Domino benzylic-amination-sonogashira-heterocyclisation reaction: Direct access to dipyrido[1,2-a:3',4'-d]imidazole salts

Article abstract of DOI:10.1002/ejoc.201200856

A new one-pot domino process, involving four chemical transformations, for the synthesis of new dipyrido[1,2-a:3',4'-d]imidazole salts in a multicomponent reaction is reported. Various dipyrido[1,2-a:3',4'-d]imidazoles were obtained in moderate to good yi

Full text of DOI:10.1002/ejoc.201200856

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FULL PAPER
DOI: 10.1002/ejoc.201200856
Domino Benzylic-Amination–Sonogashira–Heterocyclisation Reaction: Direct
Access to Dipyrido[1,2-a:3Ј,4Ј-d]imidazole Salts
Nicolas Henry,[a] Emilie Thiery,[a] Julien Petrignet,[a] Hassan Halouchi,[a]
Jérôme Thibonnet,[a] and Mohamed Abarbri*[a]
Keywords: Domino reactions / Palladium / Cross-coupling / Cyclization / Multicomponent reactions / Nitrogen heterocycles
A new one-pot domino process, involving four chemical
transformations, for the synthesis of new dipyrido[1,2-a:3Ј,4Ј-
d]imidazole salts in a multicomponent reaction is reported.
Various dipyrido[1,2-a:3Ј,4Ј-d]imidazoles were obtained in
moderate to good yields. The scope and limitations of the
process and the reaction mechanism are discussed.
the molecular diversity of functional heterocycles and open
up new perspectives for the discovery of potential drugs. In
an earlier study in this area, Gueiffier et al. reported the
direct access of dipyrido[1,2-a:3Ј,4Ј-d]imidazole promoted
by Grignard reagents.[5] To the best of our knowledge, few
reports on the synthesis of this original polycyclic N-het-
eroaromatic system have been published,[6] and no attention
has been paid to the dual reactivity of dihaloimidazo[1,2-a]-
pyridine 5 with its aromatic iodide and benzylic chloride
groups.
Moreover, ammonium and iminium salts are another
class of molecules that possess various biological activities.
Indeed, examples of such structures have shown antimalar-
ial and antileishmania activity,[7] and compounds contain-
ing heteroaromatic fused ring cations such as the γ-carboli-
nium core have been reported to be promising antiprolifera-
tive agents for human cancer cell lines.[8]
Introduction
N-heteroaromatic structures are very important in or-
ganic chemistry, since compounds containing these motifs
are known to possess various biological activities.[1] Indeed,
such substructures are present in a wide variety of pharma-
ceutical agents (Figure 1). Examples include Zolpidem
(1),[2] a synthetic drug used for the treatment of insomnia,
and based on an imidazo[1,2-a]pyridine skeleton. Alprazo-
lam (2), a member of the benzodiazepine family, is pre-
scribed for anxiety and panic disorders and for the treat-
ment of nausea.[3] Pyrido[3,4-b]indole 3 has been shown to
have significant memory-enhancing effects in humans
through interaction with a receptor in the central nervous
system.[4]
In order to obtain a synergistic effect between these two
classes of compounds, we investigated a novel palladium-
catalysed domino reaction for the synthesis of dipyrido[1,2-
a:3Ј,4Ј-d]imidazole salts. This approach involved benzylic
amination and Sonogashira cross-coupling, followed by a
heterocyclisation–aromatisation sequence using readily
available primary amines, alkynes, and dihaloimidaz[1,2-a]-
Figure 1. Examples of biologically active N-heteroaromatic fused
ring compounds.
Owing to the high proportion of bioactive molecules
based on these scaffolds, it would seem to be important to
develop strategies for the synthesis of novel families of N-
heterocyclic fused ring systems. Such research may increase
[a] Laboratoire d’Infectiologie et Santé Publique (UMR Université
François Rabelais/INRA 1282), Université François Rabelais,
Faculté des Sciences,
Parc de Grandmont, 37200 Tours, France
Fax: +33-2-47367073
E-mail: mohamed.abarbri@univ-tours.fr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200856.
Scheme 1. General strategy for the one-pot preparation of dipyr-
ido[1,2-a:3Ј,4Ј-d]imidazole salts 4.
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M. Abarbri et al.
FULL PAPER
pyridine 5 (Scheme 1). This type of 6-endo-dig aza-cyclis- Table 1. One-pot dual reactivity of dihaloimidazo[1,2-a]pyridine 5
using various amines.[a]
ation promoted by organopalladium complexes has been
extensively used by Larock et al. for the preparation of pol-
ysubstituted isoquinoline structures.[9] Other transition
metal salts such as copper(I)[10] and silver(I)[11] have also
been used to synthesise this isoquinoline using a 6-endo-dig
N-cyclisation strategy.
Results and Discussion
Following our strategy, 5 was prepared in a two-step syn-
thesis with an overall yield of 76%. Commercially available
2-aminopyridine (6) was treated with 2 equiv. 1,3-dichlo-
ropropanone to yield intermediate 7.[12] This unstable com-
pound was directly treated with iodine monochloride in
chloroform to obtain the expected precursor (i.e., 5;
Scheme 2).
Scheme 2. Preparation of imidazo[1,2-a]pyridine 5.
[a] Reaction conditions: phenylacetylene (1.1 equiv.), amine
(3 equiv.), PdCl2(PPh3)3 (10 mol-%), CuI (10 mol-%), DMF,
110 °C, overnight. [b] Isolated yields. [c] Complex mixture. [d] De-
gradation was observed.
To investigate the viability of the anticipated domino re-
action, several sets of reaction conditions were screened in
DMF, a commonly used solvent in the Sonogashira reac-
tion. Optimisation studies revealed that the best conditions
for this multicomponent reaction involved heating dihaloge-
nated compound 5 (1.0 equiv.), alkyne (1.1 equiv.), and
amine (3.0 equiv.) in DMF overnight at 110 °C with the
standard catalysts for the Sonogashira reaction [i.e.,
PdCl2(PPh3)2 (10 mol-%) and CuI (10 mol-%)]. An excess
of amine had to be used because of its dual role of base and
reactant. With phenylacetylene as the alkyne component in
Figure 2. X-ray structure of compound 4a.
the presence of n-butylamine, pyridoimidazopyridinium salt
4a was isolated in good yield (44%) (Table 1, entry 1). It is
noteworthy that the counter-anion of this salt was found to
Attempts using aniline and t-butylamine failed (Table 1,
be an iodide. The structure was confirmed by 2D NMR entries 4 and 5). In both cases, the starting material was
experiments and X-ray diffraction (Figure 2).[13] Next, the not recovered but the characteristic signals of the expected
1
scope and limitations of this four-component coupling pro- products (i.e., 4 or 8) were not observed in the crude H
cess were examined with respect to the primary amine com- NMR spectra. Only degradation products were obtained
ponent. The results are summarised in Table 1. Interest- with aniline, whereas with tert-butylamine, the product re-
ingly, when allylamine and benzylamine were used under sulting from benzylic amination was detected, mixed with
the same conditions, the reaction did not yield the corre- several unidentified by-products.
sponding iodide salt but rather led to neutral dipyridoimad-
The scope and limitations of the methodology with re-
azole 8, in yields of 36 and 54%, respectively. This result spect to the alkyne component were then investigated, using
can be explained by the loss of the benzyl and allyl groups n-butylamine as the amine (Table 2). The use of aliphatic
that here acted as nitrogen-protecting groups (Table 1, en- alkynes such as pentyne and 1-cyclopropylethyne led to the
tries 2 and 3).
expected dipyrido[1,2-a:3Ј,4Ј-d]imidazole salts (i.e., 4b and
2
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Domino Multicomponent Reaction
4c) in good yields (Table 2, entries 1 and 2). The domino Table 2. Scope and limitations of the one-pot procedure with vari-
ous alkyne partners.[a]
reaction was not observed in the presence of a bulky alkyne
(Table 2, entry 3). In this case, 6-endo-dig cyclisation did not
occur, and the major product (i.e., 9)[14] resulted from nucle-
ophilic substitution of the benzylic chloride by n-but-
ylamine, followed by Sonogashira coupling with tert-butyl
alkyne.
The reaction was also performed with p-tolylacetylene,
and the expected product (i.e., 4e) was formed in a lower
yield than 4a (Table 2, entry 4). A number of functional
groups on the alkyne components were tolerated, including
acetal, ether, and amine groups (Table 2, entries 5–7). Note
that conjugated alkynes bearing an electron-withdrawing
group such as ketone or ester groups did not yield the de-
sired cyclisation products. Only the formation of compound
10[14] was observed, resulting from substitution of the benz-
ylic chloride by n-butylamine and subsequent loss of the
iodide from the 3-position (Table 2, entries 8 and 9).
A plausible mechanism accounting for the domino pro-
cess is shown in Scheme 3. An initial benzylic amination
may take place to yield intermediate A. This compound was
found to be unstable under the reaction conditions, and
may react immediately in the next step of the domino pro-
cess. Indeed, we were not able to isolate it, even in a metal-
free process, and compound 10, resulting from the loss of
iodine in the 3-position was recovered, as in previous exam-
ples (Table 2, entries 8 and 9). According to Larock et al.,
a palladium-catalysed C–C bond formation and cyclisation
process could be envisaged for the transformation from A
to G.[9e] However the copper-free reaction led only to the
amination product 10, as in the palladium-free reaction.
At this stage, a Sonogashira cross-coupling reaction be-
tween A and the alkyne, and involving intermediates B and
C, was envisaged to form D after reductive elimination. It
is noteworthy that only a few studies relating examples of
Sonogashira coupling reactions to 3-haloimidazo[1,2-a]pyr-
idines have been reported in the literature. Our group has
reported a general study on the convenient synthesis of alk-
enyl-, alkynyl- and allenyl-substituted imidazo[1,2-a]pyr-
idines.[15] It appeared the reactivity of the heterocyclic sys-
tem depended on the substituent at the 2-position. For ex-
ample, an ester group in this position reduced the reactivity
towards Sonogashira coupling, so that such a cross-cou-
pling was only achieved by coupling with phenylacetyl-
ene.[15,16] More recent papers have reported the reaction of
3-haloimidazo[1,2-a]pyridines substituted by a hydrogen, a
phenyl group,[17] or a cyano group[18] at the 2-position.
However, to the best of our knowledge, such cross-coupling
reactions have never been reported with 2-chloromethyl or
2-aminomethyl-3-haloimidazo[1,2-a]pyridines.
The next step involved a metal-catalysed 6-endo-dig aza-
cyclisation. This transformation can be promoted by both
metals used in the domino process.[19] But in the presence
of both copper and palladium, Larock et al. proposed a
copper(I) catalyst for this transformation.[20] The coordina-
tion of the copper catalyst to the triple bond allowed N-
[a] Reaction conditions: alkyne (1.1 equiv.), n-butylamine
(3.0 equiv.), PdCl2(PPh3)3 (10 mol-%), CuI (10 mol-%), DMF,
cyclisation, leading to vinyl-copper species F, which is trans-
formed into G in the presence of the base. Finally, this inter-
110 °C, overnight. [b] Isolated yields. [c] Compound detected in the
crude H NMR spectrum.
1
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Scheme 3. Proposed mechanism.
2-(Chloromethyl)-3-iodoimidazo[1,2-a]pyridine (5): 1,3-Dichloropro-
panone (13.5 g, 106 mmol) was added to a solution of 2-aminopyr-
idine (5.0 g, 53.2 mmol) in dimethoxyethane (10 mL). The solution
was stirred at room temperature for 15 min, and then the solvent
was removed under vacuum. The residue was dissolved in absolute
ethanol and was heated at reflux overnight. The solvent was then
evaporated, the residue was hydrolysed with a saturated solution of
sodium carbonate, and the product was extracted with CH2Cl2 (3ϫ
50 mL). The combined organic extracts were dried with magnesium
sulfate, filtered, and concentrated under reduced pressure. The un-
stable 2-(chloromethyl)imidazo[1,2-a]pyridine (7; 6.8 g, 77%) was
obtained as a yellow solid, and was directly used in the next step
without further purification.
mediate undergoes deprotonation and subsequent oxidation
to form the desired iodide salt (i.e., 4). Similar transforma-
tions with different substrates have already been reported in
the presence of iodine[7a] or triphenylmethyl trifluorometh-
anesulfonate.[21]
Conclusions
In conclusion, we have developed a novel one-pot benz-
ylic amination/palladium-catalysed Sonogashira cross-cou-
pling and heterocyclisation process that allows the direct
synthesis of new 1,2-disubstituted dipyrido[1,2-a:3Ј:4Ј-d]-
imidazole salts starting from readily available dihalogenated
imidazo[1,2-a]pyridine. It is of particular note that four
A solution of iodine monochloride (5.6 g, 34.5 mmol) in methanol
(30 mL) was added dropwise to a solution of 7 (5.2 g, 31.3 mmol)
in chloroform (100 mL). After being stirred for 1 h at room tem-
chemical transformations occurred in this one-pot opera- perature, the reaction mixture was hydrolysed with a saturated solu-
tion of Na2CO3, and extracted with CH2Cl2 (3ϫ 50 mL). The com-
bined organic extracts were dried with MgSO4, filtered, and con-
centrated under reduced pressure. The residue was purified by col-
umn chromatography on neutral alumina with CH2Cl2 as eluent to
tion, and three new bonds were formed. The domino se-
quence took place with total regioselectivity, and the nature
of the amine for this reaction is a crucial parameter.
give 5 (9.1 g, 99%) as a yellow solid; m.p. 197.5–198.0 °C. IR (neat):
1
ν = 2957, 1654, 1626, 1483, 1256, 1219, 1134, 728 cm–1. H NMR
˜
Experimental Section
(300 MHz, CDCl3): δ = 8.07 (dt, J = 6.9, 1.2 Hz 1 H, 5-H), 7.57
(dt, J = 0.9, 9.1 Hz, 1 H, 2-H), 7.27 (ddd, J = 9.2, 6.6, 1.2 Hz, 1
H, 3-H), 6.93 (td, J = 6.9, 1.2 Hz, 1 H, 4-H), 4.78 (s, 2 H, 8-H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 148.1 (C-1) 146.0 (C-7),
126.1, 126.0 (C-3, C-5) 117.9 (C-4), 113.7 (C-2), 63.0 (C-6) 39.3 (C-
8) ppm. HRMS (ESI): calcd. for C8H7N2ClI [M + H]+ 292.9343;
found 292.9345.
General Remarks: Copper and palladium catalysts were obtained
from commercial sources and were used without further purifica-
tion. All reactions were carried out under an argon atmosphere.
TLC spots were examined under UV light. Dimethyl formamide
and dichloromethane were distilled from calcium hydride. NMR
spectra were obtained at 300 MHz for 1H and 75 MHz for 13C with
a Bruker Avance 300 spectrometer. Chemical shifts are given in
parts per million (δ) and are referenced to the residual chloroform
peak (δ = 7.26 ppm) Assignments of 1H and 13C resonances for
complex structures were confirmed by 2D experiments (COSY,
HMQC, HMBC). Electrospray ionisation mass spectrometry ex-
periments (HRMS) were obtained with a hybrid tandem quadru-
pole/time-of-flight (Q-TOF) instrument, equipped with a pneumat-
ically assisted electrospray (Z-spray) ion source (Micromass, Man-
chester, U. K.) operating in positive mode.
General Procedure for the Preparation of Dipyrido[1,2-a:3Ј,4Ј-d]-
imidazole Iodide Salts 4: A sealed tube was loaded with 5 (200 mg,
0.68 mmol), copper iodide (13 mg, 0.07 mmol), and PdCl2(PPh3)2
(48 mg, 0.07 mmol), after which it was submitted to vacuum for
10 min and then filled with argon. Then n-butylamine (197 μL,
2.04 mmol), alkyne (0.75 mmol), and DMF (1 mL) were added.
The tube was sealed, and the mixture was heated overnight at
110 °C. After cooling, the reaction mixture was diluted with water
(20 mL), and the aqueous phase was washed with ethyl acetate (3ϫ
4
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Domino Multicomponent Reaction
10 mL). The organic layer was extracted once with water (10 mL),
then the combined aqueous phases were extracted with dichloro-
methane (5ϫ 20 mL). The chlorinated organic extracts were com-
bined, dried with MgSO4, filtered, and concentrated under reduced
pressure. The residue was purified by column chromatography on
neutral aluminium oxide with CH2Cl2/MeOH or Et2O/MeOH as
eluent.
(C-19), 19.4 (C-13), 13.3 (C-14) ppm. HRMS (ESI): calcd. for
C21H22N3 [M – I]+ 316.1814; found 316.1815.
Iodide 4e: Eluent for chromatography: CH2Cl2/MeOH (100:0 to
99:1); yield 80 mg (36%). Yellow solid; m.p. 137.0–137.5 °C. IR
(neat): ν = 2965, 1630, 1470, 1248, 1052, 763 cm–1. 1H NMR
˜
(300 MHz, CDCl3): δ = 11.94 (s, 1 H, 8-H), 10.18 (dt, J = 6.8,
1.2 Hz, 1 H, 5-H), 8.26 (s, 1 H, 9-H), 7.98 (ddd, J = 9.3, 6.8, 1.2 Hz,
1 H, 3-H), 7.92 (dt, J = 9.3, 1.2 Hz, 1 H, 2-H), 7.40 (td, J = 6.8,
1.2 Hz, 1 H, 4-H), 5.77 (s, 1 H, 15-H), 4.98 (t, J = 8.1 Hz, 2 H, 11-
H), 3.77–3.62 (m, 4 H, 16-H), 2.18–2.08 (m, 2 H, 12-H), 1.67–1.54
(m, 2 H, 13-H), 1.30 (t, J = 6.9 Hz, 6 H, 17-H), 1.04 (t, J = 7.5 Hz,
3 H, 14-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 155.7, 152.1,
145.1 (C-1, C-6, C-7), 137.5, 135.8, 131.8 (C-3, C-5, C-8), 127.4 (C-
10), 117.8, 115.5, 115.5 (C-2, C-4, C-9), 97.8 (C-15), 63.4 (C-16),
57.0 (C-11), 34.8 (C-12), 19.9 (C-13), 15.0 (C-17), 13.6 (C-14) ppm.
HRMS (ESI): calcd. for C19H26N3O2 [M – I]+ 328.2025; found
328.2026.
Iodide 4a: Eluent for chromatography: CH2Cl2/MeOH (100:0 to
99:1); yield 90 mg (44%). Yellow solid; m.p. 197.5–198 °C. IR
(neat): ν
= 2957, 1654, 1626, 1483, 1256, 1219, 1134, 728 cm–1.
˜
max
1H NMR (300 MHz, CDCl3): δ = 11.78 (s, 1 H, 8-H), 10.10 (d, J
= 6.9 Hz, 1 H, 5-H), 8.00 (ddd, J = 9.2, 6.9, 1.2 Hz, 1 H, 3-H),
7.90 (d, J = 9.2 Hz, 1 H, 2-H), 7.85 (s, 1 H, 9-H), 7.64–7.57 (m, 3
H, HAr), 7.50–7.46 (m, 2 H, HAr), 7.39 (td, J = 6.9, 0.9 Hz, 1 H,
4-H), 4.68 (t, J = 7.8 Hz, 2 H, 11-H), 1.93–1.83 (m, 2 H, 12-H),
1.30–1.17 (sext, 2 H, 13-H), 0.74 (t, J = 7.2 Hz, 3 H, 14-H) ppm.
13C NMR (75 MHz, CDCl3): δ = 155.8, 152.1, 149.3 (C-1, C-6, C-
7), 137.6 (C-3), 134.6 (C-8), 132.4 (CAr), 131.7 (C-5), 131.0 (CHAr),
129.4, 129.2 (CHAr), 127.4 (C-10), 117.8, 117.3 (C-2, C-9), 115.4
(C-4), 57.5 (C-11), 33.9 (C-12), 19.3 (C-13), 13.3 (C-14) ppm.
Iodide 4f: Eluent for chromatography: CH2Cl2/MeOH (100:0 to
99:1); yield 40 mg (22%). Yellow solid. IR (neat): ν = 2927, 1628,
˜
1470, 1253, 1089, 765 cm–1. 1H NMR (300 MHz, CDCl3): δ = 11.85
(s, 1 H, 8-H), 10.09 (d, J = 6.6 Hz, 1 H, 5-H), 8.06 (s, 1 H, 9-H),
7.97–7.89 (m, 2 H, 2-H, 3-H), 7.39 (t, J = 6.6, Hz, 1 H, 4-H), 4.85–
4.82 (m, 4 H, 11-H, 15-H), 3.56 (s, 3 H, 16-H), 2.15–2.05 (m, 2 H,
12-H), 1.57 (sext, J = 7.5 Hz, 2 H, 13-H), 1.02 (t, J = 7.5 Hz, 3 H,
14-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 155.8, 152.5, 144.9
(C-1, C-6, C-7), 137.6 (C-3), 135.8 (C-8), 131.8 (C-5), 127.5 (C-10),
117.9, 116.4, 115.6 (C-2, C-4, C-9), 70.4 (C-15), 59.3 (C-16), 56.8
(C-11), 34.4 (C-12), 19.9 (C-13), 13.8 (C-14) ppm. HRMS (ESI):
calcd. for C16H20ON3 [M – I]+ 270.1602; found 270.1606.
Iodide 4b: Eluent for chromatography: Et2O/MeOH (100:0 to
80:20); yield 90 mg (49%). Yellow solid; m.p. 194.0–195.0 °C. IR
(neat): ν = 2924, 1660, 1483, 1258, 1133, 768 cm–1. 1H NMR
˜
(300 MHz, CDCl3): δ = 11.89 (s, 1 H, 8-H), 10.07 (dt, J = 6.8,
1.1 Hz, 1 H, 5-H), 7.94 (ddd, J = 9.1, 6.8, 1.1 Hz, 1 H, 3-H), 7.90
(dt, J = 9.1 Hz, 1.1 1 H, 2-H), 7.83 (s, 1 H, 9-H), 7.37 (td, J = 6.8,
1.1 Hz, 1 H, 4-H), 4.81 (t, J = 7.8 Hz, 2 H, 11-H), 3.05 (t, J =
7.8 Hz, 2 H, 15-H), 2.12–2.02 (m, 2 H, 12-H), 1.91 (sext, J =
7.8 Hz, 2 H, 16-H), 1.66–1.50 (m, 2 H, 13-H), 1.16 (t, J = 7.4 Hz,
3 H, 14-H or 17-H), 1.04 (t, J = 7.4 Hz, 3 H, 14-H or 17-H) ppm.
13C NMR (75 MHz, CDCl3): δ = 155.6, 152.9, 149.8 (C-1, C-6, C-
7), 137.6, 135.3, 131.9 (C-3, C-5, C-8), 126.5 (C-10), 117.8, 115.5,
115.4 (C-2, C-4, C-9), 56.6 (C-11), 34.5, 34.3 (C-12, C-15), 22.7 (C-
16), 19.9 (C-13), 13.9, 13.8 (C-14, C-17) ppm. HRMS (ESI): calcd.
for C17H22N3 [M – I]+ 268.1814; found 268.1816.
Iodide 4g: Eluent for chromatography: Et2O/MeOH (100:0 to
80:20); yield 27 mg (12%). Yellow solid; m.p. 212.0–212.5 °C. IR
1
(neat): ν = 3466, 3406, 2961, 1627, 1466, 1257, 1142, 751 cm–1. H
˜
NMR (300 MHz, CDCl3): δ = 11.86 (s, 1 H, 8-H), 10.08 (dt, J =
6.8, 1.2 Hz, 1 H, 5-H), 8.40 (s, 1 H, 9-H), 7.94 (ddd, J = 9.3, 6.8,
1.2 Hz, 1 H, 3-H), 7.88 (dt, J = 9.3, 1.2 Hz, 1 H, 2-H), 7.36 (td, J
= 6.8, 1.2 Hz, 1 H, 4-H), 4.94 (t, J = 7.8 Hz, 2 H, 11-H), 4.02 (s, 2
H, 15-H), 3.13 (sept, J = 6.6 Hz, 2 H, 16-H), 2.12–2.02 (m, 2 H,
12-H), 1.65–1.52 (m, 2 H, 13-H), 1.09 (d, J = 6.6 Hz, 12 H, 17-H),
1.05 (t, J = 7.5 Hz, 3 H, 14-H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 155.7, 152.8, 150.7 (C-1, C-6, C-7), 137.4, 135.2, 131.8 (C-3,
C-5, C-8), 127.0 (C-10), 117.8, 116.3, 115.2 (C-2, C-4, C-9), 55.9
(C-11), 49.3 (C-16), 47.0 (C-15), 34.2 (C-12), 20.7 (C-17), 19.8 (C-
13), 13.9 (C-14) ppm. HRMS (ESI): calcd. for C21H31N4 [M – I]+
339.2558; found 339.2549.
Iodide 4c: Eluent for chromatography: CH2Cl2/MeOH (100:0 to
99:1); yield 90 mg (50%). Yellow solid; m.p. 200.0–200.5 °C. IR
(neat): ν = 2930, 1627, 1465, 1241, 1131, 775 cm–1. 1H NMR
˜
(300 MHz, CDCl3): δ = 11.70 (s, 1 H, 8-H), 10.07 (d, J = 6.0 Hz,
1 H, 5-H), 7.95 (dd, J = 9.2, 6.6 Hz, 1 H, 3-H), 7.88 (d, J = 9.2 Hz,
1 H, 2-H), 7.75 (s, 1 H, 9-H), 7.39 (t, J = 6.0, Hz, 1 H, 4-H), 5.00
(t, J = 7.8 Hz, 2 H, 11-H), 2.32–2.22 (m, 1 H, 15-H), 2.17–2.10 (m,
2 H, 12-H), 1.69–1.55 (m, 2 H, 13-H), 1.45–1.39 (m, 2 H, 16-H),
1.14–1.09 (m, 2 H, 16Ј-H), 1.06 (t, J = 7.4 Hz, 3 H, 14-H) ppm.
13C NMR (75 MHz, CDCl3): δ = 155.7, 152.8, 150.7 (C-1, C-6, C-
7), 137.4, 135.1, 131.7 (C-3, C-5, C-8), 126.7 (C-10), 117.7, 115.2,
113.9 (C-2, C-4, C-9), 56.7 (C-11), 33.7 (C-12), 19.9 (C-13), 13.8
(C-14), 13.7 (C-15), 8.7 (C-16, C-16Ј) ppm. HRMS (ESI): calcd.
for C17H20N3 [M – I]+ 266.1657; found 266.1648.
Dipyrido[1,2-a:3Ј,4Ј-d]imidazole (8): Eluent for chromatography:
EtOAc/MeOH (100:0 to 80:20); yield 90 mg (54%). White solid;
m.p. 180.0–180.5 °C. IR (neat): ν = 3034, 1640, 1565, 1469, 1239,
˜
1
758, 700 cm–1. H NMR (300 MHz, CDCl3): δ = 9.45 (s, 1 H, 8-
H), 8.56 (d, J = 7.2 Hz, 1 H, 5-H), 8.25 (s, 1 H, 9 H), 8.13 (d, J =
8.4 Hz, 2 H), 7.81 (d, J = 9.3 Hz, 1 H), 7.60–7.35 (m, 4 H), 7.00
(t, J = 6.3 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 149.6,
148.9, 143.2, 140.2, 139.8, 134.3, 131.0, 128.9, 128.4, 127.0, 125.6,
119.1, 111.5, 101.9 ppm. HRMS (ESI): calcd. for C16H12N3 [M +
H]+ 246.1031; found 246.1031.
Iodide 4d: Eluent for chromatography: Et2O/MeOH (100:0 to
80:20); yield 53 mg (25%). Yellow solid; m.p. 207.5–208.0 °C. IR
1
(neat): ν = 3012, 1624, 1486, 1145, 765 cm–1. H NMR (300 MHz,
˜
CDCl3): δ = 11.92 (s, 1 H, 8-H), 10.18 (d, J = 6.8 Hz, 1 H, 5-H),
7.99 (ddd, J = 9.1, 6.8, 1.3 Hz, 1 H, 3-H), 7.92 (dt, J = 9.1, 1.3 Hz,
1 H, 2-H), 7.84 (s, 1 H, 9-H), 7.43–7.33 (m, 5 H, 4-H, 16-H, 17-
H), 4.71 (t, J = 7.8 Hz, 2 H, 11-H), 2.50 (s, 3 H, 19-H), 1.95–1.85
(m, 2 H, 12-H), 0.79 (sext, J = 7.5 Hz, 2 H, 13-H), 1.02 (t, J =
7.5 Hz, 3 H, 14-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 155.8
152.2, 149.6 (C-1, C-6, C-7), 141.5, 137.6, 131.9 (C-3, C-5, C-8),
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of the H and 13C NMR spectra.
Acknowledgments
134.6 (C-15), 130.1, 129.1 (C-16, C-17), 129.6 (C-18), 127.4 (C-10), We thank the “Département d’Analyses Chimiques et Médicales”
117.8, 117.4, 115.4 (C-2, C-4, C-9), 57.5 (C-11), 34.0 (C-12), 21.5 (Tours, France) for chemical analysis, and Dominique Harakat and
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Job/Unit: O20856
/KAP1
Date: 12-09-12 17:31:55
Pages: 7
M. Abarbri et al.
FULL PAPER
[9] a) G. Dai, R. C. Larock, Org. Lett. 2001, 3, 4035–4038; b)
K. R. Roesch, H. Zhang, R. C. Larock, J. Org. Chem. 2001,
66, 8042–8051; c) G. Dai, R. C. Larock, J. Org. Chem. 2002,
67, 7042–7047; d) Q. Huang, J. A. Hunter, R. C. Larock, J.
Org. Chem. 2002, 67, 3437–3444; e) G. Dai, R. C. Larock, J.
Org. Chem. 2003, 68, 920–928.
[10] a) H. Sard, J. Heterocycl. Chem. 1994, 31, 1085–1087; b) S.
Roy, S. Roy, B. Neuenswander, D. Hill, R. C. Larock, J. Comb.
Chem. 2009, 11, 1061–1065.
[11] a) K. R. Roesch, R. C. Larock, J. Org. Chem. 2002, 67, 86–94;
b) S. Hwang, Y. Lee, P. O. Lee, S. Shin, Tetrahedron Lett. 2009,
50, 2305–2308; c) Y.-N. Niu, Z.-Y. Yan, G.-L. Gao, H.-L.
Wang, Y.-Z. Shu, K.-G. Ji, Y.-M. Liang, J. Org. Chem. 2009,
74, 2893–2896.
[12] P. Vanelle, N. Madadi, C. Rubaud, J. Maldonado, M. P. Crozet,
Tetrahedron 1991, 47, 5173–5184.
the plateforme analytique PlAneT de l’ICMR UMR7312 (Uni-
versité de Reims Champagne Ardenne) for HRMS.
[1]
[2]
[3]
D. H. Horton, G. T. Bourne, M. L. Smythe, Chem. Rev. 2003,
103, 893–930.
S. Arbilla, J. Allen, A. Wick, S. Langer, Eur. J. Pharmacol.
1986, 130, 257–263.
a) G. W. Dawson, S. G. Jue, R. N. Brogden, Drugs 1984, 27,
132–147; b) M. V. Rudorfer, W. Z. Potter, Drugs 1989, 37, 713–
738.
[4]
a) L. H. Jensen, E. M. Petersen, C. Braedsterup, T. Honoré, W.
Kehr, D. N. Stephens, H. Schneider, D. Seidelmann, R.
Schmiechen, Psychopharmacology 1984, 83, 249–256; b) T.
Duca, D. Stephens, W. Krause, R. Dorow, Psychopharmacology
1987, 93, 421–427.
[13] The crystal structures of compounds 4a and 4c have been de-
posited at the Cambridge Crystallographic Data Centre.
CCDC-875158 and -875159 contain the supplementary crystal-
lographic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
[5] R. Oudot, P. Costes, H. Allouchi, M. Pouvreau, M. Abarbri,
A. Gueiffier, C. Enguhard-Gueiffier, Tetrahedron 2011, 67,
9576–9581.
[6] a) O. Chavignon, J.-C. Teulade, D. Roche, M. Madesclaire, Y.
Blache, A. Gueiffier, J.-L. Chabard, G. Dauphin, J. Org. Chem.
1994, 59, 6413–6418; b) J.-M. Chezal, E. Moreau, O. Chavig-
non, C. Lartigue, Y. Blache, J.-C. Teulade, Tetrahedron Lett.
2003, 59, 5869–5878; c) J.-M. Chezal, E. Moreau, N. Desbois,
Y. Blache, O. Chavignon, J.-C. Teulade, Tetrahedron Lett. 2004,
45, 553–556; d) M. Andaloussi, J.-M. Chezal, E. Moreau, C.
Lartigue, A. El Laghdach, J.-C. Teulade, O. Chavignon, Het-
erocycles 2005, 65, 1071–1078; e) M. W. Cartwright, L. K. Con-
very, G. S. Thomas, D. S. Yufit, J. A. K. Howard, J. A. Christo-
pher, M. D. Miller, Tetrahedron 2010, 66, 519–529.
[7] a) J. Howarth, K. Hanlon, Tetrahedron Lett. 2001, 42, 751–
754; b) J. Howarth, K. Hanlon, Bioorg. Med. Chem. Lett. 2003,
13, 2017–2020; c) J. M. Nyangulu, S. L. Hargreaves, S. L.
Sharples, S. P. Mackay, R. D. Waigh, O. Duval, E. K. Mberu,
W. Watkins, Bioorg. Med. Chem. Lett. 2005, 15, 2007–2010.
[8] V. Martinez, C. Burgos, J. Alvarez-Builla, G. Fernandez, A.
Domingo, R. Garcia-Nieto, F. Gago, I. Manzanares, C.
Cuevas, J. J. Vaquero, J. Med. Chem. 2004, 47, 1136–1148.
[14] 1H NMR data for these intermediates is given in the Support-
ing Information.
[15] C. Enguehard-Gueiffier, C. Croix, M. Hervet, J.-Y. Kazock, A.
Gueiffier, M. Abarbri, Helv. Chim. Acta 2007, 90, 2349–2367.
[16] M. Hellal, J.-J. Bourguignon, F. Bihel, Tetrahedron 2008, 49,
62–65.
[17] A. El Akkaouia, I. Bassoudea, J. Koubachia, S. Berteina-Ra-
boina, A. Mouaddib, G. Guillaumet, Tetrahedron 2011, 67,
7128–7138.
[18] R. Oudot, P. Costes, H. Allouchi, M. Pouvreau, M. Abarbri,
A. Gueiffier, C. Enguehard-Gueiffier, Tetrahedron 2011, 67,
9576–9581.
[19] F. Alonso, I. P. Beletskaya, M. Yus, Chem. Rev. 2004, 104,
3079–3159.
[20] H. Zhang, R. C. Larock, J. Org. Chem. 2002, 67, 7048.
[21] X. Cattoën, D. Bourissou, G. Bertrand, Tetrahedron Lett. 2006,
47, 531–534.
Received: June 27, 2012
Published Online: ᭿
6
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20856
/KAP1
Date: 12-09-12 17:31:55
Pages: 7
Domino Multicomponent Reaction
Multicomponent Reactions
N. Henry, E. Thiery, J. Petrignet,
H. Halouchi, J. Thibonnet,
M. Abarbri* ...................................... 1–7
Domino
Benzylic-Amination–Sonoga-
shira–Heterocyclisation Reaction: Direct
Access to Dipyrido[1,2-a:3Ј,4Ј-d]imidazole
Salts
A new multicomponent reaction involving
palladium and copper catalysts for the syn-
thesis of an original family of N-heteroaro-
matic fused-ring cation is described. The
reaction was performed with various alk-
ynes, and dipyrido[1,2-a:3Ј,4Ј-d]imidazole
salts were obtained in moderate to good
yields.
Keywords: Domino reactions / Palladium /
Cross-coupling / Cyclization / Multicom-
ponent reactions / Nitrogen heterocycles
Eur. J. Org. Chem. 0000, 0–0
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7