; Marsaud, V.; Renoir, J.-M.; Alami, M. Bioorg. Med.
Chem. Lett. 2008, 18, 2495–2498; (d) Radanyi, C.; Le Bras, G.; Marsaud, V.;
Peyrat, J.-F.; Messaoudi, S.; Catelli, M. G.; Brion, J.-D.; Alami, M.; Renoir, J.-M.
Cancer Lett. 2008, 274, 88–94; (e) Radanyi, C.; Le Bras, G.; Bouclier, C.;
Messaoudi, S.; Peyrat, J.-F.; Brion, J.-D.; Alami, M.; Renoir, J.-M. Biochem.
Biophys. Res. Commun. 2009, 379, 514–518; (f) Audisio, D.; Messaoudi, S.; Ijjaali,
I.; Dubus, E.; Petitet, F.; Peyrat, J.-F.; Brion, J.-D.; Alami, M. Eur. J. Med. Chem.
2010, 45, 2000–2009; (g) Sahnoun, S.; Messaoudi, S.; Peyrat, J.-F.; Brion, J.-D.;
Alami, M. Tetrahedron Lett. 2008, 49, 7279–7283; (h) Sahnoun, S.; Messaoudi,
S.; Brion, J.-D.; Alami, M. Org. Biomol. Chem. 2009, 7, 4271–4278; (i) Sahnoun,
S.; Messaoudi, S.; Brion, J.-B.; Alami, M. Eur. J. Org. Chem. 2010, 6097–6102.
13. (a) Lee, K.-S.; Lim, Y.-K.; Cho, C.-G. Tetrahedron Lett. 2002, 43, 7463–7467; (b)
Ellames, G. J.; Gibson, J. S.; Herbert, J. M.; McNeill, A. H. Tetrahedron 2001, 57,
9487–9497; (c) Alonso, F.; Radivoy, G.; Yus, M. Tetrahedron 2000, 56, 8673–
8678.
5a
Scheme 2. Palladium-catalyzed synthesis of unsymmetrical N,N0-diaryl-1-amino-
indole 5a. For a general procedure; see Ref. 18.
electron-releasing groups as well as heteroaromatic bromides, suc-
cessfully participated in the reactions affording symmetrically N,N-
diaryl-1-aminoindoles 4a–d in good yields (Scheme 1, 59–83%).
Finally, we examined the Pd-catalyzed synthesis of unsymmet-
rical N,N0-diaryl-1-aminoindoles. In
a typical experiment, we
achieved this transformation by mixing 3a (1 equiv) with 2-bro-
mopyridine (2 equiv) as a partner, Pd2(dba)3/Xantphos as the cata-
lytic system in toluene at 100 °C for 12 h. Thus, under this protocol,
we were pleased to observe that the reaction worked well and pro-
vided the desired product 5a in a 49% yield, despite the fact that
the reaction conditions had never been optimized (Scheme 2).
In conclusion, we successfully described a simple and selective
protocol for the concise synthesis of diversified N-(hetero)aryl-1-
aminoindoles 3 from the corresponding N-aminoindoles and (het-
ero)aryl halides using Pd2(dba)3/Josiphos as the catalytic system.
We also have demonstrated that the use of Xantphos as the ligand
enlarges the scope of this work with the synthesis of symmetrical
N,N0-biaryl 1-aminoindoles 4 in good to excellent yields. Investiga-
tions on further expanding the scope of the method to other re-
lated heterocycles are in progress in our laboratory and will be
reported in due course.
14. (a) Cacchi, S.; Fabrizi, G.; Goggiamani, A.; Licandro, E.; Maiorana, S.; Perdicchia,
D. Org. Lett. 2005, 7, 1497–1500; (b) Cacchi, S.; Fabrizi, G.; Goggiamani, A.;
Sgalla, S. Adv. Synth. Catal. 2007, 349, 453–458.
15. General procedure for Pd-catalyzed monocoupling of 1-aminoindoles with various
aryl halides: A flame-dried resealable Schlenk tube was charged with Pd2(dba)3
(0.025 mmol, 2.5 mol %), Josiphos (0.05 mmol, 5 mol %), the solid reactant(s)
(1.0 mmol of the 1-aminoindole, 2.0 mmol of the aryl halide), LiCl (2.0 mmol)
and KOtBu (1.4 mmol). The Schlenk tube was capped with a rubber septum,
evacuated, and backfilled with argon; this evacuation/backfill sequence was
repeated one additional time. The liquid reactant(s) and toluene (2 mL/mmol)
were added through the septum. The septum was replaced with a teflon
screwcap. The Schlenk tube was sealed, and the mixture was stirred at 130 °C
for 3 h. The resulting suspension was cooled to room temperature and filtered
through a pad of celite eluting with ethyl acetate, and the inorganic salts were
removed. The filtrate was concentrated and purification of the residue by silica
gel column chromatography gave the desired product. All the compounds gave
satisfactory spectroscopic data. Data for the selected compounds are given
below:
Acknowledgment
Compound 3a: Yield: 94%; TLC : Rf 0.39 (c-hexane/AcOEt 8:2). IR (neat): 3306,
1604, 1508, 1446, 1359, 1246, 1220, 1112, 1063, 832, 754 cmꢀ1 1H NMR
;
(CDCl3, 300 MHz) : d 7.55 (dd, 1H, J = 6.5, 2.3 Hz), 7.25–6.95 (m, 4H), 6.65 (d,
2H, J = 8.9 Hz), 6.42 (d, 1H, J = 3.3 Hz), 6.37 (d, 2H, J = 8.9 Hz), 6.32 (s, 1H), 3.62
(s, 3H).13C NMR (75 MHz, CDCl3) d 154.5, 141.0, 135.9, 128.7, 126.6, 122.3,
121.1, 120.3, 114.7 (2C), 114.2 (2C), 109.5, 100.6, 55.6. m/z MS (ES+) 239.0
(M+H+).
The CNRS is gratefully acknowledged for support of this
research.
References and notes
Compound 3i: Yield: 63%; TLC : Rf 0.40 (c-hexane/AcOEt 8:2). IR (neat): 3326,
1521, 1466, 1236, 1220, 1125, 1103, 832, 754 cmꢀ1 1H NMR (CDCl3, 300 MHz)
;
1. (a) Andersen, K.; Perregaard, J.; Arnt, J.; Bay Nielsen, J.; Begtrup, M. J. Med. Chem.
1992, 35, 4823–4831; (b) Frontana-Uribe, B. A.; Moinet, C.; Toupet, L. Eur. J. Org.
Chem. 1999, 419–430; c Le Ridant, A.; Harpey, C. FR2911143, 2008.; (d) Huger,
F. P.; Smith, C. P.; Kongsamut, S.; Tang, L. U.S. Patent 5, 776, 955, 1998.; (e)
Effland, R. C.; Klein, J. T.; Davis, L.; Olson, G. E. EP0402752, 1990.; (f) Gurkan, A.
S.; Karabay, A.; Buyukbingol, Z.; Adejare, A.; Buyukbingol, E. Arch. Pharm. Chem.
Life Sci. 2005, 338, 67–733; (g) Itoh, T.; Miyazaki, M.; Maeta, H.; Matsuya, Y.;
Nagata, K.; Ohsawa, A. Bioorg. Med. Chem. 2000, 8, 1983–1989.
2. Morin, D.; Zini, A.; Urien, S.; Tillement, J. P. J. Pharmacol. Exp. Ther. 1989, 249,
288–296.
3. (a) Brion, J.-D.; Bintein, F.; Razet, R.; Razon, P.; Renko, Z.-D.; Levoisier, E.; Pujol,
J. F.; Weissmann, D.; Le Ridant, A.; Harpey, C. WO/2007/006922, 2007.; (b)
Brion, J.-D.; Galtier, C.; Hervet, M.; Le Strat, F.; Moreau, A.; Renko, Z.-D.; Le
Ridant, A.; Harpey, C. WO/2008/099082, 2008.
4. (a) Klein, J. T.; Davis, L.; Olsen, G. E.; Wong, G. S.; Huger, F. P.; Smith, C. P.; Petko,
W. W.; Cornfeldt, M.; Wilker, J. C.; Blitzer, R. D.; Landau, E.; Haroutunian, V.;
Martin, L. L.; Effland, R. C. J. J. Med. Chem. 1996, 39, 570–581; (b) Smith, C. P.;
Bores, G. M.; Petko, W.; Li, M.; Selk, D. E.; Rush, D. K.; Camacho, F.; Winslow, J.
T.; Fishkin, R.; Cunningham, D. M.; Brooks, K. M.; Roehr, J.; Hartman, H. B.;
Davis, L.; Vargas, H. M. J. Pharmacol. Exp. Ther. 1997, 280, 710–720.
5. Lafay, J.; Rondot, B.; Bonnet, P.; Clerc, T.; Shields, J.; Duc, I.; Duranti, E.; Puccio,
F.; Blot, C.; Maillos, P. WO/2005/058842, 2005.
6. (a) Somei, M.; Natsume, M. Tetrahedron Lett. 1974, 3605; (b) Somei, M.;
Matsubara, M.; Natsume, M. Chem. Pharm. Bull. 1975, 23, 2891–2898; (c) Shen,
J.-K.; Katayama, H.; Takatsu, N.; Shiro, I. J. Chem. Soc., Perkin Trans. 1 1993,
2087–2097; (d) Melnyk, P.; Gasche, J.; Thal, C. Tetrahedron Lett. 1993, 34, 5449–
5450; (e) Melnyk, P.; Legrand, B.; Gasche, J.; Ducrot, P.; Thal, C. Tetrahedron
1995, 51, 1941–1952.
7. Watanabe, M.; Yamamoto, T.; Nishiyama, M. Angew. Chem., Int. Ed. 2000, 39,
2501–2504.
8. Melkonyan, F.; Topolyan, A.; Yurovskaaya, M.; Karchava, A. Eur. J. Org. Chem.
2008, 5952–5956.
: d 7.79–7.61 (m, 1H), 7.33–7.10 (m, 4H), 6.99–6.83 (m, 2H), 6.55 (dd, 1H,
J = 3.3, 0.7 Hz), 6.54, (br s, 1H), 6.46 (dd, 2H, J = 9.0, 4.4 Hz). 13C NMR (75 MHz,
CDCl3) d 159.4 (d, 1C, JCꢀF = 237.0 Hz), 143.4, 135.6, 128.5, 126.7, 122.5, 121.2,
120.4, 116.0 (d, 2C, JCꢀF = 23.5 Hz), 114.0 (d, 2C, JCꢀF = 8.3 Hz), 109.3, 100.9. m/z
MS (ES+) 227.0 (M+H+).
16. (a) Messaoudi, S.; Tréguier, B.; Hamze, A.; Provot, O.; Peyrat, J.-F.; De Losada, J.
R.; Liu, J.-M.; Bignon, J.; Wdzieczak-Bakala, J.; Thoret, S.; Dubois, J.; Brion, J.-D.;
Alami, M. J. Med. Chem. 2009, 52, 4538–4542; (b) Hamze, A.; Giraud, A.;
Messaoudi, S.; Provot, O.; Peyrat, J.-F.; Bignon, J.; Liu, J.-M.; Wdzieczak-Bakala,
J.; Thoret, S.; Dubois, J.; Brion, J.-D.; Alami, M. Chem. Med. Chem. 2009, 4, 1912–
1924; (c) Messaoudi, S.; Hamze, A.; Provot, O.; Tréguier, B.; De Losada, J. R.;
Bignon, J.; Liu, J.-M.; Wdzieczak-Bakala, J.; Thoret, S.; Dubois, J.; Brion, J.-D.;
Alami, M. Chem. Med. Chem. 2011, 6, 488–497.
17. General procedure for Pd-catalyzed synthesis of N,N0-diaryl-1-aminoindoles 4: A
flame-dried resealable Schlenk tube was charged with Pd2(dba)3 (0.025 mmol,
2.5 mol %), Xantphos (0.05 mmol, 5 mol %), the solid reactant(s) (1.0 mmol of
the 1-aminoindole, 2.0 mmol of the aryl halide), LiCl (2.0 mmol) and NaOtBu
(2.8 mmol). The Schlenk tube was capped with a rubber septum, evacuated,
and backfilled with argon; this evacuation/backfill sequence was repeated one
additional time. The liquid reactant(s) and toluene (2 mL per mmol) were
added through the septum. The septum was replaced with a teflon screwcap.
The Schlenk tube was sealed, and the mixture was stirred at 130 °C for 3 h. The
resulting suspension was cooled to room temperature and filtered through a
pad of celite eluting with ethyl acetate, and the inorganic salts were removed.
The filtrate was concentrated and purification of the residue by silica gel
column chromatography gave the desired product. All the compounds gave
satisfactory spectroscopic data. Data for the selected compounds are given
below:
Compound 4a: Yield: 60%; TLC : Rf 0.62 (c-hexane/AcOEt 8:2 IR (neat): 3311,
1608, 1581, 1455, 1368, 1252, 1131, 911, 821 cmꢀ1; NMR (300 MHz) d 7.52 (d,
1H, J = 7.6 Hz), 7.30 (d, 1H, J = 9.0 Hz), 7.15 (d, 1H, J = 3.4 Hz), 7.10–6.99 (m,
2H), 6.79 (d, 4H, J = 8.9 Hz), 6.66 (d, 4H, J = 8.9 Hz), 6.45 (d, 1H, J = 3.4 Hz), 3.62
(s, 3H), 3.61 (s, 3H). 13C NMR (75 MHz, CDCl3) d 155.6 (2C), 139.8 (2C), 135.6,
9. Halland, N.; Nazare, M.; Alonso, J.; R’kyek, O.; Lindenschmidt, A. Chem.
Commun. 2011, 47, 1042–1044.

S. Messaoudi et al. / Tetrahedron Letters 52 (2011) 2687–2691
2691
127.6, 126.2, 122.7, 121.1, 120.5 (5C), 114.6 (4C), 109.9, 101.6, 55.5 (2C). m/z
MS (ES+) 344.0 (M+).
temperature and filtered through a pad of celite eluting with ethyl acetate, and
the inorganic salts were removed. The filtrate was concentrated and
purification of the residue by silica gel column chromatography gave the
desired product 5a.
18. Palladium-catalyzed synthesis of unsymmetrical N,N0-diaryl-1-aminoindole 5a: A
flame-dried resealable Schlenk tube was charged with Pd2(dba)3 (0.025 mmol,
2.5 mol %), Xantphos (0.05 mmol, 5 mol %), 3a (1.0 mmol), and NaOtBu
(2.8 mmol). The Schlenk tube was capped with a rubber septum, evacuated
and backfilled with argon; this evacuation/backfill sequence was repeated one
additional time. The liquid reactant(s) (2-bromopyridine) (2.0 mmol) and
toluene (4 mL/mmol) were added through the septum. The septum was
replaced with a teflon screwcap. The Schlenk tube was sealed, and the mixture
was stirred at 100 °C for 12 h. The resulting suspension was cooled to room
Compound 5a: Yield: 49%; TLC : Rf 0.25 (c-hexane/CH2Cl2 5:5 IR (neat): 1587,
1507, 1431, 1246, 1032, 825, 742 cmꢀ1 1H NMR (300 MHz, CDCl3) d 8.16 (d,
;
J = 4.2 Hz, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.30-7.00 (m, 7H), 6.78 (d, J = 8.9 Hz, 2H),
6.75–6.64 (m, 1H), 6.54 (d, J = 3.2 Hz, 1H), 5.97 (d, J = 8.5 Hz, 1H), 3.69 (s, 3H).
13C NMR (75 MHz, CDCl3) d 157.8, 157.3, 147.8, 138.2, 136.2, 135.1, 127.5,
126.5, 124.9 (2), 123.0, 121.3, 120.8, 116.2, 114.4 (2), 109.5, 108.5, 102.2, 55.4.
m/z MS (ES+) 316.0 (M+H+).