N -heterocyclic carbene-palladium(II)-1-methylimidazole complex-catalyzed direct C-H bond arylation of (Benz)imidazoles with aryl chlorides

Article abstract of DOI:10.1021/jo5010058

(Benz)imidazoles can be efficiently functionalized by (hetero)aryl chlorides via direct C-H bond arylation in the presence of a well-defined NHC-Pd(II)-Im complex. Under the optimal conditions, various activated, unactivated, and deactivated (hetero)aryl chlorides were successfully applied as the arylating reagents to achieve the 2-(hetero)aryl (benz)imidazoles in acceptable to high yields, giving a facile and alternative methodology for the direct C-H bond arylation of (benz)imidazoles.

Full text of DOI:10.1021/jo5010058

Article
pubs.acs.org/joc
N‑Heterocyclic Carbene-Palladium(II)-1-Methylimidazole Complex-
Catalyzed Direct C−H Bond Arylation of (Benz)imidazoles with Aryl
Chlorides
Zheng-Song Gu,† Wen-Xin Chen,† and Li-Xiong Shao*,†,‡
†College of Chemistry and Materials Engineering, Wenzhou University, Chashan University Town, Wenzhou, Zhejiang Province
325035, People’s Republic of China
‡College of Chemistry and Life Sciences, Zhejiang Normal University, Jinhua, Zhejiang Province 321004, People’s Republic of China
S
* Supporting Information
ABSTRACT: (Benz)imidazoles can be efficiently functionalized
by (hetero)aryl chlorides via direct C−H bond arylation in the
presence of a well-defined NHC-Pd(II)-Im complex. Under the
optimal conditions, various activated, unactivated, and deactivated
(hetero)aryl chlorides were successfully applied as the arylating
reagents to achieve the 2-(hetero)aryl (benz)imidazoles in
acceptable to high yields, giving a facile and alternative method-
ology for the direct C−H bond arylation of (benz)imidazoles.
equiv) in the presence of NHC-Pd(II)-Im complex 1 (2.0 mol
%) under various conditions. For example, in the first round,
toluene/H2O (2.0 mL/0.5 equiv) was chosen as the solvents to
evaluate the effect of bases. The best result was achieved using
KOtBu as the base to give the desired product 4a in 89% yield
(Table 1, entry 6), while in the presence of other bases such as
K2CO3, KOH, K3PO4·3H2O, LiOtBu and NaOtBu, almost no
product could be detected (Table 1, entries 1−5). The
replacement of solvents from toluene/H2O to THF/H2O and
dioxane/H2O resulted in product 4a only being isolated in 48
and 40% yields, respectively (Table 1, entries 7 and 8). In
addition, in the presence of other solvents such as DMSO/
H2O, DMF/H2O, CH3CN/H2O and DME/H2O, no desired
product could be detected (Table 1, entries 9−12).
Furthermore, after careful investigations, it was found that the
amount of H2O dramatically affected the reaction. That is, the
introduction of 0.5 equiv of H2O was found to be necessary for
such transformation. For instance, only 18% yield of product 4a
was obtained when dry toluene was used as the solvent (Table
1, entry 13). When 1.0 equiv of H2O was added, a significantly
higher yield (84%) was achieved (Table 1, entry 14). However,
when the amount of H2O was increased to 3.0 equiv, the yield
of 4a drastically decreased to 5% (Table 1, entry 15). These
results thus encouraged us to further investigate the effect of
H2O.
INTRODUCTION
■
C2-arylated (benz)imidazoles are frequently found in various
pharmaceuticals, biologically active compounds and materials.1
Recently, the transition metal-catalyzed direct C−H bond
arylation of (benz)imidazoles has been noticed as a potentially
more efficient and convenient alternative for the straightfor-
ward synthesis of such compounds.2 However, during the past
years, the scope of the arylating reagents is limited to the more
active aryl iodides and bromides.3 To the best of our
knowledge, only very few examples on the palladium-catalyzed
direct C2-arylation of (benz)imidazoles using aryl chlorides in
the presence of phosphine ligands were reported to date,
despite their lower cost and more easy availability.4 Therefore,
despite that some progress has been made in the direct C2-
arylation of (benz)imidazoles, the research for efficient
methods using the more applicable, while less active, aryl
chlorides as the arylating reagents is still in great demand.5
Previously, we have reported that a well-defined N-heterocyclic
carbene-Pd(II)-1-methylimidazole [NHC-Pd(II)-Im] complex
1 can easily activate aryl chlorides in traditional C−C couplings
such as α-arylation of carbonyl compounds,6 Suzuki−Miyaura
coupling,7 Mizoroki−Heck reaction,8 Hiyama reaction9 and C−
N coupling.10 Furthermore, in a very recent communication, we
found that NHC-Pd(II)-Im complex 1 can also efficiently
catalyze the direct C−H bond arylation of (benzo)oxazoles
using aryl chlorides as the arylating reagents.11 These results
thus prompted us to further investigate its application in
activating aryl chlorides toward the direct C2-arylation of
(benz)imidazoles. Herein, we report these results in detail.
It is known that KOtBu will be partially hydrolyzed to KOH
and HOtBu under the above reaction conditions. Therefore,
three more control experiments were carried out: (1) the
combination of KOtBu (1.5 equiv), KOH (0.5 equiv) and
HOtBu (0.5 equiv) was introduced instead of KOtBu (2.0
RESULTS AND DISCUSSION
■
Initially, 1-methylbenzimidazole 2a (0.49 mmol) was chosen as
the model substrate for the reaction with chlorobenzene 3a (2.0
Received: May 9, 2014
© XXXX American Chemical Society
A
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substrates tested (Table 2). It seems that the substituents on
the aryl chlorides 3 affected the reactions to some extent. For
Table 1. Optimization for Complex 1 Catalyzed Direct C−H
Bond Arylation of 1-Methylbenzimidazole 2a with
Chlorobenzene 3a
Table 2. NHC-Pd(II)-Im 1 Catalyzed Direct C−H Bond
Arylation of 1-Methylbenzimidazole 2a with Aryl Chlorides
3
a
entry
solvent
base
K2CO3
yield (%)
1
toluene/H2O
toluene/H2O
toluene/H2O
toluene/H2O
toluene/H2O
toluene/H2O
THF/H2O
ND
ND
ND
ND
<5
2
KOH
3
K3PO43H2O
LiOtBu
NaOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
4
5
6
89
7
48
8
dioxane/H2O
DMSO/H2O
DMF/H2O
40
9
ND
ND
ND
ND
18
10
11
12
13
CH3CN/H2O
DME/H2O
toluene
b
a
14
c
toluene/H2O
toluene/H2O
84
If not otherwise specified, all reactions were carried out using 2a
(0.49 mmol), 3 (2.0 equiv), 1 (X mol %), KOtBu (2.0 equiv) in
toluene/H2O (2.0 mL/0.5 equiv) at 120 °C for 6 h. The temperature
15
5
b
a
If not otherwise specified, all reactions were carried out using 2a
was 130 °C.
(0.49 mmol), 3a (2.0 equiv), base (2.0 equiv), 1 (2.0 mol %) in
organic solvents (2.0 mL) and H2O (0.5 equiv) at 120 °C for 6 h.
b
c
H2O (1.0 equiv) was added. H2O (3.0 equiv) was added.
example, for the reaction involving sterically hindered 2-
methylphenyl chloride 3d, good yields are obtained by simply
increasing the catalyst loading, although only moderate yield
can be obtained under the optimal reaction conditions (Table
2, entries 3 and 4). For electron-rich aryl chlorides such as 4-
methoxyphenyl chloride 3e and 4-dimethylaminophenyl
chloride 3g, slightly higher catalyst loading or elevated
temperature is necessary for the achievement of higher yields
(Table 2, entries 5 and 6; entries 8 and 9). In addition,
heteroaryl chlorides such as 2-chloropyridine 3k and 2-
chlorothiophene 3l could be used, giving rise to the desired
products 4k and 4l in acceptable yields, respectively (Table 2,
entries 13 and 14).
equiv) and H2O (0.5 equiv), and product 4a was obtained in a
comparable yield (84%) (Table 1, entry 6 and Scheme 1, eq 1);
Scheme 1. Three Control Experiments
The reaction was further investigated using a variety of
benzimidazoles 2 and aryl chlorides 3 as the substrates under
the optimal conditions. As can be seen from Table 3, all 1-
methylbenzimidazoles 2, regardless of electron-rich substituents
such as 5,6-Me2 (2b), 5-Me (2c), 5-MeO (2e) or electron-poor
substituents such as 5-F (2d) attaching on the phenyl groups,
could react with aryl chlorides 3 smoothly to give the desired
C2-arylated products 4 in good to high yields (Table 3, entries
1−17). In addition, it seems that for the reactions involving
electron-poor 5-F-benzimidazole 2d, better yields can be
achieved under identical conditions (Table 3, entries 11−15).
1-Benzylbenzimidazole 2f was also suitable for this reaction to
give the corresponding products 4ad−4ag in good yields
(Table 3, entries 18−21).
(2) the combination of KOtBu (1.5 equiv) and HOtBu (0.5
equiv) was introduced, and product 4a was also formed in a
comparable yield (82%) (Table 1, entry 6 and Scheme 1, eq 2);
(3) the combination of KOtBu (1.0 equiv) and HOtBu (1.0
equiv) was introduced, and a similar yield of product 4a was
observed (84%) (Table 1, entry 14 and Scheme 1, eq 3). On
the basis of these results, although the real function of H2O was
unclear at this stage, it could be inferred that when a
combination of toluene and H2O was used as the solvent,
HOtBu derived from the hydrolysis of KOtBu might play an
important role in such transformation.12
We next explored the scope of the C2-arylation of 1-
methylbenzimidazole 2a with a variety of aryl chlorides 3 under
the identical optimal experimental conditions. Under the
suitable conditions, the procedure proved to be general on all
Encouraged by the above results using benzimidazoles as the
substrates, the optimal conditions were then expanded to the
B
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Table 3. NHC-Pd(II)-Im 1 Catalyzed Direct C−H Bond
Arylation of Benzimidazoles 2 with Aryl Chlorides 3
Table 4. NHC-Pd(II)-Im 1 Catalyzed Direct C−H Bond
Arylation of 1-Methylimidazole 5 with Aryl Chlorides 3
a
entry
3 (R1)
3a (H)
[X]
t (°C)
yield (%)
a
entry
2 (R2/R3)
3 (R1)
3a (H)
yield (%)
1
2
3
4
5
6
2
3
3
4
4
3
120
140
130
140
140
130
4ah, 86
4ai, 99
4aj, 97
4ak, 74
4al, 84
4am, 87
1
2
2b (5,6-Me2/Me)
4m, 87
4n, 84
4o, 82
4p, 86
4q, 84
4r, 86
3b (4-Me)
3c (3-Me)
3d (2-Me)
3i (4-F)
2b
3b (4-Me)
b
3
2b
3e (4-OMe)
4
2b
3i (4-F)
b
5
2b
3j (4-vinyl)
3j (4-vinyl)
6
7
2c (5-Me/Me)
3a
3b
3e
3i
a
All reactions were carried out using 5 (2.0 equiv), 3 (0.75 mmol),
2c
4s, 85
KOtBu (2.0 equiv), 1 (X mol %) in toluene/H2O (2.0 mL/0.5 equiv)
b
8
2c
4t, 84
for 12 h.
9
2c
4u, 88
4v, 86
4w, 97
4x, 96
4y, 86
4z, 96
4aa, 88
4ab, 86
4ac, 84
4ad, 84
4ae, 85
4af, 82
4ag, 84
b
10
2c
3j
11
12
13
14
15
16
17
18
19
2d (5-F/Me)
3a
3b
3e
3i
arylated products in good to high yields.13 For instance, both
substrates bearing electron-rich, -neutral, and -poor substituents
are tolerated in such transformation. The NHC-Pd(II) complex
catalyzed direct C−H bond arylation between (benz)imidazoles
and aryl chlorides reported in this paper will become a good,
economical, and efficient supplement to the traditional
methods for the formation of 2-aryl (benz)imidazoles.
2d
2d
2d
2d
3j
2e (5-OMe/Me)
3a
3b
3a
3b
3e
3j
2e
2f (H/benzyl)
2f
2f
2f
b
EXPERIMENTAL SECTION
20
■
21
General Remarks. Melting points are uncorrected. NMR spectra
were recorded at 300/500 (for H NMR) or 75/125 MHz (for 13C
1
a
If not otherwise specified, all reactions were carried out using 2a
NMR), respectively. 1H NMR and 13C NMR spectra recorded in
CDCl3 solutions were referenced to TMS (0.00 ppm) and the residual
solvent peak (77.0 ppm), respectively. J-values are in Hz. Organic
solvents used were dried by standard methods. The mass analyzer type
for the high resolution mass spectra (HRMS, ESI) is quadrupole.
Other commercially obtained reagents were used without further
purification. Flash column chromatography was performed on silica
gel.
(0.49 mmol), 3 (2.0 equiv), 1 (2.0 mol %), KOtBu (2.0 equiv) in
b
toluene/H2O (2.0 mL/0.5 equiv) at 120 °C for 6 h. NHC-Pd(II)-Im
1 (3.0 mol %) was added.
reactions between 1-methylimidazole and aryl chlorides. It was
found that the ratio between two substrates dramatically
affected the reaction. For example, when the reaction between
1-methylimidazole (0.49 mmol) and chlorobenzene (2.0 equiv)
was carried out under the optimal conditions shown in Table 1,
entry 6, the desired C2-arylated product was obtained only in
29% yield, along with the 2,5-diarylated byproduct in 8% yield.
To our pleasure, subtly changing the ratio of the substrates will
result in exclusive C2-arylated selectivity. For instance, when
excess 1-methylimidazole (2.0 equiv) was used as the substrate,
the desired C2-arylated products could be achieved in good to
high yields as the sole product under the optimal conditions.
The results are shown in Table 4. It seems that substituents on
the aryl chlorides have some effect on the reaction. For
example, aryl chlorides having electron-rich groups such as 4-
Me (3b) and 3-Me (3c) gave better yields than that having
electron-neutral (3a) and electron-poor 4-F group (3i) (Table
4, entries 2 and 3 vs entries 1 and 5). In addition, 2-
methylphenyl chloride 3d gave inferior result (74%), maybe
partially due to its steric hindrance (Table 4, entry 4).
General Procedure for the NHC-Pd(II)-Im Complex 1
Catalyzed Reactions Between (Benz)imidazoles and Aryl
Chlorides. Under N2 atmosphere, KOtBu (0.98 mmol), NHC-
Pd(II)-Im complex 1 (0.0098 mmol), toluene (2.0 mL), H2O (0.245
mmol), benzimidazoles 2 (0.49 mmol) and aryl chlorides 3 (0.98
mmol) were successively added into a Schlenk reaction tube. The
mixture was stirred vigorously at 120 °C for 6 h. Then the solvent was
removed under reduced pressure, and the residue was purified by flash
chromatography (eluent: petroleum ether/ethyl acetate = 10:1 for
benzimidazole derivatives and 3:1 for imidazole derivatives) to give the
pure products 4.
Compound 4a:3j white solid (90.7 mg, 89%); H NMR (CDCl3,
1
300 MHz, TMS) δ 7.85−7.76 (m, 3H), 7.57−7.52 (m, 3H), 7.41−7.29
(m, 3H); 13C{H} NMR (CDCl3, 75 MHz) δ 153.7, 142.9, 136.5,
130.1, 129.7, 129.4, 128.6, 122.7, 122.4, 119.8, 109.6, 31.7.
Compound 4b:3j white solid (92.6 mg, 85%); H NMR (CDCl3,
1
300 MHz, TMS) δ 7.85−7.80 (m, 1H), 7.64 (d, J = 8.1 Hz, 2H),
7.36−7.25 (m, 5H), 3.80 (s, 3H), 2.42 (s, 3H); 13C{H} NMR (CDCl3,
75 MHz) δ 153.8, 142.8, 139.7, 136.4, 129.24, 129.17, 127.1, 122.5,
122.2, 119.5, 109.5, 31.5, 21.3.
Compound 4c:3j white solid (94.0 mg, 86%); H NMR (CDCl3,
1
CONCLUSIONS
■
500 MHz, TMS) δ 7.83−7.81 (m, 1H), 7.60 (s, 1H), 7.49 (d, J = 7.5
Hz, 1H), 7.37 (t, J = 7.5 Hz, 1H), 7.34−7.28 (m, 4H), 3.79 (s, 3H),
2.42 (s, 3H); 13C{H} NMR (CDCl3, 75 MHz) δ 153.8, 142.7, 138.5,
136.4, 130.4, 130.1, 129.9, 128.3, 126.2, 122.6, 122.3, 119.6, 109.5,
31.5, 21.3.
In conclusion, NHC-Pd(II)-Im complex, as the nonphosphine
complex, was first used as the catalyst in the direct C−H bond
arylation of (benz)imidazoles using the less expensive, less
active, and easily available aryl chlorides as the arylating
reagents. Under the optimal conditions, various (benz)-
imidazoles can react with kinds of activated, unactivated, and
deactivated aryl chlorides smoothly to give the desired C2-
Compound 4d:14 white solid (80.4 mg, 74%); H NMR (CDCl3,
1
500 MHz, TMS) δ 7.84−7.82 (m, 1H), 7.44−7.30 (m, 7H), 3.63 (s,
3H), 2.27 (s, 3H); 13C{H} NMR (CDCl3, 75 MHz) δ 153.7, 142.9,
C
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The Journal of Organic Chemistry
Article
137.9, 135.5, 130.4, 130.2, 129.9, 129.8, 125.7, 122.5, 122.2, 119.8,
109.4, 30.5, 19.6.
Compound 4o: white solid (107.0 mg, 82%); mp 147−148 °C; 1H
NMR (CDCl3, 300 MHz, TMS) δ 7.72 (d, J = 8.7 Hz, 2H), 7.56 (s,
1H), 7.13 (s, 1H), 7.01 (d, J = 8.7 Hz, 2H), 3.86 (s, 3H), 3.82 (s, 3H),
2.41 (s, 3H), 2.38 (s, 3H); 13C{H} NMR (CDCl3, 75 MHz) δ 160.6,
153.0, 141.5, 135.2, 131.6, 131.0, 130.7, 122.9, 119.6, 114.0, 109.7,
55.4, 31.6, 20.6, 20.3; HRMS (ESI) calcd for C17H19N2O [M + H]+
267.1492, found 267.1495; IR (neat) ν 1610, 1481, 1436, 1382, 1320,
1289, 1242, 1171, 1022, 875, 831, 792, 750, 717 cm−1.
Compound 4e:3j white solid (96.2 mg, 82%); H NMR (CDCl3,
1
300 MHz, TMS) δ 7.82−7.78 (m, 1H), 7.72 (d, J = 7.5 Hz, 2H),
7.40−7.29 (m, 3H), 7.05 (d, J = 7.5 Hz, 2H), 3.89 (s, 3H), 3.86 (s,
3H); 13C{H} NMR (CDCl3, 75 MHz) δ 160.6, 153.6, 142.8, 136.5,
130.7, 122.38, 122.37, 122.2, 119.4, 114.0, 109.4, 55.3, 31.6.
Compound 4f:15 white solid (96.8 mg, 83%); H NMR (CDCl3,
1
Compound 4p: white solid (107.0 mg, 86%); mp 172−173 °C; 1H
NMR (CDCl3, 300 MHz, TMS) δ 7.74−7.68 (m, 2H), 7.55 (s, 1H),
7.20−7.12 (m, 3H), 3.77 (s, 3H), 2.41 (s, 3H), 2.38 (s, 3H); 13C{H}
NMR (CDCl3, 75 MHz) δ 163.5 (d, JC−F = 248.8 Hz), 151.6, 140.6,
134.8, 132.2, 131.6, 131.3 (d, JC−F = 8.4 Hz), 130.2, 126.0, 123.5,
119.4, 115.7 (d, JC−F = 21.7 Hz), 109.9, 31.6, 28.8, 20.5, 20.2; MS
(ESI) 255 [M + H]+; HRMS (ESI) calcd for C16H15N2F [M + H]+
255.1292, found 255.1294; IR (neat) ν 1607, 1525, 1436, 1377, 1318,
1219, 1157, 1003, 837, 809, 730, 706, 674 cm−1.
500 MHz, TMS) δ 7.84−7.82 (m, 1H), 7.46−7.40 (m, 2H), 7.34−7.30
(m, 4H), 7.07−7.05 (m, 1H), 3.89 (s, 3H), 3.88 (s, 3H); 13C{H}
NMR (CDCl3, 75 MHz) δ 159.7, 153.6, 142.8, 136.5, 131.3, 129.6,
122.8, 122.4, 121.6, 119.8, 115.9, 114.6, 109.6, 55.4, 31.7.
Compound 4g:16 white solid (83.8 mg, 68%); H NMR (CDCl3,
1
500 MHz, TMS) δ 7.80 (dd, J = 6.0, 2.5 Hz, 1H), 7.69 (d, J = 9.0 Hz,
2H), 7.35 (dd, J = 6.0, 2.5 Hz, 1H), 7.36−7.27 (m, 2H), 6.81 (d, J =
9.0 Hz, 2H), 3.87 (s, 3H), 3.05 (s, 6H); 13C{H} NMR (CDCl3, 75
MHz) δ 154.6, 151.0, 143.0, 136.6, 130.3, 121.94, 121.91, 119.1, 117.2,
111.6, 109.2, 40.1, 31.7.
Compound 4q: white solid (107.9 mg, 84%); mp 142−143 °C; 1H
NMR (CDCl3, 300 MHz, TMS) δ 7.74 (d, J = 8.4 Hz, 2H), 7.58 (s,
1H), 7.53 (d, J = 8.4 Hz, 2H), 7.15 (s, 1H), 6.75 (dd, J = 17.4, 11.1 Hz,
1H), 5.85 (d, J = 17.4 Hz, 1H), 5.36 (d, J = 11.1 Hz, 1H), 3.84 (s, 3H),
2.41 (s, 3H), 2.38 (s, 3H); 13C{H} NMR (CDCl3, 75 MHz) δ 152.2,
140.7, 138.7, 136.0, 134.9, 132.1, 131.5, 129.4, 129.0, 126.3, 119.4,
115.2, 109.8, 31.7, 20.5, 20.2; MS (ESI) 263 [M + H]+; HRMS (ESI)
calcd for C18H19N2 [M + H]+ 263.1543, found 263.1545; IR (neat) ν
1627, 1461, 1382, 1323, 1143, 1059, 1008, 990, 903, 841, 761, 716,
686 cm−1.
1
Compound 4h: yellow liquid (107.2 mg, 87%); H NMR (CDCl3,
300 MHz, TMS) δ 7.86−7.80 (m, 1H), 7.39−7.28 (m, 4H), 7.12−7.11
(m, 1H), 7.01−6.97 (m, 1H), 6.87−6.83 (m, 1H), 3.84 (s, 3H), 3.01
(s, 6H); 13C{H} NMR (CDCl3, 75 MHz) δ 154.7, 150.6, 142.8, 136.5,
130.7, 129.0, 122.5, 122.2, 119.6, 117.2, 113.6, 113.4, 109.5, 40.5, 31.6;
MS (ESI) 252 [M + H]+; HRMS (ESI) calcd for C16H18N3 [M + H]+
252.1495, found 252.1506; IR (neat) ν 2363, 1607, 1483, 1436, 1348,
1284, 1242, 1126, 1062, 990, 956, 845, 776, 737, 695 cm−1.
Compound 4i:17 white solid (90.8 mg, 82%); H NMR (CDCl3,
1
1
Compound 4r: white solid (93.6 mg, 86%); mp 122−123 °C; H
500 MHz, TMS) δ 7.82−7.80 (m, 1H), 7.74 (dd, J = 8.5, 5.0 Hz, 2H),
7.38−7.29 (m, 3H), 7.21 (t, J = 8.5 Hz, 2H), 3.82 (s, 3H); 13C{H}
NMR (CDCl3, 125 MHz) δ 163.6 (d, JC−F = 249.0 Hz), 152.7, 142.8,
136.5, 131.3 (d, JC−F = 8.5 Hz), 130.2, 126.3 (d, JC−F = 3.1 Hz), 123.8,
122.8, 122.5, 119.8, 115.8 (d, JC−F = 21.6 Hz), 109.6, 31.6.
NMR (CDCl3, 500 MHz, TMS) δ 7.73−7.71 (m, 2H), 7.61 (s, 1H),
7.50−7.46 (m, 3H), 7.22 (d, J = 8.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H),
3.77 (s, 3H), 2.49 (s, 3H); 13C{H} NMR (CDCl3, 125 MHz) δ 153.3,
142.6, 134.4, 132.0, 129.8, 129.5, 129.2, 128.5, 124.2, 119.2, 109.1,
31.5, 21.4; MS (ESI) 223 [M + H]+; HRMS (ESI) calcd for C15H15N2
[M + H]+ 223.1230, found 223.1232; IR (neat) ν 1494, 1461, 1372,
1322, 1013, 927, 862, 793, 768, 743, 701, 675 cm−1.
1
Compound 4j: white solid (98.6 mg, 86%); mp 116−117 °C; H
NMR (CDCl3, 300 MHz, TMS) δ 7.84−7.81 (m, 1H), 7.71 (d, J = 8.1
Hz, 2H), 7.52 (d, J = 8.1 Hz, 2H), 7.35−7.27 (m, 3H), 6.75 (dd, J =
17.7, 10.8 Hz, 1H), 5.84 (d, J = 17.7 Hz, 1H), 5.34 (d, J = 10.8 Hz,
1H), 3.80 (s, 3H); 13C{H} NMR (CDCl3, 75 MHz) δ 153.1, 142.3,
138.8, 136.3, 135.9, 129.5, 128.9, 126.3, 122.8, 122.5, 119.4, 115.4,
109.6, 31.6; MS (ESI) 235 [M + H]+; HRMS (ESI) calcd for
C16H15N2 [M + H]+ 235.1230, found 235.1228; IR (neat) ν 1630,
1464, 1402, 1377, 1322, 1250, 993, 909, 851, 821, 760, 745, 738, 702
cm−1.
1
Compound 4s: white solid (98.4 mg, 85%); mp 118−119 °C; H
NMR (CDCl3, 300 MHz, TMS) δ 7.75 (d, J = 8.1 Hz, 2H), 7.60 (s,
1H), 7.31 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.1 Hz, 1H), 7.13 (d, J = 8.1
Hz, 1H), 3.81 (s, 3H), 2.49 (s, 3H), 2.42 (s, 3H); 13C{H} NMR
(CDCl3, 75 MHz) δ 153.3, 142.1, 140.0, 134.3, 132.3, 129.33, 129.26,
126.6, 124.3, 119.0, 109.1, 31.7, 21.5, 21.4; MS (ESI) 237 [M + H]+;
HRMS (ESI) calcd for C16H17N2 [M + H]+ 237.1386, found
237.1401; IR (neat) ν 1613, 1475, 1444, 1377, 1318, 1020, 878,
848, 821, 789, 747, 727 cm−1.
Compound 4k:18 white solid (57.5 mg, 56%); H NMR (CDCl3,
1
300 MHz, TMS) δ 8.69−8.67 (m, 1H), 8.38 (d, J = 8.1 Hz, 1H),
7.85−7.80 (m, 2H), 7.44−7.28 (m, 4H), 4.25 (s, 3H); 13C{H} NMR
(CDCl3, 75 MHz) δ 150.5, 150.2, 148.5, 142.3, 137.2, 136.8, 124.7,
123.7, 123.3, 122.6, 119.9, 109.9, 32.6.
1
Compound 4t: white solid (103.7 mg, 84%); mp 105−106 °C; H
NMR (CDCl3, 300 MHz, TMS) δ 7.66 (d, J = 8.7 Hz, 2H), 7.58 (s,
1H), 7.18 (d, J = 8.4 Hz, 1H), 7.08 (d, J = 8.1 Hz, 1H), 6.98 (d, J = 9.0
Hz, 2H), 3.82 (s, 3H), 3.74 (s, 3H), 2.48 (s, 3H); 13C{H} NMR
(CDCl3, 75 MHz) δ 160.6, 153.2, 142.5, 134.4, 131.9 130.6 123.8,
122.1, 118.9, 113.9, 108.9, 55.2, 31.5, 21.4; MS (ESI) 253 [M + H]+;
HRMS (ESI) calcd for C16H17N2O [M + H]+ 253.1335, found
253.1344; IR (neat) ν 1607, 1481, 1464, 1448, 1385, 1328, 1179,
1245, 1109, 833, 781, 763, 738, 682 cm−1.
Compound 4l:16 white solid (61.0 mg, 58%); H NMR (CDCl3,
1
300 MHz, TMS) δ 7.81−7.77 (m, 1H), 7.57−7.55 (m 1H), 7.51−7.49
(m, 1H), 7.35−7.26 (m, 3H), 7.19−7.16 (m, 1H), 3.94 (s, 3H);
13C{H} NMR (CDCl3, 75 MHz) δ 147.7, 142.6, 136.4, 132.3, 128.5,
127.9, 127.8, 122.9, 122.6, 119.6, 109.3, 31.6.
Compound 4m: white solid (100.6 mg, 87%); mp 171−172 °C; 1H
NMR (CDCl3, 300 MHz, TMS) δ 7.76−7.73 (m, 2H), 7.57 (s, 1H),
7.54−7.47 (m, 3H), 7.15 (s, 1H), 3.81 (s, 3H), 2.42 (s, 3H), 2.40 (s,
3H); 13C{H} NMR (CDCl3, 75 MHz) δ 152.9, 141.5, 135.2, 131.9,
131.2, 130.5, 129.4, 129.3, 128.6, 119.8, 109.8, 31.6, 20.6, 20.3; MS
(ESI) 237 [M + H]+; HRMS (ESI) calcd for C16H17N2 [M + H]+
237.1386, found 237.1402; IR (neat) ν 1601, 1534, 1438, 1381, 1318,
1176, 1020, 1000, 924, 846, 818, 771, 690 cm−1.
Compound 4u: white solid (103.4 mg, 88%); mp 129−130 °C; 1H
NMR (CDCl3, 300 MHz, TMS) δ 7.77−7.68 (m, 2H), 7.58 (s, 1H),
7.27−7.11 (m, 4H), 3.81 (s, 3H), 2.49 (s, 3H); 13C{H} NMR (CDCl3,
75 MHz) δ 163.6 (d, JC−F = 249.1 Hz), 152.3, 142.2, 134.3, 132.5,
131.4 (d, JC−F = 8.5 Hz), 125.8, 124.5, 123.5, 119.1, 115.8 (d, JC−F
=
21.7 Hz), 109.2, 31.6, 28.8, 21.5; MS (ESI) 241 [M + H]+; HRMS
(ESI) calcd for C15H14N2F [M + H]+ 241.1136, found 241.1132; IR
(neat) ν 1607, 1537, 1467, 1381, 1315, 1235, 1152, 838, 804, 791, 756,
733, 682 cm−1.
Compound 4n: white solid (103.0 mg, 84%); mp 122−123 °C; 1H
NMR (CDCl3, 300 MHz, TMS) δ 7.63 (d, J = 7.8 Hz, 2H), 7.57 (s,
1H), 7.29 (d, J = 7.8 Hz, 2H), 7.12 (s, 1H), 3.77 (s, 3H), 2.41 (s, 3H),
2.40 (s, 3H), 2.38 (s, 3H); 13C{H} NMR (CDCl3, 75 MHz) δ 152.7,
140.6, 139.7, 134.8, 131.9, 131.3, 129.25, 129.18, 126.9, 119.3, 109.8,
31.6, 21.3, 20.5, 20.2; MS (ESI) 251 [M + H]+; HRMS (ESI) calcd for
C17H19N2 [M + H]+ 251.1543, found 251.1552; IR (neat) ν 1604,
1478, 1461, 1377, 1323, 1180, 1140, 1107, 1014, 871, 850, 819, 729,
681 cm−1.
1
Compound 4v: white solid (104.5 mg, 86%); mp 121−122 °C; H
NMR (CDCl3, 300 MHz, TMS) δ 7.68 (d, J = 8.1 Hz, 2H), 7.60 (s,
1H), 7.49 (d, J = 8.1 Hz, 2H), 7.19 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 8.4
Hz, 1H), 6.73 (dd, J = 17.7, 10.8 Hz, 1H), 5.82 (d, J = 17.7 Hz, 1H),
5.32 (d, J = 10.8 Hz, 1H), 3.75 (s, 3H), 2.48 (s, 3H); 13C{H} NMR
(CDCl3, 75 MHz) δ 152.9, 142.6, 138.6, 135.9, 134.5, 132.0, 129.4,
129.0, 126.2, 124.2, 119.1, 115.2, 109.0, 31.6, 21.4; MS (ESI) 249 [M
+ H]+; HRMS (ESI) calcd for C17H17N2 [M + H]+ 249.1386, found
D
dx.doi.org/10.1021/jo5010058 | J. Org. Chem. XXXX, XXX, XXX−XXX

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249.1390; IR (neat) ν 1621, 1455, 1382, 1323, 1250, 1146, 1059,
1017, 985, 899, 843, 791, 739, 686 cm−1.
Compound 4ad:20 white solid (117.1 mg, 84%); 1H NMR (CDCl3,
300 MHz, TMS) δ 7.88 (d, J = 8.1 Hz, 1H), 7.68−7.66 (m, 2H),
7.44−7.38 (m, 3H), 7.31−7.23 (m, 4H), 7.20−7.15 (m, 2H), 7.06 (d, J
= 6.6 Hz, 2H), 5.40 (s, 2H); 13C{H} NMR (CDCl3, 75 MHz) δ 154.0,
143.0, 136.2, 136.0, 129.9, 129.8, 129.1, 128.9, 128.6, 127.6, 125.8,
122.9, 122.5, 119.8, 110.4, 48.2.
Compound 4w: white solid (107.5 mg, 97%); mp 102−103 °C; 1H
NMR (CDCl3, 300 MHz, TMS) δ 7.73−7.70 (m, 2H), 7.50−7.45 (m,
4H), 7.25−7.22 (m, 1H), 7.02 (td, J = 9.0, 2.4 Hz, 1H), 3.80 (s, 3H);
13C{H} NMR (CDCl3, 75 MHz) δ 159.4 (d, JC−F = 236.0 Hz), 154.8,
142.7 (d, JC−F = 12.6 Hz), 132.9, 129.9, 129.3 (d, JC−F = 19.1 Hz),
128.6, 111.1, 110.7, 109.9 (d, JC−F = 10.2 Hz), 105.1 (d, JC−F = 24.1
Hz), 31.7; MS (ESI) 227 [M + H]+; HRMS (ESI) calcd for
C14H12N2F [M + H]+ 227.0979, found 227.0976; IR (neat) ν 1621,
1593, 1489, 1472, 1424, 1374, 1326, 1143, 1020, 956, 900, 852, 791,
776, 751, 702 cm−1.
Compound 4ae:20 white solid (124.2 mg, 85%); 1H NMR (CDCl3,
300 MHz, TMS) δ 7.88 (d, J = 7.8 Hz, 1H), 7.58 (d, J = 7.8 Hz, 2H),
7.29−7.15 (m, 8H), 7.07 (d, J = 6.9 Hz, 2H), 5.41 (s, 2H), 2.38 (s,
3H); 13C{H} NMR (CDCl3, 75 MHz) δ 154.0, 142.5, 140.1, 136.2,
135.8, 129.4, 129.0, 128.9, 127.6, 126.6, 125.8, 122.9, 122.6, 119.6,
110.4, 48.3, 21.3.
Compound 4x: a white solid (113.0 mg, 96%); mp 117−118 °C; 1H
NMR (CDCl3, 300 MHz, TMS) δ 7.63 (d, J = 8.1 Hz, 2H), 7.47 (dd, J
= 9.3, 2.4 Hz, 1H), 7.33−7.25 (m, 3H), 7.04 (td, J = 9.3, 2.4 Hz, 1H),
3.83 (s, 3H), 2.43 (s, 3H); 13C{H} NMR (CDCl3, 75 MHz) δ 159.5
Compound 4af:20 white solid (126.2 mg, 82%); H NMR (CDCl3,
1
300 MHz, TMS) δ 7.86 (d, J = 8.1 Hz, 1H), 7.63 (d, J = 8.7 Hz, 2H),
7.34−7.25 (m, 4H), 7.23−7.15 (m, 2H), 7.10−7.07 (m, 2H), 6.97−
6.92 (m, 2H), 5.42 (s, 2H), 3.81 (s, 3H); 13C{H} NMR (CDCl3, 75
MHz) δ 160.9, 153.8, 142.4, 136.2, 135.8, 130.6, 129.0, 127.7, 125.8,
122.8, 122.7, 121.7, 119.4, 114.1, 110.3, 55.2, 48.3.
(d, JC−F = 236.3 Hz), 154.9, 142.4, 142.3, 140.4, 132.8, 129.3 (d, JC−F
=
14.7 Hz), 126.3, 111.2, 110.8, 110.0 (d, JC−F = 10.2 Hz), 105.0 (d, JC−F
= 24.2 Hz), 31.8, 21.4; MS (ESI) 241 [M + H]+; HRMS (ESI) calcd
for C15H14N2F [M + H]+ 241.1136, found 241.1147; IR (neat) ν 1618,
1593, 1483, 1430, 1382, 1326, 1242, 1124, 1014, 955, 855, 828, 803,
775, 734, 716 cm−1.
Compound 4ag: white solid (127.6 mg, 84%); mp 134−135 °C; 1H
NMR (CDCl3, 300 MHz, TMS) δ 7.90 (d, J = 7.8 Hz, 1H), 7.67 (d, J
= 7.2 Hz, 2H), 7.47 (d, J = 7.2 Hz, 2H), 7.30−7.08 (m, 8H), 6.73 (dd,
J = 17.4, 10.5 Hz, 1H), 5.82 (d, J = 17.4 Hz, 1H), 5.45 (s, 2H), 5.33 (d,
J = 10.5 Hz, 1H); 13C{H} NMR (CDCl3, 75 MHz) δ 153.5, 142.5,
138.9, 136.0, 135.81, 135.78, 129.2, 128.9, 128.7, 127.6, 126.4, 125.7,
123.0, 122.7, 119.6, 115.4, 110.4, 48.2; MS (ESI) 311 [M + H]+;
HRMS (ESI) calcd for C22H19N2 [M + H]+ 311.1543, found
311.1551; IR (neat) ν 1604, 1452, 1388, 1354, 1326, 1242, 1157,
1076, 980, 917, 854, 778, 761, 724, 716, 695 cm−1.
1
Compound 4y: white solid (107.9 mg, 86%); mp 105−106 °C; H
NMR (CDCl3, 300 MHz, TMS) δ 7.67 (d, J = 8.7 Hz, 2H), 7.44 (dd, J
= 9.0, 2.4 Hz, 1H), 7.23 (dd, J = 9.0, 4.5 Hz, 1H), 7.04−6.98 (m, 3H),
3.85 (s, 3H), 3.80 (s, 3H); 13C{H} NMR (CDCl3, 75 MHz) δ 160.9,
159.4 (d, JC−F = 235.7 Hz), 154.8, 142.6 (d, JC−F = 12.8 Hz), 132.8,
130.7, 121.6, 114.1, 110.8, 110.5, 109.8 (d, JC−F = 10.2 Hz), 104.9 (d,
JC−F = 24.1 Hz), 55.3, 31.8; MS (ESI) 257 [M + H]+; HRMS (ESI)
calcd for C15H14N2FO [M + H]+ 257.1085, found 257.1098; IR (neat)
ν 1610, 1481, 1436, 1334, 1292, 1242, 1183, 1115, 1020, 955, 844,
826, 796, 778, 741, 716 cm−1.
Compound 4ah:21 colorless liquid (101.9 mg, 86%); 1H NMR (500
MHz, CDCl3, TMS) δ 7.62 (d, J = 8.0 Hz, 2H), 7.45−7.38 (m, 3H),
7.11 (s, 1H), 6.95 (s, 1H), 3.72 (s, 3H); 13C{H} NMR (125 MHz,
CDCl3) δ 147.7, 130.5, 128.5, 128.45, 128.36, 128.3, 122.2, 34.3.
Compound 4ai:22 colorless liquid (127.8 mg, 99%); 1H NMR (500
MHz, CDCl3, TMS) δ 7.52 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 8.0 Hz,
2H), 7.10 (d, J = 0.9 Hz, 1H), 6.95 (d, J = 0.9 Hz, 1H), 3.73 (s, 3H),
2.40 (s, 3H); 13C{H} NMR (125 MHz, CDCl3) δ 147.9, 138.4, 129.1,
128.4, 128.2, 127.7, 122.0, 34.6, 21.2.
Compound 4z: a white solid (114.8 mg, 96%); mp 124−125 °C; 1H
NMR (CDCl3, 300 MHz, TMS) δ 7.73 (dd, J = 8.4, 5.4 Hz, 2H), 7.45
(dd, J = 9.3, 2.4 Hz, 1H), 7.29−7.18 (m, 3H), 7.04 (td, J = 9.3, 2.4 Hz,
1H), 3.82 (s, 3H); 13C{H} NMR (CDCl3, 75 MHz) δ 163.7 (d, JC−F
=
249.6 Hz), 159.5 (d, JC−F = 236.3 Hz), 153.9, 142.6 (d, JC−F = 12.8
Hz), 132.8, 131.3 (d, JC−F = 8.5 Hz), 130.2, 125.6 (d, JC−F = 3.2 Hz),
115.9 (d, JC−F = 21.8 Hz), 111.3, 111.0, 110.0 (d, JC−F = 10.1 Hz),
105.1 (d, JC−F = 24.1 Hz), 31.7; MS (ESI) 245 [M + H]+; HRMS
(ESI) calcd for C14H11N2F2 [M + H]+ 245.0885, found 245.0895; IR
(neat) ν 1587, 1483, 1430, 1388, 1326, 1233, 1155, 1121, 1090, 961,
850, 803, 733 cm−1.
Compound 4aj:23 colorless liquid (125.1 mg, 97%); 1H NMR (500
MHz, CDCl3, TMS) δ 7.47 (s, 1H), 7.38 (d, J = 7.5 Hz, 1H), 7.32 (t, J
= 7.5 Hz, 1H), 7.20 (d, J = 7.5 Hz, 1H), 7.10 (d, J = 1.5 Hz, 1H), 6.93
(d, J = 1.5 Hz, 1H), 3.71 (s, 3H), 2.39 (s, 3H); 13C{H} NMR (125
MHz, CDCl3) δ 147.8, 138.1, 130.3, 129.3, 129.2, 128.11, 128.10,
125.3, 122.1, 34.3, 21.2.
Compound 4aa: white solid (108.8 mg, 88%); mp 144−145 °C; 1H
NMR (CDCl3, 300 MHz, TMS) δ 7.74 (d, J = 7.8 Hz, 2H), 7.54 (d, J
= 7.8 Hz, 2H), 7.47 (d, J = 9.0 Hz, 1H), 7.31 (dd, J = 9.0, 4.5 Hz, 1H),
7.08 (t, J = 9.0 Hz, 1H), 6.77 (dd, J = 17.4, 10.8 Hz, 1H), 5.87 (d, J =
17.7 Hz, 1H), 5.38 (d, J = 10.8 Hz, 1H), 3.88 (s, 3H); 13C{H} NMR
(CDCl3, 75 MHz) δ 159.4 (d, JC−F = 236.2 Hz), 154.5, 142.7 (d, JC−F
= 12.8 Hz), 139.0, 135.8, 132.9, 129.4, 128.6, 126.4, 115.5, 111.0 (d,
JC−F = 26.0 Hz), 109.9 (d, JC−F = 10.3 Hz), 105.1 (d, JC−F = 24.1 Hz),
31.8; MS (ESI) 252 [M + H]+; HRMS (ESI) calcd for C16H14N2F [M
+ H]+ 253.1136, found 253.1150; IR (neat) ν 1624, 1481, 1438, 1405,
1326, 1273, 1143, 1000, 959, 909, 895, 851, 803, 738, 712 cm−1.
Compound 4ab:19 white solid (100.4 mg, 86%); 1H NMR (CDCl3,
300 MHz, TMS) δ 7.75−7.72 (m, 2H), 7.53−7.47 (m, 3H), 7.31 (d, J
= 2.1 Hz, 1H), 7.23 (d, J = 8.7 Hz, 1H), 6.95 (dd, J = 9.0, 5.4 Hz, 1H),
3.86 (s, 3H), 3.80 (s, 3H); 13C{H} NMR (CDCl3, 75 MHz) δ 156.4,
153.5, 142.9, 130.9, 129.7, 129.6, 129.2, 128.6, 112.9, 110.0, 101.5,
55.7, 31.6.
1
Compound 4ak: colorless liquid (95.5 mg, 74%); H NMR (500
MHz, CDCl3, TMS) δ 7.34−7.24 (m, 4H), 7.13 (s, 1H), 6.97 (s, 1H),
3.47 (s, 3H), 2.22 (s, 3H); 13C{H} NMR (125 MHz, CDCl3) δ 147.6,
138.2, 130.3, 130.22, 130.18, 129.1, 128.0, 125.4, 120.4, 33.2, 19.5; MS
(ESI) 173 [M + H]+; HRMS (ESI) calcd for C11H13N2 [M + H]+
173.1073, found 173.1088; IR (neat) ν 1623, 1557, 1471, 1401, 1338,
1282, 1143, 1116, 1013, 987, 914, 906, 844, 791, 750, 717, 685 cm−1.
Compound 4al:24 colorless liquid (110.8 mg, 84%); 1H NMR (500
MHz, CDCl3, TMS) δ 7.60 (dd, J = 8.5, 5.5 Hz, 2H), 7.14 (t, J = 8.5
Hz, 2H), 7.10 (d, J = 1.0 Hz, 1H), 6.96 (d, J = 1.0 Hz, 1H), 3.72 (s,
3H); 13C{H} NMR (125 MHz, CDCl3) δ 162.9 (d, JC−F = 247.1 Hz),
146.9, 130.5 (d, JC−F = 8.3 Hz), 128.3, 126.8 (d, JC−F = 3.3 Hz), 122.3,
115.5 (d, JC−F = 21.6 Hz), 34.3.
1
Compound 4am: colorless liquid (120.0 mg, 87%); H NMR (500
Compound 4ac: white solid (103.7 mg, 84%); mp 100−101 °C; 1H
NMR (CDCl3, 300 MHz, TMS) δ 7.63 (d, J = 8.1 Hz, 2H), 7.32−7.30
(m, 3H), 7.23 (d, J = 8.7 Hz, 1H), 6.95 (dd, J = 8.7, 2.4 Hz, 1H), 3.87
(s, 3H), 3.80 (s, 3H), 2.43 (s, 3H); 13C{H} NMR (CDCl3, 75 MHz) δ
156.3, 153.9, 143.4, 139.7, 131.2, 129.3, 129.1, 127.2, 112.6, 109.8,
101.7, 55.8, 31.7, 21.3; MS (ESI) 253 [M + H]+; HRMS (ESI) calcd
for C16H17N2O [M + H]+ 253.1335, found 253.1351; IR (neat) ν
1618, 1590, 1486, 1433, 1377, 1332, 1273, 1194, 1160, 1028, 948, 826,
798, 729, 713 cm−1.
MHz, CDCl3, TMS) δ 7.60 (d, J = 8.5 Hz, 2H), 7.48 (d, J = 8.5 Hz,
2H), 7.11 (d, J = 1.0 Hz, 1H), 6.94 (d, J = 1.0 Hz, 1H), 6.74 (dd, J =
18.0, 10.5 Hz, 1H), 5.81 (dd, J = 18.0, 0.5 Hz, 1H), 5.30 (dd, J = 10.5,
0.5 Hz, 1H), 3.72 (s, 3H); 13C{H} NMR (125 MHz, CDCl3) δ 147.4,
137.5, 136.1, 129.8, 128.5, 128.3, 126.1, 122.4, 114.6, 34.4; MS (ESI)
185 [M + H]+; HRMS (ESI) calcd for C12H13N2 [M + H]+ 185.1073,
found 185.1083; IR (neat) ν 1600, 1504, 1467, 1454, 1338, 1275,
1129, 1017, 949, 914, 846, 804, 778, 727, 692 cm−1.
E
dx.doi.org/10.1021/jo5010058 | J. Org. Chem. XXXX, XXX, XXX−XXX

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Article
C.; Wiedemann, S. H.; Bergman, R. G.; Ellman, J. A. Org. Lett. 2004, 6,
35−38.
ASSOCIATED CONTENT
■
S
* Supporting Information
(4) (a) Chiong, H. A.; Daugulis, O. Org. Lett. 2007, 9, 1449−1451.
(b) Liu, B.; Wang, Z.; Wu, N.-J.; Li, M.-L.; You, J.-S.; Lan, J.-B.
Chem.Eur. J. 2012, 18, 1599−1603.
1
Copy of H and 13C NMR spectra of compounds 4. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(5) In 2011, Lee and co-workers reported the direct C5-arylation of
imidazoles with aryl chlorides by Pd complexes bearing phosphines
and N-heterocyclic carbenes; please see: Vijaya Kumar, P.; Lin, W.-S.;
Shen, J.-S.; Nandi, D.; Lee, H. M. Organometallics 2011, 30, 5160−
5169.
AUTHOR INFORMATION
Corresponding Author
*Fax: 86-577-86689300. E-mail: shaolix@wzu.edu.cn.
Notes
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(6) (a) Yin, H.-Y.; Liu, M.-Y.; Shao, L.-X. Org. Lett. 2013, 15, 6042−
6045. (b) Xiao, Z.-K.; Yin, H.-Y.; Shao, L.-X. Org. Lett. 2013, 15,
1254−1257. (c) Xiao, Z.-K.; Shao, L.-X. Synthesis 2012, 44, 711−716.
(7) (a) Tang, Y.-Q.; Lu, J.-M.; Shao, L.-X. J. Organomet. Chem. 2011,
696, 3741−3744. (b) Zhou, X.-X.; Shao, L.-X. Synthesis 2011, 3138−
3142.
(8) Gao, T.-T.; Jin, A.-P.; Shao, L.-X. Beilstein J. Org. Chem. 2012, 8,
1916−1919.
(9) Gu, Z.-S.; Shao, L.-X.; Lu, J.-M. J. Organomet. Chem. 2012, 700,
132−134.
(10) (a) Chen, W.-X.; Shao, L.-X. J. Org. Chem. 2012, 77, 9236−
9239. (b) Zhu, L.; Ye, Y.-M.; Shao, L.-X. Tetrahedron 2012, 68, 2414−
2420. (c) Zhu, L.; Gao, T.-T.; Shao, L.-X. Tetrahedron 2011, 67,
5150−5155.
(11) Shen, X.-B.; Zhang, Y.; Chen, W.-X.; Xiao, Z.-K.; Hu, T.-T.;
Shao, L.-X. Org. Lett. 2014, 16, 1984−1987.
(12) For some selected reviews on the transition metal-catalyzed
reactions in the presence of water, please see: (a) Li, B.; Dixneuf, P. H.
Chem. Soc. Rev. 2013, 42, 5744−5767. (b) Velazquez, H. D.; Verpoort,
F. Chem. Soc. Rev. 2012, 41, 7032−7060. (c) Lipshutz, B. H.; Ghorai,
S. Aldrichimica Acta 2008, 41, 59−72. (d) Carril, M.; SanMartin, R.;
Domínguez, E. Chem. Soc. Rev. 2008, 37, 639−647. (e) Cornils, B.;
Herrmann, W. Aqueous-Phase Organometallic Catalysis 2; Wiley-VCH:
Weinheim, Germany, 2004. (f) Genet, J. P.; Savignac, M. J. Organomet.
Chem. 1999, 576, 305−317.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from Open Research Fund of Top Key
Discipline of Chemistry in Zhejiang Provincial Colleges and
Key Laboratory of the Ministry of Education for Advanced
Catalysis Materials (Zhejiang Normal University) (No.
ZJHX201305) is greatly appreciated.
REFERENCES
■
(1) For some selected examples, please see: (a) Zhou, B.-H.; Li, B.-J.;
Yi, W.; Bu, Z.-Z.; Ma, L. Bioorg. Med. Chem. Lett. 2013, 23, 3759−
3763. (b) Do, T. T.; Bae, J. H.; Yoo, S. I.; Lim, K. T.; Woo, H. Y.; Kim,
J. H. Mol. Cryst. Liq. Cryst. 2013, 581, 31−37. (c) Rahim, A. S. A.;
Salhimi, S. M.; Arumugam, N.; Pi, L. C.; Yee, N. S.; Muttiah, N. N.;
Keat, W. B.; Hamid, S. A.; Osman, H.; Mat, I. b. J. Enzyme Inhib. Med.
Chem. 2013, 28, 1255−1260. (d) Kamal, A.; Kashi Reddy, M.; Shaik,
T. B.; Rajender; Srikanth, Y. V. V.; Santhosh Reddy, V.; Bharath
Kumar, G.; Kalivendi, S. V. Eur. J. Med. Chem. 2012, 50, 9−17.
(e) Vitale, G.; Corona, P.; Loriga, M.; Carta, A.; Paglietti, G.; La Colla,
P.; Busonera, B.; Marongiu, E.; Collu, D.; Loddo, R. Med. Chem. 2009,
5, 507−516. (f) Dahiya, R.; Pathak, D. Eur. J. Med. Chem. 2007, 42,
(13) While we were preparing this manuscript, Huynh and co-worker
reported the example of NHC-Pd complex catalyzed direct C5-
arylation of 1-methylimidazole with aryl bromides and chlorides in low
to moderate yields; please see: Guo, S.; Huynh, H. V. Organometallics
2014, 33, 2004−2011.
(14) Hachiya, H.; Hirano, K.; Satoh, T.; Miura, M. Angew. Chem., Int.
Ed. 2010, 49, 2202−2205.
772−798. (g) Falco,
́ ́ ́
J. L.; Pique, M.; Gonzalez, M.; Buira, I.; Terencio,
J.; Perez, C.; Príncep, M.; Palomer, A.; Guglietta, A. Eur. J. Med. Chem.
́
2006, 41, 985−990. (h) Bhongade, B. A.; Gouripur, V. V.; Gadad, A.
K. Bioorg. Med. Chem. 2005, 13, 2773−2782.
(2) For recent selected reviews on the transition metal-catalyzed
direct C−H bond functionalizations, please see: (a) Kuhl, N.;
Hopkinson, M. N.; Wencel-Delord, J.; Glorius, F. Angew. Chem., Int.
Ed. 2012, 51, 10236−10254. (b) Engle, K. M.; Mei, T.-S.; Wasa, M.;
Yu, J.-Q. Acc. Chem. Res. 2012, 45, 788−802. (c) Arockiam, P. B.;
Bruneau, C.; Dixneuf, P. H. Chem. Rev. 2012, 112, 5879−5918.
(d) Yamaguchi, J.; Yamaguchi, A. D.; Itami, K. Angew. Chem., Int. Ed.
2012, 51, 8960−9009. (e) Shibahara, F.; Murai, T. Asian J. Org. Chem.
2013, 2, 624−636. (f) Mousseau, J. J.; Charette, A. B. Acc. Chem. Res.
2013, 46, 412−424. (g) Bonin, H.; Sauthier, M.; Felpin, F.-X. Adv.
Synth. Catal. 2014, 356, 645−671. (h) Zhao, C.; Crimmin, M. R.;
Toste, F. D.; Bergman, R. G. Acc. Chem. Res. 2014, 47, 517−529.
(3) (a) Shibahara, F.; Yamauchi, T.; Yamaguchi, E.; Murai, T. J. Org.
Chem. 2012, 77, 8815−8820. (b) Zhang, W.; Zeng, Q.-L.; Zhang, X.-
M.; Tian, Y.-J.; Yue, Y.; Guo, Y.-J.; Wang, Z.-H. J. Org. Chem. 2011, 76,
4741−4745. (c) Yan, X.-M.; Mao, X.-R.; Huang, Z.-Z. Heterocycles
2011, 83, 1371−1376. (d) Shibahara, F.; Yamaguchi, E.; Murai, T. J.
(15) Huang, J.-K.; Chan, J.; Chen, Y.; Borths, C. J.; Baucom, K. D.;
Larsen, R. D.; Faul, M. M. J. Am. Chem. Soc. 2010, 132, 3674−3675.
(16) Chakrabarty, M.; Mukherji, A.; Mukherjee, R.; Arimab, S.;
Harigaya, Y. Tetrahedron Lett. 2007, 48, 5239−5242.
(17) Jin, X.-K.; Liu, Y.-X.; Lu, Q.-Q.; Yang, D.-J.; Sun, J.-K.; Qin, S.-
S.; Zhang, J.-W.; Shen, J.-X.; Chu, C.-H.; Liu, R.-H. Org. Biomol. Chem.
2013, 11, 3776−3780.
(18) Huang, W.-K.; Cheng, C.-W.; Chang, S.-M.; Lee, Y.-P.; Diau, E.
W.-G. Chem. Commun. 2010, 46, 8992−8994.
(19) Hubbard, J. W.; Piegols, A. M.; Soderberg, B. C. C. Tetrahedron
̈
2007, 63, 7077−7085.
(20) Guru, M. M.; Ali, M. A.; Punniyamurthy, T. J. Org. Chem. 2011,
76, 5295−5308.
(21) Truong, T.; Daugulis, O. J. Am. Chem. Soc. 2011, 133, 4243−
4245.
́
Org. Chem. 2011, 76, 2680−2693. (e) Joo, J. M.; Barry Toure, B.;
́
(22) Joselglesias, M. J.; Prieto, A.; Carmen Nicasio, M. Org. Lett.
Sames, D. J. Org. Chem. 2010, 75, 4911−4920. (f) Lewis, J. C.;
Berman, A. M.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2008,
130, 2493−2500. (g) Yoshizumi, T.; Tsurugi, H.; Satoh, T.; Miura, M.
Tetrahedron 2008, 49, 1598−1600. (h) Bellina, F.; Calandri, C.;
Cauteruccio, S.; Rossi, R. Tetrahedron 2007, 63, 1970−1980.
(i) Bellina, F.; Cauteruccio, S.; Rossi, R. J. Org. Chem. 2007, 72,
8543−8546. (j) Lewis, J. C.; Wu, J. Y.; Bergman, R. G.; Ellman, J. A.
Angew. Chem., Int. Ed. 2006, 45, 1589−1591. (k) Bellina, F.;
Cauteruccio, S.; Mannina, L.; Rossi, R.; Viel, S. Eur. J. Org. Chem.
2006, 693−703. (l) Bellina, F.; Cauteruccio, S.; Rossi, R. Eur. J. Org.
Chem. 2006, 1379−1382. (m) Bellina, F.; Cauteruccio, S.; Mannina,
L.; Rossi, R.; Viel, S. J. Org. Chem. 2005, 70, 3997−4005. (n) Lewis, J.
2012, 14, 4318−4321.
(23) Oi, S.; Sato, H.; Sugawara, S.; Inoue, Y. Org. Lett. 2008, 10,
1823−1826.
(24) Brauer, D. J.; Kottsieper, K. W.; Like, C.; Stelzer, O.;
Waffenschmidt, H.; Wasserscheid, P. J. Organomet. Chem. 2001, 630,
177−184.
F
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