Straightforward Bienayme and copper catalyzed N-arylation sequence to access diverse 5H-pyrido[2′,1′:2,3]imidazo[4,5-b]indoles and analogues

Article abstract of DOI:10.1016/j.tet.2012.07.081

A two-step sequence is reported giving access to diverse 5H-pyrido[2′,1′:2,3]imidazo[4,5-b]indoles and analogues via a Bienayme multicomponent reaction followed by N-arylation. The desired polycylic scaffolds were obtained in high yield using copper iodide in association with TMEDA in aqueous or dioxane media.

Full text of DOI:10.1016/j.tet.2012.07.081

Tetrahedron 68 (2012) 9131e9138
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
ꢀ
Straightforward Bienayme and copper catalyzed N-arylation sequence to access
diverse 5H-pyrido[20,10:2,3]imidazo[4,5-b]indoles and analogues
,
,
*
Ahmed El Akkaoui a b, Marie-Aude Hiebel a, Abderrahim Mouaddib b, Sabine Berteina-Raboin a
,
a
ꢀ
Gerald Guillaumet
a
ꢀ
ꢀ
ꢀ
Institut de Chimie Organique et Analytique, Universite d’Orleans, UMR CNRS 7311, BP 6759, 45067 Orleans Cedex 2, France
Faculte des Sciences et Techniques, Universite Sultan Moulay Slimane, BP 523, 23000 Beni-Mellal, Morocco
b
ꢀ
ꢀ
a r t i c l e i n f o
a b s t r a c t
A two-step sequence is reported giving access to diverse 5H-pyrido[20,10:2,3]imidazo[4,5-b]indoles and
Article history:
Received 6 April 2012
Received in revised form 18 July 2012
Accepted 24 July 2012
Available online 14 August 2012
ꢀ
analogues via a Bienayme multicomponent reaction followed by N-arylation. The desired polycylic
scaffolds were obtained in high yield using copper iodide in association with TMEDA in aqueous or di-
oxane media.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Multicomponent reaction
ꢀ
Bienayme reaction
N-Arylation
Isocyanide
Heterocycle
1. Introduction
Based on the recent development of multicomponent reactions
(MCRs), novel complex products can be efficiently obtained in
Polycyclic scaffolds containing heteroatoms like nitrogen con-
tinuously arise interest in the drug discovery field. Some indolic
structures fused with other heterocycles have already been studied
and reported to exhibit diverse interesting biological activities.1 For
instance, benzofuroindoles 1, benzothioindoles 2, and indo-
loindoles 3 show activities against sexual hormone disorders1d and
different types of cancer due to their extensive antitumour effect
(Fig. 1).1b Furthermore these scaffolds can also modulate the po-
tassium channels controlling muscular contractions, which can
relevant for the treatment of irritable bowel syndrome, asthma,
congestive heart failure, and cerebral vascular diseases.1c
a short number of steps, while still introducing wide and versatile
ꢀ5
chemical variations.2 Passerini,3 Ugi,3b,4 Bienayme and Groeb-
keeBlackburn6 reactions relying on the special reactivity of iso-
nitrile offer a powerful tool to generate chemical libraries. Based on
the concern of the group to synthetize new nitrogen containing
polycyclic compounds,7 our interest focuses on pyr-
idoeimidazoindoles analogues, which remain until lately a rather
undescribed scaffold.8 Chauhan et al. reported a method combining
ꢀ
Bienayme reaction followed by a copper catalyzed Hart-
a
wigeBuchwald N-arylation (Scheme 1).9 Several analogues of the
desired scaffold were isolated in moderate to good yield after
heating the MCR products in DMF in presence of caesium carbon-
ate, copper, and 1,10-phenanthroline. This recent communication
induced us to disclose herein a similar straightforward method.
However in our approach, we focused on the potent use of an
aqueous media and an inexpensive ligand, which could also give
efficiently access to pyridoimidazolindoles without restraining the
scope of reagents.
R1
N
R1
N
R1
N
R2
R2
R2
R3
R3
R3
N
O
S
2
R4
1
3
Fig. 1.
2. Results and discussion
We focused our study on the N-arylation step and decided to
optimize the condition on N-benzyl-2-(2-bromophenyl)-6-
chloroimidazo[1,2-a]pyridin-3-amine 4a.
* Corresponding author. Tel.: þ33 238 494 856; fax: þ33 238 417 281; e-mail
address: sabine.berteina-raboin@univ-orleans.fr (S. Berteina-Raboin).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.07.081

9132
A. El Akkaoui et al. / Tetrahedron 68 (2012) 9131e9138
Br
With these conditions in hand, we decided to investigate
NH2
CHO
MeOH,
PTSA
N
further the scope of the reaction. Several polycyclic nitrogen-
containing scaffolds were synthetized in excellent yield with
electron withdrawing and donating groups (Table 2 products
+
Br
N
N
rt, 18 h
R-NC
NH
R
ꢀ
4aej) using the Bienayme MCR reaction. Then, two experimental
62 - 93 %
13 examples
R: alkyl
conditions were tested: CuI (10 mol %), TMEDA (3 equiv), H2O,
120 ꢀC (method A) or CuI (10 mol %), TMEDA (20 mol %), Cs2CO3
(2 equiv), dioxane, 100 ꢀC (method B). With 2-aminopyridines,
these methods enabled to obtain in excellent yield 5H-pyrido
[20,10:2,3]imidazo[4,5-b]indoles (entries 1e6). When halogen-
CuI (10 mol %)
DMF,
L (10 mol %),
120 °C
Cs2CO3 (2 equiv.)
N
N
L : 1,10-phenanthroline
N
substituted imidazo[1,2-a]pyridin were used, method
B
N
appeared to be the most appropriate. With electron withdrawing
groups, the products 5e and 5f were cleanly isolated in aqueous
media (method A, entries 5 and 6). The same conditions were
also suitable for moderate electron donating group (entry 4). It
is worth noticing that N-arylation reaction gave also excellent
results with chlorinated adducts (Table 2, entry 2; Table 3, entry
5). In order to invalidate a possible SnAr reaction, 4o was used
in reaction without copper iodide and starting material was
completely recovered. Then, the method was extended to the
formation of 10H-pyridazino-[60,10:2,3]imidazo[4,5-b]indoles, 6H-
pyrazino [20,10:2,3]imidazo-[4,5-b]indoles (entries 7e10). With
N
R
52 - 72 %
13 examples
Scheme 1.
This product 4a was obtained in good yield following the
Bienayme condensation between 2-amino-5-chloropyridine, ben-
ꢀ
zylisonitrile, and 2-bromobenzaldehyde in the presence of a cata-
lytic amount of acid. Once synthetized, the imidazole adduct was
tested in the N-arylation step. First, the conditions described by
Buchwald using palladium/xantphos system were tried.10 The de-
sired compound 5a was obtained with an excellent yield, but the
reaction was not complete and gave rise to the formation of an
these poly-nitrogen-containing products, method
most efficient. Low conversion was noticed in this case with
method A.
In order to prevent the residual formation of imine, a new series
of imidazo[1,2-a]pyridine was studied (Table 3). p-Methox-
yphenylisonitrile was this time used for the Bienayme reaction to
B was the
ꢀ
imine by-product coming from a b-H elimination (Table 1, entry 1).
obtain N-arylated product and then avoid the b-H elimination. The
Then based on our concern to develop environmentally sound re-
actions, copper catalyst was used.11 It was already reported to be an
efficient alternative to palladium.12 Surprisingly with 1,10-
phenanthroline as ligand, the starting material was mainly re-
covered (entry 2).9,13
MCR products 4keo were isolated using the same acidic experi-
mental condition without noticing any loss of reactivity. Then the
cyclization was achieved following method B. The expected 5H-
pyrido[20,10:2,3]imidazo[4,5-b]indoles 5keo were obtained cleanly
in excellent to quantitative yield, confirming the significance of the
Table 1
Br
N
N
N
N
Cl
Cl
NH
N
4a
5a
Entry
Conditions
Base (equiv)
Solvent
T (ꢀC)
t (h)
Amount recovered %
Yield %
4a
5a
1
2
3
4
5
Pd(OAc)2 (10 mol %), Xantphos (20 mol %),
CuI (10 mol %), 1,10-phenanthroline (20 mol %)
CuI (10 mol %), TMEDA (20 mol %)
CuI (10 mol %), TMEDA (20 mol %)
CuI (10 mol %), TMEDA (3 equiv)
K2CO3 (20)
Cs2CO3 (2)
Cs2CO3 (2)
d
Dioxane
Dioxane
Dioxane
Dioxane
H2O
100
100
100
100
120
12
24
12
12
12
10
90
0
60
0
75a
Traces
66a
25
d
80
a
Presence of an imine-by-product.
Then the strategy chosen was based on previous work pioneered
by Tellitu on benzofuroindoles, using copper iodide with tetrame-
thylethylenediamine (TMEDA).1aec With caesium carbonate in di-
oxane, 5a was isolated in 66% yield, but these conditions did not
prevent the formation of a benzylimine byproduct resulting from
choice of the substituent on the amine. The efficiency of the
Buchwald coupling was indeed noticeably improved with aryl
amines compared to alkyl amines (Table 2).
3. Conclusion
a b-H elimination. Nevertheless, by removing the base and con-
ducting the reaction in water, 5a was this time obtained in excellent
ꢀ
To conclude, MCR via the Bienayme reaction enabled the diverse
yield as a single product.
and efficient formation of imidazo[1,2-a]pyridines, imidazo[1,2-b]

A. El Akkaoui et al. / Tetrahedron 68 (2012) 9131e9138
9133
Table 2
Br
N
Br
N
BnNC (1.05 equiv.),
HClO4 (0.05 equiv.)
NH2
N
Method A or B
N
+
N
OHC
N
NH
MeOH, RT
1.00 equiv.
1.05 equiv.
4a-j
5a-j
Entry
1
Starting materials
Yield % (4)
91 (4a)
Methoda (time)
Yieldb % (5)
NH2
N
Br
A (12 h)
B (12 h)
80 (5a)
66c (5a)
Cl
Cl
Br
OHC
N
NH2
N
Cl
2
3
4
5
6
94 (4b)
92 (4c)
93 (4d)
89 (4e)
84 (4f)
B (8 h)
90 (5b)
OHC
OMe
NH2
N
Br
A (12 h)
B (12 h)
d
62c (5c)
OHC
Br
NH2
A (12 h)
A (24 h)
A (12 h)
86 (5d)
80 (5e)
78c (5f)
N
OHC
Br
NH2
NH2
N
N
NC
OHC
Br
F3C
OHC
Br
NH2
7
8
9
86 (4g)
92 (4h)
90 (4i)
A
B
20d (5g)
80c (5g)
N
Cl
N
N
OHC
Br
NH2
A
B
20e (5h)
83 (5h)
N
OHC
Br
NH2
NH2
N
N
A
B
24f (5i)
85 (5i)
N
N
Br
Br
OHC
Br
OMe
OMe
10
95 (4j)
B
85 (5j)
OHC
a
Method A: CuI (10 mol %), TMEDA (3 equiv), H2O, 120 ꢀC, sealed tube; method B: CuI (10 mol %), TMEDA (20 mol %), Cs2CO3 (2 equiv), dioxane, 100 ꢀC.
Isolated yield.
Presence of an imine byproduct.
70% of 4g was recovered.
65% of 4h was recovered.
60% of 4i was recovered.
b
c
d
e
f
pyridazines, imidazo[1,2-a]pyrazines, which were successfully used
sequence. Infrared (IR) spectra were obtained on FTIR Thermo
Scientific Nicolet iS10. High-resolution mass spectra (HRMS) were
recorded with a TOF spectrometer in the electrospray ionisation
(ESI) mode or with a Finnigan MAT 95 XL in the chemical ionisation
(CI) mode at the Regional Center of Physical Measurement Uni-
versity Blaise Pascal. All commercial solvents were used without
further purification. Column chromatography was carried out using
in a copper catalyzed N-arylation cyclization. Two methods were
developed around the use of the inexpensive TMEDA as ligand in
water or dioxane media and these were compatible with chlorinated
and brominated adducts. Complex N-fused polycyclic heterocycles
were then obtained in this straightforward two steps sequence.
Silica gel 60 N (spherical, neutral, 40e63 mm, Merck). Thin layer
4. Experimental section
chromatography (TLC) was carried out on Merck silica gel 60F254
precoated plates. Visualization was made with ultraviolet light.
4.1. General remarks and methods
ꢀ
General procedure for the Bienayme reaction: To a solution of 2-
amino-heteroaryl (1 equiv) in methanol (1 M), aldehyde
(1.05 equiv) and perchloric acid (0.05 equiv) were sequentially
added at room temperature. Finally, isonitrile (1.05 equiv) was in-
troduced. Once TLC indicated complete consumption of starting
material, the reaction mixture was concentrated under reduced
pressure. The residue was then purified by flash chromatography.
Solvents and reagents were purchased from commercial sup-
pliers and used without further purification. Melting points were
€
determined with Buchi SMP-20 melting point apparatus and were
uncorrected. 1H NMR and 13C NMR were recorded on a Bruker
Avance DPX250 spectrometer using tetramethylsilane as the in-
ternal standard, multiplicities were determined by the DEPT 135

9134
A. El Akkaoui et al. / Tetrahedron 68 (2012) 9131e9138
Table 3
MeO
MeO
N
OMe
CuI, TMEDA,
Cs2CO3, dioxane
HClO4, MeOH
RT, 12-24 h
N
CN
R2
NH
R3
R2
+
100 °C
N
R2
R3
R1
NH2
N
OHC
R3
N
R1
R1
N
X
X
4 k-o
5 k-o
Entry
1
Starting materials
Yield % (4)
90 (4k)
Yield % (5)
96 (5k)
NH2
Br
OHC
OHC
Br
N
N
N
Cl
NH2
NH2
O
O
2
3
91 (4l)
92 (5l)
Cl
Br
Br
87 (4m)
91 (5m)
OHC
Br
NH2
NH2
4
5
89 (4n)
89 (4o)
96 (5n)
85 (5o)
N
OHC
OHC
Cl
N
Br
Cl
5. Experimental data
124.6, 123.2, 120.9, 119.2, 117.5, 105.9, 55.6, 50.0; HRMS (ESþ): MHþ,
calcd for C24H19Cl2N4O 449.0930. Found 449.0930.
5.1. N-Benzyl-2-(2-bromophenyl)-6-chloroimidazo[1,2-a]
pyridin-3-amine (4a)
5.3. N-Benzyl-6-bromo-2-(2-bromopyridin-3-yl)imidazo
[1,2-a]pyridin-3-amine (4c)
ꢀ
Following the general GroebkeeBienayme procedure with 2-
amino-5-chloropyridine,
2-bromobenzaldehyde,
and
(iso-
ꢀ
Following the general GroebkeeBienayme procedure with 2-
cyanomethyl)benzene. Column chromatography on silica gel with
(AcOEt/Hexanes: 2/8) provided N-benzyl-2-(2-bromophenyl)-6-
chloroimidazo[1,2-a]pyri-din-3-amine 4a (292 mg, 91%) as a yel-
low solid; mp¼95 ꢀC; nmax (ATR) 3210, 2968, 1565, 1469, 1324, 1219,
amino-5-bromopyridine,
cyanomethyl)benzene. Column chromatography on silica gel with
(AcOEt/Hexanes: 2/8) provided N-benzyl-6-bromo-2-(2-
2-bromobenzaldehyde,
and
(iso-
bromopyridin-3-yl)imidazo[1,2-a]pyridin-3-amine 4c (242 mg,
1022, 757 cmꢁ1; 1H NMR (400 MHz, CDC13)
d¼8.12 (1H, d, J 1.3 Hz),
92%) as a yellow solid; mp¼97 ꢀC; nmax (ATR) 3178, 2898,1566,1474,
7.64 (1H, dd, J 8.0, 0.9 Hz), 7.47 (1H, d, J 9.5 Hz), 7.42 (1H, dd, J 7.6,
1.7 Hz), 7.34 (1H, ddd, J 7.6, 7.4, 1.1 Hz), 7.23 (1H, ddd, J 7.8, 7.6,
1.8 Hz), 7.27e7.21 (3H, m), 7.11e7.08 (3H, m), 3.95 (2H, d, J 6.2 Hz,
CH2), 3.66 (1H, t, J 6.1 Hz, NH); 13C NMR (100.6 MHz, CDCl3)
1021, 757 cmꢁ1
;
1H NMR (400 MHz, CDC13)
d¼8.19e8.14 (1H, m),
7.59 (1H, d, J 7.7 Hz), 7.38 (1H, dd, J 7.6, 1.7 Hz), 7.33 (1H, d, J 9.5 Hz),
7.27 (1H, dd, J 7.3, 6.9 Hz), 7.16 (2H, ddd, J 7.9, 7.7, 1.6 Hz), 7.15e7.11
(2H, m), 7.10 (1H, dd, J 9.5, 1.8 Hz), 7.03e7.01 (2H, m), 3.90 (2H, d, J
6.0 Hz, CH2), 3.78 (1H, t, J 6.0 Hz, NH); 13C NMR (100.6 MHz, CDCl3)
d
¼139.6, 138.8, 137.7, 135.4, 132.7, 132.7, 129.8, 128.5, 128.5, 128.1,
128.1, 127.6, 127.5, 126.9, 125.3, 123.1, 120.7, 120.4, 118.2, 52.5; HRMS
(ESþ): MHþ, found 412.0197. C20H16BrClN3 requires 412.0216.
d
¼139.6, 138.8, 137.2, 135.3, 132.7, 132.7, 129.8, 128.5, 128.5, 128.1,
128.1,127.6,127.5,127.2,126.9,123.2,122.9,118.3,106.8, 52.2; HRMS
(ESþ): MHþ, calcd for C20H16Br2N3 455.9711. Found 455.9710.
5.2. N-Benzyl-6-chloro-2-(2-chloro-6-methoxyquinolin-3-yl)
imidazo[1,2-a]pyridin-3-amine (4b)
5.4. N-Benzyl-2-(2-bromophenyl)-7-methylimidazo[1,2-a]
pyridin-3-amine (4d)
ꢀ
Following the general GroebkeeBienayme procedure with
ꢀ
2-amino-5-chloropyridine, 2-chloroquinoline-3-carbaldehyde, and
(isocyanomethyl)benzene. Column chromatography on silica
gel with (AcOEt/Hexanes: 1/1) provided N-benzyl-6-chloro-2-
(2-chloro-6-methoxyquinolin-3-yl)imidazo-[1,2-a]pyridin-3-amine
4b (316 mg, 94%) as a white solid; mp¼129 ꢀC; nmax (ATR) 3210,
Following the general GroebkeeBienayme procedure with 2-
amino-4-methylpyridine, 2-bromobenzaldehyde, and (iso-
cyanomethyl)benzene. Column chromatography on silica gel with
(AcOEt/Hexanes: 3/7) provided N-benzyl-2-(2-bromophenyl)-7-
methylimidazo[1,2-a]pyridin-3-amine 4d (337 mg, 93%) as
a brown oil; nmax (ATR) 3215, 2914, 1634, 1473, 1023, 737 cmꢁ1; 1H
2968, 1565, 1469, 1324, 1219, 1022, 757 cmꢁ1 1H NMR (400 MHz,
;
DMSO-d6)
d
¼8.46 (1H, d, J 1.3 Hz), 8.13 (1H, s), 7.91 (1H, d, J 9.1 Hz),
NMR (400 MHz, CDC13)
d
¼7.98 (1H, d, J 6.9 Hz), 7.61 (1H, dd, J 8.0,
7.57 (1H, d, J 9.8 Hz), 7.48 (1H, dd, J 9.2, 2.7 Hz), 7.35 (1H, d, J 2.8 Hz),
7.26 (1H, dd, J 9.5, 2.0 Hz), 7.13e7.06 (3H, m), 7.01 (2H, dd, J 6.5,
3.0 Hz), 5.75 (1H, bs, NH), 4.04 (2H, d, J 3.0 Hz), 3.91 (3H, s, OCH3);
0.9 Hz), 7.43 (1H, dd, J 7.6, 1.6 Hz), 7.30 (1H, ddd, J 7.6, 7.4, 1.1 Hz),
7.26 (1H, s), 7.18 (1H, ddd, J 8.0, 7.5, 1.8 Hz), 7.17e7.12 (3H, m),
7.12e7.04 (2H, m), 6.59 (1H, dd, J 7.0, 1.3 Hz), 3.93 (2H, s, CH2), 3.64
13C NMR (100.6 MHz, DMSO-d6)
d¼157.7, 146.8, 142.3, 139.5, 139.3,
(1H, bs, NH), 2.35 (3H, s, CH3); 13C NMR (100.6 MHz, CDCl3)
d
¼141.6,
137.6,129.2,129.1,128.9, 127.9,127.9,127.5, 127.5, 127.0, 126.8, 125.4,
139.0, 135.7, 135.7, 134.7, 132.6, 132.4, 129.2, 128.2, 128.2, 127.9,

A. El Akkaoui et al. / Tetrahedron 68 (2012) 9131e9138
9135
127.9, 127.2, 127.2, 125.8, 122.9, 121.8, 115.7, 114.3, 52.3, 21.2; HRMS
2970, 1469, 734 cmꢁ1
;
1H NMR (400 MHz, CDC13)
d
¼8.92 (1H, d, J
(ESþ): MHþ, calcd for C21H19N3Br 392.0762. Found 392.0753.
1.1 Hz), 7.94 (1H, dd, J 4.6, 1.2 Hz), 7.78 (1H, d, J 4.6 Hz), 7.62 (1H, d, J
8.0 Hz), 7.35 (1H, dd, J 7.6,1.9 Hz), 7.31 (1H, dd, J 7.8, 7.6 Hz), 7.21 (1H,
ddd, J 7.8, 7.4,1.8 Hz), 7.17e7.13 (3H, m), 7.04e7.02 (2H, m), 3.99 (2H,
d, J 6.0 Hz, CH2), 3.92 (1H, dd, J 6.0, 6.2 Hz, NH); 13C NMR (100.6 MHz,
5.5. 3-(Benzylamino)-2-(2-bromophenyl)imidazo[1,2-a]
pyridine-6-carbonitrile (4e)
CDCl3)
d
¼143.5, 138.4, 138.1, 136.3, 134.6, 132.6, 132.5, 130.0, 128.9,
ꢀ
Following the general GroebkeeBienayme procedure with
128.4, 128.4, 128.0, 127.8, 127.8, 127.5, 127.4, 123.1, 115.4, 51.7; HRMS
(ESþ): MHþ, calcd for C19H16N4Br 379.0558. Found 379.0568.
2-amino-5-cyanopyridine, 2-bromobenzaldehyde, and (iso-
cyanomethyl)benzene. Column chromatography on silica gel with
(AcOEt/Hexanes: 3/7) provided 3-(benzylamino)-2-(2-bromo-
phenyl)imidazo[1,2-a]pyridine-6-carbonitrile 4e (302 mg, 89%) as
a yellow solid; mp¼126 ꢀC; nmax (ATR) 3169, 2867, 2227, 1566, 1419,
5.9. N-Benzyl-6-bromo-2-(2-bromophenyl)imidazo[1,2-a]
pyrazin-3-amine (4i)
699 cmꢁ1; 1H NMR (400 MHz, CDC13)
d
¼8.47 (1H, s), 7.67 (1H, d, J
Following the general GroebkeeBienayme procedure with
ꢀ
7.9 Hz), 7.56 (1H, d, J 9.3 Hz), 7.43 (1H, d, J 7.1 Hz), 7.38 (1H, dd, J 7.4,
7.2 Hz), 7.28 (1H, dd, J 8.4, 7.4 Hz), 7.21e7.19 (4H, m), 7.07 (2H, d, J
3.1 Hz), 3.95 (2H, d, J 4.7 Hz, CH2), 3.74 (1H, bs, NH); 13C NMR
2-amino-5-bromopyridazine, 2-bromobenzaldehyde, and (iso-
cyanomethyl)benzene. Column chromatography on silica gel
with (AcOEt/Hexanes: 4/6) provided N-benzyl-6-bromo-2-(2-
bromophenyl)imidazo[1,2-a]pyrazin-3-amine 4i (236 mg, 90%) as
(100.6 MHz, CDCl3)
d
¼140.3, 138.9, 138.3, 134.6, 132.8, 132.5, 130.2,
129.2, 128.6, 128.6, 128.2, 128.2, 127.8, 127.6, 127.5, 123.6, 122.9,
118.6, 117.0, 98.0, 52.6; HRMS (ESþ): MHþ, calcd for C21H16N4Br
403.0558. Found 403.0549.
a yellow oil; nmax (ATR) 3156, 1470, 1289, 764 cmꢁ1 1H NMR
;
(400 MHz, CDC13)
(1H, d, J 7.9 Hz), 7.33 (2H, d, J 4.2 Hz), 7.30e7.25 (1H, m), 7.20e7.12
(3H, m), 7.05e7.02 (2H, m), 4.00 (2H, s, CH2), 3.96 (1H, bs, NH); 13
NMR (100.6 MHz, CDCl3)
132.7, 132.5, 130.4, 128.6, 128.6, 127.9, 127.9, 127.8, 127.5, 123.0,
122.9, 116.0, 51.7; HRMS (ESþ): MHþ, calcd for C19H15N4Br2
456.9663. Found 456.9683.
d¼8.71 (1H, d, J 1.2 Hz), 8.10 (1H, d, J 1.2 Hz), 7.65
C
5.6. N-Benzyl-2-(2-bromophenyl)-6-(trifluoromethyl)imidazo
[1,2-a]pyridin-3-amine (4f)
d
¼144.1, 142.2, 139.8, 138.0, 135.4, 134.1,
ꢀ
Following the general GroebkeeBienayme procedure with 2-
amino-5-trifluoromethylpyridine, 2-bromobenzaldehyde, and
(isocyanomethyl)benzene. Column chromatography on silica gel
with (AcOEt/Hexanes: 3/7) provided N-benzyl-2-(2-bromophenyl)-
6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-amine 4f (275 mg,
84%) as a yellow solid; mp¼95 ꢀC; nmax (ATR) 3198, 1566, 1474, 1312,
5.10. N-Benzyl-6-bromo-2-(2-bromo-4,5-dimethoxyphenyl)
imidazo[1,2-a]pyrazin-3-amine (4j)
ꢀ
Following the general GroebkeeBienayme procedure with 2-
1185, 1111, 796 cmꢁ1
;
1H NMR (400 MHz, CDC13)
d¼8.38 (1H, d, J
amino-5-bromopyridazine, 2-bromo-4,5-dimethoxybenzaldehyde,
and (isocyanomethyl)benzene. Column chromatography on silica gel
with (AcOEt/Hexanes: 4/6) provided N-benzyl-6-bromo-2-(2-bromo-
4,5-dimethoxyphenyl)imidazo[1,2-a]pyrazin-3-amine 4j (282 mg,
95%) as a yellow solid; mp¼81 ꢀC; nmax (ATR) 3178, 2898, 1566, 1492,
0.8 Hz), 7.64 (1H, d, J 8.0 Hz), 7.56 (1H, d, J 9.4 Hz), 7.44 (1H, dd, J 7.6,
1.7 Hz), 7.33 (1H, ddd, J 7.5, 7.4,0.9 Hz), 7.26e7.19 (2H, m), 7.16e7.14
(3H, m), 7.05e7.03 (2H, m), 3.93 (2H, d, J 5.7 Hz, CH2), 3.86 (1H, dd, J
5.8, 5.7 Hz, NH); 13C NMR (100.6 MHz, CDCl3)
d
¼140.7, 138.4, 138.4,
138.1, 134.9, 132.6, 132.5, 129.8, 128.4, 128.4, 128.0, 128.0, 127.6,
127.5, 127.3, 122.9, 121.8 (q, J CF3 5.8 Hz), 119.5 (q, J CF3 2.5 Hz), 118.1,
115.8 (d, JCeF 34.0 Hz), 52.5; HRMS (ESþ): MHþ, calcd for
C21H16N3BrF3 446.0480. Found 447.0479.
726 cmꢁ1; 1H NMR(400 MHz, CDC13)
d
¼8.76 (1H, d, J 1.2 Hz), 8.14 (1H,
d, J 1.2 Hz), 7.20e7.14 (3H, m), 7.08 (1H, s), 7.01 (2H, dd, J 7.4, 1.9 Hz),
6.80 (1H, s), 4.03 (2H, d, J 4.4 Hz, CH2), 3.94 (3H, s, CH3), 3.88 (1H, bs,
NH), 3.84 (3H, s, CH3); 13C NMR (100.6 MHz, CDCl3)
d¼150.2, 148.5,
142.2, 140.3, 138.2, 135.5, 128.5, 128.2, 128.2, 128.0, 128.0, 127.7, 126.4,
123.0,116.0,115.0,114.5,113.0, 56.3, 56.1, 51.7;HRMS(ESþ):MHþ, calcd
for C21H19N4O2Br2 516.9875. Found 516.9893.
5.7. N-Benzyl-2-(2-bromophenyl)-6-chloroimidazo[1,2-b]
pyridazin-3-amine (4g)
ꢀ
Following the general GroebkeeBienayme procedure with 2-
5.11. 2-(2-Bromophenyl)-6-chloro-N-(4-methoxyphenyl)
imidazo[1,2-a]pyridin-3-amine (4k)
amino-6-chloropyridazine, 2-bromobenzaldehyde, and (iso-
cyanomethyl)benzene. Column chromatography on silica gel with
(AcOEt/Hexanes: 3/7) provided N-benzyl-2-(2-bromophenyl)-6-
chloroimidazo[1,2-b]pyridazin-3-amine 4g (274 mg, 86%) as a yel-
low oil; nmax (ATR) 3360, 2977, 1557, 1469, 1289, 1098, 754 cmꢁ1; 1H
ꢀ
Following the general GroebkeeBienayme procedure with 2-
amino-5-chloropyridine, 2-bromobenzaldehyde, and 1-isocyano-
4-methoxybenzene
gave
2-(2-bromophenyl)-6-chloro-N-(4-
NMR (400 MHz, CDC13)
d
¼7.73 (1H, d, J 9.3 Hz), 7.65 (1H, dd, J 8.0,
methoxyphenyl)imidazo[1,2-a]pyridin-3-amine 4k (300 mg, 90%)
1.1 Hz), 7.38 (1H, dd, J 7.7, 1.8 Hz), 7.30 (1H, ddd, J 7.5, 7.4, 1.2 Hz),
7.24 (1H, dd, J 7.7, 1.8 Hz), 7.22e7.17 (3H, m), 7.12e7.07 (2H, m), 6.82
(1H, d, J 9.3 Hz), 4.65 (1H, dd, J 6.7, 6.6 Hz, NH), 4.22 (2H, d, J 6.6 Hz,
as a yellow solid; mp 155 ꢀC; nmax (ATR) 3169, 1489, 1324, 1022,
757 cmꢁ1
;
1H NMR (400 MHz, CDC13)
d
¼7.90e7.87 (1H, dd, J 1.9,
0.7 Hz), 7.62 (1H, dd, J 9.1, 1.0 Hz), 7.58 (1H, d, J 9.5, 0.6 Hz), 7.51 (1H,
dd, J 7.6, 1.6 Hz), 7.31 (1H, ddd, J 7.6, 7.5, 1.1 Hz), 7.22e7.17 (2H, m),
6.71 (2H, d, J 8.9 Hz), 6.41 (2H, d, J 8.9 Hz), 5.65 (1H, s), 3.71 (3H, s);
NHCH2); 13C NMR (100.6 MHz, CDCl3)
d¼146.5, 138.6, 135.3, 132.6,
132.6,131.8,131.7, 129.8, 129.6, 128.4,128.4,127.5,127.4,127.4,127.0,
126.5, 124.4, 115.2, 49.1; HRMS (ESþ): MHþ, calcd for C19H15N4BrCl
413.0169. Found 413.0181.
13C NMR (100.6 MHz, CDCl3)
d¼153.8, 140.5, 139.9, 137.8, 134.6,
132.9, 132.4, 129.9,127.5,126.2,123.2,121.3,121.0,120.8,118.5,115.1,
115.1, 115.1, 115.1, 55.7; HRMS (ESþ): MHþ, calcd for C20H16N3OClBr
428.0165. Found 428.0171.
5.8. N-Benzyl-2-(2-bromophenyl)imidazo[1,2-a]pyrazin-
3-amine (4h)
5.12. 2-(6-Bromobenzo[d][1,3]dioxol-5-yl)-6-chloro-N-
(4-methoxyphenyl)imidazo[1,2-a]pyridin-3-amine (4l)
ꢀ
Following the general GroebkeeBienayme procedure with 2-
aminopyridazine, 2-bromobenzaldehyde, and (isocyanomethyl)
benzene. Column chromatography on silica gel with (AcOEt/Hex-
anes: 3/7) provided N-benzyl-2-(2-bromophenyl)imidazo[1,2-a]
pyrazin-3-amine 4 h (370 mg, 92%) as a yellow oil; nmax (ATR) 3161,
ꢀ
Following the general GroebkeeBienayme procedure with 2-
amino-5-chloropyridine, 6-bromobenzo[d][1,3]dioxole-5-carbalde
hyde, and 1-isocyano-4-methoxybenzene gave 2-(6-bromobenzo

9136
A. El Akkaoui et al. / Tetrahedron 68 (2012) 9131e9138
[d][1,3]dioxol-5-yl)-6-chloro-N-(4-methoxyphenyl)imidazo[1,2-a]
pyridin-3-amine 4l (334 mg, 91%) as yellow solid; mp 122e123 ꢀC;
was heated to 120 ꢀC. After completion, the mixture was extracted
two times with DCM and the combined organic phase was dried
with MgSO4 and concentrated under reduced pressure. The resi-
due was then purified by flash chromatography using 32e63 mm
silica gel.
Method B: Under an inert atmosphere of argon, Cs2CO3 (2 equiv)
and TMEDA (0.2 equiv) were added to a solution of 4 (1 equiv) in
dioxane (2 mL). After 10 min, CuI (10 mol %) was introduced before
heating the reaction at 100 ꢀC. The reaction mixture was concen-
trated under reduced pressure. The residue was diluted in water
and DCM and the aqueous phase extracted two times with DCM.
The combined organic phase was dried with MgSO4, concentrated
under reduced pressure and purified by flash chromatography
using 32e63 mm silica gel.
nmax (ATR) 3081, 2900, 1506, 1477, 1231, 1036, 830, 703 cmꢁ1 1H
;
NMR (400 MHz, CDC13)
d
¼7.47 (1H, d, J 1.0 Hz), 7.43 (1H, d, J 9.7 Hz),
7.31 (1H, s), 7.27 (2H, d, J 8.8 Hz), 6.98 (2H, d, J 8.8 Hz), 6.83 (1H, d, J
9.6 Hz), 6.66 (1H, s), 5.83 (2H, s), 5.60 (1H, s), 3.79 (3H, s); 13C NMR
(100.6 MHz, CDCl3)
d
¼159.4, 146.1, 143.3, 143.3, 138.0, 133.1, 128.7,
128.6, 127.9, 127.9, 122.4, 119.3, 118.6, 118.1, 115.3, 115.3, 111.6, 101.1,
98.9, 92.8, 55.7; HRMS (ESþ): MHþ, calcd for C21H16N3O3ClBr
472.0064. Found 472.0057.
5.13. 6-Bromo-N-(4-methoxyphenyl)-2-phenylimidazo[1,2-a]
pyridin-3-amine (4m)
ꢀ
Following the general GroebkeeBienayme procedure with 2-
amino-5-bromopyridine, 2-bromobenzaldehyde, and 1-isocyano-
6.1. 5-Benzyl-8-chloro-5H-pyrido[20,10:2,3]imidazo[4,5-b]
4-methoxybenzene
gave
6-bromo-N-(4-methoxyphenyl)-2-
indole (5a)
phenylimidazo[1,2-a]pyridin-3-amine 4m (237 mg, 87%) as yel-
low solid; mp 191e192 ꢀC; nmax (ATR) 3173, 2895, 1507, 1232, 1185,
Following method B (12 h). Column chromatography on silica
gel with (AcOEt/Hexanes: 1/4) provided 5-benzyl-8-chloro-5H-
pyrido[20,10:2,3]imidazo[4,5-b]indole 5a (64.0 mg, 80%) as a grey
1025, 823, 761 cmꢁ1 1H NMR (400 MHz, CDC13)
d
¼7.94 (1H, bs),
7.68 (1H, dd, J 9.3, 0.5 Hz), 7.61 (1H, dd, J 8.0, 1.0 Hz), 7.54 (1H, dd, J
7.7, 1.7 Hz), 7.35 (1H, dd, J 9.3, 1.8 Hz), 7.31 (1H, ddd, J 7.6, 7.5, 1.1 Hz),
7.19 (1H, ddd, J 7.8, 7.6, 1.6 Hz), 6.69 (2H, d, J 8.9 Hz), 6.42 (2H, d, J
8.9 Hz), 5.67 (1H, s), 3.69 (3H, s); 13C NMR (100.6 MHz, CDCl3)
solid; mp¼201 ꢀC; nmax (ATR) 32,921, 1557, 1452, 1098, 733 cmꢁ1
;
1H NMR (400 MHz, CDC13)
d
¼8.10 (1H, bdd, J 8.4, 3.7 Hz), 7.66 (1H,
d, J 1.2 Hz), 7.54 (1H, d, J 9.7 Hz), 7.31e7.29 (2H, m), 7.30e7.24 (4H,
m), 7.09e7.07 (2H, m), 6.92 (1H, dd, J 9.7, 1.8 Hz), 5.48 (2H, s, CH2);
d
¼153.7, 146.1, 140.4, 137.7, 134.5, 132.8, 132.4, 129.9, 129.9, 127.4,
126.1, 123.1, 121.3, 120.8, 118.4, 115.0, 115.0, 109.6, 109.6, 55.7; HRMS
(ESþ): MHþ, calcd for C20H16N3OBr2 471.9660. Found 471.9678.
13C NMR (100.6 MHz, CDCl3)
d
¼143.6, 141.7, 136.8, 132.4, 130.0,
129.4,129.4,128.4,126.2,126.2,124.1,122.9,120.5,119.7,119.4,119.1,
118.4, 117.9, 109.9, 47.9; HRMS (ESþ): MHþ, calcd for C20H15N3Cl
332.0955. Found 332.0938.
5.14. N-(4-Methoxyphenyl)-7-methyl-2-phenylimidazo[1,2-a]
pyridin-3-amine (4n)
6.2. 6-Benzyl-10-chloro-2-methoxy-6H-pyrido[100,200:10,20]
imidazo[40,50:4,5]pyrrolo[2,3-b]quinoline (5b)
ꢀ
Following the general GroebkeeBienayme procedure with 2-
amino-4-methylpyridine, 2-bromobenzaldehyde, and 1-isocyano-
4-methoxybenzene
gave
N-(4-methoxyphenyl)-7-methyl-2-
Following method B (8 h). Column chromatography on silica gel
with (AcOEt/Hexanes: 4/6) provided 6-benzyl-10-chloro-2-
phenylimidazo[1,2-a]pyridin-3-amine 4n (337 mg, 89%) as yellow
solid; mp 170e171 ꢀC; nmax (ATR) 3249, 2920, 1558, 1221, 1028,
methoxy-6H-pyrido[100,200:10,20]
imidazo[40,50:4,5]pyrrolo[2,3-b]
737 cmꢁ1; 1H NMR (400 MHz, CDC13)
d
¼7.62 (1H, d, J 6.9 Hz), 7.51
quinoline 5b (82.0 mg, 90%) as a grey solid; mp¼199e200 ꢀC; nmax
(1H, d, J 7.8 Hz), 7.45 (1H, dd, J 7.6, 1.3 Hz), 7.28 (1H, s), 7.21 (1H, dd, J
7.4, 7.4 Hz), 7.10 (1H, ddd, J 8.0, 7.8,1.5 Hz), 6.63 (2H, d, J 8.8 Hz), 6.52
(1H, dd, J 7.6, 1.3 Hz), 6.35 (2H, d, J 8.8 Hz), 5.89 (1H, s), 3.62 (3H, s),
(ATR) 2920, 1557, 1450, 1098, 731 cmꢁ1; 1H NMR (400 MHz, CDC13)
d
¼8.76 (1H, s), 8.01 (1H, d, J 9.4 Hz), 7.67 (1H, s), 7.57 (1H, d, J
8.4 Hz), 7.36e7.00 (7H, m), 6.80 (1H, d, J 9.4 Hz), 5.94 (2H, s, CH2),
3.99 (3H, s, CH3); 13C NMR (100.6 MHz, CDCl3)
2.32 (3H, s); 13C NMR (100.6 MHz, CDCl3)
d¼153.1, 142.5, 138.5,
d
¼158.7, 146.8, 142.3,
138.5, 135.4, 135.1, 132.6, 132.3, 129.3, 127.1, 123.2, 122.3, 120.1, 116.1,
114.8,114.8,114.7, 114.7, 77.4, 55.5, 21.3; HRMS (ESþ): MHþ, calcd for
C21H19N3OBr 408.0711. Found 408.0701.
139.5, 139.3, 137.6, 129.2, 129.1, 128.4, 127.9, 127.9, 127.5, 127.5, 127.0,
126.8, 125.4, 124.6, 123.2, 120.9, 119.2, 118.5, 104.9, 55.6, 50.0; HRMS
(ESþ): MHþ, calcd for C24H18N4OCl 413.1169. Found 413.1183.
5.15. 6-Bromo-2-(2,5-dichlorophenyl)-N-(4-methoxyphenyl)
imidazo[1,2-a]pyridin-3-amine (4o)
6.3. 5-Benzyl-8-chloro-5H-pyrido[20,10:2,3]imidazo[4,5-b]
indole (5c)
ꢀ
Following the general GroebkeeBienayme procedure with
Following method B (12 h). Column chromatography on silica
gel with (AcOEt/Hexanes: 4/6) provided 5-benzyl-8-chloro-5H-
pyrido[20,10:2,3]imidazo[4,5-b]indole 5c (51.0 mg, 62%) as a braun
2-amino-5-bromopyridine, 2,5-dichlorobenzaldehyde, and 1-
isocyano-4-methoxybenzene gave 6-bromo-2-(2,5-dichlorophenyl)-
N-(4-methoxyphenyl)imidazo[1,2-a]pyridin-3-amine 4o (237 mg,
89%) as yellow solid; mp 82e83 ꢀC; nmax (ATR) 2975,1586,1509,1238,
solid; mp¼186 ꢀC; nmax (ATR) 2921,1557,1452,1098, 733, 696 cmꢁ1
;
1H NMR (400 MHz, CDC13)
d
¼8.13 (1H, d, J 7.4 Hz), 7.83 (1H, d, J
1144,1031, 820, 789 cmꢁ1; 1H NMR (400 MHz, CDC13)
d¼7.98 (1H, dd,
0.9 Hz), 7.54 (1H, d, J 9.6 Hz), 7.40 (1H, d, J 7.4 Hz), 7.39e7.35 (1H,
m), 7.35e7.29 (4H, m), 7.17e7.12 (2H, m), 7.06 (1H, dd, J 9.6, 1.7 Hz),
J 1.0, 0.7 Hz), 7.60 (1H, d, J 8.0 Hz), 7.53e7.49 (2H, m), 7.30e7.27 (1H,
m), 7.19 (1H, ddd, J 8.0, 7.8, 1.6 Hz), 6.70 (2H, d, J 8.9 Hz), 6.40 (2H, d,
J 8.9 Hz), 5.64 (1H, s), 3.70 (3H, s); 13C NMR (100.6 MHz, CDCl3)
5.58 (2H, s, CH2); 13C NMR (100.6 MHz, CDCl3)
d
¼143.7, 141.8, 136.8,
132.4, 130.0, 129.5, 129.5, 128.5, 126.3, 126.3, 124.9, 124.2, 121.6,
120.6, 119.9, 118.9, 118.0, 110.0, 105.6, 48.1; HRMS (ESþ): MHþ, calcd
for C20H15N3Br 376.0449. Found 376.0463.
d
¼153.8, 140.6, 139.8, 137.8, 134.6, 132.9, 132.4, 129.9, 128.2, 127.5,
123.2, 123.1, 121.2, 118.7, 115.1, 115.1, 115.1, 115.1, 107.3, 55.7; HRMS
(ESþ): MHþ, calcd for C20H15N3OCl2Br 461.9776. Found 461.9777.
6.4. 5-Benzyl-9-methyl-5H-pyrido[20,10:2,3]imidazo[4,5-b]
6. General methods of N-arylation
indole (5d)
Method A: Under an inert atmosphere of argon, 4 (1 equiv) was
loaded in a sealed tube with water (2 mL), and TMEDA (3 equiv).
After 10 min, CuI (10 mol %) was introduced. Then the reaction
Following method A (12 h). Column chromatography on silica
gel with (AcOEt/Hexanes: 4/6) provided 5-benzyl-9-methyl-5H-
pyrido[20,10:2,3]imidazo[4,5-b]indole 5d (68.0 mg, 86%) as a grey

A. El Akkaoui et al. / Tetrahedron 68 (2012) 9131e9138
9137
oil; nmax (ATR) 2923, 1557, 1449, 1317, 1110, 687 cmꢁ1
(400 MHz, CDC13)
;
1H NMR
126.2, 125.4, 120.9, 120.5, 117.8, 114.5, 110.1, 48.1; HRMS (ESþ): MHþ,
calcd for C19H15N4 299.1297. Found 299.1297.
d
¼8.13e8.07 (1H, m), 7.56 (1H, d, J 6.9 Hz),
7.30e7.28 (4H, m), 7.21e7.18 (3H, m), 7.04e7.02 (2H, m), 6.32 (1H, d,
J 6.7 Hz), 5.41 (2H, s, CH2Ph), 2.26 (3H, s, CH3); 13C NMR (100.6 MHz,
6.9. 6-Benzyl-3-bromo-6H-pyrazino[20,10:2,3]imidazo[4,5-b]
CDCl3)
d
¼145.8, 140.9, 137.1, 132.7, 130.7, 129.7, 129.1, 129.1, 127.9,
indole (5i)
126.0, 126.0, 123.0, 120.8, 120.0, 119.3, 118.2, 116.4, 113.6, 109.7, 47.6,
21.5; HRMS (ESþ): MHþ, calcd for C21H18N3 312.1501. Found
312.1487.
Following method B (12 h). Column chromatography on silica
gel with (AcOEt/Hexanes: 4/6) provided 6-benzyl-3-bromo-6H-
pyrazino[20,10:2,3]imidazo[4,5-b]indole 5i (69.0 mg, 85%) as a grey
solid; mp¼209 ꢀC; nmax (ATR) 2945, 1436, 731 cmꢁ1
;
1H NMR
6.5. 5-Benzyl-5H-pyrido[20,10:2,3]imidazo[4,5-b]indole-8-
carbonitrile (5e)
(400 MHz, CDC13)
d
¼8.87e8.84 (1H, m), 8.17 (1H, d, J 7.7 Hz), 7.55
(1H, d, J 1.2 Hz), 7.46e7.43 (2H, m), 7.37e7.33 (4H, m), 7.17e7.15
(2H, m), 5.57 (2H, s, CH2); 13C NMR (100.6 MHz, CDCl3)
d¼143.5,
Following method A (24 h). Column chromatography on silica
gel with (AcOEt/Hexanes: 4/6) provided 5-benzyl-5H-pyrido
[20,10:2,3]imidazo[4,5-b]indole-8-carbonitrile 5e (63.0 mg, 80%) as
a grey solid; mp¼180 ꢀC; nmax (ATR) 2934, 2223, 1557, 1449,
142.3, 136.0, 129.7, 129.7, 128.9, 126.4, 126.4, 126.4, 126.4, 126.1,
121.6, 121.3, 120.8, 117.4, 114.5, 111.8, 110.3, 48.3; HRMS (ESþ): MHþ,
calcd for C19H14N4Br 377.0402. Found 377.0401.
687 cmꢁ1; 1H NMR (400 MHz, CDC13)
d¼8.17 (1H, d, J 8.1 Hz), 8.04
6.10. 6-Benzyl-3-bromo-8,9-dimethoxy-6H-pyrazino[20,10:2,3]
imidazo[4,5-b]indole (5j)
(1H, s), 7.72 (1H, d, J 9.2 Hz), 7.54 (1H, d, J 8.1 Hz), 7.47 (1H, dd, J 7.8,
7.6 Hz), 7.39e7.36 (4H, m), 7.19e7.17 (2H, m), 7.10 (1H, dd, J 9.5,
1.1 Hz), 5.58 (2H, s, CH2); 13C NMR (100.6 MHz, CDCl3)
d¼141.3,
Following method
B (12 h). Column chromatography on
138.9, 138.5, 134.6, 132.8, 132.5, 131.2, 129.2, 128.6, 128.6, 128.2,
127.8, 127.8, 127.7, 127.5, 123.6, 122.9, 118.6, 117.2, 98.0, 49.6; HRMS
(ESþ): MHþ, calcd for C21H15N4 323.1297. Found 323.1294.
silica gel with (AcOEt/Hexanes: 4/6) provided 6-benzyl-3-bromo-
8,9-dimethoxy-6H-pyrazino[20,10:2,3] imidazo[4,5-b]indole 5j
(73.0 mg, 85%) as a grey solid; mp¼185 ꢀC; nmax (ATR) 2932, 1566,
1474, 1250, 1085, 735 cmꢁ1; 1H NMR (400 MHz, CDC13)
d
¼8.80 (1H,
6.6. 5-Benzyl-8-(trifluoromethyl)-5H-pyrido[20,10:2,3] imidazo
[4,5-b]indole (5f)
s), 7.62 (1H, s), 7.56 (1H, s), 7.38e7.36 (3H, m), 6.19e6.17 (2H, m),
6.92 (1H, s), 5.55 (2H, s, CH2), 4.00 (3H, s, CH3), 3.95 (3H, s, CH3); 13
NMR (100.6 MHz, CDCl3)
136.1, 129.7, 129.7, 129.5, 128.9, 126.4, 126.4, 121.6, 114.0 109.5, 102.7,
94.3, 56.5, 56.4. 48.6; HRMS (ESþ): MHþ, calcd for C21H18N4O2Br
437.0613. Found 437.0614.
C
d
¼149.6, 145.6, 141.6, 139.6, 138.6, 136.2,
Following method
A (12 h). Column chromatography on
silica gel with (AcOEt/Hexanes: 4/6) provided 5-benzyl-8-(tri-
fluoromethyl)-5H-pyrido[20,10:2,3]imidazo[4,5-b]indole 5f (63.0 mg,
78%) as a yellow solid; nmax (ATR) 2989, 1470, 1312, 1185, 1111 cmꢁ1
;
1H NMR (400 MHz, CDC13)
d
¼8.14 (1H, d, J 7.6 Hz), 7.95 (1H, s), 7.69
6.11. 8-Chloro-5-(4-methoxyphenyl)-5H-pyrido[20,10:2,3] imi-
dazo[4,5-b]indole (5k)
(1H, d, J 9.5 Hz), 7.45 (1H, d, J 8.1 Hz), 7.37 (1H, dd, J 7.5, 7.3 Hz),
7.32e7.30 (4H, m), 7.19e7.17 (2H, m), 7.11 (1H, dd, J 9.5, 1.1 Hz), 5.59
(2H, s, CH2Ph); 13C NMR (100.6 MHz, CDCl3)
d¼144.6, 141.8, 136.6,
Following method B (12 h) after purification gave 8-chloro-
5-(4-methoxyphenyl)-5H-pyrido[20,10:2,3]imidazo[4,5-b]indole 5k
(78 mg, 96%) as a yellow solid; mp¼241 ꢀC; nmax (ATR) 2989, 1579,
133.0, 130.3, 129.6, 129.6, 128.7, 126.4, 126.4, 124.9, 124.4, 122.3,
120.1 (q, J CF3 5.9 Hz), 120.7, 119.9, 118.7, 117.2 (q, J CF3 2.3 Hz), 115.2
(q, J CF3 33.9 Hz), 110.0, 48.2; HRMS (ESþ): MHþ, calcd for
C21H15N3F3 366.1218. Found 366.1211.
1452, 1098, 726 cmꢁ1; 1H NMR (400 MHz, CDC13)
d
¼8.15e8.10 (1H,
m), 7.70 (1H, d, J 1.2 Hz), 7.66 (1H, d, J 9.7 Hz), 7.45 (2H, bd, J 8.8 Hz),
7.39e7.35 (1H, m), 7.34e7.30 (2H, m), 7.15 (2H, bd, J 8.8 Hz), 7.04
(1H, dd, J 9.7, 1.9 Hz), 3.95 (3H, s); 13C NMR (100.6 MHz, CDCl3)
6.7. 10-Benzyl-2-chloro-10H-pyridazino[60,10:2,3] imidazo
[4,5-b]indole (5g)
d
¼159.5, 143.7, 142.7, 132.9, 129.8, 128.8, 128.2, 128.2, 124.3, 123.0,
121.1, 119.8, 119.7, 119.0, 118.7, 118.4, 115.5, 115.5, 110.9, 55.9; HRMS
(ESþ): MHþ, calcd for C20H15N3OCl 348.0904. Found 348.0905.
Following method B (12 h). Column chromatography on silica
gel with (AcOEt/Hexanes: 4/6) provided 10-benzyl-2-chloro-10H-
pyridazino[60,10:2,3] imidazo[4,5-b]indole 5 g (64.0 mg, 80%) as
a greenish solid; mp¼182 ꢀC; nmax (ATR) 2940, 1585, 1436, 1258,
6.12. 8-Chloro-5-(4-methoxyphenyl)-5H-[1,3]dioxolo[4,5-f]
pyrido[20,10:2,3]imidazo[4,5-b]indole (5l)
1108, 731 cmꢁ1; 1H NMR (400 MHz, CDC13)
d¼8.11 (1H, d, J 7.7 Hz),
7.94 (1H, d, J 9.5 Hz), 7.45 (1H, d, J 8.2 Hz), 7.40e7.36 (1H, m),
7.32e7.30 (1H, m), 7.30e7.26 (4H, m), 7.25e7.22 (1H, m), 6.93 (1H,
Following method B (12 h) after purification gave 8-chloro-5-
(4-methoxyphenyl)-5H-[1,3]dioxolo[4,5-f]pyrido[20,10:2,3]imidazo
[4,5-b]indole 5l (76 mg, 92%) as a yellow solid; mp¼208e209 ꢀC;
d, J 9.5 Hz), 5.81 (2H, s, CH2); 13C NMR (100.6 MHz, CDCl3)
d¼145.2,
nmax (ATR) 2985, 1562, 1458, 1248, 1157, 844, 782 cmꢁ1 1H NMR
;
142.2, 137.7, 137.1, 137.1, 133.2, 128.9, 128.9, 127.9, 127.4, 127.4, 126.8,
125.0, 120.8, 120.3, 118.3, 115.1, 111.0, 48.0; HRMS (ESþ): MHþ, calcd
for C19H14N4Cl 333.0907. Found 333.0916.
(400 MHz, CDC13)
d
¼7.59e7.58 (1H, d, J 1.0 Hz), 7.55 (1H, d, J
9.7 Hz), 7.43 (1H, s), 7.39 (2H, d, J 8.8 Hz), 7.11 (2H, d, J 8.8 Hz), 6.95
(1H, dd, J 9.7, 1.8 Hz), 6.78 (1H, s), 5.94 (2H, s), 3.91 (3H, s); 13C NMR
6.8. 6-Benzyl-6H-pyrazino[20,10:2,3]imidazo[4,5-b]indole (5h)
(100.6 MHz, CDCl3)
d
¼159.5, 146.2, 143.5, 143.4, 138.1, 133.2, 128.9,
128.9, 128.1, 128.1, 122.5, 119.5, 118.8, 118.3, 115.5, 115.5, 111.7, 101.2,
99.0, 92.8, 55.8; HRMS (ESþ): MHþ, calcd for C21H15N3O3Cl
392.0802. Found 392.0820.
Following method B (12 h). Column chromatography on silica
gel with (AcOEt/Hexanes: 4/6) provided 6-benzyl-6H-pyrazino
[20,10:2,3]imidazo[4,5-b]indole 5h (65.0 mg, 83%) as a grey solid;
Mp¼174 ꢀC; nmax (ATR) 2895, 1571, 1438, 1258, 731 cmꢁ1; 1H NMR
6.13. 8-Bromo-5-(4-methoxyphenyl)-5H-pyrido[20,10:2,3] imi-
dazo[4,5-b]indole (5m)
(400 MHz, CDC13)
d
¼9.09 (1H, bs), 8.18 (1H, d, J 7.6 Hz), 7.63 (1H,
bs), 7.59 (1H, s), 7.44e7.41 (2H, m), 7.37e7.29 (4H, m), 7.17e7.12
(2H, m), 5.60 (2H, s, CH2); 13C NMR (100.6 MHz, CDCl3)
¼144.2,
143.1, 140.2, 136.5, 134.0, 130.2, 129.5, 129.5, 128.5, 128.0, 126.2,
d
Following method B (12 h) after purification gave 8-bromo-5-
(4-methoxyphenyl)-5H-pyrido[20,10:2,3]imidazo[4,5-b]indole 5m

9138
A. El Akkaoui et al. / Tetrahedron 68 (2012) 9131e9138
(76 mg, 91%) as a yellow solid; mp¼240e242 ꢀC; nmax (ATR) 2986,
References and notes
1561, 1449, 1246, 1025, 736 cmꢁ1 1H NMR (400 MHz, CDC13)
;
1. (a) Carril, M.; SanMartin, R.; Domíguez, E.; Tellitu, I. Green. Chem. 2007, 9,
219e220; (b) Bair, K. W. U.K. Patent EP 0447703 A1, 1991; Chem. Abstr. 1991,
116, 6540. (c) Butera, J. A.; Antane, S. A.; Hirth, B.; Lennox, J. R.; Sheldon, J. H.;
Norton, N. W.; Warga, D.; Argentieri, T. M. Bioorg. Med. Chem. Lett. 2001, 11,
2093e2097; (d) Sui, Z.; Zhang, X.; Li, X. Be. Patent WO 047017 A1, 2006; Chem.
Abstr. 2006, 144, 450694.
2. (a) Hulme, C.; Gore, V. Curr. Med. Chem. 2002, 10, 51e80; (b) Zhu, J.; Bienayme,
H. Multicomponent Reactions; Wiley-VCH: Weinheim, 2005; (c) Sunderhaus, J.
D.; Martin, S. F. Chem.dEur. J. 2009, 15, 1300e1308.
d
¼8.11e8.08 (1H, m), 7.79 (1H, bs), 7.58 (1H, d, J 9.7 Hz), 7.43 (2H, bd,
J 8.9 Hz), 7.36e7.33 (1H, m), 7.32e7.27 (2H, m), 7.14 (2H, bd, J 8.9 Hz),
7.09 (1H, dd, J 9.7, 1.8 Hz), 3.92 (3H, s); 13C NMR (100.6 MHz, CDCl3)
d
¼159.5, 143.7, 142.7, 132.7, 129.6, 128.8, 128.1, 128.1, 125.0, 124.3,
121.9, 121.1, 119.8, 118.9, 118.3, 115.4, 115.4, 110.9, 105.4, 55.8; HRMS
(ESþ): MHþ, calcd for C20H15N3OBr 392.0398. Found 392.0415.
ꢀ
3. (a) Banfi, L.; Riva, R. Org. React. 2005, 65, 1e140; (b) Sadjadi, S.; Heravi, M. M.
Tetrahedron 2011, 67, 2707e2752.
6.14. 5-(4-Methoxyphenyl)-9-methyl-5H-pyrido[20,10:2,3] imi-
dazo[4,5-b]indole (5n)
4. Ugi, I. Angew. Chem., Int. Ed. Engl. 1962, 1, 8e21.
ꢀ
5. Bienayme, H.; Bouzid, K. Angew. Chem., Int. Ed. 1998, 37, 2234e2237.
6. (a) Huffman, J. J. Heterocycl. Chem. 1987, 24, 549e553; (b) Groebke, K.; Weber,
L.; Mehlin, F. Synlett 1998, 661e663; (c) Blackburn, C.; Guan, B.; Fleming, P.;
Shiosaki, K.; Tsai, S. Tetrahedron Lett. 1998, 39, 3635e3638; (d) Kercher, T.; Rao,
C.; Bencsik, J. R.; Josey, J. A. J. Comb. Chem. 2007, 9, 1177e1187; (e) Meng, T.;
Zhang, Z.; Hu, D.; Lin, L.; Ding, J.; Wang, X.; Shen, J. J. Comb. Chem. 2007, 9,
739e741; (f) Rhee, H. K.; Lim, S. Y.; Jung, M. J.; Kwon, Y.; Kim, M. H.; Park Choo,
H. Y. Bioorg. Med. Chem. 2009, 17, 7537e7541.
Following method
B (12 h) after purification gave 5-(4-
methoxyphenyl)-9-methyl-5H-pyrido[20,10:2,3]imidazo[4,5-b]indole
5n (77 mg, 96%) as a yellow solid; mp¼182e183 ꢀC; nmax (ATR) 2989,
1510, 1440, 1251, 1028, 737 cmꢁ1 1H NMR (400 MHz, CDC13)
;
d
¼8.11e8.08 (1H, m), 7.56 (1H, d, J 7.0 Hz), 7.45e7.42 (3H, m),
7. (a) El Kazzouli, S.; Lavecchia, G.; Berteina-Raboin, S.; Guillaumet, G. Tetrahedron
Lett. 2006, 47, 4437e4440; (b) Nyffenegger, C.; Pasquinet, E.; Suzenet, F.;
7.37e7.35 (1H, m), 7.29e7.25 (2H, m), 7.10 (2H, d, J 8.8 Hz), 6.47 (1H,
dd, J 7.0,1.3 Hz), 3.91 (3H, s), 2.38 (3H, s); 13C NMR (100.6 MHz, CDCl3)
ꢀ
Poullain, D.; Jarry, C.; Leger, J.-M.; Guillaumet, G. Tetrahedron 2008, 64,
d
¼159.0,146.0,142.1,132.8,131.4,129.7,129.4,128.1,128.1,123.4,121.4,
9567e9573; (c) Nyffenegger, C.; Pasquinet, E.; Suzenet, F.; Poullain, D.; Guil-
laumet, G. Synlett 2009, 1318e1320; (d) Koubachi, J.; Berteina-Raboin, S.;
Mouaddib, A.; Guillaumet, G. Tetrahedron 2010, 66, 1937e1946; (e) Bassoude, I.;
Berteina-Raboin, S.; Leger, J.-M.; Jarry, C.; Essassi, E. M.; Guillaumet, G. Tetra-
hedron 2011, 67, 2279e2286; (f) El Akkaoui, A.; Bassoude, I.; Koubachi, J.; Ber-
teina-Raboin, S.; Mouaddib, A.; Guillaumet, G. Tetrahedron 2011, 67, 7128e7138.
8. (a) Gueiffier, A.; Blache, Y.; Viols, H.; Chapat, J. P. J. Heterocycl. Chem. 1992, 29,
283e287; (b) Lu, Y.; Zhang, W. QSAR Comb. Sci. 2004, 23, 827e835; (c) DiMauro,
E. F.; Kennedy, J. M. J. Org. Chem. 2007, 72, 1013e1016.
120.8, 119.5, 118.8, 116.7, 115.2, 115.2, 113.5, 110.7, 55.7, 21.6; HRMS
(ESþ): MHþ, calcd for C21H18N3O 328.1450. Found 328.1458.
6.15. 8-Bromo-2-chloro-5-(4-methoxyphenyl)-5H-pyrido
[20,10:2,3]imidazo[4,5-b]indole (5o)
Following method B (12 h) after purification gave 8-bromo-
2-chloro-5-(4-methoxyphenyl)-5H-pyrido[20,10:2,3]imidazo[4,5-b]
indole 5o (78 mg, 85%) as a yellow solid; mp¼218e219 ꢀC; nmax
9. Tyagi, V.; Khan, S.; Bajpai, V.; Gauniyal, H. M.; Kumar, B.; Chauhan, P. M. S. J. Org.
Chem. 2012, 77, 1414e1421.
10. (a) Yin, J.; Buchwald, S. L. Org. Lett. 2000, 2, 1101e1104; (b) Yin, J.; Buchwald, S.
L. J. Am. Chem. Soc. 2002, 124, 6043e6048; (c) Garnier, E.; Audoux, J.; Pasquinet,
E.; Suzenet, F.; Guillaumet, G. J. Org. Chem. 2004, 69, 7809e7815.
(ATR) 2987,1556, 1515, 1455, 1205, 1026, 917, 780 cmꢁ1 1H NMR
;
11. (a) El Kazzouli, S.; Berteina-Raboin, S.; Agrofoglio, L. A. Nucleosides, Nucleotides
Nucleic Acids 2007, 1395e1398; (b) Fresneau, N.; Hiebel, M.-A.; Agrofoglio, L. A.;
Berteina-Raboin, S. Tetrahedron Lett. 2012, 53, 1760e1763.
(400 MHz, CDC13)
d
¼7.95 (1H, d, J 8.3 Hz), 7.71 (1H, d, J 0.9 Hz), 7.54
(1H, d, J 9.1 Hz), 7.41 (2H, d, J 8.9 Hz), 7.28 (1H, d, J 1.6 Hz), 7.23 (1H,
dd, J 8.1, 1.8 Hz), 7.13 (2H, d, J 8.9 Hz), 7.09 (1H, dd, J 7.8, 1.2 Hz), 3.92
12. (a) Klapars, A.; Antilla, J. C.; Huang, X. H.; Buchwald, S. L. J. Am. Chem. Soc. 2001,
123, 7727e7729; (b) Klapard, A.; Huang, X. H.; Buchwald, S. L. J. Am. Chem. Soc.
2002, 124, 7421e7428; (c) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003,
42, 5400e5449; (d) Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. Rev. 2004,
248, 2337e2364; (e) Shafir, A.; Lichtor, A. A.; Buchwald, S. L. J. Am. Chem. Soc.
2007, 129, 3490e3491; (f) Minatti, A.; Buchwald, S. L. Org. Lett. 2008, 10,
(3H, s); 13C NMR (100.6 MHz, CDCl3)
d
¼159.7, 143.8, 142.7, 131.9,
129.9, 129.7,128.0, 128.0, 125.3, 121.7,121.5,120.4,118.8,116.6,115.4,
115.4, 111.0, 105.5, 55.7; HRMS (ESþ): MHþ, calcd for C20H14N3OClBr
426.0009. Found 425.9989.
ꢀ
2721e2724; (g) Coste, A.; Toumi, M.; Wright, K.; Razafimahaleo, V.; Couty, F.;
Marrot, J.; Evano, G. Org. Lett. 2008, 10, 3841e3844; (h) Zhao, Q.; Li, C. Org. Lett.
2008, 10, 4037e4040; (i) Chemler, S. R.; Fuller, P. H.; Ma, D.; Cai, O. Acc. Chem.
Res. 2008, 41, 1450e1460; (j) Kumar, S.; Ila, H.; Junjappa, H. J. Org. Chem. 2009,
74, 7046e7051.
Acknowledgements
This work was supported by Programme Hubert Curien
Volubilis.
13. Altman, R. A.; Buchwald, S. L. Org. Lett. 2006, 8, 2779e2782.