1
598
Y. Wan et al.
SPECIAL TOPIC
high temperature (130 °C or 180 °C) under non-inert con-
ditions. Both electron-rich and electron-poor aryl bro-
mides undergo reactions with amines with different
nucleophilic properties. Imidazole could be used as reac-
tant under these controlled microwave reaction condi-
tions, provided that 4-bromobenzonitrile served as a co-
reactant. Although, the yields are only fair to good we still
believe that the reported procedure, characterized by a
high reproducibility and relying on adequate temperature
control, will attract attention from synthetic organic
chemists engaged in high throughput chemistry and drug
discovery programs.
1H and 13C NMR spectra were recorded at 270.2 and 67.9 MHz, re-
spectively. Chemical shifts are given as values (ppm) downfield
from tetramethylsilane. Flash column chromatography was per-
formed on silica gel 60 (0.04–0.063 mm). TLC was performed on
precoated silica gel F-254 plates (0.25 m) and was visualized with
Figure Temperature curves of amination reactions promoted by
microwave irradiation: A: 130 °C, 4 min with 4-bromotoluene and
benzylamine as reactants (Table, entry 1) and B: 180 °C, 15 min with
4
-bromobenzonitrile and imidazole as reactants (Scheme 2).
the latter case (entry 4) addition of excess amine led to no UV light or ninhydrin in EtOH. Pd(OAc) was bought from Merck
2
improvement of the yield. With aniline as amine the reac- Company and dppf from Strem Chemicals Company. All other
chemicals were purchased from Aldrich or Fluka and were used di-
tions with 4-bromoanisole and, somewhat surprisingly,
rectly without further purification. All microwave reactions were
the reaction with 4-bromobenzonitrile both required a
carried out in SmithProcessvials (2 mL). Microwave heating was
higher temperature of 180 °C, to accomplish full conver-
carried out with Smith Creator and Smith Synthesizer (Personal
sions of the starting materials within 4 minutes (entries 11
Chemistry AB, Uppsala, Sweden). It is recommended to perform
and 12). As apparent from entry 13, N-arylpiperazines, an these pressurized high-temperature reactions in a dedicated and safe
12
important compound class in medicinal chemistry, could microwave reactor. GC-MS was performed with an HP-5890 series
II equipped with an electron impact (70 eV) mass selective detector,
be prepared, although in a more moderate yield that is ac-
and a HP-1 capillary column using 70-305 temperature gradient.
counted for by a competing diarylation reaction.
1
4
15a,b
16a,b
16a,17
18b,25
The isolated compounds in the Table: entry: 1, 2,
3,
4,
It should be noted that heating by focused microwave ir-
18a,b
18b,19
18a,b
18a,20
21a,b
22a,b
23a,b
1224 and 13,
5
,
6,
7,
8,
9,
10,
11,
radiation is not a prerequisite for carrying out the reac- have previously been characterized and corresponded satisfactorily
2
6
tions. Hence, the amination in entry 1, for example, could with the NMR literature data. 4-Imidazol-1-ylbenzonitrile have
previously been characterized and corresponded satisfactorily with
the melting point data.
be conducted equally successfully in a pre-heated oil-bath
at 130 °C; with these conditions delivering the 4-benzyl-
aminosubstituted toluene in 77% isolated yield after 4
minutes. Experiments in pre-heated oil-bath at 180 °C
were not attempted (cf. entries 11 and 12).
Microwave-Induced Amination of Aryl Bromides; General
Procedure
A SmithProcessvial was charged with aryl bromide (0.75 mmol),
1
3
amine (3.00 mmol), Pd(OAc) (8.5 mg, 0.038 mmol), binap (23.7
2
In an ongoing medicinal chemistry program we required
aryl substituted imidazoles and were encouraged to pre-
pare these according to the fast synthetic protocol reported
herein. Unfortunately the electron-rich aryl bromides, that
mg, 0.038 mmol), t-BuOK (84.2 mg, 0.75 mmol) and DMF (1 mL)
and the cap was tightened thoroughly. The vessel was exposed to
microwave irradiation for 4 min at 130 or 180 °C. The reaction tube
was thereafter cooled to r.t. and the mixture was extracted with
were used as model compounds were all reluctant to react EtOAc. The organic layer was washed with H O and brine, dried
2
with imidazole under the above reaction conditions and (K
CO ) and the solvent was removed under reduced pressure. The
products were purified by column chromatography on silica gel
hexane–acetone, 8–20%) (Table).
2
3
thus the desired N-arylimidazoles could not be obtained
(
by this method. However, electron-deficient 4-bromoben-
zonitrile could be converted to the corresponding N-
arylimidazole but only after a reaction time of 15 min at
4
-Imidazol-1-yl-benzonitrile
A SmithProcessvial was charged with 4-bromobenzonitrile (0.75
1
80 °C (Scheme 2). In the latter reaction dppf served as a mmol), imidazole (3.00 mmol), Pd(OAc) (8.5 mg, 0.038 mmol),
2
better ligand than binap.
dppf (21.1 mg, 0.038 mmol), t-BuOK (84.2 mg, 0.75 mmol) and
DMF (1 mL) and the cap was tightened thoroughly. The vessel was
exposed to microwave irradiation for 15 min at 180 °C. The reac-
tion tube was thereafter cooled to r.t. and the mixture was extracted
Pd(OAc)2, dppf
DMF
N
N
NC
Br
HN
NC
N
with EtOAc. The organic layer was washed with H O and brine,
2
15 min, 180 °C
dried (K CO ) and the solvent was removed under reduced pressure.
8
4%
2
3
Microwave Heating
The products were purified by column chromatography on silica gel
(
CHCl –MeOH, 50:1).
3
Scheme 2
1
H NMR (CDCl ): = 8.10 (s, 1 H), 7.78 (m, 2 H), 7.55 (d, 2 H,
3
J = 8.6 Hz), 7.36 (s, 1 H), 7.19 (s, 1 H).
In summary, it has been demonstrated that the powerful
Buchwald/Hartwig amination can be performed rapidly at
13
C NMR (CDCl ): = 139.9, 135.1, 134.1, 129.8, 121.4, 117.9,
3
1
17.6, 111.2.
Synthesis 2002, No. 11, 1597–1600 ISSN 0039-7881 © Thieme Stuttgart · New York