Grignard reagent-promoted 6-endo-dig cyclization: Instantaneous synthesis of original dipyrido[1,2-a:3′,4′-d]imidazole

Article abstract of DOI:10.1016/j.tet.2011.09.120

Dipyrido[1,2-a:3′,4′-d]imidazole derivatives can be readily synthetized from various 3-alkyne-2-cyanoimidazo[1,2-a]pyridines via an efficient Grignard reagent-promoted 6-endo-dig cyclization of nitrile to alkynes. A previous optimization of the Sonogashir

Full text of DOI:10.1016/j.tet.2011.09.120

Tetrahedron 67 (2011) 9576e9581
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Grignard reagent-promoted 6-endo-dig cyclization: instantaneous synthesis
of original dipyrido[1,2-a:30,40-d]imidazole
*
ꢀ
Romain Oudot, Philippe Costes, Hassan Allouchi, Melanie Pouvreau, Mohamed Abarbri, Alain Gueiffier ,
Cecile Enguehard-Gueiffier
ꢀ
ꢀ
PCMB EA4244, Universite Franc¸ ois Rabelais, 31 avenue Monge, 37200 Tours, France
a r t i c l e i n f o
a b s t r a c t
Dipyrido[1,2-a:30,40-d]imidazole derivatives can be readily synthetized from various 3-alkyne-2-
cyanoimidazo[1,2-a]pyridines via an efficient Grignard reagent-promoted 6-endo-dig cyclization of
nitrile to alkynes. A previous optimization of the Sonogashira coupling reaction at C(3) of the
2-cyanoimidazo[1,2-a]pyridine was necessary as this coupling reaction is known to be largely influenced
by the nature of the 2-substituent.
Article history:
Received 5 September 2011
Received in revised form 27 September 2011
Accepted 28 September 2011
Available online 6 October 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Imidazo[1,2-a]pyridine
Dipyrido[1,2-a:30,40-d]imidazole
Grignard reagent
6-endo-Dig cyclization
Sonogashira coupling reaction
1. Introduction
2. Results and discussion
The significant and potential biological activities of compounds
sharing the imidazo[1,2-a]pyridine moiety have been widely
exploited in various pharmacological areas.1 Consequently, there is
a continued demand for the development of analogous heterocyclic
systems as part of drug discovery programme.
The intramolecular cyclization was performed on the various
alkynes 5. These compounds were obtained in four steps starting
from the ethyl imidazo[1,2-a]pyridine-2-carboxylate 1 (Scheme 1).
Compounds 1e3 were prepared according to literature.5,6 Com-
pound 3 afforded 98% of the expected iodinated carbonitrile 4 using
iodide monochloride in chloroform. The original iodinated com-
pound 4 was then submitted to Sonogashira coupling reaction.
However, we previously noticed that this cross-coupling procedure
applied at C(3) of the imidazo[1,2-a]pyridine scaffold, is largely
influenced by the nature of the 2-substituent. We then started
a rapid optimization study in the case of the carbonitrile 4 to
evaluate suitable reaction conditions for the phenylacetylene cou-
pling (Table 1).
To our knowledge, dipyrido[1,2-a:30,40-d]imidazole systems
have rarely been reported and principally by Teulade group. Mainly
three convenient syntheses are proposed for these
In 2005, Andaloussi et al. reported the first synthesis of
b
-azacarbolines.
-aza-
b
carbolines by palladium-catalyzed iminoannulation from tert-
butylimine of 3-haloimidazo[1,2-a]pyridine-2-carbaldehyde in the
presence of alkynes (around 36% yield).2 In 2006, Frolov described
a
photocyclization of 2-chloro-N-(pyridin-2-yl)pyridin-3-amine
leading to 65% yield of 1-chlorodipyrido[1,2-a;30,40-d]imidazole.3
More recently, Cartwright et al. reported the annealation reaction
between pentafluoropyridine or various tetrafluoropyridine de-
rivatives, and 2-aminopyridine.4
NH4OH
N
N
THF
CO2Et
CONH2
N
N
overnight
74%
2
1
We report herein an efficient 6-endo-dig cyclization of nitrile to
alkynes leading to new dipyrido[1,2-a:30,40-d]imidazole de-
rivatives. To our knowledge, this 6-endo-dig cyclization type re-
action was not previously described in the literature.
POCl3
115°C
N
N
ICl/CHCl3
CN
CN
N
N
overnight
98%
1h, 91%
I
3
4
Scheme 1. Synthetic route to compound 4.
* Corresponding author. Tel.: þ33 247 367 172; fax: þ33 247 367 288; e-mail
address: alain.gueiffier@univ-tours.fr (A. Gueiffier).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.120

R. Oudot et al. / Tetrahedron 67 (2011) 9576e9581
9577
Table 1
R
H (2 eq)
Optimization studies on the Sonogashira cross-coupling reaction of
4 with
N
Pd2(dba)3 (5 mol%)
N
phenylacetylenea
CN
CN
N
N
CuI (10 mol%)
TEA/dioxane
5 mn at RT
I
5a-d
N
N
4
Ph
H
CN
CN
R
5a R = Ph (62%)
N
N
5b R = n-C5H11 (55%)
[Pd], CuI,
TEA, RT
5c
R = cy-C3H5 (83%)
I
5d R = tert-C4H9 (74%)
4
5a
Scheme 2. Sonogashira cross-coupling of 4 with various alkynes.
Ph
The direct anionic cyclization was then performed by treatment
with Grignard reagents of the various 3-ethynylimidazo[1,2-a]
pyridine-2-carbonitrile derivatives 5. In a first attempt, the addition
of the organomagnesium to 5 proceeded smoothly in diethylether
(Table 2). After overnight stirring at room temperature, moderate
yields of compounds 6e9 were obtained (10e45% yields) along
with starting material. Two different heteroaromatic rings were
expected from the 6-endo-dig cyclization or the 5-exo-dig ring
closure. Actually, only the 6-endo-dig cyclization was detected. We
then changed the solvent to cyclopropylmethylether (Table 3) and
thus increasingly improved the cyclization yield from 45 to 80% for
9. We also noticed that the conversion was completed after 5 min of
stirring, that is, an interesting feature of the protocol. With the
optimal conditions in hand, the scope of the cyclization was next
explored. Various dipyridoimidazoles 9e15 were thus obtained in
good yields (60e89%) (Table 3). This protocol allows the in-
troduction of alkyl or aryl groups in both positions 1 and 3 of the
tricyclic compounds. The nature of these groups does not influence
the efficacy of the 6-endo-dig cyclization. Only compound 12 was
obtained in a lower yield of 60% but this result was not optimized.
The tricyclic structure of compound 14 was confirmed by X-ray
crystallographic analysis10 (Fig. 1).
In the case of compound 12, we determined the presence of
a by-product along with the attempted tricyclic compound. The
structural determination of this by-product was based on the NMR
spectroscopy and ascertained by X-ray crystallographic analysis.10
The 13C NMR spectrum presented a signal around 195 ppm at-
tributed to a carbonyl function present in position 2 of the imidazo
[1,2-a]pyridine. This 2-acetyl-3-(2-cyclopropylethyn-1-yl)imidazo
[1,2-a]pyridine derivative 16 was formed from the organo-
magnesium attack of the carbonitrile, followed by the hydrolysis
of the imine intermediate, thus preventing the cyclization step to
occur.
Entry
[Pd] (mol %)
CuI (mol %)
Solvent
Time
Yieldb (%)
1
2
3
4
5
Pd2(dba)3 (10)
PdCl2(PPh3)2 (10)
Pd2(dba)3 (10)
Pd2(dba)3 (10)
Pd2(dba)3 (5)
20
20
20
20
10
DMF
DMF
Dioxane
Dioxane
Dioxane
15 h
15 h
15 h
5 min
5 min
77
65
65
65
62
a
Reaction conditions:
4 (2 mmol), phenylacetylene (4.4 mmol), [Pd] (0.1 or
0.2 mmol), CuI (0.2 or 0.4 mmol), TEA (2 mL), DMF or dioxane (2 mL), rt.
b
Isolated yields.
From the literature, only few studies related examples of Sonoga-
shira coupling reactions to the 3-halogenoimidazo[1,2-a]pyridines.
In 2007, our group presented a general study on the convenient
synthesis of alkenyl-, alkynyl- and allenyl-substituted imidazo[1,2-
a]pyridines.7 It appeared that the presence of an ester group in
position 2 of the heterocyclic system reduced its reactivity towards
the Sonogashira reaction. We then proposed the following coupling
procedure in the case of the 2-ester compound: Pd2(dba)3
(10 mol %), CuI (10 mol %), TEA in DMF for 24 h at room temperature
(64% yield). In 2007, the cross-coupling of phenylacetylene to the 3-
bromo-2-esterimidazo[1,2-a]pyridine was performed by Hellal
et al. using PdCl2(PPh3)2 as catalyst (5 mol %) in the presence of CuI
(4 mol %), TEA in acetonitrile under microwaves irradiation for
20 min at 120 ꢀC (90% yield).8 These drastic conditions confirm the
poor reactivity of the 2-ester derivative. Only one example of 3-
alkyne-2-cyanoimidazo[1,2-a]pyridine was reported in the litera-
ture. In this case, the nitrile was introduced after the alkyne group
starting
from
a
2-bromo-3-iodoimidazo[1,2-a]pyridine
derivatives.9
In a first approach, the Sonogashira coupling conditions applied
to 4 was inspired from the protocol we previously determined in
the case of the ethyl 3-iodoimidazo[1,2-a]pyridine-2-carboxylate:
Pd2(dba)3 (10 mol %), CuI (20 mol %), TEA (1 mL/mmol) overnight at
room temperature in DMF (Table 1, entry 1). The yield of phenyl-
acetylene coupling was slightly better in the case of the 2-
carbonitrile 4 (77%) than starting from the 2-ester (64%). This can
be explained by the amount of alkyne and copper iodide that was
increased to 2.2 equiv and 20 mol %, respectively, in the present
work (compared to 1.2 equiv and 10 mol % in the previous
publication).
We also decided to evaluate PdCl2(PPh3)2 as catalyst (entry 2).
The coupling product was obtained with a slightly lowered yield
(65%). We thus decided to hold Pd2(dba)3 as catalyst but to switch
to dioxane as solvent in place of DMF, leading to 5a in 65% yield
(entry 3). Working on the reaction time, it appeared that the con-
version in these conditions was completed in 5 min compared to
the 15 h of the previous methods (entry 4). This represents an
important advantage of this methodology. In a last attempt, we
tried to lower the palladium catalyst and copper iodide amounts
(entry 5) to 5 mol % and 10 mol %, respectively. The attempted 5a
was obtained in 62% yield.
In summary, an efficient approach has been developed to as-
semble dipyrido[1,2-a;3040-d]imidazole by employing a Grignard
reagent-promoted 6-endo-dig cyclization of a nitrile to an alkyl
group. The protocol features mild conditions and allows the func-
tionalization of the positions 1 and 3 of the tricyclic compounds with
alkyl or aryl groups with the same efficacy. The two steps of Sono-
gashira coupling reaction and heterocyclization present the advan-
tage to be performed in avery short reaction time and in good yields.
3. Experimental section
3.1. General
1H and 13C NMR spectra were recorded on a 200 MHz, 300 MHz
or 500 MHz spectrometer in CDCl3. Mass spectra were determined
on a Hewlett Packard 5988A spectrometer or on a Shimadzy QP
2010 spectrometer by direct inlet at 70 eV. All products were
identified by 1H and 13C NMR, MS, and Element Analysis. The
melting points were determined in a capillary apparatus and are
uncorrected. Commercial reagents were used as received without
additional purification.
We then exemplified the optimized coupling conditions to vari-
ous alkynes (hept-1-yne, ethynylcyclopropane and 3,3-dimethylbut-
1-yne) with moderate to good yields (55e83%) (Scheme 2).

9578
R. Oudot et al. / Tetrahedron 67 (2011) 9576e9581
Table 2
Heterocyclization of 5a,b using Grignard reagents in diethylethera
N
N
R'MgBr/(C2H5)2O
RT, 1 nuit
R'
CN
N
N
N
5a-b
6-9
R
R
Entry
Alkyne
Dipyridoimidazole
Yieldb (%)
Entry
Alkyne
Dipyridoimidazole
Yieldb (%)
N
N
N
N
N
N
Ph
CN
CN
N
N
1
42
3
10
N
N
5a
5a
8
6
Ph
Ph
Ph
Ph
N
N
N
N
CN
CN
N
N
N
N
2
39
4
45
N
N
5b
5a
9
7
C5H11
Ph
C5H11
Ph
a
Reaction conditions: 5 (1 mmol), R0MgBr (2 mmol), Et2O (10 mL), rt overnight.
b
Yields after silica gel column chromatography.
3.2. 3-Iodoimidazo[1,2-a]pyridine-2-carbonitrile (4)
J¼6.8 Hz, 1H, H-5); 13C NMR Jmode (50 MHz, CDCl3)
d
73.5, 104.2,
114.7, 115.7, 116.4, 119.3, 121.7, 121.8, 126.1, 128.9, 129.2 (2C), 130.4,
132.3 (2C), 145.7. Anal. Calcd for C16H9N3: C, 79.00; H, 3.73; N, 17.27.
Found: C, 79.05; H, 3.78; N, 17.14. IR (neat, cmꢁ1) 3086, 2230, 1634,
1480, 1442, 1350, 1280, 1261, 1233. GCeMS (IE, m/z): 243.
To a solution of 1 g (7 mmol) of 3 in 100 mL of CHCl3 cooled at
0 ꢀC, is added dropwise a solution of 3.4 g (21.3 mmol) of iodide
monochloride in 150 mL of CHCl3. After stirring at room tempera-
ture overnight, the reaction mixture is washed with 5% aqueous
sodium thiosulfate saturated with Na2CO3. The organic phase is
dried over MgSO4, filtered and evaporated to dryness. The residue is
chromatographed on alumina eluting with CH2Cl2 to yield 1.85 g
3.3.2. 3-(Hept-1-yn-1-yl)imidazo[1,2-a]pyridine-2-carbonitrile
(5b). Compound 5b 261 mg (55% yield). Mp 212 ꢀC; 1H NMR
(200 MHz, CDCl3)
d
0.98 (t, J¼6.9 Hz, 3H, CH3), 1.47 (m, 4H, 2 CH2),
(98%) of 4. Mp 224 ꢀC; 1H NMR (200 MHz, DMSO-d6)
d
7.22 (t,
1.72 (m, 2H, CH2), 2.65 (t, J¼6.9 Hz, 2H, CH2), 7.06 (td, J¼6.8, 1.1 Hz,
1H, H-6), 7.41 (ddd, J¼9.2, 6.8,1.1 Hz,1H, H-7), 7.66 (dt, J¼9.2,1.1 Hz,
1H, H-8), 8.25 (dt, J¼6.8, 1.1 Hz, 1H, H-5); 13C NMR (50 MHz, CDCl3)
J¼6.8 Hz, 1H, H-6), 7.54 (dd, J¼9.2, 6.8 Hz, 1H, H-7), 7.71 (dd, J¼9.2,
1.0 Hz, 1H, H-8), 8.41 (dd, J¼6.8, 1.0 Hz, 1H, H-5); 13C NMR (75 MHz,
CDCl3)
d
114.7, 115.5, 116.5, 117.9, 118.8, 126.8, 127.9, 147.8. IR (neat,
d 14.3, 20.3, 22.5, 28.3, 31.4, 65.4, 106.4, 114.7, 115.2, 116.7, 118.7,
cmꢁ1) 2981, 2918, 2849, 2233, 1632, 1504, 1463, 1343, 1261, 1231,
120.5, 125.7, 128.4, 144.9. Anal. Calcd for C15H15N3: C, 75.92; H, 6.37;
N, 17.71. Found: C, 76.04; H, 6.43; N, 17.53. IR (neat, cmꢁ1) 3107,
3090, 2952, 2933, 2859, 2237, 1635, 1499, 1466, 1347, 1250, 1055,
1031. GCeMS (IE, m/z): 237.
1089, 1015. GCeMS (IE, m/z): 269.
3.3. General procedure for the Sonogashira coupling reaction
3.3.3. 3-(Cyclopropylethynyl)imidazo[1,2-a]pyridine-2-carbonitrile
To
a screw-capped test tube were added 538 mg of
(5c). Compound 5c 344 mg (83% yield). Mp 125 ꢀC; 1H NMR
3-iodoimidazo[1,2-a]pyridine-2-carbonitrile 4 (2 mmol), copper (I)
iodide (38 mg, 0.2 mmol), Pd2[dba]3 (92 mg, 0.1 mmol). The tube
was evacuated and back filled with nitrogen. Triethylamine (2 mL),
1,4-dioxane (2 mL) and alkyne (4.4 mmol) were added successively
by syringe at room temperature. The tube was sealed with a Teflon-
lined cap and the reaction mixture was stirred 5 min at room
temperature. The suspension was then diluted with a saturated
aqueous ammonium chloride solution and extracted with CH2Cl2.
The organic phase was dried over MgSO4. After concentration to
dryness, the residue is flash chromatographied on silica gel eluting
with a mixture of petroleum ether and diethylether (100:0 to
50:50).
(200 MHz, CDCl3)
d 1.05 (m, 4H, 2 CH2), 1.64 (m, 1H, CH), 7.04 (td,
J¼6.8, 1.2 Hz, 1H, H-6), 7.39 (ddd, J¼9.2, 6.8, 1.2 Hz, 1H, H-7), 7.61
(dt, J¼9.2, 1.2 Hz, 1H, H-8), 8.22 (dt, J¼6.8, 1.2 Hz, 1H, H-5); 13C NMR
(50 MHz, CDCl3) d 0.9, 10.0 (2C), 60.1, 109.5, 114.7, 115.2, 116.6, 118.6,
120.6, 125.7, 128.4, 144.8. Anal. Calcd for C13H9N3: C, 75.35; H, 4.38;
N, 20.28. Found: C, 75.29; H, 4.31; N, 20.37. IR (neat, cmꢁ1) 3104,
3086, 2226, 1634, 1500, 1450, 1428, 1349, 1274, 1251, 1059, 1039,
951, 926. GCeMS (IE, m/z): 207.
3.3.4. 3-(3,3-Dimethylbut-1-yn-1-yl)imidazo[1,2-a]pyridine-2-
carbonitrile (5d). Compound 5d 330 mg (74% yield). Mp 106 ꢀC; 1H
NMR (200 MHz, CDCl3)
d
1.39 (br s, 9H, 3 CH3), 7.03 (ddd, J¼6.9, 6.7,
1.1 Hz, 1H, H-6), 7.35 (ddd, J¼9.2, 6.7, 1.2 Hz, 1H, H-7), 7.56 (d,
3.3.1. 3-(Phenylethynyl)imidazo[1,2-a]pyridine-2-carbonitrile
J¼9.2 Hz, 1H, H-8), 8.14 (d, J¼6.9 Hz, 1H, H-5); 13C NMR (50 MHz,
(5a). Compound 5a 302 mg (62% yield). Mp 146 ꢀC; 1H NMR
CDCl3)
d 29.1, 31.0 (3C), 64.1, 114.1, 114.7, 115.2, 116.6, 118.8, 120.5,
(200 MHz, CDCl3)
3,4,5), 7.67 (m, 2H, Ph-2,6), 7.73 (d, J¼9.2 Hz, 1H, H-8), 8.37 (d,
d
7.13 (t, J¼6.8 Hz, 1H, H-6), 7.47 (m, 4H, H-7, Ph-
125.6, 128.3, 145.0. Anal. Calcd for C14H13N3: C, 75.31; H, 5.87; N,

R. Oudot et al. / Tetrahedron 67 (2011) 9576e9581
9579
Table 3
Heterocyclization of 5bed using Grignard reagents in cyclopropylmethylethera
N
N
R'MgBr/CPME
R'
CN
N
N
RT, 5'
N
5b-d
9-15
R
R
Entry
Alkyne
Dipyridoimidazole
Yieldb(%)
Entry
Alkyne
Dipyridoimidazole
Yieldb(%)
N
N
N
N
CN
CN
N
N
N
N
N
1
80
5
72
84
83
N
C5H11
5c
5b
13
9
C5H11
CN
N
N
N
N
N
N
Ph
N
N
CN
CN
N
N
N
N
N
2
76
6
N
5c
5b
14
10
C5H11
C5H11
CN
Ph
N
N
N
N
N
N
3
89
7
5d
5b
15
11
C5H11
C5H11
CN
N
N
N
N
N
4
60
5c
12
a
Reaction conditions: 5 (1 mmol), R0MgBr (2 mmol), CPME (10 mL), rt for 5 min.
Yields after silica gel column chromatography.
b
18.82. Found: C, 75.26; H, 5.69; N, 19.00. IR (neat, cmꢁ1) 2971, 2932,
2869, 2235, 2219,1636,1499, 1457,1365,1344,1274,1256, 1137, 901.
GCeMS (IE, m/z): 223.
residue was chromatographed on silica gel eluting with a mixture
of petroleum ether and diethylether (50:50 to 0:100).
Method
Bddiethylether
was
replaced
by
cyclo-
propylmethylether and the reaction mixture was stirred for 5 min
at room temperature.
3.4. General procedure for the heterocyclisation
Method Ada solution of 3-ethynylimidazo[1,2-a]pyridine-2-
carbonitrile derivative 5 (1 mmol) in 10 mL of diethylether was
introduced in a dried round bottom flask and stirred in nitrogen
atmosphere. A 3 M solution of alkylmagnesium bromide in dieth-
ylether (2 mmol) was introduced dropwise to the reaction mixture.
After overnight stirring at room temperature, a saturated aqueous
sodium chloride solution was added to the reaction and the aque-
ous phase was extracted with ethyl acetate. The organic phases
were dried over MgSO4, filtered and concentrated to dryness. The
3.4.1. 1-Methyl-3-phenyldipyrido[1,2-a:30,40-d]imidazole
(6). Method A. 109 mg (42% yield). Mp 202 ꢀC; 1H NMR (500 MHz,
CDCl3)
d
3.09 (s, 3H, CH3), 6.90 (dd, J¼7, 6.5 Hz, 1H, H-7), 7.38 (t,
J¼7.0 Hz, 1H, Ph-4), 7.45e7.50 (m, 3H, Ph-3,5, H-8), 7.74 (d,
J¼9.5 Hz, 1H, H-9), 7.99 (s, 1H, H-4), 8.07 (d, J¼7.0 Hz, 2H, Ph-2,6),
8.42 (d, J¼7 Hz, 1H, H-6); 13C NMR (50 MHz, CDCl3)
d 21.1, 100.4,
111.8, 119.2, 126.1, 127.4 (2C), 128.5, 129.1 (2C), 130.9, 133.9, 139.3,
140.5, 148.6, 149.0, 152.6. Anal. Calcd for C17H13N3: C, 78.74; H, 5.05;
N, 16.20. Found: C, 78.82; H, 5.11; N, 16.01. IR (neat, cmꢁ1) 3029,

9580
R. Oudot et al. / Tetrahedron 67 (2011) 9576e9581
7.79; N, 15.67. IR (neat, cmꢁ1) 2955, 2926, 2856, 1640, 1581, 1505,
1448, 1356, 1236, 1149, 913. GCeMS (IE, m/z): 267.
3.4.6. 3-Pentyl-1-phenyldipyrido[1,2-a:30,40-d]imidazole
(11). Method B. 281 mg (89% yield). Mp 68 ꢀC; 1H NMR (300 MHz,
CDCl3)
d 0.94 (m, 3H, CH3), 1.45 (m, 4H, 2 CH2), 1.96 (m, 2H, CH2),
3.13 (t, J¼7.6 Hz, 2H, CH2), 6.90 (dd, J¼6.9e6.6 Hz, 1H, H-7),
7.45e7.61 (m, 5H, H-8, Ph-3,4,5, H-4), 7.79 (d, J¼9.3 Hz, 1H, H-9),
8.41 (d, J¼6.9 Hz, 1H, H-6), 8.73 (m, 2H, Ph-2,6); 13C NMR (50 MHz,
CDCl3)
d 14.5, 23.1, 30.5, 32.1, 39.1, 102.6, 111.4, 119.5, 125.8, 128.8
(3C), 129.3, 129.9 (2C), 130.6, 135.5, 137.6, 138.7, 149.0, 153.3. Anal.
Calcd for C21H21N3: C, 79.97; H, 6.71; N, 13.32. Found: C, 80.01; H,
6.63; N, 13.25. IR (neat, cmꢁ1) 2952, 2920, 2855, 1637, 1601, 1566,
1495, 1427, 1377, 1354, 1295, 1246, 1142, 1027. GCeMS (IE, m/z): 315.
3.4.7. 3-Cyclopropyl-1-methyldipyrido[1,2-a:30,40-d]imidazole
Fig. 1. X-ray crystal structure of 14.11
(12). Method B. 134 mg (60% yield). Mp 170 ꢀC; 1H NMR (300 MHz,
CDCl3) d 1.08 (m, 4H, 2 CH2), 2.41 (m, 1H, CH), 3.03 (s, 3H, CH3), 6.89
2919,1641,1584,1567,1500,1439,1361,1346,1301,1258,1164,1142.
GCeMS (IE, m/z): 259.
(td, J¼6.9, 1.2 Hz, 1H, H-7), 7.42 (s, 1H, H-4), 7.46 (ddd, J¼9.3, 6.9,
1.2 Hz, 1H, H-8), 7.73 (dd, J¼9.3, 1.2 Hz, 1H, H-9), 8.37 (dd, J¼6.9,
1.2 Hz, 1H, H-6); 13C NMR (50 MHz, CDCl3)
d 9.8 (2C), 18.0, 20.9,
3.4.2. 1-Ethyl-3-phenyldipyrido[1,2-a:30,40-d]imidazole (7). Method
99.6, 111.2, 119.1, 125.8, 130.2, 133.6, 138.3, 148.3, 152.0, 153.3. Anal.
Calcd for C14H13N3: C, 75.31; H, 5.87; N, 18.82. Found: C, 75.49; H,
5.65; N, 18.65. IR (neat, cmꢁ1) 3020, 3000, 2922, 1638, 1580, 1507,
1455, 1362, 1286, 1257, 1233, 1155, 1049, 1024, 958, 917. GCeMS (IE,
m/z): 223.
A. 106 mg (39% yield). Mp 136 ꢀC; 1H NMR (300 MHz, CDCl3)
d 1.60
(t, J¼7.5 Hz, 3H, CH3), 3.52 (q, J¼7.5 Hz, 2H, CH2), 6.96 (t, J¼6.9 Hz,
1H, H-7), 7.41e7.55 (m, 4H, Ph-3,4,5, H-8), 7.82 (d, J¼9.3 Hz, 1H, H-
9), 8.07 (s, 1H, H-4), 8.14 (d, J¼7.5 Hz, 2H, Ph-2,6), 8.51 (d, J¼6.9 Hz,
1H, H-6); 13C NMR (125 MHz, CDCl3)
d 13.1, 27.4, 99.9, 111.4, 119.0,
125.6, 127.1 (2C), 128.2, 128.8 (2C), 130.5, 133.8, 138.3, 140.1, 148.1,
148.6, 156.9. Anal. Calcd for C18H15N3: C, 79.10; H, 5.53; N, 15.37.
Found: C, 79.07; H, 5.46; N, 15.35. IR (neat, cmꢁ1) 3061, 3016, 2970,
2933, 2874, 1641, 1587, 1573, 1505, 1435, 1352, 1261, 1136, 1052, 907.
GCeMS (IE, m/z): 273.
3.4.8. 3-Cyclopropyl-1-ethyldipyrido[1,2-a:30,40-d]imidazole
(13). Method B. 171 mg (72% yield). Mp 79 ꢀC; 1H NMR (200 MHz,
CDCl3)
d
1.03 (m, 4H, 2 CH2), 1.46 (t, J¼7.5 Hz, 3H, CH3), 2.19 (m, 1H,
CH), 3.34 (q, J¼7.5 Hz, 2H, CH2), 6.79 (td, J¼6.8, 1.0 Hz, 1H, H-7), 7.36
(s, 1H, H-4), 7.37 (ddd, J¼9.4, 6.8, 1.3 Hz, 1H, H-8), 7.68 (d, J¼9.4 Hz,
1H, H-9), 8.28 (d, J¼6.8 Hz, 1H, H-6); 13C NMR (75 MHz, CDCl3)
3.4.3. 1,3-Diphenyldipyrido[1,2-a:30,40-d]imidazole (8). Method A.
d 9.55 (2C), 13.1, 17.6, 27.2, 99.2, 110.9, 118.9, 125.4, 129.8, 133.5,
32 mg (10% yield). Mp 190 ꢀC; 1H NMR (500 MHz, CDCl3)
d
6.95 (dd,
137.3, 148.0, 152.9, 156.5. Anal. Calcd for C15H15N3: C, 75.92; H, 6.37;
N, 17.71. Found: C, 75.86; H, 6.41; N, 17.65. IR (neat, cmꢁ1) 2973,
2929, 2866, 2853, 1639, 1578, 1505, 1440, 1355, 1321, 1279, 1265,
1233, 1203, 1138, 1052, 930, 913. GCeMS (IE, m/z): 237.
J¼7.0, 6.5 Hz, 1H, H-7), 7.38 (dd, J¼7.5 Hz, 1H, Ph-4), 7.45e7.65 (m,
6H, Ph-3,5, H-8, Ph0-3,4,5), 7.86 (d, J¼9.5 Hz, 1H, H-9), 8.16 (s, 1H, H-
4), 8.28 (d, J¼7.5 Hz, 2H, Ph-2,6), 8.51 (d, J¼6.5 Hz, 1H, H-6), 8.93 (d,
J¼8 Hz, 2H, Ph0-2,6); 13C NMR (125 MHz, CDCl3)
d 100.3, 111.6, 119.2,
125.5, 127.0 (2C), 127.2, 127.3, 128.3, 128.5 (2C), 128.8 (2C), 129.2,
129.6 (2C), 130.9, 135.6, 138.2, 140.0, 147.9, 149.0. Anal. Calcd for
C22H15N3: C, 82.22; H, 4.70; N, 13.08. Found: C, 82.25; H, 4.80; N,
12.92. IR (neat, cmꢁ1): 3056, 3030, 1639, 1559, 1492, 1427, 1349,
1295, 1245, 1142, 906. GCeMS (IE, m/z): 321.
3.4.9. 3-Cyclopropyl-1-phenyldipyrido[1,2-a:30,40-d]imidazole
(14). Method B. 240 mg (84% yield). Mp 166 ꢀC; 1H NMR (300 MHz,
CDCl3)
d
1.18 (m, 4H, 2 CH2), 2.46 (br s, 1H, CH), 6.92 (dd, J¼6.9,
0.9 Hz, 1H, H-7), 7.47e7.61 (m, 5H, H-8, H-4, Ph-3,4,5), 7.81 (d,
J¼9.3 Hz, 1H, H-9), 8.43 (d, J¼6.9 Hz, 1H, H-6), 8.75 (dd, J¼6.9 Hz,
2H, Ph-2,6); 13C NMR (50 MHz, CDCl3)
d 10.0 (2C), 17.5, 100.8, 111.2,
3.4.4. 1-Methyl-3-pentyldipyrido[1,2-a:30,40-d]imidazole
119.0, 125.4, 128.4, 129.1 (2C), 129.5, 130.4 (3C), 135.3, 137.0, 137.9,
148.5, 152.9. Anal. Calcd for C19H15N3: C, 79.98; H, 5.30; N, 14.73.
Found: C, 79.91; H, 5.39; N, 14.64. IR (neat, cmꢁ1) 3067, 2999, 2922,
1638, 1603, 1564, 1494, 1450, 1434, 1353, 1291, 1250, 1146, 1028, 931.
GCeMS (IE, m/z): 285.
(9). Method B. 202 mg (80% yield). Mp 83 ꢀC; 1H NMR (500 MHz,
CDCl3)
d
0.87 (t, J¼5.2 Hz, 3H, CH3), 1.36 (m, 4H, 2 CH2), 1.78 (qt,
J¼6.5 Hz, 2H, CH2), 2.92 (t, J¼8.7 Hz, 2H, CH2), 2.97 (s, 3H, CH3), 6.80
(dd, J¼7.3, 6.6 Hz, 1H, H-7), 7.38 (m, 1H, H-8), 7.40 (s, 1H, H-4), 7.65
(d, J¼9.5 Hz,1H, H-9), 8.29 (d, J¼7.3 Hz,1H, H-6); 13C NMR (50 MHz,
CDCl3)
d
14.2, 20.8, 23.0, 30.8, 32.0, 39.0, 101.7, 111.3, 119.0, 125.8,
3.4.10. 1-Methyl-3-(tert-butyl)dipyrido[1,2-a:30,40-d]imidazole
130.4, 133.5, 138.2, 148.4, 152.0, 153.0. Anal. Calcd for C16H19N3: C,
75.85; H, 7.56; N, 16.59. Found: C, 75.92; H, 7.53; N, 16.51. IR (neat,
cmꢁ1) 3356, 3194, 2959, 2923, 2872, 2856, 1725, 1642, 1586, 1503,
1453, 1362, 1256, 1156, 1137, 1071, 920. GCeMS (IE, m/z): 253.
(15). Method B. 199 mg (84% yield). Mp 181 ꢀC; 1H NMR (200 MHz,
CDCl3)
d
1.50 (s, 9H), 3.03 (s, 3H), 6.87 (t, J¼6.8 Hz, 1H, H-7), 7.45 (m,
1H, H-8), 7.64 (s, 1H, H-4), 7.74 (d, J¼9.3 Hz, 1H, H-9), 8.43 (d,
J¼6.8 Hz, 1H, H-6); 13C NMR (50 MHz, CDCl3)
d 21.1, 31.1 (3C), 37.9,
98.2, 111.2, 119.3, 125.9, 130.2, 133.5, 138.0, 148.6, 151.5, 160.3. Anal.
Calcd for C15H17N3: C, 75.28; H, 7.16; N, 17.56. Found: C, 75.30; H,
7.21; N, 17.30. IR (neat, cmꢁ1) 3465, 2950, 2918, 1644, 1587, 1500,
1444, 1357, 1306, 1267, 1239, 1168, 1142, 909. GCeMS (IE, m/z): 239.
3.4.5. 1-Ethyl-3-pentyldipyrido[1,2-a:30,40-d]imidazole (10). Method
B. 203 mg (76% yield). Oil; 1H NMR (200 MHz, CDCl3)
d 0.81 (t,
J¼7.5 Hz, 3H, CH3), 1.29 (m, 4H, 2 CH2), 1.41 (t, J¼7.6 Hz, 3H, CH3),
1.69 (m, 2H, CH2), 2.87 (t, J¼7.5 Hz, 2H, CH2), 3.28 (q, J¼7.6 Hz, 2H,
CH2), 6.69 (t, J¼6.9 Hz, 1H, H-7), 7.23 (dd, J¼9.3, 6.9 Hz, 1H, H-8),
7.32 (s, 1H, H-4), 7.58 (d, J¼9.3 Hz, 1H, H-9), 8.21 (d, J¼6.9 Hz, 1H, H-
Acknowledgements
6); 13C NMR (50 MHz, CDCl3)
d 14.0, 14.3, 22.8, 27.8, 30.5, 31.9, 38.8,
101.5, 111.1, 118.7, 125.7, 130.1, 133.6, 137.4, 148.2, 152.9, 156.7. Anal.
Calcd for C17H21N3: C, 76.37; H, 7.92; N, 15.72. Found: C, 76.50; H,
The authors thank SAVIT, Tours (France) for NMR spectrometry,
ꢀ
and Cecilia Brambilla for technical assistance.

R. Oudot et al. / Tetrahedron 67 (2011) 9576e9581
9581
2. Andaloussi, M.; Chezal, J.-M.; Moreau, E.; Lartigue, C.; El Laghdach, A.; Teulade,
J.-C.; Chavignon, O. Heterocycles 2005, 65, 1071.
Supplementary data
3. Frolov, A. N. Russ. J. Org. Chem. 2006, 42, 883.
These data include NMR spectra of compounds 4, 5aed, 6aec,
7aec, 8aec, 9a and X-ray crystallographic data for compounds 14
and 16. Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tet.2011.09.120.
4. Cartwright, M. W.; Convery, L.; Kraynck, T.; Sandford, G.; Yufit, D. S.; Howard, J.
A. K.; Christopher, J. A.; Miller, D. D. Tetrahedron 2010, 66, 519.
5. Lombardino, J. G. J. Org. Chem. 1965, 30, 2403.
6. Fischer, M. H.; Lusi, A. J. Med. Chem. 1972, 15, 982.
7. Enguehard-Gueiffier, C.; Croix, C.; Hervet, M.; Kazock, J.-Y.; Gueiffier, A.; Abar-
bri, M. Helv. Chim. Acta 2007, 90, 2349.
8. Hellal, M.; Bourguignon, J.-J.; Bihel, F. J.-J. Tetrahedron Lett. 2007, 49, 62.
9. Terinek, M.; Nordhoff, S.; Soeberdt, M.; Rummey, C.; Feurer, A.; Weyermann, P.
WO 2010034500.
10. CCDC 835972 and 835973 contain the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.Ccdc.cam.ac.uk/data_request/
cif.
References and notes
1. See for examples (a) Kim, O.; Jeong, Y.; Lee, H.; Hong, S.; Hong, S. J. Med. Chem.
2011, 54 (7), 2455; (b) Hori, Y.; Imanishi, A.; Matsukawa, J.; Tsukimi, Y.; Nishida,
H.; Arikawa, Y.; Hirase, K.; Kajino, M.; Inatomi, N. J. Pharmacol. Exp. Ther. 2010,
335, 231; (c) Chezal, J.-M.; Paeshuyse, J.; Gaumet, V.; Canitrot, D.; Maisonial, A.;
Lartigue, C.; Gueiffier, A.; Moreau, E.; Teulade, J.-C.; Chavignon, O.; Neyts, Y. Eur.
J. Med. Chem. 2010, 45, 2044.
11. Spek, A. L. J. Appl. Crystallogr. 2003, 36, 7.