Oxidative Cyclization of β,γ-Unsaturated Carboxylic Acids Using Hypervalent Iodine Reagents: An Efficient Synthesis of 4-Substituted Furan-2-ones

Article abstract of DOI:10.1055/s-0036-1588987

The oxidative cyclization of β-substituted β,γ-unsaturated carboxylic acids using a hypervalent iodine reagent to provide 4-substituted furan-2-one products, is reported. In this cyclization, the use of a highly electrophilic PhI(OTf) ₂, which is in situ prepared from PhI(OAc) ₂ and Me ₃ SiOTf, is crucial. Depending on the substitution pattern at the α-position of the substrates, furan-2(5 H)-ones or furan-2(3 H)-ones are produced. Thus, the present method offers a useful tool for accessing various types of 4-substituted furan-2-ones that are important structural motifs in the field of organic chemistry and medicinal chemistry.

Full text of DOI:10.1055/s-0036-1588987

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–F
special topic
A
en
K. Kiyokawa et al.
Special Topic
Synthesis
Oxidative Cyclization of β,γ-Unsaturated Carboxylic Acids Using
Hypervalent Iodine Reagents: An Efficient Synthesis of 4-Substi-
tuted Furan-2-ones
Kensuke Kiyokawa*
Kenta Takemoto
Shunsuke Yahata
Takumi Kojima
O
CO2H
O
R1
R1
OTf
I
R2
R2
O
Ph
Satoshi Minakata*
OTf
CO2H
O
R1
R1
R3 R4
R4
Department of Applied Chemistry, Graduate School of
Engineering, Osaka University, Yamadaoka 2-1, Suita,
Osaka 565-0871, Japan
Oxidative cyclization
R3
R
R
1 = aryl, alkyl
17 examples
34−90%
2 = alkyl, H
R3, R4 = alkyl
kiyokawa@chem.eng.osaka-u.ac.jp
minakata@chem.eng.osaka-u.ac.jp
Published as part of the Special Topic Modern Strategies
with Iodine in Synthesis
Received: 16.02.2017
Accepted after revision: 09.03.2017
Published online: 30.03.2017
valent iodine reagents (Scheme 1).6 During the course of
the study, we observed that oxidative cyclization proceeded
smoothly when Me3SiOTf was added to the reaction mix-
ture, providing 4-substituted furan-2(5H)-ones 2, which are
particularly important structural motifs in medicinal
chemistry (Scheme 1). This preliminary result prompted us
to further investigate this oxidative cyclization to expand
the synthetic utility of the method. We herein report the
oxidative cyclization of β-substituted β,γ-unsaturated car-
boxylic acids using a hypervalent iodine reagent, enabling
easy access to a variety of 4-substituted furan-2-ones.
DOI: 10.1055/s-0036-1588987; Art ID: ss-2017-c0096-st
Abstract The oxidative cyclization of β-substituted β,γ-unsaturated
carboxylic acids using a hypervalent iodine reagent to provide 4-substi-
tuted furan-2-one products, is reported. In this cyclization, the use of a
highly electrophilic PhI(OTf)2, which is in situ prepared from PhI(OAc)2
and Me3SiOTf, is crucial. Depending on the substitution pattern at the
α-position of the substrates, furan-2(5H)-ones or furan-2(3H)-ones are
produced. Thus, the present method offers a useful tool for accessing
various types of 4-substituted furan-2-ones that are important struc-
tural motifs in the field of organic chemistry and medicinal chemistry.
PhI(X)2
Key words hypervalent iodine, oxidation, cyclization, β,γ-unsaturated
carboxylic acids, furanones
Previous work
X
(ref. 6a)
R
decarboxylative
functionalization
(X = OAc or NTs2)
CO2H
R
Furan-2(5H)-one derivatives are an important class of
compounds that are frequently found in natural products
and biologically active molecules.1 Therefore, the develop-
ment of simple and efficient methods for the synthesis of
furan-2(5H)-one derivatives from readily available starting
materials is an important research topic in the field of or-
ganic chemistry as well as medicinal chemistry.2 An intra-
molecular cyclization is a fundamental transformation for
the construction of furan-2(5H)-one scaffolds, and, indeed,
several useful methods have been developed to date.3 How-
ever, although the oxidative 5-endo cyclization of β,γ-unsat-
urated carboxylic acids is one of the most straightforward
methods for preparing the furan-2(5H)-one motif, only a
limited number of examples of the use of this approach
have been reported.4 Wirth et al. recently reported that a
hypervalent iodine reagent was effective for this type of ox-
idative cyclization with the rearrangement of 4-arylbut-3-
enoic acids, affording 4-arylfuran-2(5H)-ones, albeit the
substrate scope was limited.5 Meanwhile, our group report-
ed on the decarboxylative functionalization of β-substitut-
ed β,γ-unsaturated carboxylic acids 1 via the use of hyper-
PhI(OAc)2
Me3SiOTf
1
O
This work
O
cyclization
R
2
Scheme 1 Oxidative functionalization of β,γ-unsaturated carboxylic
acids using hypervalent iodine reagents
Our initial experiments intended to optimize the reac-
tion conditions for the oxidative cyclization were per-
formed with 3-phenylbut-3-enoic acid (1a) as a model sub-
strate. When the reactions were carried out using PhI(OAc)2
and PhI(OCOCF3)2 as oxidants in dichloromethane at room
temperature, no cyclized product was formed (Table 1, en-
tries 1 and 2). Meanwhile, the highly electrophilic Koser’s
reagent, PhI(OH)(OTs), was found to provide the furan-
2(5H)-one 2a in a moderate yield (entry 3). Encouraged by
this result, we next examined the activation of hypervalent
iodine reagents with Me3SiOTf, to generate the highly elec-
trophilic PhI(OTf)2.7 A brief screening of hypervalent iodine
reagents revealed that the use of PhI(OAc)2 with two equiv-
alents of Me3SiOTf provided 2a in the highest yield (88% iso-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

B
K. Kiyokawa et al.
Special Topic
Synthesis
lated yield) (entries 4–6). Decreasing the amount of
Me3SiOTf to one equivalent reduced the yield of 2a slightly,
and further decrease of the reagent resulted in an even low-
er yield (entries 7 and 8). In addition, the oxidative cycliza-
tion also proceeded by the use of TfOH instead of Me3SiOTf,
but yields were somewhat lower than those obtained with
Me3SiOTf (entries 9 and 10).8 It should be noted that no cy-
clized products were formed when iodine oxidants that
function as an iodonium source, such as bis(pyridine)iodo-
nium tetrafluoroborate (IPy2BF4) and N-iodosuccinimide
(NIS), were used (entries 11 and 12). Solvent screening in-
dicated that a halogenated solvent was effective for the re-
action (entry 13). The use of MeCN resulted in low yield,
and reactions conducted in toluene and THF did not pro-
vide 2a at all (entries 14–16).
sponding 4-substituted furan-2(5H)-ones. Halogen substit-
uents, such as fluoro 2b, chloro 2c, and bromo 2d groups,
on the aromatic ring at the β-position were well tolerated
and had only a minor effect on product yield. Because sub-
strates bearing a highly electron-withdrawing trifluoro-
methyl group were less reactive, these reactions were con-
ducted at 80 °C in 1,2-dichloroethane, furnishing furanone
products 2e and 2f in high yields. On the other hand, under
standard reaction conditions, carboxylic acids containing
PhI(OAc)2 (1 equiv)
O
Me3SiOTf (2 equiv)
CO2H
O
R1
R1
CH2Cl2, r.t.
R2
R2
1 (0.3 mmol)
2
O
O
Table 1 Optimization of Reaction Conditionsa
O
O
oxidant (1 equiv)
additive (2 equiv)
F
Cl
O
2b 82% (1.5 h)
2c 90% (1.5 h)
CO2H
O
CH2Cl2, r.t., 1.5 h
Ph
Ph
O
O
1a (0.3 mmol)
2a
O
O
Entry
Oxidant
Additive
Solvent
Yield (%)b
Br
F3C
2d 77% (2.5 h)
2e 88% (1 h)a
1
2
PhI(OAc)2
PhI(OCOCF3)2
PhI(OH)(OTs)
PhI(OAc)2
PhI(OCOCF3)2
PhIO
none
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
0
0
O
none
O
O
F3C
O
3
none
42
92 (88)c
62
51
87
65
76
72
0
4
Me3SiOTf
Me3SiOTf
Me3SiOTf
Me3SiOTf
Me3SiOTf
TfOH
MeO
CF3
2f 70% (3 h)a
5
2g 34% (1 h)b
6
O
O
7d
8e
9
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
IPy2BF4
O
O
2h 76% (1 h)b
2i 61% (3 h)c
10f
11
12
13g
14g
15g
16g
TfOH
O
O
none
O
O
NIS
none
0
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
Me3SiOTf
Me3SiOTf
Me3SiOTf
Me3SiOTf
ClCH2CH2Cl
MeCN
88
40
0
2j 86% (1.5 h)
2k 78% (3 h)c
O
O
toluene
THF
O
O
Ph
0
2m 45% (1.5 h)
a Standard reaction conditions: 1a (0.3 mmol), oxidant (0.3 mmol), addi-
tive (0.6 mmol), CH2Cl2 (3 mL), r.t., 1.5 h.
b Determined by 1H NMR analysis of the crude product using 1,1,2,2-tetra-
chloroethane as an internal standard.
2l 60% (3 h)b,d
O
O
O
c Isolated yield in parentheses.
O
d Me3SiOTf (1 equiv) was used.
e Me3SiOTf (0.5 equiv) was used.
2n 34% (1.5 h)
2o 40% (3 h)
f TfOH (1 equiv) was used.
g Reaction was run for 1 h.
Scheme 2 Scope of β,γ-unsaturated carboxylic acids. Unless otherwise
noted, the following reaction conditions were employed: 1 (0.3 mmol),
PhI(OAc)2 (0.3 mmol), Me3SiOTf (0.6 mmol), CH2Cl2 (3 mL), r.t. Reac-
tion time is shown in parentheses. Yields are isolated yields. a The reac-
tion was conducted at 80 °C in ClCH2CH2Cl. b 2,6-Di-tert-butylpyridine
(DTBP) (2 equiv) was added. c PhI(OAc)2 (1.5 equiv), Me3SiOTf (3 equiv),
and DTBP (3 equiv) were used. d The reaction was conducted at 60 °C in
ClCH2CH2Cl.
With the optimized reaction conditions identified (Ta-
ble 1, entry 4), the substrate scope for the oxidative cycliza-
tion was investigated next (Scheme 2). Various types of β-
substituted β,γ-unsaturated carboxylic acids were found to
be applicable and were efficiently converted into the corre-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

C
K. Kiyokawa et al.
Special Topic
Synthesis
an electron-donating methoxy group on the aromatic ring
gave a very low yield of 2g, along with the formation of un-
identified by-products probably because the substrate un-
derwent decomposition in the presence of the in situ gen-
erated TfOH.9 To avoid this type of side reaction, we exam-
ined the use of a base to trap the TfOH. After screening a
number of bases, 2,6-di-tert-butylpyridine (DTBP) was
found to increase the yield of 2g, albeit the yield was rela-
tively low. Employing DTBP also improved the yield of 2h
and 2i containing p- and o-tolyl substituents, respectively.
Meanwhile, m-tolyl group at the β-position had a negligible
effect on reactivity, furnishing 2j in high yield under the
standard reaction conditions. Fused-ring systems 2k and 2l
including 1- and 2-naphthyl groups were also well tolerat-
ed. In addition to substrates with aromatic substituents,
this oxidative cyclization could also be expanded to sub-
strates with β-aliphatic substituents, such as benzyl 2m
and n-butyl 2n groups. Notably, benzylic and allylic C–H
bonds were well tolerated under the oxidative reaction con-
ditions. Furthermore, the cyclization of a carboxylic acid
with an α-substituent proceeded successfully to afford the
3,4-disubstituted furan-2(5H)-one 2o.
a)
OAc
I
OTf
I
2 Me3SiOTf
Ph
Ph
– 2 Me3SiOAc
OAc
OTf
b)
TfO–
Ph
TfO
+
I
O
O
PhI(OTf)2
R1
OH
OH
R1
R2 R3
R2 R3
1
4
TfO–
O
Ph
I
R1
O+
TfO
O
H
R3
O
R2
R3 = H
O
O
R1
– TfOH
– PhI
– TfOH
Ph
I
R2
2
O
TfO
R1
R3
O
R2
R2, R3 ≠ H
5
R1
– TfOH
– PhI
R3
R2
3
Scheme 4 Plausible reaction pathway
To expand the utility of this method, the use of α,α-
disubstituted acids in the reaction was examined next
(Scheme 3). It is noteworthy that 3-aryl-2,2-dimethylbut-3-
enoic acids 1p and 1q underwent oxidative cyclization on
treatment with PhI(OTf)2 in dichloromethane at room tem-
perature, furnishing the corresponding furan-2(3H)-one
products, which are difficult to access by other methods.
In conclusion, we have developed the oxidative cycliza-
tion of β-substituted β,γ-unsaturated carboxylic acids using
a highly electrophilic PhI(OTf)2. The use of PhI(OTf)2 was
found to be crucial for achieving this oxidative cyclization
to occur in preference to decarboxylation.6 The present
method provides valuable furan-2(5H)-one and furan-
2(3H)-one derivatives, some of which are difficult to syn-
thesize by other methods, thus offering a new, straightfor-
ward approach to the preparation of furanones.
O
PhI(OAc)2 (1 equiv)
O
CO2H
Me3SiOTf (2 equiv)
CH2Cl2, r.t., 3 h
X
X
1
New compounds were characterized by H, 13C, and 19F NMR, IR, MS,
1p X = H
1q X = Br
3a X = H 68%
3b X = Br 54%
and HRMS. 1H, 13C, and 19F NMR spectra were recorded on a Jeol
JMTC-400/54/SS spectrometer (1H NMR, 400 MHz; 13C NMR, 100
Scheme 3 Oxidative cyclization of α,α-disubstituted substrates
MHz; 19F NMR, 377 MHz). H NMR chemical shifts were determined
1
relative to Me4Si (0.0 ppm) as an internal standard. 13C NMR chemical
shifts were determined relative to CDCl3 (77.0 ppm). 19F NMR chemi-
cal shifts were determined relative to C6F6 (–164.9 ppm) as an exter-
nal standard. IR spectra were recorded on a Shimadzu IRAffinity-1 FT-
IR spectrophotometer. Mass spectra were obtained on a Shimadzu
GCMS-QP2010 and a Jeol JMS-DX303HF mass spectrometer. High-
resolution mass spectra were obtained on a Jeol JMS-DX303HF mass
spectrometer. Melting points were determined on a Stanford Re-
search Systems MPA100 OptiMelt Automated Melting Point System.
All reactions were carried out under N2. Products were purified by
chromatography on silica gel BW-300 (Fuji Silysia Chemical Ltd.). An-
alytical TLC was performed on precoated silica gel glass plates (Merck
silica gel 60 F254). Compounds were visualized with UV lamp or treat-
ment with an ethanolic solution of phosphomolybdic acid followed
by heating. Anhyd CH2Cl2 was used as obtained. β,γ-Unsaturated car-
boxylic acids were prepared according to literature procedures.6 All
other solvents and reagents were purchased and used as obtained.
A plausible reaction pathway is shown in Scheme 4. Ac-
cording to previous reports,7 the highly electrophilic
PhI(OTf)2 is generated in situ by a ligand exchange between
PhI(OAc)2 and Me3SiOTf (Scheme 4, a). In addition, the oxi-
dative cyclization proceeded effectively with one equiva-
lent of Me3SiOTf (Table 1, entry 7), indicating that
PhI(OAc)(OTf) and [PhIOIPh](OTf)2 (the Zefirov’s reagent)
would also function as active iodine reagents.10 The result-
ing PhI(OTf)2 then participates in the activation of the
alkene moiety of acid 1 via the formation of a cyclic iodoni-
um intermediate 4, which would subsequently undergo an
intramolecular cyclization rather than decarboxylation,
thus constructing a γ-lactone framework (Scheme 4, b). Fi-
nally, the elimination of iodobenzene as well as TfOH from
intermediate 5 affords the furanone product. Substrates
containing a proton at the α-position provide furan-2(5H)-
ones 2, while, in the case of α,α-disubstituted substrates,
furan-2(3H)-ones 3 are formed.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

D
K. Kiyokawa et al.
Special Topic
Synthesis
Furan-2(5H)-ones 2 and Furan-2(3H)-ones 3; General Procedure
4-[4-(Trifluoromethyl)phenyl]furan-2(5H)-one (2e)
A heat-gun-dried two-necked reaction flask containing a magnetic
stir bar was charged with PhI(OAc)2 (0.30 mmol), CH2Cl2 (3 mL), and
Me3SiOTf (0.60 mmol), and the reaction mixture was stirred for 10
min. To the mixture, carboxylic acid 1 (0.30 mmol) was added. The
resulting solution was stirred at r.t. for the appropriate time. The re-
action was quenched with aq 1 M Na2S2O3 (5 mL). The mixture was
extracted with CH2Cl2 (3 × 10 mL), and the combined organic layers
were dried (Na2SO4). The solution was concentrated under reduced
pressure to give the crude product, which was analyzed by 1H NMR
spectroscopy using 1,1,2,2-tetrachloroethane as an internal standard.
Purification was performed by flash column chromatography on sili-
ca gel (hexane/EtOAc).
According to the general procedure, the reaction using PhI(OAc)2
(96.7 mg, 0.30 mmol), Me3SiOTf (109 μL, 0.60 mmol), and 3-[4-(triflu-
oromethyl)phenyl]but-3-enoic acid (68.6 mg, 0.30 mmol) in 1,2-di-
chloroethane (3 mL) was conducted at 80 °C for 1 h. Purification by
flash column chromatography on silica gel (hexane/EtOAc) gave the
product as a white solid; yield: 59.7 mg (88%); mp 168.9–169.3 °C.
IR (ATR): 1757, 1323 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.75 (d, J = 8.0 Hz, 2 H), 7.64 (d, J = 8.0
Hz, 2 H), 6.50 (t, J = 2.0 Hz, 1 H), 5.26 (d, J = 2.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 173.1, 162.1, 133.1 (q, JC,F = 32.9 Hz),
132.9, 126.8, 126.3 (q, JC,F = 3.3 Hz), 123.4 (q, JC,F = 270.8 Hz), 115.3,
70.8.
4-Phenylfuran-2(5H)-one (2a)
19F NMR (377 MHz, CDCl3): δ = –66.3.
MS (EI): m/z (%) = 228 (M+, 60), 199 (79), 171 (44), 170 (47), 151
(100), 120 (32), 115 (28), 102 (45), 75 (37), 69 (56), 63 (30), 62 (24),
51 (34), 50 (30).
According to the general procedure, the reaction using PhI(OAc)2
(96.9 mg, 0.30 mmol), Me3SiOTf (109 μL, 0.60 mmol), and 3-phenyl-
but-3-enoic acid (48.4 mg, 0.30 mmol) in CH2Cl2 (3 mL) was conduct-
ed at r.t. for 1.5 h. Purification by flash column chromatography on
silica gel (hexane/EtOAc) gave the product as a white solid; yield: 42.0
mg (88%). The analytical and spectral data for this compound were in
excellent agreement with the reported data.11
HRMS (EI): m/z [M]+ calcd for C11H7F3O2: 228.0398; found: 228.0398.
4-[3,5-Bis(trifluoromethyl)phenyl]furan-2(5H)-one (2f)
According to the general procedure, the reaction using PhI(OAc)2
(96.2 mg, 0.30 mmol), Me3SiOTf (110 μL, 0.60 mmol), and 3-[3,5-
bis(trifluoromethyl)phenyl]but-3-enoic acid (89.4 mg, 0.30 mmol) in
1,2-dichloroethane (3 mL) was conducted at 80 °C for 3 h. Purification
by flash column chromatography on silica gel (hexane/EtOAc) gave
the product as a white solid; yield: 62.2 mg (70%); mp 138.5–
139.1 °C.
4-(4-Fluorophenyl)furan-2(5H)-one (2b)
According to the general procedure, the reaction using PhI(OAc)2
(96.9 mg, 0.30 mmol), Me3SiOTf (109 μL, 0.60 mmol), and 3-(4-fluo-
rophenyl)but-3-enoic acid (53.7 mg, 0.30 mmol) in CH2Cl2 (3 mL) was
conducted at r.t. for 1.5 h. Purification by flash column chromatogra-
phy on silica gel (hexane/EtOAc) gave the product as a white solid;
yield: 44.4 mg (82%); mp 155.3–155.7 °C.
IR (ATR): 1802, 1775, 1275, 1111, 1063 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.07–7.90 (m, 3 H), 6.60 (t, J = 2.0 Hz, 1
H), 5.30 (d, J = 2.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 172.3, 160.2, 133.1 (q, JC,F = 33.0 Hz),
131.8, 126.3, 125.0–124.8 (m), 122.7 (q, JC,F = 271.8 Hz), 116.8, 70.6.
19F NMR (377 MHz, CDCl3): δ = –66.2.
MS (EI): m/z (%) = 296 (M+, 22), 277 (21), 267 (100), 239 (36), 238
IR (ATR): 1732, 1510, 1159, 835 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.56–7.48 (m, 2 H), 7.22–7.10 (m, 2 H),
6.34 (t, J = 1.6 Hz, 1 H), 5.21 (d, J = 1.6 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 173.7, 164.6 (d, JC,F = 252.8 Hz), 162.6,
128.6 (d, JC,F = 9.0 Hz), 126.0 (d, JC,F = 3.3 Hz), 116.6 (d, JC,F = 22.3 Hz),
112.8 (d, JC,F = 1.6 Hz), 70.9.
(29), 219 (41), 169 (24), 69 (35).
HRMS (EI): m/z [M]+ calcd for C12H6F6O2: 296.0272; found: 296.0275.
19F NMR (377 MHz, CDCl3): δ = –109.8
MS (EI): m/z (%) = 178 (M+, 66), 149 (100), 121 (76), 120 (100), 101
(49), 75 (22).
4-(4-Methoxyphenyl)furan-2(5H)-one (2g)
HRMS (EI): m/z [M]+ calcd for C10H7FO2: 178.0430; found: 178.0429.
According to the general procedure, the reaction using PhI(OAc)2
(96.5 mg, 0.30 mmol), Me3SiOTf (109 μL, 0.60 mmol), 2,6-di-tert-bu-
tylpyridine (113.4 mg, 0.59 mmol), and 3-(4-methoxyphenyl)but-3-
enoic acid (57.4 mg, 0.30 mmol) in CH2Cl2 (3 mL) was conducted at r.t.
for 1 h. Purification by flash column chromatography on silica gel
(hexane/EtOAc) gave the product as a yellow solid; yield: 19.2 mg
(34%). The analytical and spectral data for this compound were in ex-
cellent agreement with the reported data.12
4-(4-Chlorophenyl)furan-2(5H)-one (2c)
According to the general procedure, the reaction using PhI(OAc)2
(96.4 mg, 0.30 mmol), Me3SiOTf (109 μL, 0.60 mmol), and 3-(4-chlo-
rophenyl)but-3-enoic acid (58.7 mg, 0.30 mmol) in CH2Cl2 (3 mL) was
conducted at r.t. for 1.5 h. Purification by flash column chromatogra-
phy on silica gel (hexane/EtOAc) gave the product as a yellow solid;
yield: 52.5 mg (90%). The analytical and spectral data for this com-
pound were in excellent agreement with the reported data.3d
4-(4-Tolyl)furan-2(5H)-one (2h)
According to the general procedure, the reaction using PhI(OAc)2
(96.6 mg, 0.30 mmol), Me3SiOTf (109 μL, 0.60 mmol), 2,6-di-tert-bu-
tylpyridine (121.8 mg, 0.64 mmol), and 3-(4-tolyl)but-3-enoic acid
(52.6 mg, 0.30 mmol) in CH2Cl2 (3 mL) was conducted at r.t. for 1 h.
Purification by flash column chromatography on silica gel (hex-
ane/EtOAc) gave the product as a white solid; yield: 43.7 mg (76%).
The analytical and spectral data for this compound were in excellent
agreement with the reported data.12
4-(4-Bromophenyl)furan-2(5H)-one (2d)
According to the general procedure, the reaction using PhI(OAc)2
(96.7 mg, 0.30 mmol), Me3SiOTf (109 μL, 0.60 mmol), and 3-(4-bro-
mophenyl)but-3-enoic acid (73.6 mg, 0.31 mmol) in CH2Cl2 (3 mL)
was conducted at r.t. for 2.5 h. Purification by flash column chroma-
tography on silica gel (hexane/EtOAc) gave the product as a yellow
solid, yield: 50.9 mg (77%). The analytical and spectral data for this
compound were in excellent agreement with the reported data.11
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

E
K. Kiyokawa et al.
Special Topic
Synthesis
4-(2-Tolyl)furan-2(5H)-one (2i)
3-Isopropyl-4-phenylfuran-2(5H)-one (2o)
According to the general procedure, the reaction using PhI(OAc)2
(145.1 mg, 0.45 mmol), Me3SiOTf (164 μL, 0.90 mmol), 2,6-di-tert-bu-
tylpyridine (170.2 mg, 0.89 mmol), and 3-(2-tolyl)but-3-enoic acid
(52.5 mg, 0.30 mmol) in CH2Cl2 (3 mL) was conducted at r.t. for 3 h.
Purification by flash column chromatography on silica gel (hex-
ane/EtOAc) gave the product as a white solid; yield: 31.7 mg (61%).
The analytical and spectral data for this compound were in excellent
agreement with the reported data.12
According to the general procedure, the reaction using PhI(OAc)2
(94.4 mg, 0.29 mmol), Me3SiOTf (105 μL, 0.58 mmol), and 2-isopro-
pyl-3-phenylbut-3-enoic acid (59.5 mg, 0.29 mmol) in CH2Cl2 (3 mL)
was conducted at r.t. for 3 h. Purification by flash column chromatog-
raphy on silica gel (hexane/EtOAc) gave the product as a yellow vis-
cous liquid; yield: 23.2 mg (40%).
IR (ATR): 1746, 1649 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.55–7.40 (m, 3 H), 7.40–7.30 (m, 2 H),
4.94 (s, 2 H), 3.07 (sept, J = 7.2 Hz, 1 H), 1.30 (d, J = 7.2 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 173.4, 155.3, 132.4, 131.6, 129.8,
4-(3-Tolyl)furan-2(5H)-one (2j)
According to the general procedure, the reaction using PhI(OAc)2
(96.6 mg, 0.30 mmol), Me3SiOTf (109 μL, 0.60 mmol), and 3-(3-
tolyl)but-3-enoic acid (51.8 mg, 0.29 mmol) in CH2Cl2 (3 mL) was con-
ducted at r.t. for 1.5 h. Purification by flash column chromatography
on silica gel (hexane/EtOAc) gave the product as a yellow solid; yield:
44.2 mg (86%). The analytical and spectral data for this compound
were in excellent agreement with the reported data.12
129.0, 127.4, 70.6, 25.1, 20.1.
MS (EI): m/z (%) = 202 (M+, 91), 201 (81), 157 (63), 143 (69), 142 (38),
141 (49), 131 (28), 130 (22), 129 (69), 128 (100), 127 (28), 117 (20),
115 (61), 105 (49), 91 (56), 77 (44), 51 (28).
HRMS (EI): m/z [M]+ calcd for C13H14O2: 202.0994; found: 202.0992.
3,3-Dimethyl-4-phenylfuran-2(3H)-one (3a)
4-(1-Naphthyl)furan-2(5H)-one (2k)
According to the general procedure, the reaction using PhI(OAc)2
(96.8 mg, 0.30 mmol), Me3SiOTf (110 μL, 0.60 mmol), and 2,2-dimeth-
yl-3-phenylbut-3-enoic acid (55.8 mg, 0.29 mmol) in CH2Cl2 (3 mL)
was conducted at r.t. for 3 h. Purification by flash column chromatog-
raphy on silica gel (hexane/EtOAc) gave the product as a yellow solid;
yield: 37.5 mg (68%); mp 68.7–69.6 °C.
According to the general procedure, the reaction using PhI(OAc)2
(144.3 mg, 0.45 mmol), Me3SiOTf (165 μL, 0.90 mmol), 2,6-di-tert-bu-
tylpyridine (174.5 mg, 0.91 mmol), and 3-(1-naphthyl)but-3-enoic
acid (63.6 mg, 0.30 mmol) in CH2Cl2 (3 mL) was conducted at r.t. for 3
h. Purification by flash column chromatography on silica gel (hex-
ane/EtOAc) gave the product as a yellow solid; yield: 49.1 mg (78%).
The analytical and spectral data for this compound were in excellent
agreement with the reported data.3d
IR (ATR): 1798, 1622 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.40–7.30 (m, 5 H), 7.05 (s, 1 H), 1.51
(s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 182.5, 136.2, 131.1, 129.5, 128.8,
128.0, 126.3, 45.0, 23.9.
MS (EI): m/z (%) = 188 (M+, 88), 160 (61), 145 (95), 142 (20), 132 (48),
131 (89), 130 (25), 129 (42), 128 (40), 127 (25), 118 (21), 117 (100),
116 (88), 115 (100), 91 (100), 89 (39), 78 (22), 77 (46), 65 (35), 63
(50), 53 (21), 51 (46), 50 (21).
4-(2-Naphthyl)furan-2(5H)-one (2l)
According to the general procedure, the reaction using PhI(OAc)2
(96.6 mg, 0.30 mmol), Me3SiOTf (109 μL, 0.60 mmol), 2,6-di-tert-bu-
tylpyridine (112.8 mg, 0.59 mmol), and 3-(2-naphthyl)but-3-enoic
acid (63.7 mg, 0.30 mmol) in 1,2-dichloroethane (3 mL) was conduct-
ed at 60 °C for 3 h. Purification by flash column chromatography on
silica gel (hexane/EtOAc) gave the product as a yellow solid; yield:
38.1 mg (60%). The analytical and spectral data for this compound
were in excellent agreement with the reported data.3d
HRMS (EI): m/z [M]+ calcd for C12H12O2: 188.0837; found: 188.0835.
4-(4-Bromophenyl)-3,3-dimethylfuran-2(3H)-one (3b)
According to the general procedure, the reaction using PhI(OAc)2
(96.2 mg, 0.30 mmol), Me3SiOTf (109 μL, 0.60 mmol), and 3-(4-bro-
mophenyl)-2,2-dimethylbut-3-enoic acid (79.9 mg, 0.30 mmol) in
CH2Cl2 (3 mL) was conducted at r.t. for 3 h. Purification by flash col-
umn chromatography on silica gel (hexane/EtOAc) gave the product
as a white solid; yield: 42.9 mg (54%); mp 89.8–90.6 °C.
4-Benzylfuran-2(5H)-one (2m)
According to the general procedure, the reaction using PhI(OAc)2
(96.9 mg, 0.30 mmol), Me3SiOTf (109 μL, 0.60 mmol), and 3-benzyl-
but-3-enoic acid (52.9 mg, 0.30 mmol) in CH2Cl2 (3 mL) was conduct-
ed at r.t. for 1.5 h. Purification by flash column chromatography on
silica gel (hexane/EtOAc) gave the product as a yellow viscous liquid;
yield: 23.3 mg (45%). The analytical and spectral data for this com-
pound were in excellent agreement with the reported data.13
IR (ATR): 1782, 1634 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.50 (d, J = 8.4 Hz, 2 H), 7.22 (d, J = 8.4
Hz, 2 H), 7.07 (s, 1 H), 1.49 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 182.2, 136.6, 132.0, 130.0, 128.5,
4-(n-Butyl)furan-2(5H)-one (2n)
127.8, 122.0, 44.9, 23.8.
According to the general procedure, the reaction using PhI(OAc)2
(97.2 mg, 0.30 mmol), Me3SiOTf (109 μL, 0.60 mmol), and 3-meth-
ylideneheptanoic acid (40.1 mg, 0.28 mmol) in CH2Cl2 (3 mL) was
conducted at r.t. for 1.5 h. Purification by flash column chromatogra-
phy on silica gel (hexane/EtOAc) gave the product as a yellow viscous
liquid; yield: 13.3 mg (34%). The analytical and spectral data for this
compound were in excellent agreement with the reported data.14
MS (EI): m/z (%) = 266 (M+, 58), 268 (59), 240 (29), 238 (31), 159
(100), 144 (26), 131 (97), 130 (46), 129 (37), 128 (20), 116 (35), 115
(71), 91 (26).
HRMS (EI): m/z [M]+ calcd for C12H11BrO2: 265.9942; found: 265.9944.
Acknowledgment
This work was supported by JSPS KAKENHI Grant Number
JP16K17868.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

F
K. Kiyokawa et al.
Special Topic
Synthesis
Supporting Information
(3) For selected examples, see: (a) Danieli, N.; Mazur, Y.;
Sondheimer, F. J. Am. Chem. Soc. 1962, 84, 875. (b) Danieli, N.;
Mazur, Y.; Sondheimer, F. Tetrahedron 1966, 22, 3189.
(c) Krauser, S. F.; Watterson, A. C. Jr. J. Org. Chem. 1978, 43, 3400.
(d) Kagabu, S.; Shimizu, Y.; Ito, C.; Moriya, K. Synthesis 1992,
830. (e) Renard, M.; Ghosez, L. A. Tetrahedron 2001, 57, 2597.
(f) Bassetti, M.; D’Annibale, A.; Fanfoni, A.; Minissi, F. Org. Lett.
2005, 7, 1805. (g) Liu, Y.; Song, F.; Guo, S. J. Am. Chem. Soc. 2006,
128, 11332. (h) Tejedor, D.; Santos-Expośito, A.; García-Tellado,
F. Synlett 2006, 1607. (i) Alfonsi, M.; Arcadi, A.; Chiarini, M.;
Marinelli, F. J. Org. Chem. 2007, 72, 9510. (j) Li, S.; Miao, B.;
Yuan, W.; Ma, S. Org. Lett. 2013, 15, 977.
(4) (a) Kasahara, A.; Izumi, T.; Sato, K.; Maemura, M.; Hayasaka, T.
Bull. Chem. Soc. Jpn. 1977, 50, 1899. (b) Browne, D. M.;
Niyomura, O.; Wirth, T. Org. Lett. 2007, 9, 3169. (c) Bajracharya,
G. B.; Koranne, P. S.; Nadaf, R. N.; Gabr, R. K. M.; Takenaka, K.;
Takizawa, S.; Sasai, H. Chem. Commun. 2010, 46, 9064.
(d) Kawamata, Y.; Hashimoto, T.; Maruoka, K. J. Am. Chem. Soc.
2016, 138, 5206.
(5) Singh, F. V.; Rehbein, J.; Wirth, T. ChemistryOpen 2012, 1, 245.
(6) (a) Kiyokawa, K.; Yahata, S.; Kojima, T.; Minakata, S. Org. Lett.
2014, 16, 4646. For iodine-catalyzed decarboxylative amidation,
see: (b) Kiyokawa, K.; Kojima, T.; Hishikawa, Y.; Minakata, S.
Chem. Eur. J. 2015, 21, 15548.
(7) (a) Zefirov, N. S.; Safronov, S. O.; Kaznacheev, A. A.; Zhdankin, V.
V. Zh. Org. Khim. 1989, 25, 1807. (b) Lutz, K. E.; Thomson, R. J.
Angew. Chem. Int. Ed. 2011, 50, 4437. (c) Farid, U.; Wirth, T.
Angew. Chem. Int. Ed. 2012, 51, 3462.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588987.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
References
(1) (a) Kupchan, S. M.; Court, W. A.; Dailey, R. G. Jr.; Gilmore, C. J.;
Bryan, R. F. J. Am. Chem. Soc. 1972, 94, 7194. (b) Pelter, A.; Ward,
R. S.; Rao, E. V.; Raju, N. R. J. Chem. Soc., Perkin Trans. 1 1981,
2491. (c) De Guzman, F. S.; Schmitz, F. J. J. Nat. Prod. 1990, 53,
926. (d) Bezuidenhoudt, B. C. B.; Swanepoel, A.; Brandt, E. V.;
Ferreira, D. J. Chem. Soc., Perkin Trans. 1 1990, 2599. (e) Miao, S.;
Andersen, R. J. J. Org. Chem. 1991, 56, 6275. (f) Miles, D. H.;
Chittawong, V.; Lho, D.-S.; Payne, A. M.; de la Cruz, A. A.; Gomez,
E. D.; Weeks, J. A.; Atwood, J. L. J. Nat. Prod. 1991, 54, 286.
(g) Nohara, T.; Kinjo, J.; Furusawa, J.; Sakai, Y.; Inoue, M.;
Shirataki, Y.; Ishibashi, Y.; Yokoe, I.; Komatsu, M. Phytochemistry
1993, 33, 1207. (h) Cerri, A.; Mauri, P.; Mauro, M.; Melloni, P.
J. Heterocycl. Chem. 1993, 30, 1581. (i) Evidente, A.; Sparapano,
L. J. Nat. Prod. 1994, 57, 1720. (j) Figadère, B. Acc. Chem. Res.
1995, 28, 359. (k) Midland, S. L.; Keen, N. T.; Sims, J. J. J. Org.
Chem. 1995, 60, 1118. (l) Honda, T.; Mizutani, H.; Kanai, K. J. Org.
Chem. 1996, 61, 9374. (m) Gunasekera, S. P.; McCarthy, P. J.;
Kelly-Borges, M.; Lobkovsky, E.; Clardy, J. J. Am. Chem. Soc. 1996,
118, 8759. (n) Smith, C. J.; Hettich, R. L.; Jompa, J.; Tahir, A.;
Buchanan, M. V.; Ireland, C. M. J. Org. Chem. 1998, 63, 4147.
(o) Ortega, M. J.; Zubía, E.; Ocaña, J. M.; Naranjo, S.; Salvá, J. Tet-
rahedron 2000, 56, 3963. (p) Bellina, F.; Anselmi, C.; Viel, S.;
Mannina, L.; Rossi, R. Tetrahedron 2001, 57, 9997. (q) Ueda, J.;
Tezuka, Y.; Banskota, A. H.; Tran, Q. L.; Tran, Q. K.; Saiki, I.;
Kadota, S. J. Nat. Prod. 2003, 66, 1427. (r) Braña, M. F.; García, M.
L.; López, B.; de Pascual-Teresa, B.; Ramos, A.; Pozuelo, J. M.;
Domínguez, M. T. Org. Biomol. Chem. 2004, 2, 1864. (s) Keyzers,
R. A.; Davies-Coleman, M. T. Chem. Soc. Rev. 2005, 34, 355.
(t) Ohsaki, A.; Kobayashi, Y.; Yoneda, K.; Kishida, A.; Ishiyama,
H. J. Nat. Prod. 2007, 70, 2003. (u) Zhang, H.; Conte, M. M.;
Huang, X.-C.; Khalil, Z.; Capon, R. J. Org. Biomol. Chem. 2012, 10,
2656.
(8) (a) Zefirov, N. S.; Zhdankin, V. V.; Dan’kov, Y. V.; Koz’min, A. S.
J. Org. Chem. USSR 1984, 20, 401; Zh. Org. Khim. 1984, 20, 446.
(b) Zefirov, N. S.; Zhdankin, V. V.; Dan’kov, Y. V.; Sorokin, V. D.;
Semerikov, V. N.; Koz’min, A. S.; Caple, R.; Berglund, B. A. Tetra-
hedron Lett. 1986, 27, 3971.
(9) Upon treatment with TfOH in CH2Cl2, methoxy-substituted sub-
strate 1g completely isomerized into the corresponding α,β-
unsaturated carboxylic acid, which decomposed into a complex
mixture under the standard cyclization conditions.
(10) Izquierdo, S.; Essafi, S.; del Rosal, I.; Vidossich, P.; Pleixats, R.;
Vallribera, A.; Ujaque, G.; Lledós, A.; Shafir, A. J. Am. Chem. Soc.
2016, 138, 12747.
(2) For reviews, see: (a) Rao, Y. S. Chem. Rev. 1976, 76, 625.
(b) Avetisyan, A. A.; Dangyan, M. T. Russ. Chem. Rev. 1977, 46,
643. For selected examples, see: (c) Wu, J.; Zhu, Q.; Wang, L.;
Fathi, R.; Yang, Z. J. Org. Chem. 2003, 68, 670. (d) Boukouvalas, J.;
Loach, R. P. J. Org. Chem. 2008, 73, 8109. (e) Hyde, A. M.;
Buchwald, S. L. Org. Lett. 2009, 11, 2663. (f) Matsuo, K.; Shindo,
M. Org. Lett. 2010, 12, 5346. (g) Lee, D.; Newman, S. G.; Taylor,
M. S. Org. Lett. 2009, 11, 5486. (h) Cheng, J.; Chen, P.; Liu, G. Org.
Chem. Front. 2014, 1, 289. (i) Mao, W.; Zhu, C. Org. Lett. 2015, 17,
5710.
(11) Gronnier, C.; Kramer, S.; Odabachian, Y.; Gagosz, F. J. Am. Chem.
Soc. 2012, 134, 828.
(12) Hu, Y.; Ding, Q.; Ye, S.; Peng, Y.; Wu, J. Tetrahedron 2011, 67,
7258.
(13) Carter, N. B.; Mabon, R.; Richecœur, A. M. E.; Sweeney, J. B. Tet-
rahedron 2002, 58, 9117.
(14) Pelletier, S. W.; Djarmati, Z.; Lajšić, S. D.; Mićović, I. V.; Yang, D.
T. C. Tetrahedron 1975, 31, 1659.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F