N-heterocyclic carbene-palladium(II)-1-methylimidazole complex-catalyzed Suzuki-Miyaura coupling of benzyl sulfonates with arylboronic acids

Article abstract of DOI:10.1039/c4ob02675f

The first example of palladium-catalyzed Suzuki-Miyaura coupling between benzyl sulfonates and arylboronic acids was reported in this paper. In the presence of a well-defined, air-stable and easily available NHC-Pd(ii)-Im complex, all reactions worked well to give the desired products in good to almost quantitative yields under the optimal conditions. Electron-rich, -neutral, -poor and sterically-hindered substituents on both substrates are tolerated in such transformation, providing a convenient, efficient and alternative method for the synthesis of diarylmethanes.

Full text of DOI:10.1039/c4ob02675f

Organic &
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PAPER
N-heterocyclic carbene–palladium(II)-
1-methylimidazole complex-catalyzed
Suzuki–Miyaura coupling of benzyl sulfonates
with arylboronic acids†
Cite this: Org. Biomol. Chem., 2015,
13, 4925
Xiao-Xia Wang, Bin-Bin Xu, Wen-Ting Song, Kai-Xin Sun and Jian-Mei Lu*
The first example of palladium-catalyzed Suzuki–Miyaura coupling between benzyl sulfonates and aryl-
boronic acids was reported in this paper. In the presence of a well-defined, air-stable and easily available
NHC–Pd(II)–Im complex, all reactions worked well to give the desired products in good to almost quanti-
tative yields under the optimal conditions. Electron-rich, -neutral, -poor and sterically-hindered substitu-
ents on both substrates are tolerated in such transformation, providing a convenient, efficient and
alternative method for the synthesis of diarylmethanes.
Received 27th December 2014,
Accepted 19th March 2015
DOI: 10.1039/c4ob02675f
www.rsc.org/obc
these two reactions, we then turned our recent interest to the
coupling reaction between benzyl sulfonates and arylboronic
Introduction
Transition metal catalyzed Suzuki–Miyaura coupling reactions acids for the formation of diarylmethanes,6 which are impor-
are among the most important reactions for the formation of tant subunits in molecules with pharmaceutical activities7 and
carbon–carbon bonds.1 In such transformations, aryl halides supramolecules.8 Herein, we report the first example of
are usually used as the electrophiles. Disappointingly, some Pd-catalyzed coupling reactions of benzyl sulfonates with aryl-
obvious drawbacks are involved with the use of aryl halides as boronic acids in detail.
they are not easily available and are not environmentally
friendly both in themselves and the halides-containing by-pro-
ducts. During recent years, O-based alternative electrophiles
have attracted much attention because they are more easily
Results and discussion
available from phenol derivatives or carbonyl enolates and
they are also sometimes cheaper.2 In addition, the use of
O-based electrophiles instead of their halide counterparts will
avoid the toxic halide-containing by-products. However, com-
pared to the abundant papers on transition metal catalyzed
coupling reactions of O-based electrophiles derived from
phenols with aryl organoborons, similar electrophiles derived
from benzyl alcohols are rarely reported,3 suggesting great
potential in this field.
Recently, Shao and our group have successfully developed a
well-defined N-heterocyclic carbene–Pd(II)-1-methylimidazole
[NHC–Pd(II)–Im] complex 1,4 and found it to be an efficient
catalyst for the Suzuki–Miyaura coupling of benzyl chlorides
and aryl tosylates with aryl organoborons.5 Considering our
successful experience with the applications of this complex in
The reaction between benzyl tosylate 2a (1.2 equiv.) and phenyl-
boronic acid 3a (0.70 mmol) in the presence of NHC–Pd(II)–Im
complex 1 (1.0 mol%) was chosen as the first model reaction
to test the effects of bases and solvents. The results are sum-
marized in Table 1. For instance, in the first round, the reac-
tion was performed in THF (2.0 mL) at 100 °C for 12 h to
evaluate various bases (Table 1, entries 1–8). Of the bases
screened, K3PO4·3H2O and NaOH showed the best yields
(Table 1, entries 2 and 4). Product 4a can also be obtained in
good yields when KOH and Cs2CO3 were used, respectively
(Table 1, entries 6 and 7). In the presence of other bases such
as K2CO3, NaHCO3, Na2CO3 and KHCO3, very low yields were
observed (Table 1, entries 1, 3, 5 and 8). Considering the lower
molecular weight and lower cost, NaOH was chosen as the best
base for further optimization. Further study showed that
100 °C was necessary for such transformations.9 For example,
when the model reaction was performed in THF at 90 °C for
12 h, product 4a was obtained in lower yield (80%). Using
NaOH as the base, a variety of solvents was also examined,
giving inferior yields in most cases. For example, when other
solvents such as CH3CN and toluene were used, very low yields
College of Chemistry and Materials Engineering, Wenzhou University, Chashan
University Town, Wenzhou, Zhejiang Province 325035, People’s Republic of China.
E-mail: ljm@wzu.edu.cn; Fax: +86 57786689300; Tel: +86 57786689300
†Electronic supplementary information (ESI) available: Copy of 1H and 13C NMR
spectra of compounds 4. See DOI: 10.1039/c4ob02675f
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Table 1 Optimization for complex 1 catalyzed reaction between benzyl
tosylate 2a and phenylboronic acid 3a
Table 2 NHC–Pd(II)–Im complex 1-catalyzed reactions between
benzyl tosylate 2a and arylboronic acids 3
Entrya
3 (R)
Yieldb (%)
1
2
3
4
5
6
7
8
3b (4-OMe)
3c (3-OMe)
3d (2-OMe)
3e (4-Me)
4b, 92
4c, 96
4d, 97
4e, 89
4f, 94
4g, 88
4h, 96
4i, 91
4j, 81
4k, 83
4l, 88
4m, 82
4n, 99
3f (2-Me)
Entrya
Base
Solvent
Yieldb (%)
3g (2,6-Me2)
3h (3,5-Me2)
3i (4-Ph)
3j (4-vinyl)
3k (4-F)
3l (4-CO2Et)
3m (4-CF3)
3n (1-naphthalenyl)
1
2
3
4
5
6
7
8
K2CO3
K3PO·3H2O
NaHCO3
NaOH
Na2CO3
KOH
Cs2CO3
KHCO3
NaOH
NaOH
NaOH
NaOH
NaOH
THF
THF
THF
THF
THF
THF
THF
THF
Morpholine
CH3CN
DMF
Toluene
DMSO
Dioxane
26
96
7
9
10
11
12
13
93
25
80
88
11
<5
29
6
a All reactions were carried out using 2a (0.84 mmol), 3 (0.7 mmol),
NaOH (1.5 equiv.), 1 (1.0 mol%) in THF (2.0 mL) at 100 °C for 12 h.
b Isolated yields.
9
10
11
12
13
14
60
NR
90
NaOH
a All reactions were carried out using 2a (0.84 mmol), 3a (0.7 mmol),
base (1.5 equiv.), 1 (1.0 mol%) in solvent (2.0 mL) at 100 °C for 12 h.
b Isolated yields.
ducts 4 in good to very high yields. In addition, sterically-
hindered substituents on the arylboronic acids 3 were also tol-
erated in this transformation. For instance, for the reactions
involving 2-methoxyphenylboronic acid 3d, 2-methyl-
phenylboronic acid 3f and 2,6-dimethylphenylboronic acid 3g,
good to high yields were obtained (Table 2, entries 3, 5 and 6).
were observed (Table 1, entries 10 and 12). In addition, when The same substituent on a different position of the phenyl
using morpholine, DMF and DMSO as the solvent, respectively, groups of arylboronic acids 3 also did not affect the reactions.
almost no desired product can be formed (Table 1, entries 9, For example, comparable yields can be obtained when aryl-
11 and 13). It is noteworthy that in Shao’s previous papers, it boronic acids 3, having a methoxy group on the 2-, 3- or 4-posi-
was found that morpholine was the best solvent for the tion on the phenyl ring, were used as the substrates (Table 2,
Suzuki–Miyaura coupling of aryl sulfonates and sulfamates entries 1–3).
with arylboronic acids, perhaps due to the formation of
The scope of this reaction was further tested using different
NHC–Pd(II)–morpholine complex as the real precatalyst.5b,10 benzyl tosylates 2 and arylboronic acids 3 under the optimized
However, in the current reaction between benzyl tosylate 2a conditions. The results are summarized in Table 3. All reac-
and phenylboronic acid 3a, morpholine was not a suitable tions took place to give the desired products 4 in good to
solvent, suggesting that the NHC–Pd(II)–morpholine complex almost quantitative yields. Electron-rich, -neutral, -poor and
was not the active precatalyst in the current transformation. sterically-hindered substituents on both substrates were tol-
Using dioxane as the solvent, a comparable yield was obtained erated. For instance, reactions involving sterically-hindered
(Table 1, entry 14).
substituted substrates such as 2-methylbenzyl tosylate 2d,
With the optimal reaction conditions established, the reac- 2-methylphenylboronic acid 3f and 2-methoxyphenylboronic
tions between phenyl tosylate 2a and various arylboronic acids acid 3d proceeded well to give the corresponding coupling pro-
3 were then investigated (Table 2). As can be seen from ducts 4 in good to almost quantitative yields (Table 3, entries
Table 2, all reactions proceeded smoothly to give the desired 3, 7, 12–14, 16 and 19). Benzyl tosylate 2f, having a strongly
coupling products 4 in good to almost quantitative yields. It electron-withdrawing group such as nitro group on the phenyl
seemed that substituents on the arylboronic acids 3 almost ring, was also a suitable substrate to give product 4p in high
had no effect on the reactions. For example, electron-rich sub- yield (Table 3, entry 5). Substrate 2g having heteroaryl ring sub-
stituents such as MeO and Me or electron-poor substituents stituent was also suitable for such transformation to afford
such as F atom and even strongly electron-withdrawing products 4ab and 4ac in good yields under appropriate con-
groups such as CO2Et and CF3 were all tolerated, giving pro- ditions (Table 3, entries 18 and 19).
4926 | Org. Biomol. Chem., 2015, 13, 4925–4930
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Table 3 NHC–Pd(II)–Im complex 1-catalyzed reactions between
benzyl tosylates 2 and arylboronic acids 3
Table 4 NHC–Pd(II)–Im complex 1-catalyzed reactions between
benzyl mesylates 2 and arylboronic acids 3
Entrya
2 (R′)
3 (R)
Yieldb (%)
Entrya
2 (R′)
3 (R)
Yieldb (%)
1
2
3
4
5
6
7
8
2b (3-OMe)
2c (3-Me)
2d (2-Me)
2e (4-F)
3a (H)
3a
3a
3a
4c, 96
4o, 99
4f, 94
4k, 99
4p, 94
4q, 99
4r, 93
4s, 99
4t, 99
4u, 94
4v, 97
4w, 99
4x, 93
4r, 88
4y, 96
4z, 99
4aa, 82
4ab, 83
4ac, 82
1
2
3
4
5
6
7
8
2g (H)
2g
2g
2g
2h (4-OMe)
2h
2h
2h
2i (4-F)
2i
2i
2i
3a (H)
3b (4-OMe)
3f (2-Me)
3k (4-F)
3a
3b
3f
4a, 99
4b, 99
4f, 86
4k, 85
4b, 98
4ad, 97
4w, 99
4ae, 92
4k, 88
4y, 93
4z, 90
4af, 90
2f (4-NO2)
3a
2b
2b
2b
2c
2c
2c
2d
2d
2d
2e
2e
2e
3b (4-OMe)
3f (2-Me)
3k (4-F)
3b
3i (4-Ph)
3c (3-OMe)
3b
3i
3c
3b
3f
3k
3i (4-Ph)
9
9
3a
3b
3f
10
11
12
13
14
15
16
17
18c
19c
10
11
12
3i
a All reactions were carried out using 2 (0.84 mmol), 3 (0.7 mmol),
NaOH (1.5 equiv.), 1 (1.0 mol%) in THF (2.0 mL) at 100 °C for 12 h.
b Isolated yields.
3b
3d (2-OMe)
Conclusions
a If not otherwise specified, all reactions were carried out using 2
(0.84 mmol), 3 (0.7 mmol), NaOH (1.5 equiv.), 1 (1.0 mol%) in THF
(2.0 mL) at 100 °C for 12 h. b Isolated yields. c Reaction conditions: 1
(2.0 mol%), 140 °C.
In conclusion, the first example of a palladium-catalyzed
Suzuki–Miyaura coupling between benzyl sulfonates and aryl-
boronic acids is reported in this paper. Under the optimal con-
ditions, various aryl tosylates and mesylates reacted with
arylboronic acids very well to give the desired coupling pro-
ducts in good to almost quantitative yields. The scope and
limitations of this transformation was fully discussed in this
paper, and it was found that electron-rich, -neutral, -poor and
sterically-hindered substituents on both substrates can be tol-
erated in such transformation, thus providing a convenient,
efficient and alternative method for the synthesis of
diarylmethanes.
Besides tosylates, it seems that mesylates are more attractive
because they are more atom economical substrates than
tosylates due to their lower molecular weight. However,
mesylates are more inert than tosylates due to the higher stabi-
lity of the C–O bonds in such materials,11 resulting in difficul-
ties in C–O bond activation/cleavage in the oxidative step in
the metal-catalyzed coupling reactions, implying that mesy-
lates are more challenging substrates in coupling reactions.
Therefore, based on the above successful results in the NHC–
Experimental
General remarks
Pd(II)–Im complex
1 catalyzed Suzuki–Miyaura coupling
Melting points are uncorrected. NMR spectra were recorded at
500 (for H NMR) or 125 MHz (for 13C NMR), respectively. H
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 used
for high resolution mass spectra (HRMS, EI) is FT-ICR. Other
commercially obtained reagents were used without further
purification. Flash column chromatography was performed on
silica gel.
1
1
between benzyl tosylates and arylboronic acids, we then turned
our interest to such transformations using the more challen-
ging benzyl mesylates as the substrates. To our pleasure, the
optimal reaction conditions are also suitable for benzyl
mesylates. For instance, as can be seen from Table 4, all reac-
tions worked well to afford the desired products 4 in good to
almost quantitative yields under identical conditions. Elec-
tron-rich, -neutral, -poor and sterically-hindered substituents
on both substrates were also tolerated. For example, all reac-
tions of benzyl mesylate 2g with phenylboronic acid 3a,
4-methoxyphenylboronic acid 3b, 2-methylphenylboronic acid
3f and 4-fluorophenylboronic acid 3k worked well enough to
General procedure for the NHC–Pd(II)–Im complex 1-catalyzed
reactions between benzyl sulfonates 2 and arylboronic acids 3
give products 4 in good to almost quantitative yields (Table 4, Under N2 atmosphere, benzyl sulfonates 2 (0.84 mmol), aryl-
entries 1–4).
boronic acids 3 (0.7 mmol), NHC–Pd(II)–Im complex 1
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(1.0 mol%), NaOH (1.5 equiv.) and THF (2.0 mL) were succes- 140.8, 136.6, 135.5, 129.1, 128.9, 128.5, 126.3, 126.1, 113.2,
sively added to a sealed tube. The mixture was stirred vigor- 41.6.
ously at 100 °C for 12 h. Then the solvent was removed under
Compound 4k.5a Yellow liquid (108.0 mg, 83%). 1H NMR
reduced pressure and the residue was purified by flash column (500 MHz, CDCl3, TMS) δ 7.29 (t, J = 7.5 Hz, 2H), 7.20 (t, J =
chromatography (petroleum ether as the eluent) to give the 7.5 Hz, 1H), 7.19–7.12 (m, 4H), 6.96 (t, J = 8.5 Hz, 2H), 3.95 (s,
pure products 4.
2H). 13C NMR (125 MHz, CDCl3) δ 161.41 (d, JC–F = 242.5 Hz),
1
Compound 4a.5a Colorless liquid (109.5 mg, 93%). H NMR 140.9, 136.7 (d, JC–F = 3.25 Hz), 130.2 (d, JC–F = 7.875 Hz),
(500 MHz, CDCl3, TMS) δ 7.28–7.25 (m, 4H), 7.19–7.17 128.8, 128.5, 126.2, 115.2 (d, JC–F = 21.0 Hz), 41.0.
(m, 6H), 3.97 (s, 2H). 13C NMR (125 MHz, CDCl3) δ 141.1,
128.9, 128.4, 126.0, 41.9.
Compound 4l.14 Yellow liquid (147.8 mg, 88%). 1H NMR
(500 MHz, CDCl3, TMS) δ 7.96 (d, J = 8.5 Hz, 2H), 7.29–9.19 (m,
Compound 4b.5a Yellow liquid (127.5 mg, 92%). 1H NMR 5H), 7.16 (d, J = 7.5 Hz, 2H), 4.35 (q, J = 7.0 Hz, 2H), 4.01
(500 MHz, CDCl3, TMS) δ 7.257 (t, J = 8.0 Hz, 2H), 7.16 (t, J = (s, 2H), 1.36 (t, J = 7.0 Hz, 3H). 13C NMR (125 MHz, CDCl3)
8.0 Hz, 3H), 7.08 (d, J = 8.0 Hz, 2H), 6.80 (d, J = 8.0 Hz, 2H), δ 166.5, 146.3, 140.1, 129.7, 128.9, 128.8, 128.5, 128.4, 126.3,
3.90 (s, 2H), 3.73 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 158.0, 60.7, 41.8, 14.3.
141.5, 133.2, 129.8, 128.8, 128.4, 125.9, 113.9, 55.1, 41.0.
Compound 4m.15 Colorless liquid (135.5 mg, 82%). 1H
Compound 4c.12 Yellow liquid (133.1 mg, 96%). 1H NMR NMR (500 MHz, CDCl3, TMS) δ 7.52 (d, J = 8.0 Hz, 2H),
(500 MHz, CDCl3, TMS) δ, 7.26 (t, J = 7.5 Hz, 2H), 7.20–7.17 (m, 7.31–7.27 (m, 4H), 7.23–7.20 (m, 1H), 7.17 (d, J = 7.0 Hz, 2H),
4H), 6.77 (d, J = 7.5 Hz, 1H), 6.74–6.72 (m, 2H), 3.94 (s, 2H), 4.02 (s, 2H). 13C NMR (125 MHz, CDCl3) δ 145.2, 140.0, 129.2,
3.74 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 159.7, 142.7, 140.9, 128.9, 128.5 (q, JC–F = 32.125 Hz), 127.6, 126.5, 125.39 (q, JC–F
=
129.4, 128.9, 128.4, 126.0, 121.3, 114.8, 111.3, 55.0, 41.9.
3.75 Hz), 124.3 (q, JC–F = 270.125 Hz), 41.7.
Compound 4n.5a Colorless liquid (151.1 mg, 99%). H NMR
1
Compound 4d.5a Yellow liquid (134.4 mg, 97%). 1H NMR
(500 MHz, CDCl3, TMS) δ 7.25 (t, J = 7.5 Hz, 2H), 7.20–7.14 (m, (500 MHz, CDCl3, TMS) δ 7.78–7.72 (m, 3H), 7.61 (s, 1H),
4H), 7.05 (d, J = 7.5 Hz, 1H), 6.87 (d, J = 7.5 Hz, 1H), 6.84 (d, J = 7.44–7.38 (m, 2H), 7.30–7.26 (m, 3H), 7.22–7.16 (m, 3H), 4.12
8.0 Hz, 1H), 3.97 (s, 2H), 3.78 (s, 3H). 13C NMR (125 MHz, (s, 2H). 13C NMR (125 MHz, CDCl3) δ 140.9, 138.5, 133.6,
CDCl3) δ 157.3, 141.0, 130.3, 129.6, 128.9, 128.2, 127.4, 125.7, 132.1, 129.0, 128.4, 128.0, 127.6, 127.5, 127.1, 126.1, 125.9,
120.4, 110.4, 55.3, 35.8.
Compound 4e.5a Colorless liquid (113.4 mg, 89%). H NMR
125.3, 42.0.
Compound 4o.5a Colorless liquid (126.1 mg, 99%). H NMR
1
1
(500 MHz, CDCl3, TMS) δ 7.26 (t, J = 7.5 Hz, 2H), 7.19–7.165 (500 MHz, CDCl3, TMS) δ 7.27 (t, J = 7.5 Hz, 2H), 7.18–7.15 (m,
(m, 3H), 7.08 (d, J = 9.0 Hz, 2H), 7.07 (d, J = 9.0 Hz, 2H), 3.93 4H), 7.00–6.97 (m, 3H), 3.93 (s, 2H), 2.30 (s, 3H). 13C NMR
(s, 2H), 2.30 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 141.4, 138.0, (125 MHz, CDCl3) δ 141.2, 141.0, 138.0, 129.7, 128.9, 128.4,
135.4, 129.1, 128.83, 128.78, 128.4, 125.9, 41.5, 21.0.
Compound 4f.12 Colorless liquid (119.7 mg, 94%). H NMR
128.3, 126.8, 125.99, 125.96, 41.9, 21.4.
1
Compound 4p.16 Yellow liquid (140.2 mg, 94%). 1H NMR
(500 MHz, CDCl3, TMS) δ 7.26 (t, J = 7.5 Hz, 2H), 7.19–7.08 (m, (500 MHz, CDCl3, TMS) δ 8.13 (d, J = 9.0 Hz, 2H), 7.34–7.30 (m,
7H), 3.98 (s, 2H), 2.23 (s, 3H). 13C NMR (125 MHz, CDCl3) 4H), 7.26–7.23 (m, 1H), 7.17 (d, J = 7.5 Hz, 2H), 4.07 (s, 2H).
δ 140.4, 138.9, 136.6, 130.3, 129.9, 128.7, 128.4, 126.4, 126.0, 13C NMR (125 MHz, CDCl3) δ 148.8, 146.5, 139.2, 129.6, 128.9,
125.9, 39.4, 19.6.
Compound 4g.13 Colorless liquid (120.7 mg, 88%). H NMR
128.8, 126.7, 123.7, 41.7.
1
Compound 4q. Yellow liquid (158.0 mg, 99%). 1H NMR
(500 MHz, CDCl3, TMS δ 7.20 (d, J = 7.5 Hz, 2H), 7.16–7.12 (m, (500 MHz, CDCl3, TMS) δ 7.18 (t, J = 7.5 Hz, 1H), 7.09 (d, J =
1H), 7.10–7.04 (m, 3H), 7.00 (d, J = 7.5 Hz, 2H), 4.05 (s, 2H), 8.5 Hz, 2H), 6.81 (d, J = 8.5 Hz, 2H), 6.77–6.71 (m, 3H), 3.88 (s,
2.23 (s, 6H). 13C NMR (125 MHz, CDCl3) δ 139.8, 137.1, 136.8, 2H), 3.75 (s, 3H), 3.74 (s, 3H). 13C NMR (125 MHz, CDCl3)
128.3, 128.1, 127.8, 126.3, 125.7, 35.0, 20.2.
δ 159.7, 158.0, 143.1, 133.0, 129.8, 129.3, 121.2, 114.6, 113.8,
1
Compound 4h.5a Colorless liquid (131.7 mg, 96%). H NMR 111.2, 55.1, 55.0, 41.0. MS (EI, %) m/z 212 (M+, 100), 197 (57),
(500 MHz, CDCl3, TMS) δ 7.26 (t, J = 7.5 Hz, 2H), 7.19–7.16 (m, 121 (28). HRMS (EI) calcd for C15H16O2: 228.1150, found:
3H), 6.82 (s, 1H), 6.80 (s, 2H), 3.89 (s, 2H), 2.26 (s, 6H). 13C 228.1147. IR (neat) ν 2935, 2829, 1606, 1583, 1483, 1436, 1298,
NMR (125 MHz, CDCl3) δ 141.3, 140.9, 137.9, 128.9, 128.4, 1245, 1172, 1149, 1036, 830, 819, 783, 753, 741, 690 cm−1
127.7, 126.8, 125.9, 41.8, 21.2.
.
Compound 4r. Yellow liquid (138.0 mg, 93%). 1H NMR
Compound 4i.5a White solid (155.4 mg, 91%). 1H NMR (500 MHz, CDCl3, TMS) δ 7.19–7.09 (m, 5H), 6.72 (t, J = 6.5 Hz,
(500 MHz, CDCl3, TMS) δ 7.56 (d, J = 7.5 Hz, 2H), 7.51 (d, J = 2H), 6.67 (s, 1H), 3.95 (s, 2H), 3.74 (s, 3H), 2.24 (s, 3H). 13C
8.0 Hz, 2H), 7.40 (t, J = 7.5 Hz, 2H), 7.32–7.19 (m, 8H), 4.01 (s, NMR (125 MHz, CDCl3) δ 159.7, 142.1, 138.7, 136.6, 130.2,
2H). 13C NMR (125 MHz, CDCl3) δ 141.0, 140.2, 139.0, 129.3, 129.9, 129.3, 126.4, 126.0, 121.2, 114.7, 111.1, 55.1, 39.4, 19.6.
128.9, 128.7, 128.5, 127.2, 127.1, 127.0, 126.1, 41.6.
MS (EI, %) m/z 212 (M+, 100), 197 (43), 104 (42). HRMS (EI)
1
Compound 4j.12 Colorless liquid (110.0 mg, 81%). H NMR calcd for C15H16O: 212.1201, found: 212.1202. IR (neat) ν 2934,
(500 MHz, CDCl3, TMS) δ 7.33 (d, J = 7.0 Hz, 2H), 7.28 2828, 1596, 1487, 1454, 1315, 1255, 1139, 1053, 765, 735,
(t, J = 7.0 Hz, 2H), 7.21–7.14 (m, 5H), 6.68 (dd, J = 17.5, 690 cm−1
.
11.0 Hz, 1H), 5.70 (dd, J = 17.5, 1.0 Hz, 1H), 5.19 (dd, J = 11.0,
1.0 Hz, 1H), 3.96 (s, 2H). 13C NMR (125 MHz, CDCl3) δ 141.0, (500 MHz, CDCl3, TMS) δ 7.19 (t, J = 7.5 Hz, 1H), 7.12 (dd, J =
Compound 4s. Yellow liquid (149.7 mg, 99%). 1H NMR
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8.5, 5.5 Hz, 2H), 6.94 (t, J = 8.5 Hz, 2H), 6.75–6.73 (m, 2H), 130.1 (d, JC–F = 7.75 Hz), 129.7, 115.1 (d, JC–F = 21.0 Hz), 113.9,
6.70 (s, 1H), 3.90 (s, 2H), 3.74 (s, 3H). 13C NMR (125 MHz, 55.2, 40.2.
CDCl3) δ 161.4 (d, JC–F = 242.375 Hz), 159.8, 142.5, 136.6 (d,
Compound 4z. Colorless liquid (138.6 mg, 99%). 1H NMR
JC–F = 3.125 Hz), 130.2 (d, JC–F = 7.75 Hz), 129.4, 121.2, (500 MHz, CDCl3, TMS) δ 7.16–7.13 (m, 3H), 7.07–7.04
115.1 (d, JC–F = 21.125 Hz), 114.7, 111.3, 55.0, 41.0. MS (EI, %) (m, 3H), 6.94 (t, J = 8.5 Hz, 2H), 3.93 (s, 2H), 2.21 (s, 3H).
m/z 216 (M+, 100). HRMS (EI) calcd for C14H13FO: 216.0950, 13C NMR (125 MHz, CDCl3) δ 161.3 (d, JC–F = 242.25 Hz),
found: 216.0945. IR (neat)
ν 2941, 2829, 1597, 1580, 138.7, 136.5, 136.0 (d, JC–F = 3.125 Hz), 130.4, 130.0 (d, J =
1487, 1454, 1434, 1252, 1219, 1156, 1050, 821, 781, 741, 7.75 Hz), 129.8, 126.6, 126.1, 115.1 (d, JC–F = 21.0 Hz), 38.6,
690 cm−1
.
19.6. MS (EI, %) m/z 200 (96), 185 (M+, 100), 165 (29). HRMS
Compound 4t.17 Yellow liquid (147.0 mg, 99%). 1H NMR (EI) calcd for C14H13F: 200.1001, found: 200.1002. IR (neat)
(500 MHz, CDCl3, TMS) δ 7.16 (t, J = 7.5 Hz, 1H), 7.10 (d, J = ν 3018, 2917, 1606, 1511, 1228, 1157, 1092, 842, 819, 778,
8.0 Hz, 2H), 7.00–6.96 (m, 3H), 6.82 (d, J = 8.0 Hz, 2H), 3.88 737 cm−1
.
(s, 2H), 3.77 (s, 3H), 2.30 (s, 3H). 13C NMR (125 MHz, CDCl3)
δ 157.9, 141.5, 138.0, 133.4, 129.8, 129.6, 128.3, 126.7, 125.8, (500 MHz, CDCl3, TMS) δ 7.11 (dd, J = 8.5, 5.5 Hz, 2H), 6.97 (t,
113.9, 55.2, 41.0, 21.4.
J = 8.5 Hz, 4H), 3.92 (s, 2H). 13C NMR (125 MHz, CDCl3)
Compound 4aa. Colorless liquid (117.1 mg, 82%). H NMR
1
Compound 4u. Colorless liquid (169.8 mg, 94%). Mp: δ 161.5 (d, JC–F = 242.75 Hz), 136.6 (d, JC–F = 3.125 Hz), 130.2
60–62 °C. 1H NMR (500 MHz, CDCl3, TMS) δ 7.54 (d, J = (d, JC–F = 7.75 Hz), 115.3 (d, JC–F = 21.125 Hz), 40.2. MS (EI, %)
8.0 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 7.38 (t, J = 7.5 Hz, 2H), m/z 204 (M+, 100), 183 (47). HRMS (EI) calcd for C13H10F2:
7.28 (t, J = 7.5 Hz, 1H), 7.23 (d, J = 8.0 Hz, 2H), 7.17 (t, J = 204.0751, found: 204.0749. IR (neat) ν 3034, 2927, 1603, 1507,
7.5 Hz, 1H), 7.02–7.00 (m, 3H), 3.95 (s, 2H), 2.30 (s, 3H). 13C 1225, 1156, 1099, 1010, 851, 819, 763 cm−1
NMR (125 MHz, CDCl3) δ 141.0, 140.9, 140.4, 139.0, 138.0,
.
Compound 4ab.17 Yellow liquid (115.6 mg, 83%). 1H NMR
129.7, 129.3, 128.7, 128.4, 127.1, 127.02, 126.96, 126.9, 126.0, (500 MHz, CDCl3, TMS) δ 8.52 (d, J = 4.0 Hz, 1H), 7.54 (t, J =
41.5, 21.4. MS (EI, %) m/z 258 (M+, 100), 243 (45), 165 (38). 7.5 Hz, 1H), 7.17 (d, J = 8.5 Hz, 2H), 7.08–7.06 (m, 2H), 6.83 (d,
HRMS (EI) calcd for C20H18: 258.1409, found: 258.1407. IR J = 8.5 Hz, 2H), 4.09 (s, 2H), 3.75 (s, 3H). 13C NMR (125 MHz,
(neat) ν 1606, 1484, 1411, 1335, 1003, 915, 882, 848, 818, 785, CDCl3) δ 161.3, 158.1, 149.1, 136.3, 131.5, 129.9, 122.8, 121.0,
765, 740, 688 cm−1
Compound 4v. Yellow liquid (143.9 mg, 97%). 1H NMR
.
113.9, 55.1, 43.7.
Compound 4ac.18 Yellow liquid (114.2 mg, 82%). 1H NMR
(500 MHz, CDCl3, TMS) δ 7.19–7.12 (m, 2H), 7.05–6.97 (m, (500 MHz, CDCl3, TMS) δ 8.52 (d, J = 4.5 Hz, 1H), 7.52 (t, J =
4H), 6.87–6.83 (m, 2H), 3.93 (s, 2H), 3.78 (s, 3H), 2.29 (s, 3H). 8.0 Hz, 1H), 7.22 (t, J = 8.0 Hz, 1H), 7.18 (d, J = 8.0 HZ, 1H),
13C NMR (125 MHz, CDCl3) δ 157.3, 140.9, 137.7, 130.3, 129.8, 7.09–7.05 (m, 2H), 6.92–6.86 (m, 2H), 4.17 (s, 2H), 3.78 (s, 3H).
129.7, 128.1, 127.3, 126.5, 126.0, 120.4, 110.4, 55.3, 35.7, 21.4. 13C NMR (125 MHz, CDCl3) δ 161.0, 157.4, 149.0, 136.2, 130.8,
MS (EI, %) m/z 212 (M+, 100), 197 (53), 181 (38), 165 (39). 127.9, 127.7, 122.9, 120.8, 120.6, 110.5, 55.3, 38.7.
HRMS (EI) calcd for C15H16O: 212.1201, found: 212.1199.
IR (neat) ν 3021, 2921, 2835, 1600, 1494, 1457, 1249, 1186, (500 MHz, CDCl3, TMS) δ 7.07 (d, J = 9.0 Hz, 4H), 6.80 (d, J =
1106, 1050, 1033, 798, 750, 695 cm−1 9.0 Hz, 4H), 3.84 (s, 2H), 3.74 (s, 6H). 13C NMR (125 MHz,
Compound 4w.17 Yellow liquid (146.9 mg, 99%). 1H NMR CDCl3) δ 157.9, 133.7, 129.7, 113.8, 55.2, 40.1.
Compound 4ad.19 White solid (154.8 mg, 97%). 1H NMR
.
(500 MHz, CDCl3, TMS) δ 7.13–7.11 (m, 3H), 7.07–7.06 (m,
Compound 4ae. White solid (176.4 mg, 92%). Mp: 86–88 °C.
1H), 7.02 (d, J = 8.0 Hz, 2H), 6.80 (d, J = 8.0 Hz, 2H), 3.90 (s, 1H NMR (500 MHz, CDCl3, TMS) δ 7.55 (d, J = 8.0 Hz, 2H), 7.49
2H), 3.74 (s, 3H), 2.22 (s, 3H). 13C NMR (125 MHz, CDCl3) (d, J = 8.0 Hz, 2H), 7.38 (t, J = 8.0 Hz, 2H), 7.29 (t, J = 8.0 Hz,
δ 157.8, 139.3, 136.4, 132.4, 130.2, 129.7, 129.6, 126.3, 125.9, 1H), 7.22 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 8.5 Hz, 2H), 6.82 (d, J =
113.8, 55.1, 38.5, 19.5.
8.5 Hz, 2H), 3.93 (s, 2H), 3.74 (s, 3H). 13C NMR (125 MHz,
Compound 4x. White solid (168.0 mg, 93%). Mp: 72–73 °C. CDCl3) δ 158.0, 141.0, 140.7, 138.9, 133.1, 129.8, 129.2, 128.7,
1H NMR (500 MHz, CDCl3, TMS) δ 7.54 (d, J = 7.5 Hz, 2H), 7.48 127.1, 127.0, 126.9, 113.9, 55.2, 40.6. MS (EI, %) m/z 274
(d, J = 7.5 Hz, 2H), 7.39 (t, J = 7.5 Hz, 2H), 7.29 (t, J = 7.5 Hz, (M+, 100). HRMS (EI) calcd for C20H18O: 274.1358, found:
1H), 7.18–7.14 (m, 6H), 4.00 (s, 2H), 2.25 (s, 3H). 13C NMR 274.1354. IR (neat) ν 3023, 2946, 2923, 2828, 1612, 1579, 1505,
(125 MHz, CDCl3) δ 141.0, 139.5, 138.9, 138.8, 136.6, 130.3, 1313, 1293, 1245, 1171, 1106, 1030, 908, 855, 817, 802, 766,
129.9, 129.1, 128.7, 127.1, 127.0, 126.9, 126.5, 126.0, 39.1, 19.7. 756, 728, 700 cm−1
.
MS (EI, %) m/z 258 (M+, 100), 243 (49), 165 (36), 104 (37).
Compound 4af. White solid (165.1 mg, 90%). Mp: 58–59 °C.
HRMS (EI) calcd for C20H18: 258.1409, found: 258.1413. 1H NMR (500 MHz, CDCl3, TMS) δ 7.55 (d, J = 8.0 Hz, 2H), 7.50
IR (neat) ν 2954, 1597, 1507, 1481, 1441, 1401, 1378, 1109, (d, J = 8.0 Hz, 2H), 7.39 (t, J = 7.5 Hz, 2H), 7.30 (t, J = 7.5 Hz,
1070, 1003, 904, 814, 771, 756, 746, 725, 695 cm−1
.
1H), 7.20 (d, J = 8.0 Hz, 2H), 7.14 (dd, J = 8.0, 5.5 Hz, 2H), 6.96
Compound 4y.17 Yellow liquid (145.2 mg, 96%). 1H NMR (t, J = 8.0 Hz, 2H), 3.95 (s, 2H). 13C NMR (125 MHz, CDCl3)
(500 MHz, CDCl3, TMS) δ 7.10 (dd, J = 8.5, 5.5 Hz, 2H), 7.07 (d, δ 161.5 (d, JC–F = 242.625 Hz), 140.9, 140.0, 139.2, 136.6 (d, JC–F
=
J = 8.5 Hz, 2H), 6.94 (t, J = 8.5 Hz, 2H), 6.82 (d, J = 8.5 Hz, 2H), 3.125 Hz), 130.3 (d, JC–F = 7.75 Hz), 129.2, 128.7, 127.2, 127.1,
3.87 (s, 2H), 3.76 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 161.4 127.0, 115.2 (d, JC–F = 21.0 Hz), 40.7. MS (EI, %) m/z 262
(d, JC–F = 242.25 Hz), 158.1, 137.2 (d, JC–F = 3.25 Hz), 133.0, (M+, 100). HRMS (EI) calcd for C19H15F: 262.1158, found:
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262.1157. IR (neat) ν 2917, 2846, 1600, 1505, 1488, 1437, 1402,
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R. P. Martinez, M. A. Lewis, H. R. Almond and A. B. Reitz,
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M. Labelle, C. F. Sturino, N. Sawyer, N. Tremblay,
S. Lamontagne, M. C. Carriere, D. Denis and K. M. Metters,
Bioorg. Med. Chem., 2001, 9, 1977; (f) K. L. McPhail,
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L. S. Payne, T. E. Fisher, M. W. Embrey, L. O. Tran,
J. Y. Melamed, H. M. Langford, J. P. Guare Jr., L. Zhuang,
V. E. Grey, J. P. Vacca, M. K. Holloway, A. M. Naylor-Olsen,
D. J. Hazuda, P. J. Felock, A. L. Wolfe, K. A. Stillmock,
W. A. Schleif, L. J. Gabryelski and S. D. Young, J. Med.
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S. F. Queener, J. Med. Chem., 1997, 40, 3032.
1216, 1157, 865, 824, 807, 775, 745, 728, 686 cm−1
.
Acknowledgements
Financial support from the National Natural Science Foun-
dation of China (no. 21471115) is greatly appreciated.
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