An efficient C-C bond formation reaction for the synthesis of α-arylated ketones under mild conditions

Article abstract of DOI:10.1016/j.tetlet.2012.11.024

A wide range of substituted α-arylated ketones were synthesized in moderate to excellent yields via a Truce Smiles rearrangement. The main scaffold has various applications in medical and biochemical fields. This process also provides a facile and direct method for the C-C bond formation.

Full text of DOI:10.1016/j.tetlet.2012.11.024

Tetrahedron Letters 54 (2013) 402–405
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An efficient C–C bond formation reaction for the synthesis of
under mild conditions
a-arylated ketones
Yanli Liu a, , Xinhai Zhang a, , Ying Ma a, , Chen Ma a,b,
⇑
⇑
a School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, PR China
b State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 June 2012
Revised 29 October 2012
Accepted 6 November 2012
Available online 20 November 2012
A wide range of substituted
a-arylated ketones were synthesized in moderate to excellent yields via a
Truce Smiles rearrangement. The main scaffold has various applications in medical and biochemical
fields. This process also provides a facile and direct method for the C–C bond formation.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
a-Arylated ketones
Truce Smiles rearrangement
C–C bond formation
Mild reaction condition
O
O
Z1
Z2
Introduction
Y
X
3a-f
K2CO3 DMSO r.t.
Z3 Z2
Z1
Z3
Y
+
The a-arylated ketones are important components of many nat-
OH
Cs2CO3 CH3CN reflux
OH
ural products, synthetic intermediates, and precursors of natural
analogues such as Coumestan,1 Phenylbenzofurans,2 and Isoflav-
ones (Fig. 1).3 Therefore, many synthetic approaches have been re-
ported to construct these scaffolds, including the Friedel–Crafts
reaction of phenols with various phenylacetic acids in BF3–Et2O,4
3g-m
3
1
2
Z1 = CH, N
Z2 = CH, N
Z3 = CH, N
Z1 = CH, N
Z2 = CH, N
Z3 = CH, N
the palladium-catalyzed
a
-arylation of ketones and esters,5 (N-
heterocyclic carbene)-Pd-catalyzed anaerobic oxidation of secondary
alcohols and domino oxidation-arylation reactions,5 the Grignard
reaction of benzamides with benzylmagnesium halides,6 and nick-
el catalyzed electrosynthesis of ketones from organic halides and
iron pentacarbonyl.7 However, most of the procedures use metal
Scheme 1. Synthesis of substituted
a
-arylated ketones.
Table 1
Optimization of the reaction conditions
N
THP
O
O
O
N
Cl
N
+
N
Cl
THP
Cl
O
OH
OH
O
1a
2a
3a
O
Ph
R
O
O
Entry
Base
Solvent
Temp/°C
Time/h
Yield/%
Coumestan
Isoflavones
Phenylbenzofurans
O
1
2
3
4
5
6
7
8
K2CO3
Cs2CO3
NaH
DMF
DMF
DMF
DMF
DMSO
DMSO
DMF
DMSO
DMSO
CH3CN
CH3CN
120
120
120
rt
rt
rt
80
80
80
80
80
0.8
0.9
1.2
21
20
20
4
4
4
30
23
58
52
41
77
97
84
76
68
62
89
93
R
Ph
K2CO3
K2CO3
Cs2CO3
K2CO3
K2CO3
Cs2CO3
K2CO3
Cs2CO3
O
Figure 1. Structure of coumestan, phenylbenzofuran, and isoflavones.
9
10
11
⇑
Corresponding authors.
E-mail addresses: Maying@sdu.edu.cn (Y. Ma), chenma@sdu.edu.cn (C. Ma).
These authors contributed equally to this work.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.11.024

Y. Liu et al. / Tetrahedron Letters 54 (2013) 402–405
403
Table 2
Synthesis of a variety of
Table 2 (continued)
Entry 2a–m
a
-arylated ketones10
Base
Solvent Time/h Yield/%
O
O
Z1
Z2
Y
K2CO3 DMSO r.t. 3a-f
F
Z3
Z2
Z3
Y
+
14
15
Cs2CO3 CH3CN
10
8
Not detected
OH
X
Z1
Cs2CO3 CH3CN reflux
OH
O2N
3g-m
2n
3a-m
1
2
F
Z1 = CH, N
Z2 = CH, N
Z3 = CH, N
Z1 = CH, N
Z2 = CH, N
Z3 = CH, N
Cs2CO3 CH3CN
Not detected
O2N
2o
NH
O
Entry 2a–m
Base
Solvent Time/h Yield/%
O
N
THP
O
Cl
O
N
THP
O
N
N
N
1
K2CO3
DMSO
DMSO
DMSO
14.5
4
97
69
88
Cl
2a
Cl
NO2
OH
OH3b
NO2
3a
2
K2CO3
K2CO3
N
Cl
F
NO2
F
2b
O
O
F
3
17
NO2
O2N
F
OH
3c
OH 3d
2c
F
OH
O
CF3
CN
O
N
4
K2CO3
DMSO
23
65
O
F
NO2
2d
O
Cl
NO2
O2N
F3C
Cl
OH
3e
5
K2CO3
K2CO3
DMSO
DMSO
1
84
64
3f
N
2e
N
Cl
O
O
F
F
N
6
11
O2N
NO2
NO2
NO2
F
2f
OH
OH
Cl
3h
3g
7
8
9
Cs2CO3 CH3CN
Cs2CO3 CH3CN
Cs2CO3 CH3CN
6
5
4
70
50
77
CF3
CN
O
N
NO2
NC
2g
O
N
NO2
OH
OH
N
Cl
2h
3j
3i
Cl
NO2
O
O
F3C
2i
NO2
Cl
NO2
Cl
OH
N
OH3k
10
11
Cs2CO3 CH3CN
Cs2CO3 CH3CN
1
1
91
63
3l
2j
F
F
O
NC
2k
NO 2
OH
Cl
Cl
3m
12
13
Cs2CO3 CH3CN
Cs2CO3 CH3CN
9
8
50
55
O2N
Figure 2. Structures of desired compounds 3a–m.
2l
NO2
catalysts or the Grignard reagent, which is not eco-friendly or sen-
sitive to air and moisture.
F
2m
Truce Smiles rearrangement has become a powerful and flexible
method in pharmaceutical, biomedical, and optical chemistry.8

404
Y. Liu et al. / Tetrahedron Letters 54 (2013) 402–405
O
O
Cl
N
N
Base
+
N
OH
Cl
O
N
O
THP
THP
O
Cl
1
2a
4
O
N
THP
O
O
N
Base
O
O
N
N
N
Cl
O
N
OH
Cl
THP
THP
Cl
O
O
3
5
6
Scheme 2. A plausible reaction mechanism.
N
THP
O
Table 3
O
O
N
Exploration to the scope of the methodology
Cl
Cl
K2CO3 DMSO
r.t.-80 oC
N
N
+
F
F
Cl
THP
O
O
O2N
K2CO3 DMSO r.t.
2a
7
8
3n-q
R
+
O
OH
Scheme 3. An evidence on the Truce Smiles rearrangement.
Cl
Cl
THP
N
N
R = Cl, Me
Recently, our lab has reported the synthesis of several different
kinds of heterocyclic compounds via the Smiles rearrangement.9
Herein, we report an efficient C–C bond formation reaction for
2
1
Entry
1
Substrate 1
Substrate 2
Time/h
Yields/%
81
the synthesis of a variety of substituted
a-arylated ketones
O
F
using readily available 1-(2-hydroxyphenyl)ethanone and substi-
tuted benzenes or pyridines via a Truce Smiles rearrangement
(Scheme 1).
Cl
10
O2N
F
OH
O
F
Results and discussion
2
3
4
8
82
71
79
O2N
F
At first, 2a and 1 were chosen as the starting materials to
optimize the reaction conditions including bases and solvents. As
shown in Table 1, it is interesting to find that K2CO3 was the most
suitable base while DMSO was the best solvent, affording the
desired product in 97% yield (Table 1, entry 6). The following
investment on the condition suggested Cs2CO3–CH3CN system also
performed well in this case (entry 11).
Under the optimized reaction conditions, we investigated the
scope of the substituted benzenes 2. The reaction of 2a–e with 1
gave the corresponding products in good to excellent yields from
65–97% (Table 2, entries 1–5). However, the reaction of 2f with 1
did not proceed as the route we thought, instead, 3f was observed
as the sole product (Table 2, entry 6).
OH
O
O
Cl
Cl
THP
N
18
N
Cl
OH
O
O
Cl
THP
N
15
N
Cl
OH
In order to shorten the reaction time, we treated 1 with 2g–m
in the presence of Cs2CO3 in CH3CN at reflux temperature, and
the corresponding products were obtained in moderate to excel-
lent yields (Table 2, entries 7–13). We note that the methodology
has better tolerance to substrate with electron-withdrawing group.
We have examined several examples with electron-donating
group, but only 2-fluoro-4-methyl-1-nitrobenzene could lead to
NO2
NO2
O
O
Cl
F
F
OH
OH
3n
3o
N
THP
O
N
O N
THP
O
the desired product. Obviously
a substrate with electron-
O
N
withdrawing group performed better. The structures of desired
compounds were shown in Figure 2.
The plausible mechanism was presented in Scheme 2. 1 reacted
with 2a to give 4, which then underwent the Smiles rearrange-
ment, affording the desired product 3. The reaction of acetophe-
none with 2 did not occur even when the temperature was up to
Cl
Cl
Cl
OH
OH
3p
3q
Figure 3. Structures of desired compounds 3n–q.

Y. Liu et al. / Tetrahedron Letters 54 (2013) 402–405
405
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80 °C, which indicated that the reaction did proceed via the Truce
Smiles rearrangement (Scheme 3).
To explore the scope of the methodology, we employed
1-(5-chloro-2-hydroxyphenyl)ethanone and 1-(2-hydroxy-5-
methylphenyl)ethanone as substrates. The result was listed in
Table 3 and Figure 3. We are pleased to find the remarkable toler-
ance for the substrates to benzene and heterocyclic compound
with the yields ranging from 71% to 82%.
Conclusion
In conclusion, a variety of functionalized
a-arylated ketones
were systematically obtained in moderate to excellent yields via
the Truce Smiles rearrangement under mild conditions. This C–C
bond formation method for the construction of the a-arylated ke-
tones has wide applications in medicinal chemistry.
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10. A typical synthetic process and characterization data (NMR and MS): To a solution
of 1-(2-hydroxyphenyl)ethanone (150 mg, 1.1 mmol) in DMSO (10 mL) were
added 1,2-difluoro-4-nitrobenzene (150 mg, 0.92 mmol) and K2CO3 (380 mg,
2.76 mmol), then the mixture was stirred for 17 h at room temperature, and
then H2O (30 mL) was added and the mixture was extracted with EtOAc
(3 Â 25 mL). The combined organic layers were washed with sat. brine
(2 Â 20 mL), dried over MgSO4, filtered, and evaporated in vacuo. The crude
product was purified by column chromatography on silica gel (PE/EtOAc = 5:1)
to afford the desired product 3c as a yellow solid (222 mg, 88%). 1H NMR
(100 MHz, CDCl3) d 11.84 (s, 1H), 8.05–8.08 (dd, 1H, J = 1.92, 8.36 Hz), 7.99–
8.02 (dd, 1H, J = 2.2, 9.24 Hz), 7.85–7.88 (dd, 1H, J = 1.4, 8.04 Hz), 7.52–7.56 (m,
1H), 7.44–7.48 (m, 1H), 7.26 (s, 1H), 7.02–7.04 (dd, 1H, J = 0.6, 8.4 Hz). 6.96–
7.00 (m, 1H), 4.48 (s, 1H). 13C NMR (75 MHz, CDCl3) d 200.5, 162.7, 162.2,
158.9, 137.2, 132.5, 132.5, 129.7, 129.1, 128.9, 119.4, 119.3, 118.9, 118.7, 115.5,
111.2, 38.4. HRMS Calcd for C14H10FNO4, 275.0594. Found, 275.0667.
Acknowledgment
We are grateful to the National Science Foundation of China
(No. 21172131), IIFSDU (No. 2010TS052), and the State Key Labo-
ratory of Natural and Biomimetic Drugs of Peking University
(K20090205) for financial support of this research.
Supplementary data
Supplementary data (representative experimental procedures
and spectral data of compounds 3a–q are detailed.) associated with
this article can be found, in the online version, at http://dx.doi.org/
10.1016/j.tetlet.2012.11.024.
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