Palladium catalyzed synthesis of 4-substituted-2-phenylimidazoles from N-propargyl-benzamidine

Article abstract of DOI:10.1016/j.tetlet.2007.09.153

Preliminary results of an original approach to 4-substituted-2-phenylimidazoles starting from readily available N-propargyl-benzamidine and aryl halides are reported. Best yields were obtained using aryl halides bearing an electron-withdrawing group. Plausible mechanisms are also discussed.

Full text of DOI:10.1016/j.tetlet.2007.09.153

Available online at www.sciencedirect.com
Tetrahedron Letters 48 (2007) 8491–8495
Palladium catalyzed synthesis of 4-substituted-2-phenylimidazoles
from N-propargyl-benzamidine
Giorgio Abbiati,a,* Antonio Arcadi,b Valentina Canevaria and Elisabetta Rossia
a
` `
Istituto di Chimica Organica ‘Alessandro Marchesini’, Facolta di Farmacia, Universita degli Studi di Milano,
Via G. Venezian 21, 20133 Milano, Italy
Dipartimento di Chimica, Ingegneria Chimica e Materiali, Universita degli Studi dell’Aquila,
Via Vetoio, 67010 Coppito (AQ), Italy
b
`
Received 20 July 2007; revised 20 September 2007; accepted 26 September 2007
Available online 29 September 2007
Abstract—Preliminary results of an original approach to 4-substituted-2-phenylimidazoles starting from readily available
N-propargyl-benzamidine and aryl halides are reported. Best yields were obtained using aryl halides bearing an electron-withdraw-
ing group. Plausible mechanisms are also discussed.
ꢀ 2007 Elsevier Ltd. All rights reserved.
The interest for imidazoles is connected with the pres-
ence of their structure in a great number of molecules
characterized by a variety of biological and pharmaco-
logical activities.1 For instance, the imidazole nucleus
is the skeleton of a wide range of historical antimycotic
and antiprotozoic agents.2 Moreover, cimetidine, the
prototypical histamine H2-receptor antagonist, contains
an imidazole moiety. More recently, some new 4-amino-
methyl-2-phenylimidazoles showed a strong affinity for
dopaminergic D4-receptors becoming potential candi-
dates for the treatment of schizophrenia.3
by metalation followed by reaction with a proper
electrophile (such as an aldehyde or an isocyanate)6
or, more recently, by the reaction of an azolium ylide
with a reactive carbonyl.7
Surprisingly, only few catalytic reactions which produce
imidazoles have been reported.8 For instance, Abell and
co-workers developed a new synthetic method for tri-
substituted imidazoles based on the palladium catalyzed
intramolecular amino-Heck reaction of N-allyl-N-
benzyl-N0-perfluorobenzoyloxyamidines.9 Siamaki and
Arndtsen recently reported a direct synthesis of tetra-
substituted imidazoles by a palladium catalyzed multi-
component coupling reaction starting from two imines
and acid chlorides under CO atmosphere.10 On the basis
of a classical preparative method an improved multi-
component approach has been developed by Sharma
and co-workers starting from aldehydes, benzil and
ammonium acetate in the presence of a catalytic amount
of ZrCl4.11 The synthesis of imidazole nucleus by means
of homodimerization of isocyanates catalyzed by silver12
or copper13 has also been reported. Finally, Frantz et al.
developed the one-pot strategy that involves the synthe-
sis of a-ketoamides via the thiazolium catalyzed addition
of aldehydes to acylimines and subsequent treatment
with amines.14
Due to their importance, many methodologies have
been developed for assembling the imidazole ring. Con-
ventional methods usually consist of cyclocondensation
reactions. Representative strategies are the reaction of a-
diketones and a-haloketones (or their derivatives) with
formamide, usually known as Bredereck synthesis and
the base-promoted cyclization between p-tosylmethyl-
isocyanide and aldimines (or imidoyl chlorides) known
as van Lausen’s Tos-MIC chemistry.4 Some other origi-
nal approaches have also been reported recently.5 On
the other hand, starting from the preformed imidazole
nucleus, the functionalization on C2 has been obtained
Keywords: Imidazole; Amidine; Alkynes; Homogeneous catalysis;
Palladium; Domino reaction; Aminopalladation.
In connection with our ongoing interest in the study of
cyclization reaction involving alkynes and heteronucleo-
philes,15 we herein report the preliminary results of a
*
Corresponding author. Tel.: +39 02 50314474; fax: +39 02
50314476; e-mail: giorgio.abbiati@unimi.it
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.09.153

8492
G. Abbiati et al. / Tetrahedron Letters 48 (2007) 8491–8495
Table 1. Reactions of benzamidine 1 with aryl halides 2a
Entry
Ar-X
t (h)
Yieldsb (%)
1
24
2a 42
Scheme 1.
2
1
2b 65
new tandem palladium catalyzed synthesis of 4-substi-
tuted-2-phenyl imidazoles 2a–g starting from readily
available N-propargyl-benzamidine 1 and aryl halides
(Scheme 1).
3
4
5
2
1
1
2c 83
2d 86
2e 77
Similar synthetic approaches using acetylenes contain-
ing proximate nitrogen nucleophiles have been reported
for the synthesis of indoles,16 pyrroles,17 pyrrolo[2,3-
b]quinoxalines,18 alkyliden-oxazolidinones,19 alkyliden-
pyrrolidines20 and alkyliden-piperidines.21 Nevertheless,
two key features characterize our domino synthesis: (1)
the unprecedented use of an ammidine substrate and
(2) the involvement of a nitrogen nucleophile lacking
acidic hydrogens.22
6
7
2
2
2f 86
2g 40
An example of the potential of N-propargyl-benz-
amidine in heterocyclic synthesis has been reported by
Tice and Bryman.23 In the course of a more extensive
investigation on the regioselective preparation of
4-pyrimidones, the authors found that unpurified
N-propargyl-benzamidine in acetonitrile spontaneously
cyclize over the course of several days at rt to afford
the corresponding 4-methyl-2-phenylimidazole. The pro-
cess is accelerated by heat and by acidic conditions but
the yields are always moderate (56%). We were able to
prepare and purify the N-propargyl-benzamidine 1 in
76% yield,24 thus we found that such cyclization is
efficiently promoted by catalytic amounts of Lewis
a Reaction conditions: ratio 1:2:K2CO3:Pd(PPh3)4:CuI = 1:1.05:5:
0.02:0.04 in anhydrous DMF ([1] = 0.3 M) at 60 ꢁC under a N2.
b Yields refer to single runs and are given for isolated products.
25
26
acids such as TiCl4 and NaAuCl4 yielding the 4-
methyl-2-phenylimidazole in almost quantitative yields.
After that, we decided to extend the approach to internal
alkynes. Thus, we planned to functionalize the triple
bond of N-propargyl-benzamidine by means of a typical
Sonogashira coupling. Thus 1 was reacted with aryl
halides in DMF at 60 ꢁC in the presence of a catalytic
system constituted by Pd(PPh3)4, CuI and K2CO3.
Nevertheless, under these reaction conditions a seren-
dipitous direct formation of the coupling/5-exo-dig
cycloisomerization products has been observed (Scheme
1, Table 1).27
Scheme 2.
All compounds were identified on the basis of analytical
and spectral data (IR, H NMR, 13C NMR, MS). The
1
well known tautomeric equilibrium of imidazole nucleus
made, in some cases, the NMR identification of the C2,
C4 and C5-H of the heterocyclic ring difficult. The C5-H
carbon has been unequivocally identified through a C–H
HETCOR experiment for compound 2c.
From a mechanistic point of view, two different mecha-
nisms can justify in the formation of the imidazole ring
(Scheme 3). The first (Path A) implies the functionaliza-
tion of triple bond by a Sonogashira coupling28 followed
by an intramolecular nucleophilic attack of nitro-
gen on the triple bond activated by one of the metal
species present in the reaction environment (palladium
or copper).29 Afterwards, the resulting alkyliden-dihydro-
imidazole spontaneously rearranges in the more stable
imidazole isomer 2. The second (Path B) involves the
coordination of the organopalladium compound to tri-
ple bond followed by the intramolecular nucleophilic
attack of nitrogen to give the aminopalladation
adduct.30 Finally, the reductive elimination of Pd(0)
The reaction worked well with aryl halides bearing an
electron-withdrawing group on the ring (entries 2–5)
and with activated heteroaryl halides as pyrimidine (en-
try 6), whereas unactivated aryl halides gave poorer
yield and required longer reaction time (entry 1). Also
sterically hindered 1-iodo-2-nitrobenzene quickly
reacted with 1 although the yields were moderate (entry
7). Interestingly, the reaction of aryl halides bearing
electron-donating groups, even if sterically demanding,
gave lower yields of the imidazole derivatives, beside
small amounts of the corresponding pyrimidines rising
from a formal coupling/cyclization/oxidation reaction
(Scheme 2).

G. Abbiati et al. / Tetrahedron Letters 48 (2007) 8491–8495
8493
Scheme 3.
affords the alkyliden-dihydroimidazole which rearranges
in the more stable aromatic isomer 2. Moreover, the
formation of the pyrimidines 3a–b arising from a 6-
endo-dig type cyclization can be ascribed to a different
polarization of triple bond induced by the presence of
the electron-donating substituent on the phenyl ring.
With the aim to deduce some additional information on
the mechanism, we did some additional experiments
reacting 1 and p-chloroiodobenzene under different cat-
alytic conditions.
Under standard conditions but in the absence of palla-
dium, no reaction products were observed and 1 was
recovered in quantitative yield after 24 h, that means
copper alone is unable to catalyze the coupling nor the
cyclization of propargyl-benzamidine 1. On the other
hand, the reaction took place very slowly also in the ab-
sence of copper salt. After 24 h at 60 ꢁC, the formation
of imidazole 2b was observed in a mixture with 4-
methyl-2-phenylimidazole and the unreacted reagent 1
in a ratio 2:1:4 (Scheme 4). Moreover, the reaction per-
formed in the presence of triethylamine (that is known
to play a key role promoting the formation of Sonogash-
ira coupling product versus the heteropalladation ad-
duct)31 resulted in the formation of a mixture of 2b
and 4-methyl-2-phenylimidazole in a ratio 4:1 (Scheme
4). Finally, the reaction performed under standard
Sonogashira conditions but without aryl halides failed
giving rise to a complex mixture of by-products in which
only traces of 4-methyl-2-phenylimidazole were detect-
Scheme 4.
aminopalladation/reductive elimination (Path B) is the
most probable one. Nevertheless, the Sonogashira
coupling/cyclization mechanism (Path A) as competitive
pathway cannot be definitively ruled out, although we
have never been able to isolate the internal alkyne or
identify it by analyzing the NMR of the crude reaction
mixtures.
In conclusion, we have found a new versatile domino
palladium catalyzed approach to 4-substituted-2-
phenyl imidazoles starting from readily available N-
propargyl-benzamidine. Current efforts are now directed
to fully explore the scope and limitation of this
approach, for instance, optimizing the reaction condi-
tions, testing the reactivity of other aryl and vinyl
halides or triflates, and performing the reaction in the
presence of carbon monoxide to obtain 4-acyl-2-phenyl
imidazoles.
1
able by H NMR.
On the basis of these results and the literature data it
is our opinion that the mechanism involving the

8494
G. Abbiati et al. / Tetrahedron Letters 48 (2007) 8491–8495
23. Tice, C. M.; Bryman, L. M. Tetrahedron 2001, 57, 2689–
References and notes
2700.
24. Preparation of N-propargyl-benzamidine 1: A suspension
of ethyl benzimidate hydrochloride (6.00 g, 32.4 mmol)
and sodium bicarbonate (3.26 g, 33.9 mmol) in anhydrous
dichloromethane (18 mL) was stirred vigorously at rt for
40 min. After that, propargylamine (1.87 g, 33.9 mmol)
was added and the mixture was stirred for further 2 h. The
mixture was quickly filtered in vacuum over a celite pad,
and the pad washed with anhydrous dichloromethane
(10 mL). The solvent was evaporated at low temperature
(25 ꢁC) under reduced pressure, and the crude was purified
by flash chromatography on a silica gel column (eluent:
hexane/ethyl acetate/triethylamine = 8:2:3) yielding 3.90 g
(76%) of N-propargyl-benzamidine as waxy light yellow
solid. The pure product is stable at ꢀ24 ꢁC for several
weeks. 1H NMR (200 MHz, CDCl3): d = 2.28 (t, 1H, Csp-
H, J = 2.6 Hz), 4.15 (d, 2H, CH2, J = 2.6 Hz), 4.70 (bs,
2H, NH2), 7.36–7.43 (m, 3H, C–H arom.), 7.44–7.58 (m,
2H, C–H arom.) ppm. 13C NMR (200 MHz, CDCl3):
d = 33.9 (CH2), 71.6 (Csp-H), 81.1 (Csp), 99.0 (C10-H),
102.9 (C4-H), 109.2 (C6-H), 121.0 (C8-H), 121.8 126.4,
128.8, 130.4 (CH arom.), 137.1 (C arom.), 162.2
(C@N) ppm. IR (NaCl) m = 3292, 3202, 2115, 1643,
1. (a) Grimmett, M. R. Imidazole and Benzimidazole Synthe-
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1610, 1573, 1378, 701 cmꢀ1
. ESI-MS m/z (%): 159
[M++1] (100). ESI-MS/MS m/z (%) (parent ion: 159):
142 (100), 133 (25), 104 (38), 56 (21). Anal. calcd for
C10H10N2 (158.20): C, 75.92; H, 6.37; N, 17.71. Found: C,
75.70; H, 6.31; N, 17.78.
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appropriate aryl halide (0.66 mmol) is added to a stirred
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suspension of N-propargyl-benzamidine
0.63 mmol) and K2CO3 (437 mg, 3.16 mmol) in anhydrous
DMF (2 mL) under nitrogen atmosphere. Then,
1
(100 mg,
a
Pd(PPh3)4 (15 mg, 0.013 mmol) and CuI (5 mg, 0.025
mmol) were added. The reaction mixture was stirred at
60 ꢁC until no more starting product was detectable by
TLC, poured in to a saturated solution on NaCl (100 mL)
and extracted with EtOAc (3 · 30 mL). The combined
organic layers were dried over sodium sulfate and the
solvent removed under reduced pressure. The crude was
purified by flash chromatography over a silica gel column.
Compound 2b: Eluent for chromatography: hexane/ethyl
acetate (7:3). Yellow ochre solid. Yield 110 mg (65%). Mp:
166–168 ꢁC. 1H NMR (300 MHz, CDCl3): d = 3.94 (s, 2H,
CH2), 4.20 (bs, 1H, NH), 6.74 (s, 1H, C5-H), 7.16 (d, 2H,
C–H arom., J = 8.4 Hz), 7.24 (d, 2H, C–H arom.,
J = 8.4 Hz), 7.35–7.37 (m, 3H, C–H arom.), 7.79 (dd,
2 H, C–H arom., J = 7.8 and 1.5 Hz) ppm. 13C NMR
(200 MHz, CDCl3): d = 33.2 (CH2), 119.2 (C5-H), 96.0
(C1-H), 125.4, 128.8, 128.9, 129.1, 130.3 (C–H arom),
130.2, 132.4, 138.0 (C arom., one signal obscured), 146.8
(N@CAN) ppm. IR (KBr) m = 3436, 1571, 1490, 1463,
1438, 1407, 1139, 1095, 780, 707, 688 cmꢀ1. ESI-MS m/z
(%): 269 [M++1] (100). ESI-MS/MS m/z (%) (parent ion:
269): 157 (100), 125 (13). Anal. calcd for C16H15ClN2
(270.76): C, 70.98; H, 5.58; N, 10.35. Found: C, 71.11; H,
5.55; N, 10.36.
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