Convenient synthesis of polysubstituted 3-iodofurans through the tandem ring-opening/cyclization reaction of 1-alkynyl-2,3-epoxy alcohols

Article abstract of DOI:10.1055/s-2007-990830

A novel method for the synthesis of highly substituted iodine-containing furans has been developed by the cyclization of 1-(arylethynyl)-2,3-epoxy alcohols (1-aryl-4,5-epoxyalk-1-yn-3-ols) with alcohols as nucleophiles under very mild reaction conditions.

Full text of DOI:10.1055/s-2007-990830

PAPER
3295
Convenient Synthesis of Polysubstituted 3-Iodofurans through the Tandem
Ring-Opening/Cyclization Reaction of 1-Alkynyl-2,3-epoxy Alcohols
C
onvenient Sy
h
nthesis of
M
u
ultisubstitute
-
d
3-Iodo
g
furans uang Wen,a,b Wei-min Liu,a Yong-min Liang*a,c
a
State Key Laboratory of Solid Lubrication, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences,
Lanzhou 730000, P. R. of China
b
c
Graduate School of Chinese Academy of Sciences, Beijing 100039, P. R. of China
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. of China
Fax +86(931)8912582; E-mail: liangym@lzu.edu.cn
Received 10 July 2007; revised 9 August 2007
of C–C, C–N, or C–S bond-forming reactions.12 Since the
HOMO coefficient is greater for the a-C than for the b-C,
electrophilic reactions at the 3- or 4-positions are general-
ly more difficult than substitution at the 2- or 5-posi-
Abstract: A novel method for the synthesis of highly substituted
iodine-containing furans has been developed by the cyclization of
1-(arylethynyl)-2,3-epoxy alcohols (1-aryl-4,5-epoxyalk-1-yn-3-
ols) with alcohols as nucleophiles under very mild reaction condi-
tions. The resulting iodine-containing furans can be readily elabo- tions.13
rated to more complex products using known organopalladium
In our efforts to develop new methodologies for the syn-
chemistry.
thesis of heterocycles, we have succeeded in the construc-
tion of highly substituted 3-iodofurans by electrophilic
cyclization of 1-aryl-4,5-epoxyalk-1-yn-3-ols. In this pa-
per, we will report our results.
Key word: iodofuran, tandem reaction, epoxide, electrophilic cy-
clization
The synthesis of the starting materials is illustrated in
Scheme 1 with 3a as an example. Treatment of 1a with the
Grignard reagent of phenylacetylene afforded the allylic
alcohol 2a. Then epoxidation of the latter with 3-chloro-
peroxybenzoic acid yielded the (hydroxymethyl)oxirane
3a.
The furan core is one of the most important five-mem-
bered-ring heterocycles and it can be found in a number of
natural products1 and pharmaceuticals.2 Encouraged by
their important biological activity and great utility, a vari-
ety of methods have been developed for the synthesis of
furans.3,4 The transition-metal-catalyzed cyclization is an
effective approach and many substrates such as an alkynyl
or allenyl ketone,5 alcohol,6 or epoxide7 can be subjected
to cyclization in this way. In addition, the electrophilic cy-
clization of unsaturated compounds has also proven to be
an efficient method for the one-step construction and
functionalization of furan units.8–11 This method provides
an alternative route to complex furan derivatives.
Compound 3a was then subjected to copper(II) triflate
(0.2 equiv) in methanol at room temperature. The reaction
afforded the epoxide ring-opening product of 5a in 85%
yield. Hence, we predicted that the iodofuran would be
produced by the addition of iodine.10b When 3a was ex-
posed to the mixture of copper(II) triflate (0.2 equiv) and
iodine (1.5 equiv) in methanol–tetrahydrofuran (1:1) for
12 hours, the product 4a was separated in 35% yield;
when the reaction time was prolonged to 24 hours at 20
°C, 4a was obtained in 70% yield. Then, various Lewis
Halofurans are important intermediates that provide an
opportunity for further functionalization. In particular, io-
do- and bromofurans are useful as substrates in a variety
Ph
Ph
Ph
I
Cu(OTf)2 (0.2 equiv)
O
HO
HO
I
2 (1.5 equiv)
O
PhC CMgBr
THF
MCPBA
O
CH2Cl2
43%
MeOH–THF (1:1), r.t.
OMe
87%
1a
3a
4a
2a
Ph
HO
I2, Cu(OTf)2
THF–MeOH
OH
Cu(OTf)2
MeOH
85%
OMe
56%
5a
Scheme 1 General synthetic scheme to (hydroxymethyl)oxirane 3a and its cyclization to give 4a
SYNTHESIS 2007, No. 21, pp 3295–3300
x
x.
x
x
.
2
0
0
7
Advanced online publication: 16.10.2007
DOI: 10.1055/s-2007-990830; Art ID: F13107SS
© Georg Thieme Verlag Stuttgart · New York

3296
S.-g. Wen et al.
PAPER
Table 1 Selection of the Catalysta
Table 2 Cyclization of 1-Aryl-4,5-epoxyalk-1-yn-3-olsa
Entry
Catalyst
Yieldb (%)
Entry Substrate
Nucleo- Product
phile
Yieldb
(%)
1
2
3
4
5
6
7
8
I2, K2CO3
0
70
45
trace
0
R
R
I
Cu(OTf)2, I2
Zn(OTf)2, I2
AlCl3, I2
HO
O
O
OMe
BF3·OEt2, I2
TiCl4, I2
1
2
R = Ph 3a
MeOH
EtOH
4a
70
56
0
Ph
I
CeCl3·7H2O, I2
LiClO4·3H2O, I2
59
44
O
R = Ph 3a
OEt
Ph
a All reactions were carried out using 3a (0.20 mmol), catalyst (0.04
mmol), I2 (0.30 mmol), MeOH–THF (1:1, 2 mL), 20 °C, 24 h.
b Isolated yields.
4b
I
O
3
R = Ph 3a
i-PrOH
43
acids were examined and the results showed that cop-
per(II) triflate was the most appropriate catalyst (Table 1).
O
Then various substrates were investigated and the results
are summarized in Table 2. When ethanol and propan-2-
ol were selected as the nucleophiles (entries 2 and 3), the
yields were lower than that of methanol (4a > 4b > 4c).
This result shows the steric hindrance of the alcohol great-
ly affects the yield. Alkynes bearing either electron-poor
or electron-rich aryl groups are readily accommodated in
the iodine-induced cyclizations (entries 4–7); 4d and 4e
were obtained in 75% and 63% yields, which were higher
than 4f and 4g although the latter proceeded more rapidly
and the reaction was complete within four hours.
4c
4d
4
5
6
7
R = 4-BrC6H4 3b
R = 4-ClC6H4 3c
R = 4-MeOC6H4 3d
R = 4-MeC6H4 3e
MeOH
MeOH
MeOH
MeOH
75
4e
4f
63
45c
44c
4g
OH
O
R
OMe
Ph
O
MeOH
Ph
I
R
8
9
R = Ph 3f
MeOH
MeOH
MeOH
MeOH
MeOH
4h
63
A range of acyclic substrates 3f–j was also investigated
and the yields of 4h–l were comparable to that of the cy-
clic compounds; the results for various substituted aryl
groups showed similar trends (entries 9–12). In addition
to the successful cyclization of 1-aryl-5-phenyl-4,5-ep-
oxypent-1-yn-3-ols 3f–j, 2,3-epoxy-1-phenylhex-1-yn-3-
ol (3k) afforded iodofuran 3m in 58% yield.
R = 4-BrC6H4 3g
4i
69
10 R = 4-ClC6H4 3h
11 R = 4-MeOC6H4 3i
12 R = 4-MeC6H4 3j
4j
4k
4l
50
45c
53c
OH
O
The utility of 3-iodofurans produced by this chemistry as
useful synthetic intermediates for further elaboration was
briefly investigated by the palladium-catalyzed Sono-
gashira reaction of 3a, which afforded alkynylated prod-
uct 7 in 61% yield (Scheme 2).
Ph
OMe
O
13
Ph
3k
MeOH
58
I
4m
a All reactions were run under the following conditions, unless other-
wise specified: 3 (0.20 mmol), Cu(OTf)2 (0.04 mmol), I2 (0.30 mmol),
MeOH–THF (1:1, 2 mL), stirring, 20 °C, 24 h.
b Isolated yield.
Ph
Ph
I
Ph
Ph
(1.5 equiv)
c The reaction took 4 h.
O
O
PdCl2(Ph3P)2 (5 mol%)
CuI (10 mol%)
ple bond promotes nucleophilic attack of the oxygen onto
the triple bond to generate the intermediate 6, which then
undergoes anti elimination of water to produce iodofuran
4. The (hydroxymethyl)oxirane 3 generated from the ep-
oxidation of allylic alcohols with 3-chloroperoxybenzoic
acid is a mixture of threo and erythro products especially
for the acyclic allylic alcohols.14 According to our pro-
posed mechanism, the threo product would produce the
OMe
Et2NH, r.t., 24 h
OMe
4a
7, 61%
Scheme 2
An epoxide ring-opening/iodocyclization mechanism is
proposed for this reaction10b (Scheme 3). The epoxide is
regioselectively opened by the alcohol in the presence of
the Lewis acid. Coordination of the electrophile to the tri-
Synthesis 2007, No. 21, 3295–3300 © Thieme Stuttgart · New York

PAPER
Convenient Synthesis of Polysubstituted 3-Iodofurans
3297
R
I
R
R
O
I
I
(II)
Cu
HO
I2
HO
+
– H2O
– H+
OH
OH
OH
H
O
H
electrophilic
cyclization
ring-opening
MeOH
Ph
OMe
OMe
OMe
3
5
4
6
Scheme 3
2-[2-(4-Bromophenyl)ethynyl]-7-oxabicyclo[4.1.0]heptan-2-ol
(3b)
White solid; yield: 50% for two steps; mp 62–64 °C.
iodofuran 4 smoothly and the erythro product would not,
which might be the reason for the moderate yield.
In conclusion, an efficient synthesis of highly substituted
furans has been developed through the cyclization of 1-
aryl-4,5-epoxyalk-1-yn-3-ols in the presence of alcohol.
An iodide is readily introduced into the 3-position by us-
ing iodine as the electrophile. This methodology accom-
modates iodofurans in moderate to good yields under very
mild reaction conditions. The resulting iodine-containing
products can be readily elaborated to more complex prod-
ucts using known organopalladium chemistry.
IR (neat): 3433, 2949, 2253, 1486, 908, 733 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.54–1.56 (m, 2 H), 1.79–1.88 (m,
2 H), 1.90–1.95 (m, 2 H), 3.09 (s, 1 H), 3.42 (m, 1 H), 3.45–3.46 (m,
1 H), 7.29 (d, J = 8.7 Hz, 2 H), 7.43 (d, J = 8.7 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 18.3, 22.2, 34.1, 55.8, 58.2, 67.8,
84.6, 90.4, 122.0, 122.8, 131.4, 131.2.
Anal. Calcd for C14H13BrO2: C, 57.36; H, 4.47. Found: C, 57.21; H,
4.68.
2-[2-(4-Chlorophenyl)ethynyl]-7-oxabicyclo[4.1.0]heptan-2-ol
(3c)
White solid; yield: 55% for two steps; mp 49–51 °C.
IR (neat): 3436, 2949, 2253, 1490, 909, 735 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.55–1.64 (m, 2 H), 1.70–1.89 (m,
2 H), 1.90–1.93 (m, 2 H), 2.89 (s, 1 H), 3.41–3.46 (m, 2 H), 7.28 (d,
J = 8.7 Hz, 2 H), 7.38 (d, J = 8.7 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 18.3, 22.3, 34.2, 55.8, 58.2, 67.8,
84.4, 90.2, 120.6, 128.6, 133.0, 134.6.
Column chromatography was carried out on silica gel and the petro-
leum ether (PE) used was the fraction boiling in the range 60–90 °C.
1H NMR spectra were recorded on 300 MHz or 400 MHz in CDCl3
and 13C NMR spectra were recorded on 75 MHz or 100 MHz in
CDCl3 using TMS as internal standard. IR spectra were recorded on
a FT-IR spectrometer and only major peaks are reported in cm–1.
Melting points were determined on a microscopic apparatus and are
uncorrected. All new compounds were further characterized by ele-
mental analysis. Commercially available reagents and solvents
were used without further purification. THF was distilled immedi-
ately before use from Na/benzophenone.
Anal. Calcd for C14H13ClO2: C, 67.61; H, 5.27. Found: C, 67.38; H,
5.33.
2-(Phenylethynyl)-7-oxabicyclo[4.1.0]heptan-2-ol (3a); Typical
Procedure
2-[2-(4-Methoxyphenyl)ethynyl]-7-oxabicyclo[4.1.0]heptan-2-
ol (3d)
A soln of EtMgBr was prepared using Mg turnings (6 mmol), EtBr
(6 mmol), and THF (3 mL). Then phenylacetylene (6 mmol) was
added dropwise and the mixture was stirred at 50 °C for 15 min. The
soln was cooled to r.t. and a soln of cyclohex-2-enone (1a, 5 mmol)
in THF (5 mL) was added dropwise. After the reaction was complet-
ed, sat. NH4Cl soln was added. The aqueous phase was extracted
with Et2O. The combined organic phases were dried (anhyd
MgSO4) and concentrated. The crude product was purified by col-
umn chromatography (PE–EtOAc, 10:1) to give the alcohol 2a (861
mg, 87%) as a colorless oil.
Colorless oil; yield: 41% for two steps.
IR (neat): 3411, 2947, 2254, 1510, 909, 733 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.56–1.63 (m, 2 H), 1.79–1.83 (m,
2 H), 1.89–1.92 (m, 2 H), 2.67 (s, 1 H), 3.41–3.45 (m, 2 H), 3.81 (s,
3 H), 6.83 (d, J = 8.7 Hz, 2 H), 7.39 (d, J = 8.7 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 18.4, 22.3, 34.4, 55.2, 55.8, 58.4,
67.9, 85.5, 87.8, 113.9, 114.1, 133.3, 159.8.
Anal. Calcd for C15H16O3: C, 73.75; H, 6.60. Found: C, 73.48; H,
6.45.
To the soln of 2a (2 mmol) in CH2Cl2 (20 mL) was added MCPBA
(3 mmol) portionwise at 0–5 °C. The mixture was stirred at r.t. over-
night and then filtered. The organic solvent was washed with 5% aq
NaHSO3, 5% aq Na2CO3, and then thoroughly with H2O. The or-
ganic phase was dried (Na2SO4) and concentrated. The crude prod-
uct was purified by column chromatography (PE–EtOAc, 10:1) to
give 3a (205 mg, 48%) as a colorless oil.
2-[2-(4-Methylphenyl)ethynyl]-7-oxabicyclo[4.1.0]heptan-2-ol
(3e)
Colorless oil; yield: 45% for two steps.
IR (neat): 3413, 2945, 2250, 1510, 910, 734 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.56–1.65 (m, 2 H), 1.79–1.83 (m,
2 H), 1.87–1.92 (m, 2 H), 2.42 (s, 3 H), 2.74 (s, 1 H), 3.41–3.46 (m,
2 H), 7.10 (d, J = 8.4 Hz, 2 H), 7.34 (d, J = 8.4 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 18.4, 21.4, 22.3, 34.3, 55.8, 58.4,
67.9, 85.7, 88.5, 119.0, 129.0, 131.7, 138.7.
IR (neat): 3427, 2947, 2252, 1490, 909, 733 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.56–1.67 (m, 2 H), 1.80–1.87 (m,
2 H), 1.89–1.92 (m, 2 H), 3.03 (s, 1 H), 3.41 (m, 1 H), 3.46–3.48 (m,
1 H), 7.27–7.32 (m, 3 H), 7.45–7.48 (m, 2 H).
Anal. Calcd for C15H16O2: C, 78.92; H, 7.06. Found: C, 79.08; H,
7.20
13C NMR (75 MHz, CDCl3): d = 18.4, 22.2, 34.1, 55.7, 58.3, 67.9,
85.5, 89.2, 122.1, 128.2, 128.5, 131.7.
Anal. Calcd for C14H14O2: C, 78.48; H, 6.59. Found: C, 78.62; H,
6.35.
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3298
S.-g. Wen et al.
PAPER
3-Phenyl-1-(3-phenyloxiran-2-yl)prop-2-yn-1-ol (3f)
Colorless oil; yield: 53% for two steps.
IR (neat): 3431, 2252, 1491, 909, 733 cm–1.
13C NMR (75 MHz, CDCl3): d (6:4 mixture of diastereoisomers) =
21.4, 55.9, 56.2, 61.5, 62.1, 63.4, 64.1, 84.4 85.1, 118.8, 125.8,
125.9, 128.3, 128.4,129.0, 131.7, 135.9, 136.1, 138.8.
Anal. Calcd for C18H16O2: C, 81.79; H, 6.10. Found: C, 81.75; H,
6.39.
1H NMR (300 MHz, CDCl3): d (7:3 mixture of diastereoisomers) =
3.24–3.28 (m, 1 H), 3.41–3.44 (m, 1 H), 4.03 and 4.14 (2 d, J = 2.4
Hz, 1 H), 4.75–4.76 and 4.96–4.97 (2 m, 1 H), 7.19–7.41 (m, 8 H),
7.42–7.45 (m, 2 H).
13C NMR (75 MHz, CDCl3): d (7:3 mixture of diastereoisomers) =
55.9, 56.2, 61.4, 62.1, 63.4, 64.1, 85.1, 85.8, 86.1, 86.6, 121.8,
125.7, 125.8, 128.2, 128.3, 128.4, 128.7, 131.8, 135.8, 136.0.
1-(3-Methyloxiran-2-yl)-3-phenylprop-2-yn-1-ol (3k)
Colorless oil; yield: 65% for two steps.
IR (neat): 3433, 2253, 1490, 911, 741 cm–1.
1H NMR (300 MHz, CDCl3): d (5:5 mixture of diastereoisomers) =
1.29–1.34 (m, 3 H), 3.02–3.07 (m, 1 H), 3.09–3.26 (m, 2 H), 4.50–
4.53 and 4.77–4.79 (2 m, 1 H), 7.26–7.28 (m, 3 H), 7.38–7.43 (m, 2
H).
Anal. Calcd for C17H14O2: C, 81.58; H, 5.64. Found: C, 81.47; H,
5.82.
3-(4-Bromophenyl)-1-(3-phenyloxiran-2-yl)prop-2-yn-1-ol (3g)
White solid; yield: 38% for two steps; mp 86–88 °C.
IR (neat): 3432, 2254, 1486, 908, 733 cm–1.
13C NMR (75 MHz, CDCl3): d (5:5 mixture of diastereoisomers) =
16.8, 16.9, 52.5, 52.7, 60.7, 61.5, 62.5, 85.5, 85.7, 86.0, 86.1, 122.0,
128.2, 128.6, 131.7.
Anal. Calcd for C12H12O2: C, 76.57; H, 6.43. Found: C, 76.53; H,
6.39.
1H NMR (300 MHz, CDCl3): d (3:7 mixture of diastereoisomers) =
2.70–2.73 (m, 1 H), 3.40–3.43 (m, 1 H), 4.03 and 4.12 (2 d, J = 2.1
Hz, 1 H), 4.73–4.76 and 4.93–4.95 (2 m, 1 H), 7.25–7.39 (m, 7 H),
7.42–7.45 (m, 2 H).
13C NMR (75 MHz, CDCl3): d (3:7 mixture of diastereoisomers) =
55.9, 56.1, 61.4, 61.9, 63.1, 63.9, 85.1, 85.7, 86.1, 87.1, 120.8,
123.1, 125.8, 128.5, 131.6, 133.2, 135.8, 135.9.
Iodofurans 4; General Procedure
To a soln of 3 (0.20 mmol) in THF–MeOH (1:1, 2 mL) were added
Cu(OTf)2 (0.04 mmol) and I2 (0.30 mmol). The mixture was stirred
at 20 °C for until the reaction was complete (monitored by TLC).
The soln was quenched with aq Na2S2O3 and extracted with Et2O.
The combined organic phases were washed with sat. NaCl, dried
(MgSO4), and concentrated. The residue was purified by column
chromatography to give iodofuran 4.
Anal. Calcd for C17H13BrO2: C, 63.02; H, 3.98. Found: C, 63.27; H,
4.15.
3-(4-Chlorophenyl)-1-(3-phenyloxiran-2-yl)prop-2-yn-1-ol (3h)
White solid; yield: 47% for two steps; mp 103–105 °C.
IR (neat): 3438, 2254, 1489, 909, 734 cm–1.
1H NMR (300 MHz, CDCl3): d (4:6 mixture of diastereoisomers) =
2.88–2.90 (m, 1 H), 3.41–3.42 (m, 1 H), 4.03 and 4.13 (2 d, J = 1.8
Hz, 1 H), 4.73–4.77 and 4.93–4.95 (2 m, 1 H), 7.25–7.38 (m, 9 H).
13C NMR (75 MHz, CDCl3): d (4:6 mixture of diastereoisomers) =
55.9, 56.2, 61.4, 61.9, 63.2, 64.0, 85.1, 85.6, 86.0, 86.8, 120.3,
125.8, 125.9, 128.5, 128.6, 133.0, 134.8, 135.7, 135.9.
3-Iodo-7-methoxy-2-phenyl-4,5,6,7-tetrahydrobenzofuran (4a)
Colorless oil.
IR (neat): 2938, 2821, 1602, 1481, 1444, 1090 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.77–1.91 (m, 3 H), 2.10–2.16 (m,
1 H), 2.21–2.31 (m, 1 H), 2.38–2.45 (m, 1 H), 3.52 (s, 3 H), 4.32 (t,
J = 3.6 Hz, 1 H), 7.30–7.35 (m, 1 H), 7.39–7.44 (m, 2 H), 7.98 (m,
2 H).
13C NMR (75 MHz, CDCl3): d = 18.7, 23.5, 29.5, 57.0, 66.2, 70.5,
126.3, 127.0, 128.0, 128.3, 130.4, 150.3, 150.6.
Anal. Calcd for C17H13ClO2: C, 71.71; H, 4.60. Found: C, 71.38; H,
4.32.
Anal. Calcd for C15H15IO2: C, 50.87; H, 4.27. Found: C, 50.73; H,
4.19.
3-(4-Methoxyphenyl)-1-(3-phenyloxiran-2-yl)prop-2-yn-1-ol
(3i)
Colorless oil; yield: 35% for two steps.
IR (neat): 3419, 2254, 1490, 908, 733 cm–1.
7-Ethoxy-3-iodo-2-phenyl-4,5,6,7-tetrahydrobenzofuran (4b)
Colorless oil.
IR (neat): 2932, 2864, 1603, 1481, 1444, 1088 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.17 (t, J = 6.9 Hz, 3 H), 1.67–
1.78 (m, 2 H), 1.80–1.89 (m, 1 H), 2.01–2.09 (m, 1 H), 2.12–2.24
(m, 1 H), 2.30–2.38 (m, 1 H), 3.59–3.72 (m, 2 H), 4.32 (t, J = 3.6
Hz, 1 H), 7.21–7.26 (m, 1 H), 7.31–7.36 (m, 2 H), 7.89 (m, 2 H).
1H NMR (300 MHz, CDCl3): d (7:3 mixture of diastereoisomers) =
2.89 (m, 1 H), 3.41–3.44 (m, 1 H), 3.80 (s, 3 H), 4.03 and 4.14 (2 d,
J = 2.4 Hz, 1 H), 4.74–4.75 and 4.95–4.96 (2 m, 1 H), 6.81–6.85 (m,
2 H), 7.30–7.42 (m, 7 H).
13C NMR (75 MHz, CDCl3): d = 15.6, 18.8, 23.5, 29.9, 64.7, 66.2,
13C NMR (75 MHz, CDCl3): d (7:3 mixture of diastereoisomers) =
55.2, 55.9, 56.2, 63.4, 64.1, 83.7, 84.3, 86.2, 86.8, 113.9, 125.9,
125.9, 128.4, 128.5, 133.4, 136.1, 159.9.
68.9, 126.3, 126.8, 128.0, 128.3, 130.5, 150.5, 150.6.
Anal. Calcd for C16H17IO2: C, 52.19; H, 4.65. Found: C, 52.01; H,
4.45.
Anal. Calcd for C18H16O3: C, 77.12; H, 5.75. Found: C, 77.20; H,
5.58.
3-Iodo-7-isopropoxy-2-phenyl-4,5,6,7-tetrahydrobenzofuran
(4c)
Colorless oil.
1-(3-Phenyloxiran-2-yl)-3-(4-methylphenyl)prop-2-yn-1-ol (3j)
Colorless oil; yield: 40% for two steps.
IR (neat): 2969, 2867, 1603, 1481, 1446, 1066 cm–1.
IR (neat): 3440, 2253, 1509, 909, 739 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.23–1.26 (m, 6 H), 1.76–1.84 (m,
2 H), 1.89–2.08 (m, 2 H), 2.19–2.29 (m, 1 H), 2.37–2.45 (m, 1 H),
3.90–3.98 (m, 1 H), 4.50 (t, J = 3.6 Hz, 1 H), 7.29–7.34 (m, 1 H),
7.39–7.44 (m, 2 H), 7.96 (d, J = 7.5 Hz, 2 H).
1H NMR (300 MHz, CDCl3): d (6:4 mixture of diastereoisomers) =
2.38 (s, 3 H), 3.25 (s, 1 H), 3.41–3.42 (m, 1 H), 4.02 and 4.13 (2 d,
J = 2.4 Hz, 1 H], 4.73–4.74 and 4.94–4.95 (2 m, 1 H), 7.06–7.09 (m,
2 H), 7.21–7.35 (m, 7 H).
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Convenient Synthesis of Polysubstituted 3-Iodofurans
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13C NMR (75 MHz, CDCl3): d = 18.8, 22.6, 22.8, 23.5, 30.8, 66.2,
66.5, 70.3, 126.2, 126.6, 127.9, 128.3, 130.6, 150.3, 150.7.
13C NMR (75 MHz, CDCl3): d = 57.1, 61.1, 78.6, 118.8, 126.2,
127.1, 128.2, 128.3, 128.5, 130.0, 138.3, 151.8, 154.8.
Anal. Calcd for C17H19IO2: C, 53.42; H, 5.01. Found: C, 53.05; H,
4.78.
Anal. Calcd for C18H15IO2: C, 55.40; H, 3.87. Found: C, 55.57; H,
3.95.
2-(4-Bromophenyl)-3-iodo-7-methoxy-4,5,6,7-tetrahydroben-
zofuran (4d)
2-(4-Bromophenyl)-3-iodo-5-[methoxy(phenyl)methyl]furan
(4i)
Colorless oil.
White solid; mp 96–98 °C.
IR (neat): 2940, 2821, 1622, 1477, 1439, 1091 cm–1.
IR (neat): 2941, 2820, 1617, 1474, 1452, 1073 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.75–1.94 (m, 3 H), 2.10–2.16 (m,
1 H), 2.20–2.30 (m, 1 H), 2.37–2.44 (m, 1 H), 3.53 (s, 3 H), 4.32 (t,
J = 3.6 Hz, 1 H), 7.36 (d, J = 9.0 Hz, 2 H), 7.98 (d, J = 9.0 Hz, 2 H).
1H NMR (300 MHz, CDCl3): d = 3.41 (s, 3 H), 5.27 (s, 1 H), 6.31
(s, 1 H), 7.34–7.45 (m, 5 H), 7.50 (d, J = 8.1 Hz, 2 H), 7.80 (d,
J = 8.1 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 18.6, 23.4, 29.3, 57.0, 66.9, 70.5,
122.0, 127.2, 127.6, 129.3, 131.5, 150.0, 150.3.
13C NMR (75 MHz, CDCl3): d = 57.2, 61.8, 78.6, 119.0, 122.2,
127.1, 127.7, 128.4, 128.6, 128.9, 131.5, 138.1, 150.8, 155.2.
Anal. Calcd for C15H14BrIO2: C, 41.60; H, 3.26. Found: C, 41.56;
H, 3.15.
Anal. Calcd for C18H14BrIO2: C, 46.07; H, 3.01. Found: C, 46.14;
H, 3.01.
2-(4-Chlorophenyl)-3-iodo-7-methoxy-4,5,6,7-tetrahydroben-
zofuran (4e)
2-(4-Chlorophenyl)-3-iodo-5-[methoxy(phenyl)methyl]furan
(4j)
Colorless oil.
White solid; mp 89–91 °C.
IR (neat): 2940, 2821, 1622, 1474, 1439, 1088 cm–1.
IR (neat): 2931, 2822, 1647, 1478, 1453, 1093 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.78–1.86 (m, 3 H), 2.09–2.16 (m,
1 H), 2.19–2.30 (m, 1 H), 2.37–2.40 (m, 1 H), 3.52 (s, 3 H), 4.31 (t,
J = 3.6 Hz, 1 H), 7.52 (d, J = 9.0 Hz, 2 H), 7.86 (d, J = 9.0 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 18.7, 23.5, 29.4, 57.0, 66.7, 70.5,
127.2, 127.5, 128.6, 128.9, 133.8, 149.7, 150.6.
1H NMR (300 MHz, CDCl3): d = 3.42 (s, 3 H), 5.27 (s, 1 H), 6.31
(s, 1 H), 7.34–7.45 (m, 7 H), 7.86 (d, J = 8.7 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 57.2, 61.7, 78.6, 119.0, 127.1,
127.4, 128.4, 128.5, 128.6, 133.9, 138.2, 150.8, 155.1.
Anal. Calcd for C18H14ClIO2: C, 50.91; H, 3.32. Found: C, 51.03; H,
3.24.
Anal. Calcd for C15H14ClIO2: C, 46.36; H, 3.63. Found: C, 46.48; H,
3.59.
3-Iodo-2-(4-methoxyphenyl)-5-[methoxy(phenyl)methyl]furan
(4k)
3-Iodo-7-methoxy-2-(4-methoxyphenyl)-4,5,6,7-tetrahydroben-
zofuran (4f)
Colorless oil.
Colorless oil.
IR (neat): 2934, 2829, 1612, 1494, 1457, 1255 cm–1.
IR (neat): 2936, 2837, 1611, 1493, 1459, 1252, 1087 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.42 (s, 3 H), 3.83 (s, 3 H), 5.27
(s, 1 H), 6.27 (s, 1 H), 6.91 (d, J = 8.7 Hz, 2 H), 7.33–7.46 (m, 5 H),
7.85 (d, J = 8.7 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 55.3, 57.1, 59.9, 113.7, 118.7,
118.7, 122.9, 127.1, 127.9, 128.2, 128.5, 138.4, 152.1, 154.2, 159.5.
1H NMR (300 MHz, CDCl3): d = 1.78–1.91 (m, 3 H), 2.10–2.16 (m,
1 H), 2.25–2.31 (m, 1 H), 2.37–2.44 (m, 1 H), 3.52 (s, 3 H), 3.85 (s,
3 H), 4.32 (t, J = 3.6 Hz, 1 H), 6.93 (d, J = 6.9 Hz, 2 H), 7.89 (d,
J = 6.9 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 18.7, 23.5, 29.5, 55.3, 57.0, 64.7,
70.6, 113.7, 123.3, 126.8, 127.9, 149.8, 151.0, 159.4.
Anal. Calcd for C19H17IO3: C, 54.30; H, 4.08. Found: C, 54.22; H,
3.91.
Anal. Calcd for C16H17IO3: C, 50.02; H, 4.46. Found: C, 50.39; H,
4.31.
3-Iodo-5-[methoxy(phenyl)methyl]-2-(4-tolyl)furan (4l)
Colorless oil.
3-Iodo-7-methoxy-2-(4-tolyl)-4,5,6,7–tetrahydrobenzofuran
(4g)
Colorless oil.
IR (neat): 2926, 2822, 1621, 1492, 1450, 1088 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.79–1.90 (m, 3 H), 2.10–2.16 (m,
1 H), 2.21–2.30 (m, 1 H), 2.39–2.44 (m, 4 H), 3.51 (s, 3 H), 4.32 (t,
J = 3.6 Hz, 1 H), 7.20 (d, J = 8.1 Hz, 2 H), 7.84 (d, J = 8.1 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 18.7, 21.3, 23.5, 29.6, 35.5, 57.0,
65.5 70.5, 126.3, 126.9, 127.8, 129.0, 138.0, 150.1, 151.0.
IR (neat): 2926, 2822, 1606, 1493, 1452, 1090 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.36 (s, 3 H), 3.42 (s, 3 H), 5.3 (s,
1 H), 6.29 (s, 1 H), 7.19 (d, J = 8.1 Hz, 2 H), 7.33–7.46 (m, 5 H),
7.80 (d, J = 8.1 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 21.3, 57.1, 60.4, 78.7, 118.7,
126.2, 127.1, 127.3, 128.2, 128.5, 129.0, 138.2, 138.4, 152.1, 154.5.
Anal. Calcd for C19H17IO2: C, 56.45; H, 4.24. Found: C, 56.54; H,
3.95.
Anal. Calcd for C16H17IO2: C, 52.19; H, 4.65. Found: C, 52.42; H,
4.58.
3-Iodo-5-(1-methoxyethyl)-2-phenylfuran (4m)
Colorless oil.
IR (neat): 2929, 2820, 1603, 1482, 1444, 1116 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.53 (d, J = 5.7 Hz, 3 H), 3.34 (s,
3 H), 4.35 (q, 1 H), 6.47 (s, 1 H), 7.31–7.45 (m, 3 H), 7.96 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 19.5, 56.4, 60.9, 71.9, 117.6,
126.2, 128.1, 128.3, 130.1, 151.3, 155.8.
3-Iodo-5-[methoxy(phenyl)methyl]-2-phenylfuran (4h)
Colorless oil.
IR (neat): 2930, 2823, 1602, 1485, 1449, 1090 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.42 (s, 3 H), 5.28 (s, 1 H), 6.32
(s, 1 H), 7.26–7.47 (m, 8 H), 7.95 (m, 2 H).
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S.-g. Wen et al.
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(4) Brown, R. C. D. Angew. Chem. Int. Ed. 2005, 44, 850.
Anal. Calcd for C13H13IO2: C, 47.58; H, 3.99. Found: C, 47.55; H,
3.84.
(5) (a) Sheng, H.; Lin, S.; Huang, Y. Tetrahedron Lett. 1986, 27,
4893. (b) Fukuda, Y.; Shiragami, H.; Utimoto, K.; Nozaki,
H. J. Org. Chem. 1991, 56, 5816. (c) Kel’in, A. V.;
Gevorgyan, V. J. Org. Chem. 2002, 67, 95. (d) Ma, S.;
Zhang, J. Chem. Commun. 2000, 117. (e) Hashmi, A. S. K.;
Schwarz, L.; Choi, J.-H.; Frost, T. M. Angew. Chem. Int. Ed.
2000, 39, 2285. (f) Marshall, J. A.; Wang, X.-J. J. Org.
Chem. 1991, 56, 960. (g) Marshall, J. A.; Bartley, G. S. J.
Org. Chem. 1994, 59, 7169.
(6) (a) Wakabayashi, Y.; Fukuda, Y.; Shiragami, H.; Utimoto,
K.; Nozaki, H. Tetrahedron 1985, 41, 3655. (b) Gabriele,
B.; Salerno, G.; Lauria, E. J. Org. Chem. 1999, 64, 7687.
(c) Seiller, B.; Bruneau, C.; Dixneuf, P. H. J. Chem. Soc.,
Chem. Commun. 1994, 493. (d) Seiller, B.; Bruneau, C.;
Dixneuf, P. H. Tetrahedron 1995, 51, 13089.
7-Methoxy-2-phenyl-3-(phenylethynyl)-4,5,6,7-tetrahydroben-
zofuran (7)
Colorless oil.
IR (neat): 2932, 2821, 2211, 1600, 1482, 1444, 1091 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.80–1.96 (m, 3 H), 2.10–2.15 (m,
1 H), 2.42–2.50 (m, 1 H), 2.63–2.69 (m, 1 H), 3.55 (s, 3 H), 4.36 (t,
J = 3.6 Hz, 1 H), 7.25–7.55 (m, 8 H), 8.12 (d, J = 6.8 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 18.8, 21.2, 29.4, 57.0, 70.6, 82.0,
95.5, 103.3, 123.6, 124.9, 127.9, 128.2, 128.4, 128.5, 130.7, 131.4,
149.4, 154.1.
Anal. Calcd for C23H20IO2: C, 84.12; H, 6.24. Found: C, 84.18; H,
6.47.
(7) (a) Lo, C.-Y.; Guo, H.; Lian, J.-J.; Shen, F.-M.; Liu, R.-S. J.
Org. Chem. 2002, 67, 3930. (b) Marshall, J. A.; DuBay, W.
J. J. Am. Chem. Soc. 1992, 114, 1450. (c) Hashmi, A. S. K.;
Sinha, P. Adv. Synth. Catal. 2004, 346, 432.
Acknowledgment
The authors thank the NSFC (NSFC-20621091, NSFC-20672049)
and the ‘Hundred Scientist Program’ from the Chinese Academy of
Sciences for financial support.
(8) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F.; Moro, L.
Synlett 1999, 1432.
(9) Arcadi, A.; Cacchi, S.; Di Giuseppe, S.; Fabrizi, G.;
Marinelli, F. Org. Lett. 2002, 4, 2409.
(10) (a) El-Taeb, G. M. M.; Evans, A. B.; Jones, S.; Knight, D. W.
Tetrahedron Lett. 2001, 42, 5945. (b) Bew, S. P.; Knight, D.
W. Chem. Commun. 1996, 1007.
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Synthesis 2007, No. 21, 3295–3300 © Thieme Stuttgart · New York