A novel solvent-free approach to imidazole containing nitrogen-bridgehead heterocycles

Article abstract of DOI:10.1021/ol4015267

A very simple domino reaction under solvent-free conditions of various pyridine-like heterocycles with 1,2-diaza-1,3-dienes produces in good yields imidazo[1,2-a]pyridines, imidazo[1,2-a]quinolines, and imidazo[2,1-a] isoquinolines. The advantage of this one-pot transformation lies in the use of simple pyridine-like compounds without prefunctionalization of the starting heterocycles.

Full text of DOI:10.1021/ol4015267

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
A Novel Solvent-Free Approach
to Imidazole Containing Nitrogen-
Bridgehead Heterocycles
Orazio A. Attanasi, Luca Bianchi, Linda A. Campisi, Lucia De Crescentini,
Gianfranco Favi, and Fabio Mantellini*
Department of Biomolecular Sciences, Section of Organic Chemistry and Organic
Natural Compounds, University of Urbino “Carlo Bo”, Via I Maggetti 24, 61029
Urbino (PU), Italy
fabio.mantellini@uniurb.it
Received May 30, 2013
ABSTRACT
A very simple domino reaction under solvent-free conditions of various pyridine-like heterocycles with 1,2-diaza-1,3-dienes produces in good yields
imidazo[1,2-a]pyridines, imidazo[1,2-a]quinolines, and imidazo[2,1-a]isoquinolines. The advantage of this one-pot transformation lies in the use of
simple pyridine-like compounds without prefunctionalization of the starting heterocycles.
The skeleton of a great number of the biologically active
compounds is represented by heterocycles.1 In this con-
text, the chemistry of imidazo[1,2-a]pyridines (IPs) have
attracted increasing attention since this nitrogen-bridgehead
heterocycle is an important pharmacophore, and it is amply
found in many biologically active compounds.2 For exam-
ple, IPs show antiprotozoal, anti-inflammatory, antiulcer,
antiviral, antibacterial, and antifungal activities.3 Other
therapeutic properties of IPs include melatonin receptor
ligands, agonists of benzodiazepine receptors, β-amyloid
formation inhibitors, or ligands for detecting β-amyloids.4
Besides, IPs constitute a novel class of orally active
nonpeptide bradykinin B2 receptor antagonists.5 Drugs
containing an IP core such as Alpidem, Necopidem,
Saripidem, Zolpidem, Olprinone, Minodronic acid, Dival-
pon, and Zolimidine are available commercial products
(Figure 1).6 Among the IP benzo-derivatives, imidazo-
[1,2-a]quinolines (IQs) have been described to be contra-
ceptive, hypotensive, antiallergic, and antiasthmatic agents,7
while their isomers imidazo[2,1-a]isoquinolines (IIQs) show
cytotoxic and PARP-1 inhibitory activities.8
(1) Progress in Heterocyclic Chemistry; Gribble, G. W., Joule, J. A.;
Eds.; Elsevier, Oxford, 2008.
(4) (a) El Kazzouli, S.; du Bellay, A. G.; Berteina-Raboin, S.;
Delagrange, P.; Caignard, D.-H.; Guillaumet, G. Eur. J. Med. Chem.
2011, 46, 4252–4257. (b) Trapani, G.; Franco, M.; Latrofa, A.; Ricciardi,
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1999, 42, 3934–3941. (c) Fuchs, K.; Romig, M.; Mendla, K.; Briem, H.;
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F.V., Taylor, R. J. K., Eds.; Pergamon-Elsevier Science: Oxford, 2008;
pp 409À499 and references cited therein.
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Wenzler, T.; Brun, R.; Tanious, F. A.; Wilsona, W. D.; Boykina,
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J. J.; Doweyko, A. M. J. Med. Chem. 1997, 40, 427–436. (e) Rival, Y.;
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r
10.1021/ol4015267
XXXX American Chemical Society

three-component coupling,17 MoritaÀBaylisÀHilmann
reaction,18 and silver-catalyzed oxidative cross-coupling
reaction.19 Also in all these latter cases various aminopyr-
idine derivatives were employed as starting materials.
Recently, Cronin reported an interesting five-step one-
pot procedure leading to imidazo-pyridine derivatives
that does not require R-amino functionalized starting
materials.20
Domino processes represent an inviting method for a
facile construction of the molecular architecture because
they represent an access to the formation of several new
bonds in a single manipulation. These processes are oper-
ationally simple and minimize the production of chemical
waste.21 From the perspective of green chemistry,22
domino processes under solvent-free conditions (SFC)
are fascinating since they involve the best reaction medium
with “no medium”.23
By exploiting our experience in the field of 1,2-diaza-
1,3-dienes (DDs) in the syntheses of several five- and
six-membered azaheterocycles,24 we have thought to plan
a more simple methodology for the assembly of IPs, IQs,
and IIQs based on their use. In the nitrogen-bridgehead
heterocycles construction (Scheme 1) two strategic discon-
nections of the imidazole core can be envisaged along the
N(1)ÀC(8a) and N(4)ÀC(3) bonds.
Figure 1. Drugs based on imidazo[1,2-a]pyridines.
On the other hand, IPs, IQs, and IIQs have been investi-
gated as biomarkers and photochemical sensors, since
they are important organic fluorophores.9 By virtue of
these relevant applications, efficient strategies for their
synthesis have been developed.10 In particular, the most
employed method for the synthesis of IPS involves the
use of 2-aminopyridines in the coupling reactions with
R-halocarbonyl compounds, and in the condensations
with aldehydes or isonitriles.11 Usually, these syntheses
require harsh conditions. Some other recent examples
include a water-mediated hydroamination,12 silver-cata-
lyzed cyclization,13 copper-catalyzed dehydrogenative
aminooxygenation,14 TBAI-catalyzed oxidative coupling,15
copper-catalyzed aromatic amination,16 copper-catalyzed
Scheme 1. Comparison between the Retrosynthetic Analysis to
Assemble IPs Proposed in This Work and the Most Commonly
Employed
(7) Iminov, R. T.; Tverdokhlebov, A. V.; Tolmachev, A. A.;
Volovenko, Y. M.; Kostyuk, A. N.; Chernega, A. N.; Rusanov, E, B.
Synthesis 2008, 1535–1540 and references cited therein.
(8) (a) Deady, L. W.; Rodemann, T.; Finlay, G. J.; Baguley, B.;
Denny, W. A. C. Anti-Cancer Drug Des. 2001, 15, 339–346. (b) Rhee, H.-
K.; So Lim, S. Y.; Jung, M.-J.; Kwon, Y.; Kim, M.-H.; Choo, H.-Y. P.
Bioorg. Med. Chem. 2009, 17, 7537–7541.
(9) (a) Hodgkiss, R. J.; Middleton, R. W.; Parrick, J.; Rami, H. K.;
Wardman, P.; Wilson, G. D. J. Med. Chem. 1992, 35, 1920–1936.
(b) Shao, N.; Pang, G. X.; Yan, C. X.; Shi, G. F.; Cheng, Y. J. Org.
Chem. 2011, 76, 7458–7465.
(10) Katrizky, A. R.; Xu, Y.-J.; Tu, H. J. Org. Chem. 2003, 68, 4935–
4937 and reference therein.
(11) For some example: (a) Gueiffier, A.; Mavel, S.; Lhassani, M.;
Elhakmaoui, A.; Snoeck, R.; Andrei, G.; Chavignon, O.; Teulade, J.-C.;
Witvrouw, M.; Balzarini, J.; De Clercq, E.; Chapat, J.-P. J. Med. Chem.
1998, 41, 5108–5112. (b) Groebke, K.; Weber, L.; Mehlin, F. Synlett
1998, 661–663. (c) Koubachi, J.; El Kazzouli, S.; Berteina,-Raboin, S.;
Mouaddib, A.; Guillaumet, G. J. Org. Chem. 2007, 72, 7650–7655.
(d) Herath, A.; Dahl, R.; Cosford, N. P. D. Org. Lett. 2010, 12, 412–415.
(e) Shukla, N. M.; Salunke, D. B.; Yoo, E.; Mutz, C. A.; Balakrishna, R.;
David, S. A. Bioorg. Med. Chem. 2012, 20, 5850–5863.
(12) Mohan, D. P.; Rao, S. N.; Adimurthy, S. J. Org. Chem. 2013, 78,
1266–1272.
(13) Chioua, M.; Soriano, E.; Infantes, L.; Jimeno, M. L.; Marco-
Contelles, J.; Samadi, A. Eur. J. Org. Chem. 2013, 35–39.
(14) Wang, H. G.; Wang, Y.; Liang, D. D.; Liu, L. Y.; Zhang, J. C.;
Zhu, Q. Angew. Chem., Int. Ed. 2011, 50, 5678–5681.
(15) Ma, L. J.; Wang, X. P.; Yu, W.; Han, B. Chem. Commun. 2011,
47, 11333–11135.
Thus, two subunits can be evidenced: a pyridine ring 2,
and an unusual zwitterion B bearing an electrophilic center
in R-position to the imine moiety, instead of the ordinary
nucleophilic site. Fortunately, DDs 1 constitute an umpo-
lung of the classical carbonyl reactivity,24a since these
neutral compounds enable nucleophilic additions at the
terminal carbon atom of the azo-ene system. Thus, the
initial conjugate 1,4-addition of the pyridine 2 to DD 1
(19) He, C.; Hao, I.; Xu, H.; Mo, Y.; Liu, H.; Han, J.; Lei, A. Chem.
Commun. 2012, 48, 11073–11075.
(20) Parenty, A. D. C.; Song, Y.-F.; Richmond, C. J.; Cronin, L. Org.
Lett. 2007, 9, 2253–2256.
(16) Yan, R. L.; Yan, H.; Ma, C.; Ren, Z. Y.; Gao, X. A.; Hang,
G. S.; Liang, Y. M. J. Org. Chem. 2012, 77, 2024–2028 and references
therein.
(17) (a) Chernyak, N.; Gevorgyan, V. Angew. Chem., Int. Ed. 2010,
49, 2743–2746. (b) Guchait, S. K.; Changude, A. L.; Priyadarshani, G.
J. Org. Chem. 2012, 77, 4438–4444.
(21) Reviews on domino reactions: (a) Tietze, L. F. Chem. Rev. 1996,
96, 115–136. (b) Pellissier, H. Tetrahedron 2006, 62, 2143–2173.
(c) Grondal, C.; Jeanty, M.; Enders, D. Nat. Chem. 2010, 2, 167–178.
(22) Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and
Practice; Oxford: New York, 1998.
(23) (a) Martins, M. A. P.; Frizzo, C. P.; Moreira, N. D.; Buriol, L.;
Machado, P. Chem. Rev. 2009, 109, 4140–4182. (b) Tanaka, K. Solvent-
Free Organic Synthesis; Wiley-VCH: Weinheim, Germany, 2009.
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14, 4580–4583 and references therein.
B
Org. Lett., Vol. XX, No. XX, XXXX

would permit the N(4)ÀC(3) junction, while the subse-
quent regioselective intramolecular cyclization would fur-
nish the second connection N(1)ÀC(8a). It is noteworthy
that, in this synthetic approach, the N(1) of the desired
IPs derives from the DDs 1, allowing the use of simple
pyridines as starting materials unlike the majority of
methods that employ functionalized 2-amino pyridine
derivatives, usually obtained via the Chichibabin reaction,
or by a regioselective halogenation followed by nucleophi-
lic substitution by ammonia.
Table 1. Screening of Different Conditions in the Reaction
between DD 1a and P 2a
molar
ratio
3a
reaction
time
t
yield
(%)a
The domino reaction between DDs 1 and pyridine
derivatives carried out in this work have confirmed our
hypothesis for the construction of IPs 3. We began our
investigation by studying the reaction between DD 1a and
pyridine (P) 2a chosen as a representative model (Table 1).
Different solvents, such as dichloromethane, tetrahy-
drofuran, and acetonitrile, were tested, whether at rt or
under reflux. In all these cases, IP 3a was achieved in very
moderate yield (Table 1, entries 1À6) and the reactions
required 12À24 h. With an incremental increase in the
amount of P 2a, a reduction in yield of IP 3a was observed,
while by increasing the molar ratio of DD 1a from 1 to 3
equiv, the yield of the IP 3a slightly improved (Table 1,
entries 7, 8). These poor results have led us to extend our
investigations to testing solvent-free conditions. To our
delight, we have found that under SFC, at rt, by employing
3 equiv of DD 1a, the reaction time was reduced and the
yield was significantly increased (Table 1, entry 11).
A mechanistic hypothesis for this reaction provides
a Michael-type nucleophilic attack of the heterocyclic
nitrogen of P 2a to the terminal carbon atom of the
azo-ene system of DD 1a, to form a nonisolable zwitter-
ionic hydrazone intermediate I. The proton shift from
the C- to N-atom produces the intermediate II that is able
to promote further nucleophilic attack of the hydrazone
sp2 nitrogen to the formed iminium function leading to
the formation of the imidazoline derivative III. Final
aromatization by elimination of the carbamate residue
through cleavage of the NÀN bond25 furnishes the desired
IP 3a (Scheme 2).
entry
solvent
THF
1a/2a
(°C)
(h)
1a
2a
3a
4a
5a
6a
7a
8c
1/1
1/1
1/1
1/1
1/1
1/1
1/3
3/1
1/1
1/3
3/1
rt
10b
13b
26b
13b
13b
26b
18b
32d
39b
12b
86d
24
18
18
15
12
18
18
15
8
CH3CN
CH2Cl2
THF
rt
rt
reflux
reflux
reflux
rt
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
no solvent
no solvent
no solvent
rt
9e
10e
11f
rt
rt
10
3.5
rt
a The reactions were performed at a 0.5 mmol scale of DD 1a in 5 mL
of solvent. b Yields of isolated IP 3a based on DD 1a. c The reactions
were performed at a 0.5 mmol scale of P 2a in 5 mL of solvent. d Yields
of isolated IP 3a based on P 2a. e The reactions were performed at a
0.5 mmol scale of DD 1a. f The reactions were performed at a 0.5 mmol
scale of P 2a.
Scheme 2. Plausible Mechanism
With the optimal conditions in hand, the scope of this
SFC one-pot reaction was broadenedusing a range of DDs
1bÀf with various Ps 2aÀc (Table 2, entries 1À6). The IPs
(24) For a review on the chemistry of DDs, see: (a) Attanasi, O. A.;
De Crescentini, L.; Favi, G.; Filippone, P.; Mantellini, F.; Perrulli, F. R.;
Santeusanio, S. Eur. J. Org. Chem. 2009, 3109–3127. For some recent
examples, see: (b) Chen, J.-R.; Dong, W.-R.; Candy, M.; Pan, F.-F.;
€
Jorres, M.; Bolm, C. J. Am. Chem. Soc. 2012, 134, 6924–6927.
(c) Attanasi, O. A.; Favi, G.; Mantellini, F.; Moscatelli, G.; Santeusanio,
S. J. Org. Chem. 2011, 76, 2860–2866. (d) Attanasi, O. A.; Favi, G.;
Mantellini, F.; Moscatelli, G.; Santeusanio, S. Adv. Synth. Catal. 2011,
353, 595–605. (e) Attanasi, O. A.; Berretta, S.; De Crescentini, L.; Favi,
G.; Giorgi, G.; Mantellini, F.; Nicolini, S. Adv. Synth. Catal. 2011, 353,
1519–1524. (f) Hatcher, J. M.; Coltart, D. M. J. Am. Chem. Soc. 2010,
132, 4546–4547. (g) Attanasi, O. A.; Favi, G.; Filippone, P.; Mantellini,
F.; Moscatelli, G.; Perrulli, F. R. Org. Lett. 2010, 12, 468–471.
(h) Attanasi, O. A.; De Crescentini, L.; Favi, G.; Filippone, P.; Giorgi,
G.; Mantellini, F.; Moscatelli, G.; Behalo, M. S. Org. Lett. 2009, 11,
2265–2268. (i) Attanasi, O. A.; Berretta, S.; De Crescentini, L.; Favi, G.;
Giorgi, G.; Mantellini, F. Adv. Synth. Catal. 2009, 351, 715–719.
(25) For two examples of NÀN bond cleavage, see: (a) Tang, Q.;
Zhang, C.; Luo, M. J. Am. Chem. Soc. 2008, 130, 5840–5841.
(b) Attanasi, O. A.; Caselli, E.; Davoli, P.; Favi, G.; Mantellini, F.;
Ori, C.; Prati, F. Org. Lett. 2009, 11, 2840–2843.
3bÀe derived from P 2a were obtained in excellent yields
(82À92%) (Table 2, entries 1À4), and the reactions were
completed in 3.0À5.0 h.26 An electron-donating group
(EDG), such as the methoxy one in the starting Ps 2b,c,
significantly reduces the reaction times (1À3 min),26 and
the final IPs 3f,g were achieved in good yields (60, 71%)
(Table 2, entries 5, 6).
(26) For the detailed reaction times, see Supporting Information.
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 2. One-Pot SFC Synthesis of IPs 3bÀg: Reaction Scope
with Respect to Ps 2aÀca
Table 4. One-Pot SFC Synthesis of IIQs 7aÀe: Reaction Scope
with Respect to IQ 6aa
yield
(%)b
entry
1
R1
R2
2
R3
R4
3
1
2
3
4
5
6
1b
1c
1d
1e
1f
Et
Me
Me
Me
Me
Et
2a
2a
2a
2a
2b
2c
H
H
3b
3c
3d
3e
3f
87
92
85
82
60
71
i-Pr
allyl
Bn
H
H
H
H
H
H
Me
H
OMe
H
yield
(%)b
entry
1
R1
R2
7
1f
Me
Et
OMe
3g
a Reagents and conditions: 1bÀf (3.0 mmol), 2aÀc (1.0 mmol).
b Yield of pure isolated products 3 referred to Ps 2aÀc.
1
2
3
4
5
1a
1b
1c
1f
OMe
OEt
Me
Me
Me
Et
7a
7b
7c
7d
7e
91
92
96
89
85
Oi-Pr
OMe
NMe2
To further enlarge the scope of this method, we have
examined the one-pot SFC reactions between DDs 1aÀe
and quinoline (Q) 4a. The corresponding IQs 5aÀe were
produced in good yields (78À91%) (Table 3, entries 1À5)
requiring 3.0À4.5 h.26
1g
Me
a Reagents and conditions: 1aÀc,f,g (3.0 mmol), 6a (1.0 mmol).
b Yield of pure isolated products 7 referred to IQ 6a.
Scheme 3. Regioselectivity in the Reaction between DDs 1 and
IQ 6a; 1H NMR spectrum portion of IIQ 7b
Table 3. One-Pot SFC Synthesis of IQs 5aÀe: Reaction Scope
with Respect to Q 4a.a
yield
(%)b
entry
1
R1
R2
5
1
2
3
4
5
1a
1b
1c
1d
1e
Me
Et
Me
Me
Me
Me
Me
5a
5b
5c
5d
5e
83
78
86
91
89
In conclusion, we report a novel and very simple solvent-
and metal-free methodology that leads to the synthe-
sis of a range of imidazo-pyridine-like derivatives such
as imidazo[1,2-a]pyridines, imidazo[1,2-a]quinolines, and
imidazo[2,1-a]isoquinoline starting from simple pyridine,
quinoline, and isoquinoline derivatives. The synthetic
route that combines the advantages of the domino reac-
tions with the solvent-free conditions is itself completely
different from the previous ones and avoids the prefunc-
tionalization of the starting heterocycles.
i-Pr
allyl
Bn
a Reagents and conditions: 1aÀe (3.0 mmol), 4a (1.0 mmol). b Yield
of pure isolated products 5 referred to Q 4a.
Also when the isoquinoline (IQ) 6a was employed
as the starting nucleophile, the SFC reaction with DDs
1aÀc,f,g produced excellent outcomes. The IIQs 7aÀe were
achieved in very shorts times (0.5À1 min),26 in excellent
yields (85%À96%) (Table 4, entries 1À5), and in a regio-
selective manner.
In this case, the iminium intermediate I has two suitable
R positions for the ring closure process (C(1) and C(3))
(Scheme 3). As reported by Cronin,20 the azahetero-
cyclization involves only the C(1) site. In this manner, only
the aromaticity of the heterocycle b is lost during the
cyclization process. The absence of singlets in 1H NMR
unambiguously confirms the structure of compounds
7aÀe (Scheme 3).
Acknowledgment. This work was supported by financial
ꢀ
assistance from the Ministero dell’Universita, dell’Istru-
ꢀ
degli Studi di Urbino “Carlo Bo”.
zione e della Ricerca (MIUR)ÀRoma, and the Universita
Supporting Information Available. Experimental pro-
cedures and characterization data for all compounds.
This material is available free of charge via the Internet
at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX