Efficient catalytic cyclizations of three and two imine assemblies: Direct access to tetrahydroimidazo[1,5-c]imidazol-7-ones and imidazoles

Article abstract of DOI:10.1039/c2cc32760k

A cascade cyclization involving union of three imines by an organocatalyst proline is established to afford new fused-tetrahydroimidazo[1,5-c]imidazol-7- ones with excellent regio- and stereoselectivity. Another dehydrogenative cyclization by union of two imines is developed using the Cu(OTf) ₂-Ag₂O combo catalyst to furnish functionalized imidazoles.

Full text of DOI:10.1039/c2cc32760k

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COMMUNICATION
Efficient catalytic cyclizations of three and two imine assemblies: direct
access to tetrahydroimidazo[1,5-c]imidazol-7-ones and imidazolesw
Yasmin Saima, Saikat Khamarui, Krishnanka S. Gayen, Palash Pandit and Dilip K. Maiti*
Received 14th March 2012, Accepted 1st May 2012
DOI: 10.1039/c2cc32760k
A cascade cyclization involving union of three imines by an
organocatalyst proline is established to afford new fused-
tetrahydroimidazo[1,5-c]imidazol-7-ones with excellent regio-
and stereoselectivity. Another dehydrogenative cyclization by
union of two imines is developed using the Cu(OTf)2–Ag2O
combo catalyst to furnish functionalized imidazoles.
Nitrogen-containing heterocycles are abundant in nature and have
found tremendous applications as lead drugs, pharmaceuticals,
agrochemicals and other resources.1 Thus, direct access to new and
novel N-heterocycles is considered as one of the active research
areas. For example, imidazole is an important structural unit of
purines, proteins, various natural products and valuable synthetic
N-heterocycles.2 Imidazole compounds metronidazole, tinidazole,
clotrimazole and ketoconazole are important amoebicidal and
antifungal pharmaceuticals.3 Substituted imidazoles are developed
as potential drugs with antiviral, antifungal, anti-inflammatory,
anticytokine, anti-cancer, P-38 kinase and platelet aggregation
inhibitory activities.2–4 Recently, N-fused imidazoles have found
special attention in medicinal chemistry because imidazo[1,5-c]-
imidazoles and their analogues are found to be potent and selective
drug candidates with antithrombotic, anticancer, anti-Alzheimer,
human A3 adenosine receptor antagonist and 5-HT3 receptor
agonist activities.5 During the past decade, Li(I), Ag(I), Cu(I),
Cu(II), Zn(II)-catalyzed regio- and stereoselective 1,3-dipolar
cycloaddition (DC)6 of azomethine ylides with electron deficient
alkenes has evolved as one of the best strategies in organic synthesis
to afford pyrrolidines,7 spiropyrrolidines, spirotryprostatins, horsfi-
line and Manzamine A.8 We envisioned straightforward catalytic
strategies for an intermolecular cascade cyclization (path a) and a
dehydrogenative cyclization (path b) involving union of three and
two imine molecules, respectively, leading to construction of a new
class of N-fused bicyclic tetrahydroimidazo[1,5-c]imidazol-7-ones
(5, Scheme 1) and highly substituted imidazoles (7).
Scheme 1 Sequential and dehydrogenative cyclization of imines.
through azeotropic removal of generated water. Initial attempts
to use metal Lewis acid catalyst directed activated-imines to
construct the desired heterocycles were unsuccessful under different
conditions (entries 1–6, Table 1). Interestingly, in the presence of
either Cu2(OTf)2 or Cu(OTf)2 affords 1,3,5-tris-(4-chlorophenyl)-
6-ethoxycarbonylmethyl-7-oxo-tetrahydroimidazo[1,5-c]imidazol-
2-yl]-acetic acid ethyl ester (5a) in 58–70% (entries 7–9). In our
previous reports, we have introduced organic Lewis acid-like
oxidants for 1,3-DC reactions to access valuable N-heterocycles
with outstanding selectivities.6d,9,10 Recently, organocatalysts
Table 1 Development and optimization of the reaction
Yield
(%)
Reaction
Entry Catalyst
Reaction conditions (%)
5a 7a
1
2
3
4
5
6
7
8
AgOTfa
AgVO3
PhCH3, 110 1C, 12 h nrd
Toluene, reflux, 48 h nr
Toluene,100 1C, 28 h nr
Toluene, 120 1C, 24 h nr
nde nd
nd nd
nd nd
nd nd
nd nd
nd nd
58 nd
70 nd
66 nd
81 nd
nd nd
nd nd
nd nd
nd 78
nd nd
nd nd
nd nd
b
AgFb
b
Cu(acac)2a
Cu(OTf)2a
Cu(OTf)2
Cu2(OTf)2
Cu(OTf)2a
Cu(OTf)2
CH2Cl2, rt, 24 h
nr
DCE, reflux, 12 h
nr
PhCH3, 100 1C, 2 h 100
PhCH3, 100 1C, 5 h 100
Dioxane, reflux, 12 h 100
PhCH3, 100 1C, 4 h 100
a
We have prepared aldimines in situ by coupling ethyl
glycinate (1a) and 4-chlorobenzaldehyde (2a) in toluene
9
10
11
12
13
14
15
16
17
DL-Prolinea
DL-Prolinea
Diphenylamine
BF3ÁEt2Of
DCE, 80 1C, 7 h
nr
PhCH3, 100 1C, 12 h nr
PhCH3, 100 1C, 12 h nr
Department of Chemistry, University of Calcutta,
University College of Science, 92, A. P. C. Road, Kolkata-700009,
India. E-mail: dkmchem@caluniv.ac.in; Fax: +91-33-2351-9755;
Tel: +91-33-2350-9937
w Electronic supplementary information (ESI) available: Experimental
procedures, characterization data, NMR spectra. CCDC 865937 (5a).
For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c2cc32760k
Cu(OTf)2b–Ag2Oc Xylene, 130 1C, 5 h 100
Cu(OTf)2b–AgOTfc Xylene, 130 1C, 5 h nr
Cu(OTf)2b–AgVO3 Xylene, 130 1C, 5 h nr
c
Cu(OTf)2b–Ag2Oc Toluene, 80 1C, 12 h nr
a
e
7 mol%. b 3 mol%. c 10 mol%. d No reaction. Not detected. f 1 mole.
c
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Chem. Commun., 2012, 48, 6601–6603 6601

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have found valuable applications in synthetic chemistry for
their catalytic efficiency, excellent selectivities, fast reaction
convergence and eco-friendly nature.11 Gratifyingly, upon
treatment with a catalytic amount of DL-proline (7 mol%),
formation of the desired N-fused bicyclic framework is significantly
improved (81%, entry 10). Lowering of temperature and use of
other organocatalysts are not effective for the cyclization process
(entries 11–13). Proline is an abundant and inexpensive amino acid
with secondary amine functionality and is found to be an efficient
catalyst in aldol, Mannich, Michael addition and other organic
transformations.11,12 A striking difference is that although intra-
molecular 1,3-DC between an ylide dipole and an alkyne/alkene
dipolarophile is commonly employed to synthesize fused-bicyclic
heterocycles, herein an intermolecular cascade cyclization between
three imines leads to construction of new N-heterocycles.
Surprisingly, use of the organocatalyst in the 1,3-DC of
azomethine ylides has received only scant attention.13 Proline
has emerged as a powerful catalyst for cyclization of different
substrates to afford the N-fused-heterocycles with moderate to
high yield (68–81%, Table 2). Aromatic aldehydes (2) possessing
electron withdrawing groups (chloro, bromo, nitro, cyano,
entries 1–7 and 11), electron donating functionalities (methoxy,
entry 10), phenyl (entries 8 and 9) and naphthyl (entry 12)
substituents are tolerated in this catalytic process. Development
of a new strategy with excellent regio- and stereoselectivity is an
important and challenging goal in organic synthesis. Herein, the
fused-heterocycle bearing four stereogenic centers is obtained as
only one stereoisomer with cis–cis (5a: C3–Ar–C5–Ar and
C8–H–C1–Ar: Ar = 4-Cl–C6H4) orientation of the substituents.
Structure of the new compound is determined by means of
spectroscopic and X-ray crystallographic14 analyses (ESIw).
We presume that activation of imines occurs due to protonation
by the organocatalyst (I, eqn (1), Scheme 2). Proline-stabilized
intermediate II undergoes cascade bimolecular cyclization
leading to complete regio- and stereoselective formation of
tetrahydroimidazole (4). In the presence of the proton source,
intermediate 4 undergoes cyclization with a third molecule of
imine (III) involving amidification of protonated ester and
release of R2OH. Formation of tetrahydroimidazole inter-
mediate 4 in the cyclization process is confirmed by isolation
of 4a using an imine derived from sterically hindered tert-butyl
glycinate ester (1c, eqn (2)).
Table 2 Synthesis of highly substituted fused-heterocycles (5)
Glycine
Entry ester
Time/ Yield
h
Aldehyde
Product
(%)
1
2
5.0
6.5
5a, 81
5b, 75
3
4
6.0
7.0
5c, 81
5d, 78
5
5.0
5e, 76
6
7
6.0
5.0
5f, 68
5g, 78
8
9
5.0
6.0
5h, 78
5i, 72
10
4.0
5j, 75
11
12
5.5
5.5
5k, 70
5l, 77
Transition metal catalyzed C–H bond functionalization and
cyclization has emerged as an attractive strategy in organic
synthesis over the past few years.15 Herein, we have developed
another catalytic cyclization process which simultaneously
performs regioselective bimolecular cyclization between two
imine molecules to construct tetrahydroimidazolines (4) and
their dehydrogenation with molecular oxygen (air) to directly
access functionalized imidazoles (7, path b, Scheme 1). In
general, intermolecular catalytic cyclization of imines with
simultaneous dehydrogenation to achieve functionalized imidazole
is a very difficult task. For example, Wu and co-workers have
developed AgOAc catalyzed excellent 1,3-DC (IV, eqn (1),
Scheme 3) of a predesigned imine precursor to form tetra-
hydroimidazole (4). It is dehydrogenated upon treatment with
DDQ (1 equiv.) to imidazoline (6). The desired imidazole (7)
is obtained by treating 6 with BrCCl3 (1.1 equiv.) and DBU
(1 equiv.).4e Synthesis of imidazole was first reported by H.
Debus in 1858 and its tremendous application has led it to grow
over the years.2–4 Earlier, we have also reported a metal-free
synthesis of regioisomer 8 (eqn (2)) utilizing iodosobenzene as
a Lewis acid-like stoichiometric oxidant.4d In our present
study, an efficient metal combo catalyst Cu(OTf)2 (3 mol%)–
Ag2O(10 mol%) is developed toward direct access of another
regioisomer, 2,5-bis-(4-chlorophenyl)-1-ethoxycarbonylmethyl-1H-
imidazole-4-carboxylic acid ethyl ester (7a, entry 14, Table 1).
However, a one-pot cyclization cum double dehydrogenation
process by the combo catalyst is completely blocked by changing
the silver catalysts or reducing temperature (entries 15–17). The
versatility of the combo-catalytic approach is explored using a
c
6602 Chem. Commun., 2012, 48, 6601–6603
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corresponding tetrahydroimidazole intermediate 4b (ESIw)
supports the possible reaction path (eqn (2)).
Financial support from DST (SR/NM/NS-29/2010 and SR/
S1/OC-22/2006) and CRNN, India, and research fellowships
[FDP-UGC (Y.S.), JRF-CSIR (S.K.) and JRF-SPM-CSIR
(KSG), India] are gratefully acknowledged.
Notes and references
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Scheme 2 Possible reaction path and isolation of intermediate 4a.
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Scheme 3 Synthesis of imidazole by dehydrogenative cyclization.
variety of in situ prepared aldimines (3). In all cases the corre-
sponding substituted imidazoles are obtained (7a–k, Scheme 3)
with good yield (70–81%). Traces (2–5%) of regioisomers 8 are
found in the post reaction mixture which are uncharacterized.
The reaction has not only tolerated a range of functional groups
present in the aldimines but also at the same time proceeded
equally well with electron withdrawing (7a–f,k), electron-rich
(7h,i), phenyl (7g) and naphthyl (7j) substituents. C–H activa-
tion16 and redox property of the Cu(OTf)2–Ag2O combo
catalyst play an important role in the dehydrogenation process
(eqn (2)) to afford the ubiquitous heterocycle (7). However, the
reaction is unsuccessful with 4-cyanophenyl aldimines and
does not provide the desired compound. Isolation of the
16 J. Roithova and D. Schroder, J. Am. Chem. Soc., 2007, 129, 15311.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 6601–6603 6603