One-pot synthesis of imidazoles from aromatic nitriles with nickel catalysts

Article abstract of DOI:10.1039/c1cc13497c

Nickel(0) catalysts were used to produce substituted imidazoles in good to high yields using benzonitrile, p-substituted benzonitriles and 4-cyanopyridine as starting materials. The Royal Society of Chemistry 2011.

Full text of DOI:10.1039/c1cc13497c

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COMMUNICATION
One-pot synthesis of imidazoles from aromatic nitriles with nickel
catalystsw
Juventino J. Garcıa,* Paulina Zerecero-Silva, Grisell Reyes-Rios, Marco G. Crestani,
´
´
Alma Arevalo and Rigoberto Barrios-Francisco
Received 13th June 2011, Accepted 26th July 2011
DOI: 10.1039/c1cc13497c
Nickel(0) catalysts were used to produce substituted imidazoles
in good to high yields using benzonitrile, p-substituted benzo-
nitriles and 4-cyanopyridine as starting materials.
The use of alkaline metals and hydrides for the preparation
of TPI from benzonitrile by metal-mediated reactions has also
been documented: NaH yields 27% of TPI and 34% of the
triphenyltriazine.5 These procedures, however, are impractical
for their scaling up due to the requirement of stoichiometric
NaH, in addition to laborious separations needed to remove
produced triazine from the reaction mixture.
Imidazoles are
a very important family of heterocyclic
compounds that possess a wide range of applications within
the academic and industrial arenas. Imidazoles can be found in
several types of drugs (e.g. anti-inflammatory, anticancer agents
and blood pressure regulators), natural products and metallo-
enzymes.1 Existing methodologies for the synthesis of imid-
azoles are limited in terms of the starting materials, conversion
and product selectivity, which consistently result in low yields.2
The use of catalysts is a potentially useful strategy to overcome
low conversions of traditional synthetic methods, minimize the
amount of reaction byproducts and undesired impurities, and
even promote formation of complex imidazole-derivatives by
incorporation of other functionalities.3
The metal-mediated synthesis of TPI via tungsten–
iminocarbene complexes and BN was reported by Wulff and
co-workers.6 This is a rather elaborate procedure with a good
yield (84% TPI). As a downside, in addition to it not being a
catalytic process, the iminocarbenes need to be prepared
independently, prior to the reaction with BN.
There are a handful of reported catalytic processes to
prepare imidazoles3 none of which refers to the use of organic
nitriles as starting materials for direct synthesis of these
organics. Usually the procedures involve multi-component
reactions with a variety of reagents and a metal catalyst
introduced in high loads (15–20% mol) to drive the cyclo-
addition reactions. It is worth mentioning that a paper by
Siamaki and Arndsten has been published,7 wherein they
describe the synthesis of tetra-substituted imidazoles by a
palladium-catalyzed (5% mol) process involving two imines
and an acid chloride under a CO atmosphere. The corresponding
imidazoles are obtained in low to moderate yields.
There are very few reports on the use of nitriles––especially
aromatic ones––as starting materials for the synthesis of imid-
azoles; even less documented by metal-mediated or catalytic
transformations. A relevant example of catalysis was disclosed
by Bochkarev et al., using lanthanides (Tm, Nd and Dy) for the
reduction, cyclization and cyclotrimerization of benzonitrile
(BN), which yielded 2,4,5-triphenylimidazole (TPI) (best isolated
yield = 9% using Tm), 2,4,6-triphenyltriazine (Nd, 39%, Dy,
15%, Tm, 6%) and 2,3-,20-30-tetraphenylpyrazine (Nd, 10%,
Dy, 3%, Tm, 2%) all in very low amounts (Scheme 1).4
In recent years, our group has been interested in the
chemistry of nickel compounds employed for several synthetic
processes relevant for academia and industry, related to
nitriles.8 In all of these processes, formation of nickel(0)
compounds with a formula, [(L–L)Ni(Z2-NC-R)] ((L–L) =
chelating diphosphine; R = alkyl, aryl), was initially observed
when reacting an alkyl-, aryl- or heteroarylnitrile in the
presence of the nickel(I) dimer, [(dippe)NiH]2 (1) (dippe =
1,2-bis(diisopropylphosphino)ethane).
Scheme 1
Recently we reported a study dealing with the hydrogena-
tion of aryl-nitriles and aryl-dinitriles or dicyanobenzenes,
DCB (1,2-, 1,3- and 1,4-DCB), using nickel(0) catalysts
and THF as solvent.9 The reactions took place under
relatively mild conditions and the corresponding products of
condensation for each substrate were obtained. In particular,
the hydrogenation of BN produced a mixture of N-benzyl-
benzylimine (BBI) and the total hydrogenation product,
dibenzylamine (DBA; the major product), with overall
´
Facultad de Quımica, Universidad Nacional Autonoma de Mexico,
Circuito Interior, Me´xico City 04510, Me´xico.
E-mail: juvent@servidor.unam.mx; Fax: +52 5556 223514;
Tel: +52 5556 162010
w Electronic supplementary information (ESI) available: Includes
detailed experimental procedures, relevant analytical and spectro-
scopic data (1D-, 2D-NMR spectra and MS) of produced imidazoles.
See DOI: 10.1039/c1cc13497c
´
´
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 10121–10123 10121

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Scheme 2
Table 1 Catalytic cyclization of BN: synthesis of TPI
Entry
Time/h
Temp./1C
H2 pressure/psi
Yield of TPI (%)
Scheme 3
1
2
3
4
24
48
24
48
48
48
180
180
230
230
180
180
60
60
120
120
120
60
54
93
66
98
98
92
test the homogeneity of the catalytic process (entry 6), without
any inhibition observed in its presence. Formation of NH3 (see
Scheme 2) was verified in all reactions by gently bubbling a
stream of gases released from the reactor after completion of
the respective runs, into a saturated aqueous solution of CuSO4.
A distinctive color change to deep blue is attributed to forma-
tion of the ammonia–copper(II) complex, [Cu(NH3)6][SO4].11
A mechanistic proposal for this transformation is based on
our previous findings for the catalytic reduction of BN using
H2 and a variety of solvents;9 from which studies, formation of
the Schiff base, BBI, as the main product was established.
To a much lesser extent, BBI underwent further reduction to
N-dibenzylamine. In perspective, the synthesis of BBI con-
stituted a definite proof of a catalytic tandem hydrogenation–
condensation process during which NH3 is also extruded. In
the current work we envision BBI to act as a key organic
intermediate towards the final cyclization product, TPI, via a
series of basic reactions depicted in Scheme 3.
Initial Z2-coordination of BBI to nickel(0) through the
CQN bond is proposed in Scheme 3 as intermediate (i),
inspired in closely related complexes displaying a coordinated
fluorinated imine reported by our group.12 The latter
complexes were structurally characterized and later on also
used in catalysis under low pressure of hydrogen, coupled to a
hydrogen-transfer system in methanol.13 In the current
catalytic cycle we propose a C–H bond activation from the
related iminic-nickel(0) species (i), to give the alkyl-hydrido
intermediate (ii). Insertion of a second nitrile molecule to give
a C,C-addition reaction is then proposed to give intermediate (iii),
5
6a
General reaction conditions: a stainless steel autoclave pressurized at
the indicated pressure (psi) of H2. Reaction mixtures were charged in a
dry-box under neat conditions (no solvent added). Catalyst loading:
a
0.5 mol% of 1 relative to the nitrile. Mercury drop test.
conversion above 95%. Herein we disclose our findings
relative to the efficient catalytic, one-pot preparation of
2,4,5-trisubstituted imidazoles using simple aromatic nitriles
as starting materials. Reactions are run under H2 pressure and
under neat conditions.
It is well known that the reaction of [(dippe)Ni(m-H)]2 (1)
with aromatic nitriles yields the formation of the Ni(0)
complex10 [(dippe)Ni(Z2-NC-Ar)]. The synthesis of TPI was
made via the in situ hydrogenation of BN using complex 1 as a
catalyst precursor under a variety of reaction conditions
(Scheme 2). Relevant experimental details are summarized in
Table 1.
From the data in Table 1, high yields of TPI can be obtained
at 180 1C and 60 psi of H2 over 48 h (entry 2). An increase of
temperature (230 1C) and pressure (120 psi) allows to improve
the yield of such product, although only slightly with respect
to the same reaction times under milder conditions (entries 4
and 5). In all cases just minute amounts of triazine were
observed (o1%), and it was barely observed on using high
H2 pressure. A mercury drop experiment was performed to
Table 2 Catalytic cyclization of aromatic nitriles to yield imidazoles
Entry
Substrate
Time/h
Temp./1C
H2 pressure/psi
Yield of imidazole (%)
1
2
3
4
5
4-Methyl-benzonitrile
4-Methoxy-benzonitrile
4-Fluoro-benzonitrile
4-Cyanopyridine
48
48
48
48
48
180
180
180
180
180
120
120
120
60
98
97
83
77
91
4-Cyanopyridine
120
General reaction conditions: a stainless steel autoclave pressurized at the indicated pressure (psi) of H2. Reaction mixtures were charged in a
dry-box under neat conditions (no solvent added). Catalyst loading: 0.5 mol% of 1 relative to the nitrile.
c
10122 Chem. Commun., 2011, 47, 10121–10123
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which is followed by an intramolecular cyclization reaction to
form (iv). A b-hydride elimination reaction leads to the
free organic (v) with concomitant formation of a nickel
dihydride (the hydride source), from which reductive elimina-
tion of H2 with re-coordination of BBI completes the turn-
over by reforming of (i). Ultimately, tautomerization of (v)
produces TPI.
method can be used to prepare a variety of valuable imidazoles
from cheap raw materials such as p-substituted benzonitriles
and N-heterocycles such as 4-cyanopyridine under neat
conditions and relatively low H2 pressure. The generation of
byproducts such as triazines can be substantially or totally
inhibited by increasing the pressure of H2 in the system.
Current studies are underway to extend the scope of this
reaction to other hetero-aromatic and alkyl nitriles.
Using the optimized conditions in Table 1 we decided to
extend the scope of this reaction to p-substituted aryl-nitriles
(Rp–C6H4–CN) and 4-cyanopyridine. The results are summar-
ized in Table 2.
We thank CONACyT (080606) and DGAPA-UNAM
(IN-201010) for the financial support to this work. P. Z.-S.
also thanks CONACyT for a graduate studies grant. We are
grateful with Prof. Federico del Rio for helping on NMR
assignments and with Mr. Ernesto Bribiesca-Contreras for
technical assistance.
Very good yields of the corresponding imidazoles were
obtained in all cases, under the optimized reaction conditions.
Only in the case of 4-cyanopyridine was the initial yield low
(entry 4), due to the unexpected production of the corres-
ponding triazine. The latter was overcome by increasing the
pressure of H2 (entry 5), which substantially disfavors cyclo-
trimerization. No inhibition of the activity of nickel(0) was
observed on using mercury with any of the substrates listed in
Table 2. The latter is consistent with examples of homo-
geneous catalysis, similarly to BN.
Notes and references
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Further studies to extend the scope of this reaction to
asymmetric imidazoles were made. These experiments were
also intended to provide mechanistic insights of the current
cyclization reaction. The independent preparation of BBI and
its use in the reaction, employing the conditions described in
Table 1, entry 2, produced always pure TPI, confirming the
intermediacy of BBI for the TPI formation. Similarly, the
independent preparation of asymmetric analogs to BBI under
the very same reaction conditions gave mixtures where the
production of the symmetrical imidazole (via BBI) was always
the favored product, due to the use of an excess of the
corresponding nitrile (neat conditions).
5 W. Zhang, S. Liao, Y. Xu and Y. Zhang, Synth. Commun., 1997,
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10 (a) J. J. Garcia and W. D. Jones, Organometallics, 2000, 19, 5544;
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11 H. Elliott and B. J. Hathaway, Inorg. Chem., 1966, 5, 885.
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J. Organomet. Chem., 2007, 692, 3498.
The catalytic one-pot cyclization of aromatic nitriles to yield
2,4,5-trisubstituted imidazoles in high yield using single-site
nickel catalysts is reported for the first time. This synthetic
13 A. L. Iglesias and J. J. Garcı
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c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 10121–10123 10123