Regioselective synthesis of 4,5-diaryl-1-methyl-1H-imidazoles including highly cytotoxic derivatives by Pd-catalyzed direct C-5 arylation of 1-methyl-1H-imidazole with aryl bromides

Article abstract of DOI:10.1002/ejoc.200800738

A general and efficient three-step procedure for the highly regioselective synthesis of 1-methyl-1H-imidazoles possessing electron-rich, electron-neutral, and/or electron-deficient aryl moieties at their 4- and 5-positions is described. The first step involves the Pd-catalyzed direct C-5 arylation of commercially available 1-methyl-1H-imidazole with aryl bromides, and the second and third steps of the sequence involve the selective C-4 bromination of the resulting 5-aryl-1-methyl-1H-imidazoles with NBS, followed by a PdCl ₂(dppf)-catalyzed Suzuki-type reaction between 5-aryl-4-bromo-1- methyl-1H-imidazoles and arylboronic acids under phase-transfer conditions. Two 4,5-diaryl-1-methyl-1H-imidazoles so prepared, which can be regarded as Z-restricted analogues of naturally occurring combretastatin A-4 (CA-4), proved to be highly cytotoxic against a variety of human tumor cell lines, and one of these derivatives has been shown to be more cytotoxic than CA-4 and all of the imidazole derivatives investigated in the literature thus far. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800738

FULL PAPER
DOI: 10.1002/ejoc.200800738
Regioselective Synthesis of 4,5-Diaryl-1-methyl-1H-imidazoles Including
Highly Cytotoxic Derivatives by Pd-Catalyzed Direct C-5 Arylation of
1-Methyl-1H-imidazole with Aryl Bromides
Fabio Bellina,*[a] Silvia Cauteruccio,[a] Annarita Di Fiore,[a] and Renzo Rossi*[a]
Keywords: Direct arylation / Regioselectivity / Palladium / Imidazoles / Cytotoxicity
A general and efficient three-step procedure for the highly
regioselective synthesis of 1-methyl-1H-imidazoles pos-
4-bromo-1-methyl-1H-imidazoles and arylboronic acids un-
der phase-transfer conditions. Two 4,5-diaryl-1-methyl-1H-
sessing electron-rich, electron-neutral, and/or electron-de- imidazoles so prepared, which can be regarded as Z-restric-
ficient aryl moieties at their 4- and 5-positions is described.
The first step involves the Pd-catalyzed direct C-5 arylation
of commercially available 1-methyl-1H-imidazole with aryl
bromides, and the second and third steps of the sequence
involve the selective C-4 bromination of the resulting 5-aryl-
ted analogues of naturally occurring combretastatin A-4 (CA-
4), proved to be highly cytotoxic against a variety of human
tumor cell lines, and one of these derivatives has been shown
to be more cytotoxic than CA-4 and all of the imidazole de-
rivatives investigated in the literature thus far.
1-methyl-1H-imidazoles with NBS, followed by
PdCl2(dppf)-catalyzed Suzuki-type reaction between 5-aryl-
a
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
logues of the latter compound in order to have a better
understanding of its structure-activity relationships and to
enhance both its cytotoxic and selective vascular targeting
activity.[4,7,8]
Introduction
Microtubules are polymers of tubulin α,β-dimers that are
essential in all eukaryotic cells. Their importance in mitosis
makes microtubules an important target for anticancer
drugs.[1] Natural products, as well as synthetic, low-molecu-
lar-weight compounds of varied structure have been shown
to inhibit tubulin polymerization through an interaction
with tubulin at different binding sites. The taxol, Vinca al-
kaloid, and colchicine sites are the best known among
them.[2] Among all the colchicine-site agents, combretasta-
tin A-4 (CA-4, 1), isolated from the South African tree
Combretum caffrum,[3] has received special attention re-
cently.[4] In addition to potent inhibitory activity on tubulin
polymerization, CA-4 displays potent cytotoxic activity
against a broad spectrum of human cancer cell lines, includ-
ing multidrug-resistant cells.[3,5] The more water-soluble
prodrug of CA-4, CA-4 disodium phosphate (CA-4P, 2),
has been shown to cause vascular shutdown within 1 h of
administration, leading to haemorrhagic necrosis at the
core of the tumour, while leaving viable tumour cells at the
periphery that can cause rapid tumour regrowth.[6] The en-
couraging antivascular activity of 2 and the potent cytotox-
icity of 1 have stimulated the synthesis of numerous ana-
To overcome the problem of stereomutation of the Z-
configuration of 1, which is important for optimal cytotoxic
activity, many CA-4 analogues have been developed with a
locked cis-type bridge between the two aryl groups identical
or similar to those of 1. This result has frequently been
achieved by the introduction of a four- or five-membered,
heterocyclic, ring system between two vicinal aryl moie-
ties.[8a,8d–8h,8j] As far as the imidazole derivatives are con-
cerned, it should be noted that in 2002, Wang and co-
workers[8j] reported that among a small series of 5-aryl-1-
(3,4,5-trimethoxyphenyl)-1H-imidazoles, 3a and 3b had sig-
nificant antitubulin activity and antiproliferative properties
against two lines of human cancer cells.
[a] Dipartimento di Chimica e Chimica Industriale, University of
Pisa,
In the context of our studies on the synthesis and evalu-
ation of the cytotoxic activity of vicinal diaryl-substituted
five-membered-ring heterocycles, which can be considered
Z-restricted analogues of 1,[9] we also thought it right to
investigate the synthesis and bioactivity of vicinal diaryl-
substituted imidazoles. In fact, in case of bioactivity prob-
Via Risorgimento 35, 56126 Pisa, Italy
Fax: +39-050-2219260
E-mail: bellina@dcci.unipi.it
Rossi@dcci.unipi.it
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Regioselective Synthesis of 4,5-Diaryl-1-methyl-1H-imidazoles
lems associated with the poor solubility of these heterocy- the literature before the beginning of our studies involve the
cles in aqueous media, these derivatives can be easily con- construction of their imidazole ring by multi-step sequenc-
verted into more soluble salts by treatment with organic or es[8j] or are based on a Negishi-type cross-coupling reaction
inorganic acids. Thus, we developed selective and efficient between a haloheteroarene and an imidazol-4-ylzinc rea-
general procedures for the synthesis of 1,5- and 1,2-diaryl- gent, which is not easily available.[15] It was also our aim
1H-imidazoles of general formula 3[10] and 4,[11] respec- to identify and prepare 4,5-diaryl-1-methyl-1H-imidazoles
tively, by the direct transition-metal-catalyzed arylation of 6 possessing cytotoxic activity much higher than that of the
1-aryl-1H-imidazoles with aryl halides.[12]
derivatives described by Wang and co-workers by an inex-
pensive and environmentally friendly procedure suitable to
be scaled up for producing amounts of these heterocycles
adequate for biological testing.
Our continuing interest in the regioselective synthesis of
arylazole derivatives by transition-metal-catalyzed direct ar-
ylation[10,11,12a,16] led us to look for a new method for the
synthesis of 6 analogs involving the Pd-catalyzed direct
An evaluation of the in vitro antitumor activity of these arylation of 1-methyl-1H-imidazole (7) with aryl halides as
compounds against the NCI panel of 60 human tumor cell a key step. Recently, we preliminarily developed such a
lines indicated that 3c and 3d were more cytotoxic than CA- method and briefly described its use for the synthesis of 6c–
4.[13] It was also observed that imidazoles 3c–e caused pro- e in a review on the synthesis and bioactivity of vicinal di-
found changes in the morphology of endothelial cells and, aryl-substituted 1H-imidazoles.[17] Scheme 1 summarizes
following a single treatment, caused massive central necro- the reaction sequence used to prepare 6c–e. In this paper,
sis of tumours.[14] More recently, we turned our attention we report the experimental details of this three-step pro-
to the synthesis and evaluation of the cytotoxic activity cedure. The first step involves the Pd-catalyzed direct C-5
against human tumour cell lines of 4,5-diaryl-1-methyl-1H- arylation of 7 with aryl iodides 8a and 8b and aryl bromide
imidazoles 6. In fact, Wang and co-workers had previously 9a, followed by the regioselective C-4 bromination of the
demonstrated that some 4,5-diaryl-1H-imidazoles 5 have resulting 5-aryl-1-methyl-1H-imidazoles 10a–c by treatment
cytotoxic and antitubulin activities higher than those of 3 with NBS in the second step. The last step consists of a
and had shown that the incorporation of an N-methyl PdCl2(PPh3)2-catalyzed Suzuki-type reaction between 5-
group into the imidazole ring of 5 can lead to substances, aryl-4-bromo-1-methyl-1H-imidazoles 11a–c and aryl-
such as 6a and 6b, with improved pharmacokinetic proper- boronic acids 12 with CsF as the base under phase-transfer
ties and excellent bioavailability.[8j] Our interest in the devel- conditions. Moreover, we describe an improvement of this
opment of a general and efficient protocol for the synthesis three-step route, which allowed us to synthesize conve-
of 6 analogs was due to the fact that methods reported in niently, regioselectively, and in high overall yields, a variety
Scheme 1.
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F. Bellina, S. Cauteruccio, A. Di Fiore, R. Rossi
FULL PAPER
of 4,5-diaryl-1-methyl-1H-imidazoles characterized by elec- undesirable side reactions involving aryl/aryl exchange be-
tron-rich, electron-neutral, and/or electron-deficient aryl tween Pd- and phosphane-bound phenyl groups.[21] Com-
moieties.
pound 13a was identified by comparison of its physical and
This improved route involves the use of reactions similar spectral properties with those of an authentic sample of 2-
to those depicted in Scheme 1. In the first step, a variety of (4-methoxyphenyl)-1-methyl-1H-imidazole, which had been
5-aryl-1-methyl-1H-imidazoles 10 were efficiently prepared previously synthesized in excellent yield by the Pd-catalyzed
with significantly higher regioselectivity than that obtained and Cu-mediated direct C-2 arylation of 7 with 8a under
in our preliminary investigation. This was accomplished by ligandless conditions.[11] Compound 10a was obtained in
a Pd(OAc)2/P(2-furyl)3-catalyzed direct arylation of 7 with 50% isolated yield and 64% selectivity. We then attempted
deactivated, unactivated, and activated aryl bromides in to improve the yield and selectivity of the arylation reaction
DMF at 110 °C with K2CO3 as the base. Moreover, our and to minimize the formation of byproducts. Thus, the ef-
modification of the catalyst system in the Suzuki-type reac- fects of the ligand and solvent were examined. As far as
tion between arylboronic acids and 5-aryl-4-bromo-1- the selectivity is concerned, we found that when PPh3 was
methyl-1H-imidazoles 11 allowed us to prepare the required replaced by AsPh3 (Table 1, Entry 2,) or P(2-furyl)3
4,5-diaryl-1-methyl-1H-imidazoles 6 in shorter reaction (Table 1, Entries 3 and 4), the selectivity increased, and
times than those shown in Scheme 1 and with comparable cleaner reaction mixtures were obtained, which did not con-
or higher isolated yields. Finally, we report that two com- tain compounds derived from the scrambling of the aryl
pounds of general formula 6 were evaluated for their antitu- moiety of 8a with the organic group of the ligand. We were
moral activity against the NCI panel of 60 human tumor also pleased to find that switching to toluene as solvent and
cell lines and were found to be highly cytotoxic. Remark- with a catalyst precursor consisting of a mixture of
ably, imidazole 6d possessed cytotoxic activity higher than Pd(OAc)2 and P(2-furyl)3 in a 1:2 mole ratio (Table 1, Entry
that of CA-4 and all of the imidazole derivatives investi- 4), the reaction produced a significant increase in the yield.
gated in the literature thus far.
Table 1. Screening reaction conditions for the C-5 arylation of 7
with 8a.
Results and Discussion
Synthesis of 5-Aryl-1-methyl-1H-imidazoles
Several methods have been reported in the literature for
the synthesis of 5-aryl-1-methyl-1H-imidazoles 10, which in
our synthetic plan represent key intermediates. The meth-
ods include the CuCl-mediated reaction of aryl nitriles with
(methylamino)acetaldehyde
dimethyl
acetal,[18]
the
van Leusen chemistry of a tosmic reagent,[8j] the Pd-cata-
lyzed Suzuki reaction of arylboronic acids with 5-bromo-
1-methyl-1H-imidazole,[19] and the Pd-catalyzed direct C-5
arylation of 1-methyl-1H-imidazole (7) with aryl halides.[20]
The latter methodology offers a number of advantages over
the other procedures, including convenience, simplicity, and
the use of readily available starting materials, but the dif-
ferent protocols used thus far to perform the direct aryl-
ation reaction met with limited success because of modest
yields,[20a,b,d] low regioselectivity,[20b,d] and the use of elec-
trophiles represented exclusively by activated aryl ha-
lides.[20c] With the aim of overcoming these problems, at the
outset of our studies on the synthesis of compounds 10,
we investigated the synthesis of 10a by reacting 7 with 4-
iodoanisole (8a) under experimental conditions very similar
to those used for the selective C-5 arylation of 1-aryl-1H-
imidazoles.[10] Thus, 7 was treated with 2 equiv. of 8a with
5 mol-% Pd(OAc)2, 10 mol-% PPh3, and 2 equiv. of CsF in
DMF at 140 °C for 48 h (Table 1, Entry 1). After this
period of time, the arylation had proceeded to 98% conver-
sion and provided a mixture of compounds, which proved
Entry Ligand
Solvent Temp. GLC 10a/13a/14a/15a Isolated
[°C]
conv. GLC mole ratio yield
of 7
of 10a
[%]
[%]
1
2
3
4
PPh3
AsPh3
P(2-furyl)3 DMF
P(2-furyl)3 PhMe
DMF
DMF
140
140
140
110
98
94
90
94
64:1:3:32
72:1:2:25
73:2:11:14
75:2:1:22
50
50
36
66
This satisfactory result prompted us to apply the reaction
to contain monoarylation derivatives 10a, 13a, and 14a and conditions of Entry 4 of Table 1 to the synthesis of 5-aryl-
a diarylated 1-methyl-1H-imidazole (15a), along with very 1-methyl-1H-imidazoles 10b and 10c from 7 and 5-iodo-
small amounts of monophenyl-substituted 1-methyl-1H- 1,2,3-trimethoxybenzene (8b) and 2-bromonaphthalene
imidazoles. The latter compounds presumably derived from (9a), respectively. In these reactions, we found regioselectiv-
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Regioselective Synthesis of 4,5-Diaryl-1-methyl-1H-imidazoles
ity very similar to that of the arylation of 7 with 8a in Entry
4 of Table 1, and as shown in Scheme 1, furnished the re-
quired compounds 10b and 10c in 56 and 72% yield, respec-
tively.
Since the use of unactivated aryl bromide 9a in the C-5
arylation of 7 gave better results than those obtained with
aryl iodides 8a and 8b, we then investigated the Pd-cata-
lyzed direct arylation of 7 with a variety of aryl bromides
9, including deactivated and activated derivatives. In fact,
many aryl bromides 9 are commercially available and less
expensive than the corresponding iodides 8. Moreover, we
examined the possibility of decreasing the aryl halide/7
mole ratio from 2:1 (as in Scheme 1) to 1.5:1. Thus, we be-
gan this investigation by examining the effects of variables
such as the reaction temperature and the nature of the base,
solvent, and phosphane ligand on the outcome of the direct
arylation of 7 with 1.5 equiv. of 4-bromoanisole (9b), a typi-
cal deactivated aryl bromide, with a catalytic amount of
Pd(OAc)2 (Scheme 2). A wide range of bases that included
K2CO3, Cs2CO3, KOAc, CsOAc, KF, CsF, and piperidine
were tested in the reaction of 7 with 9b, which we performed
in DMF at 110 °C with a mixture of Pd(OAc)2 (5 mol-%)
and P(2-furyl)3 (10 mol-%). Reasonable isolated yields (46–
49%) of the required arylation product 10a were obtained
only when K2CO3 or CsOAc was used; other bases proved
to be ineffective in the arylation. However, the highest GLC
and isolated yields of 10a (55 and 49%, respectively) were
obtained when K2CO3 was employed as the base. In fact,
CsOAc afforded somewhat lower selectivity in the reaction
(the 10a/13a/15a mole ratio was 91:0:9), and 10a was iso-
lated in 46% yield. Other major factors controlling the re-
gioselectivity of the reaction were found to be the solvent
and reaction temperature (Table 2). More polar solvents
favoured the desired C-5 arylation, and DMF was the pre-
ferred solvent at the preferred temperature of 110 °C
(Table 2, Entries 1 and 4).
The use of other polar solvents such as DMA (Table 2,
Entry 2) or DMSO (Table 2, Entry 5) produced 10a in
yields comparable to that obtained in DMF at 110 °C, but
the selectivity was significantly lower. On the other hand,
the use of less polar solvents such as toluene (Table 2, Entry
7) or xylenes (Table 2, Entry 8) resulted in low GLC yields
of 10a and unsatisfactory regioselectivity. The identity of
the byproduct 15a from reactions lacking complete regiose-
lectivity (Table 2, Entries 2, 4, 5, 7 and 8) was confirmed by
its isolation and comparison with an authentic sample of
2,5-bis(4-methoxyphenyl)-1-methyl-1H-imidazole, synthe-
sized in 22% yield by the Pd-catalyzed bis-arylation reac-
tion of 7 with 2.0 equiv. of 9b, as depicted in Scheme 3.
The choice of the ligand was also an important factor,
with P(2-furyl)3 being preferred over P(c-C6H11)3 or biden-
Scheme 2.
Table 2. Solvent and reaction temperature optimization for the
Pd(OAc)2/P(2-furyl)3-catalyzed reaction of 7 with 9b.
Entry[a] Solvent
Reaction temp. 10a/13a/15a
GLC yield
[°C]
mole ratio
of 10a [%][b]
1
2
3
4
5
6
7
8
DMF
DMA
NMP
110
110
110
140
140
85
100:0:0
96:4:0
100:0:0
63:0:37
90:6:4
–
55
54
8
44
44
–
DMF
DMSO
MeCN
PhMe
Me2C6H4
110
140
93:6:1
10:3:87
32
9
[a] The reactions were performed with 1 mmol of 7, 1.5 mmol of
9b, 5 mol-% Pd(OAc)2, and 10 mol-% P(2-furyl)3 with 2 equiv. of
K2CO3 for 24 h. [b] Evaluated with biphenyl as an internal stan-
dard.
Scheme 3.
tate phosphane ligands such as dppf or Xantphos (Table 3). tained in 39% GLC yield when the reaction of 7 with 9b
In fact, the use of 10 mol-% of P(2-furyl)3 in the reaction was run in DMF with 5 mol-% of Xantphos (Table 3, Entry
of 7 with 9b with 2 equiv. of K2CO3 and 5 mol-% Pd- 4), but the regioselectivity of the reaction was significantly
(OAc)2 in DMF at 110 °C produced 10a with regioselectiv- lower than that of the reactions of Entries 1 and 3 of
ity and a GLC yield higher than that observed for the same Table 3. It is interesting to note that 10a was synthesized in
reaction with P(c-C6H11)3 instead of P(2-furyl)3 (compare 33% GLC yield and 100% regioselectivity when the aryl-
Table 3, Entries 1 and 3). On the other hand, 10a was ob- ation was performed under ligandless conditions (Table 3,
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F. Bellina, S. Cauteruccio, A. Di Fiore, R. Rossi
FULL PAPER
Entry 6). Ultimately, the preferred conditions found in the C-5 regioselectivity and without the formation of signifi-
reaction screen were a Pd(OAc)2/P(2-furyl)3 catalyst system cant amounts of 2,2Ј-binaphthyl (16), derived from the
and K2CO3 as the base in DMF at 110 °C. With the stan- homocoupling of 9a.
dard reaction conditions in hand, we then proceeded to test
the generality of the reaction with a number of aryl bro-
mides. Entries 1, 2, and 7 of Table 4 show that deactivated
aryl bromides, including strongly deactivated bromide 9c,
efficiently participated in the completely regioselective Pd-
catalyzed C-5 arylation of 7. The yields of 10a and 10b were
slightly lower than those obtained when 2 equiv. of the
more expensive aryl iodides 8a and 8b were used. The re-
sults reported also indicate that both unactivated and acti-
vated aryl bromides provided the required 5-aryl-1-methyl-
1H-imidazoles 10 generally in good yields and with satisfac-
tory to excellent selectivity (Table 4, Entries 3–5, 8, and 10).
Nevertheless, a comparison of Entry 3 of Table 4 with
Scheme 1 indicates that the protocol for the C-5 arylation
of 7 with 1.5 equiv. of 9a with K2CO3 as the base furnished
10c in a slightly lower yield than that obtained with 2 equiv.
of 9a and CsF as the base (67% vs. 72%) but with complete
It should also be noted that, unexpectedly, no arylation
occurred in the reaction of 7 with methyl 2-bromobenzoate
(9i, Table 4, Entry 9), and a low yield (24%) of the required
arylation product, 10f, was obtained when the moderately
deactivated, sulfur-containing, heteroaryl bromide 9f was
used (Table 4, Entry 6). Interestingly, a modification of the
procedure illustrated in Table 4 that involved a large molar
excess of 7 with respect to the electrophile produced 1,4-
bis(1-methyl-1H-imidazol-5-yl)benzene (17) in 81% isolated
yield from 7 and 1,4-dibromobenzene (9k, Scheme 4).
Table 3. Ligand optimization for the reaction of 7 with 9b with
K2CO3 and a catalytic amount of Pd(OAc)2.
Entry[a] Ligand
Solvent
10a/13a/15a
mole ratio
GLC yield
of 10a [%][b]
1
2
3
4
5
6
P(2-furyl)3
dppf
DMF
DMF
100:0:0
100:0:0
96:0:4
87:2:11
–
55
9
50
39
–
P(c-C6H13)3 DMF
Xantphos DMF
P(c-C6H13)3 PhMe
DMF
–
100:0:0
33
[a] The reactions were performed h at 110 °C for 24 with 1 mmol
of 7, 2.0 mmol of 9b, 5 mol-% Pd(OAc)2, and 10 mol-% of a mono-
dentate ligand or 5 mol-% of a bidentate ligand with 2 equiv. of
K2CO3. [b] Evaluated with biphenyl as an internal standard.
Scheme 4.
Synthesis of 5-Aryl-4-bromo-1-methyl-1H-imidazoles
We then investigated the selective C-4 bromination of 5-
aryl-1-methyl-1H-imidazoles 10, and we envisaged that this
reaction might be efficiently performed with experimental
conditions similar to those previously employed to convert
both 1,5-diaryl-1H-imidazoles and 1-benzyl-5-methyl-1H-
imidazole into the corresponding 4-halo derivatives.[22,23] To
test this hypothesis, we reacted 10i with 1.05 equiv. of N-
bromosuccinimide (NBS) in acetonitrile at room tempera-
ture and obtained a mixture of 4-bromo derivative 11g and
a small amount (about 3–4%) of 2-bromo derivative 18.
Chromatographic purification of this mixture provided 11g
in 72% yield (Table 5, Entry 1). As reported in the next
section, the structural assignment of this compound was
confirmed by its conversion into 4,5-diphenyl-1-methyl-1H-
imidazole (6f) by a Suzuki-type reaction with phenylbo-
ronic acid and a comparison of the physical and spectral
properties of this imidazole derivative with those of an au-
thentic sample of 6f, prepared by the N-methylation of
commercially available 4,5-diphenyl-1H-imidazole (5a) by a
reaction with a large molar excess of dimethyl carbonate
with K2CO3 and 5 mol-% 18-crown-6 (Figure 1).[24]
Table 4. Pd-catalyzed synthesis of 5-aryl-1-methyl-1H-imidazoles
10 from 1-methyl-1H-imidazole 7 and aryl bromides 9.
Entry Aryl bromides Ar1
Reaction Products
Sel.
[%]
Isolated
yield [%]
9
time [h]
10
1
2
3
4
5
6
7
8
4-MeOC6H4
3,4,5-(MeO)3C6H2 9c
2-naphthyl
3-pyridyl
4-CF3C6H4
2-iPr-5-thienyl
6-MeO-2-naphthyl 9g
4-ClC6H4 9h
2-(MeOOC)C6H4 9i
C6H5 9j
9b
24
48
48
51
48
72
90
48
48
48
10a
10b
10c
10d
10e
10f
10g
10h
–
100
100
100
100
93
100
100
80
49
55
67
66
74
24
70
66
–
9a
9d
9e
9f
9[a]
10
–
98
10i
80
[a] The reaction was run in DMA at 160 °C.
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Regioselective Synthesis of 4,5-Diaryl-1-methyl-1H-imidazoles
Table 5. C-4 bromination of 5-aryl-1-methyl-1H-imidazoles 10.
thylboronic acid (12c), respectively, in a 1:1 mixture of tolu-
ene and water at 60 °C with 5 mol-% PdCl2(PPh3)2, 5 mol-
% BnEt3NCl, and 3 equiv. of CsF (Method A). As shown in
Scheme 1 and Entries 1, 2, and 3 of Table 6, these reactions
provided the required products, 6c, 6e, and 6d, in 91, 54,
and 55% yield, respectively. Remarkably, the cross-coupling
reactions producing 6d and 6e, unlike the arylation of 3,4-
dichloro-2(5H)-furanone[25] and 4(5)-bromo-1H-imid-
azole[16d] under very similar experimental conditions, were
not accompanied by an undesirable side reaction of aryl/
aryl interchange between Pd- and phosphane-bound phenyl
groups. Nevertheless, the arylation of 11c and 11b met with
limited success, providing modest yields but requiring long
reaction times (Table 6, Entries 2 and 3). Therefore, we in-
vestigated an alternative procedure for the cross-coupling of
bromoimidazoles 11 with arylboronic acids. After extensive
experimentation, we found that when PdCl2(dppf) replaced
PdCl2(PPh3)2 and the reactions were performed in a re-
fluxing 1:1 mixture of toluene and water with a catalytic
amount of BnEt3NCl, the arylation of bromoimidazoles
11b–g (Method B) occurred in good to excellent yields and
with a significant reduction in the reaction time compared
to those of Method A (Table 6, Entries 4–11). A compari-
son between Entries 5 and 6 and Entries 2 and 3, respec-
tively, of Table 6 highlights the synthetic advantage of
Method B over Method A. The results of Table 6 also indi-
cates that the Suzuki-type reactions performed with
Method B allowed us to efficiently introduce electron-neu-
tral, electron-rich, or electron-deficient aryl groups at the 4-
position of bromoimidazoles 11.
Finally, we note that three 4,5-diaryl-1-methyl-1H-imid-
azoles prepared herein (i.e. 6d, 6e, and 6j), which can be
regarded as Z-restricted analogues of combretastatin-A4,
were selected by the NCI for cytotoxic activity testing
against the panel of 60 human tumour cell lines. The results
for 6j are nor available yet, but those for 6d and 6e indicate
that both of these compounds are highly cytotoxic. In fact,
the mean molar drug concentration value of Log GI50
(MG_MID Log GI50) for all tested human cancer cell lines
over a 5-log dose range was –6.8 for 6e and –7.36 for 6d.
Remarkably, the latter imidazole derivative, which is an iso-
mer of 6e, proved to be more cytotoxic than CA-4 (1,
MG_MID Log GI50 –7.00)[13] and all the other imidazole
derivatives tested thus far.
Entry
5-Aryl-1-methyl-1H-imidazole Reaction Product
time
[h]
10
Ar1
11
Isolated
yield [%]
1
2
3
4
5
6
7
10i
C6H5
0.83
11g
11a
11b
11c
11d
11e
11f
72
55
72
58
71
72
76
10a
10b
10c
10d
10g
10h
4-MeOC6H4
3,4,5-(MeO)3C6H2
2-naphthyl
3-pyridyl
6-MeO-2-naphthyl
4-ClC6H4
1
1
2
4
1
1
Figure 1. Chemical structures of 11g, 18, 6f, and 5a.
We then tested the viability of the envisioned protocol
for the C-4 bromination of 10i for the preparation of a vari-
ety of 5-aryl-4-bromo-1-methyl-1H-imidazoles 11 dis-
playing electron-rich, electron-deficient, or electron-neutral
aryl moieties. We found that all the reactions were highly
regioselective and provided the required bromo derivatives
11 in short reaction times and good yields. Table 5 summa-
rizes the results obtained in the preparation of 11a–g. Inter-
estingly, the yields of these 4-bromo derivatives did not sig-
nificantly differ from those recently obtained in the C-4
bromination of 5-aryl-1-benzyl-1H-imidazoles with a pro-
cedure similar to that illustrated in Table 5.[16c]
Synthesis and Cytotoxicity of 4,5-Diaryl-1-methyl-1H-
imidazoles
Having secured good access to 11 analogs, we next
turned our attention to the conversion of these bromoimid-
Conclusions
azoles into 4,5-diaryl-1-methyl-1H-imidazoles
6 by a
Suzuki-type reaction with arylboronic acids 12. We thought
In this study, we have developed a general procedure for
it right to perform the Pd-catalyzed cross-coupling reac- the highly regioselective synthesis of 4,5-diaryl-1-methyl-
tions under phase-transfer conditions according to a pro- 1H-imidazoles in three steps starting from inexpensive com-
cedure similar to one we previously employed for the C-4 mercially available materials. The most important charac-
arylation of 3,4-dichloro-2(5H)-furanone[9a] and the synthe- teristics of this new procedure, which compares favourably
sis of 4(5)-aryl-1H-imidazoles from 4(5)-bromo-1H-imid- with those previously developed to prepare this interesting
azole.[16d]
class of imidazole derivatives,[8j,15] include high yields of op-
We first attempted the C-4 arylation of bromoimidazoles erationally simple reactions, very high regioselectivity, and
11a, 11b, and 11c with 2 equiv. of phenylboronic acid (12a), the possibility to introduce electron-neutral, electron-rich,
3,4,5-trimethoxyphenylboronic acid (12b), and 2-naph- or electron-deficient (hetero)aryl moieties at the 4- and/or
Eur. J. Org. Chem. 2008, 5436–5445
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5441

F. Bellina, S. Cauteruccio, A. Di Fiore, R. Rossi
FULL PAPER
Table 6. Suzuki-type reactions of bromoimidazoles 11 with arylboronic acids 12.
Entry
Bromoimid-
azole 11
Arylboronic
acid 12
Pd
derivative
Reaction Reaction
time [h] temp. [°C]
Product
6
Ar1
Ar2
Yield [%]
[a]
[a]
[a]
1
2
3
4
5
6
7
8
11a
11c
11b
11d
11c
11b
11f
11b
11b
11e
11g
4-MeOC6H4
2-naphthyl
3,4,5-(MeO)3C6H2
3-pyridyl
2-naphthyl
3,4,5-(MeO)3C6H2
4-ClC6H4
3,4,5-(MeO)3C6H2
3,4,5-(MeO)3C6H2
6-MeO-2-naphthyl
C6H5
12a
12b
12c
12d
12b
12c
12e
12f
C6H5
3,4,5-(MeO)3C6H2
2-naphthyl
4-FC6H4
3,4,5-(MeO)3C6H2
2-naphthyl
2,4-Cl2C6H3
3-F,4-MeOC6H3
6-MeO-2-naphthyl
4-MeCOC6H4
C6H5
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
48
72
168
24
24
24
24
24
19
24
24
60
60
60
6c
6e
6d
6g
6e
6d
6h
6i
91
54
55
99
90
99
42
84
83
86
68
PdCl2(dppf)[b]
PdCl2(dppf)[b]
PdCl2(dppf)[b]
PdCl2(dppf)[b]
PdCl2(dppf)[b]
PdCl2(dppf)[b]
PdCl2(dppf)[b]
PdCl2(dppf)[b]
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
9
10
11
12g
12h
12a
6j
6k
6f
[a] PdCl2(PPh3)2 was employed as the catalyst precursor in Method A. The reactions according to this method (Entries 1–3) were
performed in a mixture of toluene and water at 60 °C. [b] PdCl2(dppf) was employed as the catalyst precursor in Method B. The reactions
according to this method (Entries 4–11) were performed in a refluxing mixture of toluene and water.
trimethoxyphenyl)-1H-imidazole (10b) from 7 and 5-iodo-1,2,3-tri-
methoxybenzene (8b), and 1-methyl-5-(2-naphthyl)-1H-imidazole
(10c) from 7 and 2-bromonaphthalene (9a, Scheme 1).
5-position of the imidazole ring. Remarkably, two 4,5-di-
aryl-1-methyl-1H-imidazoles prepared in this study have
proven to be highly cytotoxic against human tumor cell
lines, and one of these compounds was significantly more
cytotoxic than naturally-occurring combretastatin-A4 and
all of the imidazole derivatives tested thus far. Finally, it is
worth mentioning that in the context of this investigation,
we succeeded in the development of a general and efficient
method for the concise synthesis of diversified 5-aryl-1-
methyl-1H-imidazoles from commercially available 1-
methyl-1H-imidazole and activated, unactivated, and deac-
tivated aryl bromides. This new protocol has proven to be
significantly more regioselective than the Pd-catalyzed aryl-
ation reactions of 1-methyl-1H-imidazole previously de-
scribed in the literature.[20]
5-(4-Methoxyphenyl)-1-methyl-1H-imidazole (10a): The crude reac-
tion product obtained in Scheme 1 from the Pd-catalyzed reaction
of 7 with 8a was purified by MPLC on silica gel with CH2Cl2/
methanol (95:5) as the eluent to give 10a (99.7 mg, 66%) as a pale
yellow solid: m.p. 106–108 °C. 1H NMR (300 MHz, CDCl3): δ =
7.50 (s, 1 H), 7.31 (m, 2 H), 7.04 (s, 1 H), 6.97 (m, 2 H), 3.84 (s, 3
H), 3.63 (s, 3 H) ppm. 13C NMR (75.4 MHz, CDCl3): δ = 159.4,
138.6, 133.2, 128.7 (2 C), 127.5, 122.2, 114.1 (2 C), 55.3, 32.3 ppm.
EI-MS: m/z (%) = 189 (13), 188 (100), 174 (9), 173 (77), 145 (13).
C11H12N2O (188.23): calcd. C 70.19, H 6.43, N 14.88; found C
70.09, H 6.37, N 14.73.
1-Methyl-5-(2-naphthyl)-1H-imidazole (10c): The crude reaction
product obtained from the Pd-catalyzed reaction of 7 with 9a (see
Scheme 1) was purified by MPLC on silica gel with CH2Cl2/meth-
anol (95:5) as the eluent to give 10c (149.7 mg, 72%) as a pale
yellow solid: m.p. 109–111 °C (ref.[25] 103 °C). 1H NMR (300 MHz,
CDCl3): δ = 7.86 (m, 4 H), 7.51 (m, 4 H), 7.21 (s, 1 H), 3.70 (s, 1
H) ppm. 13C NMR (75.4 MHz, CDCl3): δ = 139.4, 133.4, 132.8,
128.7, 128.6 (2 C), 128.1, 127.9 (2 C), 127.3, 126.8, 126.5, 126.4,
32.8 ppm. EI-MS: m/z (%) = 209 (16), 208 (100), 207 (12), 180 (15),
Experimental Section
General Procedure for the Pd-Catalyzed Synthesis of 5-Aryl-1-
methyl-1H-imidazoles 10a, 10b, and 10c from 1-Methyl-1H-imid-
azole (7) and Aryl Halides 8a, 8b, and 9a, Respectively, in Toluene
with CsF as the Base: The appropriate aryl halide 8 (2.0 mmol),
Pd(OAc)2 (11.2 mg, 0.05 mmol), P(2-furyl)3 (23.2 mg, 0.1 mmol),
and CsF (303.8 mg, 2.0 mmol) were placed in a reaction vessel un-
der a stream of argon. The reaction vessel was fitted with a silicon
septum, evacuated and back-filled with argon, and this sequence
1
166 (12). The H NMR spectroscopic data of this compound were
in agreement with those previously reported.[25]
General Procedure for the Pd-Catalyzed Synthesis of 5-Aryl-1-
methyl-1H-imidazoles 10 from 7 and Aryl Bromides 9 in DMF with
was repeated twice. Deaerated 1-methyl-1H-imidazole (7, 82.1 mg, K2CO3 as the Base: The appropriate aryl bromide 9 (1.5 mmol),
1.0 mmol) and dry toluene (5 mL) were then added successively by
syringe under a stream of argon, and the resulting reaction mixture
was stirred for 48 h under argon at 110 °C. The reaction was moni-
tored by GLC and GLC/MSD analyses of a filtered sample of the
reaction mixture. After being cooled to room temperature, the mix-
ture was filtered through Celite and concentrated under reduced
pressure, and the residue was purified by MPLC on silica gel. This
procedure was used to prepare 5-(4-methoxyphenyl)-1-methyl-1H-
imidazole (10a) from 7 and 4-iodoanisole (8a), 1-methyl-5-(3,4,5-
Pd(OAc)2 (11.2 mg, 0.05 mmol), P(2-furyl)3 (23.2 mg, 0.1 mmol),
and K2CO3 (27.6 mg, 2.0 mmol) were placed in a reaction vessel
under a stream of argon. The reaction vessel was fitted with a sili-
con septum, evacuated and back-filled with argon, and this se-
quence was repeated twice. Deaerated 1-methyl-1H-imidazole (7,
82.1 mg, 1.0 mmol) and deaerated DMF (5 mL) were then added
successively by syringe under a stream of argon, and the resulting
mixture was stirred at 110 °C for the period of time reported in
Table 4. After this period, the reaction, monitored by GLC and
5442
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Regioselective Synthesis of 4,5-Diaryl-1-methyl-1H-imidazoles
GLC/MS analyses of a filtered sample of the reaction mixture, was
complete. The reaction mixture was then cooled to room tempera-
ture, diluted with AcOEt/CH2Cl2 (1:1, 80 mL), and filtered through
Celite. The filtrate was concentrated under reduced pressure, and
the residue was purified by MPLC on silica gel. This procedure
was used to prepare 10a–g (Table 4).
122.8, 114.2 (2 C), 114.0 (2 C), 55.4 (2 C), 33.6 ppm. EI-MS: m/z
(%) = 295 (20), 294 (100), 293 (34), 279 (38), 147 (11). C18H20N2O2
(294.35): calcd. C 73.45, H 6.16, N 9.52; found: C 73.33, H 6.04,
N 9.38.
1,4-Bis(1-methyl-1H-imidazol-5-yl)benzene (17): The crude reaction
product obtained from the reaction of 7 (164.2 mg, 2.0 mmol) with
1,4-dibromobenzene (9k) (236.0 mg, 1.0 mmol) in DMF at 110 °C
for 65 h, with 5 mol-% Pd(OAc)2, 10 mol-% P(2-furyl)3, and
2.0 equiv. of K2CO3, was purified by recrystallization from acetoni-
trile to give 17 (192.8 mg, 81%) as a yellow solid: m.p. 233–235 °C.
1H NMR (200 MHz, [D6]DMSO): δ = 7.74 (s, 2 H), 7.58 (s, 4 H),
7.13 (s, 2 H), 3.72 (s, 6 H) ppm. 13C NMR (50.3 MHz, [D6]DMSO):
δ = 140.8 (2 C), 132.9 (2 C), 129.6 (2 C), 128.7 (2 C), 127.7 (2 C),
33.2 (2 C) ppm. EI-MS: m/z (%) = 239 (21), 238 (100), 210 (8), 184
(8), 183 (8). C14H14N4 (238.29): calcd. C 70.56, H 5.92, N 23.51;
found C 70.51, H 5.80, N 23.39.
1-Methyl-5-(3,4,5-trimethoxyphenyl)-1H-imidazole (10b): The crude
reaction product obtained in Entry 2 of Table 4 from the Pd-cata-
lyzed reaction of 7 with 5-bromo-1,2,3-trimethoxybenzene (9c) was
purified by MPLC on silica gel with CH2Cl2/methanol (95:5) as the
eluent to give 10b (136.4 mg, 55%) as a yellow solid: m.p. 115–
1
117 °C. H NMR (300 MHz, CDCl3): δ = 7.51 (s, 1 H), 7.07 (s, 1
H), 6.59 (s, 2 H), 3.89 (s, 1 H), 3.68 (s, 3 H) ppm. 13C NMR
(75.4 MHz, CDCl3): δ = 153.2 (2 C), 138.9, 138.0, 133.4, 128.7,
125.3, 106.1 (2 C), 60.8, 56.2 (2 C), 32.4 ppm. EI-MS: m/z (%) =
249 (15), 248 (100), 234 (10), 205 (19), 190 (14). C13H16N2O3
(248.28): calcd. C 62.89, H 6.49, N 11.28; found C 62.73, H 6.35,
N 11.14.
General Procedure for the Synthesis of 5-Aryl-4-bromo-1-methyl-
1H-imidazoles 11: N-Bromosuccinimide (186.9 mg, 1.05 mmol) was
This same compound was prepared in 56% yield by the Pd-cata-
lyzed reaction of 7 with 5-iodo-1,2,3-trimethoxybenzene (8b) in tol-
uene at 110 °C with CsF as the base (Scheme 1).
added to
a solution of a 5-aryl-1-methyl-1H-imidazole 10
(1.0 mmol) in dry acetonitrile (2 mL) at room temperature, and the
resulting mixture was stirred at 20 °C for the period of time re-
ported in Table 5. After this period, the reaction, monitored by
GLC and GLC/MS analyses of a sample of the reaction mixture
diluted with AcOEt, was complete. The reaction mixture was con-
centrated under reduced pressure, and the residue was purified by
MPLC on silica gel. Compounds 11a–g were prepared according
to this general procedure (Table 5).
1-Methyl-5-[4-(trifluoromethyl)phenyl]-1H-imidazole (10e): The
crude reaction product obtained in Entry 5 of Table 4 from the Pd-
catalyzed reaction of 7 with 1-bromo-4-(trifluoromethyl)benzene
(9e) was purified by MPLC on silica gel with CH2Cl2/methanol
(94:6) as the eluent to give 10e (167.4 mg, 74%) as a pale yellow
1
liquid. H NMR (200 MHz, CDCl3): δ = 7.69 (m, 2 H), 7.52 (m, 3
H), 7.17 (s, 1 H), 3.71 (s, 3 H) ppm. 13C NMR (50.3 MHz, CDCl3):
δ = 140.0, 133.5, 132.2, 129.2 (2 C), 129.0, 128.4 (2 C), 125.8 (q, J
= 382 Hz, CF3), 121.4, 32.7 ppm. EI-MS: m/z (%) = 227 (13), 226
(100), 198 (13), 186 (9), 171 (10). C11H9F3N2 (226.20): calcd. C
58.41, H 4.01, N 12.38; found C 58.37, H 3.85, N 12.34.
4-Bromo-1-methyl-5-(3,4,5-trimethoxyphenyl)-1H-imidazole (11b):
The crude reaction product obtained in Entry 3 of Table 5 from
the C-4 bromination of 10b with NBS was purified by MPLC on
silica gel with CH2Cl2/methanol (99:1) as the eluent to give 11b
1
(235.5 mg, 72%) as an orange oil. H NMR (300 MHz, CDCl3): δ
= 7.48 (s, 1 H), 6.59 (s, 2 H), 3.92 (s, 3 H), 3.89 (s, 6 H), 3.61 (s, 3
H) ppm. 13C NMR (75.4 MHz, CDCl3): δ = 153.4 (2 C), 138.5,
137.2, 130.3, 123.3, 114.5, 107.4 (2 C), 60.9, 56.3 (2 C), 33.4 ppm.
EI-MS: m/z (%) = 329 (14), 328 (96), 327 (15), 326 (100), 313 (58),
311 (59). C13H15BrN2O3 (327.17): calcd. C 37.72, H 4.62, Br 24.42;
found C 47.58, H 4.55, Br 24.32.
5-(6-Methoxynaphthalen-2-yl)-1-methyl-1H-imidazole (10g): The
crude reaction product obtained in Entry 7 of Table 4 from the Pd-
catalyzed reaction of 7 with 6-methoxy-2-bromonaphthalene (9g)
was purified by MPLC on silica gel with CH2Cl2/methanol (95:5)
as the eluent to give 10g (166.8 mg, 70%) as a pale yellow solid:
1
m.p. 157–159 °C. H NMR (200 MHz, CDCl3): δ = 7.76 (m, 3 H),
7.53 (s, 1 H), 7.44 (dd, J = 8.4, 2.0 Hz, 1 H), 7.18 (m, 3 H), 3.92
(s, 3 H), 3.68 (s, 3 H) ppm. 13C NMR (50.3 MHz, CDCl3): δ =
178.8, 158.0, 138.9, 133.7, 129.7, 129.1, 128.7, 128.4, 127.3, 126.7,
124.9, 119.4, 105.6, 55.3, 32.5 ppm. EI-MS: m/z (%) = 239 (17),
238 (100), 223 (35), 195 (28), 127 (7). C15H14N2O (238.28): calcd.
C 75.61, H 5.92, N 11.76; found C 75.54, H 5.87, N 11.68.
4-Bromo-1-methyl-5-(2-naphthyl)-1H-imidazole (11c): The crude re-
action product obtained in Entry 4 of Table 5 from the C-4 bromi-
nation of 10c with NBS was purified by MPLC on silica gel with
CH2Cl2/methanol (99:1) as the eluent to give 11c (166.5 mg, 58%)
1
as a yellow-orange oil. H NMR (300 MHz, CDCl3): δ = 7.91 (m,
4 H), 7.52 (m, 4 H), 3.61 (s, 3 H) ppm. 13C NMR (75.4 MHz,
CDCl3): δ = 137.4, 133.1, 133.0, 130.4, 129.6, 128.4, 128.1, 127.8,
127.1, 126.9, 126.7, 125.5, 115.0, 33.3 ppm. EI-MS: m/z (%) = 289
(15), 288 (96), 287 (18), 286 (100), 153 (19). C14H11BrN2 (287.15):
calcd. C 58.56, H 3.86, Br 27.83; found C 68.43, H 3.81, Br 27.71.
2,5-Bis(4-methoxyphenyl)-1-methyl-1H-imidazole (15a): 4-Bromo-
anisole (9b) (374.0 mg, 2.0 mmol), Pd(OAc)2 (11.2 mg, 0.05 mmol),
P(2-furyl)3 (23.2 mg, 0.1 mmol), and K2CO3 (276.2 mg, 2.0 mmol)
were placed in a reaction vessel under a stream of argon. The reac-
tion vessel was fitted with a silicon septum, evacuated and back-
filled with argon, and this sequence was repeated twice. Deaerated
DMF (5 mL), pivalic acid (307.0 mg, 0.3 mmol) and 1-methyl-1H-
imidazole (7, 82.1 mg, 1.0 mmol) were then sequentially added by
syringe under a stream of argon, and the resulting mixture was
stirred at 110 °C for 24 h. It was then cooled to room temperature,
diluted with CH2Cl2/AcOEt (1:1, 50 mL), and filtered through Ce-
lite. The filtrate was concentrated under reduced pressure, and the
solid residue was purified by MPLC on silica gel with CH2Cl2/
methanol (95:5) as the eluent to give 15a (64.7 mg, 22%) as a pale
yellow solid: m.p. 138–139 °C. 1H NMR (200 MHz, CDCl3): δ =
7.62 (m, 2 H), 7.37 (m, 2 H), 7.11 (s, 1 H), 7.02 (m, 2 H), 6.97 8
(m, 2 H), 3.86 (s, 6 H), 3.62 (s, 3 H) ppm. 13C NMR (50.3 MHz,
CDCl3): δ = 159.9, 159.4, 148.8, 130.4, 130.1 (4 C), 126.7, 123.6,
3-(4-Bromo-1-methyl-1H-imidazol-5-yl)pyridine (11d): The crude re-
action product obtained in Entry 5 of Table 5 from the C-4 bromi-
nation of 10d with NBS was purified by MPLC on silica gel with
CH2Cl2/methanol (93:7) as the eluent to give 11d (169.0 mg, 71%)
as a yellow solid: m.p. 77–80 °C. 1H NMR (200 MHz, CDCl3): δ
= 8.68 (s, 1 H), 7.78 (d, J = 7.8 Hz, 2 H), 7.49 (m, 2 H), 3.63 (s, 3
H) ppm. 13C NMR (50.3 MHz, CDCl3): δ = 150.4, 149.8, 138.3,
137.4, 137.4, 127.1, 125.9, 123.6, 116.2, 33.5 ppm. EI-MS: m/z (%)
= 240 (11), 239 (97), 238 (12), 237 (100), 119 (16). C9H8BrN3
(238.08): calcd. C 45.40, H 3.39, Br 33.56; found C 45.31, H 3.21,
Br 33.43.
General Procedure for the Synthesis of 4,5-Diaryl-1-methyl-1H-
imidazoles 6 from Bromoimidazoles 11 and Arylboronic Acids 12:
Eur. J. Org. Chem. 2008, 5436–5445
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5443

F. Bellina, S. Cauteruccio, A. Di Fiore, R. Rossi
FULL PAPER
4,5-Diaryl-1-methyl-1H-imidazoles 6 were synthesized from bro-
moimoidazoles 11 and arylboronic acids 12 according two pro-
cedures: Method A and Method B.
3-[4-(4-Fluorophenyl)-1-methyl-1H-imidazol-5-yl]pyridine (6g): The
crude reaction product obtained in Entry 4 of Table 6 from the
Suzuki-type reaction of 11d with 4-fluorophenylboronic acid (12d)
according to Method B was purified by MPLC on silica gel with
CH2Cl2/methanol (93:7) as the eluent to give 6g (125.2 mg, 99%)
Method A:
A deaerated mixture of a bromoimidazole 11
(0.5 mmol), an arylboronic acid 12 (1.0 mmol), PdCl2(PPh3)2
(17.6 mg, 0.025 mmol), BnEt3NCl (5.7 mg, 0.025 mmol), and CsF
(227.8 mg, 1.5 mmol) in toluene (3.5 mL) and water (3.5 mL) was
stirred at 60 °C under an atmosphere of argon for the period of
time indicated in Table 6. After this period, a GLC/MS analysis of
a sample of the reaction mixture, which was extracted with AcOEt,
showed that the reaction was complete. The reaction mixture was
then cooled to room temperature and extracted with AcOEt
(4ϫ39 mL). The organic extract was washed with brine, dried, and
concentrated under reduced pressure. The residue was purified by
MPLC on silica gel to provide the required product. This method
was used to prepare 6b–e (Entries 1, 2, and 3, respectively, Table 6).
1
as a pale brown liquid. H NMR (200 MHz, CDCl3): δ = 8.65 (m,
2 H), 7.65 (m, 2 H), 7.38 (m, 3 H), 6.92 (m, 2 H), 3.54 (s, 3 H)
ppm. 13C NMR (50.3 MHz, CDCl3): δ = 163.5, 150.5, 150.2, 149.4,
134.2, 133.0, 130.6 (2 C), 129.6, 128.3, 125.6, 122.9, 116.1 (2 C),
30.1 ppm. EI-MS: m/z (%) = 254 (17), 253 (100), 252 (60), 225 (10),
184 (28). C15H12FN3 (253.27): calcd. C 71.13, H 4.78, N 16.59;
found C 71.01, H 4.65, N 16.44.
4,5-Diphenyl-1-methyl-1H-imidazole (6f): The crude reaction prod-
uct obtained in Entry 11 of Table 6 from the Suzuki-type reaction
of 11g with phenylboronic acid (12a), according to Method B, was
purified by MPLC on silica gel with CH2Cl2/methanol (98:2) as the
eluent to give 6f (79.6 mg, 68%) as a pale yellow solid: m.p. 162–
Method B:
A deaerated mixture of a bromoimidazole 11
1
164 °C (ref.[26]159–160 °C) H NMR (200 MHz, CDCl3): δ = 7.56
(0.5 mmol), an arylboronic acid 12 (1.0 mmol), PdCl2(dppf)
(20.4 mg, 0.025 mmol), BnEt3NCl (5.7 mg, 0.025 mmol), and CsF
(227.8 mg, 1.5 mmol) in toluene (3.5 mL) and water (3.5 mL) was
refluxed whilst stirring in an atmosphere of argon for the period of
time reported in Table 6. After this period, a GLC/MS analysis of
a sample of the reaction mixture, which was extracted with AcOEt,
showed that the reaction was complete. The reaction mixture was
then worked up and purified by a procedure very similar to that
employed in Method A. Method B was used to prepare 6d–k
(Table 6, Entries 4–11).
(s, 1 H), 7.51–7.13 (m, 10 H), 3.48 (s, 3 H) ppm. 13C NMR
(50.3 MHz, CDCl3): δ = 138.3, 137.4, 134.7, 130.7 (2 C), 129.0 (2
C), 128.6, 128.4, 128.1 (2 C), 127.0, 126.6 (2 C), 126.3, 32.1 ppm.
EI-MS: m/z (%) = 235 (17), 234 (100), 233 (68), 218 (17), 165 (43).
This same compound was synthesized in 62% yield by the N-meth-
ylation of commercially available 4,5-diphenyl-1H-imidazole (5a)
with a very large molar excess of dimethyl carbonate at 100 °C for
48 h with K2CO3 (8 equiv.) and a catalytic amount of 18-crown-6
according to a literature procedure.[24]
Supporting Information (see also the footnote on the first page of
this article): Experimental procedures and characterization for 10d,
10f, 10h, 10i, 11a, 11e–g, 6c, and 6h–k. This material is available
free of charge via the Internet.
1-Methyl-5-(naphthalen-2-yl)-4-(3,4,5-trimethoxyphenyl)-1H-
imidazole (6e): The crude reaction product obtained in Entry 5 of
Table 6 from the Suzuki-type reaction of 11c with 3,4,5-trimethoxy-
phenylboronic acid (12b), according to Method B was purified by
MPLC on silica gel with CH2Cl2/methanol (97:3) as the eluent to
give 6e (168.3 mg, 90%) as a pale brown liquid. 1H NMR
(600 MHz, CDCl3): δ = 8.80 (br. s, 1 H), 8.00 (d, J = 8.5 Hz, 1 H),
7.93 (s, 1 H), 7.92 (m, 1 H), 7.88 (m, 1 H), 7.61 (m, 1 H), 7.58 (m,
1 H), 7.45 (d, J = 8.5 Hz, 1 H), 6.83 (s, 2 H), 3.78 (s, 3 H), 3.74 (s,
3 H), 3.52 (s, 6 H) ppm. 13C NMR (150.3 MHz, CDCl3): δ = 153.2
(2 C), 137.8, 136.0, 133.9, 133.4, 133.3, 130.8, 129.4, 128.9, 128.2,
127.9, 127.7, 127.5, 127.2, 125.3, 125.0, 104.1 (2 C), 60.8, 56.0 (2
C), 33.6 ppm. EI-MS: m/z (%) = 375 (26), 374 (100), 360 (21), 359
(84), 245 (10). C23H22N2O3 (374.43): calcd. C 73.78, H 5.92, N
7.48; found C 73.66, H 5.85, N 7.41.
Acknowledgments
Thanks are due to the University of Pisa for financial support.
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This same compound was synthesized in 54% yield with Method
A (Table 6, Entry 2).
1-Methyl-4-(naphthalen-2-yl)-5-(3,4,5-trimethoxyphenyl)-1H-imid-
azole (6d): The crude reaction product obtained in Entry 6 of
Table 6 from the Suzuki-type reaction of 11b with 2-naphthylbo-
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on silica gel with CH2Cl2/methanol (97:3) as the eluent to give 6d
(185.3 mg, 99%) as an pale orange liquid. 1H NMR (600 MHz,
CDCl3): δ = 9.26 (br. s, 1 H), 8.28 (d, J = 1.5 Hz, 1 H), 7.80 (m, 1
H), 7.75 (m, 1 H), 7.71 (d, J = 8.6 Hz, 1 H), 7.53 (dd, J = 8.6,
1.5 Hz, 1 H), 7.45 (m, 1 H), 7.44 (m, 1 H), 6.60 (s, 2 H), 3.96 (s, 3
H), 3.82 (s, 3 H), 3.80 (s, 6 H) ppm. 13C NMR (150.3 MHz,
CDCl3): δ = 154.1 (2 C), 139.7, 136.0, 133.2, 133.0, 132.0, 129.6,
128.7, 128.4, 127.5, 126.81, 126.76, 126.5, 125.6, 124.1, 122.1, 107.9
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(100), 360 (5), 359 (19), 171 (6). C23H22N2O3 (374.43): calcd. C
73.78, H 5.92, N 7.48; found C 73.70, H 5.79, N 7.37.
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5444
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Eur. J. Org. Chem. 2008, 5436–5445

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Received: July 25, 2008
Published Online: October 7, 2008
Eur. J. Org. Chem. 2008, 5436–5445
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5445