Potassium Persulfate Mediated Oxidative Radical Cyclization of 1,3-Dicarbonyl Compounds with Styrenes for the Synthesis of Dihydrofurans

Article abstract of DOI:10.1055/s-0034-1378806

A potassium persulfate promoted tandem radical addition/cyclization of 1,3-dicarbonyl compounds with styrenes has been developed. This transition-metal-free procedure provides an efficient approach to a diverse set of substituted dihydrofurans in moderate to good yields.

Full text of DOI:10.1055/s-0034-1378806

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
©
Georg Thieme Verlag Stuttgart · New York
2015, 47, 3191–3197
3191
paper
Synthesis
S. Wang et al.
Paper
Potassium Persulfate Mediated Oxidative Radical Cyclization of
,3-Dicarbonyl Compounds with Styrenes for the Synthesis of
1
Dihydrofurans
Shun Wang
Lin-Ye He
O
O
H
O
R3
R1
R1
K2S2O8 (1 equiv)
Ar
Li-Na Guo*
+
DCE–H2O (1:1), 100 °C
R3
R2
Ar
R2
O
Department of Chemistry, School of Science and MOE Key Laboratory
for Nonequilibrium Synthesis and Modulation of Condensed Matter,
Xi’an Jiaotong University, Xi’an 710049, P. R. of China
guoln81@mail.xjtu.edu.cn
1
9 examples
up to 88% yield
Received: 01.04.2015
Accepted after revision: 04.06.2015
Published online: 21.07.2015
Recently, transition-metal-free coupling reactions have
attracted much attention, as they provide beneficial com-
plementary tools for the construction of carbon–carbon
and carbon–heteroatom bonds.7 Potassium persulfate is
widely used as an environmentally friendly, easily handled,
DOI: 10.1055/s-0034-1378806; Art ID: ss-2015-h0215-op
Abstract A potassium persulfate promoted tandem radical addi-
tion/cyclization of 1,3-dicarbonyl compounds with styrenes has been
developed. This transition-metal-free procedure provides an efficient
approach to a diverse set of substituted dihydrofurans in moderate to
good yields.
8
and efficient oxidant in organic synthesis. Several efforts
have also been made to develop potassium persulfate medi-
ated oxidative coupling reactions for C–C bond formation.
However, only a few potassium persulfate promoted tan-
dem approaches to valuable heterocycles have been report-
Key words dicarbonyl compounds, styrenes, free radicals, cycliza-
tions, tandem reactions, furans
9
ed. We recently developed a potassium persulfate mediat-
ed oxidative spirocyclization of hydroxymethylacrylamides
with 1,3-dicarbonyl compounds for the synthesis of spiro-
Dihydrofurans are one of the most important classes of
heterocycles, and they are widely found in various bioactive
9a
oxindoles. Based on this success and results from other
groups,9 we surmised that coupling of nonactivated
alkenes, instead of acrylamide, with 1,3-dicarbonyl com-
pounds in the presence of potassium persulfate as an oxi-
dant might provide a practical and reliable method for the
1
natural products and pharmaceuticals. As a result, numer-
ous methods for their preparation have been developed.2
Classical procedures for the synthesis of dihydrofurans typ-
ically involve oxidative cyclization of active methylene
compounds with alkenes,3a–c allenes, or aldehydes in the
presence of metal salts or hypervalent iodine reagents.3
In addition, the coupling/cyclization of activated allenes
3d
3e
synthesis of oxa-heterocycles. Here, we report a potassium
3
f–h
persulfate promoted, transition-metal-free, tandem oxida-
tive cyclization of 1,3-dicarbonyl compounds with readily
available styrenes to give substituted dihydrofurans.
4a–c
with organic halides
or of terminal alkenes with aryl ke-
4d
4e
4f
tones, aldehydes, or benzyl hydrocarbons in the pres-
ence of transition-metal catalysts provides another effi-
cient and convenient route to these heterocycles. Other
common methods for the synthesis of dihydrofurans in-
Initially, we investigated the cyclization of cyclohexane-
1,3-dione (1a) with styrene (2a) under our previous condi-
tions.9a Unfortunately, only a trace amount of the desired
dihydrofuran 3a was detected (Table 1, entry 1). To our de-
light, however, when we used a 1:1 mixture of dichloro-
methane and water as the solvent, we isolated the expected
product 3a in 48% yield (entry 2). Other solvents such as
1,2-dichloroethane–water, ethyl acetate–water, toluene–
water, or chlorobenzene–water were also tested (entries 3–
6), and, of these, 1,2-dichloroethane–water gave the best
yield. These results implied that a two-phase system favors
the cyclization. The use of water as the sole solvent was also
found to be appropriate for the reaction, although it gave a
somewhat lower yield (entry 7). Note that increasing the
5
volve cyclizations of enones with various ylides. Recently,
Miura and co-workers developed an interesting alkyne
cross-coupling reaction that gives fluorescent dihydrofu-
6
rans in moderate to good yields. However, most of these
methods require transition metals, special starting materi-
als, or multistep processes. Therefore, the development of
more efficient and environmentally benign procedures
2
leading to dihydrofurans is still highly desirable.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3191–3197

3
192
Synthesis
S. Wang et al.
Paper
loading of the oxidant to two equivalents did not signifi-
cantly affect the yield of dihydrofuran 3a (entry 8). Further
optimization studies revealed that potassium persulfate
was the most effective oxidant for the reaction (entries 9
and 10). No reaction was observed when Oxone (potassium
peroxymonosulfate) was used instead of potassium persul-
fate (entry 11). When we examined the effect of the tem-
perature, 100 °C was found to be optimal (entries 12–14).
Finally, no reaction occurred in the absence of potassium
persulfate (entry 15). In an attempt to obtain the corre-
sponding furan product, we tested the oxidant 2,3-di-
chloro-5,6-dicyano-1,4-benzoquinone for the dehydroge-
nation of 3a under various conditions; however, the desired
product was not obtained.
conditions, and gave the desired products 3e and 3g in 48%
and 46% yields, respectively. 1-Vinylnaphthalene (2i) also
reacted smoothly with dione 1a to afford the corresponding
dihydrofuran 3i in moderate yield. Furthermore, various α-
methylstyrenes were also found to be suitable substrates
for this reaction, providing the corresponding dihydrofu-
rans 3j–n containing a quaternary carbon center. α-Methyl-
styrenes with electron-donating or electron-withdrawing
groups at the para-position of the aromatic ring reacted
readily with dione 1a to give the corresponding dihydrofu-
rans 3j–n in moderate to good yields. Surprisingly, when 4-
(trifluoromethyl)styrene was used, only a small amount of
the corresponding dihydrofuran was detected, and 82% of
the dione 1a was recovered. Styrenes with an ethyl or phe-
nyl group at the α-position also afforded the desired prod-
ucts 3o and 3p in 43% and 33% yields, respectively. Notably,
the scope of alkenes was not limited to styrenes, because
Table 1 Optimization of the Reaction Conditionsa
O
O
1
H-indene also gave the corresponding cyclized product in
good yield (3q). When other terminal aliphatic alkenes such
as but-3-en-1-ylbenzene or pent-4-en-1-yl benzoate were
tested as potential substrates, none of the desired product
was obtained, even at 120 °C. Other 1,3-dicarbonyl com-
pounds, such as 5,5-dimethylcyclohexane-1,3-dione and
pentane-2,4-dione were also suitable substrate for this tan-
dem cyclization reaction (3r and 3s). Unfortunately, when
benzoylacetone was used as substrate, no reaction oc-
curred, possibly as a result of the steric hindrance by the
phenyl group; in attempts to prepare the desired cycliza-
tion product, a range of catalysts, oxidants, and solvent
were tested, but no satisfactory result was obtained. Under
the optimized conditions, ethyl acetoacetate afforded a
complex mixture containing only a trace amount of the de-
sired product. Finally, no reaction occurred when β-keto al-
dehydes and malonates were used as substrates in the cy-
clization reaction under the standard conditions.
Some control experiments were performed to elucidate
the mechanism of the cyclization reaction. When a radical-
trapping reagent, such as (2,2,6,6-tetramethylpiperidin-1-
yl)oxyl (TEMPO) or butylated hydroxytoluene (BHT), was
added to a mixture of 1a and 2a under the standard condi-
tions (Scheme 2), the reaction was suppressed markedly,
indicating that the transformation probably involves a radi-
cal process.
oxidant
+
Ph
Ph
solvent, 50 °C
O
O
1
a
2a
3a
Entry
Oxidant (equiv)
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
9
K
K
K
K
K
K
K
K
2
2
2
2
2
2
2
2
S
S
S
S
S
S
S
S
2
2
2
2
2
2
2
2
O
O
O
O
O
O
O
O
8
8
8
8
8
8
8
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(2)
MeCN–H
CH Cl –H
DCE–H O (1:1)
EtOAc–H O (1:1)
toluene–H O (1:1)
PhCl–H O (1:1)
2
O (1:1)
trace
48
2
2
2
O (1:1)
2
61
2
37
2
49
2
50
H
2
O
29
8
DCE–H
DCE–H
DCE–H
DCE–H
DCE–H
DCE–H
DCE–H
DCE–H
2
2
2
2
2
2
2
2
O (1:1)
O (1:1)
O (1:1)
O (1:1)
O (1:1)
O (1:1)
O (1:1)
O (1:1)
62
Na
(NH
Oxone (1)
2
S
2
O
8
(1)
56
1
0
1
2
3
4
5
4
)
2
S
2
O
8
(1)
43
1
1
1
1
n.r.c
67d
K
K
K
–
2
2
2
S
S
S
2
2
2
O
O
O
8
8
8
(1)
(1)
(1)
e
f
88 (73)
78g
1
n.r.c
a
Reaction conditions: 1a (0.3 mmol, 1.5 equiv), 2a (0.2 mmol, 1 equiv),
solvent (1 mL), oxidant (1 equiv), 50 °C, 28 h.
b
Based on these experimental results and our previous
Yield of isolated product.
c
No reaction.
9a
reports, we proposed the mechanism shown in Scheme 3.
d
At 80 °C.
e
Firstly, oxidation of dione 1a by potassium persulfate gen-
erates the corresponding alkyl radical I, which attacks the
carbon–carbon double bond of styrene (2a) to give radical
II. Secondly, radical II is oxidized to the corresponding car-
At 100 °C.
f
Yield on a 1 mmol scale.
g
At 120 °C.
3
Having identified the optimal reaction conditions, we
investigated the substrate scope of this cyclization reaction.
As shown in Scheme 1, a wide range of substituents at the
para-, meta-, or ortho-position of the styrene were compat-
ible with this transformation (3b–h). Gratifyingly, styrenes
having a bromo substituent were also tolerated under the
bocation III, which undergoes an intramolecular cycliza-
tion to produce the dihydrofuran 3a. However, a radical cy-
clization process, in which radical II undergoes a radical 5-
4e,f,10
endo-trig cyclization to give the desired product 3a,
is
also possible.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3191–3197

3
193
Synthesis
S. Wang et al.
Paper
O
O
R3
R1
K2S2O8 (1 equiv)
R1
Ar
+
Ar
DCE–H2O (1:1), 100 °C
R3
R2
R2
O
O
1
2
3
O
O
O
O
t-Bu
Me
OMe
O
O
O
3c, 68%
O
3
a, 88%
3b, 75%
3d, 42%
O
O
O
Cl
O
Br
Me
Br
O
O
O
O
3e, 48%
3f, 67%
3g, 46%
3h, 65%
Me
Cl
O
O
O
O
Me
Me
Me
O
O
O
O
3i, 66%
3j, 83%
3k, 65%
3l, 84%
O
F
NO2
O
O
O
O
O
Me
Me
Et
O
O
O
3
m, 48%
3n, 81%
3o, 43%
3p, 33%
O
O
O
O
O
3q, 65%
3r, 75%
3s, 82%a
Scheme 1 Scope of nonactivated alkenes and 1,3-dicarbonyl compounds. Reagents and conditions: 1 (0.3 mmol, 1.5 equiv), 2 (0.2 mmol, 1 equiv),
a
DCE–H O (1:1; 1 mL), K S O (1 equiv), 100 °C, 28 h. K S O (2.5 equiv) was used.
2
2
2
8
2
2
8
O
O
O
Ph
K2S2O8
2a
O
O
standard
conditions
O
O
O
+
Ph
Ph
1a
II
I
TEMPO (1 equiv)
O
O
1a
2a
3a, trace
[O]
O
O
O
standard
conditions
Ph
+
Ph
Ph
3a
BHT (1 equiv)
– H+
O
OH
O
1a
2a
3a, 41%
III
Scheme 2 Control experiments
Scheme 3 Proposed mechanism
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3191–3197

3
194
Synthesis
S. Wang et al.
Paper
In summary, we have developed a simple transition-
metal-free approach for the synthesis of substituted dihy-
drofurans by a tandem radical addition/cyclization process.
This method has the advantages of using commercially
available starting materials with nontoxic and inexpensive
potassium persulfate as a radical initiator.
2-(4-Methoxyphenyl)-3,5,6,7-tetrahydro-1-benzofuran-4(2H)-one
3c)
(
Pale-yellow solid; yield: 33.2 mg (68%); mp 77–79 °C; R
= 0.2 (EtOAc–
f
PE, 1:3).
IR (KBr): 1631, 1514, 1401, 1249, 1178 cm–1
.
1
H NMR (400 MHz, CDCl ): δ = 7.29–7.26 (d, J = 8.4 Hz, 2 H), 6.92–6.90
3
(d, J = 8.4 Hz, 2 H), 5.73–5.68 (dd, J = 10.4, 8.4 Hz, 1 H), 3.82 (s, 3 H),
3.27–3.21 (m, 1 H), 2.92–2.86 (dd, J = 14.4, 8.0 Hz, 1 H), 2.50–2.47 (t,
J = 6.4 Hz, 2 H), 2.41–2.38 (t, J = 6.0 Hz, 2 H), 2.11–2.05 (m, 2 H).
All reactions were carried out under N2 with strict exclusion of air.
1
13C NMR (100 MHz, CDCl ): δ = 195.4, 177.0, 159.8, 132.4, 127.6,
Column chromatography was carried out on silica gel. H NMR and
3
13
114.1, 113.0, 86.4, 55.3, 36.5, 33.6, 24.0, 21.7.
C NMR spectra were recorded on a Bruker Advance III-400 spec-
trometer in the solvents indicated. Chemical shift are reported in
HRMS (ESI): m/z [M + Na]+ calcd for C15H16NaO : 267.0992; found:
3
ppm relative to CDCl with TMS as internal standard. IR spectra were
3
267.1005.
recorded on a Bruker Tensor 27 spectrometer, and only the major
peaks are reported. High-resolution mass spectra were obtained on a
Q-TOF micro spectrometer. Styrenes 1 were purchased from TCI, Alfa,
or Acros. All other commercially available compounds were used
without further purification.
2
-(4-tert-Butylphenyl)-3,5,6,7-tetrahydro-1-benzofuran-4(2H)-
one (3d)
White solid; yield: 22.7 mg (42%); mp 79–81 °C; R = 0.4 (EtOAc–PE,
f
1:3).
IR (KBr): 1633, 1400, 1230, 1181 cm–1
.
Dihydrofurans 3; General Procedure
1
H NMR (400 MHz, CDCl ): δ = 7.42–7.40 (d, J = 8.4 Hz, 2 H), 7.29–7.26
A 10 mL, oven-dried, Schlenk-tube was charged with the appropriate
3
(d, J = 8.4 Hz, 2 H), 5.75–5.71 (dd, J = 10.4, 8.0 Hz, 1 H), 3.29–3.23 (m,
1,3-dicarbonyl compound 1 (0.3 mmol, 1.5 equiv.) and K S O (0.2
2 2 8
1
2
H), 2.95–2.93 (m, 1 H), 2.51–2.48 (m, 2 H), 2.41–2.38 (m, 2 H), 2.14–
.05 (m, 2 H), 1.32 (s, 9 H).
mmol, 1.0 equiv.). The tube was evacuated and backfilled with N2
three times). A solution of aralkene 2 (0.2 mmol, 1.0 equiv) in DCE–
(
13
H O (1:1; 1 mL) was added from a syringe. The tube was sealed and
C NMR (100 MHz, CDCl ): δ = 195.5, 177.1, 151.7, 137.4, 125.9,
2
3
the mixture was stirred for 28 h at 100 °C. The resulting mixture was
diluted with EtOAc (10 mL), and the organic phase was washed suc-
cessively with H O (2 × 10 mL) and brine (10 mL) then dried (Na SO )
and concentrated in vacuo. The residue was purified by column chro-
matography [silica gel, EtOAc–PE (gradient 1:10 to 1:25)].
125.8, 113.1, 86.4, 36.5, 34.6, 33.6, 31.3, 24.0, 21.8.
HRMS (ESI): m/z [M + H]+ calcd for C18H23O : 271.1693; found:
2
2
2
4
271.1697.
2-(4-Bromophenyl)-3,5,6,7-tetrahydro-1-benzofuran-4(2H)-one
(3e)
2-Phenyl-3,5,6,7-tetrahydro-1-benzofuran-4(2H)-one (3a)
Colorless oil; yield: 28.0 mg (48%); R = 0.1 (EtOAc–PE, 1:3).
f
Colorless oil; yield: 37.7 mg (88%); R = 0.3 (EtOAc–PE, 1:3).
f
IR (KBr): 1636, 1399, 1229, 1180 cm–1
.
IR (KBr): 1634, 1402, 1232, 1180 cm–1
.
1
H NMR (400 MHz, CDCl ): δ = 7.52–7.50 (d, J = 8.4 Hz, 2 H), 7.21–7.19
3
1
H NMR (400 MHz, CDCl ): δ = 7.41–7.31 (m, 5 H), 5.77–5.72 (dd,
3
(d, J = 8.4 Hz, 2 H), 5.72–5.68 (dd, J = 10.4, 8.4 Hz, 1 H), 3.31–3.25 (dd,
J = 10.4, 8.0 Hz, 1 H), 3.31–3.25 (m, 1 H), 2.90–2.84 (m, 1 H), 2.53–2.41
J = 14.4, 10.4 Hz, 1 H), 2.84–2.79 (dd, J = 14.8, 8.0 Hz, 1 H), 2.53–2.49
t, J = 6.4 Hz, 2 H), 2.41–2.38 (t, J = 6.0 Hz, 2 H), 2.12–2.06 (m, 2 H).
(m, 2 H), 2.39–2.37 (m, 2 H), 2.12–2.05 (m, 2 H).
(
13
C NMR (100 MHz, CDCl ): δ = 195.5, 177.1, 140.6, 128.8, 128.5,
13
3
C NMR (100 MHz, CDCl ): δ = 195.4, 176.9, 139.7, 131.9, 127.5,
3
125.8, 113.0, 86.3, 36.4, 33.9, 23.9, 21.7.
122.4, 112.9, 85.4, 36.5, 34.0, 23.9, 21.7.
HRMS (ESI): m/z [M + Na]+ calcd for C14H14NaO : 237.0886; found:
2
+
HRMS (ESI): m/z [M + Na] calcd for C14H13BrNaO : 314.9991; found:
2
237.0891.
315.0000.
2
-(4-Tolyl)-3,5,6,7-tetrahydro-1-benzofuran-4(2H)-one (3b)
2
-(3-Tolyl)-3,5,6,7-tetrahydro-1-benzofuran-4(2H)-one (3f)
White solid; yield: 34.2 mg (75%); mp 75–76 °C; R = 0.2 (EtOAc–PE,
f
Yellow sticky oil; yield: 30.6 mg (67%); R = 0.3 (EtOAc–PE, 1:3).
IR (KBr): 1634, 1401, 1231, 1180 cm–1
f
1:3).
.
IR (KBr): 1634, 1401, 1229, 1180 cm–1
.
1
H NMR (400 MHz, CDCl ): δ = 7.28–7.26 (d, J = 6.0 Hz, 1 H), 7.17–7.14
3
1
H NMR (400 MHz, CDCl ): δ = 7.24–7.18 (m, 4 H), 5.74–5.69 (dd,
3
(m, 3 H), 5.74–5.69 (dd, J = 10.4, 8.0 Hz, 1 H), 3.30–3.24 (m, 1 H),
J = 10.4, 8.0 Hz, 1 H), 3.29–3.22 (dd, J = 14.4, 10.4 Hz, 1 H), 2.91–2.85
2.91–2.86 (dd, J = 14.4, 8.0 Hz, 1 H), 2.53–2.50 (m, 2 H), 2.42–2.37 (m,
(dd, J = 14.4, 8.0 Hz, 1 H), 2.51–2.48 (t, J = 6.4 Hz, 2 H), 2.41–2.38 (t,
5
H), 2.13–2.06 (m, 2 H).
J = 6.0 Hz, 2 H), 2.36 (s, 3 H), 2.11–2.05 (m, 2 H).
13
C NMR (100 MHz, CDCl ): δ = 195.5, 177.1, 140.5, 138.6, 129.3,
3
13
C NMR (100 MHz, CDCl ): δ = 195.5, 177.1, 138.4, 137.5, 129.4,
3
128.7, 126.6, 123.0, 113.1, 86.5, 36.5, 33.9, 24.0, 21.8, 21.5.
126.0, 113.0, 86.4, 36.5, 33.8, 24.0, 21.7, 21.2.
HRMS (ESI): m/z [M + Na]+ calcd for C15H16NaO : 251.1043; found:
2
HRMS (ESI): m/z [M + Na]+ calcd for C15H16NaO : 251.1043; found:
2
251.1051.
251.1053.
2-(3-Bromophenyl)-3,5,6,7-tetrahydro-1-benzofuran-4(2H)-one
(3g)
Colorless oil; yield: 26.9 mg (46%); R = 0.3 (EtOAc–PE, 1:3).
f
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3191–3197

3
195
Synthesis
S. Wang et al.
Paper
IR (KBr): 1635, 1340, 1230, 1180 cm–1
.
1
H NMR (400 MHz, CDCl ): δ = 7.28–7.26 (d, J = 8.4 Hz, 2 H), 7.19–7.17
3
1
(d, J = 8.0 Hz, 2 H), 3.11–3.08 (d, J = 14.4 Hz, 1 H), 3.01–2.97 (d,
J = 14.4 Hz, 1 H), 2.54–2.51 (t, J = 6.0 Hz, 2 H), 2.40–2.36 (m, 5 H),
H NMR (400 MHz, CDCl ): δ = 7.48–7.46 (m, 2 H), 7.29–7.24 (m, 2 H),
.73–5.69 (dd, J = 10.4, 8.0 Hz, 1 H), 3.33–3.26 (m, 1 H), 2.86–2.80 (m,
H), 2.56–2.52 (m, 2 H), 2.42–2.39 (t, J = 6.0 Hz, 2 H), 2.14–2.09 (m, 2
3
5
1
H).
2
.12–2.05 (m, 2 H), 1.72 (s, 3 H).
13
C NMR (100 MHz, CDCl ): δ = 195.7, 175.9, 142.6, 137.2, 129.1,
3
1
3
124.2, 112.6, 92.6, 40.5, 36.4, 29.6, 24.1, 21.7, 21.0.
C NMR (100 MHz, CDCl ): δ = 195.4, 176.9, 143.0, 131.5, 130.4,
3
1
28.8, 124.4, 122.9, 112.9, 85.2, 36.5, 34.2, 23.9, 21.7.
HRMS (ESI): m/z [M + Na]+ calcd for C16H18NaO : 265.1199; found:
2
HRMS (ESI): m/z [M + H]+ calcd for C14H14BrO : 293.0172; found:
265.1213.
2
293.0172.
2-(4-Chlorophenyl)-2-methyl-3,5,6,7-tetrahydro-1-benzofuran-
4(2H)-one (3l)
2-(2-Chlorophenyl)-3,5,6,7-tetrahydro-1-benzofuran-4(2H)-one
(
3h)
Colorless oil; yield: 44.0 mg (84%); R
IR (KBr): 1637, 1400, 1250, 1184 cm–1
f
= 0.3 (EtOAc–PE, 1:3).
.
Colorless oil; yield: 32.3 mg (65%); R = 0.4 (EtOAc–PE, 1:3).
f
IR (KBr): 1640, 1400, 1231, 1180 cm–1
.
1
H NMR (400 MHz, CDCl ): δ = 7.34–7.28 (m, 4 H), 3.06–2.96 (m, 2 H),
3
1
2.54–2.50 (m, 2 H), 2.39–2.35 (m, 2 H), 2.11–2.04 (m, 2 H), 1.69 (s, 3
H).
H NMR (400 MHz, CDCl ): δ = 7.41–7.25 (m, 4 H), 6.08–6.03 (dd,
3
J = 10.4, 7.6 Hz, 1 H), 3.46–3.40 (dd, J = 14.8, 10.8 Hz, 1 H), 2.74–2.68
13
(dd, J = 14.8, 7.6 Hz, 1 H), 2.59–2.56 (t, J = 6.4 Hz, 2 H), 2.42–2.38 (m, 2
C NMR (100 MHz, CDCl ): δ = 195.6, 175.7, 144.1, 133.3, 128.6,
3
H), 2.15–2.08 (m, 2 H).
125.8, 112.5, 92.0, 40.5, 36.4, 29.7, 24.0, 21.7.
13
HRMS (ESI): m/z [M + H]+ calcd for C15H16ClO : 263.0833; found:
C NMR (100 MHz, CDCl ): δ = 195.5, 176.9, 138.7, 131.5, 129.8,
3
2
129.2, 127.1, 126.0, 112.9, 83.0, 36.5, 33.8, 23.8, 21.7.
263.0844.
+
HRMS (ESI): m/z [M + Na] calcd for C14H13ClNaO : 271.0496; found:
2
271.0506.
2-(4-Fluorophenyl)-2-methyl-3,5,6,7-tetrahydro-1-benzofuran-
4(2H)-one (3m)
Pale-yellow oil; yield: 23.6 mg (48%); R = 0.3 (EtOAc–PE, 1:3).
f
2-(1-Naphthyl)-3,5,6,7-tetrahydro-1-benzofuran-4(2H)-one (3i)
White solid; yield: 34.9 mg (66%); mp 118–120 °C; R = 0.2 (EtOAc–PE,
IR (KBr): 1636, 1511, 1400, 1250 cm–1
.
f
1
:3).
1
H NMR (400 MHz, CDCl ): δ = 7.35–7.31 (m, 2 H), 7.06–7.02 (m, 2 H),
3
IR (KBr): 1635, 1401, 1233, 1180 cm–1
.
3.07–2.97 (m, 2 H), 2.54–2.50 (m, 2 H), 2.39–2.35 (m, 2 H), 2.10–2.06
(m, 2 H), 1.70 (s, 3 H).
1
H NMR (400 MHz, CDCl ): δ = 7.91–7.89 (m, 1 H), 7.85–7.83 (m, 2 H),
3
13
7
1
2
.57–7.45 (m, 4 H), 6.45–6.40 (dd, J = 10.8, 8.0 Hz, 1 H), 3.53–3.46 (m,
H), 2.96–2.90 (m, 1 H), 2.64–2.60 (m, 2 H), 2.45–2.41 (m, 2 H), 2.18–
.11 (m, 2 H).
C NMR (100 MHz, CDCl ): δ = 195.6, 175.7, 162.0 (d, J = 244.9 Hz),
3
141.4 (d, J = 3.0 Hz), 126.1 (d, J = 8.1 Hz), 115.3 (d, J = 21.3 Hz), 112.6,
92.1, 40.6, 36.4, 29.7, 24.1, 21.7.
13
HRMS (ESI): m/z [M + Na]+ calcd for C15H15FNaO : 269.0948; found:
C NMR (100 MHz, CDCl ): δ = 195.5, 177.1, 136.0, 133.9, 129.7,
3
2
1
2
29.0, 128.8, 126.5, 125.9, 125.2, 122.9, 122.3, 113.2, 84.2, 36.5, 34.0,
4.0, 21.8.
269.0946.
HRMS (ESI): m/z [M + Na]+ calcd for C18H16NaO : 287.1043; found:
2-Methyl-2-(4-nitrophenyl)-3,5,6,7-tetrahydro-1-benzofuran-
2
287.1055.
4(2H)-one (3n)
Yellow oil; yield: 44.2 mg (81%); R = 0.2 (EtOAc–PE, 1:3).
f
2
-Methyl-2-phenyl-3,5,6,7-tetrahydro-1-benzofuran-4(2H)-one
IR (KBr): 1638, 1520, 1400, 1249 cm–1
.
(3j)
1
H NMR (400 MHz, CDCl ): δ = 8.24–8.22 (d, J = 8.8 Hz, 2 H), 7.55–7.53
3
Yellow sticky oil; yield: 37.9 mg (83%); R = 0.4 (EtOAc–PE, 1:3).
IR (KBr): 1634, 1400, 1252, 1184 cm–1
f
(d, J = 8.8 Hz, 2 H), 3.11–3.01 (m, 2 H), 2.58–2.54 (m, 2 H), 2.40–2.36
(m, 2 H), 2.14–2.10 (m, 2 H), 1.74 (s, 3 H).
.
1
13
H NMR (400 MHz, CDCl ): δ = 7.37–7.36 (m, 4 H), 7.31–7.26 (m, 1 H),
C NMR (100 MHz, CDCl ): δ = 195.5, 175.4, 152.7, 147.2, 125.3,
3
3
3.11–3.08 (d, J = 14.4 Hz, 1 H), 3.02–2.99 (d, J = 14.4 Hz, 1 H), 2.55–
123.9, 112.4, 91.6, 40.6, 36.4, 29.8, 23.7, 21.6.
2
.52 (m, 2 H), 2.39–2.35 (m, 2 H), 2.12–2.05 (m, 2 H), 1.72 (s, 3 H).
+
HRMS (ESI): m/z [M + Na] calcd for C15H15NNaO : 296.0893; found:
296.0892.
4
13
C NMR (100 MHz, CDCl ): δ = 195.7, 175.9, 145.6, 128.5, 127.5,
3
124.2, 112.6, 92.6, 40.5, 36.4, 29.7, 24.1, 21.7.
HRMS (ESI): m/z [M + Na]+ calcd for C15H16NaO : 251.1043; found:
2-Ethyl-2-phenyl-3,5,6,7-tetrahydro-1-benzofuran-4(2H)-one (3o)
2
251.1052.
Colorless oil; yield: 20.8 mg (43%); R = 0.3 (EtOAc–PE, 1:3).
f
IR (KBr): 1638, 1450, 1248, 1139 cm–1
.
2
-Methyl-2-(4-tolyl)-3,5,6,7-tetrahydro-1-benzofuran-4(2H)-one
1
H NMR (400 MHz, CDCl ): δ = 7.38–7.29 (m, 4 H), 7.27–7.25 (m, 1 H),
3
(3k)
3.05–3.04 (m, 2 H), 2.55–2.51 (m, 2 H), 2.39–2.28 (m, 2 H), 2.10–2.05
Colorless sticky oil; yield: 31.5 mg (65%); R = 0.4 (EtOAc–PE, 1:3).
IR (KBr): 1635, 1400, 1251, 1184 cm–1
f
(m, 2 H), 2.03–1.93 (m, 2 H), 0.84–0.81 (t, J = 7.2 Hz, 3 H).
.
13
C NMR (100 MHz, CDCl ): δ = 195.6, 176.2, 144.5, 128.3, 127.3,
3
124.7, 112.8, 95.5, 38.5, 36.4, 35.8, 23.9, 21.7, 8.0.
HRMS (ESI): m/z [M + Na]+ calcd for C16H18NaO : 265.1199; found:
2
265.1188.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3191–3197

3
196
Synthesis
S. Wang et al.
Paper
2,2-Diphenyl-3,5,6,7-tetrahydro-1-benzofuran-4(2H)-one (3p)
Supporting Information
Colorless sticky oil; yield: 19.1 mg (33%); R = 0.5 (EtOAc–PE, 1:3).
f
Supporting information for this article is available online at
IR (KBr): 1639, 1397, 1245, 1181 cm–1
.
http://dx.doi.org/10.1055/s-0034-1378806.
S
u
p
p
o
nrtIo
i
g
f
rm oaitn
S
u
p
p
ortioIgnfmr oaitn
1
H NMR (400 MHz, CDCl ): δ = 7.38–7.32 (m, 7 H), 7.30–7.26 (m, 3 H),
3
3.57–3.56 (t, J = 1.6 Hz, 2 H), 2.61–2.58 (m, 2 H), 2.39–2.36 (t, J = 6.4
Hz, 2 H), 2.13–2.06 (m, 2 H).
References
13
C NMR (100 MHz, CDCl ): δ = 195.4, 175.6, 144.5, 128.4, 127.8,
3
(1) For selected examples, see: (a) Wang, X.; Nakagawa-Goto, K.;
125.7, 112.9, 95.4, 40.6, 36.4, 24.0, 21.7.
Bastow, K. F.; Don, M.-J.; Lin, Y.-L.; Wu, T.-S.; Lee, K.-H. J. Med.
Chem. 2006, 49, 5631. (b) Yang, S.-W.; Chan, T.-M.; Terracciano,
J.; Boehm, E.; Patel, R.; Chen, G.; Loebenberg, D.; Patel, M.; Gullo,
V.; Pramanik, B.; Chu, M. J. Nat. Prod. 2009, 72, 484. (c) Koike, T.;
Takai, T.; Hoashi, Y.; Nakayama, M.; Kosugi, Y.; Nakashima, M.;
Yoshikubo, S.-i.; Hirai, K.; Uchikawa, O. J. Med. Chem. 2011, 54,
HRMS (ESI): m/z [M + Na]+ calcd for C20H18NaO : 313.1199; found:
2
313.1204.
4b,6,7,8,9b,10-Hexahydro-9H-benzo[b]indeno[2,1-d]furan-9-one
(3q)
4
207. (d) Zhang, Y.; Zhong, H.; Wang, T.; Geng, D.; Zhang, M.; Li,
Pale-yellow solid; yield: 29.4 mg (65%); mp 103–104 °C; R = 0.4
f
K. Eur. J. Med. Chem. 2012, 48, 69. (e) Sugimoto, K.; Tamura, K.;
Ohta, N.; Tohda, C.; Toyooka, N.; Nemoto, H.; Matsuya, Y. Bioorg.
Med. Chem. Lett. 2012, 22, 449. (f) Somerville, M. J.; Katavic, P.
L.; Lambert, L. K.; Pierens, G. K.; Blanchfield, J. T.; Cimino, G.;
Mollo, E.; Gavagnin, M.; Banwell, M. G.; Garson, M. J. J. Nat. Prod.
(
EtOAc–PE, 1:3).
IR (KBr): 1639, 1397, 1246, 1181 cm–1
1
.
H NMR (400 MHz, CDCl ): δ = 7.50–7.48 (d, J = 7.2 Hz, 1 H), 7.36–7.26
3
(m, 3 H), 6.21–6.18 (d, J = 8.8 Hz, 1 H), 4.05–4.01 (td, J = 8.8, 1.2 Hz, 1
H), 3.39–3.32 (dd, J = 16.8, 8.4 Hz, 1 H), 3.20–3.16 (dd, J = 16.8, 2.0 Hz,
1
2012, 75, 1618.
H), 2.47–2.29 (m, 4 H), 2.05–1.94 (m, 2 H).
(
2) For reviews, see: (a) Iqbal, J.; Bhatia, B.; Nayyar, N. K. Chem. Rev.
1994, 94, 519. (b) Snider, B. B. Chem. Rev. 1996, 96, 339.
(c) Godoi, B.; Schumacher, R. F.; Zeni, G. Chem. Rev. 2011, 111,
1
3
C NMR (100 MHz, CDCl ): δ = 195.6, 176.5, 143.4, 139.4, 129.8,
3
1
27.0, 125.8, 125.6, 116.8, 93.3, 41.8, 37.4, 36.7, 24.0, 21.6.
2
(
937. (d) Le Bras, J.; Muzart, J. Chem. Soc. Rev. 2014, 43, 3003.
e) Zimmer, R.; Reissig, H.-U. Chem. Soc. Rev. 2014, 43, 2888.
3) (a) Baciocchi, E.; Ruzziconi, R. J. Org. Chem. 1991, 56, 4772.
b) Bar, G.; Parsons, A. F.; Thomas, C. B. Chem. Commun. 2001,
350. (c) Huang, J.-W.; Shi, M. J. Org. Chem. 2005, 70, 3859.
d) Yuan, W.; Wei, Y.; Shi, M. Tetrahedron 2011, 67, 7139.
HRMS (ESI): m/z [M + Na]+ calcd for C15H14NaO : 249.0886; found:
2
249.0897.
(
(
1
(
6
,6-Dimethyl-2-phenyl-3,5,6,7-tetrahydro-1-benzofuran-4(2H)-
one (3r)
Yellow sticky oil; yield: 36.3 mg (75%); R = 0.4 (EtOAc–PE, 1:3).
IR (KBr): 1636, 1402, 1220, 1144 cm–1
f
(e) Yao, C.; Wang, Y.; Li, T.; Yu, C.; Li, L.; Wang, C. Tetrahedron
2013, 69, 10593. (f) Asouti, A.; Hadjiarapoglou, L. P. Tetrahedron
Lett. 1998, 39, 9073. (g) Ye, Y.; Wang, L.; Fan, R. J. Org. Chem.
.
1
H NMR (400 MHz, CDCl ): δ = 7.41–7.30 (m, 5 H), 5.79–5.74 (dd,
3
2010, 75, 1760. (h) Kalpogiannaki, D.; Martini, C.-I.;
J = 10.4, 8.0 Hz, 1 H), 3.32–3.26 (dd, J = 14.4, 10.4 Hz, 1 H), 2.90–2.85
Nikopoulou, A.; Nyxas, J. A.; Pantazi, V.; Hadjiarapoglou, L. P.
Tetrahedron 2013, 69, 1566.
(dd, J = 14.4, 7.6 Hz, 1 H), 2.37 (s, 2 H), 2.27 (s, 2 H), 1.14 (s, 6 H).
13
C NMR (100 MHz, CDCl ): δ = 194.7, 176.0, 140.7, 128.8, 128.5,
3
(4) (a) Ma, S.; Zheng, Z.; Jiang, X. Org. Lett. 2007, 9, 529. (b) Deng, Y.;
Yu, Y.; Ma, S. J. Org. Chem. 2008, 73, 585. (c) Deng, Y.; Shi, Y.; Ma,
S. Org. Lett. 2009, 11, 1205. (d) Naveen, T.; Kancherla, R.; Maiti,
D. Org. Lett. 2014, 16, 5446. (e) Lv, L.; Lu, S.; Guo, Q.; Shen, B.; Li,
Z. J. Org. Chem. 2015, 80, 698. (f) Guo, L.-N.; Wang, S.; Duan, X.-
H.; Zhou, S.-L. Chem. Commun. 2015, 51, 4803.
125.8, 111.4, 86.5, 50.9, 37.8, 34.1, 33.8, 28.8, 28.5.
HRMS (ESI): m/z [M + Na]+ calcd for C16H18NaO : 265.1199; found:
2
265.1206.
1-(2-Methyl-5-phenyl-4,5-dihydrofuran-3-yl)ethanone (3s)
(
5) (a) Yang, Z.; Fan, M.; Mu, R.; Liu, W.; Liang, Y. Tetrahedron 2005,
Colorless oil; yield: 33.1 mg (82%); R = 0.4 (EtOAc–PE, 1:5).
IR (KBr): 1719, 1373, 1236 cm–1
f
61, 9140. (b) Cao, W.; Zhang, H.; Chen, J.; Zhou, X.; Shao, M.;
.
McMills, M. C. Tetrahedron 2008, 64, 163. (c) Wang, Q.-F.; Hou,
H.; Hui, L.; Yan, C.-G. J. Org. Chem. 2009, 74, 7403. (d) Chen, Z.;
Zhang, J.; Chen, J.; Deng, H.; Shao, M.; Zhang, H.; Cao, W. Tetra-
hedron 2010, 66, 6181. (e) Chagarovsky, A. O.; Budynina, E. M.;
Ivanova, O. A.; Villemson, E. V.; Rybakov, V. B.; Trushkov, I. V.;
Melnikov, M. Y. Org. Lett. 2014, 16, 2830.
1
H NMR (400 MHz, CDCl ): δ = 7.41–7.31 (m, 5 H), 5.63–5.58 (dd,
3
J = 10.4, 8.4 Hz, 1 H), 3.43–3.37 (ddd, J = 12.4, 10.8, 1.6 Hz, 1 H), 3.01–
2.95 (ddd, J = 9.6, 8.4, 1.6 Hz, 1 H), 2.32 (t, J = 1.6 Hz, 3 H), 2.22 (s, 3 H).
13
C NMR (100 MHz, CDCl ): δ = 194.8, 167.8, 141.6, 129.1, 128.6,
3
126.0, 112.2, 83.5, 39.1, 29.9, 15.4.
(
(
(
6) (a) Funayama, A.; Satoh, T.; Miura, M. J. Am. Chem. Soc. 2005,
HRMS (ESI): m/z [M + Na]+ calcd for C13H14NaO : 225.0886; found:
2
127, 15354. (b) Horita, A.; Tsurugi, H.; Funayama, A.; Satoh, T.;
225.0888.
Miura, M. Org. Lett. 2007, 9, 2231.
7) For reviews, see: (a) Mousseau, J. J.; Charette, A. B. Acc. Chem.
Res. 2013, 46, 412. (b) Sun, C.-L.; Shi, Z.-J. Chem. Rev. 2014, 114,
Acknowledgment
9219.
8) For selected examples, see: (a) Thu, H.-Y.; Yu, W.-Y.; Che, C.-M.
J. Am. Chem. Soc. 2006, 128, 9048. (b) Seiple, I. B.; Su, S.;
Rodriguez, R. A.; Gianatassio, R.; Fujiwara, Y.; Sobel, A. L.; Baran,
P. S. J. Am. Chem. Soc. 2010, 132, 13194. (c) Chu, L.; Yue, X.; Qing,
F.-L. Org. Lett. 2010, 12, 1644. (d) Lou, S.-J.; Xu, D.-Q.; Shen, D.-
F.; Wang, Y.-F.; Liu, Y.-K.; Xu, Z.-Y. Chem. Commun. 2012, 48,
Financial support from the National Natural Science Foundation of
China (No 21102111) and the Natural Science Basic Research Plan of
Shaanxi Province of China (No. 2014JQ2071) are greatly appreciated.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3191–3197

3
197
Synthesis
S. Wang et al.
Paper
1
1993. (e) Shi, Z.; Glorius, F. Chem. Sci. 2013, 4, 829. (f) Xie, Z.;
2014, 79, 4225. (f) Laha, J. K.; Tummalapalli, K. S. S.; Gupta, A.
Org. Lett. 2014, 16, 4392. (g) Yang, H.; Duan, X.-H.; Zhao, J.-F.;
Guo, L.-N. Org. Lett. 2015, 17, 1998.
Cai, Y.; Hu, H.; Lin, C.; Jiang, J.; Chen, Z.; Wang, L.; Pan, Y. Org.
Lett. 2013, 15, 4600.
(
9) (a) Wang, H.; Guo, L.-N.; Duan, X.-H. Org. Lett. 2013, 15, 5254.
(10) (a) Mendenhall, G. D.; Protasiewicz, J. D.; Brown, C. E.; Ingold, K.
U.; Lusztyk, J. J. Am. Chem. Soc. 1994, 116, 1718. (b) Yamamoto,
Y.; Ohno, M.; Eguchi, S. J. Org. Chem. 1996, 61, 9264. (c) Cui, X.;
Xu, X.; Wojtas, L.; Kim, M. M.; Zhang, X. P. J. Am. Chem. Soc.
2012, 134, 19981. (d) Jiang, H.; Cheng, Y.; Zhang, Y.; Yu, S. Org.
Lett. 2013, 15, 4884. (e) Liu, D.; Tang, S.; Yi, H.; Liu, C.; Qi, X.;
Lan, Y.; Lei, A. Chem. Eur. J. 2014, 20, 15605.
(b) Li, Y.-M.; Wei, X.-H.; Li, X.-A.; Yang, S.-D. Chem. Commun.
2013, 49, 11701. (c) Li, Y.-M.; Shen, Y.; Chang, K.-J.; Yang, S.-D.
Tetrahedron 2014, 70, 1991. (d) Wei, W.; Wen, J.; Yang, D.; Du, J.;
You, J.; Wang, H. Green Chem. 2014, 16, 2988. (e) Wei, W.; Wen,
J.; Yang, D.; Liu, X.; Guo, M.; Dong, R.; Wang, H. J. Org. Chem.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3191–3197