One-pot sequential direct C-H bond arylation of azoles catalyzed by [Pd(phen)2](PF6)2: Synthetic methods for triarylated azoles

Article abstract of DOI:10.1021/jo301621t

Synthetic methods for triarylated azoles containing three different aryl groups via one-pot sequential multiple C-H bond arylations are described. The one-pot sequential diarylation of C5-monoarylated azoles was achieved by the simple sequential addition of two different aryl iodides with a [Pd(phen) ₂]PF₆ catalytic system. The one-pot triarylation of N-methylimidazole was achieved by the combination of a previously reported Pd(OAc)₂-P(2-furyl)₃ system and the present [Pd(phen) ₂]PF₆ system. In this case, portionwise addition of aryl halide, base and the catalyst in the final step significantly improved the overall yield of the desired triarylated product. These protocols led to triarylated azoles without a loss of efficiency compared to the corresponding previously reported stepwise syntheses via direct C-H bond arylation.

Full text of DOI:10.1021/jo301621t

Note
pubs.acs.org/joc
One-pot Sequential Direct C−H Bond Arylation of Azoles Catalyzed
by [Pd(phen)2](PF6)2: Synthetic Methods for Triarylated Azoles
Fumitoshi Shibahara,* Takayuki Yamauchi, Eiji Yamaguchi, and Toshiaki Murai*
Department of Chemistry, Faculty of Engineering, Gifu University, Yanagido, Gifu 501-1193, Japan
S
* Supporting Information
ABSTRACT: Synthetic methods for triarylated azoles containing three different aryl groups via one-pot sequential multiple C−
H bond arylations are described. The one-pot sequential diarylation of C5-monoarylated azoles was achieved by the simple
sequential addition of two different aryl iodides with a [Pd(phen)2]PF6 catalytic system. The one-pot triarylation of N-
methylimidazole was achieved by the combination of a previously reported Pd(OAc)2−P(2-furyl)3 system and the present
[Pd(phen)2]PF6 system. In this case, portionwise addition of aryl halide, base and the catalyst in the final step significantly
improved the overall yield of the desired triarylated product. These protocols led to triarylated azoles without a loss of efficiency
compared to the corresponding previously reported stepwise syntheses via direct C−H bond arylation.
olyarylated azole structures are frequent constituents of
natural products, functional materials, and pharmaceut-
envisioned the use of our catalytic system for the multiple C−H
bond arylation of azoles with different aryl iodides in one-pot as
a time-integration approach,8,9 which would make it possible to
avoid chromatographic purification in each step. Recently, we
reported the diarylation of the azole derivative imidazo[1,5-
a]pyridine with this one-pot multiple arylation strategy (eq
1).10 As a result, diarylation proceeded without a significant loss
P
icals, and their synthesis has been extensively studied for over a
century.1 Classically, such multifunctionalized azole derivatives
have been obtained by the condensation-cyclization of carbonyl
compounds and nitrogen-containing compounds,2 but these
methods require substrates in which the desired functional
groups are incorporated at the early stage of the synthesis.
Thus, the entire synthesis has to be repeated to obtain diverse
derivatives. In contrast, those with aryl groups can be directly
introduced to the parent azole frameworks in the late stage of
the synthesis by the cross-coupling reactions of organometallic
reagents and halides.3 These methods lead to a variety of
arylated azoles in a short step from common platforms.
However, some issues still remain, such as the generation and
stability of the corresponding azole metallic species.4 Mean-
while, direct C−H arylation has recently emerged as an
alternative to cross-coupling reactions since it does not require
labile azole metallic species.5,6 In this context, we have
developed multiple arylation reactions of azoles with aryl
halides catalyzed by Pd-phenanthroline complexes such as
[Pd(phen)2](PF6)2 (phen = 1,10-phenanthroline).7 This
reaction does not require stoichiometric amounts of organo-
metallic reagents. More importantly, the stepwise operation of a
similar catalytic reaction allows for the incorporation of three
different aryl groups at all three C−H bonds in azoles. We then
of efficiency compared to a conventional stepwise method. We
report here the further investigation of the one-pot sequential
multiple arylation of imidazoles, oxazole and thiazole.
Initially, the C2, C4-sequential one-pot diarylation of C5-
arylated N-methylimidazoles was carried out. The combination
that showed the best overall yield in our previous stepwise
synthesis of triarylated azoles (Scheme 1) was adopted for the
one-pot sequential arylation of 5-(4-trifluoromethylphenyl)-N-
Received: August 1, 2012
Published: September 13, 2012
© 2012 American Chemical Society
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Note
methoxyphenyl iodide (entries 3 and 4). The catalyst was likely
deactivated after 48 h in the first step, and the subsequent
second arylation scarcely proceeded (entry 5).
Scheme 1. Previous Example of the Stepwise Sequential
Arylation of N-Methylimidazole
With the results in hand, the scope of the one-pot diarylation
was then investigated (Table 2).11 Regioisomers 3a and 3b
Table 2. Examples of the One-pot Sequential Arylation of
a
C5-Arylated N-Methylimidazoles
methylimidazole with p-methoxyphenyl iodide and phenyl
iodide (Table 1).7b On the basis of the previous stepwise
Table 1. Optimization of the One-pot Sequential Arylation
of N-Methylimidazole
a
yield (%)
entry
X (equiv)
Y (mol %)
time (h)
3a
4
1
2
3
4
1
15
5
3.5
3.5
4
48
56
19
14
30
53
13
a
Isolated yields are indicated and formal average yields of the two
1.1
1.3
1.5
b
steps are shown in parentheses. The amount of Ar2−I: 3 equiv.
5
47
5
4
38
were selectively obtained by simply changing the order of the
addition of aryl iodides (entries 1 vs 2). Sterically hindered aryl
groups such as 2-methoxyphenyl and 1-naphthyl groups were
also allowed to couple at both the C2 and C4 positions under
identical conditions in a selective manner (entries 3−5). In
addition, a heteroaryl iodide, 4-pyridyl iodide, also coupled with
the imidazole under the one-pot reaction conditions without a
significant loss of efficiency (entry 6). It is noteworthy that
those products were also easily isolated by flash column
chromatography even if some byproducts formed.
This strategy could be applied to a substrate bearing a
different substituent on the amino nitrogen of imidazole. For
example, the one-pot sequential arylation of 5-phenyl-N-
benzylimidazole (5) with p-methoxyphenyl iodide and
trifluoromethylphenyl iodide gave the corresponding triarylated
imidazole 6 in 41% overall yield, although a slightly higher
catalyst loading was required (eq 2). In addition, the obtained 6
was readily debenzylated under conventional Pd/C-catalyzed
hydrogenolysis conditions to give the imidazole 7 in
quantitative yield (eq 3).
b
5
1.1
5
48
trace
a
b
Isolated yields. Monoarylated products containing PMP or phenyl at
the C2 position were obtained in respective yields of 54 and 19%.
conditions, 15 mol % (total amount of the two steps) of
[Pd(phen)2](PF6)2 and 3 equiv (excess amount for the two
reactions) of Cs2CO3 were initially used, and p-methoxyphenyl
iodide (1 equiv) and phenyl iodide (1.5 equiv) were added
sequentially to the reaction solution in this order. In the first
arylation, 1 was consumed within 3.5 h as confirmed by GC
analysis. After the first arylation was complete, phenyl iodide
was added to the reaction solution, and the mixture was stirred
for a further 20 h at that temperature to give the desired
imidazole 3a containing three different aryl groups, along with
bismethoxyphenylated imidazole 4, in respective yields of 48
and 19% (entry 1). Notably, 3a could be readily isolated by
conventional flash column chromatography on silica gel. The
yield of 3a improved with a lower catalyst loading (5 mol %)
probably due to suppression of a competitive over-reaction (C2
and C4 diarylation) in the first step (entry 2). Even in this case,
the yield of 4 significantly increased with a higher amount of p-
The one-pot sequential C2, C4-diarylation of oxazole and
thiazole was then investigated (Table 3). The first C2-arylation
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Note
affect the yield of products 9, perhaps due to deactivation of the
catalyst.
Finally, the one-pot triarylation of N-methylimidazole (11)
was investigated. In the first step, due to the high activity of the
catalyst [Pd(phen)2](PF6)2, further competitive C2 arylation
could not be avoided unless excess amount of N-methyl-
imidazole was used as we reported.7b Therefore, the first
monoarylation was carried out under Rossi’s conditions.12
Under these conditions, the substrate of N-methylimidazole
was completely consumed after 4 h, as confirmed by GC
analysis. As a first attempt, [Pd(phen)2](PF6)2 (5 mol %),
Cs2CO3 (3 equiv), and phenyl iodide (1.1 equiv) were added to
the reaction mixture based on the conditions for the previous
one-pot sequential diarylation (Table 2, entry 2). The resulting
mixture was stirred for 4 h at 150 °C, and p-methoxyphenyl
iodide (2 equiv) was then added to the reaction mixture. The
resulting mixture was stirred for a further 20 h, but this did not
lead to the formation of any of the desired product 3b (Table 4,
entry 1). Meanwhile, a small amount of 3b was obtained by
split additions of base in each step (total 2.5 equiv) and further
addition of the catalyst in the final step (entry 2). Finally, the
further portionwise addition of catalyst, halide, and base in the
final step improved the yield of 3b to 37% (average of each of
the three steps: 72%) (entry 3). This result was comparable to
the overall yield of 3b from N-methylimidazole with the
stepwise method (23−40%).7b
In conclusion, one-pot syntheses of triarylated azoles were
developed based on [Ph(phen)2](PF6)2-catalyzed sequential
C−H bond arylation reactions. With these protocols, the
resulting overall yields were comparable to those in the
corresponding stepwise methods, and fewer chromatographic
purification steps are necessary. Therefore, the one-pot
protocols should be used as time- and cost-effective methods
for the synthesis of triarylated azoles. Also, these protocols may
be used as an attractive method for the high-throughput
synthesis of triarylated azoles since the final products can be
readily isolated by conventional chromatographic purification.
Table 3. One-pot Sequential Arylation of Oxazole and
Thiazole
EXPERIMENTAL SECTION
■
1
General. H NMR (400 MHz), 13C NMR (100 MHz) and 19F
NMR (376 MHz) spectra were recorded in CDCl3. Chemical shifts of
1H and 13C are reported in δ values with reference to tetramethylsilane
and CDCl3 as internal standards, respectively. The 19F chemical shifts
are expressed in δ values deshielded with respect to CF3COOH as an
external standard. The mass spectra (MS) and high-resolution mass
spectra (HRMS) were obtained by ionizing samples via electron
ionization (EI) in positive mode with a magnetic sector analyzer. All
reactions were carried out in an argon atmosphere.
a
yield (%)
entry
X
Y
Z
time1
time2
9
10
1
2
3
4
5
O
O
O
S
5
2
2
3
2
3
3
4
4
4
4
20
48
72
20
72
26
36
52
21
64
41
26
15
51
32
10
5
Materials. Unless otherwise noted, reagents were obtained
commercially and used without purification. DMA was distilled over
10
10
S
13
calcium hydride under reduced pressure. [Pd(phen)2](PF6)2 and 5-
a
Isolated yields.
(4-methoxy-6-naphth-2-yl)-N-methylimidazole (1b)7b were prepared
as described in the literature. Silica gel 60N (Spherical, Neutral, 40−50
mm) from Kanto Chemical Co., Inc. was used for flash column
chromatography.
of monoarylated azoles 8a and 8b with p-methoxyphenyl iodide
was complete within 4 h regardless of the catalyst loading, as in
the reaction of imidazoles. Meanwhile, longer reaction times
were required for sufficient conversion in the second arylation
in reactions of both substrates of azoles compared to that of N-
methylimidazole. For example, the yield of triarylated 9a
improved to 52% when the reaction time of the second
arylation was increased (entries 1−3). Similarly, the yield of 9b
reached 64% when the second reaction was carried out for 72 h
(entry 5). Further prolongation of the reaction time did not
General Procedure for the C5 Arylation of Azoles. DMA (0.5
M) was added to a screw-capped test tube and degassed by a freeze−
pump−thaw cycle (3 times). To this was added Pd(OAc)2 (5 mol %),
tri(2-furyl)phosphine (10 mol %), K2CO3 (1 equiv), azoles, and aryl
bromides (1 equiv). The resulting mixture was stirred overnight at 150
°C under an argon atmosphere. The reaction mixture was filtered
through a Celite pad and concentrated in vacuo. The residue was
purified by flash column chromatography on silica gel or by Kugelrohr
distillation to give C5-arylated azoles 1a, 5 and 8.
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Table 4. One-pot Sequential Triarylation of N-Methylimidazole 8
a
entry
conditions A
conditions B
yield (%)
1
2
Ph-I (1 equiv) [Pd(phen)2](PF6)2 (5 mol %) Cs2CO3 (3 equiv)
PMP-I (2 equiv)
N.D.
7
Ph-I (1 equiv) [Pd(phen)2](PF6)2 (5 mol %) Cs2CO3 (1 equiv) PMP-I (1.5 equiv) [Pd(phen)2](PF6)2 (5 mol %) Cs2CO3 (1.5 equiv)
b
3
Ph-I (1 equiv) [Pd(phen)2](PF6)2 (5 mol %) Cs2CO3 (1 equiv) PMP-I (3 equiv) [Pd(phen)2](PF6)2 (15 mol %) Cs2CO3 (3 equiv)
37
a
b
Isolated yields. In the final step, the catalyst, PMP-I, and Cs2CO3 were split into 6 portions, and the portions were added every 0.5 h.
N-Methyl-5-(4-trifluoromethylphenyl)imidazole (1a).7b Col-
orless oil (154 mg, 68% yield), Rf = 0.10 (CH2Cl2/MeOH = 100:1).
1H NMR (CDCl3) δ 3.71 (s, 3H), 7.18 (s, 1H), 7.52 (d, J = 8.3 Hz,
2H), 7.56 (s, 1H), 7.70 (d, J = 8.3 Hz, 2H).
145.6, 157.6, 158.4. MS (EI) m/z 420 (M+). HRMS (EI): Calcd for
C28H24N2O2 (M+) 420.1838, Found 420.1841.
5-(6-Methoxynaphth-2-yl)-2-(2-methoxyphenyl)-N-methyl-
4-(4-trifluoromethylphenyl)imidazole (3d) (Table 2, entry 4).
Yellow solid (42 mg, 34% yield), mp 88−89 °C, Rf = 0.68 (hexane/
EtOAc = 1:1). IR (KBr) 2924, 1617, 1493, 1325, 1251, 1165, 1122,
N-Benzyl-5-(4-trifluoromethylphenyl)imidazole (5).14 Yellow
1
solid (112 mg, 48% yield), Rf = 0.25 (CH2Cl2/MeOH = 100:3). H
1
1064 cm−1. H NMR (CDCl3) δ 3.34 (s, 3H), 3.89 (s, 3H), 3.96 (s,
NMR (CDCl3) δ 5.16 (s, 2H), 7.00−7.02 (m, 2H), 7.16 (s, 1H),
3H), 7.03 (d, J = 8.1 Hz, 2H), 7.11−7.15 (m, 1H), 7.21−7.23 (m,
3H), 7.38−7.44 (m, 3H), 7.66−7.71 (m, 2H), 7.76 (d, J = 9.4 Hz,
1H), 7.85 (d, J = 8.1 Hz, 2H). 13C NMR (CDCl3) δ 32.4, 55.5, 55.7,
105.9, 111.1, 114.3, 119.7, 121.2, 124.1 (q, J = 271.5 Hz), 125.1 (q, J =
3.8 Hz), 125.7, 126.8, 127.9, 127.9 (q, J = 32.0 Hz), 128.6, 129.0,
129.8, 130.0, 131.1, 131.4, 132.8, 134.6, 135.9, 138.0, 146.0, 157.6,
158.7. 19F NMR (CDCl3) δ −58.7. MS (EI) m/z 488 (M+). HRMS
(EI): Calcd for C29H23F3N2O2 (M+) 488.1712, Found 488.1707.
2-(4-Methoxyphenyl)-N-methyl-4-(naphth-1-yl)-5-(4-
trifluoromethylphenyl)imidazole (3e) (Table 2, entry 5).
Colorless solid (35 mg, 31% yield), mp 93−94 °C, Rf = 0.18
(hexane/EtOAc = 1:4). IR (KBr) 2936, 2360, 1613, 1455, 1323, 1252,
1168, 1122 cm−1. 1H NMR (CDCl3) δ 3.71 (s, 3H), 3.87 (s, 3H), 7.03
(d, J = 8.5 Hz, 2H), 7.30−7.33 (m, 2H), 7.33 (d, J = 8.1 Hz, 2H),
7.41−7.45 (m, 2H), 7.50 (d, J = 8.1 Hz, 2H), 7.76−7.78 (m, 3H),
7.81−7.84 (dd, J = 6.8 Hz, 1.8 Hz, 1H), 8.20 (d, J = 8.2 Hz, 1H). 13C
NMR (CDCl3) δ 34.2, 55.5, 114.1, 124.1 (q, J = 272.1 Hz), 123.0,
125.3, 125.6 (q, J = 3.8 Hz), 125.7, 126.0, 126.6, 128.1, 128.2, 128.6,
129.5 (q, J = 32.3 Hz), 130.2, 130.6, 130.9, 132.0, 132.6, 134.0, 134.3,
139.0, 149.0, 160.3. 19F NMR (CDCl3) δ −59.0. MS (EI) m/z 458
(M+). HRMS (EI): Calcd for C28H21F3N2O (M+) 458.1606, Found
458.1602.
7.26−7.33 (m, 5H), 7.35−7.39 (m, 3H), 7.73 (s, 1H).
5-(4-Trifluoromethylphenyl)oxazole (8a).15 Colorless solid (62
mg, 29% yield), Rf = 0.45 (hexane/EtOAc = 4:1). 1H NMR (CDCl3) δ
7.47 (s, 1H), 7.69 (d, J = 8.3 Hz, 2H), 7.78 (d, J = 8.3 Hz, 2H), 7.98
(s, 1H).
5-(4-Trifluoromethylphenyl)thiazole (8b).16 Yellow solid (108
mg, 47% yield), Rf = 0.60 (hexane/EtOAc = 4:1). 1H NMR (CDCl3) δ
7.66 (d, J = 8.9 Hz, 2H), 7.69 (d, J = 8.9 Hz, 2H), 8.15 (s, 1H), 8.83
(s, 1H).
General Procedure for the One-pot Sequential Direct
Diarylation of C5-Arylated Azoles (Tables 2 and 3, eq 2).
DMA (0.5 M) was added to a screw-capped test tube and degassed by
a freeze−pump−thaw cycle (3 times). To this was added [Pd-
(phen)2](PF6)2 (5−10 mol %), Cs2CO3 (3 equiv), C5-arylated azoles
(0.25 mmol), and aryl iodide (1.1 equiv). The reaction mixture was
stirred for 3−5 h at 150 °C under an argon atmosphere and monitored
by GC and TLC analysis. After the reaction was complete, the mixture
was cooled to room temperature. To the resulting mixture was added
another aryl iodide (2−3 equiv), and this was stirred for 20−72 h at
150 °C under an argon atmosphere. The reaction mixture was filtered
through a Celite pad and concentrated in vacuo. The residue was
purified by flash column chromatography on silica gel to give the 2,4-
diarylated products 3, 6 and 9 and 2-monoarylated products 10.
2-(4-Methoxyphenyl)-N-methyl-4-phenyl-5-(4-
trifluoromethylphenyl)imidazole (3a)7b (Table 1, entry 1).
Colorless solid (57 mg, 56% yield), Rf = 0.45 (hexane/EtOAc =
1:1). 1H NMR (CDCl3) δ 3.51 (s, 3H), 3.88 (s, 3H), 7.04 (d, J = 8.8
Hz, 2H), 7.19−7.25 (m, 3H), 7.51 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 7.8
Hz, 2H), 7.68 (d, J = 8.8 Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H).
4-(4-Methoxyphenyl)-N-methyl-2-phenyl-5-(4-
trifluoromethylphenyl)imidazole (3b)7b (Table 2, entry 2).
Yellow solid (37 mg, 36% yield), Rf = 0.45 (hexane/EtOAc = 1:1).
1H NMR (CDCl3) δ 3.53 (s, 3H), 3.79 (s, 3H), 6.79 (d, J = 8.9 Hz,
2-(4-Methoxyphenyl)-N-methyl-4-pyridyl-5-(4-
trifluoromethylphenyl)imidazole (3f) (Table 2, entry 6). Yellow
solid (52 mg, 51% yield), mp 178−179 °C, Rf = 0.10 (hexane/EtOAc
1
= 1:2), IR (KBr) 2923, 1600, 1332, 1255, 1121, 1072, 830 cm−1. H
NMR (CDCl3) 3.48 (s, 3H), 3.87 (s, 3H), 7.03 (d, J = 8.6 Hz, 2H),
7.34 (d, J = 6.3 Hz, 2H), 7.55 (d, 8.1 Hz, 2H), 7.64 (d, 8.6 Hz, 2H),
7.78 (d, J = 8.1 Hz, 2H), 8.42 (d, 6.3 Hz, 2H). 13C NMR (CDCl3)
33.3, 55.4, 114.2, 121.1, 122.2, 123.8 (q, J = 271.8 Hz), 126.4 (q, J =
3.3 Hz), 130.4, 130.7, 131.4 (q, J = 33.0 Hz), 131.6, 134.0, 134.9,
143.3, 148.0, 149.4, 160.5. 19F NMR (CDCl3) −59.1. MS (EI) m/z
409 (M+). HRMS(EI): Calcd for C23H18F3N3O (M+) 409.1402,
Found 409.1401.
2H), 7.45−7.48 (m, 5H), 7.50 (d, J = 8.1 Hz, 2H), 7.70 (d, J = 8.1 Hz,
2H), 7.83 (br, 2H).
N-Benzyl-2-(4-methoxyphenyl)-4-(4-trifluoromethylphenyl)-
5-phenylimidazole (6) (eq 2). Colorless solid (50 mg, 41% yield),
mp 134−136 °C, Rf = 0.18 (hexane/EtOAc = 4:1), IR (KBr) 2930,
5-(6-Methoxynaphth-2-yl)-2-(2-methoxyphenyl)-N-methyl-
4-phenylimidazole (3c) (Table 2, entry 3). Yellow solid (51 mg,
48% yield), mp 87−88 °C, Rf = 0.15 (hexane/EtOAc = 4:1), IR (KBr)
2933, 1606, 1496, 1469, 1387, 1251, 1023, 909, 759, 726, 697 cm−1.
1H NMR (CDCl3) δ 3.35 (s, 3H), 3.90 (s, 3H), 3.97 (s, 3H), 7.02 (d, J
= 8.5 Hz, 1H), 7.10−7.22 (m, 6H), 7.46−7.50 (m, 2H), 7.60 (d, J =
7.2 Hz, 2H), 7.67 (d, J = 7.1 Hz, 1H), 7.77 (d, J = 9.4 Hz, 1H), 7.84
(d, J = 8.5 Hz, 1H), 7.87 (s, 1H). 13C NMR (CDCl3) 32.4, 55.5, 55.7,
105.8, 111.0, 121.1, 126.3, 126.4, 126.7, 127.0, 127.4, 127.6, 128.1,
128.3, 128.5, 128.6, 128.8, 129.1, 129.8, 129.9, 131.1, 132.8, 134.4,
1
1616, 1577, 1251, 1162, 1120, 1065 cm−1. H NMR (CDCl3) δ 3.83
(s, 3H), 5.09 (s, 2H), 6.79−6.82 (m, 2H), 6.93 (d, J = 8.8 Hz, 2H)
7.18−7.23 (m, 5H), 7.32−7.41 (m, 3H) 7. 44 (d, J = 8.3 Hz, 2H), 7.58
(d, J = 8.8 Hz, 2H), 7.66 (d J = 8.3 Hz, 2H). 13C NMR (CDCl3) δ
48.2, 55.3, 114.1, 122.9, 124.4 (q, J = 271.8 Hz), 125.0 (q, J = 4.1 Hz),
125.9, 126.5, 127.4, 127.9 (q, J = 32.2 Hz), 128.6, 128.9, 129.0, 130.4,
130.6, 130.9, 131.0, 136.4, 137.3, 138.0, 148.3, 160.2. 19F NMR
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Note
(CDCl3) δ −58.7. HRMS (EI): m/z 484 (M+) Calcd for
[Pd(phen)2](PF6)2 (15 mol %) were split into 6 portions, respectively,
and added portionwise to the reaction mixture every 0.5 h at 150 °C.
The resulting mixture was stirred at that temperature for 20 h under an
argon atmosphere. The reaction mixture was filtered through a Celite
pad and concentrated in vacuo. The residue was purified by flash
column chromatography on silica gel (hexane/EtOAc = 10:1) to give
N-methyl-4-(4-methoxyphenyl)-2-phenyl-5-(4-trifluoromethylphenyl)-
imidazole (3b) in 37% yield (151 mg).
C30H23F3N2O (M+) 484.1762, Found 484.1766.
2-(4-Methoxyphenyl)-4-phenyl-5-(4-trifluoromethylphenyl)-
oxazole (9a) (Table 3, entry 3). Colorless solid (51 mg, 52% yield),
mp 130−131 °C, Rf = 0.18 (hexane/EtOAc = 1:4). IR (KBr) 2360,
1615, 1500, 1326, 1257, 1169, 839 cm−1. 1H NMR (CDCl3) δ 3.88 (s,
3H), 7.00 (d, J = 8.9 Hz, 2H), 7.39−7.45 (m, 3H), 7.60 (d, J = 8.1 Hz,
2H), 7.67−7.69 (m, 2H), 7.75 (d, J = 8.1 Hz, 2H), 8.10 (d, J = 8.9 Hz,
2H). 13C NMR (CDCl3) δ 55.4, 114.2, 119.6, 125.3 (q, J = 271.8 Hz),
125.6 (q, J = 4.1 Hz), 126.1, 128.3, 128.3, 128.7, 128.8, 129.8 (q, J =
32.3 Hz), 132.2, 132.4, 138.4, 143.4, 160.9, 161.6. 19F NMR (CDCl3)
δ −63.1. MS (EI) m/z 395 (M+). HRMS (EI): Calcd for
C23H16F3NO2 (M+) 395.1133, Found 395.1123.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
1
Copies of H and 13C NMR for novel compounds and H
NMR for known compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
2-(4-Methoxyphenyl)-5-(4-trifluoromethylphenyl)oxazole
(10a)17 (Table 3, entry 3). Colorless solid (12 mg, 15% yield), Rf =
1
0.11 (hexane/EtOAc = 20:1). H NMR (CDCl3) 3.88 (s, 3H), 7.00
(d, J = 9.0 Hz, 2H), 7.51 (s, 1H), 7.68 (d, J = 8.1 Hz, 2H), 7.80 (d, J =
8.1 Hz, 2H), 8.07 (d, J = 9.0 Hz, 2H).
AUTHOR INFORMATION
Corresponding Author
*fshiba@gifu-u.ac.jp; mtoshi@gifu-u.ac.jp
Notes
■
2-(4-Methoxyphenyl)-4-phenyl-5-(4-trifluoromethylphenyl)-
thiazole (9b) (Table 3, entry 5). Yellow solid (66 mg, 64% yield),
mp 105−107 °C, Rf = 0.63 (hexane/EtOAc = 4:1). IR (KBr) 1605,
1
1326, 1257, 1169, 1119, 1070, 826, 699 cm−1. H NMR (CDCl3) δ
The authors declare no competing financial interest.
3.87 (s, 3H), 6.97 (d, J = 8.8 Hz, 2H), 7.33−7.35 (m, 3H), 7.49 (d, J =
8.3 Hz, 2H), 7.55−7.57 (m, 4H), 7.96 (d, J = 8.8 Hz, 2H). 13C NMR
(CDCl3) δ 55.4, 114.3, 124.0 (q, J = 271.8 Hz), 125.7 (q, J = 4.1 Hz),
126.3, 128.0, 128.2, 128.5, 129.2, 129.7, 129.8 (q, J = 32.2 Hz), 130.1,
134.6, 136.0, 151.7, 161.4, 166.3. 19F NMR (CDCl3) δ −59.0. MS (EI)
m/z 411 (M+). HRMS (EI): Calcd for C23H16F3NOS (M+) 411.0905,
Found 411.0890.
ACKNOWLEDGMENTS
■
This work was partly supported by a Grants-in-Aid for Scientific
Research on Innovative Areas “Organic Synthesis based on
Reaction Integration. Development of New Methods and
Creation of New Substances” (No. 2105) from MEXT.
2-(4-Methoxyphenyl)-5-(4-trifluoromethylphenyl)thiazole
(10b) (Table 3, entry 5). Orange solid (27 mg, 32% yield), mp 160−
162 °C, Rf = 0.63 (hexane/EtOAc = 4:1). IR (KBr) 1603, 1438, 1330,
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Debenzylation of N-Benzyl-2-(4-methoxyphenyl)-4-(4-tri-
fluoromethylphenyl)-5-phenyl-imidazole (6) Leading to 2-(4-
Methoxyphenyl)-5-phenyl-4-(4-trifluoromethylphenyl)-1H-
imidazole 7 (eq 3). To a solution of 1-benzyl-2-(4-methoxyphenyl)-
4-(4-trifluoromethylphenyl)-5-phenylimidazole (6) (0.15 mmol) in
EtOH (1 mL) was added Pd/C (10 mol %). The suspension was
stirred overnight at 50 °C under a H2 atmosphere. The reaction
mixture was filtered through a Celite pad and concentrated in vacuo.
The residue was purified by flash column chromatography on silica gel
(hexane/EtOAc = 4:1) to give 2-(4-methoxyphenyl)-5-phenyl-4-(4-
trifluoromethylphenyl)-1H-imidazole 7 in quantitative yield (59 mg).
Yellow solid, mp 187−188 °C, Rf = 0.25 (hexane/EtOAc = 4:1), IR
(KBr) 1614, 1469, 1410, 1250, 1163, 1118, 1065, 1021, 849 cm−1. 1H
NMR (CDCl3) δ 3.83 (s, 3H), 6.96 (d, J = 8.5 Hz, 2H), 7.35−7.40 (m,
3H), 7.48 (d, J = 7.6 Hz, 2H), 7.54 (d, J = 8.1 Hz, 2H), 7.71 (d, J = 7.6
Hz, 2H), 7.88 (d, J = 8.1 Hz, 2H). 13C NMR (CDCl3) δ 55.4, 114.4,
120.7, 124.2 (q, J = 271.5 Hz), 125.3 (q, J = 3.7 Hz), 127.8, 128.0,
128.3, 128.5, 128.9, 129.3 (q, J = 32.8 Hz), 129.8, 130.4, 132.4, 135.7,
146.3, 161.0. 19F NMR (CDCl3) δ −62.8. MS (EI) m/z 394 (M+).
HRMS (EI): Calcd for C23H17F3N2O (M+) 394.1293, Found
394.1292.
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