Iodocyclization of ethoxyethyl ethers to ynamides: An immediate construction to benzo[ b ]furans

Article abstract of DOI:10.1021/jo500903y

The iodocyclization of ethoxyethyl ethers to ynamides was completed within three seconds. The corresponding benzo[b]furans were obtained in high yields (84%-quant.) under mild conditions.

Full text of DOI:10.1021/jo500903y

Note
pubs.acs.org/joc
Iodocyclization of Ethoxyethyl Ethers to Ynamides: An Immediate
Construction to Benzo[b]furans
Takashi Okitsu,* Kohei Nakata, Kenji Nishigaki, Naoyuki Michioka, Mitsuaki Karatani, and Akimori Wada
Department of Organic Chemistry for Life Science, Kobe Pharmaceutical University, 4-19-1, Motoyamakita-machi, Higashinada-ku,
Kobe 658-8558, Japan
S
* Supporting Information
ABSTRACT: The iodocyclization of ethoxyethyl ethers to
ynamides was completed within three seconds. The corre-
sponding benzo[b]furans were obtained in high yields (84%−
quant.) under mild conditions.
Scheme 1. Benzo[b]furan Synthesis by Iodocyclization
odocyclization, an electrophilic cyclization by iodonium ion,
is one of the most powerful methodologies for the creation
I
of not only ring structures but also further functionalizable iodo
components.1,2 In general, the ease of iodocyclization for
alkyne-containing substrates depends on the substituent effect
of alkynes: conjugated sp2 carbon, sulfur, and selenium-
substituted alkynes are good substrates for the iodocyclization
because the formed iodonium intermediates are stabilized by
the resonance and/or inductive effects.3 Thus, nitrogen-
substituted alkynes would also be desirable substrates for
iodocyclization.
Ynamides, amide-substituted alkynes, have been established
by Hsung as the ultimate synthetic units because of their
electron-rich and relatively stable nature.4 Although there have
been several reports on the electrophilic cyclization of
ynamides,5 their electrophiles have been limited to Brønsted
acids,6 transition metals,7 and carbocations.8 Very recently,
iodine-mediated electrophilic cyclization of o-anisole-substi-
tuted ynamides 1 for the synthesis of 2-amidobenzo[b]furans 2
was accomplished by Cao et al. (Scheme 1, eq 1).9 The
iodocyclization of ynamides by their methods afforded
benzo[b]furans 2 in moderate to high yields, and one of the
reactions was finished less than 1 h, albeit each reaction time
was not reported. We thought this type of the iodocyclization
would be accelerated if the leaving group on phenolic oxygen
and the iodonium reagent were appropriately chosen.
We have already achieved the versatile synthesis of
benzo[b]furans 4 by iodocyclization of the corresponding
ethoxyethyl ether-substituted alkynes 3 (Scheme 1, eq 2).10,11
The ethoxyethyl ether serves not only as the protecting group
and the directing group for the preparation of the precursors
but also as a good leaving group for the cyclization step. In
addition, the formed byproducts based on the N,O-acetal salt 5
can be easily removed by extraction and column chromatog-
raphy. Thus, we applied our methodology to the ynamides 6
and found that the iodocyclization was finished within only 3 s
under milder conditions than those previously reported
(Scheme 1, eq 3). To the best of our knowledge, this reaction
time is the shortest among the reported iodocyclization. In this
paper, we present a remarkable reaction of ynamides having
ethoxyethyl ether mediated by bis(2,4,6-collidine)iodonium
hexafluorophosphate [I(coll)2PF6] as the iodonium re-
agent.2q,12
Initially, ynamide 6a was used as a precursor for the
examination of iodocyclization (Table 1). In previous work, the
iodocyclization of alkyne 3a was performed in 2 equiv of
I(coll)2PF6 and the same molar amount of BF3·OEt2 as an
activator (entry 1), and the conditions without BF3·OEt2
required 24 h for almost complete consumption of 3a (entry
Received: April 23, 2014
Published: May 28, 2014
© 2014 American Chemical Society
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equiv of iodine and a short reaction time resulted in a poor
yield of 2a and the recovery of 1a (entry 2). These results
indicated that the use of iodine caused the production of
undesirable side-product 7 and the reaction time of 1a was
longer than that of 6a (Table 1, entry 7). NIS was also adopted
for the iodocyclization of 1a; however, the yield of 2a was low
when the reaction was quenched 3 s later (entry 3). On the
other hand, the use of I(coll)2PF6 as the iodinating reagent
resulted in the complete consumption of 1a within 3 s affording
2a in moderate yield (entry 4). Therefore, the choices of the
ether unit and the iodinating reagent were important for the
effective iodocyclization of the ynamide. Although the substrate
having no protected phenolic hydroxyl group would be an
alternative precursor for this reaction, we could not prepare
such a compound due to its instability.
Table 1. Comparison of Reactivity with Alkyne 3a and
Ynamide 6a
a
b
entry substrate [I+] source (equiv)
time
product (% yield)
c
1
2
3
4
5
6
7
8
3a
3a
6a
6a
6a
6a
6a
6a
I(coll)2PF6 (2)
I(coll)2PF6 (2)
I(coll)2PF6 (1)
I(coll)2PF6 (1)
I(coll)2PF6 (1)
I(coll)2PF6 (1)
I2 (1)
10 min
24 h
20 min
1 min
10 s
4a (quant.)
4a (92%)
2a (91%)
2a (86%)
2a (95%)
2a (98%)
2a (43%)
2a (81%)
Having defined the optimized conditions and substrate
system for the iodocyclization (Table 1, entry 6), we next
examined the scope and limitations of the benzo[b]furan
substrates (Table 3). Toward the substrate scope, all ynamides
3 s
10 s
NIS (1)
5 s
a
b
c
All reactions were carried out in CH2Cl2 (0.1 M). Isolated yields. 2
a
equiv of BF3·OEt2 were added.
Table 3. Iodocyclization of Ynamides 6a−m
2).10 On the other hand, iodocyclization of ynamide 6a was
accomplished with only 1 equiv of I(coll)2PF6 (entry 3).
Surprisingly, this reaction was very rapid: when reaction time
was shortened gradually from 20 min to 10 s, starting material
6a was completely consumed and benzo[b]furan 2a was
obtained in high yields for each case (entries 3−5). Finally we
found that this reaction time could be shortened to only 3 s to
afford 2a in 98% yield (entry 6). At this time, I(coll)2PF6
quickly dissolved in CH2Cl2. In contrast with the reported
method by Cao,9 6a was treated with iodine for 10 s to obtain
2a in 43% yield, and the partially insoluble iodine was observed
before the reaction mixture was quenched (entry 7). N-
Iodosuccinimide (NIS) was also applicable for this rapid
reaction to yield 2a in 81%, but the starting material 6a was
recovered in 19% (entry 8). Therefore, I(coll)2PF6 was the
most suitable iodinating reagent for the rapid synthesis of
iodobenzo[b]furan 2 using ethoxyethyl ether-tethered ynamide
6.13,14
Next, we examined the iodocyclization of methyl ether 1a to
compare with ethoxyethyl ether 6a (Table 2). By a previously
reported method,9 1a was completely consumed for 30 min and
benzo[b]furan 2a was obtained in 68% yield along with
diiodinated enamide 7 in 25% yield (entry 1). The use of 1
Table 2. Reactivity of Ynamide 1a
a
All reactions were carried out in CH2Cl2 (0.1 M). Isolated yields are
listed.
6a−m were prepared by the oxidative coupling with
corresponding terminal alkynes and amides according to Stahl’s
procedure.15 Notably, the ethoxyethyl ether has important roles
as the protecting group and the directing group for the
preparation of precursors. For example, α-lithiation and
subsequent iodination of 1-(1-ethoxyethyl)naphthalene, Sono-
gashira coupling with ethynyltrimethylsilane, deprotection of
silyl group,10 and the oxidative coupling of corresponding
terminal alkyne with N-methyl-p-tosylamide provided ynamide
6m. As the amide part, sulfonamide 6a−b, oxazolidinone 6c−d,
imidazolidinone 6e−f, and lactam 6g−h were applicable for this
reaction. In addition, 6i, a substituted indole having an
electron-withdrawing group at the 3-position, also worked
a
entry [I+] source (equiv)
time
product (% yield)
b
d
1
2
3
4
I2 (1.5)
30 min
10 s
3 s
2a (68%), 7 (25%)
c
c
c
d
I2 (1)
2a (7%), 7 (40%), 1a (49%)
NIS (1)
2a (9%), 1a (74%)
2a (60%)
I(coll)2PF6 (1)
3 s
a
b
Isolated yields. Reaction was carried out in CH2Cl2 (0.125 M).
Reactions were carried out in CH2Cl2 (0.1 M). Ratio of
c
d
stereoisomers of 7 is 2:1 in each case.
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well to afford benzo[b]furan-indole biaryl system 2i in 89%
yield. The reactions were not affected by the presence of phenyl
(6j), methoxy (6k), and nitro (6l) substituents. A bicyclic
system such as naphthalene derivative 6m gave the
corresponding naphtho[1,2-b]furan 2m in 94% yield. This
reaction could be applied to gram scale synthesis and 1.18 g of
2c was prepared at once in 85% yield within 3 s, albeit this
reaction was not performed in a microflow reaction system. It is
noteworthy that the efficient construction of benzo[b]furan was
accomplished within 3 s to afford 2a−m in high yields in all
cases.
Scheme 3. Transformation of 2c to 9
On the basis of the outcomes of these reactions, we have
proposed a plausible mechanism for the iodocyclization as
illustrated in Scheme 2. An electrophilic addition of ynamide 6
Scheme 2. Plausible Reaction Mechanism
In summary, we have developed the most rapid construction
of benzo[b]furans by iodocyclization of ethoxyethyl ethers to
ynamides. Our protocol was user-friendly and the benzo[b]-
furans were obtained in high yields under mild conditions. In
addition, we found a new tandem reaction of the Suzuki-
Miyaura coupling/decarboxylation/lactamization leading to a
polycyclic isoquinolinone structure.
EXPERIMENTAL SECTION
General Information. IR spectra were measured using CHCl3.
Chemical shifts (δ) are reported in ppm relative to tetramethylsilane as
■
1
internal reference (CDCl3: δ = 0 ppm for H) and residual solvent
signal (CDCl3: δ = 77.0 ppm for 13C; DMSO-d6: δ = 39.5 ppm for
13C). J-values are given in Hz. MS was performed on an Exactive
Orbitrap mass spectrometer.
N-((2-Methoxyphenyl)ethynyl)-N,4-dimethylbenzenesulfo-
namide (1a). According to the literature,17 to a mixture of N-methyl-
p-toluenesulfonamide (643 mg, 3.47 mmol), K2CO3 (959 mg, 6.94
mmol), CuSO4·5H2O (86.6 mg, 0.347 mmol), and 1,10-phenanthro-
line (125 mg, 0.694 mmol) in a reaction vial was added a solution of 1-
(bromoethynyl)-2-methoxybenzene (805 mg, 3.81 mmol) in toluene
(3.81 mL). The reaction mixture was filled with argon and heated at
70 °C for 24 h. The reaction mixture was cooled to room temperature
and diluted with EtOAc and filtered through Celite, and the filtrate
was concentrated in vacuo. The residue was purified by flash
chromatography on silica gel eluting with hexane/EtOAc = 4:1 to
yield 1a (817 mg, 75%): Colorless solid; IR νmax: 3013, 2241, 1598,
with the iodinating reagent, I(coll)2PF6, forms keteniminium
ion A and 2,4,6-collidine. The nucleophilic addition of the
oxygen of the ethoxyethyl ether A gives intermediate B, which
undergoes the loss of the ethoxyethyl group by the trap of
2,4,6-collidine to afford benzo[b]furan 2 and collidinium salt
5.10,16 We consider that all steps, the formation of A,
cyclization, and the elimination of the ethoxyethyl group, are
very rapid so that this reaction finished within 3 s. In contrast,
the iodocyclization of alkyne 3 with I(coll)2PF6 was slow
(Table 1, entry 2) because the formation of the iodonium ion
might be the rate-determining step due to its thermodynamic
instability. In addition, the ethoxyethyl group is a better leaving
group than methyl ether 1 so that the transformation from B to
benzo[b]furan 2 proceeds effectively by being trapped by 2,4,6-
collidine. Moreover, our method produced 1 equiv of
collidinium salt 5 and same molar amount of 2,4,6-collidine,
which were easily removable by column chromatography on
silica gel. Thus, the reaction could proceed under mild
conditions, and our synthetic protocol was handy to user.
The 3-iodobenzofurans can be further functionalized by
palladium-catalyzed coupling reactions at the C−I bond. Cao et
al. reported the Suzuki-Miyaura coupling, the Sonogashira
coupling, and Heck reaction of 2.9 To discover the new
transformation, we developed a novel one-pot, tandem reaction
of the Suzuki-Miyaura coupling/decarboxylation/lactamization
of 2c and arylboronic acid 8 to afford tetracyclic isoquinolinone
9 in 57% yield (Scheme 3).
1
1367, 1249, 1168 cm−1; H NMR (300 MHz, CDCl3) δ 7.90 (d, J =
8.4 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 7.32 (dd, J = 7.5, 1.8 Hz, 1H),
7.28−7.22 (m, 1H), 6.88 (td, J = 7.5, 1.2 Hz, 1H), 6.85 (d, J = 8.4 Hz,
1H) 3.87 (s, 3H), 3.16 (s, 3H), 2.46 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 159.8, 144.6, 133.3, 133.2, 129.7, 129.2, 128.0, 120.4, 111.9,
110.6, 87.6, 65.3, 55.7, 39.4, 21.6; HR-ESIMS calcd for C17H18NO3S
[M + H]+ 316.1002. Found 316.1005.
General Procedure for the Preparation of Ynamides 6a-m
(GP-1). According to the literature,15 in a 1 L three-neck round-
bottom flask equipped with a stir-bar, CuCl2 (0.2 equiv), amide B (4−
5 equiv) and Na2CO3 (2.0 equiv) were combined. The reaction flask
was purged with oxygen gas. A solution of pyridine (2 equiv) in 0.1 M
dry toluene was added to the reaction flask via a syringe. A balloon
filled with oxygen gas was connected to the reaction flask via a needle.
The flask was placed in an oil-bath and heated to 70 °C. A solution of
terminal alkyne A (1 equiv) in 0.1 M dry toluene was added to the
flask over 4 h by using a syringe pump. After the addition of 1 in
toluene solution, the reaction mixture was allowed to stir at 70 °C for
another 4 h, and then cooled to room temperature. After the crude
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mixture was concentrated in vacuo, the reaction mixture was purified
by flash chromatography on silica gel to yield the ynamide 6.
N-((2-(1-Ethoxyethoxy)phenyl)ethynyl)-N,4-dimethylbenze-
nesulfonamide (6a). According to GP-1, 6a (780 mg, 79%) was
obtained from 1-(1-ethoxyethoxy)-2-ethynylbenzene10 (502 mg, 2.64
mmol). Eluent: hexane/EtOAc = 7:1. Yellow oil; IR νmax: 3034, 2241,
7.40−7.37 (m, 2H), 7.35−7.32 (m, 1H), 7.29−7.26 (m, 3H), 7.13−
7.09 (m, 1H), 6.96 (dd, J = 8.5, 1.0 Hz, 0.5H), 6.95 (dd, J = 8.5, 1.0
Hz, 0.5H), 6.87 (td, J = 7.5, 1.5 Hz, 0.5H), 6.86 (td, J = 7.5, 1.5 Hz,
0.5H), 5.26−5.20 (m, 1H), 5.06 (d, J = 6.0 Hz, 0.5H), 5.04 (d, J = 6.0
Hz, 0.5H), 3.97−3.92 (m, 1H), 3.68−3.57 (m, 1H), 3.47−3.34 (m,
1H), 2.86 (s, 3H), 1.27 (d, J = 5.0 Hz, 1.5H), 1.24 (d, J = 5.0 Hz,
1.5H), 1.12 (t, J = 7.0 Hz, 1.5H), 1.09 (t, J = 7.0 Hz, 1.5H), 0.79 (d, J
= 6.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 157.62, 157.61, 156.7,
156.5, 134.8, 133.1, 132.9, 128.5, 128.42, 128.40, 128.3, 128.2, 127.71,
127.70, 122.0, 121.8, 118.4, 117.9, 115.5, 115.4, 100.6, 100.1, 85.1,
67.94, 67.88, 64.1, 61.3, 61.0, 55.7, 28.9, 20.04, 20.00, 15.15, 15.12,
14.8; HR-ESIMS calcd for C23H27N2O3 [M + H]+ 379.2016. Found
379.2016.
1-((2-(1-Ethoxyethoxy)phenyl)ethynyl)-3-methyl-1H-benzo-
[d]imidazol-2(3H)-one (6f). According to GP-1, 6f (206 mg, 42%)
was obtained from 1-(1-ethoxyethoxy)-2-ethynylbenzene10 (278 mg,
1.46 mmol). Eluent: hexane/EtOAc = 3:1. Yellow oil; IR νmax: 3012,
2259, 1732, 1621 cm−1; 1H NMR (300 MHz, CHCl3) δ 7.54 (dd, J =
7.5, 1.2 Hz, 1H), 7.38−7.35 (m, 1H), 7.31−7.25 (m, 1H), 7.23−7.14
(m, 2H), 7.09 (d, J = 7.8 Hz, 1H), 7.02−6.97 (m, 1H), 5.52 (q, J = 5.4
Hz, 1H), 3.92−3.82 (m, 1H), 3.67−3.55 (m, 1H), 3.44 (s, 3H), 1.59
(d, J = 5.4 Hz, 3H), 1.20 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 157.4, 152.9, 133.0, 129.7, 129.4, 128.3, 123.4, 122.1, 121.7,
116.7, 113.5, 109.9, 107.8, 100.5, 79.1, 71.9, 61.5, 27.5, 20.4, 15.1; HR-
ESIMS calcd for C20H20N2NaO3 [M + Na]+ 359.1366. Found
359.1359.
1
1599, 1368, 1169 cm−1; H NMR (300 MHz, CDCl3) δ 7.91 (d, J =
8.7 Hz, 2H), 7.37 (d, J = 8.7 Hz, 2H), 7.33 (dd, J = 7.5, 1.8 Hz, 1H),
7.24−7.19 (m, 1H), 7.01 (dd, J = 8.1, 1.5 Hz, 1H), 6.94 (dt, J = 7.5,
1.2 Hz, 1H), 5.42 (q, J = 5.4 Hz, 1H), 3.89−3.79 (m, 1H), 3.60−3.50
(m, 1H), 3.15 (s, 3H), 2.45 (s, 3H), 1.52 (d, J = 5.4 Hz, 3H) 1.19 (t, J
= 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 157.2, 144.6, 133.3,
132.9, 129.7, 128.9, 127.9, 121.8, 117.0, 114.2, 100.7, 87.5, 65.5, 61.7,
39.3, 21.6, 20.4, 15.1; HR-ESIMS calcd for C20H24NO4S [M + H]+
374.1421. Found 374.1423.
N-Benzyl-N-((2-(1-ethoxyethoxy)phenyl)ethynyl)-4-methyl-
benzenesulfonamide (6b). According to GP-1, 6b (221 mg, 33%)
was obtained from 1-(1-ethoxyethoxy)-2-ethynylbenzene10 (285 mg,
1.50 mmol). Eluent: hexane/EtOAc = 5:1. Yellow oil; IR νmax: 3034,
2238, 1598, 1366, 1170 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.83 (d,
J = 8.7 Hz, 2H), 7.38−7.34 (m, 2H), 7.31−7.26 (m, 5H), 7.20−7.14
(m, 2H), 6.98 (d, J = 8.1 Hz, 1H), 6.88 (t, J = 8.7 Hz, 1H), 5.35 (q, J =
5.4 Hz, 1H), 4.62 (d, J = 14.1 Hz, 1H), 4.55 (d, J = 14.1 Hz, 1H),
3.80−3.70 (m, 1H), 3.52−3.42 (m, 1H), 2.41 (s, 3H), 1.42 (d, J = 5.1
Hz, 3H), 1.14 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
156.9, 144.4, 134.8, 134.5, 132.7, 129.6, 128.74, 128.70, 128.4, 128.1,
127.7, 121.6, 116.7, 114.2, 100.2, 86.2, 67.7, 61.5, 55.7, 21.5, 20.2, 15.1;
HR-ESIMS calcd for C26H28NO4S [M + H]+ 450.1734. Found
450.1735.
1-((2-(1-Ethoxyethoxy)phenyl)ethynyl)azetidin-2-one (6g).
According to GP-1, 6g (514 mg, 87%) was obtained from 1-(1-
ethoxyethoxy)-2-ethynylbenzene10 (432 mg, 2.27 mmol). Eluent:
hexane/EtOAc = 5:1. Yellow oil; IR νmax: 3012, 2243, 1770, 1597
(4R)-3-((2-(1-Ethoxyethoxy)phenyl)ethynyl)-4-phenyloxazo-
lidin-2-one (6c). According to GP-1, 6c (1.55 g, 49%) was obtained
as 1:1 diastereomer mixture from 1-(1-ethoxyethoxy)-2-ethynylben-
zene10 (1.71 g, 8.98 mmol). Eluent: hexane/EtOAc = 2:1. Yellow oil;
1
cm−1; H NMR (300 MHz, CDCl3) δ 7.39 (dd, J = 7.5, 1.8 Hz, 1H),
7.25−7.21 (m, 1H), 7.05 (dd, J = 8.4, 1.2 Hz, 1H), 6.96 (dd, J = 7.5,
0.9 Hz, 1H), 5.41 (q, J = 5.1 Hz, 1H), 3.91−3.80 (m, 1H), 3.72 (t, J =
4.8 Hz, 2H), 3.64−3.54 (m, 1H), 3.10 (t, J = 4.8 Hz, 2H), 1.54 (d, J =
5.1 Hz, 3H), 1.22 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
166.5, 157.3, 133.4, 129.4, 122.0, 117.5, 113.8, 101.0, 82.2, 66.3, 61.7,
43.1, 37.9, 20.4, 15.2; HR-ESIMS calcd for C15H17NNaO3 [M + Na]+
282.1101. Found 282.1099.
22
[α]D −169 (c 1.02, CHCl3); IR νmax: 3013, 2257, 1776, 1597 cm−1;
1H NMR (500 MHz, CDCl3) δ 7.47−7.44 (m, 2H), 7.42−7.39 (m,
3H), 7.26 (d, J = 8.0 Hz, 1H), 7.19−7.15 (m, 1H), 6.99 (dd, J = 3.0,
1.0 Hz, 0.5H), 6.97 (dd, J = 2.5, 1.0 Hz, 0.5H), 6.90−6.86 (m, 1H),
5.28−5.25 (m, 1H), 5.16 (t, J = 6.5 Hz, 0.5H), 5.14 (t, J = 6.5 Hz,
0.5H), 4.78 (t, J = 9.0 Hz, 1H), 4.31−4.26 (m, 1H), 3.73−3.61 (m,
1H), 3.43−3.39 (m, 1H), 1.32 (d, J = 5.0 Hz, 1.5H), 1.31 (d, J = 5.0
Hz, 1.5H), 1.15 (t, J = 7.0 Hz, 1.5H), 1.12 (t, J = 7.0 Hz, 1.5H); 13C
NMR (125 MHz, CDCl3) δ 157.1, 157.0, 155.50, 155.49, 136.3, 136.2,
133.3, 133.2, 129.37, 129.35, 129.27, 129.26, 129.25, 129.20, 126.85,
126.78, 121.8, 117.45, 117.44, 113.84, 113.81, 100.4, 100.2, 81.5,
70.76, 70.72, 69.3, 69.2, 62.18, 62.16, 61.3, 61.0, 20.0, 19.9, 15.13,
15.11; HR-ESIMS calcd for C21H21NNaO4 [M + Na]+ 374.1363.
Found 374.1357.
1-((2-(1-Ethoxyethoxy)phenyl)ethynyl)pyrrolidin-2-one (6h).
Modifying to GP-1 (Cs2CO3 was used as a base instead of Na2CO3
and pyridine; DMSO was used as solvent instead of toluene), 6h (218
mg, 33%) was obtained from 1-(1-ethoxyethoxy)-2-ethynylbenzene10
(460 mg, 2.42 mmol), pyrrolidin-2-one (1.03 g, 12.1 mmol), CuCl2
(650 mg, 4.83 mmol), and Cs2CO3 (1.57 g, 4.83 mmol). Eluent:
hexane/EtOAc = 3:1 to 1:1. Yellow oil; IR νmax: 3012, 2250, 1714,
1
1597 cm−1; H NMR (300 MHz, CDCl3) δ 7.42 (d, J = 7.5 Hz, 1H),
7.28−7.20 (m, 1H), 7.04 (d, J = 7.5 Hz, 1H), 6.96 (t, J = 7.5 Hz, 1H),
5.43 (q, J = 5.1 Hz, 1H), 3.90−3.78 (m, 1H), 3.79 (t, J = 7.2 Hz, 2H),
3.64−3.54 (m, 1H), 2.48 (t, J = 7.8 Hz, 2H), 2.22−2.12 (m, 2H), 1.55
(d, J = 5.1 Hz, 3H), 1.20 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 175.5, 157.1, 133.2, 129.0, 121.9, 117.5, 114.3, 100.9, 84.0,
68.9, 61.6, 50.0, 29.6, 20.3, 18.7, 15.1; HR-ESIMS calcd for
C16H19NNaO3 [M + Na]+ 296.1257. Found 296.1252.
(4R)-4-Benzyl-3-((2-(1-ethoxyethoxy)phenyl)ethynyl)oxa-
zolidin-2-one (6d). According to GP-1, 6d (384 mg, 70%) was
obtained as 1:1 diastereomer mixture from 1-(1-ethoxyethoxy)-2-
ethynylbenzene10 (285 mg, 1.50 mmol). Eluent: hexane/EtOAc = 3:2.
23
Yellow oil; [α]D −77.5 (c 1.12, CHCl3); IR νmax: 3025, 2258, 1772,
1
1598 cm−1; H NMR (500 MHz, CDCl3) δ 7.45 (td, J = 7.5, 1.5 Hz,
1H), 7.37−7.34 (m, 2H), 7.31−7.24 (m, 4H), 7.07 (d, J = 7.5 Hz,
1H), 6.97 (dt, J = 7.5, 1.5 Hz, 1H), 5.47 (t, J = 5.5 Hz, 0.5H), 5.46 (t, J
= 5.5 Hz, 0.5H), 4.40−4.33 (m, 2H), 4.20−4.15 (m, 1H), 3.86−3.78
(m, 1H), 3.61−3.53 (m, 1H), 3.32 (td, J = 14.0, 3.5 Hz, 1H), 3.10−
3.05 (m, 1H), 1.54 (d, J = 5.5 Hz, 1.5H), 1.53 (d, J = 5.5 Hz, 1.5H),
1.19 (t, J = 7.0 Hz, 1.5H), 1.16 (t, J = 7.0 Hz, 1.5H); 13C NMR (125
MHz, CDCl3) δ 157.5, 157.4, 155.3, 134.17, 134.16, 133.2, 133.1,
129.49, 129.47, 129.42, 129.39, 129.0, 127.5, 121.73, 121.71, 116.56,
116.50, 113.57, 113.55, 100.5, 100.4, 81.52, 81.49, 70.03, 70.00, 67.3,
67.2, 61.52, 61.47, 58.6, 58.5, 37.6, 37.5, 20.4, 15.2, 15.1; HR-ESIMS
calcd for C22H23NNaO4 [M + Na]+ 388.1525. Found 388.1511.
(4S,5R)-1-((2-(1-Ethoxyethoxy)phenyl)ethynyl)-1,5-dimeth-
yl-4-phenyl-imidazolidin-2-one (6e). According to GP-1, 6e (56.4
mg, 13%) was obtained as 1:1 diastereomer mixture from 1-(1-
ethoxyethoxy)-2-ethynylbenzene10 (218 mg, 1.15 mmol). Eluent:
Methyl 1-((2-(1-ethoxyethoxy)phenyl)ethynyl)-1H-indole-3-
carboxylate (6i). According to GP-1, 6i (470 mg, 86%) was obtained
from 1-(1-ethoxyethoxy)-2-ethynylbenzene10 (285 mg, 1.50 mmol).
Eluent: hexane/EtOAc = 7:1. Red oil; IR νmax: 3012, 2258, 1708, 1597
1
cm−1; H NMR (300 MHz, CDCl3) δ 8.20−8.17 (m, 1H), 7.98 (s,
1H), 7.76−7.73 (m, 1H), 7.51 (dd, J = 7.8, 1.8 Hz, 1H), 7.44−7.28
(m, 3H), 7.12 (d, J = 8.4 Hz, 1H), 7.02 (dt, J = 7.8, 0.9 Hz, 1H), 5.52
(q, J = 5.4 Hz, 1H), 3.94 (s, 3H), 3.92−3.82 (m, 1H), 3.66−3.56 (m,
1H), 1.60 (d, J = 5.4 Hz, 3H), 1.21 (t, J = 7.2 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 164.3, 157.4, 138.5, 134.5, 132.8, 129.7, 125.3, 124.4,
123.6, 121.8, 121.7, 116.3, 112.8, 111.6, 110.8, 100.3, 82.7, 68.8, 61.4,
51.3, 20.3, 15.1; HR-ESIMS calcd for C22H21NNaO4 [M + Na]+
386.1363. Found 386.1368.
N-((4-(1-Ethoxyethoxy)-[1,1′-biphenyl]-3-yl)ethynyl)-N,4-di-
methylbenzenesulfonamide (6j). According to GP-1, 6j (418 mg,
58%) was obtained from 4-(1-ethoxyethoxy)-3-ethynyl-1,1′-biphenyl10
(428 mg, 1.61 mmol). Eluent: hexane/EtOAc = 5:1. Yellow oil; IR
21
hexane/EtOAc = 1:1. Yellow oil; [α]D +167 (c 0.792, CHCl3); IR
1
νmax: 3018, 2246, 1720, 1602 cm−1; H NMR (500 MHz, CDCl3) δ
5917
dx.doi.org/10.1021/jo500903y | J. Org. Chem. 2014, 79, 5914−5920

The Journal of Organic Chemistry
Note
νmax: 3011, 2239, 1599, 1368, 1168 cm−1; 1H NMR (300 MHz,
CDCl3) δ 7.94−7.89 (m, 2H), 7.56−7.51 (m, 3H), 7.45−7.29 (m,
6H), 7.09 (d, J = 8.4 Hz, 1H), 5.46 (q, J = 5.4 Hz, 1H), 3.92−3.82 (m,
1H), 3.63−3.53 (m, 1H), 3.17 (s, 3H), 2.45 (s, 3H), 1.55 (d, J = 5.4
Hz, 3H), 1.21 (t, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
156.6, 144.7, 139.9, 134.9, 133.4, 131.4, 129.8, 128.7, 127.9, 127.5,
127.1, 126.7, 117.2, 114.6, 100.7, 87.6, 65.6, 61.7, 39.3, 21.6, 20.4, 15.2;
HR-ESIMS calcd for C26H28NO4S [M + H]+ 450.1734. Found
450.1732.
N-((2-(1-Ethoxyethoxy)-5-methoxyphenyl)ethynyl)-N,4-di-
methylbenzenesulfonamide (6k). According to GP-1, 6k (426 mg,
64%) was obtained from 1-(1-ethoxyethoxy)-2-ethynyl-4-methoxy-
benzene (364 mg, 1.65 mmol). Eluent: hexane/EtOAc = 5:1. Yellow
oil; IR νmax: 2962, 2156, 1603, 1384, 1175 cm−1; 1H NMR (300 MHz,
CDCl3) δ 7.89 (d, J = 8.1 Hz, 2H), 7.36 (d, J = 8.1 Hz, 2H), 6.96 (d, J
= 9.0 Hz, 1H), 6.85 (d, J = 3.3 Hz, 1H), 6.77 (dd, J = 9.0, 3.3 Hz, 1H),
5.29 (q, J = 5.4 Hz, 1H), 3.88−3.78 (m, 1H), 3.76 (s, 3H), 3.60−3.50
(m, 1H), 3.15 (s, 3H), 2.45 (s, 3H), 1.46 (d, J = 5.4 Hz, 3H), 1.18 (t, J
= 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 154.4, 151.0, 144.7,
133.2, 129.7, 127.8, 119.7, 117.0, 115.5, 115.0, 101.6, 87.4, 65.6, 61.9,
55.6, 39.3, 21.6, 20.4, 15.1; HR-ESIMS calcd for C21H25NNaO5S [M +
Na]+ 426.1346. Found 426.1345.
(d, J = 8.1 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 7.28−7.19 (m, 7H), 4.72
(s, 2H), 2.48 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 152.3, 147.8,
144.4, 135.7, 134.2, 130.4, 129.8, 128.9, 128.4, 128.2, 128.1, 126.3,
123.5, 122.0, 111.3, 67.5, 53.9, 21.7; HR-ESIMS calcd for
C22H19INO3S [M + H]+ 504.0125. Found 504.0126.
(R)-3-(3-Iodobenzofuran-2-yl)-4-phenyloxazolidin-2-one
(2c). According to GP-2, 2c (53.3 mg, 91%) was obtained from 6c
(50.5 mg, 0.144 mmol). Eluent: hexane/EtOAc = 3:1. Colorless
amorphous solid; [α]D24 −177 (c 0.874, CHCl3); IR νmax: 3028, 1775,
1613, 1082 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.47−7.43 (m, 2H),
7.39−7.28 (m, 5H), 7.27−7.21 (m, 2H), 5.56 (t, J = 8.4 Hz, 1H), 4.89
(t, J = 8.4 Hz, 1H), 4.39 (t, J = 8.4 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 154.2, 152.0, 145.7, 136.1, 130.3, 129.4, 129.1, 127.2, 125.9,
123.6, 121.4, 111.3, 70.9, 62.4, 61.3; HR-ESIMS calcd for C17H13INO3
[M + H]+ 405.9935. Found 405.9934.
(R)-4-Benzyl-3-(3-iodobenzofuran-2-yl)oxazolidin-2-one
(2d). According to GP-2, 2d (94.2 mg, 91%) was obtained from 6d
(90.1 mg, 0.247 mmol). Eluent: hexane/EtOAc = 2:1. Colorless
amorphous solid; [α]D23 −29.2 (c 0.806, CHCl3); IR νmax: 3030, 1774,
1613, 1094 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.40−7.39 (m, 3H),
7.36−7.29 (m, 1H), 7.25−7.12 (m, 5H), 4.76−4.66 (m, 1H), 4.49 (t, J
= 8.4 Hz, 1H), 4.28 (dd, J = 8.4, 6.6 Hz, 1H), 3.09 (dd, J = 13.5, 4.8
Hz, 1H), 2.91 (dd, J = 13.5, 9.3 Hz, 1H); 13C NMR (75 MHz, CDCl3)
δ 154.3, 152.2, 145.6, 134.6, 130.4, 128.9, 128.8, 127.2, 126.2, 123.8,
121.6, 111.5, 68.1, 63.2, 58.4, 39.3; HR-ESIMS calcd for C18H15INO3
[M + H]+ 420.0091. Found 420.0090.
(4S,5R)-1-(3-Iodobenzofuran-2-yl)-3,4-dimethyl-5-phenyli-
midazolidin-2-one (2e). According to GP-2, 2e (50.7 mg, 92%) was
obtained from 6e (48.3 mg, 0.128 mmol). Eluent: hexane/EtOAc =
7:3. Colorless oil; [α]D21 +132 (c 0.658, CHCl3); IR νmax: 3026, 1720,
1612, 1078 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.37−7.35 (m, 2H),
7.31−7.28 (m, 3H), 7.26−7.20 (m, 4H), 5.53 (d, J = 9.0 Hz, 1H),
4.07−4.01 (m, 1H), 2.92 (s, 3H), 0.86 (d, J = 6.5 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ 156.8, 151.8, 148.4, 135.2, 130.9, 128.41, 128.39,
127.9, 125.1, 123.2, 121.0, 111.1, 62.7, 60.6, 56.0, 28.9, 14.7; HR-
ESIMS calcd for C19H18IN2O2 [M + H]+ 433.0407. Found 433.0404.
1-(3-Iodobenzofuran-2-yl)-3-methyl-1H-benzo[d]imidazol-
2(3H)-one (2f). According to GP-2, 2f (88.5 mg, 97%) was obtained
from 6f (78.5 mg, 0.234 mmol). Eluent: hexane/EtOAc = 2:1.
Colorless amorphous solid; IR νmax: 3023, 1728, 1612, 1088 cm−1; 1H
NMR (300 MHz, CDCl3) δ 7.51−7.47 (m, 2H), 7.47−7.34 (m, 2H),
7.21 (d, J = 7.8 Hz, 1H), 7.09 (d, J = 7.8 Hz, 2H), 6.97−6.94 (m, 1H),
3.51 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 152.8, 152.1, 144.2,
130.6, 130.3, 128.2, 126.4, 123.9, 123.1, 122.0, 121.8, 111.7, 109.7,
108.1, 63.5, 27.5; HR-ESIMS calcd for C16H12IN2O2 [M + H]+
390.9938. Found 390.9934.
N-((2-(1-Ethoxyethoxy)-4-nitrophenyl)ethynyl)-N,4-dime-
thylbenzenesulfonamide (6l). According to GP-1, 6l (542 mg,
41%) was obtained from 2-(1-ethoxyethoxy)-1-ethynyl-4-nitrobenzene
(743 mg, 3.16 mmol). Eluent: hexane/EtOAc = 4:1. Yellow oil; IR
1
νmax: 3030, 2232, 1598, 1520, 1373, 1342, 1170 cm−1; H NMR (300
MHz, CDCl3) δ 7.92−7.89 (m, 3H), 7.84−7.80 (m, 1H), 7.41−7.37
(m, 3H), 5.54 (q, J = 5.1 Hz, 1H), 3.90−3.80 (m, 1H), 3.65−3.55 (m,
1H), 3.20 (s, 3H), 2.46 (s, 3H), 1.60 (d, J = 5.1 Hz, 3H), 1.22 (t, J =
6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 156.5, 146.9, 145.1, 133.2,
131.6, 129.9, 127.8, 121.5, 116.7, 110.8, 100.7, 93.0, 65.7, 61.7, 39.2,
21.7, 20.0, 15.1; HR-ESIMS calcd for C20H22N2NaO6S [M + Na]+
441.1091. Found 441.1092.
N-((1-(1-Ethoxyethoxy)naphthalen-2-yl)ethynyl)-N,4-dime-
thylbenzenesulfonamide (6m). According to GP-1, 6m (387 mg,
59%) was obtained from 1-(1-ethoxyethoxy)-2-ethynylnaphthalene10
(374 mg, 1.56 mmol). Eluent: hexane/EtOAc = 5:1. Yellow oil; IR
νmax: 3010, 2236, 1598, 1369, 1169 cm−1; 1H NMR (300 MHz,
CDCl3) δ 8.36−8.32 (m, 1H), 7.88−7.86 (m, 2H), 7.77−7.74 (m,
1H), 7.51−7.47 (m, 3H), 7.39−7.34 (m, 3H), 5.78 (q, J = 5.1 Hz,
1H), 3.52−3.36 (m, 2H), 3.20 (s, 3H), 2.45 (s, 3H), 1.55 (d, J = 5.1
Hz, 3H), 1.00 (t, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
155.3, 144.9, 134.2, 133.3, 129.9, 129.7, 129.0, 128.0, 127.8, 127.4,
127.0, 126.2, 123.3, 110.3, 104.4, 88.2, 66.6, 64.9, 39.3, 21.7, 21.6, 15.3;
HR-ESIMS calcd for C24H26NO4S [M + H]+ 424.1577. Found
424.1579.
General Procedure for the Iodocyclization of Ynamides 6
(Table 1, entry 6 and Table 3, GP-2). Three seconds was precisely
counted by stopwatch just after I(coll)2PF6 (1 equiv) was added in one
portion to a stirred solution of 6a (1 equiv) in CH2Cl2 (0.1 M) at 23
°C, and the reaction mixture was immediately quenched with a
saturated aqueous solution of Na2S2O3/NaHCO3 (1:1) and was
extracted with CH2Cl2. The organic layer was dried over Na2SO4,
filtered, and evaporated in vacuo. The residue was purified by flash
column chromatography on silica gel to give 2.
1-(3-Iodobenzofuran-2-yl)azetidin-2-one (2g). According to
GP-2, 2g (67.4 mg, 84%) was obtained from 6g (66.0 mg, 0.255
mmol). Eluent: hexane/EtOAc = 2:1. Colorless amorphous solid; IR
1
νmax: 3027, 1769, 1606, 1099 cm−1; H NMR (300 MHz, CDCl3) δ
7.42−7.41 (m, 1H), 7.40−7.26 (m, 3H), 4.00 (t, J = 4.8 Hz, 2H), 3.26
(t, J = 4.8 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 163.5, 151.1, 146.5,
130.5, 125.1, 123.9, 120.8, 111.1, 49.5, 41.2, 38.2; HR-ESIMS calcd for
C11H9INO2 [M + H]+ 313.9672. Found 313.9671.
1-(3-Iodobenzofuran-2-yl)pyrrolidin-2-one (2h). According to
GP-2, 2h (74.9 mg, 92%) was obtained from 6h (87.2 mg, 0.260
mmol). Eluent: hexane/EtOAc = 1:1. Colorless amorphous solid; IR
N-(3-Iodobenzofuran-2-yl)-N,4-dimethylbenzenesulfona-
mide (2a). According to GP-2, 2a (90.6 mg, 98%) was obtained from
6a (80.7 mg, 0.216 mmol). Eluent: hexane/EtOAc = 5:1. Colorless
1
νmax: 3011, 1720, 1608, 1103 cm−1; H NMR (300 MHz, CDCl3) δ
7.40−7.35 (m, 2H), 7.31 (dd, J = 7.8, 1.8 Hz, 2H), 3.90 (t, J = 7.2 Hz,
2H), 2.60 (t, J = 8.1 Hz, 2H), 2.32−2.22 (m, 2H); 13C NMR (75
MHz, CDCl3) δ 174.3, 151.8, 148.0, 130.6, 125.6, 123.5, 121.2, 111.2,
59.6, 48.7, 30.8, 19.1; HR-ESIMS calcd for C12H11INO2 [M + H]+
327.9829. Found 327.9828.
1
amorphous solid; IR νmax: 3032, 1602, 1362, 1172, 1068 cm−1; H
NMR (300 MHz, CDCl3) δ 7.77 (d, J = 8.4 Hz, 2H), 7.39−7.28 (m,
6H), 3.22 (s, 3H), 2.47 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 155.2,
149.6, 144.4, 134.7, 130.4, 129.8, 128.2, 126.4, 123.7, 122.0, 111.4,
64.7, 37.3, 21.7; HR-ESIMS calcd for C16H15INO3S [M + H]+
427.9812. Found 427.9803.
Methyl 1-(3-iodobenzofuran-2-yl)-1H-indole-3-carboxylate
(2i). According to GP-2, 2i (74.6 mg, 89%) was obtained from 6i
(72.8 mg, 0.200 mmol). Eluent: hexane/EtOAc = 5:1. Colorless
N-Benzyl-N-(3-iodobenzofuran-2-yl)-4-methylbenzenesulfo-
namide (2b). According to GP-2, 2b (89.6 mg, 90%) was obtained
from 6b (88.4 mg, 0.197 mmol). Eluent: hexane/EtOAc = 6:1.
Colorless amorphous solid; IR νmax: 3020, 1600, 1362, 1168, 1092
1
amorphous solid; IR νmax: 3017, 1710, 1614, 1061 cm−1; H NMR
(300 MHz, CDCl3) δ 8.29−8.25 (m, 1H), 8.18 (s, 1H), 7.54−7.49 (m,
3H), 7.44 (dd, J = 7.2, 1.8 Hz, 2H), 7.39−7.35 (m, 2H), 3.97 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 164.7, 152.0, 147.1, 136.8, 133.7, 130.6,
1
cm−1; H NMR (300 MHz, CDCl3) δ 7.79 (d, J = 8.1 Hz, 2H), 7.35
5918
dx.doi.org/10.1021/jo500903y | J. Org. Chem. 2014, 79, 5914−5920

The Journal of Organic Chemistry
Note
126.4, 126.3, 124.34, 124.30, 123.4. 122.0, 121.9, 112.2, 111.5, 111.4,
57.8, 51.4; HR-ESIMS calcd for C18H13INO3 [M + H]+ 417.9935.
Found 417.9931.
using TLC, water (0.20 mL) was added and the mixture was heated
under reflux for 24 h. Then, the mixture was diluted with water, and
extracted with EtOAc. The organic layer was washed with brine, dried
over Na2SO4, filtered, and evaporated in vacuo. The residue was
purified by flash column chromatography on silica gel eluting with
N-(3-Iodo-5-phenylbenzofuran-2-yl)-N,4-dimethylbenzene-
sulfonamide (2j). According to GP-2, 2j (95.2 mg, quant.) was
obtained from 6j (81.2 mg, 0.181 mmol). Eluent: hexane/EtOAc =
5:1. Colorless amorphous solid; IR νmax: 3033, 1602, 1362, 1171, 1068
cm−1; 1H NMR (300 MHz, CDCl3) δ 7.78 (d, J = 8.1 Hz, 2H), 7.63−
7.56 (m, 4H), 7.45 (t, J = 7.8 Hz, 2H), 7.41−7.33 (m, 4H), 3.23 (s,
3H), 2.46 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 151.7, 150.1, 144.4,
140.9, 137.5, 134.7, 130.8, 129.8, 128.8, 128.2, 127.4, 127.2, 126.0,
120.4, 111.7, 64.9, 37.3, 21.6; HR-ESIMS calcd for C22H19INO3S [M +
H]+ 504.0125. Found 504.0124.
hexane/EtOAc = 3:1 to 2:1 to give 9 (40.3 mg, 57%). Colorless
24
crystals; mp 167−168 °C; [α]D −6.6 (c 0.501, CHCl3); IR νmax
:
3421, 3013, 1652, 1620, 1587 cm−1; 1H NMR (300 MHz, DMSO-d6)
δ 8.39 (d, J = 7.8 Hz, 1H), 8.34 (dd, J = 7.8, 3.3 Hz, 1H), 8.24 (dd, J =
7.8, 3.6 Hz, 1H), 7.91 (t, J = 7.8 Hz, 1H), 7.69 (d, J = 8.1 Hz, 1H),
7.56 (t, J = 7.8 Hz, 1H), 7.50−7.41 (m, 3H), 7.39−7.25 (m, 4H), 6.48
(br s, 1H), 5.30 (t, J = 5.7 Hz, 1H), 4.69 (ddd, J = 11.4, 9.9, 5.7 Hz,
1H), 4.45 (dt, J = 11.4, 5.7 Hz, 1H); 13C NMR (125 MHz, DMSO-d6)
δ 161.1, 151.2, 151.1, 137.1, 133.7, 132.1, 129.1, 128.5, 127.6, 127.2,
125.4, 124.5, 124.0, 123.4, 122.7, 122.5, 119.7, 111.4, 94.5, 60.2, 59.2;
HR-ESIMS calcd for C23H18NO3 [M + H]+ 356.1281. Found
356.1281.
N-(3-Iodo-5-methoxybenzofuran-2-yl)-N,4-dimethylbenze-
nesulfonamide (2k). According to GP-2, 2k (74.9 mg, 84%) was
obtained from 6k (79.1 mg, 0.196 mmol). Eluent: hexane/EtOAc =
5:1. Colorless amorphous solid; IR νmax: 3030, 1600, 1361, 1168, 1073
1
cm−1; H NMR (300 MHz, CDCl3) δ 7.76 (d, J = 8.4 Hz, 2H), 7.34
(d, J = 8.4 Hz, 2H), 7.24 (d, J = 9.0 Hz, 1H), 6.96 (dd, J = 9.0, 2.7 Hz,
1H), 6.82 (d, J = 2.7 Hz, 1H), 3.87 (s, 3H), 3.21 (s, 3H), 2.46 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 156.6, 150.0, 146.9, 144.4, 134.7, 130.9,
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra of 1a, 6a-m, 2a-m, 7, and
129.7, 128.2, 115.6, 112.2, 103.8, 64.7, 55.9, 37.3, 21.6; HR-ESIMS
calcd for C17H17INO4S [M + H]+ 457.9916. Found 457.9917.
N-(3-Iodo-6-nitrobenzofuran-2-yl)-N,4-dimethylbenzenesul-
fonamide (2l). According to GP-2, 2l (78.1 mg, 91%) was obtained
from 6l (76.1 mg, 0.182 mmol). Eluent: hexane/EtOAc = 3:1.
Colorless amorphous solid; IR νmax: 2927, 1599, 1526, 1363, 1347,
1172, 1090 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.28 (d, J = 1.8 Hz,
1H), 8.24 (dd, J = 8.4, 1.8 Hz, 1H) 7.76 (d, J = 8.4 Hz, 2H), 7.54 (d, J
= 8.4 Hz, 1H), 7.39 (d, J = 8.4 Hz, 2H), 3.25 (s, 3H), 2.49 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 154.2, 150.6, 146.3, 145.0, 136.3, 134.2,
130.0, 128.1, 122.3, 119.2, 107.8, 64.2, 37.2, 21.7; HR-ESIMS calcd for
C16H13IN2NaO5S [M + Na]+ 494.9482. Found 494.9485.
9. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: okitsu@kobepharma-u.ac.jp.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by JSPS KAKENHI Grant Number
24590038 (T.O.).
■
N-(3-Iodonaphtho[1,2-b]furan-2-yl)-N,4-dimethylbenzene-
sulfonamide (2m). According to GP-2, 2m (88.3 mg, 94%) was
obtained from 6m (83.6 mg, 0.197 mmol). Eluent: hexane/EtOAc =
5:1. Colorless amorphous solid; IR νmax: 2927, 1600, 1361, 1171, 1068
REFERENCES
1
cm−1; H NMR (300 MHz, CDCl3) δ 8.07 (td, J = 8.1, 0.6 Hz, 1H),
■
(1) For reviews, see: (a) French, A. N.; Bissmire, S.; Wirth, T. Chem.
Soc. Rev. 2004, 33, 354. (b) Larock, R. C. Acetylene Chem. 2005, 51.
(c) Togo, H.; Iida, S. Synlett 2006, 2159. (d) Mphahlele, M. J.
Molecules 2009, 14, 4814. (e) Godoi, B.; Schumacher, R. F.; Zeni, G.
Chem. Rev. 2011, 111, 2938.
7.92 (d, J = 7.5 Hz, 1H), 7.83−7.79 (m, 2H), 7.72 (d, J = 8.7 Hz, 1H),
7.61−7.49 (m, 2H), 7.43 (d, J = 8.7 Hz, 1H), 7.36 (dd, J = 8.7, 0.6 Hz,
2H), 3.29 (s, 3H), 2.48 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 148.8,
148.0, 144.4, 134.8, 132.3, 129.7, 128.6, 128.3, 126.8, 126.1, 126.0,
124.3, 120.7, 119.8, 119.6, 65.8, 37.7, 21.7; HR-ESIMS calcd for
C20H16INNaO3S [M + Na]+ 499.9788. Found 499.9791.
(2) For selected examples of 5-endo-dig iodocyclization from the year
2010, see: (a) Cho, C.-H.; Neuenswander, B.; Larock, R. C. J. Comb.
Chem. 2010, 12, 278. (b) Mehta, S.; Larock, R. C. J. Org. Chem. 2010,
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In, Y.; Ishida, T.; Wada, A. Synlett 2010, 203. (d) Schumacher, R. F.;
N-(1,2-Diiodo-2-(2-methoxyphenyl)vinyl)-N,4-dimethylben-
zenesulfonamide (7) (Table 2, entry 1). According to the
literature,9 to a solution of 1a (52.3 mg, 0.166 mmol) in dry
CH2Cl2 (1.33 mL) was added I2 (61.1 mg, 0.249 mmol) at rt and the
reaction mixture was stirred for 30 min. The reaction mixture was
quenched with a saturated aqueous solution of Na2S2O3/NaHCO3
(1:1), and was extracted with CH2Cl2. The organic layer was dried
over Na2SO4, filtered, and evaporated in vacuo. The residue was
purified by flash column chromatography on silica gel eluting with
hexane/EtOAc = 6:1 to give 2a (48.4 mg, 68%) and 7 (23.6 mg, 25%)
as the mixture of 2:1 stereoisomer. Colorless solid; IR νmax: 2929,
1597, 1361, 1167, 1046 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.88 (d,
J = 8.0 Hz, 4/3H), 7.87 (d, J = 8.0 Hz, 2/3H), 7.36−7.31 (m, 3H),
7.21 (dd, J = 7.5, 1.5 Hz, 2/3H), 7.06 (dd, J = 7.5, 1.5 Hz, 1/3H), 7.00
(t, J = 7.5 Hz, 2/3H), 6.96 (t, J = 7.5 Hz, 1/3H), 6.91 (d, J = 8.0 Hz,
1/3H), 6.87 (d, J = 8.0 Hz, 2/3H), 3.96 (s, 1H), 3.85 (s, 2H), 2.82 (s,
1H), 2.79 (s, 2H), 2.44 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 155.7,
154.9, 144.6, 144.5, 134.1, 133.9, 133.5, 133.1, 130.6, 130.1, 129.4,
129.3, 129.2, 120.8, 120.6, 112.1, 111.6, 100.9, 99.9, 99.8, 98.8, 56.1,
55.7, 37.8, 37.2, 21.7; HR-ESIMS calcd for C17H18I2NO3S [M + H]+
569.9091. Found 569.9095.
́
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(R)-6-(2-Hydroxy-1-phenylethyl)benzofuro[2,3-c]iso-
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(108 mg, 0.600 mmol), PdCl2(PPh3)2 (14.0 mg, 0.0200 mmol) and
Cs2CO3 (195 mg, 0.600 mmol) in dry 1,4-dioxane (1.2 mL) was
heated under reflux for 48 h. After checking the consumption of 2c
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