Hypervalent iodine mediated oxidative cyclization of o -hydroxystilbenes into benzo- and naphthofurans

Article abstract of DOI:10.1055/s-0031-1290588

A new and convenient metal-free cyclization of ortho-hydroxystilbenes into 2-arylbenzofurans and 2-arylnaphthofurans mediated by hypervalent iodine reagents is described. The cyclization products are isolated in good to excellent yields using stoichiometric (diacetoxyiodo)benzene in acetonitrile. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0031-1290588

SPECIAL TOPIC
▌1171
special topic
Hypervalent Iodine Mediated Oxidative Cyclization of o-Hydroxystilbenes
into Benzo- and Naphthofurans
Hypervalent Iodine Mediated Oxidative Cyclization
Fateh V. Singh, Thomas Wirth*
School of Chemistry, Cardiff University, Park Place, Cardiff, CF10 3AT, UK
Fax +44(29)20876968; E-Mail: wirth@cf.ac.uk
Received: 06.02.2012; Accepted: 20.02.2012
sponding 2-arylbenzofurans
2
using (diacetoxy-
Abstract: A new and convenient metal-free cyclization of ortho-
hydroxystilbenes into 2-arylbenzofurans and 2-arylnaphthofurans
mediated by hypervalent iodine reagents is described. The cycliza-
tion products are isolated in good to excellent yields using stoichio-
metric (diacetoxyiodo)benzene in acetonitrile.
iodo)benzene [PhI(OAc)2] in good to excellent yields un-
der mild reaction conditions. The synthesis of precursors
1 was achieved by palladium-catalyzed Heck reactions of
2-iodophenol and various functionalized styrenes in 69–
89% yield.18 Initially, optimal reaction conditions and re-
agents for the hypervalent iodine mediated cyclization
were established using (E)-2-styrylphenol (1a) as a model
substrate. The cyclizations were performed in acetonitrile
using one equivalent of [bis(trifluoroacetoxy)iodo]benz-
ene at room temperature under an argon atmosphere. The
isolated product was characterized as 2-phenylbenzofuran
(2a) as shown in Scheme 1.
Key words: benzofurans, cyclization, hypervalent iodine reagents,
naphthofurans, stilbenes
Benzofuran scaffolds are basic structural motifs found in
various naturally occurring biologically active com-
pounds.1 Additionally, several natural products with a
naphthofuran core such as (+)-heritol2 and (±)-laevigatin3
possess interesting pharmacological and cytotoxic proper-
ties. A number of synthetic benzofurans have been report-
ed to have diverse pharmacological activities. These
compounds can act as 5-lipoxygenase inhibitors,4 as
angiotensin II inhibitors,5 calcium entry blockers,6 or
possess antifungal,7 antibacterial,8 antimicrobial,9 or
acetylcholinesterase inhibitor activity.10
hypervalent iodine
Ph
reagent
Ph
MeCN, r.t.
O
OH
1a
2a
Scheme 1 Cyclization of 1a using different hypervalent iodine re-
agents
Numerous synthetic approaches have been published for
the synthesis of benzofurans, but most of these are associ-
ated with transition-metal-catalyzed annulation reactions
of prefunctionalized substrates which were typically syn-
thesized by Heck or Sonogashira coupling reactions.11
There are few synthetic methodologies available in this
area which do not require transition metals; these include
the [3,3]-sigmatropic rearrangement of N-trifluoroacetyl-
ene-hydroxylamines,12 cycloaddition of arynes with iodo-
nium ylids13 and cyclization of o-stilbenes using iodine
with potassium carbonate as the base.14 The synthesis of
benzofurans has also been achieved by intramolecular
photochemical Wittig reaction of functionalized phospho-
nium bromides.15
In order to further optimize the reaction conditions, differ-
ent cyclic and acyclic hypervalent iodine reagents were
investigated (Table 1). The cyclized product 2a was ob-
tained in 69% yield with [bis(trifluoroacetoxy)iodo]ben-
zene (Table 1, entry 1), while the yield was increased up
to 77% by using the less reactive (diacetoxyiodo)benzene
(Table 1, entry 2). The same reaction was carried out us-
ing Koser’s reagent [PhI(OH)OTs], but the reaction prod-
uct 2a was isolated in only 67% yield (Table 1, entry 3).
The fully fluorinated and more soluble reagent [bis(tri-
fluoroacetoxy)iodo]pentafluorobenzene19 was also used,
but 2a was obtained in only 59% yield (Table 1, entry 4).
It appeared that more reactive hypervalent iodine com-
pounds were less efficient in this transformation. This was
also demonstrated with the in situ synthesis and use of a
reactive bistriflate (Table 1, entry 5) which led to benzo-
furan 2a in only 59% yield. The reaction product was ob-
served only in trace amount when using iodosylbenzene
(PhIO). Furthermore, the reaction did not occur with the
cyclic hypervalent iodine(V) reagent, 1-hydroxy-1,2-
benziodoxol-3-(1H)-one 1-oxide (IBX) (Table 1, entry 7).
Hypervalent iodine compounds have been recognized as
very promising reagents in synthetic organic chemistry.16
Their low toxicity, favorable safety profiles, easy han-
dling, and environmentally friendly nature make them at-
tractive as reagents for metal-free transformations. Our
research group has developed different oxidative cycliza-
tion reactions using hypervalent iodine reagents.17
Herein, we report a convenient procedure for the cycliza-
tion of a series of ortho-hydroxystilbenes 1 into the corre-
In addition, different polar and non-polar solvents were
investigated in the cyclization of 1a using (diacetoxyio-
do)benzene as shown in Table 2. The cyclization reaction
proceeded well in polar and aprotic solvents such as ace-
tonitrile and dichloromethane (Table 2, entries 1 and 3).
SYNTHESIS 42170012, 44,81171–1177
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DOI: 10.1055/s-0031-1290588; Art ID: SS-2012-C0114-ST
© Georg Thieme Verlag Stuttgart · New York

1172
F. V Singh, T. Wirth
SPECIAL TOPIC
Table 1 Different Hypervalent Iodine Compounds Used for the Cy-
clization of 1a
Table 3 Cyclization of (E)-2-Hydroxystilbenes 1a–k
Ar
PhI(OAc)2 (1 equiv)
MeCN, r.t., 1–3 h
Ar
Entry
Oxidant
Time (h)
Yield of 2a (%)
O
OH
1
2
3
4
5
6
7
PhI(OCOCF3)2
PhI(OAc)2
PhI(OH)OTs
C6F5I(OCOCF3)2
PhI(OSO2CF3)2
PhIO
1
1
69
77
67
59
59
trace
0
1
2
Entry
Substrate
Ar
Time (h) Yield of 2 (%)
2
1
2
1a
1b
1c
1d
1e
1f
Ph
2
2
2
2
3
3
1
2
2
1
3
77
79
77
74
68
69
87
79
83
86
79
1
4-ClC6H4
3-ClC6H4
2-ClC6H4
3-FC6H4
1
3
15
15
4
IBX
5
6
3-O2NC6H4
4-MeOC6H4
4-MeC6H4
3-MeC6H4
2-MeC6H4
2-pyridyl
The reaction also occurred in polar and protic solvents
such as diethyl ether, tetrahydrofuran and methanol, but
the cyclic product 2a was obtained in lower yields (Table
2, entries 2, 4 and 5). The cyclized product 2a was ob-
served only in trace amount in the non-polar and aprotic
solvent toluene (Table 2, entry 6). One equivalent of (di-
acetoxyiodo)benzene with a reaction time of two hours in
acetonitrile was found to be optimal conditions for the cy-
clization of 1a into benzofuran 2a.
7
1g
1h
1i
8
9
10
11
1j
1k
Table 2 Different Solvents Investigated for the Cyclization of 1a
Using (Diacetoxyiodo)benzene
pounds 3a–c were cyclized into 2-naphthofurans 4a–c by
using one equivalent of (diacetoxyiodo)benzene under the
same reaction conditions employed for the synthesis of
compounds 2. Products 4a–c were isolated in 88–95%
yields (Table 4) and were fully characterized by spectro-
scopic analysis.
Entry
Solvent
Time (h)
Yield of 2a (%)
1
2
3
4
5
6
MeCN
THF
1
15
1
77
27
CH2Cl2
Et2O
65
Table 4 Cyclization of (E)-1-Styryl-2-naphthols 3a–c
15
15
15
38
PhI(OAc)2 (1 equiv)
Ar
MeOH
toluene
46
Ar
MeCN, r.t., 1–3 h
O
trace
OH
4
3
Employing these optimal reaction conditions, a series of
2-hydroxystilbenes 1b–k was successfully cyclized to
yield the benzofuran products 2b–k in 68–87% yield as
shown in Table 3.
Entry
Substrate
Ar
Time (h) Yield of 4 (%)
1
2
3
3a
3b
3c
Ph
2
3
1
88
91
95
4-ClC6H4
3-MeOC6H4
The cyclization reactions occurred smoothly with sub-
strates 1 having both electron-donating and electron-with-
drawing group bearing aromatic substituents and the
products were isolated in good to excellent yields (Table
3). The products were obtained in higher yields when
electron-donating groups were present on the aromatic
substituent of the starting material (Table 3, entries 7–10).
All the reaction products were fully characterized by spec-
troscopic analysis.
A proposed mechanism for the hypervalent iodine in-
duced oxidative cyclization of stilbenes 1 into benzofu-
rans 2 is shown in Scheme 2. According to this
mechanism, the electrophilic iodine activates the double
bond of stilbene 1 forming a three-membered iodonium
intermediate 5. This undergoes intramolecular reaction
with the phenolic oxygen atom leading to intermediate 6.
Finally, elimination of the hypervalent iodine then gives
product 2.
After the synthesis of 2-arylbenzofurans 2, our efforts
were directed toward the cyclization of (E)-2-styrylnaph-
thols 3. The starting materials 3a–c were prepared by pal-
ladium-catalyzed Heck reactions of 1-bromonaphthalen-
2-ol and the appropriate styrenes in 48–56% yields. Com-
Synthesis 2012, 44, 1171–1177
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Hypervalent Iodine Mediated Oxidative Cyclization
1173
13C NMR (125 MHz, CDCl3): δ = 115.9, 121.2, 123.1, 124.7, 126.6,
127.3, 127.6, 128.7, 130.3, 137.6, 153.0.
OAc
Ar
Ph
I
Ar
PhI(OAc)2
(E)-2-(4-Chlorostyryl)phenol (1b)21
Yield: 0.363 g, 1.58 mmol (79%); yellow solid; mp 124–126 °C;
Rf = 0.4 (CH2Cl2).
OH
1
OH
5
IR (KBr): 3060, 3030, 1600, 1581, 1498, 1486, 1454, 1323, 1250,
1191, 1170, 1085, 1009, 975, 964, 815, 746 cm–1.
1H NMR (400 MHz, CDCl3): δ = 4.98 (s, 1 H, OH), 6.82 (dd,
J1 = 1.2 Hz, J2 = 8.0 Hz, 1 H, ArH), 6.99 (t, J = 7.6 Hz, 1 H, ArH),
7.10 (d, J = 16.4 Hz, 1 H, CH), 7.18 (dt, J1 = 1.6 Hz, J2 = 8.0 Hz, 1
H, ArH), 7.33–7.39 (m, 3 H, CH, ArH), 7.48 (td, J1 = 2.0 Hz,
J2 = 8.8 Hz, 2 H, ArH), 7.55 (dd, J1 = 1.4 Hz, J2 = 7.8 Hz, 1 H,
ArH).
Ph
OAc
H
I
Ar
–OAc
O
Ar
O
2
6
13C NMR (125 MHz, CDCl3): δ = 116.0, 121.3, 123.7, 124.4, 127.3,
127.7, 128.7, 128.8, 128.9, 133.2, 136.2, 153.0.
Scheme 2 Proposed mechanism for the cyclization of stilbenes 1
HRMS (APCI): m/z [M]+ calcd for C14H12OCl: 231.0571; found
231.0567.
In summary, we have demonstrated an alternative ap-
proach for the synthesis of 2-arylbenzofurans and 2-aryl-
naphthofurans via oxidative cyclization of o-hydroxy-
stilbenes using (diacetoxyiodo)benzene as the oxidant.
Our method to synthesize these scaffolds is very simple,
economical and metal-free. Further studies on the wider
scope of this approach are currently in progress.
(E)-2-(3-Chlorostyryl)phenol (1c)
Yield: 0.368 g, 1.60 mmol (80%); yellow solid; mp 82–84 °C;
Rf = 0.4 (CH2Cl2).
IR (KBr): 3264, 3065, 1633, 1604, 1590, 1661, 1470, 1455, 1328,
1291, 1236, 1094, 1077, 958, 908, 875, 796, 776, 748, 677 cm–1.
1H NMR (500 MHz, CDCl3): δ = 5.01 (br s, 1 H, OH), 6.83 (dd,
J1 = 1.0 Hz, J2 = 8.0 Hz, 1 H, ArH), 6.99 (t, J = 7.5 Hz, 1 H, ArH),
7.09 (d, J = 16.5 Hz, 1 H, CH), 7.19 (dt, J1 = 1.5 Hz, J2 = 8.0 Hz, 1
H, ArH), 7.24–7.26 (m, 1 H, ArH), 7.30 (t, J = 7.5 Hz, 1 H, ArH),
7.41 (d, J = 16.5 Hz, 1 H, CH), 7.41 (d, J = 7.5 Hz, 1 H, ArH),
7.53–7.57 (m, 2 H, ArH).
13C NMR (125 MHz, CDCl3): δ = 116.0, 121.3, 124.3, 124.6, 124.8,
126.4, 127.4, 127.5, 128.6, 129.1, 129.8, 134.7, 139.6, 153.1.
HRMS (APCI): m/z [M]+ calcd for C14H12OCl: 231.0571; found
231.0568.
All experiments were performed under an inert atmosphere of argon
or nitrogen. Dry THF was used from a solvent purification system
while acetonitrile of HPLC grade was used and dried over molecu-
lar sieves (4 Å). All other purchased chemicals were used without
further purification. All reactions were monitored by thin-layer
chromatography performed on pre-coated Merck sheets of silica gel
60. Flash column chromatography was performed with silica gel 60
(Merck, 230–400 mesh). Eluting solvents are indicated in the text.
Melting points were obtained in open capillary tubes using a MP–
Gallenkamp apparatus. Infrared spectra were recorded on a JASCO
FT/IR-660 Plus spectrophotometer. 1H NMR and 13C NMR spectra
were recorded on an AV-400 Bruker instrument at 400 and 100
MHz, respectively, using the solvents indicated. A DRX-500 Bruk-
er instrument was used in some cases [1H (500 MHz) and 13C (125
MHz)]. HRMS was performed using a LTQ ORBITRAP XL spec-
trometer under the conditions of electron impact (EI), electrospray
(ES) or chemical ionization (CI).
(E)-2-(2-Chlorostyryl)phenol (1d)
Yield: 0.345 g, 1.50 mmol (75%); yellow solid; mp 138–140 °C;
Rf = 0.4 (CH2Cl2).
IR (KBr): 3048, 1620, 1599, 1581, 1491, 1467, 1445, 1330, 1295,
1245, 1085, 1193, 1172, 1123, 1088, 1048, 1034, 974, 849, 753,
734, 705 cm–1.
1H NMR (500 MHz, CDCl3): δ = 5.01 (br s, 1 H, OH), 6.84 (dd,
J1 = 1.0 Hz, J2 = 8.0 Hz, 1 H, ArH), 7.01 (t, J = 7.5 Hz, 1 H, ArH),
7.17–7.24 (m, 2 H, ArH), 7.29 (t, J = 7.5 Hz, 1 H, ArH), 7.39 (d,
J = 16.5 Hz, 1 H, CH), 7.39 (dd, J1 = 1.5 Hz, J2 = 8.0 Hz, 1 H,
ArH), 7.56 (d, J = 16.5 Hz, 1 H, CH), 7.61 (dd, J1 = 1.5 Hz,
J2 = 8.0 Hz, 1 H, ArH), 7.75 (dd, J1 = 1.5 Hz, J2 = 8.0 Hz, 1 H,
ArH).
13C NMR (125 MHz, CDCl3): δ = 116.0, 121.3, 124.5, 125.7, 126.1,
126.6, 126.9, 127.6, 128.5, 129.1, 129.8, 133.4, 135.8, 153.1.
HRMS (APCI): m/z [M]+ calcd for C14H12OCl: 231.0571; found
231.0568.
(E)-2-Styrylphenols 1a–k and (E)-1-Styrylnaphthols 3a–c;
General Procedure
(E)-2-Styrylphenols and (E)-1-styrylnaphthols were prepared ac-
cording to the reported procedure.18 A mixture of 2-iodophenol
(0.438 g, 2.0 mmol) [or 1-bromonaphthol (0.446 g, 2.0 mmol)], the
styrene derivative (2.6 mmol), Et3N (0.640 mL, 4.6 mmol),
Pd(OAc)2 (0.013 g, 0.06 mmol) and PPh3 (0.038 g, 0.07 mmol) was
heated at reflux temperature (80 °C) for 3–7 h. After completion of
the reaction, ice-cold H2O (10 mL) was added and the mixture was
acidified using aq HCl (1 M) with stirring to dissolve the solids. The
mixture was extracted with EtOAc (3 × 10 mL) and the combined
organic layer dried over MgSO4, filtered and evaporated in vacuo.
Finally, the crude residue was purified by column chromatography
(hexane–CH2Cl2, 1:4).
(E)-2-(3-Fluorostyryl)phenol (1e)22
Yield: 0.306 g, 1.46 mmol (73%); yellow solid; mp 94–96 °C;
Rf = 0.4 (CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 4.98 (br s, 1 H, OH), 6.78 (dd,
J1 = 1.2 Hz, J2 = 8.0 Hz, 1 H, ArH), 6.93–6.99 (m, 2 H, ArH), 7.10
(d, J = 16.4 Hz, 1 H, CH), 7.17 (dt, J1 = 1.6 Hz, J2 = 7.6 Hz, 1 H,
ArH), 7.22–7.34 (m, 3 H, ArH), 7.39 (d, J = 16.4 Hz, 1 H, CH), 7.53
(dd, J1 = 1.4 Hz, J2 = 7.8 Hz, 1 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 113.3 (d, J = 21.4 Hz), 114.8 (d,
J = 21.3 Hz), 116.4, 121.7, 122.9 (d, J = 2.6 Hz), 124.6, 124.8,
127.4, 129.1 (d, J = 2.7 Hz), 129.5, 130.5 (d, J = 8.4 Hz), 140.5 (d,
J = 7.8 Hz), 153.5, 163.6 (d, J = 243.6 Hz).
(E)-2-Styrylphenol (1a)20
Yield: 0.286 g, 1.46 mmol (73%); yellow solid; mp 142–144 °C;
Rf = 0.4 (CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 4.99 (br s, 1 H, OH), 6.81 (dd,
J1 = 1.2 Hz, J2 = 8.0 Hz, 1 H, ArH), 6.96 (dt, J1 = 0.8 Hz, J2 = 7.6
Hz, 1 H, ArH), 7.12 (d, J = 16.4 Hz, 1 H, CH), 7.15 (dt, J1 = 1.6 Hz,
J2 = 8.0 Hz, 1 H, ArH), 7.26 (tt, J1 = 1.6 Hz, J2 = 8.0 Hz, 1 H,
ArH), 7.37 (d, J = 16.4 Hz, 1 H, CH), 7.33–7.39 (m, 2 H, ArH), 7.54
(td, J1 = 2.0 Hz, J2 = 8.0 Hz, 3 H, ArH).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1171–1177

1174
F. V Singh, T. Wirth
SPECIAL TOPIC
(E)-2-(3-Nitrostyryl)phenol (1f)
Yield: 0.428 g, 1.78 mmol (89%); yellow solid; mp 152–154 °C;
Rf = 0.2 (CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 2.46 (s, 3 H, CH3), 4.98 (br s, 1 H,
OH), 6.85 (d, J = 8.0 Hz, 1 H, ArH), 7.00 (t, J = 7.6 Hz, 1 H, ArH),
7.17–7.27 (m, 5 H, CH, ArH), 7.38 (d, J = 16.0 Hz, 1 H, CH), 7.56
(d, J = 7.6 Hz, 1 H, ArH), 7.66 (d, J = 7.6 Hz, 1 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 20.4, 116.4, 121.6, 124.7, 125.4,
125.9, 126.7, 127.8, 128.0, 128.7, 129.1, 130.8, 136.2, 137.0, 153.4.
IR (KBr): 3069, 3041, 1601, 1587, 1571, 1522, 1500, 1457, 1349,
1254, 1203, 1090, 1075, 981, 973, 964, 897, 832, 800, 752, 739,
723, 686 cm–1.
1H NMR (400 MHz, CDCl3): δ = 5.03 (br s, 1 H, OH), 6.81 (d,
J = 8.0 Hz, 1 H, ArH), 6.98 (t, J = 7.6 Hz, 1 H, ArH), 7.19 (d,
J = 16.4 Hz, 1 H, CH), 7.20 (d, J = 7.6 Hz, 1 H, ArH), 7.49–7.57
(m, 3 H, CH, ArH), 7.82 (d, J = 7.6 Hz, 1 H, ArH), 8.09 (ddd,
J1 = 1.2 Hz, J2 = 1.2 Hz, J3 = 8.0 Hz, 1 H, ArH), 8.38 (t, J = 1.6 Hz,
1 H, ArH).
HRMS (APCI): m/z [M]+ calcd for C15H15O: 211.1117; found
211.1111.
(E)-2-[2-(Pyridin-2-yl)ethenyl]phenol (1k)
Yield: 0.272 g, 1.38 mmol (69%); yellow solid; mp 142–144 °C;
Rf = 0.2 (CH2Cl2–MeOH, 99:1).
13C NMR (100 MHz, CDCl3): δ = 116.5, 121.4, 121.8, 122.4, 124.1,
126.7, 127.5, 127.9, 129.9, 130.0, 132.7, 140.0, 149.1, 153.7.
HRMS (APCI): m/z [M]+ calcd for C14H12O3N: 242.0812; found
242.0809.
IR (KBr): 3051, 2925, 2708, 1626, 1592, 1561, 1503, 1467, 1054,
1436, 1386, 1328, 1300, 1242, 1156, 1088, 1004, 967, 769, 757,
745 cm–1.
1H NMR (400 MHz, CDCl3): δ = 6.86 (dt, J1 = 0.8 Hz, J2 = 7.6 Hz,
1 H, ArH), 6.90 (d, J = 8.0 Hz, 1 H, ArH), 7.13 (dt, J1 = 1.6 Hz,
J2 = 7.6 Hz, 1 H, ArH), 7.21 (ddd, J1 = 1.0 Hz, J2 = 5.0 Hz, J3 = 7.6
Hz, 1 H, ArH), 7.45 (dd, J1 = 1.6 Hz, J2 = 7.6 Hz, 1 H, ArH), 7.61
(d, J = 8.0 Hz, 1 H, ArH), 7.72 (dd, J1 = 1.8 Hz, J2 = 7.8 Hz, 1 H,
ArH), 7.79 (d, J = 2.0 Hz, 2 H, ArH), 8.66 (d, J = 4.8 Hz, 1 H,
ArH), 10.60 (br s, 1 H, OH).
13C NMR (100 MHz, CDCl3): δ = 117.0, 120.0, 121.6, 122.3, 124.3,
128.3, 129.8, 130.0, 131.6, 137.7, 148.5, 156.7, 157.7.
HRMS (APCI): m/z [M]+ calcd for C13H12ON: 198.0913; found
198.0909.
(E)-2-(4-Methoxystyryl)phenol (1g)22
Yield: 0.312 g, 1.38 mmol (69%); light-yellow solid; mp 144–146
°C; Rf = 0.2 (CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 3.86 (s, 3 H, OCH3), 5.08 (br s, 1
H, OH), 6.83 (d, J = 8.0 Hz, 1 H, ArH), 6.93 (d, J = 8.8 Hz, 2 H,
ArH), 6.97 (t, J = 7.6 Hz, 1 H, ArH), 7.09 (d, J = 16.4 Hz, 1 H, CH),
7.16 (dt, J1 = 1.6 Hz, J2 = 7.6 Hz, 1 H, ArH), 7.26 (d, J = 16.4 Hz,
1 H, CH), 7.50 (d, J = 8.4 Hz, 2 H, ArH), 7.53 (dd, J1 = 1.2 Hz,
J2 = 7.6 Hz, 1 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 55.8, 114.5, 116.3, 121.2, 121.6,
125.4, 127.5, 128.2, 128.7, 130.2, 130.8, 153.2, 159.7.
(E)-1-Styrylnaphth-2-ol (3a)
Yield: 0.236 g, 0.96 mmol (48%); yellow oil; Rf = 0.4 (hexane–
CH2Cl2, 1:1).
(E)-2-(4-Methylstyryl)phenol (1h)21
Yield: 0.332 g, 1.58 mmol (79%); light-yellow solid; mp 128–130
°C; Rf = 0.4 (CH2Cl2).
IR (KBr): 3049, 3017, 1627, 1600, 1583, 1497, 1487, 1454, 1329,
1253, 1194, 1087, 1072, 967, 846, 787, 751, 721, 690 cm–1.
1H NMR (400 MHz, CDCl3): δ = 2.39 (s, 3 H, CH3), 4.98 (br s, 1 H,
OH), 6.83 (d, J = 8.0 Hz, 1 H, ArH), 6.98 (t, J = 7.4 Hz, 1 H, ArH),
7.12 (d, J = 16.4 Hz, 1 H, CH), 7.16 (dd, J1 = 1.6 Hz, J2 = 8.0 Hz,
1 H, ArH), 7.20 (d, J = 8.0 Hz, 2 H, ArH), 7.34 (d, J = 16.4 Hz, 1
H, CH), 7.46 (d, J = 8.0 Hz, 2 H, ArH), 7.55 (d, J = 7.6 Hz, 1 H,
ArH).
13C NMR (100 MHz, CDCl3): δ = 21.7, 116.3, 121.6, 122.3, 125.2,
126.9, 127.6, 128.9, 129.8, 130.6, 135.2, 138.0, 153.3.
HRMS (APCI): m/z [M]+ calcd for C15H15O: 211.1117; found
211.1112.
1H NMR (400 MHz, CDCl3): δ = 5.88 (br s, 1 H, OH), 7.05 (d,
J = 16.8 Hz, 1 H, CH), 7.24 (d, J = 9.2 Hz, 1 H, ArH), 7.35–7.40
(m, 2 H, ArH), 7.42–7.50 (m, 4 H, CH, ArH), 7.61 (d, J = 7.2 Hz, 2
H, ArH), 7.74 (d, J = 8.8 Hz, 1 H, ArH), 7.80 (d, J = 8.0 Hz, 1 H,
ArH), 7.91 (d, J = 8.4 Hz, 1 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 117.1, 118.1, 122.5, 124.0, 124.1,
127.0, 127.1, 128.8, 129.31, 129.34, 129.9, 133.3, 136.4, 137.0,
151.1.
HRMS (APCI): m/z [M – H]+ calcd for C18H13O: 245.0961; found
245.0954.
(E)-2-(3-Methylstyryl)phenol (1i)
Yield: 0.319 g, 1.58 mmol (79%); colorless solid; mp 118–120 °C;
Rf = 0.4 (CH2Cl2).
(E)-1-(4-Chlorostyryl)naphthalen-2-ol (3b)
Yield: 0.285 g, 1.02 mmol (51%); yellow solid; mp 162–164 °C;
Rf = 0.4 (hexane–CH2Cl2, 1:1).
IR (KBr): 3018, 2924, 1623, 1600, 1584, 1454, 1267, 1248, 1201,
1186, 1170, 1088, 1042, 972, 852, 808, 752, 732 cm–1.
IR (KBr): 3062, 1619, 1595, 1516, 1488, 1463, 1390, 1267, 1254,
1215, 1187, 1129, 1096, 1086, 1011, 989, 950, 806, 775, 741 cm–1.
1H NMR (400 MHz, CDCl3): δ = 2.41 (s, 3 H, CH3), 5.00 (br s, 1 H,
OH), 6.84 (d, J = 8.0 Hz, 1 H, ArH), 6.99 (t, J = 7.4 Hz, 1 H, ArH),
7.11 (d, J = 8.0 Hz, 1 H, ArH), 7.13 (d, J = 16.4 Hz, 1 H, CH), 7.18
(dt, J1 = 1.6 Hz, J2 = 8.0 Hz, 1 H, ArH), 7.29 (d, J = 16.0 Hz, 1 H,
CH), 7.36–7.41 (m, 3 H, ArH), 7.55 (d, J = 7.6 Hz, 1 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 21.9, 116.4, 121.6, 123.1, 124.2,
125.2, 127.6, 127.7, 128.9, 129.0, 129.1, 130.7, 137.9, 138.7, 153.3.
1H NMR (400 MHz, CDCl3): δ = 5.76 (br s, 1 H, OH), 7.01 (d,
J = 16.8 Hz, 1 H, CH), 7.22 (d, J = 8.8 Hz, 1 H, ArH), 7.36 (d,
J = 6.8 Hz, 1 H, ArH), 7.40 (d, J = 8.8 Hz, 2 H, ArH), 7.47 (d,
J = 7.2 Hz, 1 H, ArH), 7.47 (d, J = 16.8 Hz, 1 H, CH), 7.53 (d,
J = 8.4 Hz, 2 H, ArH), 7.74 (d, J = 8.8 Hz, 1 H, ArH), 7.80 (d,
J = 7.6 Hz, 1 H, ArH), 7.90 (d, J = 8.4 Hz, 1 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 116.8, 118.1, 123.2, 124.0, 124.1,
127.2, 128.2, 128.9, 129.3, 129.5, 130.0, 133.2, 134.5, 135.0, 135.5,
151.1.
HRMS (APCI): m/z [M]+ calcd for C15H15O: 211.1117; found
211.1111.
HRMS (APCI): m/z [M – H]+ calcd for C18H12OCl: 279.0571; found
279.0589.
(E)-2-(2-Methylstyryl)phenol (1j)
Yield: 0.340 g, 1.62 mmol (81%); colorless solid; mp 126–128 °C;
Rf = 0.4 (CH2Cl2).
(E)-1-(4-Methoxystyryl)naphthalen-2-ol (3c)
Yield: 0.309 g, 1.12 mmol (56%); yellow solid; mp 156–158 °C;
Rf = 0.2 (hexane–CH2Cl2, 1:1).
IR (KBr): 3017, 2924, 1600, 1584, 1498, 1454, 1330, 1267, 1247,
1200, 1185, 1170, 1088, 971, 851, 808, 751, 731 cm–1.
Synthesis 2012, 44, 1171–1177
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Hypervalent Iodine Mediated Oxidative Cyclization
1175
IR (KBr): 3371, 3038, 2980, 2939, 1602, 1585, 1508, 1456, 1350,
1259, 1230, 1172, 1091, 1017, 970, 959, 846, 817, 800, 750 cm–1.
1H NMR (400 MHz, CDCl3): δ = 6.96 (ddt, J1 = 0.6 Hz, J2 = 2.6 Hz,
J3 = 8.8 Hz, 1 H, ArH), 6.97 (s, 1 H, ArH), 7.25 (dt, J1 = 0.8 Hz,
J2 = 7.6 Hz, 1 H, ArH), 7.32 (dt, J1 = 1.2 Hz, J2 = 7.6 Hz, 1 H, ArH),
7.41 (ddd, J1 = 2.4 Hz, J2 = 5.6 Hz, J3 = 8.0 Hz, 1 H, ArH), 7.52–
7.66 (m, 4 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 102.8, 111.7, 112.2 (d, J = 23.4
Hz), 115.8 (d, J = 21.3 Hz), 121.0 (d, J = 2.8 Hz), 121.6, 123.6,
125.2, 129.4, 130.8 (d, J = 8.1 Hz), 133.0 (d, J = 8.6 Hz), 155.0 (d,
J = 2.8 Hz), 155.3, 163.6 (d, J = 243.8 Hz).
1H NMR (400 MHz, CDCl3): δ = 3.87 (s, 3 H, OCH3), 5.90 (br s, 1
H, OH), 6.96 (d, J = 8.2 Hz, 2 H, ArH), 6.97 (d, J = 15.8 Hz, 1 H,
CH), 7.24 (d, J = 8.8 Hz, 1 H, ArH), 7.28 (d, J = 16.8 Hz, 1 H, CH),
7.36 (t, J = 7.6 Hz, 1 H, ArH), 7.47 (t, J = 7.6 Hz, 1 H, ArH), 7.54
(d, J = 8.4 Hz, 2 H, ArH), 7.72 (d, J = 8.8 Hz, 1 H, ArH), 7.79 (d,
J = 8.0 Hz, 1 H, ArH), 7.90 (d, J = 8.4 Hz, 1 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 55.9, 114.7, 117.4, 118.1, 120.1,
123.9, 124.2, 127.0, 128.3, 128.8, 129.3, 129.6, 129.8, 133.4, 136.0,
151.0, 160.3.
2-(3-Nitrophenyl)benzofuran (2f)27
Yield: 0.033 g, 0.138 mmol (69%); colorless solid; mp 136–138 °C;
Rf = 0.4 (hexane–CH2Cl2, 1:1).
HRMS (APCI): m/z [M – H]+ calcd for C19H15O2: 275.1067; found
1H NMR (400 MHz, CDCl3): δ = 7.20 (s, 1 H, ArH), 7.29 (d, J = 7.6
Hz, 1 H, ArH), 7.36 (dt, J1 = 1.2 Hz, J2 = 8.0 Hz, 1 H, ArH), 7.57
(d, J = 8.4 Hz, 1 H, ArH), 7.62 (d, J = 8.4 Hz, 1 H, ArH), 7.64 (d,
J = 7.6 Hz, 1 H, ArH), 8.15–8.21 (m, 2 H, ArH), 8.71 (t, J = 1.2 Hz,
1 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 104.0, 111.9, 120.1, 121.9, 123.3,
123.9, 125.8, 129.1, 130.3, 130.7, 132.6, 149.2, 153.6, 155.5.
275.1062.
Cyclization of (E)-2-Styrylphenols 1a–k and (E)-1-Styrylnaph-
thols 3a–c; General Procedure
(E)-2-Styrylphenol 1 or (E)-1-styrylnaphthol 3 (0.2 mmol) was add-
ed to a soln of PhI(OAc)2 (0.064 g, 0.2 mmol) in MeCN (4 mL) un-
der Ar at r.t. and the mixture stirred at the same temperature for 1–
3 h. After completion of the reaction, the solvent was evaporated
under reduced pressure and the residue purified immediately by col-
umn chromatography (hexane).
2-(4-Methoxyphenyl)benzofuran (2g)23,28
Yield: 0.038 g, 0.174 mmol (87%); colorless solid; mp 148–150 °C;
Rf = 0.4 (hexane–CH2Cl2, 1:1).
2-Phenylbenzofuran (2a)9,14,23
Yield: 0.03 g, 0.154 mmol (77%); colorless solid; mp 118–120 °C;
Rf = 0.3 (hexane).
1H NMR (400 MHz, CDCl3): δ = 6.96 (s, 1 H, ArH), 7.14–7.23 (m,
2 H, ArH), 7.28 (t, J = 7.6 Hz, 1 H, ArH), 7.38 (t, J = 7.6 Hz, 2 H,
ArH), 7.45 (d, J = 8.4 Hz, 1 H, ArH), 7.52 (d, J = 7.6 Hz, 1 H,
ArH), 7.80 (d, J = 7.6 Hz, 2 H, ArH).
1H NMR (400 MHz, CDCl3): δ = 3.89 (s, 3 H, OCH3), 6.92 (s, 1 H,
ArH), 7.01 (d, J = 8.8 Hz, 2 H, ArH), 7.23–7.31 (m, 2 H, ArH), 7.54
(d, J = 7.6 Hz, 1 H, ArH), 7.59 (dd, J1 = 1.6 Hz, J2 = 8.8 Hz, 1 H,
ArH), 7.83 (d, J = 8.8 Hz, 2 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 55.8, 100.1, 111.5, 114.7, 121.0,
123.3, 123.8, 124.2, 126.9, 129.9, 155.1, 156.5, 160.4.
13C NMR (125 MHz, CDCl3): δ = 101.3, 111.2, 120.9, 122.9, 124.3,
125.0, 128.5, 128.8, 129.2, 130.5, 154.9, 155.0.
2-(4-Methylphenyl)benzofuran (2h)23
Yield: 0.032 g, 0.158 mmol (79%); colorless solid; mp 122–124 °C;
Rf = 0.3 (hexane).
1H NMR (400 MHz, CDCl3): δ = 2.43 (s, 3 H, CH3), 7.01 (s, 1 H,
ArH), 7.23–7.32 (m, 4 H, ArH), 7.55 (d, J = 8.0 Hz, 1 H, ArH), 7.60
(dd, J1 = 1.2 Hz, J2 = 8.8 Hz, 1 H, ArH), 7.80 (d, J = 8.0 Hz, 2 H,
ArH).
2-(4-Chlorophenyl)benzofuran (2b)14,15
Yield: 0.036 g, 0.158 mmol (79%); colorless solid; mp 150–152 °C;
Rf = 0.4 (hexane).
1H NMR (400 MHz, CDCl3): δ = 7.04 (s, 1 H, ArH), 7.27 (t, J = 7.2
Hz, 1 H, ArH), 7.33 (dt, J1 = 1.2 Hz, J2 = 8.0 Hz, 1 H, ArH), 7.44
(d, J = 8.4 Hz, 2 H, ArH), 7.54 (d, J = 7.6 Hz, 1 H, ArH), 7.61 (d,
J = 7.6 Hz, 1 H, ArH), 7.82 (d, J = 8.8 Hz, 2 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 21.9, 101.0, 111.5, 121.2, 123.3,
124.4, 125.3, 128.2, 129.8, 129.9, 139.1, 155.2, 156.6.
13C NMR (125 MHz, CDCl3): δ = 102.2, 111.6, 121.4, 123.5, 125.0,
126.6, 129.4, 129.5, 134.7, 155.2, 155.3.
2-(3-Methylphenyl)benzofuran (2i)23,29
Yield: 0.034 g, 0.166 mmol (83%); colorless solid; mp 76–78 °C;
Rf = 0.3 (hexane).
1H NMR (400 MHz, CDCl3): δ = 2.44 (s, 3 H, CH3), 7.02 (s, 1 H,
ArH), 7.18 (d, J = 7.6 Hz, 1 H, ArH), 7.21–7.31 (m, 2 H, ArH), 7.35
(d, J = 7.6 Hz, 1 H, ArH), 7.53 (d, J = 8.0 Hz, 1 H, ArH), 7.59 (dd,
J1 = 1.2 Hz, J2 = 8.0 Hz, 1 H, ArH), 7.68 (d, J = 7.6 Hz, 1 H, ArH),
7.71 (s, 1 H, ArH).
2-(3-Chlorophenyl)benzofuran (2c)24
Yield: 0.035 g, 0.154 mmol (77%); colorless solid; mp 96–98 °C;
Rf = 0.4 (hexane).
1H NMR (500 MHz, CDCl3): δ = 7.07 (s, 1 H, ArH), 7.26–7.29 (m,
1 H, ArH), 7.32–7.35 (m, 2 H, ArH), 7.40 (t, J = 8.0 Hz, 1 H, ArH),
7.56 (d, J = 8.0 Hz, 1 H, ArH), 7.62 (dd, J1 = 0.5 Hz, J2 = 7.5 Hz, 1
H, ArH), 7.76 (td, J1 = 1.2 Hz, J2 = 8.0 Hz, 1 H, ArH), 7.89 (t,
J = 1.8 Hz, 1 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 22.0, 101.6, 111.6, 121.3, 122.6,
123.3, 124.6, 126.0, 129.2, 129.7, 129.8, 130.8, 138.9, 155.3, 156.5.
13C NMR (125 MHz, CDCl3): δ = 100.5, 109.4, 119.3, 121.1, 121.3,
122.9, 123.1, 126.6, 127.1, 128.2, 130.4, 133.0, 152.5, 153.1.
2-(2-Methylphenyl)benzofuran (2j)30
Yield: 0.036 g, 0.172 mmol (86%); colorless oil; Rf = 0.3 (hexane).
1H NMR (400 MHz, CDCl3): δ = 2.60 (s, 3 H, CH3), 6.91 (s, 1 H,
ArH), 7.25 (t, J = 7.6 Hz, 1 H, ArH), 7.29–7.35 (m, 4 H, ArH), 7.54
(d, J = 8.0 Hz, 1 H, ArH), 7.62 (d, J = 7.2 Hz, 1 H, ArH), 7.87 (d,
J = 8.0 Hz, 1 H, ArH).
2-(2-Chlorophenyl)benzofuran (2d)25
Yield: 0.034 g, 0.148 mmol (74%); colorless solid; mp 48–50 °C;
Rf = 0.4 (hexane).
1H NMR (500 MHz, CDCl3): δ = 7.27–7.42 (m, 4 H, ArH), 7.53 (dd,
J1 = 1.0 Hz, J2 = 8.0 Hz, 1 H, ArH), 7.56–7.58 (m, 2 H, ArH), 7.67
(d, J = 8.0 Hz, 1 H, ArH), 8.09 (dd, J1 = 1.5 Hz, J2 = 8.0 Hz, 1 H,
ArH).
13C NMR (100 MHz, CDCl3): δ = 22.4, 105.6, 111.5, 121.4, 123.3,
124.7, 126.6, 128.6, 128.9, 129.6, 130.3, 131.7, 136.3, 154.8, 156.0.
2-(Benzofuran-2-yl)pyridine (2k)31
Yield: 0.031 g, 0.158 mmol (79%); colorless solid; mp 90–92 °C;
Rf = 0.2 (CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 7.23–7.28 (m, 2 H, ArH), 7.34 (dt,
J1 = 1.2 Hz, J2 = 7.6 Hz, 1 H, ArH), 7.44 (s, 1 H, ArH), 7.57 (d,
13C NMR (125 MHz, CDCl3): δ = 107.4, 111.1, 121.5, 123.0, 124.9,
127.0, 129.01, 129.04, 129.1 (2 C), 130.9, 131.4, 152.0, 154.2.
2-(3-Fluorophenyl)benzofuran (2e)26
Yield: 0.029 g, 0.136 mmol (68%); colorless solid; mp 78–80 °C;
Rf = 0.4 (hexane).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1171–1177

1176
F. V Singh, T. Wirth
SPECIAL TOPIC
J = 8.0 Hz, 1 H, ArH), 7.65 (d, J = 8.0 Hz, 1 H, ArH), 7.78 (dt,
J1 = 1.6 Hz, J2 = 7.8 Hz, 1 H, ArH), 7.91 (d, J = 7.6 Hz, 1 H, ArH),
8.67 (d, J = 4.4 Hz, 1 H, ArH).
13C NMR (125 MHz, CDCl3): δ = 105.2, 112.0, 120.3, 122.1, 123.4,
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123.6, 125.6, 129.3, 137.2, 149.7, 150.3, 155.5, 155.7.
2-Phenylnaphtho[2,1-b]furan (4a)14,32
Yield: 0.042 g, 0.176 mmol (88%); colorless solid; mp 144–146 °C;
Rf = 0.3 (hexane).
1H NMR (400 MHz, CDCl3): δ = 7.36 (t, J = 7.4 Hz, 1 H, ArH),
7.48 (t, J = 7.6 Hz, 3 H, ArH), 7.54 (s, 1 H, ArH), 7.61 (dt. J1 = 1.2
Hz, J2 = 7.6 Hz, 1 H, ArH), 7.70 (d, J = 8.8 Hz, 1 H, ArH), 7.74 (d,
J = 9.2 Hz, 1 H, ArH), 7.95 (d, J = 7.4 Hz, 3 H, ArH), 8.18 (d,
J = 8.0 Hz, 1 H, ArH).
13C NMR (125 MHz, CDCl3): δ = 100.9, 112.8, 123.9, 124.9, 125.0,
125.1, 125.6, 126.7, 128.0, 128.7, 129.2, 129.3, 130.9, 131.1, 152.8,
155.8.
2-(4-Chlorophenyl)naphtho[2,1-b]furan (4b)14
Yield: 0.051 g, 0.182 mmol (91%); colorless solid; mp 154–156 °C;
Rf = 0.4 (hexane).
1H NMR (400 MHz, CDCl3): δ = 7.47 (t, J = 8.4 Hz, 2 H, ArH),
7.51 (dt, J1 = 1.2 Hz, J2 = 8.0 Hz, 1 H, ArH), 7.52 (s, 1 H, ArH),
7.60 (dt, J1 = 1.2 Hz, J2 = 8.0 Hz, 1 H, ArH), 7.68 (d, J = 8.8 Hz, 1
H, ArH), 7.74 (d, J = 8.8 Hz, 1 H, ArH), 7.86 (d, J = 8.8 Hz, 2 H,
ArH), 7.96 (d, J = 8.4 Hz, 1 H, ArH), 8.16 (d, J = 8.4 Hz, 1 H,
ArH).
(7) Aslam, S. N.; Stevenson, P. C.; Phythian, S. J.; Vietch, N. C.;
Hall, D. R. Tetrahedron 2006, 62, 4214.
(8) Einhorn, J.; Demerseman, P.; Royer, R.; Cavier, R.; Gayral,
P. Eur. J. Med. Chem. 1984, 19, 405.
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Bioorg. Med. Chem. 2005, 13, 4796.
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Molecules 2010, 15, 8593.
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76, 4692. (b) Zhou, L.; Shi, Y.; Xiao, Q.; Liu, Y.; Ye, F.;
Zhang, Y.; Wang, J. Org. Lett. 2011, 13, 968. (c) Guo, X.;
Yu, R.; Li, H.; Li, Z. J. Am. Chem. Soc. 2009, 131, 17387.
(d) Farago, J.; Kotschy, A. Synthesis 2009, 85. (e) Ferreira,
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64, 8992. (h) Tadd, A. C.; Fielding, M. R.; Willis, M. C.
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13C NMR (100 MHz, CDCl3): δ = 101.4, 112.7, 123.9, 124.9, 125.2,
126.0, 126.3, 126.8, 128.0, 129.3, 129.5, 130.9, 134.4, 152.9, 154.7.
2-(4-Methoxyphenyl)naphtho[2,1-b]furan (4c)14
Yield: 0.052 g, 0.190 mmol (95%); colorless solid; mp 110–112 °C;
Rf = 0.4 (hexane–CH2Cl2, 1:1).
1H NMR (400 MHz, CDCl3): δ = 3.87 (s, 3 H, OMe), 7.01 (d,
J = 8.8 Hz, 2 H, ArH), 7.39 (s, 1 H, ArH), 7.50 (dt, J1 = 1.2 Hz,
J2 = 8.0 Hz, 1 H, ArH), 7.59 (dt, J1 = 1.2 Hz, J2 = 8.0 Hz, 1 H, ArH),
7.68 (d, J = 9.2 Hz, 1 H, ArH), 7.71 (d, J = 9.2 Hz, 1 H, ArH), 7.86
(d, J = 8.8 Hz, 2 H, ArH), 7.95 (d, J = 8.0 Hz, 1 H, ArH), 8.16 (dd,
J1 = 0.6 Hz, J2 = 8.2 Hz, 1 H, ArH).
13C NMR (125 MHz, CDCl3): δ = 55.8, 99.3, 112.7, 114.8, 123.9,
124.0, 124.9, 125.0, 125.2, 126.5, 126.6, 127.9, 129.2, 130.9, 152.5,
156.0, 160.2.
Acknowledgment
Financial support by the EU, FP7 IIF Marie Curie grant and the
School of Chemistry, Cardiff University, is gratefully acknow-
ledged. We thank the EPSRC National Mass Spectrometry Service
Centre, Swansea, for mass spectrometric data.
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J. H. Org. Lett. 2008, 10, 1525.
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2006, 1657.
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