Methodology to access tetrahydrodipyridoimidazole derivatives

Article abstract of DOI:10.3987/COM-12-12447

While the synthesis of β and γ-carboline derivatives were well described in the literature, the preparation of their aza-analogs such as tetrahydrodipyridoimidazole derivatives were less explored. In our laboratory we developed various methods to access t

Full text of DOI:10.3987/COM-12-12447

HETEROCYCLES, Vol. 85, No. 9, 2012
2135
HETEROCYCLES, Vol. 85, No. 9, 2012, pp. 2135 - 2145. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 13th February, 2012, Accepted, 17th July, 2012, Published online, 25th July, 2012
DOI: 10.3987/COM-12-12447
METHODOLOGY TO ACCESS TETRAHYDRODIPYRIDOIMIDAZOLE
DERIVATIVES
Mohamed El Bousmaqui,a,b Marion Donnier-Marechal,a,b Paul-Emmanuel
Larchanche,a,b Patricia Melnyk,a,b and Pascal Caratoa,b *
a Univ Lille Nord de France, F-59000 Lille, France
b UDSL, EA 4481, UFR Pharmacie, F-59000 Lille, France
Abstract – While the synthesis of  and -carboline derivatives were well
described in the literature, the preparation of their aza-analogs such as
tetrahydrodipyridoimidazole derivatives were less explored. In our laboratory we
developed various methods to access to these compounds using Bischler-
Napieralski as well as Pictet-Spengler reactions.
INTRODUCTION
The indole derivatives have long been a topic of fundamental interest to organic and medicinal chemists.
They display a wide range of biological activities and are frequently found to be active in various classes
of pharmacologically important compounds. The indole ring provides an attractive entry to a variety of
polycyclic heteroaromatic alkaloids. For example, indoles containing one additional ring fused across the
2,3-positions are widely distributed in nature and used in medicinal chemistry.1 A lot of work has been
done on the synthesis of tricyclic compounds with functionalized pyrido[3,4-b]indoles (-carbolines)2-6 or
the isomeric series of pyrido[4,3-b]indoles (-carbolines)7-10 and is well represented in the literature
(Figure 1).
NH2
R
R
N
2
X
X
N
3
Y
Y
N
R
R
N
N
H
N
N
NH2
X, Y : CH2, NH (-carbolines)
NH, CH2 (-carbolines)
X, Y : CH2, NH (tetrahydrodipyrido[1,2-a:3',4'-d]imidazole)
NH, CH2 (tetrahydrodipyrido[1,2-a:4',3'-d]imidazole)
R: aliphatic group or aryl ring
R: aliphatic group or aryl ring
Figure 1. Structures and routes to , -carboline and tetrahydrodipyridoimidazole derivatives

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HETEROCYCLES, Vol. 85, No. 9, 2012
In this paper, we have focused our attention on tetrahydrodipyrido[1,2-a:4',3'-d]imidazole and
tetrahydrodipyrido[1,2-a:3',4'-d]imidazole compounds, build starting from and 3-
2
ethylaminoimidazopyridine derivatives, which are less well described both pharmacologically and
theoretically than their  and - carboline analogs (Figure 1).
In our laboratory we synthesized a series of -carboline compounds and tested for their antioxidant
activities (Figure 2).6 In the course of our extensive studies on the chemistry and pharmacological
reactivities, we changed the indole heterocycle to its isoster imidazopyridine, possessing a bridgehead
nitrogen atom (Figure 2).
R
R2
N
H
NH
Br
N
N
Br
R1
N
H
R
N
N
N
R1 : OMe, OH, OBn
R2 : H, Me, Pr, Pent, Non, COEt
R : OMe, N(Me)2, NO2, CN
Figure 2. -Carboline compounds with antioxidant activities and their isoster tetrahydro-
dipyridoimidazole derivatives
RESULTS AND DISCUSSION
To build these tetrahydrodipyridoimidazole derivatives, isosters of -carboline compounds, the synthesis
of 8-bromo-1-substituted tetrahydrodipyridoimidazole compounds, as key intermediates, was explored by
two routes involving Bischler-Napieralski or Pictet-Spengler ring closures. These intermediates were
substituted at the 8 position by a bromo atom to insert alkyl chain, heterocyclic or heterocyclic carbonyl
moiety using palladium coupling reaction. Various alkyl or carbonylalkyl chains could be introduced at
the nitrogen atom of the tetrahydrodipyridoimidazole compounds by nucleophilic substitution (Figure 2).
In the literature, these tetrahydrodipyridoimidazole compounds were synthesised starting from 2 or 3-
ethylaminoimidazopyridine derivatives (Figure 1). The reactivity of imidazo[1,2-a]pyridine has been
described,11,12 the 2 position is known to be a less reactive than the 3 position. Indeed, this 2 position is
able to react as an electrophile to give the corresponding compound with low yield (4%) as previously
described in the reaction between an imidazopyridine compound and phenyl isocyanate in refluxing
toluene.13
To build tetrahydrodipyrido[1,2-a:4',3'-d]imidazole and tetrahydrodipyrido[1,2-a:3',4'-d]imidazole
heterocycles, we developed two routes starting from 2 or 3-ethylaminoimidazopyridine and involving
Bischler-Napieralski or Pictet-Spengler ring closures.

HETEROCYCLES, Vol. 85, No. 9, 2012
2137
O
N
Br
Br
O
O
N
O
O
2
Br
Br
Br
-
N
a or b
N
N
N
N
N
Br
+
+
O
O
N
N
NH2
O
O
4 - 5
1
CHO
Br
N
c
4a (13%)
O
O
3
N
O
NH2
2 HCl
2 position 3 position
Yields (%) Yields (%)
6 - 7
OMe
d
5 (72%)
7 (93%)
9 (89%)
4 (75%)
6 (80%)
8 (82%)
Cpd
Br
N
N
O
N
8 - 9
Reagents and conditions: (a): 1-bromoketone compound (2), EtOH or BuOH (b): i: 1-bromoketone (2) or
2-bromoaldehyde (3) compounds, EtOAc; ii: EtOH (c): NH2-NH2. H2O, EtOH (d): 3-methoxybenzoyl
chloride, K2CO3, H2O, EtOAc.
Scheme 1. Synthesis of substituted imidazopyridine compounds (4-9)
For the construction of imidazopyridine compounds, various conditions have been used in the literature.
We attempted this reaction in one step by refluxing 2-amino-5-bromopyridine (1) in ethanol or butanol14
with the corresponding 1-bromoketone or 2-bromoaldehyde compounds (2,3). In these conditions the
desired compounds (4,5) were obtained with low yields (35-39%) together with the formation of side
products (Scheme 1). Furthermore, the purification of the expected products (4,5) was difficult and the 2-
amino-5-bromopyridine (1) was not totally consumed. One explanation is the presence of a competing
side reaction such as N1-alkylation of substituted imidazopyridine as observed during the synthesis of
compound 4 (yield 35%) leading to the by product 4a (yield 13%).
To overcome this limitation, we turned our attention to the well known two-step synthesis of
imidazopyridine involving first the formation and isolation of pyridinium salts. The first step was carried
out in ethyl acetate (prefered to commonly used 1,2-dichloroethane), with 2-amino-5-bromopyridine (1)
and the corresponding 1-bromoketone or 2-bromoaldehyde compounds (2,3). After one day of stirring at
room temperature, the primary material (1) was totaly consumed and the intermediate bromide products
were filtered, washed with ethyl acetate and then refluxed for the second step in ethanol. Using this
methodology avoiding the formation of N-alkylated by products, final compounds (4,5) were obtained in
good yields (72-75%) (Scheme 1). The deprotection of phthalimide group of compounds 4,5 was
performed with hydrazine hydrate in ethanol to give the corresponding ethylamino compounds 6,7.15 It is
worth emphasizing that water was not used in the treatment to eliminate the formation of phthalhydrazide,
indeed we observed that the compounds were partially solubilised in water and could not be totally

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extracted with an organic phase, under these conditions the yield was only 50-60%. Treatment with ethyl
acetate and purification by chromatography on silica gel furnished compounds 6,7 with excellent yields
(90-93%).
R
H
N
NH2
Br
Br
a
Br
Br
NH
a
N
N
N
N
N
N
NH2
N
N
7
6
11a-d
b
b
d
MeO
O
N
Br
c
MeO
O
Br
H
N
N
c
N
Br
N
N
N
N
H
N
Br
OMe
N
N
MeO
9 (89%)
8 (82%)
10 (54%)
N
MeO
Cpd
Yields (%)
R
11a
11b
3-OMe
74
78
4-N(Me)2
11c
11d
4-NO2
4-CN
65
69
Reagents and conditions: (a): substituted benzaldehyde, TFA, MeOH (b): 3-methoxybenzoyl chloride,
K2CO3, H2O, EtOAc (c): POCl3 (d): NaBH4, MeOH.
Scheme 2. Synthesis of tetrahydrodipyridoimidazole compounds 11a-d starting from compound 6
The cyclization of imidazopyridine compounds to tetrahydrodipyridoimidazole was described in the
literature with low yields (20-25%) in methanol at room temperature and with the presence of magnesium
sulfate.16,17 In order to improve the reaction yields, the use of Bischler-Napieralski or Pictet-Spengler
reactions starting from ethylamino derivatives (6-7) was evaluated. The Bischler-Napieralski cyclization
was achieved in three steps from amino compounds (8,9).18 For the first step, amidation reaction of
ethylamino compounds (6-7) and 3-methoxybenzoyl chloride in a biphasic solution containing aqueous
5% potassium carbonate and ethyl acetate solutions gave compounds (8,9) (Scheme 1). The cyclization
step was performed in refluxing POCl3, used as solvent and reagent, and the amido products (8,9). In the
series substituted at the 3 position of the imidazopyridine derivative (9) the cyclization was not realised
and we only recovered starting material and degradation products, probably due to the lack of reactivity
of the 2 position of the imidazo[1,2-a]pyridine. For the second series, substituted at the 2 position (8), the
cyclization in POCl3 afforded compound 10 with 54% yield (Scheme 2). The next step was a reduction
with sodium borohydride of the imine group (10) which gave the cyclized compound 11a. The overall
yield of the Bischler-Napieralski pathway was 37%. The second route was accomplished starting from

HETEROCYCLES, Vol. 85, No. 9, 2012
2139
ethylamino compounds (6-7) using Pictet-Spengler reaction. A first attempt using 1.25%
TFA/dichloromethane solution and benzaldehyde reagent under various temperature conditions did not
give the corresponding cyclized compounds.19,20 The solvent was then replaced by methanol. In these
conditions and under reflux in the presence of 3-methoxybenzaldehyde, compound (6) bearing the
ethylamino chain at the 2 position of the imidazo[1,2-a]pyridine was converted in good yield (74%) into
compound 11a. (Scheme 2). This cyclization has already been described in one step, but with low yield
(20-25%).16,17 As observed previously for the Bischler-Napieralski pathway, our attempts failed to
perform cyclization at the 2 position via Pictet-Spengler reaction starting from compound 7.
In a second time, various electron donating or withdrawing groups (N(Me)2, NO2, CN) were introduced
into the phenyl ring using the more efficient Pictet-Spengler method (Scheme 2). As expected phenyl ring
bearing electron-donating groups (11a-b) gave the highest yields (74-78%) and shortest time reactions
(24 h) compared to derivatives (11c-d) with electron-withdrawing groups (65-69%; 48 h respectively).
These compounds (11a-d) could be used as intermediates in medicinal chemistry. Indeed, various
reactions at the nitrogen atom of the tetrahydrodipyridoimidazole with nucleophilic substitution and also
palladium coupling reaction with the bromo atom at the 8 position of the tetrahydrodipyridoimidazole
with Stille, Suzuki, Heck reactions.
CONCLUSION
Tetrahydrodipyridoimidazole coupounds 11a-d, bearing various substituents were synthesized using two
methods, Bischler-Napieralski and Pictet-Spengler reactions. The best yields were obtained by the Pictet-
Spengler pathway. These compounds could be used in medicinal chemistry with nucleophilic substitution
or palladium coupling reaction.
EXPERIMENTAL
TLC and column chromatography were carried out on silica gel 60 F 254 plates and on glass column silica
gel 60 (40-63 mesh). All of the reagents and solvents were AR grade. Melting points were determined by
a Büchi 510 capillary apparatus and are uncorrected. Infrared spectra were recorded on a BECKMAN
ACCULAB IV spectrometer in KBr. 1H and 13C NMR spectra were recorded on a Bruker AVANCE 300
spectrometer and chemical shifts are expressed in ppm using tetramethylsilane as internal standard. Mass
spectra were recorded on a Thermofinnigan Surveyor MSQ Single Quadrupole Mass Spectrometer
operating in electrospray, positive single ion mode to monitor m/z. The purity of final compounds was
verified by two types of high pressure liquid chromatography (HPLC) columns: C18 Deltapak (C18N)
and C4 Interchrom UP5WC4-25QS (C4).

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2-[2-(6-Bromo-1-(2-oxo-4-isoindole-1,3-dionebutyl)imidazo[1,2-a]pyridin-2-yl)ethyl]isoindole-1,3-
dione bromide (4a)
In EtOH or BuOH (100 mL), 2-amino-5-bromopyridine (2.3 g, 13.2 mmol) and 2-(4-bromo-3-
oxobutyl)isoindole-1,3-dione (3.3 g, 11.0 mmol) were added. The mixture was refluxed for 1 day. The
solution was evaporated under reduced pressure. The resulting crude product was purified by
chromatography on silica gel (40-63 mesh), eluting with CH2Cl2 / MeOH (95/5, v/v). Yield 13%, mp 176-
177 °C, HPLC (C18, 35 min) PHPLC 90%, tR 13.8 min; HPLC (C4, 35 min) PHPLC 90%, tR 22.1 min.
1
IR 1775 (CO), 1709 (CO), 1643 (CN). H NMR (DMSO-d6) δ 3.15 (m, 4H, CH2), 3.87 (m, 4H, NCH2),
5.70 (s, 2H, COCH2), 7.80 (m, 8H, HAr), 8.18 (d, 1H, H8, J = 9.7 Hz), 8.26 (dd, 1H, H7, J = 9.7 Hz, J =
1.8 Hz), 8.29 (s, 1H, H3), 9.35 (d, 1H, H5, J = 1.8 Hz). 13C NMR (DMSO-d6) δ 23.0, 33.0, 36.0, 38.0, 54.0,
112.0, 113.5, 114.0, 123.7, 124.0, 130.3, 132.4, 132.6, 135.3, 135.6, 137.0, 137.3, 139.6, 170.0, 201.0.
MS (APCI+): m/z 585.2, 587.3.
General procedure for the synthesis of compounds 4-5
In EtOAc (100 mL), 2-amino-5-bromopyridine (6.9 g, 39.7 mmol) and 2-bromo-4-(1,3-dioxo-1,3-
dihydro-2H-isoindol-2-yl)butyraldehyde or 2-(4-bromo-3-oxobutyl)isoindole-1,3-dione (9.8 g, 33.1
mmol) were added. The mixture was stirred for 1 day at room temperature. The precipitate was filtred and
washed with EtOAc (200 mL). The product was dissolved in EtOH (150 mL) and refluxed for 1 day.
After cooling to room temperature, the solvent was evaporated under vacuum. The residue obtained was
taken up with an aqueous solution of 5% potassium carbonate (100 mL) and extracted with CH2Cl2 (2 x
100 mL). The organic phase was dried over MgSO4 filtered and evaporated under reduced pressure. The
products were recrystallised in acetonitrile.
2-[2-(6-Bromoimidazo[1,2-a]pyridin-2-yl)ethyl]isoindole-1,3-dione (4)
Yield 75%, mp 195-196 °C, HPLC (C18, 35 min) PHPLC 100%, tR 9.8 min; HPLC (C4, 35 min) PHPLC
1
100%, tR 7.1 min. IR 1713 (CO), 1769 (CO), 1649 (CN). H NMR (DMSO-d6) δ 3.00 (t, 2H, CH2, J =
7.6 Hz), 3.95 (t, 2H, NCH2, J = 7.6 Hz), 7.25 (dd, 1H, H7, J = 9.6 Hz, J = 2.0 Hz), 7.40 (dd, 1H, H8, J =
13
9.6 Hz, J = 0.8 Hz), 7.75 (s, 1H, H3), 7.85 (m, 4H, HAr), 8.80 (dd, 1H, H5, J = 2.0 Hz, J = 0.8 Hz). C
NMR (DMSO-d6) δ 24.6, 36.9, 110.7, 113.5, 113.6, 123.6, 129.4, 132.0, 134.9,135.9, 140.0, 138.6, 168.2.
MS (APCI+): m/z 370.2, 372.3.
2-[2-(6-Bromoimidazo[1,2-a]pyridin-3-yl)ethyl]isoindole-1,3-dione (5)
Yield 72%, mp 172-173 °C, HPLC (C18, 35 min) PHPLC 100%, tR 9.3 min; HPLC (C4, 35 min) PHPLC
1
100%, tR 18.5 min. IR 1707 (CO), 1765 (CO), 1653 (CN). H NMR (DMSO-d6) δ 3.35 (t, 2H, CH2, J =

HETEROCYCLES, Vol. 85, No. 9, 2012
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6.4 Hz), 3.95 (t, 2H, NCH2, J = 6.4 Hz), 7.80 (m, 4H, HAr), 7.98 (d, 1H, H8, J = 9.5 Hz), 8.07 (s, 1H, H2),
8.13 (dd, 1H, H7, J = 9.5 Hz, J = 1.8 Hz), 9.40 (d, 1H, H4, J = 1.8 Hz). 13C NMR (DMSO-d6) δ 22.7, 34.8,
111.4, 114.1, 122.1, 123.6, 125.0, 127.7, 131.9, 135.0, 136.0, 138.9, 168.0. MS (APCI+): m/z 369.9,
371.9 [M+H]+.
General procedure for the synthesis of compounds 6-7
In 95% EtOH (50 mL), 2-[2-(6-bromoimidazo[1,2-a]pyridin-2 or 3-yl)ethyl]isoindole-1,3-dione (1.41 g,
3.81 mmol) and hydrazine monohydrate (0.95 g, 19 mmol) were added. The solution was refluxed for 4 h.
After cooling to room temperature, the reaction mixture was evaporated under vacuum. The precipitate
obtained was tritured with EtOAc (2 x 100 mL) and filtered. The filtrate was evaporated under reduced
pressure and the oily residue was washed with Et2O (3 x 50 mL). The resulting crude product was
purified by chromatography on silica gel (40-63 mesh), eluting with CH2Cl2 / MeOH (95/5, v/v). The
products were solubilized in dry EtOAc and treated with gazeous hydrochloric acid in diethyl ether (20
mL). The obtained precipitate was filtered and washed with EtOAc (2 x 20 mL) to afford desired
compounds.
2-(6-Bromoimidazo[1,2-a]pyridin-2-yl)ethylamine dihydrochloride (6)
Yield 90%, mp 192-193 °C, HPLC (C18, 35 min) PHPLC 100%, tR 2.8 min; HPLC (C4, 35 min) PHPLC
100%, tR 4.9 min. IR 3355, 3286 (NH2), 1656 (CN). 1H NMR (DMSO-d6) δ, 3.14 (m, 2H, CH2), 3.43 (t,
2H, NCH2, J = 6.7 Hz), 7.97 (d, 1H, H8, J = 9.5 Hz), 8.07 (dd, 1H, H7, J = 9.5 Hz, J = 1.6 Hz), 8.17 (s,
13
1H, H2), 8.35 (brs, 3H, NH+, NH2), 9.38 (s, 1H, H5). C NMR (DMSO-d6) δ 23.7, 37.9, 110.1, 113.8,
113.9, 129.1, 135.0, 135.3, 139.3. MS (APCI+): m/z 240.0, 242.0.
2-(6-Bromoimidazo[1,2-a]pyridin-3-yl)ethylamine dihydrochloride (7)
Yield 93%, mp 95-96 °C, HPLC (C18, 35 min) PHPLC 99.9%, tR 1.5 min; HPLC (C4, 35 min) PHPLC
100%, tR 5.3 min. IR 3355, 3286 (NH2), 1656 (CN). 1H NMR (DMSO-d6) δ 2.85 (t, 2H, CH2, J = 6.7 Hz),
2.95 (t, 2H, CH2, J = 6.7 Hz), 7.25 (dd, 1H, H7, J = 9.5 Hz, J = 1.9 Hz), 7.40 (s, 1H, H2), 7.50 (d, 1H, H8,
J = 9.5 Hz), 8.70 (d, 1H, H5, J = 1.9 Hz). 13C NMR (DMSO-d6) δ 21.2, 36.4, 111.1, 114.1, 122.9, 123.5,
127.8, 135.6, 139.2. MS (APCI+): m/z 240.0, 242.0 [M+H]+.
General procedure for the synthesis of compounds 8-9
In an aqueous solution of 5% potassium carbonate (50 mL) and CHCl3 (40 mL), 2-(6-bromoimidazo[1,2-
a]pyridin-3-yl)ethylamine (1.0 g, 4.16 mmol) and 3-methoxybenzoyl chloride (0.7 mL, 5 mmol) were
added. The solution was stirred at room temperature for 2 h. The organic phase was washed with water

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(30 mL), dried over MgSO4, filtered and evaporated. The obtained product was recrystallised from MeCN.
N-[2-(6-Bromoimidazo[1,2-a]pyridin-2-yl)ethyl]-3-methoxybenzamide (8)
Yield 82%, mp 115-116 °C, HPLC (C18, 35 min) PHPLC 99.9%, tR 9.4 min; HPLC (C4, 35 min)
1
PHPLC 100%, tR 7.1 min. IR 3336 (NH), 1668 (CN), 1659 (CO). H NMR (DMSO-d6) δ 2.95 (t, 2H,
CH2, J = 7.3 Hz), 3.60 (t, 2H, CH2, J = 7.3 Hz), 3.80 (s, 3H, OCH3), 7.10 (m, 1H, HAr), 7.29 (dd, 1H, H7,
J = 9.3 Hz, J = 1.7 Hz), 7.38 (m, 3H, HAr), 7.46 (dd, 1H, H8, J = 9.3 Hz, J = 0.9 Hz), 7.75 (s, 1H, H3),
13
8.60 (bsr, 1H, NH), 8.84 (dd, 1H, H5, J = 1.7 Hz, J = 0.9 Hz). C NMR (DMSO-d6) δ 29.0, 39.1, 55.7,
105.7, 111.1, 112.8, 117.4, 117.6, 119.8, 127.0, 127.4, 129.9, 136.5, 143.1, 145.8, 159.6, 166.4. MS
(APCI+): m/z 374.2, 376.2.
N-[2-(6-Bromoimidazo[1,2-a]pyridin-3-yl)ethyl]-3-methoxybenzamide (9)
Yield 89%, mp 123-124 °C, HPLC (C18, 35 min) PHPLC 100%, tR 9.8 min; HPLC (C4, 35 min) PHPLC
1
94.8%, tR 7.3 min. IR 3273 (NH), 1661 (CN), 1632 (CO). H NMR (DMSO-d6) δ 3.15 (t, 2H, CH2, J =
6.7 Hz), 3.55 (t, 2H, CH2, J = 6.7 Hz), 3.75 (s, 3H, OCH3), 7.05 (m, 1H, HAr), 7.30 (m, 2H, H7, HAr), 7.36
(m, 2H, HAr), 7.45 (s, 1H, H2), 7.52 (dd, 1H, H8, J = 9.6 Hz, J =0.6 Hz), 8.60 (brs, 1H, NH), 8.75 (dd, 1H,
H5, J = 1.75 Hz, J = 0.6 Hz). 13C NMR (DMSO-d6) δ 23.8, 37.9, 55.7, 106.5, 112.8, 117.4, 118.6, 119.8,
123.5, 125.0, 126.8, 129.9, 132.6, 136.3, 143.5, 159.6, 166.7. MS (APCI+): m/z 374.2, 376.1.
8-Bromo-1-(3-methoxyphenyl)-3,4-dihydrodipyrido[1,2-a;4’,3’-d]imidazole dihydrochloride (10)
In POCl3 (15 mL), N-[2-(6-bromoimidazo[1,2-a]pyridin-2-yl)ethyl]-3-methoxy-benzamide (1.0 g, 2.8
mmol)was added and the solution was refluxed for 2 days After cooling to room temperature, the solvent
was evaporated under reduced pressure. The residue was triturated with EtOAc (50 mL). The precipitate
obtained was filtered and recrystallised in MeCN. Yield 54%, mp > 250 °C, HPLC (C18, 35 min) PHPLC
94.8%, tR 11.9 min; HPLC (C4, 35 min) PHPLC 92.5%, tR 6.2 min. IR 3050-2450 (NH+), 1638 (CN). 1H
NMR (DMSO-d6) δ 2.75 (t, 2H, CH2, J = 7.0 Hz), 3.15 (t, 2H, CH2, J = 7.0 Hz), 3.80 (s, 3H, OCH3), 7.23
(m, 2H, HAr), 7.31 (d, 1H, HAr, J = 7.6 Hz), 7.48 (m, 1H, HAr), 7.82 (dd, 1H, H10, J = 9.3 Hz, J = 0.8 Hz),
7.88 (dd, 1H, H9, J = 9.3 Hz, J = 1.7 Hz), 8.20 (brs, 2H, NH+, NH+), 9.32 (dd, 1H, H7, J = 1.7 Hz, J = 0.8
Hz). 13C NMR (DMSO-d6) δ 27.0, 37.6, 55.9, 109.9, 113.7, 117.1, 119.5, 121.6, 121.7, 128.5, 130.6,
134.3, 140.5, 144.0, 148.9, 159.8, 185.8. MS (APCI+): m/z 356.2, 358.1 [M+H]+.
Synthesis of compound 11a by reduction of imine 10
8-Bromo-1-(3-methoxyphenyl)-3,4-dihydrodipyrido[1,2-a;4’,3’-d]imidazole dihydrochloride (10) (0.50 g,
2.1 mmol) was dissolved in MeOH (2 0 mL). Sodium borohydride (0.15 g, 4.2 mmol) was then added and

HETEROCYCLES, Vol. 85, No. 9, 2012
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the mixture was stirred for 4 h at room temperature. The solvent was then evaporated under reduced
pressure. The residue was taken up in water (50 mL) and extracted with CH2Cl2 (2 x 50 mL). The organic
phase was washed with water (100 mL), dried over MgSO4, filtered and evaporated. The resulting crude
product was purified by chromatography on silica gel (40-63 mesh), eluting with CH2Cl2 / MeOH (97/3,
v/v) to afford the desired compounds 11a with 76% yield.
General procedure for the synthesis of compounds 11a-d using Pictet-Spengler methodology
In MeOH (20 mL), 2-(6-bromoimidazo[1,2-a]pyridin-2-yl)ethylamine (6) (0.5 g, 2.1 mmol),
trifluoroacetic acid (0.25 mL, 3.2 mmol) and the desired susbtituted benzaldehyde (4.2 mmol) were added.
The solution was refluxed (24 to 48 h). The resulting crude product was purified by chromatography on
silica gel (40-63 mesh), eluting with CH2Cl2 / MeOH (97/3, v/v) to afford desired compounds 11a-d.
8-Bromo-1-(3-methoxyphenyl)-1,2,3,4-tetrahydrodipyrido[1,2-a;4',3'-d]imidazole (11a)
Yield 74% (24 h), mp 148-149 °C, HPLC (C18, 35 min) PHPLC 98.9%, tR 7.8 min; HPLC (C4, 35 min)
1
PHPLC 100%, tR 6.1 min. IR 3272 (NH), 1595 (CN). H NMR (CDCl3) δ 2.00 (brs, 1H, NH), 2.98 (m,
2H, CH2), 3.15 (m, 1H, NCH2), 3.30 (m, 1H, NCH2), 3.78 (s, 3H, OCH3), 5.20 (s, 1H, CH), 6.75 (m, 2H,
HAr), 6.91 (ddd, 1H, HAr, J = 7.5 Hz, J = 2.2 Hz, J = 1 Hz), 7.17 (dd, 1H, H9, J = 9.5 Hz, J = 1.8 Hz), 7.31
(d, 1H, HAr, J = 7.9 Hz), 7.39 (d, 1H, H7, J = 1.8 Hz), 7.48 (d, 1H, H10, J = 9.4 Hz). 13C NMR (CDCl3) δ
26.8, 41.5, 55.3, 56.0, 106.3, 113.7, 113.9, 117.6, 119.5, 120.1, 123.5, 126.9, 130.3, 140.9, 143.2, 143.6,
160.3. MS (APCI+): m/z 358.1, 360.2.
8-Bromo-1-(4-dimethylaminophenyl)-1,2,3,4-tetrahydrodipyrido[1,2-a;4',3'-d]imidazole (11b)
Yield 78% (24 h), mp 186-187 °C, HPLC (C18, 35 min) PHPLC 98.3%, tR 6.9 min; HPLC (C4, 35 min)
PHPLC 100%, tR 5.6 min. IR 3289 (NH), 1612 (CN). 1H NMR (CDCl3) δ 1.80 (brs, 1H, NH), 2.96 (s, 6H,
N(CH3)2), 3.00 (m, 2H, CH2), 3.12 (m, 1H, NCH2), 3.30 (m, 1H, NCH2), 5.17 (s, 1H, CH), 6.70 (d, 2H,
HAr, J = 8.6 Hz), 7.06 (d, 2H, HAr, J = 8.6 Hz), 7.16 (dd, 1H, H9, J = 9.4 Hz, J = 1.6 Hz), 7.42 (s, 1H, H7),
7.47 (d, 1H, H10, J =9.4 Hz). 13C NMR (CDCl3) δ 26.9, 40.5, 41.5, 55.4, 106.0, 112.8, 117.5, 120.2, 123.7,
126.5, 126.7, 128.7, 143.1, 143.5, 150.6. MS (APCI+): m/z 371.2, 373.2.
8-Bromo-1-(4-nitrophenyl)-1,2,3,4-tetrahydrodipyrido[1,2-a;4',3'-d]imidazole (11c)
Yield 65% (48 h), mp 189-190 °C, HPLC (C18, 35 min) PHPLC 93.2%, tR 7.8 min; HPLC (C4, 35 min)
PHPLC 96.1%, tR 5.5 min. IR 3350 (NH), 1602 (CN). 1H NMR (CDCl3) δ 2.10 (brs, 1H, NH), 3.03 (m,
2H, CH2), 3.20 (m, 2H, NCH2), 5.33 (s, 1H, CH), 7.15-7.38 (m, 4H, HAr, H7, H9), 7.50 (d, 1H, H10, J =
13
9.4 Hz), 8.25 (d, 2H, HAr, J = 8.1 Hz). C NMR (CDCl3) δ 26.7, 41.0, 54.9, 106.8, 117.9, 118.3, 122.8,

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124.4, 127.5, 128.2, 129.1, 143.4, 144.1, 146.7. MS (APCI+): m/z 373.1, 375.
8-Bromo-1-(4-cyanophenyl)-1,2,3,4-tetrahydrodipyrido[1,2-a;4',3'-d]imidazole (11d)
Yield 69% (48 h), mp 204-205 °C, HPLC (C18, 35 min) PHPLC 100%, tR 6.8 min; HPLC (C4, 35 min)
1
PHPLC 100%, tR 5.4 min. IR 3347 (NH), 1605 (CN). H NMR (CDCl3) δ 1.85 (brs, 1H, NH), 2.97 (m,
2H, CH2), 3.17 (t, 2H, NCH2, J = 5.6 Hz), 5.29 (s, 1H, CH), 7.22 (dd, 1H, H9, J = 9.7 Hz, J = 1.5 Hz),
13
7.28 (m, 3H, HAr, H7), 7.51 (d, 1H, H10, J = 9.7 Hz), 7.68 (d, 2H, HAr, J =8.1 Hz). C NMR (CDCl3) δ
26.7, 41.0, 55.2, 106.7, 112.5, 117.9, 118.2, 118.4, 122.9, 127.4, 128.9, 133.0, 143.4, 144.0, 144.8. MS
(APCI+): m/z 353.2, 355.1.
ACKNOWLEDGMENTS
Authors would like to acknowledge Pr Jean-Michel Chezal of the UMR990 INSERM/Auvergne
University for support and scientific contributions.
This work was supported by Lille 2 University. M.D.M. was a recipient of fellowships from the Lille 2
University. The 300 MHz NMR facilities were funded by the Région Nord-Pas de Calais (France), the
Ministère de la Jeunesse, de l'Education Nationale et de la Recherche (MJENR) and the Fonds Européens
de Développement Régional (FEDER).
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