Synthesis of 2,4-bis(aryloxy)-1,5-diarylpentane-1,5-diones by base-mediated tandem reaction

Article abstract of DOI:10.1055/s-0032-1316752

A new, practical, base-mediated method has been developed for the synthesis of 2,4-bis(aryloxy)-1,5-diarylpentane-1,5-diones by a tandem α-methylenation-Michael reaction through activation of two C-Cl bonds. This method permits the use of dichloromethane instead of dibromomethane as a source of one carbon atom for the α-methylenation reaction. The products are useful in syntheses of polysubstituted pyridines and methylenebisbenzofurans. Georg Thieme Verlag Stuttgart ? New York.

Full text of DOI:10.1055/s-0032-1316752

PAPER
▌2919
paper
Synthesis of 2,4-Bis(aryloxy)-1,5-diarylpentane-1,5-diones by Base-Mediated
Tandem Reaction
2,4-Bis(aryloxy)-1,5-diarylpentane-1,5-diones
Ren-Jie Song,a Yan-Yun Liu,a Ji-Cheng Wu,a,b Yu Liu,a Guo-Bo Deng,a Xiao-Xu Qi,b Ye-Xiang Xie,*a Lu-Bin Gong,a,b
Wei Liu,a Jin-Heng Lia
a
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University,
Changsha 410082, P. R. of China
Fax +86(731)88872531; E-mail: jhli@hnu.edu.cn; E-mail: xieyexiang@hnu.edu.cn
b
Key Laboratory of Chemical Biology and Traditional Chinese Medicine Research (Ministry of Education), Hunan Normal University,
Changsha 410081, P. R. of China
Received: 25.05.2012; Accepted after revision: 26.06.2012
to give the bis-1,5-diketone 2 (Scheme 1).5 Bis-1,5-
Abstract: A new, practical, base-mediated method has been devel-
diketones6 play an important role in the chemical and
oped for the synthesis of 2,4-bis(aryloxy)-1,5-diarylpentane-1,5-di-
pharmaceutical industries because these compounds are
ones by a tandem α-methylenation–Michael reaction through
activation of two C–Cl bonds. This method permits the use of di-
important synthetic units for constructing complicated
chloromethane instead of dibromomethane as a source of one car- heterocyclic compounds such as bisbenzofurans7 or diox-
epines.8
bon atom for the α-methylenation reaction. The products are useful
in syntheses of polysubstituted pyridines and methylenebisbenzofu-
rans.
R1
R1
R1
R1
R2
CH2Cl2
1 as Michael donor
Key words: tandem reactions, ketones, Michael additions
CH2
R2
C
R2
C–Cl activation
base
R2
H2
Michael acceptor
1
2
A
α-Methylene ketones are important units in numerous bi-
ologically active natural products, such as parthenolides,
helenalin, and (+)-sclareolide.1 They are also valuable as
intermediates in organic synthesis.1f,2–4 Consequently, the
α-methylenation of ketones is an important transforma-
tion in organic synthesis.1,2 Generally, α-methylene ke-
tones are prepared by formation of the corresponding
Mannich bases from ketone derivatives with subsequent
deamination.1f,2,3 However, in many cases it is not possi-
ble to perform both the Mannich reaction and the deami-
Scheme 1 The base-mediated tandem method
We chose the reaction of 2-phenoxy-1-phenylethanone
(1a) with dichloromethane as a model reaction to study
the optimal conditions for the reaction, and our results are
summarized in Table 1. To our delight, treatment of sub-
strate 1a with dichloromethane and cesium carbonate af-
forded the desired product 2a in quantitative yield (Table
1, entry 1). Screening revealed that the amount of cesium
carbonate affected the reaction. When 1.0 or 0.2 equiva-
lents of cesium carbonate were used, the yield of 2a fell to
48% and 18%, respectively (entries 2 and 3). The temper-
ature also had a marked effect on the reaction. Whereas
product 2a was obtained in quantitative yield at 80 °C, the
yield fell to 16% at 50 °C (entry 4), and no reaction oc-
curred at room temperature (entry 5). We then examined
a series of other bases (cesium hydroxide, potassium tert-
butoxide, potassium carbonate, sodium ethoxide, potassi-
um hydrogen carbonate, diethylamine, and triethylamine)
(entries 6–12), all of which were less effective than cesi-
um carbonate. It is noteworthy that unsatisfactory results
were observed with the efficient Mannich bases diethyl-
amine and triethylamine (entries 11 and 12).2a The opti-
mal reaction conditions were also shown to be suitable
when the reaction was scaled up to 2.0 mmol of substrate
1a (entry 13).
nation in
a
single flask.1f,2 Moreover, these
transformations require excess amounts of both dibromo-
methane (10–25 equiv) and the secondary amine base (2–
10 equiv), resulting in waste and pollution, and limiting
their usefulness in organic synthesis. Although dichloro-
methane is less expensive and is usually employed as a
medium for these reactions, no examples have been re-
ported in which it replaces dibromomethane as a reactant.
This is because the simultaneous activation of the two C–
Cl bonds in dichloromethane is very difficult to achieve
and the development of new approaches for the activation
of C–Cl bonds presents a challenge.5 After a serial of tri-
als, we identified a novel base-mediated tandem method
for the synthesis of 2,4-bis(aryloxy)-1,5-diarylpentane-
1,5-diones through activation of the C–Cl bonds of di-
chloromethane. Intermediate A (Scheme 1) is generated
by α-methylenation of ketone 1 by using dichloromethane
as the methylene precursor. Intermediate A then under-
goes Michael addition with a second molecule of ketone 1
Having identified the optimal conditions, we explored the
scope of the tandem reaction (Table 2).9 We treated a va-
riety of 2-aryloxy-1-arylethanones 1b–n with dichloro-
methane in the presence of cesium carbonate, and we
obtained the corresponding products 2b–n smoothly in
moderate-to-excellent yields (entries 1–13). Initially, we
SYNTHESIS 2012, 44, 2919–2925
Advanced online publication: 01.08.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
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2
1
0
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DOI: 10.1055/s-0032-1316752; Art ID: SS-2012-H0473-OP
© Georg Thieme Verlag Stuttgart · New York

2920
R.-J. Song et al.
PAPER
corresponding product in 78% yield (entry 12). Further-
more, the heterocyclic substrate 2-phenoxy-1-(quinolin-
8-yl)ethanone (1n) also reacted with dichloromethane and
cesium carbonate to form the expected product 2n in 50%
yield (entry 13). With 1-methoxypropan-2-one (14), how-
ever, almost no reaction took place (entry 14).
Table 1 Screening of Optimal Conditions for the Tandem Reaction
Ph
O
O
Ph
O
O
base
Ph
Ph
+
Ph
CH2
CH2Cl2
O
80 °C
O
Ph
1a
2a
Table 2 Cesium Carbonate Mediated Synthesis of 2,4-Bis(aryloxy)-
1,5-diarylpentane-1,5-diones 2
Entrya
Base (equiv)
Temp (°C)
Yieldb (%)
R2
1
Cs2CO3 (2)
Cs2CO3 (1)
Cs2CO3 (0.2)
Cs2CO3 (2)
Cs2CO3 (2)
CsOH (2)
80
80
80
50
r.t.
80
80
80
80
80
80
80
80
quant
48
18
16
0
R2
2
O
O
Cs2CO3
(2 equiv)
R2
O
3
CH2Cl2
CH2
R1
O
80 °C
4
O
O
R1
5
1
R1
6
40
23
10
0
2
7
t-BuOK (2)
K2CO3 (2)
NaOEt (2)
KHCO3 (2)
Et2NH (2)
Et3N (2)
Entrya
Substrate
Product
Yieldb
(%)
8
9
R1
O
Ph
10
11
12
13c
0
O
R1
5
Ph
O
O
trace
88
O
Ph
R1
O
Cs2CO3 (2)
1
2
3
4
R1 = 4-Me (1b)
R1 = 4-MeO (1c)
R1 = 4-Cl (1d)
R1 = 4-F (1e)
R1 = 4-Me (2b)
91
83
80
76
a Reaction conditions: 1a (0.2 mmol), base, CH2Cl2 (1 mL), 16 h.
b Isolated yield.
R1 = 4-MeO (2c)
R1 = 4-Cl (2d)
R1 = 4-F (2e)
c 1a (2 mmol) and CH2Cl2 (2 mL)
examined the effects of substituents on the aryl ring of the
2-aryloxy moiety (entries 1–5). Several functional groups,
including methyl, methoxy, chloro, and fluoro groups
were well tolerated under the optimized conditions; for
example, the chloro-substituted substrate 1d reacted suc-
cessfully with dichloromethane and cesium carbonate to
give the desired product 2d in 80% yield (entry 3). 1-(1-
Naphthyl)-2-phenoxyethanone (1f) was also found to be a
suitable substrate for the reaction under the optimized
conditions (entry 5). We then examined a number of sub-
strates 1g–l bearing methyl, methoxy, or chloro substitu-
ents on the aryl ring of the 1-arylethanone moiety, and
these were also found to be suitable substrates for the re-
action with dichloromethane and cesium carbonate (en-
tries 6–11). Moreover, good yields were achieved with the
sterically hindered substrates 1h and 1k (entries 7 and 9).
For example, the 2-methoxylated substrate 1k reacted
with dichloromethane and cesium carbonate smoothly to
give the expected product 3k in 90% yield (entry 10). In-
terestingly, 2-(4-methoxyphenoxy)-1-phenylprop-2-en-1-
one (3i) was obtained as a byproduct in 7% yield from the
reaction of substrate 1i with dichloromethane (entry 8);
this provides supporting evidence for the formation of in-
termediate A (Scheme 1). 2-(1-Naphthyloxy)-1-phenyl-
ethanone (1m) also reacted successful to give the
Ph
Ph
O
O
O
O
Ph
O
5
quant
O
(1f)
(2f)
R2
R2
R2
O
O
Ph
Ph
Ph
O
O
O
O
6
7
R2 = 4-Me (1g)
R2 = 2-Me (1h)
R2 = 4-MeO (1i)
R2 = 3-MeO (1j)
R2 = 2-MeO (1k)
R2 = 4-Cl (1l)
R2 = 4-Me (2g)
R2 = 2-Me (2h)
83
73
89c
91
90
88
8
R2 = 4-MeO (2i)
R2 = 3-MeO (2j)
R2 = 2-MeO (2k)
R2 = 4-Cl (2l)
9
10
11d
Synthesis 2012, 44, 2919–2925
© Georg Thieme Verlag Stuttgart · New York

PAPER
2,4-Bis(aryloxy)-1,5-diarylpentane-1,5-diones
2921
Table 2 Cesium Carbonate Mediated Synthesis of 2,4-Bis(aryloxy)-
1,5-diarylpentane-1,5-diones 2 (continued)
O
O
Ph
O
O
O
R2
Ph
Ph
CO3 (2 equiv)
Cs2
CH Cl
+
CH2
2
2
80 °C, 16 h
O
Ph
R2
O
O
O
Cs2CO3
(2 equiv)
R2
O
2p (35%)
1p
O
CH2Cl2
CH2
R1
O
80 °C
Scheme 2 Synthesis of a dioxepine
O
O
R1
1
In an attempt to prepare nonsymmetric 2,4-bis(aryloxy)-
1,5-diarylpentane-1,5-diones, we examined cross reac-
tions between two different 2-phenoxy-1-arylethanones
under the optimized conditions (Scheme 3). Interestingly,
treatment of a 1:1 (molar) mixture of substrates 1a and 1f
with dichloromethane and cesium carbonate gave the
product 2af exclusively in quantitative yield, whereas the
corresponding reaction of substrates 1d and 1g (1:1 mo-
lar) with dichloromethane gave a 1:4:4 mixture or prod-
ucts 2d, 2g, and 2dg in 90% total yield (Scheme 3).
R1
2
Entrya
Substrate
Product
Yieldb
(%)
O
Ph
Ph
O
O
Ph
O
12
78
O
Methylenebisbenzofurans are an important class of het-
eroaromatic ring systems that are present in a wide range
of natural products.7 We therefore decided to attempt to
use products 2 in syntheses of these heteroaromatic ring
systems (Scheme 4). To our delight, the methylenebisben-
zofuran derivative 4a was obtained by an iron(III) bro-
mide-catalyzed Friedel–Crafts tandem cyclization of
dione 2a.
O
O
(1m)
(2m)
Ph
Ph
N
N
O
O
Ph
O
13e
50
To confirm the mechanism of the tandem coupling reac-
tion (Scheme 1), we carried out two control reactions
(Scheme 5). Treatment of ketone 1a with dichlorometh-
ane-d2 and cesium carbonate gave the corresponding
product 2a-d2 exclusively in good yield, confirming that
dichloromethane acts as a one-carbon source in the reac-
tion. Furthermore, the byproduct enone 3i from the reac-
tion of ketone 1i was converted into product 2i by Michael
addition to substrate 1i in the presence of cesium carbon-
ate.
O
N
O
(1n)
(2n)
MeO
OMe
OMe
O
O
O
14
trace
(1o)
(2o)
a Reaction conditions: 1 (0.2 mmol), Cs2CO3 (2.0 equiv), CH2Cl2 (1
In summary, we have developed a new, simple, base-me-
diated method for the synthesis of 2,4-bis(aryloxy)-1,5-
diarylpentane-1,5-diones through an α-methylenation–
Michael tandem process with activation of two C–Cl
bonds. The method permits the use of dichloromethane in-
stead of dibromomethane as a new one-carbon source for
the α-methylenation reaction. Importantly, the 2,4-bis(ar-
yloxy)-1,5-diarylpentane-1,5-dione products are versatile
intermediates for syntheses of polysubstituted pyridines
or bisbenzofurans. Efforts are under way to apply the re-
action and the products in organic synthesis.
mL), 80 °C, 16 h.
b Isolated yield.
c 2-(4-Methoxyphenoxy)-1-phenylprop-2-en-1-one (3i) was also ob-
tained in 7% yield.
d 2 h.
e 48 h.
This new method can also be applied in a synthesis of di-
oxepines.8
For
example,
2,2′-[1,2-phenylene-
bis(oxy)]bis(1-phenylethanone) (1p) underwent a smooth
tandem reaction with dichloromethane and cesium car-
bonate to afford the dioxepine 2p in 35% yield after 16
hours (Scheme 2).
NMR spectra were recorded on a Bruker Avance spectrometer op-
erating at 500 MHz (1H NMR) or 125 MHz (13C NMR). Mass spec-
trometric analyses were performed on
a GC/MS analyzer
(Shimadzu GCMS-QP2010) and by using a Thermo MAT95XP-
HRMS spectrometer in the EI mode. IR spectra were recorded on a
Bruker vertex 70 FT-IR spectrophotometer. Melting points were re-
corded using a Hanon MP 100 apparatus and are uncorrected.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2919–2925

2922
R.-J. Song et al.
PAPER
Ph
O
O
O
CH2Cl2
Ph
O
O
Ph
O
Ph
O
Cs2CO3
O
Ph
CH2
+
80 oC, 16 h
Ph
O
1a (0.2 mmol)
1f (0.2 mmol)
2af (quant.)
Ph
Ph
O
OMe
CH2Cl2
OMe
Cs2CO3
O
CH2
O
2g
O
2d
+
+
+
80 °C, 16 h
O
Ph
2dg
total yield: 90% (2d/2g/2dg = 1:4:4)
O
O
Ph
1g (0.2 mmol)
1d (0.2 mmol)
Scheme 3 Cross reactions of 2-phenoxy-1-arylethanones
1H NMR (500 MHz): δ = 8.13–8.09 (m, 4 H), 7.65–7.59 (m, 2 H),
7.54–7.47 (m, 4 H), 7.24–7.19 (m, 4 H), 6.97–6.92 (m, 2 H), 6.90–
6.85 (m, 4 H), 6.00–5.83 (m, 2 H), 2.88–2.11 (m, 2 H).
13C NMR (125 MHz): δ = 196.9, 196.6, 157.4, 156.9, 134.4, 134.1,
133.9, 129.6 (2 C), 129.0, 128.9, 128.8, 128.7, 122.0, 121.8, 115.5,
115.2, 76.2, 75.5, 36.8, 35.0.
LRMS (EI, 70 eV): m/z (%) = 436 [M+] (1), 231 (100), 105 (51).
HRMS (EI): m/z [M+] calcd for C29H24O4: 436.1675; found:
Ph
Ph
Ph
O
O
FeBr3 (20 mol%)
Ph
O
O
Ph
DCE, Ar, 120 °C, 16 h
O
4a (40%)
O
Ph
2a (0.2 mmol)
436.1672.
Scheme 4 Synthesis of a methylenebisbenzofuran from dione 2a
2,4-Diphenoxy-1,5-diphenylpentane-1,5-dione-d2 (2a-d2)
Colorless oil; yield: 40.3 mg [92%; two diastereomers (1:1)].
1H NMR (500 MHz): δ = 8.04–8.00 (m, 4 H), 7.56–7.50 (m, 2 H),
7.45–7.38 (m, 4 H), 7.17–7.11 (m, 4 H), 6.89–6.84 (m, 2 H), 6.82–
6.78 (m, 4 H), 5.89 (s, 1 H), 5.75 (s, 1 H).
2,4-Bis(aryloxy)-1,5-diarylpentane-1,5-diones 2; General Pro-
cedure
A Schlenk tube was charged with the appropriate 2-(aryloxy)-1-ar-
ylethan-1-one 1 (0.2 mmol), Cs2CO3 (130.4 mg, 2 equiv), and
CH2Cl2 (1.0 mL). The mixture was then stirred at 80 °C (oil bath
temperature) under air for the indicated time until the starting mate-
rial was consumed (TLC and GC/MS). When the reaction was com-
plete, the mixture was cooled to r.t, diluted with Et2O (10 mL), and
washed with brine (3 × 3 mL). The aqueous phase was extracted
with Et2O (3 × 5 mL) and the organic phases were combined, dried
(Na2SO4), and concentrated in vacuo. The residue was purified by
column chromatography (silica gel, hexane–EtOAc).
LRMS (EI, 70 eV): m/z (%) = 438 [M+] (2), 231 (100).
2,4-Diphenoxy-1,5-bis(4-tolyl)pentane-1,5-dione (2b)
Colorless oil; yield: 42.2 mg [91%; two diastereomers (1.3:1)].
IR (KBr): 1683, 1595 cm–1.
1H NMR (500 MHz): δ = 8.04–8.00 (m, 4 H), 7.31 (d, J = 8.0 Hz, 2
H), 7.27 (d, J = 8.0 Hz, 2 H), 7.24–7.18 (m, 4 H), 6.95–6.91 (m, 2
H), 6.89–6.84 (m, 4 H), 5.97–5.79 (m, 2 H), 2.86–2.59 (m, 2 H),
2.43 (s, 3 H), 2.41 (s, 3 H).
2,4-Diphenoxy-1,5-diphenylpentane-1,5-dione (2a)
13C NMR (125 MHz): δ = 196.5, 196.2, 157.4, 157.0, 145.2, 144.9,
131.9, 131.4, 129.8, 129.7, 129.6 (2 C), 129.5, 129.0, 128.9, 128.8,
121.8, 121.6, 115.5, 115.1, 76.1, 75.4, 60.4, 37.0, 35.1, 21.7, 21.0.
Colorless oil; yield: 43.6 mg [100%; two diastereomers (1.1:1)].
IR (KBr): 1693, 1587 cm–1.
Ph
O
O
Ph
O
O
Ph
Ph
Cs2CO3 (2.0 equiv)
80 °C, 16 h
O
CD2Cl2
+
CD2
Ph
O
1a
OMe
Ph
2a-d2 (92%)
Ph
O
OMe
O
Ph
O
O
OMe
1i
O
O
MeO
O
Cs2CO3 (2.0 equiv)
Ph
CH2Cl2, 80 °C, 24 h
3i
O
Ph
2i (90%)
Scheme 5 Two control reactions
Synthesis 2012, 44, 2919–2925
© Georg Thieme Verlag Stuttgart · New York

PAPER
2,4-Bis(aryloxy)-1,5-diarylpentane-1,5-diones
2923
LRMS (EI, 70 eV): m/z (%) = 464 [M+] (1), 371 (20), 345 (26), 251
(64), 223 (26), 158 (31), 119 (100).
LRMS (EI, 70 eV): m/z (%) = 536 [M+] (3), 443 (25), 416 (5), 381
(41), 287 (71), 194 (64), 155 (100).
HRMS (EI): m/z [M+] calcd for C31H28O4: 464.1988; found:
464.1985.
HRMS (EI): m/z [M+] calcd for C37H28O4: 536.1988; found:
536.1986.
1,5-Bis(4-methoxyphenyl)-2,4-diphenoxypentane-1,5-dione (2c)
Red oil; yield: 41.1 mg [83%; two diastereomers (1.2:1)].
2,4-Bis(4-methylphenoxy)-1,5-diphenylpentane-1,5-dione (2g)
Colorless oil; yield: 38.5 mg [83%; two diastereomers (1.1:1)].
IR (KBr): 1684, 1598 cm–1.
IR (KBr): 1691, 1593 cm–1.
1H NMR (500 MHz): δ = 8.13–8.09 (m, 4 H), 7.25–7.18 (m, 4 H),
6.98 (d, J = 8.5 Hz, 2 H), 6.96–6.91 (m, 4 H), 6.87 (t, J = 7.5 Hz, 4
H), 5.93–5.74 (m, 2 H), 3.89 (s, 3 H), 3.86 (s, 3 H), 2.86–2.60 (m, 2
H).
13C NMR (125 MHz): δ = 195.4, 195.1, 164.2, 164.1, 157.4, 157.0,
131.2, 131.1, 129.6, 127.4, 126.8, 121.8, 121.6, 115.4, 115.1, 114.2,
114.0, 76.1, 75.5, 55.6, 55.5, 37.2, 35.1.
1H NMR (500 MHz): δ = 8.13–8.08 (m, 4 H), 7.63–7.58 (m, 2 H),
7.52–7.45 (m, 4 H), 7.03–6.99 (m, 4 H), 6.80–6.75 (m, 4 H), 5.96–
5.77 (m, 2 H), 2.86–2.57 (m, 2 H), 2.25 (s, 3 H), 2.23 (s, 3 H).
13C NMR (125 MHz): δ = 197.2, 196.8, 155.4, 154.9, 134.5, 134.0
(2 C), 133.8, 131.3, 131.0, 129.0, 128.8, 128.7, 115.5, 115.1, 76.5,
75.8, 36.8, 34.9, 20.4.
LRMS (EI, 70 eV): m/z (%) = 464 [M+] (1), 371 (21), 251 (63), 119
(100).
LRMS (EI, 70 eV): m/z (%) = 496 [M+] (2), 403 (12), 376 (7), 361
(26), 308 (6), 267 (27), 239 (14), 174 (33), 135 (100).
HRMS (EI): m/z [M+] calcd for C31H28O6: 496.1886; found:
HRMS (EI): m/z [M+] calcd for C31H28O4: 464.1988; found:
464.1985.
496.1883.
2,4-Bis(2-methylphenoxy)-1,5-diphenylpentane-1,5-dione (2h)
Colorless oil; yield: 33.9 mg [73%; two diastereomers (1:1)].
1,5-Bis(4-chlorophenyl)-2,4-diphenoxypentane-1,5-dione (2d)
Colorless oil; yield: 40.3 mg [80%; two diastereomers (1.1:1)].
IR (KBr): 1695, 1589, 1491 cm–1.
1H NMR (500 MHz): δ = 8.06–8.03 (m, 4 H), 7.49–7.44 (m, 4 H),
7.27–7.19 (m, 4 H), 6.99–6.94 (m, 2 H), 6.86–6.84 (m, 4 H), 5.86–
5.73 (m, 2 H), 2.84–2.60 (m, 2 H).
13C NMR (125 MHz): δ = 196.0, 195.7, 157.1, 156.7, 140.7, 140.5,
132.6, 132.2, 130.3, 130.2, 129.7, 129.4, 129.2, 122.2, 122.0, 115.4,
115.1, 76.5, 75.7, 36.5, 34.8.
LRMS (EI, 70 eV): m/z (%) = 504 [M+] (1), 377 (23), 241 (15), 141
(100).
HRMS (EI): m/z [M+] calcd for C29H2235Cl2O4: 504.0895; found:
504.0894.
Diastereomer 1
IR (KBr): 1695, 1585, 1495 cm–1.
1H NMR (500 MHz): δ = 8.14 (d, J = 7.5 Hz, 4 H), 7.63 (t, J = 7.5
Hz, 2 H), 7.52 (t, J = 7.5 Hz, 4 H), 7.16 (d, J = 7.0 Hz, 2 H), 6.98–
6.95 (m, 2 H), 6.84 (t, J = 7.5 Hz, 2 H), 6.52 (d, J = 8.0 Hz, 2 H),
6.06–6.03 (m, 2 H), 2.69 (t, J = 6.5 Hz, 2 H), 2.45 (s, 6 H).
13C NMR (125 MHz): δ = 196.8, 155.3, 134.1, 133.9, 131.2, 129.0,
128.6, 126.8, 126.8, 121.4, 111.6, 75.8, 37.0, 16.6.
LRMS (EI, 70 eV): m/z (%) = 464 [M+] (1), 251 (62), 119 (100).
HRMS (EI): m/z [M+] calcd for C31H28O4: 464.1988; found:
464.1987.
Diastereomer 2
1,5-Bis(4-fluorophenyl)-2,4-diphenoxypentane-1,5-dione (2e)
Colorless oil
Colorless oil; yield: 35.9 mg [76%; two diastereomers (1.1:1)].
IR (KBr): 1695, 1585 cm–1.
IR (KBr): 1698, 1582, 1490 cm–1.
1H NMR (500 MHz): δ = 8.09 (d, J = 7.5 Hz, 4 H), 7.59 (t, J = 7.5
Hz, 2 H), 7.47 (t, J = 7.5 Hz, 4 H), 7.13 (d, J = 7.0 Hz, 2 H), 7.07 (d,
J = 7.5 Hz, 2 H), 6.86 (t, J = 7.5 Hz, 2 H), 6.79 (d, J = 8.5 Hz, 2 H),
5.89 (t, J = 6.0 Hz, 2 H), 2.97–2.69 (m, 2 H), 2.21 (s, 6 H).
13C NMR (125 MHz): δ = 196.7, 155.1, 134.5, 133.8, 131.2, 128.8
(2 C), 127.0, 126.8, 121.3, 111.4, 75.4, 34.4, 16.5.
LRMS (EI, 70 eV): m/z (%) = 464 [M+] (1), 251 (60), 119 (100).
HRMS (EI): m/z [M+] calcd for C31H28O4: 464.1988; found:
1H NMR (500 MHz): δ = 8.16–8.12 (m, 4 H), 7.26–7.12 (m, 8 H),
6.98–6.93 (m, 2 H), 6.87–6.85 (m, 4 H), 5.88–5.86 (m, 1 H), 5.77–
5.75 (m, 1 H), 2.85–2.61 (m, 2 H).
13C NMR (125 MHz): δ = 195.5, 195.2, 166.2 (d, JC–F = 255.4 Hz,
1 C), 166.1 (d, JC–F = 255.1 Hz, 1 C), 157.2, 156.7, 131.7 (d, JC–F
12.5 Hz, 1 C), 131.6 (d, JC–F = 12.5 Hz, 1 C), 130.6 (d, JC–F = 51.5
Hz, 1 C), 130.5 (d, JC–F = 51.9 Hz, 1 C), 129.7, 122.1, 122.0, 116.3,
116.1, 116.0, 115.4, 115.1, 114.7, 76.4, 75.7, 36.6, 34.8.
=
LRMS (EI, 70 eV): m/z (%) = 472 [M+] (1), 215 (12), 125 (100).
464.1985.
HRMS (EI): m/z [M+] calcd for C29H22F2O4: 472.1486; found:
472.1483.
2,4-Bis(4-methoxyphenoxy)-1,5-diphenylpentane-1,5-dione (2i)
Red oil; yield: 44.1 mg [89%; two diastereomers (1.1:1)].
IR (KBr): 1683, 1495 cm–1.
1,5-Di-1-naphthyl-2,4-diphenoxypentane-1,5-dione (2f)
White solid; yield: 53.6 mg [quant; two diastereomers (1.2:1)]; mp
127.6–131.3 °C.
IR (KBr): 1692, 1593 cm–1.
1H NMR (500 MHz): δ = 8.74 (s, 1 H), 8.69 (s, 1 H), 8.13–8.12 (m,
2 H), 8.01 (d, J = 8.0 Hz, 1 H), 7.94–7.87 (m, 5 H), 7.66–7.58 (m, 3
H), 7.54 (t, J = 7.5 Hz, 1 H), 7.23 (t, J = 8.0 Hz, 4 H), 6.98–6.90 (m,
6 H), 6.18–6.02 (m, 2 H), 3.05–2.77 (m, 2 H).
1H NMR (500 MHz): δ = 8.10–8.07 (m, 4 H), 7.63–7.58 (m, 2 H),
7.51–7.45 (m, 4 H), 6.87–6.73 (m, 8 H), 5.92–5.72 (m, 2 H), 2.80
(s, 3 H), 2.68 (s, 3 H), 2.84–2.53 (m, 2 H).
13C NMR (125 MHz): δ = 197.4, 197.0, 154.7, 154.5, 151.7, 151.1,
134.5, 134.0, 133.8, 129.0, 128.8 (2 C), 128.7, 117.0, 116.5, 114.7,
77.3, 76.6, 55.6 (2 C), 36.9, 35.2.
LRMS (EI, 70 eV): m/z (%) = 496 [M+] (3), 373 (35), 267 (14), 237
13C NMR (125 MHz): δ = 196.8, 196.6, 157.5, 157.0, 140.0, 135.9,
132.5 (2 C), 131.7, 131.2, 130.8, 130.7, 129.9, 129.8, 129.7 (2 C),
129.1, 129.0, 128.8, 127.9, 127.8, 127.1, 126.9, 124.1, 124.0, 122.0,
121.8, 115.5, 115.2, 76.5, 75.8, 37.2, 35.8.
(100), 123 (90).
HRMS (EI): m/z [M+] calcd for C31H28O6: 496.1886; found:
496.1883.
2,4-Bis(3-methoxyphenoxy)-1,5-diphenylpentane-1,5-dione (2j)
Red oil; yield: 45.1 mg [91%; two diastereomers (1.3:1)].
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2919–2925

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R.-J. Song et al.
PAPER
IR (KBr): 1683, 1595 cm–1.
HRMS (EI): m/z [M+] calcd for C37H28O4: 536.1988; found:
536.1986.
1H NMR (500 MHz): δ = 8.10 (t, J = 7.0 Hz, 4 H), 7.64–7.58 (m, 2
H), 7.53–7.46 (m, 4 H), 7.14–7.07 (m, 2 H), 6.52–6.49 (m, 3 H),
6.49–6.43 (m, 3 H), 5.97–5.80 (m, 2 H), 3.73 (s, 3 H), 3.70 (s, 3 H),
2.70–2.59 (m, 2 H).
13C NMR (125 MHz): δ = 196.8, 196.5, 160.8, 158.6, 158.1, 134.4,
134.1, 133.9, 130.1 (2 C), 129.0, 128.9, 128.8, 128.7, 107.7, 107.5,
107.4, 107.0, 102.2, 101.8, 76.2, 75.5, 55.2 (2 C), 36.6, 34.9.
LRMS (EI, 70 eV): m/z (%) = 496 [M+] (2), 376 (9), 267 (27), 135
(100).
HRMS (EI): m/z [M+] calcd for C31H28O6: 496.1886; found:
496.1884.
1,5-Diphenyl-2,4-bis(quinolin-8-yloxy)pentane-1,5-dione (2n)
Red oil; yield: 26.9 mg (50%).
IR (KBr): 1691, 1597, 1569 cm–1.
1H NMR (500 MHz): δ = 8.45–8.40 (m, 6 H), 7.99 (d, J =8.0 Hz, 2
H), 7.62 (t, J =7.0 Hz, 2 H), 7.57–7.54 (m, 4 H), 7.32 (d, J =8.0 Hz,
2 H), 7.24–7.20 (m, 4 H), 7.08 (d, J =8.5 Hz, 2 H), 6.87 (d, J =7.0
Hz, 2 H), 2.93–2.91 (m, 2 H).
13C NMR (125 MHz): δ = 197.1, 153.9, 148.8, 140.9, 135.6, 134.3,
133.7, 129.5, 129.0, 126.3, 121.4, 121.3, 114.6, 79.7, 38.1.
LRMS (EI, 70 eV): m/z (%) = 538 [M+] (1), 394 (41), 376 (3), 288
(65), 275 (5), 170 (95), 105 (100).
HRMS (EI): m/z [M+] calcd for C35H26N2O4: 538.1893; found:
538.1889.
2,4-Bis(2-methoxyphenoxy)-1,5-diphenylpentane-1,5-dione
(2k)
Red oil; yield: 44.6 mg [90%; two diastereomers (1.3:1)].
IR (KBr): 1688, 1575 cm–1.
3,4-Dihydro-2H-1,5-benzodioxepine-2,4-diylbis(phenylmetha-
none) (2p)
Colorless oil; yield: 12.5 mg (35%).
IR (KBr): 1698, 1585 cm–1.
1H NMR (500 MHz): δ = 8.00 (d, J = 7.0 Hz, 4 H), 7.62 (t, J = 7.5
Hz, 2 H), 7.50 (t, J = 7.5 Hz, 4 H), 6.99 (s, 4 H), 5.84 (t, J = 7.5 Hz,
2 H), 2.81–2.78 (m, 2 H).
13C NMR (125 MHz): δ = 195.4, 149.0, 134.6, 133.9, 129.0, 128.8,
123.9, 121.3, 79.1, 33.9.
1H NMR (500 MHz): δ = 8.23 (d, J = 7.5 Hz, 3 H), 8.15 (d, J = 7.0
Hz, 1 H), 7.62–7.55 (m, 2 H), 7.52–7.44 (m, 4 H), 7.05–6.90 (m, 3
H), 6.86–6.81 (m, 4 H), 6.78–6.74 (m, 1 H), 6.18 (t, J = 3.5 Hz, 1
H), 5.94 (d, J = 6.5 Hz, 1 H), 3.62 (s, 3 H), 3.59 (s, 3 H), 2.93–2.56
(m, 2 H).
13C NMR (125 MHz): δ = 197.0, 196.8, 150.3, 150.2, 147.3, 146.5,
134.8, 133.9, 133.8, 133.5, 129.0, 128.9, 128.8, 128.7, 128.6, 128.0,
122.9, 122.8, 120.9, 120.7, 117.8, 117.1, 112.3, 112.0, 78.8, 76.8,
55.5, 55.4, 38.0, 34.4.
LRMS (EI, 70 eV): m/z (%) = 496 [M+] (1), 403 (10), 361 (24), 135
(100).
LRMS (EI, 70 eV): m/z (%) = 358 [M+] (6), 253 (65), 144 (28), 121
(54), 105 (100).
HRMS (EI): m/z [M+] calcd for C31H28O6: 496.1886; found:
496.1885.
HRMS (EI): m/z [M+] calcd for C23H18O4: 358.1205; found:
358.1202.
2,4-Bis(4-chlorophenoxy)-1,5-diphenylpentane-1,5-dione (2l)
1-(1-Naphthyl)-2,4-diphenoxy-5-phenylpentane-1,5-dione (2af)
White solid; yield: 48.6 mg [quant, two diastereomers (1:1)]; mp
106.4–108.1 °C.
IR (KBr): 1695, 1589, 1487 cm–1.
1H NMR (500 MHz): δ = 8.74–8.70 (m, 1 H), 8.15–8.09 (m, 3 H),
8.02–7.87 (m, 3 H), 7.66–7.46 (m, 5 H), 7.25–7.20 (m, 4 H), 6.98–
6.85 (m, 6 H), 6.18–5.83 (m, 2 H), 3.04–2.62 (m, 2 H).
13C NMR (125 MHz): δ = 196.9 (2 C), 196.8, 196.6, 171.1, 157.4 (3
C), 157.0, 156.9, 136.0, 135.9, 134.4 (2 C), 134.1, 133.9, 132.5,
132.4, 131.7 (2 C), 131.2, 130.8, 130.7 (2 C), 129.9, 129.8, 129.7 (2
C), 129.6, 129.1, 129.0 (2 C), 128.9, 128.8, 128.7 (2 C), 127.8 (2 C),
127.1, 126.9, 124.1 (2 C), 124.0, 123.9, 122.0, 121.8, 115.5, 115.2
(2 C), 76.4, 76.3, 76.2, 75.8, 75.6 (2 C), 75.5, 37.2, 37.0, 36.8, 35.3,
35.0.
Colorless oil; yield: 44.3 mg [88%; two diastereomers (1.3:1)].
IR (KBr): 1691, 1593 cm–1.
1H NMR (500 MHz): δ = 8.08–8.05 (m, 4 H), 7.66–7.61 (m, 2 H),
7.54–7.48 (m, 4 H), 7.20–7.15 (m, 4 H), 6.83–6.80 (m, 2 H), 6.80–
6.74 (m, 4 H), 5.91–5.77 (m, 2 H), 2.88–2.60 (m, 2 H).
13C NMR (125 MHz): δ = 196.4, 196.0, 155.9, 155.4, 1343, 134.1,
133.7, 129.6, 129.5, 129.1, 129.0, 128.7, 128.6, 127.1, 126.8, 116.8,
116.5, 76.5, 75.8, 36.6, 35.3.
LRMS (EI, 70 eV): m/z (%) = 504 [M+] (1), 399 (4), 377 (29), 271
(32), 241 (16), 144 (34), 105 (100).
HRMS (EI): m/z [M+] calcd for C29H2235Cl2O4: 504.0895; found:
504.0893.
LRMS (EI, 70 eV): m/z (%) = 486 [M+] (1), 393 (41), 331 (23), 287
(14), 237 (100), 105 (69).
HRMS (EI): m/z [M+] calcd for C33H26O4: 486.1831; found:
486.1834.
2,4-Bis(1-naphthyloxy)-1,5-diphenylpentane-1,5-dione (2m)
White solid, yield: 41.8 mg [78%; two diastereomers (1.3:1)]; mp
111.4–112.1 °C.
IR (KBr): 1693, 1573 cm–1.
1H NMR (500 MHz): δ = 8.50 (d, J =8.5 Hz, 1 H), 8.24 (d, J =8.5
Hz, 1 H), 8.20 (d, J =7.5 Hz, 2 H), 8.12 (d, J =8.0 Hz, 2 H), 7.80–
7.77 (m, 2 H), 7.63 (t, J =7.5 Hz, 1 H), 7.56–7.24 (m, 11 H), 7.09
(d, J =8.0 Hz, 1 H), 6.82 (d, J =7.5 Hz, 1 H), 6.57 (t, J =7.5 Hz, 1
H), 6.32 (d, J =6.5 Hz, 1 H), 6.11 (d, J =6.0 Hz, 2 H), 3.14–2.92 (m,
2 H).
13C NMR (125 MHz): δ = 196.6 (2 C), 152.8, 152.6, 134.7 (2 C),
134.3, 134.2, 134.1, 134.0, 129.1, 128.9, 128.8, 128.7, 127.7, 127.5,
126.6, 125.6, 125.5 (3 C), 122.0, 121.8, 121.5 (3 C), 106.1, 105.7,
76.5, 76.0, 36.9, 34.9.
1-(4-Methoxyphenyl)-4-(4-methylphenoxy)-2-phenoxy-5-
phenylpentane-1,5-dione (2dg)
Red oil; yield: 38.4 mg [40%, two diastereomers (1.2:1)].
IR (KBr): 1693, 1579 cm–1.
1H NMR (500 MHz): δ = 8.12–8.08 (m, 4 H), 7.63–7.57 (m, 1 H),
7.52–7.45 (m, 2 H), 7.23–7.19 (m, 2 H), 7.03 (d, J = 8.0 Hz, 1 H),
7.00–6.97 (m, 2 H), 6.94 (d, J = 8.5 Hz, 2 H), 6.88 (d, J = 8.0 Hz, 1
H), 6.84 (d, J = 8.0 Hz, 1 H), 6.78 (d, J = 8.0 Hz, 2 H), 5.94–5.75
(m, 2 H), 3.89 (s, 3 H), 2.86–2.55 (m, 2 H), 2.25 (s, 3 H).
13C NMR (125 MHz): δ = 197.2, 196.9, 195.4, 195.1, 164.2, 164.1,
157.5, 157.0, 155.4, 154.9, 134.5, 134.0 (2 C), 133.8, 131.3, 131.2,
131.1, 131.0, 130.0, 129.6 (2 C), 129.0, 128.8, 128.7, 127.4, 126.9,
LRMS (EI, 70 eV): m/z (%) = 536 [M+] (4), 393 (23), 287 (8), 257
(100), 105 (96).
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2,4-Bis(aryloxy)-1,5-diarylpentane-1,5-diones
2925
121.8, 121.6, 115.5 (2 C), 115.1, 114.2, 114.1, 76.6, 76.0, 75.9,
75.5, 55.6, 55.5, 37.0, 35.1, 22.6, 20.4.
LRMS (EI, 70 eV): m/z (%) = 480 [M+] (1), 345 (23), 251 (7), 135
Kan-Fan, C.; Potier, P. Bull. Soc. Chim. Fr. 1970, 2707.
(d) Holy, N. L.; Wang, Y. F. J. Am. Chem. Soc. 1977, 99,
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1961, 744. (f) Angeloni, A. S.; Angiolini, L.; De Maria, P.;
Fini, A. J. Chem. Soc. C 1968, 2295. (g) Johnson, W. S.;
Szmuszkovicz, J.; Rogier, E. R.; Hadler, H. I.; Wynberg, H.
J. Am. Chem. Soc. 1956, 78, 6285.
(100).
HRMS (EI): m/z [M+] calcd for C31H28O5: 480.1937; found:
480.1940.
(3) (a) Hon, Y.-S.; Hsu, T.-R.; Chen, C.-Y.; Lin, Y.-H.; Chang,
F.-J.; Hsieh, C.-H.; Szua, P.-H. Tetrahedron 2003, 59, 1509.
(b) Chang, F.-J.; Lu, L.; Lin, W.-C. Tetrahedron 1998, 54,
5233. (c) Hon, Y.-S.; Lin, W.-C. Tetrahedron Lett. 1995, 36,
7693. (d) Hon, Y.-S.; Chang, F.-J.; Lu, L. J. Chem. Soc.,
Chem. Commun. 1994, 2041.
(4) For selected papers on other methods, see: (a) Riofski, M.
V.; John, J. P.; Zheng, M. M.; Kirshner, J.; Colby, D. A.
J. Org. Chem. 2011, 76, 3676. (b) Jin, Y.-H.; Fang, F.;
Zhang, X.; Liu, Q.-Z.; Wang, H.-B.; Tian, S.-K. J. Org.
Chem. 2011, 76, 4163. (c) Erkkilä, A.; Pihko, P. M. J. Org.
Chem. 2006, 71, 2538.
2-(4-Methoxyphenoxy)-1-phenylprop-2-en-1-one (3i)
Colorless oil; yield: 3.6 mg (7%).
IR (KBr): 1698, 1558 cm–1.
1H NMR (500 MHz): δ = 7.92 (d, J = 7.5 Hz, 2 H), 7.56 (d, J = 7.5
Hz, 1 H), 7.46 (t, J = 7.5 Hz, 2 H), 7.03 (d, J = 8.5 Hz, 2 H), 6.88 (d,
J = 9.0 Hz, 2 H), 5.27 (s, 1 H), 4.94 (s, 1 H), 3.79 (s, 3 H).
13C NMR (125 MHz): δ = 191.0, 158.3, 156.5, 148.3, 136.6, 132.8,
129.6, 128.3, 121.1, 114.9, 102.8, 55.6.
LRMS (EI, 70 eV): m/z (%) = 254 [M+] (12), 119 (6), 135 (100).
HRMS (EI): m/z [M+] calcd for C16H14O3: 254.0943; found:
(5) For transition-metal-catalyzed activation of the both C–Cl
bonds in CH2Cl2, see: (a) Aguilar, D.; Contel, M.;
254.0940.
2,2′-Methylenebis(3-phenyl-1-benzofuran)(4a)
Colorless oil; yield: 32.1 mg (40%).
Urriolabeitia, E. P. Chem.–Eur. J. 2010, 16, 9287. (b) Xiang,
X.; Shen, Q.-S.; Wang, J.-L.; Zhu, Z.-Y.; Huang, W.; Zhou,
X.-G. Organometallics 2008, 27, 1959. (c) Tsai, C.-C.;
Hsieh, I.-L.; Cheng, T.-T.; Tsai, P. K.; Lin, K.-W.; Yan, T.-
H. Org. Lett. 2006, 8, 2261. (d) Yan, T.-H. TsaiChien, C.-T.;
Cho, C.-C.; Huang, P.-C. Org. Lett. 2004, 6, 4961. (e) Hunt,
C. Jr; Fronczek, F. R.; Billodeaux, D. R.; Stanley, G. G.
Inorg. Chem. 2001, 40, 5192. (f) Brunet, J.-J.; Couillens, X.;
Daran, J. C.; Diallo, O.; Lepetit, C.; Neibecker, D. Eur. J.
Inorg. Chem. 1998, 349. (g) Suisse, P.; Pellegrini, S.;
Castanet, Y.; Mortreux, A.; Lecoulier, S. J. Chem. Soc.,
Chem. Commun. 1995, 847. (h) Rondon, D.; Delbeau, J.; He,
X.-D.; Sabo-Etienne, S.; Chaudret, B. J. Chem. Soc., Dalton
Trans. 1994, 1895. (i) Suzuki, H.; Kakigano, T.; Igarashi,
M.; Tanaka, M.; Moro-oka, Y. J. Chem. Soc., Chem.
Commun. 1991, 283. (j) Marder, T. B.; Fultz, W. C.;
Calabrese, J. C.; Harlow, R. L.; Milstein, D. J. Chem. Soc.,
Chem. Commun. 1987, 1543. (k) Jandik, P.; Schubert, U.;
Schmidbaur, H. Angew. Chem., Int. Ed. Engl. 1982, 21, 73.
(6) (a) Li, H.-J.; He, Z.-H.; Guo, X.-W. Li W.-J.; Zhao, X.-H.;
Li, Z.-P. Org. Lett. 2009, 11, 4176. (b) Lecomte, V.; Bolm,
C. Adv. Synth. Catal. 2005, 347, 1666. (c) Karvembu, R.;
Natarajan, K. Polyhedron 2002, 21, 219. (d) Maruyama, K.;
Kubo, K.; Toda, Y.; Kawase, K.; Mashino, T.; Nishinaga, A.
Tetrahedron Lett. 1995, 36, 5609. (e) Wilson, B. D. J. Org.
Chem. 1962, 28, 314. (f) Martin, D. F.; Shamma, M.;
Fernelius, W. C. J. Am. Chem. Soc. 1958, 80, 5851.
(7) (a) Chilin, A.; Conconi, M. T.; Marzaro, G.; Guiotto, A.;
Urbani, L.; Tonus, F.; Parnigotto, P. J. Med. Chem. 2010, 53,
1862. (b) Icli, M.; Pamuk, M.; Algi, F.; Onal, A. M.;
Cihaner, A. Chem. Mater. 2010, 22, 4034. (c) Grenier, C. R.
G.; George, S. J.; Joncheray, T. J.; Meijer, E. W.; Reynolds,
J. R. J. Am. Chem. Soc. 2007, 129, 10694.
1H NMR (500 MHz): δ = 7.59–7.55 (m, 6 H), 7.48–7.41 (m, 6 H),
7.38–7.36 (m, 2 H), 7.29–7.23 (m, 4 H), 4.43 (s, 2 H).
13C NMR (125 MHz): δ = 154.4, 149.3, 132.0, 129.2, 128.8, 128.5,
127.4, 124.2, 122.8, 119.8, 118.8, 111.3, 25.2.
LRMS (EI, 70 eV): m/z (%) = 401 (28), 400 [M+] (100), 323 (34),
305 (16), 218 (27).
HRMS (EI): m/z [M+] calcd for C29H20O2: 400.1463; found:
400.1459.
Acknowledgment
We thank the National Natural Science Foundation of China (Nos.
21172060 and 20872112), Fundamental Research Funds for the
Central Universities (Hunan University), China Postdoctoral Sci-
ence Foundation (No. 2012M511716), and Hunan Provincial Inno-
vation Foundation For Postgraduate for financial support.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
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(9) The configuration of products 2 was unambiguously
assigned by means of an X-ray single-crystal diffraction
analysis of product 2k. See the Supporting Information for
detailed data.
(2) (a) Andrisano, R.; Angeloni, A. S.; De Maria, P.;
Tramontini, M. J. Chem. Soc. C 1967, 2307. (b) Farberov,
M. I.; Mironov, G. S. Dokl. Akad. Nauk SSSR 1963, 148,
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2919–2925