Ni(ii)-salt catalyzed activation of primary amine-sp3C α-H and cyclization with 1,2-diketone to tetrasubstituted imidazoles

Article abstract of DOI:10.1039/c3cc48437h

NiCl₂·6H₂O and Ni(OAc)₂· 4H₂O were found as efficient catalysts for C-H activation of benzyl and aliphatic amines for an unprecedented multi C-N bond forming cyclization with 1,2-diketones under refluxing toluene to furnish highly substituted and polycyclic imidazoles.

Full text of DOI:10.1039/c3cc48437h

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Ni(II)–salt catalyzed activation of primary
amine-sp3Ca–H and cyclization with 1,2-diketone
Cite this:DOI: 10.1039/c3cc48437h
to tetrasubstituted imidazoles†
Received 4th November 2013,
Accepted 3rd December 2013
Srikanta Samanta, Dipanwita Roy, Saikat Khamarui and Dilip K. Maiti*
DOI: 10.1039/c3cc48437h
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NiCl2Á6H2O and Ni(OAc)2Á4H2O were found as efficient catalysts for
C–H activation of benzyl and aliphatic amines for an unprecedented
multi C–N bond forming cyclization with 1,2-diketones under refluxing
toluene to furnish highly substituted and polycyclic imidazoles.
C–H activation is an emerging revolutionary research area in
modern science.1,2 Although significant development has been
made in recent times, C–H activation of substrate bearing a highly
reactive functionality is still lacking. For instance, metalation of
sp3Ca–H bond of primary amine is not a simple task because the
amine group has a tendency for reduction, decomplexation and
chelation and to be easily oxidized to imine with metals. To date,
Schafer and Jun et al. reported two pioneering research works using
[(PPh3)3RhCl] and metallaaziridine catalysts for C–C coupling of
primary amines with olefins to afford cyclic amines and ketones
respectively.3 Activating and exploiting C–H for direct transformation
to valuable C–N bond is challenging especially with metal catalysts.2
Scheme 1 Development and optimization of C–H activated annulation.
In a continuous effort to study C–N bond forming cyclization metal–salt catalyst for direct construction of 1,2,4,5-tetrasubstituted
reaction,2d,e we envisioned developing a metal catalyst which is and polycyclic imidazoles will be a great contribution to a limited
benign to amine functionality (1) and selectively performs dual number of existing approaches.
Ca–H bond activation with 1,2-diketones (3) leading to direct con-
Our initial experiment between benzyl amine (1a, 2.25 mmol)
struction of valuable imidazoles4 (5, Scheme 1). Recently tetrasub- and benzil (3a, 1 mmol) was screened with several readily available
stituted5 and polycyclic imidazoles6 have received considerable potential transition metal catalysts ([Ir(COD)Cl]2, PdCl2, AuCl3,
attention from researchers because of their existence in bioactive PtBr2, FeCl3 etc.).2 Unsatisfactory results were found for the desired
natural products and novel antitumor, rapid fluorescence switching, C–H activation cum cyclization process to afford 1-benzyl-2,4,5-
photochromism and semiconducting material properties.4–7 triphenyl imidazole (5a). Recently, Sunoj et al. and others reported
Tetrasubstituted imidazoles were synthesized by multicomponent some leading functionalization and cyclization reactions using Ni(0)
condensation using HBF4–SiO2, supported sulfuric acid, catalysts for aromatic C–H activation.10 This prompted us to
p-dodecylbenzenesulfonic acid, ionic liquid, Zn(BF4)2 and ZrCl4 examine the sp3Ca–H metalated cyclization reaction using nickel
catalyst under microwave irradiation or heating conditions,8 compounds. In the first experiment, tetrasubstituted imidazole 5a
and a few others.4f,5c,9 Thus, development of a new and simple was obtained with Ni(COD)2 catalyst (8 mol%) in 25% yield and it
strategy using readily available ingredients and inexpensive was improved slightly (40–69%) by the use of Ni(II) compounds
(entries 2–4). In order to improve the yield we further examined the
Department of Chemistry, University of Calcutta, University College of Science, 92,
reaction using different solvents (dioxane, DMF, ethylenedichloride,
xylene and toluene), reaction temperatures (ambient to refluxing)
and ligands [dppe (entries 5 and 8), tricyclohexyl phosphine, COD
A. P. C. Road, Kolkata-700009, India. E-mail: dkmchem@caluniv.ac.in;
Fax: +91-33-2351-9755; Tel: +91-33-2350-9937
† Electronic supplementary information (ESI) available: Experimental procedures,
and cyclopentadiene] which were unsuccessful. Inspired by the
characterization data, NMR spectra, and CIF file. CCDC 964954. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/c3cc48437h recent use of Ni(II)-catalysts11 we employed an inexpensive and
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1,2-diketones underwent the cyclization reaction smoothly to afford
desired products 7a–e in 10–11 h with good yield (75–83%). The
single-crystal XRD structure12 of 5a is displayed in Scheme 2.
In an ongoing project in nanoscience and nanotechnology, we
designed an imidazole molecule bearing long chain hydrocarbons
to fabricate unidirectionally packed nanomaterials for organic
electronics.13 However, its direct insertion is very challenging due
to the presence of relatively unactivated sp3Ca–H in aliphatic amines
bearing long chain hydrocarbons. Using NiCl2Á6H2O (10 mol%) 8a
(Scheme 3) was obtained in only 54% yield. Pleasingly, we found a
more efficient catalyst Ni(OAc)2Á4H2O (8 mol%) to obtain imidazole
derivatives (8a–f) in good yield (71–87%). Long chain hydrocarbon
decorated polycyclic imidazoles (9a–d) were obtained under similar
reaction conditions in good yield (74–81%). Interestingly, using
CuX2ÁH2O (X = OAc, Cl, Br) 5a and 8a were also obtained in moderate
yield (48–25%) under the reaction conditions. The compounds are
solid in nature and showed excellent fabricated textures via mole-
cular aggregation. Spin coating fabricated material 9d was imaged in
a scanning electron microscope and displayed disc-like two dimen-
sional nanoscale morphology.
Recently Ji et al. reported CuI–BF3ÁEt2O cocatalyzed oxidative
cyclization of acetophenones and amine to trisubstituted imidazoles
through formation of 1,2-diimine.14 No formation of the desired
product (5a) was observed with the diimine whereas monoimine of
1,2-diketone (3a) underwent smoothly to 5a. Herein, Ni(II)–salt is
expected to perform selective dual activation of Ca–H bonds of the
primary amines (1,2). It leads to formation of an intermediate I with
1,2-diketones (3,4) and subsequently amine insertion (II). Eventually
C–N coupled reductive elimination of the catalyst in the cyclization
process afforded 1,2,4,5-tetrasubstituted imidazoles (5–9, eqn (1),
Scheme 4). The reaction was incomplete in the absence of oxygen.
Scheme 2 Direct synthesis of varied tetrasubstituted imidazoles.
readily available NiCl2Á6H2O (8 mol%) and yield was significantly
improved (90%, entry 7). It was consistently low (30–45%) when
studied at ambient temperature (entries 6 and 9).
With the optimized condition identified, we next examined
the scope of this oxidative cyclization reaction of benzyl amine
derivatives with 1,2-aromatic, aliphatic and cyclic diketones
(Scheme 2). Notably, excellent yield (89–94%) of 1,2,4,5-tetra-
substitued imidazoles (5a–d) was obtained for benzyl amine and its
derivatives bearing strong electron-donating groups. In addition,
when electron-withdrawing group containing 4-fluorobenzylamine
and 4-pyridylmethylamine were used as the starting material,
slightly lower yields (85–87%) were obtained for the desired
products 5e,f. Polycyclic imidazoles are bioactive alkaloids
present in marine sponges which were synthesized by multistep
approaches.6 A simple and direct synthesis of their analogues is
desirable for research in medicinal and material science toward
launching new products for our society. Satisfactory results were
also obtained for direct construction of polycyclic imidazoles
(6a–c) under similar reaction conditions. Next, we turned our
attention to the applicability of the protocol toward synthesis of
alkyl substituted imidazoles (7). Interestingly, dialkyl and cyclic
Scheme 3 sp3Ca–H activated cyclization of aliphatic primary amines.
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in a single operation. The simple, efficient and new strategy,
sp3C–H activation with Ni(II)–salts, its unprecedented catalytic
activity and diverse scope will find immense application in the
chemical sciences.
Financial support from DST (SR/S1/OC-05/2012 and SR/NM/
NS-29/2010), CRNN and research fellowships from CSIR and
UGC (Kothari), India are gratefully acknowledged.
Notes and references
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a catalyst for activating and exploiting
sp3Ca–H of primary amines for multi C–N bond-forming robust
annulation to 1,2,4,5-tetrasubstituted and polycyclic imidazoles
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