Titanium tetraiodide-mediated diastereoselective iodo-aldol and Mannich reactions of γ-alkoxy-α,β-alkynyl ketone derivatives

Article abstract of DOI:10.1016/j.tet.2016.09.020

The development of the stereoselective synthesis of vinyl halides plays an important role in organic chemistry. The multi-functionalized vinyl iodide is one of the most important intermediates in functional organic compounds. We investigated stereoselective iodo-aldol and iodo-Mannich reactions using γ-alkoxy-α,β-alkynyl ketones. Characteristic features of titanium tetraiodide involve iodination ability and moderate Lewis acidity, which are successfully used for the present stereoselective synthesis of multi-functionalized vinyl iodides. Furthermore, we have succeeded in the synthesis of a useful tetra-substituted furan, via a Sonogashira coupling of the vinyl iodide moiety. The factors to control diastereoselectivity of the iodo-aldol reactions are explained in terms of theoretical calculations. Consequently, the obtained activation free energy and reaction energy indicate the experimentally observed E/Z-selectivity.

Full text of DOI:10.1016/j.tet.2016.09.020

Tetrahedron xxx (2016) 1e11
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Titanium tetraiodide-mediated diastereoselective iodo-aldol and
Mannich reactions of g-alkoxy-a,b-alkynyl ketone derivatives
Kai Yashiro, Shingo Ito, Shota Kayaki, Keito Sakata, Isao Mizota, Iwao Hachiya,
*
Makoto Shimizu
Department of Chemistry for Materials, Graduate School of Engineering, Mie University, Tsu, Mie 514-8507, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 July 2016
Received in revised form 6 September 2016
Accepted 11 September 2016
Available online xxx
The development of the stereoselective synthesis of vinyl halides plays an important role in organic
chemistry. The multi-functionalized vinyl iodide is one of the most important intermediates in functional
organic compounds. We investigated stereoselective iodo-aldol and iodo-Mannich reactions using
g-alk-
oxy- -alkynyl ketones. Characteristic features of titanium tetraiodide involve iodination ability and
a,b
moderate Lewis acidity, which are successfully used for the present stereoselective synthesis of multi-
functionalized vinyl iodides. Furthermore, we have succeeded in the synthesis of a useful tetra-
substituted furan, via a Sonogashira coupling of the vinyl iodide moiety. The factors to control diaster-
eoselectivity of the iodo-aldol reactions are explained in terms of theoretical calculations. Consequently, the
obtained activation free energy and reaction energy indicate the experimentally observed E/Z-selectivity.
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Titanium tetraiodide
g-Alkoxy-a,b-alkynyl ketone
Iodo-aldol
Iodo-Mannich
DFT calculation
1. Introduction
diastereoselectivity was shown, it reported only terminal alkynes.
As is evident from the above reports, several iodo-aldol reactions
The development of the stereoselective synthesis of vinyl ha-
lides plays an important role in organic chemistry. The synthesized
vinyl iodides in a stereoselective manner are important in-
termediates. In particular, multi-functionalized vinyl iodides have
diversity in synthetic organic chemistry due to their convertibility
and applicability such as the metal-catalyzed cross-coupling and
NozakieHiyamaeKishi reaction as substrates.1
Many studies over the last three decades have shown the for-
mation of vinyl iodides from alkynyl ketones. In 1986, Taniguchi
et al. reported that the stereoselective iodo-aldol reaction of ethy-
nyl ketones as terminal alkynyl ketones with aldehydes was pro-
moted by TiCl4/nBu4NI, TiCl4/TMSI (TMS¼trimethylsilyl), nBu4NF/
TMSI, BF3$OEt2/nBu4NI, Et2AlI, or TiI4.2 Among them, the TiCl4/
nBu4NI combined system was the most effective (Scheme 1). The
have been reported via b-iodoallenoate intermediates from alkynyl
ketones and esters with ZrCl4/nBu4NI,5 Et2AlI,6 TMSI,7 BF3$OEt2/
TMSI,8 CeCl3$7H2O/NaI,9 or GaI3.10 The iodo-aldol reactions using
the above promoters with aldehydes gave Z-isomers under the al-
most identical conditions. As previous asymmetric synthesis
studies, enantioselective iodo-aldol reactions have been developed
using chiral catalyst.11 Asymmetric synthesis of iodo-aldol reactions
using a chiral auxiliary such as a menthyl group has also been re-
ported.12 However, to our knowledge, the diastereoselective iodo-
Iodo-aldol reaction reported by Taniguchi et al.
OM
O
I
OH
Ph nC5H11
O
OH
Ph
O
TiCl4/nBu4NI
CH2Cl2, -78 o
PhCHO
+
nC5H11
I
nC5H11
nC5H11
C
R
vinyl iodide product by coupling of a,b-acetylenic ketone with al-
R
R
R
I
Z
E
dehyde using a TiCl4/nBu4NI system has been documented to
generate the E-isomer as the major product at 0 ꢀC.2b However, the
iodo-aldol reaction of hexynyl ketone as an internal alkynyl ketone
gave the iodo-aldol product with moderate stereoselectivity. In
contrast, Li et al. reported that the diastereoselective iodo-Mannich
R = H, 82% yield, Z/E = 98:2
R = nBu, 73% yied, Z/E = 66:34
Iodo-Mannich reaction reported by Li et al.
R2
R2
Ph
N
O
I
HN
O
OM
chemicals
Ph
R1
R1
R1
CH2Cl2, temperature
I
reaction of terminal
a,b-acetylenic esters and ketones with imine
was promoted by MgI23 or ZrCl4/TMSI4 (Scheme 1). Although good
Z
MgI2, R1 = OMe, R2 = tosyl, 0 oC, 79% yield
ZrCl4/TMSI, R1 = Me, R2 = phenyl, -78 oC to rt, 97% yield
* Corresponding
(M. Shimizu).
author.
E-mail
address:
mshimizu@chem.mie-u.ac.jp
Scheme 1. Previous works on the subject of iodo-aldol and iodo-Mannich reaction.
http://dx.doi.org/10.1016/j.tet.2016.09.020
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2
K. Yashiro et al. / Tetrahedron xxx (2016) 1e11
aldol reaction of internal alkynyl ketones has been limited to an
intramolecular cyclization.13
tetraiodide and benzaldehyde (2a). The aim of this study was to
obtain the best conditions for the iodo-aldol reaction. As shown in
Table 1, several solvents were effective on the yields and the dia-
stereoselectivity (Entries 1e4). When propionitrile (EtCN) was
used, the desired iodo-aldol product 3a was obtained in 45% yield
with a moderate diastereoselectivity (Entry 1). However, in other
solvents such as toluene, THF, and dichloromethane, the iodo-aldol
product 3a was obtained in lower yields (Entries 2e4). The best
solvent obtained from the above examinations was dichloro-
methane, because in dichloromethane the reaction proceeded most
cleanly. Therefore, the reaction temperature in dichloromethane
was next examined in detail (Entries 5e9). The reaction at ꢁ50 ꢀC
gave the iodo-aldol product 3a in moderate yield with better ma-
terial balance (Entry 7). The yields of 3a at ꢁ78 and ꢁ60 ꢀC were
much lower than that at ꢁ50 ꢀC (Entries 5e7). However, the yield of
the iodoalkenone 4 and material balance at lower temperature
were good. These results suggest the importance of the reaction
temperature at the initial step for the generation of the coordinated
enolate with titanium tetraiodide. Higher temperatures at ꢁ40 and
ꢁ20 ꢀC (Entries 8 and 9) led to formation of the undesired by-
products due to decomposition. We next investigated amounts of
titanium tetraiodide and benzaldehyde (2a) at ꢁ50 ꢀC. When the
reaction was conducted using 1.2e1.5 equiv of titanium tetraiodide
with 1.0 equiv of benzaldehyde (Entries 10e12), the iodo-aldol
product 3a was obtained in good yield with good E-selectivity. In
addition, we found that the use of an excess TiI4 remarkably re-
duced the yield of the iodoalkenone 4. From the above results, we
In an effort to use the iodination ability of titanium tetraiodide
more effectively, we have already reported the hydroiodination re-
action of alkenes and alkynes,14 the aza-Prins reaction of p-tosyli-
mine derived from ethyl glyoxylate,15 the synthesis of 2-
iodopyridines,16 and a tandem Prins reaction of alkynes.17 Titanium
tetraiodide has excellent iodination ability and superior reducing
ability. In addition, it has a mild Lewis acidity not usually found in
other metal iodides. Thus, by using titanium tetraiodide, alkynyl
ketone can be diastereoselectively transformed into the vinyl iodide
obtained via aldol and Mannich reactions. If cyclization procedure of
our methodcan be used, it is possible to synthesize heterocyclic rings
having a variety of substituents from multi-functionalized vinyl io-
dides (Scheme 2). In this paper, we would like to report the stereo-
selective synthesis of the multi-substituted vinyl iodide with
titanium tetraiodide and the computational analysis of the reaction
mechanism using a DFTcalculation. Also described is the synthesis of
tetra-substituted furan from vinyl iodide via the Sonogashira cou-
pling reaction and iodo-Mannich reaction with imino ester.18
O
OH
R4
Til4
R4CHO
O
R1
R2
R1
R2
I
R3
R3
R2 = R3 = OEt or
R2 = OMOM, R3 = H
found the optimized conditions for g-diethoxyalkynyl ketone.
In order to understand the scope and limitations of aldehyde, we
investigated use of several aldehydes under the optimized reaction
conditions (Table 2). Diastereoselectivity of all iodo-aldol products
were, in general, E-isomers as major products. Several character-
istics of this reaction are noteworthy. The reaction of p-chlor-
obenzaldehyde (2b), which has an electron-withdrawing group,
gave the product E-3b in 52% yield (Entry 2). The reaction of p-
methoxybenzaldehyde (2c), which has an electron-donating group,
also afforded only the product E-3c in 61% yield (Entry 3). The use of
p-tolualdehyde (2d) gave the product 3d in 64% yield with high
diastereoselectivity (Entry 4). When the reaction of 1-
naphthaldehyde (2e) was carried out, the iodinated product E-3e
was obtained in 34% yield (Entry 5). The reaction of 2-
thiophenecarboxaldehyde (2f) as a heteroaromatic aldehyde gave
the product E-3f in 52% yield (Entry 6). When the reactions of
O
O
OH
R4
R4
O
Pd catalyst
R5
R1
R2
R1
R2
Pd catalyst
R3
R5
R3
R5
Scheme 2. Diastereoselective iodo-aldol reaction of g-alkoxy-a,b-alkynyl ketone de-
rivatives promoted by titanium tetraiodide.
2. Results and discussion
2.1. The iodo-aldol reactions
Initially, reactivity and selectivity were examined in the iodo-
aldol reaction of the
g-diethoxyalkynyl ketone 1a with titanium
Table 1
Optimization of reaction conditionsa
Entry
TiI4 (equiv)
2a (equiv)
Solvent
Temperature (ꢀC)
Time
Yield of 3a (%)b
E/Z
Yield of 4 (%)b
Yield of 1a (%)b
1
2
3
4
5
6
7
8
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.2
1.3
1.5
1.3
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.2
EtCN
Toluene
THF
ꢁ78 to ꢁ60
ꢁ78 to ꢁ60
ꢁ78 to ꢁ60
ꢁ78 to ꢁ60
ꢁ78
85 min
110 min
110 min
80 min
2 h
2 h
2 h
2 h
2 h
2 h
2 h
2 h
2 h
45
17
11
13
4
72:28
84:16
86:14
79:21
100:0
100:0
90:10
89:11
100:0
89:11
97:3
39
19
15
25
45
38
14
3
0
6
0
4
1
42
55
47
37
26
20
0
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
ꢁ60
9
ꢁ50
55
64
28
67
65
56
36
ꢁ40
9
ꢁ20
3
10
11
12
13
ꢁ50
18
25
11
3
ꢁ50
ꢁ50
97:3
83:17
ꢁ50
29
a
Reactions were carried out with 0.15 mmol of 1a, several equivalents of TiI4 and 2a, in a solvent (3 mL) under an argon atmosphere (1 atm).
Isolated yield.
b
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K. Yashiro et al. / Tetrahedron xxx (2016) 1e11
3
Table 2
(1.0 equiv) and benzaldehyde (1.0 equiv) (Entry 7). Amounts of
titanium tetraiodide and benzaldehyde, under the optimized
conditions of Entry 7, were further examined (Entries 8e11).
When the reaction was carried out using 1.2 equiv of titanium
tetraiodide and benzaldehyde at ꢁ78 ꢀC for 3 h (Entry 10), the
product 5a was obtained in the best yield (82%) with good dia-
stereoselectivity. The diastereoselectivities of all the products
Iodo-aldol reaction with several aldehydesa
from
than those with
nificant differences in the yields were observed, E-selectivity of
the -methoxymethoxyalkynyl ketone 1b decreased. The present
study shows that E-selectivity of the product from -methox-
g
-methoxymethoxyalkynyl ketone 1b were slightly lower
Entry
2
R
3
Yield of 3 (%)b
E/Z
g
-diethoxyalkynyl ketone 1a. Although no sig-
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
Ph
3a
3b
3c
3d
3e
3f
65
52
61
64
34
52
41
35
97:3
p-ClC6H4
p-MeOC6H4
p-MeC6H4
1-Naphthyl
2-Thienyl
Cl3C
100:0
100:0
89:11
100:0
100:0
100:0
100:0
g
g
ymethoxyalkynyl ketone 1b is influenced by the substituents of
the alkynyl ketone.
2g
2h
3g
3h
Under the optimum reaction conditions for
g-methoxy
n-Pentyl
methoxyalkynyl ketone 1b, we examined several aldehydes to
clarify the scope and limitations (Table 4). The reactions with p-
chlorobenzaldehydes (2b) and p-methylbenzaldehydes (2d) gave
the iodo-aldol products 5b and 5d in good yields with good dia-
stereoselectivity (Entries 2 and 4). The reaction with p-methox-
ybenzaldehyde (2c), as with an electron-donating group, and
hexanal (2g), as an aliphatic aldehyde, gave respectively the prod-
ucts 5c and 5g in moderate yields with moderate diaster-
eoselectivity (Entries 3 and 7). Unfortunately, 1-naphthaldehyde
(2e) gave the product 5e in a low yield with no diastereoselectivity
(Entry 5). We next examined the alkyl group R1 of alkynyl ketones.
a
Reactions were carried out with 0.15 mmol of 1a and 2, 0.195 mmol of TiI4, in
dichloromethane (3 mL) under an argon atmosphere (1 atm).
b
Isolated yield.
chloral (2g) and hexanal (2h) as aliphatic aldehydes were carried
out, the products E-3g and E-3h were obtained in moderate yields
(Entries 7 and 8).
We next investigated the iodo-aldol reaction of alkynyl ketone
1b as a
g-monoalkoxyalkynyl ketone 1b instead of g-diethox-
yalkynyl ketone 1a with titanium tetraiodide and benzaldehyde
(2a). The results are summarized in Table 3. At first, we examined
-methoxymethoxyalkynyl ketone 1b under the above optimized
Use of
iodo-aldol products 5h in 74% yield with good diastereoselectivity
(Entry 8). When the reaction of -methoxymethoxyalkynyl methyl
g-methoxymethoxyalkynyl 2-thienyl ketone 1c gave the
g
reaction conditions of -diethoxyalkynyl ketone 1a (Entry 1). The
g
g
desired iodo-aldol product 5a was obtained in 65% yield with
a moderate E-selectivity. To improve both the yield and the dia-
stereoselectivity, several reaction conditions were examined.
When the temperature was lower than ꢁ50 ꢀC with each
1.0 equiv of titanium tetraiodide and benzaldehyde (Entries 2e7),
it was found that the yield and the diastereoselectivity of 5a were
improved. The yield in the case of Entry 6 was slightly reduced to
67%. However, the material balance increased by lowering the
temperature. From the above temperature investigation, the best
conditions were at ꢁ78 ꢀC and for 3.0 h with titanium tetraiodide
ketone 1d was carried out, the iodo-aldol product 5i was obtained
in a low yield with low diastereoselectivity (Entry 9). We found that
the substituents of the alkynyl ketones and aldehydes varied the
yields and selectivity. Regarding the diastereoselectivity, the E-
isomer predominated in all the cases. A detailed examination into
the reaction mechanisms may lead to a better understanding of the
diastereoselectivity.
2.2. Computational analysis
Our proposed mechanism of the iodo-aldol reaction between
g-
Table 3
Optimization of reaction conditionsa
alkoxy- -alkynyl ketone and benzaldehyde is shown in Scheme 3.
a,b
First, 1,4-addition of titanium tetraiodide to the alkynyl ketone
(React.-1) provides the titanium allenolate I-1 via the transition
Table 4
Iodo-aldol reaction of ketone 1b with several aldehydesa
-78 °C
Entry TiI4
2a
Temperature Time Yield
E/Z
Yield
(equiv) (equiv) (ꢀC)
(h)
of 5a (%)b
of 6 (%)b
1c
2c
3
4
5
6
7
8
9
1.3
1.0
1.0
1.0
1.0
1.0
1.0
1.1
1.1
1.2
1.2
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.2
1.2
1.5
ꢁ50
ꢁ50
ꢁ60
ꢁ60
ꢁ70
ꢁ78
ꢁ78
ꢁ78
ꢁ78
ꢁ78
ꢁ78
1.5
1.5
1.5
0.5
1.5
1.5
3.0
3.0
3.0
3.0
3.0
65
66
69
72
75
67
76
75
75
82
78
72:28
73:27
77:23
77:23
78:22
80:20 12
79:21
78:22 13
77:23
5
9
3
2
5
Entry
1
R1
2
R2
5
Yield of 5 (%)b
E/Z
1
2
3
4
5
6
1b
1b
1b
1b
1b
1b
1b
1c
1d
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2-Thienyl
Me
2a
2b
2c
2d
2e
2f
2g
2a
2a
Ph
5a
5b
5c
5d
5e
5f
5g
5h
5i
82
72
56
73
31
33
48
74
32
77:23
72:25
88:12
79:21
56:44
85:15
70:30
75:25
56:44
p-ClC6H4
p-MeOC6H4
p-MeC6H4
1-Naphthyl
2-Thienyl
n-Pentyl
Ph
8
7
8
8c
9c
10
11
77:23 12
75:25 11
Ph
a
a
Reactions were carried out with 0.15 mmol of 1b, several equivalents of TiI4 and
2a, in a solvent (3 mL) under an oxygen atmosphere (1 atm).
Reactions were carried out with 0.15 mmol of 1b, several equivalents of TiI4 and
2a, in a solvent (3 mL) under an oxygen atmosphere (1 atm).
b
b
Isolated yield.
Under an argon atmosphere (1 atm).
Isolated yield.
Under an argon atmosphere (1 atm).
c
c
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4
K. Yashiro et al. / Tetrahedron xxx (2016) 1e11
I
I
I
I
I
I
I
I
I
Ti
TiI3
Ph
work up
(H2O)
Ti
O
R
OH
Ph
Ti
O
R
O
I
O
O
O
O
O
O
Ph
Ph
Ph
Ph
I
Ph
Ph
Ph
Ph
I
R
I
R
I
R
O
I3Ti
Ph
O
O
O
TiI3
E-I-2
E-TS-2
E-I-3
E-I-4
E-Prod.
TiI4
Ald.-1
I
R
R
R
I
I
I
Reac.-1
TS-1
I-1
I
I
I
I
I
I
I
Ti
TiI3
Ph
work up
(H2O)
Ti
O
I
OH
Ph
Ti
O
O
O
R
O
O
O
O
O
Ph
Ph
Ph
Ph
R
Ph
Ph
Ph
Ph
R
I
I
R
I
R
I
Z-I-2
Z-TS-2
Z-I-3
Z-I-4
Z-Prod.
Scheme 3. Full mechanism for the titanium tetraiodine promoted iodo-aldol reaction.
state structure TS-1. Subsequently, the allenolate I-1 undergoes the
intramolecular coordination with the aldehyde to generate a penta-
coordinate titanium aldlate I-2. The CeC bond formation occurs
from the aldlate I-2 through a six-membered transition state E-TS-2
and/or Z-TS-2 to give the aldlate I-3, in which the generation of
a penta-coordinate enolate and a six-membered ring containing
titanium was reported by Patel et al.19,20 Diastereoselectivity of the
resulting vinyl iodide is likely to be determined at the initial CeC
bond formation stage between the allenolate (I-1) and aldehyde
(Ald.-1). Finally the protonation of the intermediate I-4 affords the
product E/Z-Prod.
alkoxy-a,b-alkynyl ketone and aldehyde with the titanium tet-
raiodide, we calculated the transition state of the reaction for both
substrates 1a and 1b using the Gaussian 09 program.21,22 Structures
were fully optimized followed by frequency calculation on the
stationary point performed with 6-31G(d) basis set for all atoms
except for the iodine, which was employed the B3LYP density
functional theory23 in combination with
a pseudo-potential
LANL2DZ basis set.24,25 In order to confirm the transition state
structures, the intrinsic reaction coordinate (IRC) calculations were
carried out at the same level of theory.
The results of the optimized structures of TS-2 and the relative
energy diagrams in each stage are shown in Figs. 1 and 2. As for the
To clarify the exact reaction mechanism and an origin of the
selectivity of the products of the iodo-aldol reaction between
g-
distance between the aldehyde carbon and the a-carbon of the
substrates, Z-TS-2 had a shorter distance than that of E-TS-2 (TS-2a:
E/Z¼2.29 vs 2.20, TS-2b: E/Z¼2.30 vs 2.26) (Fig. 1). This result in-
dicates that a tighter Z-TS-2 is more stable than the E-TS-2.26 Fur-
thermore, in terms of the relative energy analysis for each step TS-2
or I-3 in a diastereoselective manner, the reaction of the Z-isomer is
kinetically more favored than that of the E-isomer, while regarding
the reaction intermediate I-4, the E-isomer is more stable (Fig. 2).
As comparison of the reaction diagram of 1b with 1a, the activation
energy of the transition state TS-2 is lower than that of 1a. Energy
differences between E- and Z-isomers at each state I-3 or I-4 is
larger in the case of 1a. Since the present iodo-aldol reaction using
TiI4 appears to proceed under the equilibrium conditions, a retro-
aldol reaction may be involved. The small energy difference be-
tween the intermediates I-3 and I-4 in the case of 1b may promote
a retro-aldol reaction to lead a decrease in diastereoselectivity.
From these results, we suggest that when the substrate 1a is used
for the reaction, the reactivity would decrease with a better dia-
stereoselectivity, while when the substrate 1b is used, the reactivity
would increase with a decreased diastereoselectivity. These pre-
dictions support the experimental results.
2.3. The iodo-Mannich reactions
We next examined the iodo-Mannich reaction of
g
-alkoxy-a,b-
alkynyl ketones with imino ester instead of aldehydes.
g
-Dieth-
oxyalkynyl ketone 1a was treated with the p-methoxyphenyl
imino ester 7 (1.2 equiv) in the presence of titanium tetraiodide
(1.2 equiv) at ꢁ40 ꢀC for 1.5 h (Scheme 4). The reaction gave the
iodo-Mannich product E-8 as a single E-diastereomer in 41% yield.
We next examined iodo-Mannich reaction of
g-methox-
Fig. 1. Optimized geometries of diastereomeric transition state structure TS-2s for the
concerted titanium enolate to benzaldehyde. The distances are shown in A. The in-
dicated color refer to Gray-Carbon, Red-Oxygen, White-Titanium, Purple-Iodine (Hy-
drogen is not shown).
ymethoxyalkynyl ketone 1b instead of -diethoxyalkynyl ketone
g
ꢀ
1a. The reaction was carried out with 1.2 equiv of alkynyl ketone
and TiI4 at ꢁ50 ꢀC for 1.5 h (Scheme 4). Compared with
g-
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K. Yashiro et al. / Tetrahedron xxx (2016) 1e11
5
Fig. 2. The relative energy diagram of the iodo-aldol reaction intermediates at 223.15 K, 1.0 atm. The left figure shows the use of
g
-diethoxyphenyl ketone and the right figure shows
the use of g-methoxymethoxyphenyl ketone.
diethoxyalkynyl ketone 1a, the use of
ketone 1b gave the desired product 9 in good yield. As in the
cases with iodo-aldol reaction, it was found that the -alkoxy
group of alkynyl ketone showed a significant influence on the
yield and the diastereoselectivity. The use of -diethoxyalkynyl
ketone 1a gave a high diastereoselectivity and moderate yield. In
contrast, the use of the -methoxymethoxy alkynyl ketone 1b
g-methoxymethoxyalkynyl
PdCl2(PPh3)2 (5.0 mol%)
CuI (0.2 equiv)
phenylactetylene (2.0 equiv)
O
OH
Ph
O
OH
Ph
g
Ph
Ph
EtO
EtO
DMF/Et3N (1:1), 90 oC, 20 h
I
g
OEt
OEt
Ph
E-3a
10
73%
g
gave the products (E- and Z-9) in satisfactory yields with a mod-
erate diastereoselectivity.
O
O
O
Ph
Ph
PdCl2(CH3CN)2 (20 mol%)
THF, reflux, 2 h
Ph
Ph
H
+
O
O
EtO
PMP
N
Ph
Ph
OEt
11
18%
PMP
PMP
CO2Et
O
O
HN
I
O
I
HN
12
7
TiI4 (1.2 equiv) (1.2 equiv)
Ph
Ph
CO2Et Ph
+
CO2Et
OEt
36%
OEt
OEt
CH2Cl2, -40 oC, 1.5 h
EtO
OEt
E-8
OEt
Z-8
1a
PdCl2(PPh3)2 (5.0 mol%)
CuI (0.2 equiv)
phenylactetylene (2.0 equiv)
O
O
OH
Ph
Ph
O
41%, E/Z = 100:0
Ph
Ph
PMP
N
PMP
O
HN
PMP
DMF/Et3N (1:1), 90 oC, 6 d
I
O
HN
CO2Et
O
7
TiI4 (1.2 equiv)
Ph
MOMO
E-5a
MOMO
Ph
CO2Et Ph
CO2Et
+
Ph
CH2Cl2, -50 oC, 1.5 h
OMOM
13
49%
I
I
MOMO
OMOM
Z-9
80%, E/Z = 65:35
(1.2 equiv)
1b
E-9
Scheme 5. Synthesis of tetra-substituted furans derived from iodo-aldol adducts.
DMF¼N,N-dimethylformamide.
Scheme 4. The examination of the iodo-Mannich reaction under the previous iodo-
aldol reaction conditions. PMP¼p-methoxyphenyl.
3. Conclusion
In conclusion, we have developed the diastereoselective iodo-
aldol and iodo-Mannich reactions promoted by titanium tetraio-
dide. These reactions are attractive synthetic methods for producing
multi-functionalized alkenes. One of the notable features of iodo-
aldol reaction is a high diastereoselectivity by using suitable alkynyl
ketones and reaction conditions. Furthermore, the iodo-aldol prod-
ucts can be transformed into tetra-substituted furans by palladium-
catalyzed Sonogashira coupling and subsequent cyclization.
The computational analysis was also carried out to find factors
to control the diastereoselectivity of iodo-aldol reactions. From the
results of the relative energy analysis and energy differences be-
tween E- and Z-isomers, we found that the substrate 1a had a de-
creased reactivity with a better diastereoselectivity, while the
substrate 1b had increased reactivity with a decreased diaster-
eoselectivity, which supported the experimental results.
2.4. Cyclization of the iodo-aldol product
We next examined the transformation of the iodo-aldol product
into tetra-substituted furans via the enynol intermediate. Initially,
we tried the Sonogashira coupling of the iodo-aldol product E-3a
with phenylacetylene in the presence of PdCl2 (PPh3)2 and CuI to
give the enynol 10 in 73% yield.27 The cyclization reaction of the
enynol 10 with PdCl2 (CH3CN)2 in THF at reflux afforded the furans
11 and 12 in 18% and 36% yields, respectively (Scheme 5).28 Under
similar enynol synthesis conditions for E-3a, we carried out a one-
pot synthesis of the iodo-aldol product E-5a. Although it took a long
reaction time, the transformation of the iodo product E-5a directly
afforded the furan 13 in 49% yield.
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6
K. Yashiro et al. / Tetrahedron xxx (2016) 1e11
We also examined multi-functional iodo-Mannich reaction. The
(10 mL) were added to quench the reaction. The phases were
separated and the aqueous phase was extracted with diethyl ether
(10 mL). The combined organic extracts were dried over Na2SO4
and filtered. The solvents were evaporated in vacuo and then the
residue was purified by column chromatography on silica gel (n-
hexane/EtOAc¼4/1 as an eluent) to give 4-(methoxymethoxy)-1-
(thiophen-2-yl)but-2-yn-1-ol (0.726 g, 86%); Yellow oil; 1H NMR
results demonstrate for the first time, that diastereoselective iodo-
Mannich reaction of an internal alkyne using titanium tetraiodide
gives multi-functionalized vinyl iodides with nitrogen functional
groups. Iodo-Mannich reaction appears to have a high potential
with a good diastereoselectivity.
4. Experimental section
(400 MHz, CDCl3)
2H), 4.69 (s, 2H), 5.64e5.68 (m, 1H), 6.93e6.96 (m, 1H), 7.12e7.14
(m, 1H), 7.25e7.27 (m, 1H); 13C NMR (100 MHz, CDCl3)
54.2, 55.4,
59.8, 81.2, 85.5, 94.5,125.3,125.8,126.6,144.3; IR (neat): 3397, 3104,
2948, 2891, 1442, 1360, 1269, 1210, 1148, 1101, 1045, 989, 923, 857,
754, 710 cmꢁ1; HRMS (EI) calcd for C10H12O3S (M)þ 212.0507, found
212.0517.
d
3.16e3.25 (m,1H), 3.35 (s, 3H), 4.28 (d, J¼1.8 Hz,
Infrared spectra were recorded on a JASCO FT/IR-460 Plus
spectrometer. 1H NMR spectra were recorded on a JEOL ECX-400
spectrometer (400 MHz) or a JEOL JNM a-500 spectrometer
(500 MHz) with tetramethylsilane as an internal standard. 13C NMR
spectra were recorded on a JEOL ECX-400 spectrometer (100 MHz)
or a JEOL JNM a-500 spectrometer (126 MHz). Chemical sifts are
reported in d units, parts per million from the central peak of CDCl3
(d 77.0) as an internal reference. High resolution mass spectra (EI or
ESI) were recorded on a JEOL JMS-700D mass spectrometer or
a Thermo Orbitrap Velos ETD Ultimate 3000 system. Propionitrile
(EtCN) was distilled from phosphorus pentaoxide and then from
d
4.1.3. 4-(Methoxymethoxy)-1-(thiophen-2-yl)but-2-yn-1-one
(1c).18a To a suspension of MnO2 (2.97 g, 34.2 mmol) in CH2Cl2 (7.
0 mL) was added a solution of 4-(methoxymethoxy)-1-(thiophen-
2-yl)but-2-yn-1-ol (0.726 g, 3.42 mmol) in CH2Cl2 (3.0 mL) at 0 ꢀC.
The mixture was stirred for 1 h and warmed to room temperature.
After stirring at room temperature for 1 h, the reaction mixture was
filtered through a Celite pad. The solvents were removed in vacuo
and then the residue was purified by column chromatography on
silica gel (n-hexane/EtOAc¼4/1 as an eluent) to give 4-(methox-
ymethoxy)-1-(thiophen-2-yl)but-2-yn-1-one (1c) (0.672 g, 93%);
ꢀ
calcium hydride, and stored over molecular sieves 4 A. Toluene was
pre-dried with CaCl2, distilled, and stored over molecular sieves
ꢀ
4 A. Tetrahydrofuran (THF) was distilled from benzophenone ketyl
immediately before use. Dichloromethane (CH2Cl2) was pre-dried
with P2O5, distilled from CaH2, and stored over molecular sieves
4 A. Purification of products was performed by column chroma-
Yellow oil; 1H NMR (400 MHz, CDCl3)
4.73 (s, 2H), 7.11e7.16 (m, 1H), 7.68e7.71 (m, 1H), 7.87e7.91 (m, 1H);
13C NMR (100 MHz, CDCl3)
53.9, 55.6, 83.1, 88.2, 95.1, 128.3, 135.4,
d 3.38 (s, 3H), 4.44 (s, 2H),
ꢀ
tography on silica gel (Kanto Chemical Co. Inc., Silica Gel 60 N
(spherical, neutral)) and/or preparative TLC on silica gel (Merck
Kiesel Gel GF254). All reactions were carried out under an argon or
an oxygen atmosphere.
d
144.2, 169.0; IR (neat) 3100, 2950, 2229, 1625, 1516, 1411, 1359,
1280, 1231, 1208, 1152, 1105, 1047, 988, 922, 837, 729 cmꢁ1; HRMS
(EI) calcd for C10H10O3S (M)þ 210.0351, found 210.0353.
4.1. Synthesis of alkynyl ketone
4.1.4. 5-(Methoxymethoxy)pent-3-yn-2-one (1d).18a To a solution of
3-(methoxymethoxy)prop-1-yne (0.501 g, 5.00 mmol) in THF
(7.0 mL) was added nBuLi (3.05 mL, 1.64 M in n-hexane, 5.00 mmol)
at ꢁ78 ꢀC under argon. After stirring for 30 min, acetaldehyde
(0.315 g, 7.15 mmol) was added to the solution and the mixture was
stirred at ꢁ78 ꢀC for 62 h. Saturated aqueous NH4Cl (10 mL), ice, and
diethyl ether (10 mL) were added to quench the reaction. The
phases were separated and the aqueous phase was extracted with
diethyl ether (10 mL). The combined organic extracts were dried
over Na2SO4 and filtered. The solvents were removed in vacuo to
give the crude 5-(methoxymethoxy)pent-3-yn-2-ol (0.650 g); To
a suspension of MnO2 (3.97 g, 45.7 mmol) in CH2Cl2 (7.0 mL) was
added a solution of the crude 5-(methoxymethoxy)pent-3-yn-2-ol
(0.650 g) in CH2Cl2 (3.0 mL) at 0 ꢀC. The mixture was stirred at 0 ꢀC
for 10 h and warmed up to room temperature. After stirring at room
temperature for 30 min, the reaction mixture was filtered through
a Celite pad. The solvents were removed in vacuo and then the
residue was purified by column chromatography on silica gel (n-
hexane/EtOAc¼4/1 as an eluent) to give 5-(methoxymethoxy)pent-
3-yn-2-one (0.400 g, 56%); Colorless oil; 1H NMR (400 MHz, CDCl3)
g
-Alkoxy-a,b-alkynyl ketone 1a was prepared according to the
literature method.29
4.1.1. 4-(Methoxymethoxy)-1-phenylbut-2-yn-1-one
(1b).18a To
a
solution of 4-hydroxy-1-phenylbut-2-yn-1-one30 (0.845 g,
5.27 mmol) in CH2Cl2 (30.0 mL) was added N-ethyldiisopropyl-
amine (2.04 g, 15.8 mmol) at room temperature under an argon
atmosphere. The mixture was cooled to ꢁ15 ꢀC. Chlor-
omethylmethylether (0.64 g, 7.91 mmol) was added to the mixture.
The reaction mixture was gradually warmed to room temperature
during 18 h. Water (30 mL) was added to quench the reaction. The
layers were separated, and the aqueous layer was extracted with
CH2Cl2. The combined organic layers were washed with 1.5 M HCl
(20 mL), saturated aqueous NaHCO3 (20 mL), water (20 mL), brine
(20 mL), and dried over Na2SO4. The solvents were evaporated in
vacuo and then the residue was purified by chromatography on
silica gel (n-hexane/EtOAc¼4/1 as an eluent) to give 4-(methox-
ymethoxy)-1-phenylbut-2-yn-1-one (0.23 g, 21%); Red oil; 1H NMR
(400 MHz, CDCl3)
(m, 2H), 7.60e7.65 (m, 1H), 8.13e8.16 (m, 2H); 13C NMR (100 MHz,
CDCl3) 54.2, 55.8, 83.7, 89.8, 95.3, 128.6, 129.6, 134.3, 136.3, 177.4;
d 3.43 (s, 3H), 4.51 (s, 2H), 4.79 (s, 2H), 7.48e7.51
d
2.32 (s, 3H), 3.36 (s, 3H), 4.33 (s, 2H), 4.67 (s, 2H); 13C NMR
(100 MHz, CDCl3) 32.3, 53.7, 55.5, 85.1, 87.0, 95.0, 183.7; IR (neat)
d
d
IR (neat): 2948, 2230, 1652, 1599, 1451, 1312, 1264, 1149, 1106, 1047,
921, 699 cmꢁ1; HRMS (EI) calcd for C12H12O3 (M)þ 204.0786, found
204.0783.
2951, 2891, 2212, 1679, 1423, 1359, 1227, 1151, 1106, 1049, 964,
923 cmꢁ1; HRMS (EI) calcd for C7H10O3 (M)þ 142.0630, found
142.0631.
4.1.2. 4-(Methoxymethoxy)-1-(thiophen-2-yl)but-2-yn-1-ol.18a To
a solution of 3-(methoxymethoxy)prop-1-yne (0.401 g, 4.01 mmol)
in THF (7.0 mL) was added nBuLi (2.44 mL, 1.64 M in n-hexane,
4.00 mmol) at ꢁ78 ꢀC under an argon atmosphere. After stirring for
30 min, thiophene-2-carbaldehyde (0.448 g, 3.99 mmol) was added
to the solution and the mixture was stirred at ꢁ78 ꢀC for 30 min.
The reaction mixture was warmed to room temperature and stirred
for 30 min. Saturated aqueous NH4Cl (10 mL), ice, and diethyl ether
4.2. The iodo-aldol reaction
To a suspension of TiI4 (0.195 mmol) in CH2Cl2 (1.0 mL) was
added a mixture of g-diethoxyalkynyl ketone 1a (0.15 mmol) and
aldehyde 2 (0.15 mmol) in CH2Cl2 (2.0 mL) at ꢁ50 ꢀC under an argon
atmosphere. The mixture was stirred at ꢁ50 ꢀC for 2 h. The reaction
mixture was quenched with saturated aqueous NaHCO3, and EtOAc
and saturated aqueous NaHSO3 were added successively. The
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K. Yashiro et al. / Tetrahedron xxx (2016) 1e11
7
mixture was filtered through a Celite pad, and extracted with
EtOAc. The combined organic extracts were dried over Na2SO4 and
concentrated in vacuo. The residue was purified by preparative
silica gel TLC (n-hexane/EtOAc¼4/1 as an eluent, developed four
times) to give the iodo-aldol product 3 and the iodoalkenone 4.
(d, J¼5.5 Hz, 1H), 3.07e3.14 (m, 1H), 3.18e3.26 (m, 1H), 3.33e3.44
(m, 2H), 4.12 (s, 1H), 5.96 (d, J¼6.2 Hz, 1H), 7.04e7.05 (m, 2H),
7.33e7.38 (m, 4H), 7.48e7.53 (m, 1H), 7.75e7.77 (m, 2H); 13C NMR
(100 MHz, CDCl3)
d 14.6, 21.1, 62.3, 80.6, 100.4, 111.3, 126.4, 128.3,
129.0, 129.7, 133.7, 136.4, 137.2, 137.7, 148.4, 195.9; IR (neat) 3450,
2978, 2920, 1654, 1514, 1447, 1406, 1351, 1244, 1163, 1056, 951, 811,
745, 687 cmꢁ1; HRMS (EI) calcd for C22H25IO4 (M)þ 480.0798, found
480.0795.
4.2.1. (E)-4,4-Diethoxy-2-[hydroxy(phenyl)methyl]-3-iodo-1-
phenylbut-2-en-1-one (E-3a).18a White semisolid; 1H NMR
(400 MHz, CDCl3)
d
0.99 (t, J¼7.1 Hz, 3H), 1.04 (t, J¼7.1 Hz, 3H),
3.06e3.14 (m, 2H), 3.20e3.28 (m, 1H), 3.33e3.46 (m, 2H), 4.13 (s,
1H), 6.03 (d, J¼5.7 Hz, 1H), 7.12e7.25 (m, 3H), 7.31e7.35 (m, 2H),
7.46e7.51 (m, 3H), 7.71e7.73 (m, 2H); 13C NMR (126 MHz, CDCl3)
4.2.7. (Z)-4,4-Diethoxy-2-[hydroxy(p-tolyl)methyl]-3-iodo-1-ph-
enylbut-2-en-1-one (Z-3d).18a Yellow oil; 1H NMR (400 MHz, CDCl3)
d
1.24 (t, J¼7.1 Hz, 3H), 1.29 (t, J¼7.1 Hz, 3H), 2.26 (s, 3H), 3.23 (d,
d
14.6, 14.6, 62.4, 62.4, 80.7, 100.5, 111.7, 126.3, 128.0, 128.3, 128.3,
J¼5.5 Hz, 1H), 3.49e3.70 (m, 4H), 4.91 (s, 1H), 6.02 (d, J¼6.2 Hz, 1H),
7.04e7.06 (m, 2H), 7.29e7.31 (m, 2H), 7.36e7.40 (m, 2H), 7.50e7.54
129.7, 133.8, 136.2, 140.1, 148.1, 195.9; IR (neat) 3466, 2975, 2880,
1653, 1493, 1449, 1407, 1374, 1349, 1243, 1058, 951, 848, 760,
703 cmꢁ1; HRMS (EI) calcd for C21H23IO4 (M)þ 466.0641, found
466.0653.
(m, 1H), 7.82e7.85 (m, 2H); 13C NMR (100 MHz, CDCl3)
d 15.1, 15.1,
21.1, 62.8, 73.3, 99.2, 106.4, 126.5, 128.6, 129.1, 129.9, 133.5, 134.2,
137.3,137.8,151.2,197.1; IR (neat) 3449, 2976,1665,1511,1449,1255,
1146, 1105, 1061, 807 cmꢁ1; HRMS (EI) calcd for C22H25IO4 (M)þ
480.0798, found 480.0821.
4.2.2. (Z)-4,4-Diethoxy-2-[hydroxy(phenyl)methyl]-3-iodo-1-
phenylbut-2-en-1-one (Z-3a).18a Orange oil; 1H NMR (400 MHz,
CDCl3)
d
1.26 (t, J¼7.1 Hz, 3H), 1.29 (t, J¼7.1 Hz, 3H), 3.39 (br s, 1H),
4.2.8. (E)-4,4-Diethoxy-2-[hydroxy(naphthalen-1-yl)methyl]-3-iodo-
3.52e3.63 (m, 2H), 3.64e3.73 (m, 2H), 4.95 (s, 1H), 6.07 (d,
J¼5.3 Hz, 1H), 7.16e7.24 (m, 3H), 7.33e7.43 (m, 4H), 7.49e7.53 (m,
1-phenylbut-2-en-1-one (E-3e).18a Orange semisolid; 1H NMR
(400 MHz, CDCl3)
d
1.01 (t, J¼7.3 Hz, 3H), 1.02 (t, J¼7.3 Hz, 3H),
1H), 7.80e7.82 (m, 2H); 13C NMR (126 MHz, CDCl3)
d
15.1, 62.8, 62.8,
3.09e3.30 (m, 3H), 3.37e3.48 (m, 2H), 4.25 (s,1H), 6.59 (d, J¼7.3 Hz,
73.2, 99.6, 106.6, 126.5, 128.0, 128.4, 128.6, 129.9, 133.6, 134.1, 140.2,
151.0, 197.1; IR (neat) 3424, 2924, 1665, 1595, 1449, 1257, 1145, 1059,
769, 697 cmꢁ1; HRMS (EI) calcd for C21H23IO4 (M)þ 466.0641, found
466.0660.
1H), 7.10e7.18 (m, 2H), 7.27e7.77 (m, 9H), 8.16e8.18 (m, 1H); 13C
NMR (126 MHz, CDCl3)
d 14.6, 14.6, 62.3, 62.3, 78.2, 100.6, 112.4,
123.6, 124.5, 125.2, 125.6, 126.4, 127.9, 128.1, 128.6, 128.8, 129.1,
130.9, 133.4, 133.5, 135.3, 148.6, 196.0; IR (neat) 3497, 3060, 3012,
2979, 2929, 2882, 1668, 1596, 1512, 1449, 1396, 1371, 1345, 1317,
1260,1236,1216,1179,1155,1109,1062, 759 cmꢁ1; HRMS (ESI) calcd
for C25H26IO4 (MþH)þ 517.0876, found 517.0864.
4.2.3. (Z)-4,4-Diethoxy-3-iodo-1-phenylbut-2-en-1-one
(4).18a Yellow oil; 1H NMR (500 MHz, CDCl3)
d
1.30 (t, J¼7.1 Hz, 6H),
3.62 (dq, J¼7.1, 9.4 Hz, 2H), 3.70 (dq, J¼7.1, 9.4 Hz, 2H), 4.97 (d,
J¼1.2 Hz, 1H), 7.48e7.51 (m, 2H), 7.58e7.62 (m, 1H), 7.76 (d,
4.2.9. (E)-4,4-Diethoxy-2-[hydroxy(thiophen-2-yl)methyl]-3-iodo-1-
J¼1.2 Hz, 1H), 7.95e7.97 (m, 2H); 13C NMR (100 MHz, CDCl3)
d
15.1,
phenylbut-2-en-1-one (E-3f).18a Yellow semisolid; 1H NMR
62.0, 104.1, 112.8, 128.7, 128.8, 132.6, 133.6, 136.2, 191.4; IR (neat)
3422, 2975, 2882, 1668, 1598, 1448, 1314, 1263, 1222, 1177, 1121,
(500 MHz, CDCl3)
d
1.01 (t, J¼7.3 Hz, 3H) 1.03 (t, J¼7.3 Hz, 3H),
3.19e3.24 (m, 3H), 3.36e3.43 (m, 2H), 4.16 (s, 1H), 6.18 (d, J¼4.3 Hz,
1H), 6.89e6.91 (m, 1H), 7.17e7.19 (m, 2H), 7.38e7.41 (m, 2H),
7.52e7.55 (m, 1H), 7.82e7.84 (m, 2H); 13C NMR (126 MHz, CDCl3)
1061, 1023, 855, 769, 694 cmꢁ1
;
HRMS (EI) calcd for
C
14H17IO3eC2H5 (M)þ 330.9831, found 330.9845.
d
14.6, 62.4, 62.4, 77.7, 100.4, 111.6, 125.3, 125.5, 126.7, 128.4, 129.7,
4.2.4. (E)-2-[(4-Chlorophenyl)(hydroxy)methyl]-4,4-diethoxy-3-
133.8, 136.4, 143.6, 147.7, 198.4; IR (neat) 3467, 3011, 2978, 2928,
2883, 1668, 1616, 1596, 1582, 1449, 1372, 1347, 1316, 1266, 1240,
1158, 1105, 1061, 756 cmꢁ1; HRMS (ESI) calcd for C19H22IO4S
(MþH)þ 473.0284, found 473.0267.
iodo-1-phenylbut-2-en-1-one (E-3b).18a Yellow semisolid; 1H NMR
(400 MHz, CDCl3)
d
1.00 (t, J¼7.1 Hz, 3H), 1.03 (t, J¼7.1 Hz, 3H),
3.06e3.14 (m, 2H), 3.19e3.26 (m, 1H), 3.33e3.45 (m, 2H), 4.14 (s,
1H), 5.99 (d, J¼5.5 Hz, 1H), 7.18e7.22 (m, 2H), 7.34e7.43 (m, 4H),
7.50e7.55 (m, 1H), 7.72e7.74 (m, 2H); 13C NMR (100 MHz, CDCl3)
4.2.10. (E)-4,4-Diethoxy-3-iodo-1-phenyl-2-(2,2,2-trichloro-1-
d
14.6, 62.4, 80.1, 100.5, 112.1, 127.8, 128.4, 128.5, 129.6, 133.8, 134.0,
hydroxyethyl)but-2-en-1-one (E-3g).18a Yellow oil; 1H NMR
136.1, 138.6, 147.6, 195.6; IR (neat) 3440, 2979, 2925, 1650, 1594,
1492, 1448, 1405, 1350, 1249, 1056, 858, 814, 736, 687 cmꢁ1; HRMS
(EI) calcd for C21H22ClIO4 (M)þ 500.0251, found 500.0232.
(400 MHz, CDCl3)
d
0.90 (t, J¼6.9 Hz, 3H), 1.0 (t, J¼6.9 Hz, 3H),
2.77e2.83 (m, 1H), 3.16e3.30 (m, 2H), 3.47e3.54 (m, 1H), 3.96 (S,
1H), 5.51 (d, J¼8.2 Hz, 1H), 5.64 (d, J¼8.2 Hz, 1H), 7.50e7.54 (m, 2H),
7.65e7.69 (m, 1H), 8.04e8.06 (m, 2H); 13C NMR (126 MHz, CDCl3)
4.2.5. (E)-4,4-Diethoxy-2-[hydroxy(4-methoxyphenyl)methyl]-3-
d 14.6, 14.7, 62.4, 63.1, 92.8, 100.0, 101.3, 126.6, 128.8, 130.0, 134.8,
iodo-1-phenylbut-2-en-1-one (E-3c).18a Orange oil; 1H NMR
136.3, 139.5, 196.9; IR (neat) 3434, 3019, 2929, 1641, 1595, 1450,
1415, 1321, 1285, 1257, 1215, 1156, 1110, 1062, 931, 843, 824,
757 cmꢁ1; HRMS (EI) calcd for C16H18Cl3IO4eI (M)þ 379.0271, found
379.0255.
(400 MHz, CDCl3)
d
1.00 (t, J¼7.1 Hz, 3H), 1.02 (t, J¼7.1 Hz, 3H), 2.91
(br s, 1H), 3.07e3.15 (m, 1H), 3.18e3.26 (m, 1H), 3.33e3.44 (m, 2H),
3.74 (s, 3H), 4.12 (s, 1H), 5.93 (d, J¼3.5 Hz, 1H), 6.75e6.78 (m, 2H),
7.34e7.42 (m, 4H), 7.49e7.53 (m, 1H), 7.76e7.78 (m, 2H); 13C NMR
(100 MHz, CDCl3)
d
14.6, 55.2, 62.3, 80.3, 100.4, 111.0, 113.7, 127.9,
4.2.11. (E)-2-(2,2-Diethoxy-1-iodoethylidene)-3-hydroxy-1-
128.3, 129.7, 132.4, 133.7, 136.3, 148.5, 159.3, 195.9; IR (neat) 3475,
2977, 1668, 1610, 1510, 1449, 1249, 1175, 1061, 821, 755 cmꢁ1; HRMS
(EI) calcd for C22H25IO5 (M)þ 496.0747, found 496.0739.
phenyloctan-1-one (E-3h).18a Yellow oil; 1H NMR (400 MHz, CDCl3)
d
0.90 (t, J¼6.9 Hz, 3H), 1.01 (t, J¼7.3 Hz, 3H), 1.04 (t, J¼7.3 Hz, 3H),
1.23e1.81 (m, 8H), 2.15 (d, J¼5.0 Hz, 1H), 3.16e3.26 (m, 2H),
3.36e3.45 (m, 2H), 4.16 (s, 1H), 4.71e4.75 (m, 1H), 7.46e7.50 (m,
2H), 7.57e7.61 (m, 1H), 7.96e7.98 (m, 2H); 13C NMR (100 MHz,
4.2.6. (E)-4,4-Diethoxy-2-[hydroxy(p-tolyl)methyl]-3-iodo-1-ph-
enylbut-2-en-1-one (E-3d).18a White semisolid; 1H NMR (400 MHz,
CDCl3)
d 14.0,14.6,14.6, 22.5, 25.5, 31.3, 35.5, 62.3, 79.2,100.4,108.3,
CDCl3)
d
0.99 (t, J¼7.1 Hz, 3H), 1.0 (t, J¼7.1 Hz, 3H), 2.26 (s, 3H), 2.90
128.6, 129.7, 133.9, 136.5, 149.9, 195.8; IR (neat) 3504, 2954, 2930,
Please cite this article in press as: Yashiro, K.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.09.020

8
K. Yashiro et al. / Tetrahedron xxx (2016) 1e11
2867, 1667, 1615, 1595, 1448, 1374, 1315, 1249, 1167, 1115, 1062, 955,
756 cmꢁ1; HRMS (ESI) calcd for C20H30IO4 (MþH)þ 461.1189, found
461.1146.
1025, 864, 822, 745 cmꢁ1; HRMS (EI) calcd for C20H21IO5 (M)þ
468.0434, found 468.0438.
4.2.18. (Z)-2-[Hydroxy(4-methoxyphenyl)methyl]-3-iodo-4-(me-
4.2.12. (E)-2-[Hydroxy(phenyl)methyl]-3-iodo-4-(methox-
thoxymethoxy)-1-phenylbut-2-en-1-one (Z-5c).18a Yellow semi-
ymethoxy)-1-phenylbut-2-en-1-one (E-5a).18a Orange oil; 1H NMR
solid; 1H NMR (400 MHz, CDCl3)
d 3.29 (br s, 1H), 3.48 (s, 3H), 3.74
(400 MHz, CDCl3)
d
3.08 (s, 3H), 3.23 (br s, 1H), 4.05 (d, J¼12.8 Hz,
(s, 3H), 4.55 (d, J¼12.8 Hz, 1H), 4.59 (d, J¼12.8 Hz, 1H), 4.75 (d,
J¼6.9 Hz, 1H), 4.78 (d, J¼6.9 Hz, 1H), 5.93 (d, J¼5.7 Hz, 1H),
6.76e6.79 (m, 2H), 7.28e7.31 (m, 2H), 7.36e7.40 (m, 2H), 7.50e7.54
1H), 4.10 (d, J¼12.8 Hz, 1H), 4.35 (d, J¼6.8 Hz, 1H), 4.37 (d, J¼6.8 Hz,
1H), 5.95 (s, 1H), 7.15e7.25 (m, 3H), 7.30e7.34 (m, 2H), 7.44e7.49
(m, 3H), 7.66e7.69 (m, 2H); 13C NMR (100 MHz, CDCl3)
d
55.6, 72.7,
(m, 1H), 7.80e7.82 (m, 2H); 13C NMR (100 MHz, CDCl3)
d 55.3, 56.2,
81.2, 95.8, 106.5, 126.2, 128.0, 128.3, 128.4, 129.4, 133.7, 136.3, 140.1,
147.4, 195.5; IR (neat) 3446, 3016, 2930, 1668, 1449, 1253, 1150,
1051, 939, 757, 698 cmꢁ1; HRMS (EI) calcd for C19H19IO4 (M)þ
438.0328, found 438.0348.
70.3, 72.8, 95.4, 100.6, 113.9, 127.7, 128.5, 129.9, 132.3, 133.6, 151.6,
159.3, 197.3; IR (neat) 3520, 2938, 2842, 1662, 1606, 1513, 1444,
1256, 1179, 1143, 1032, 942, 815, 724, 684 cmꢁ1; HRMS (EI) calcd for
C
20H21IO5eI (M)þ 341.1389, found 341.1392.
4.2.13. (Z)-2-[Hydroxy(phenyl)methyl]-3-iodo-4-(methox-
4.2.19. (E)-2-[Hydroxy(p-tolyl)methyl]-3-iodo-4-(methoxymethoxy)-
ymethoxy)-1-phenylbut-2-en-1-one (Z-5a).18a Orange semisolid; 1H
1-phenylbut-2-en-1-one (E-5d).18a White semisolid; 1H NMR
NMR (400 MHz, CDCl3)
d
3.47 (s, 3H), 3.49 (br s, 1H), 4.60 (s, 2H),
(400 MHz, CDCl3)
d
2.26 (s, 3H), 3.06 (d, J¼6.2 Hz, 1H), 3.08 (s, 3H),
4.74 (d, J¼6.9 Hz, 1H), 4.77 (d, J¼6.9 Hz, 1H), 5.96 (s, 1H), 7.10e7.25
4.05 (d, J¼13.1 Hz,1H), 4.09 (d, J¼13.1 Hz,1H), 4.36 (d, J¼6.7 Hz,1H),
4.38 (d, J¼6.7 Hz, 1H), 5.89 (d, J¼6.2 Hz, 1H), 7.04e7.06 (m, 2H),
7.33e7.37 (m, 4H), 7.48e7.52 (m, 1H), 7.71e7.74 (m, 2H); 13C NMR
(m, 3H), 7.32e7.37 (m, 4H), 7.47e7.51 (m, 1H), 7.76e7.78 (m, 2H);
13C NMR (100 MHz, CDCl3)
d 56.2, 70.4, 72.9, 95.4,101.1,126.3,128.0,
128.5, 129.9, 133.6, 134.1, 140.1, 151.3, 197.2; IR (neat) 3521, 3058,
2933, 1660, 1587, 1449, 1387, 1272, 1033, 805, 761, 691 cmꢁ1; HRMS
(EI) calcd for C19H19IO4 (M)þ 438.0328, found 438.0324.
(100 MHz, CDCl3) d 21.1, 55.5, 72.7, 81.1, 95.8, 106.2, 126.3, 128.4,
129.0, 129.5, 133.7, 136.4, 137.2, 137.8, 147.6, 195.5; IR (neat) 3483,
2932, 1659, 1513, 1448, 1402, 1317, 1242, 1063, 928, 802, 760,
692 cmꢁ1; HRMS (EI) calcd for C20H21IO4eI (M)þ 325.1440, found
325.1429.
4.2.14. (Z)-3-Iodo-4-(methoxymethoxy)-1-phenylbut-2-en-1-one
(6).18a Yellow oil; 1H NMR (400 MHz, CDCl3)
d
3.43 (s, 3H), 4.40 (s,
2H), 4.75 (s, 2H), 7.46e7.50 (m, 2H), 7.56e7.60 (m, 1H), 7.66e7.67
(m, 1H), 7.95e7.97 (m, 2H); 13C NMR (100 MHz, CDCl3)
55.8, 76.2,
4.2.20. (Z)-2-[Hydroxy(p-tolyl)methyl]-3-iodo-4-(methox-
d
ymethoxy)-1-phenylbut-2-en-1-one (Z-5d).18a White semisolid; 1H
95.8, 112.0, 128.4, 128.6, 128.7, 133.4, 136.7, 190.3; IR (neat) 3060,
2991, 2935, 2842, 1670, 1597, 1448, 1260, 1220, 1150, 1111, 1045, 921,
863, 757, 702 cmꢁ1; HRMS (EI) calcd for C12H13IO3 (M)þ 331.9909,
found 331.9896.
NMR (400 MHz, CDCl3)
d
2.26 (s, 3H), 3.31 (d, J¼5.7 Hz, 1H), 3.48 (s,
3H), 4.55 (d, J¼13.1 Hz,1H), 4.59 (d, J¼13.1 Hz,1H), 4.74 (d, J¼6.8 Hz,
1H), 4.78 (d, J¼6.8 Hz, 1H), 5.93 (d, J¼5.7 Hz, 1H), 7.04e7.06 (m, 2H),
7.24e7.26 (m, 2H), 7.35e7.39 (m, 2H), 7.50e7.54 (m, 1H), 7.80e7.82
(m, 2H); 13C NMR (100 MHz, CDCl3)
d 21.1, 56.1, 70.3, 73.0, 77.2, 95.4,
4.2.15. (E)-2-[(4-Chlorophenyl)(hydroxy)methyl]-3-iodo-4-(methox-
100.6, 126.3, 128.5, 129.2, 129.9, 133.5, 134.2, 137.2, 137.8, 151.5,
197.2; IR (neat) 3504, 2934, 1652, 1591, 1516, 1445, 1244, 1144, 1044,
923, 806, 686 cmꢁ1; HRMS (EI) calcd for C20H21IO4 (M)þ 452.0485,
found 452.0471.
ymethoxy)-1-phenylbut-2-en-1-one (E-5b).18a Colorless oil; 1H
NMR (400 MHz, CDCl3)
d
3.10 (s, 3H), 3.21 (d, J¼6.2 Hz, 1H), 4.06 (d,
J¼13.3 Hz,1H), 4.11 (d, J¼13.3 Hz,1H), 4.36 (d, J¼6.7 Hz,1H), 4.38 (d,
J¼6.7 Hz, 1H), 5.92 (d, J¼5.9 Hz, 1H), 7.19e7.22 (m, 2H), 7.34e7.41
(m, 4H), 7.50e7.54 (m, 1H), 7.68e7.71 (m, 2H); 13C NMR (100 MHz,
4.2.21. (E)-2-[Hydroxy(naphthalen-1-yl)methyl]-3-iodo-4-(methox-
CDCl3)
d
55.7, 72.7, 80.6, 95.8, 107.1, 127.7, 128.5, 128.6, 129.4, 133.8,
ymethoxy)-1-phenylbut-2-en-1-one (E-5e).18a Orange oil; 1H NMR
134.0, 136.2, 138.7, 146.8, 195.3; IR (neat) 3440, 2990, 2880, 1667,
(400 MHz, CDCl3)
4.40 (s, 2H), 6.75 (d, J¼6.8 Hz, 1H), 7.13e7.17 (m, 2H), 7.29e7.79 (m,
9H), 8.09e8.10 (m, 1H); 13C NMR (100 MHz, CDCl3)
55.6, 72.6,
d
3.11 (s, 3H), 3.56 (d, J¼6.4 Hz, 1H), 4.14 (s, 2H),
1489, 1255, 1150, 1012, 812, 688 cmꢁ1; HRMS (EI) calcd for
C
19H18ClIO4 (M)þ 471.9938, found 471.9919.
d
78.6, 95.8, 107.4, 123.6, 124.6, 125.3, 125.6, 126.4, 128.1, 128.5, 128.9,
128.9, 130.8, 133.4, 133.6, 135.2, 135.8, 147.8, 195.7; IR (neat): 3462,
3055, 3017, 2933, 2892, 1668, 1622, 1596, 1449, 1405, 1373, 1315,
1260, 1242, 1216, 1151, 1105, 1061, 993, 936, 799, 755 cmꢁ1; HRMS
(ESI) calcd for C23H22IO4 (MþH)þ 489.0563, found 489.0530.
4.2.16. (Z)-2-[(4-Chlorophenyl)(hydroxy)methyl]-3-iodo-4-(methox-
ymethoxy)-1-phenylbut-2-en-1-one (Z-5b).18a Brown semisolid; 1H
NMR (400 MHz, CDCl3)
d
3.49 (s, 3H), 3.60 (d, J¼5.8 Hz, 1H), 4.61 (s,
2H), 4.76 (d, J¼6.8 Hz, 1H), 4.79 (d, J¼6.8 Hz, 1H), 5.94 (d, J¼5.8 Hz,
1H), 7.19e7.21 (m, 2H), 7.30e7.32 (m, 2H), 7.36e7.40 (m, 2H),
7.51e7.55 (m, 1H), 7.77e7.79 (m, 2H); 13C NMR (100 MHz, CDCl3)
4.2.22. (Z)-2-[Hydroxy(naphthalen-1-yl)methyl]-3-iodo-4-(methox-
d
56.7, 70.6, 72.1, 95.4, 101.5, 127.7, 128.6, 129.9, 133.8, 133.8, 133.9,
ymethoxy)-1-phenylbut-2-en-1-one (Z-5e).18a Light yellow semi-
138.5, 150.9, 197.1; IR (neat) 3510, 2947, 1661, 1590, 1488, 1445,
1403, 1275, 1147, 1101, 1029, 948, 850, 813, 710 cmꢁ1; HRMS (EI)
calcd for C19H18ClIO4 (M)þ 471.9938, found 471.9925.
solid; 1H NMR (400 MHz, CDCl3)
d 3.46 (s, 3H), 3.56 (br s, 1H), 4.61
(d, J¼12.8 Hz, 1H), 4.67 (d, J¼12.8 Hz, 1H), 4.77 (d, J¼6.9 Hz, 1H),
4.81 (d, J¼6.9 Hz, 1H), 6.52 (d, J¼7.8 Hz, 1H), 7.11e7.15 (m, 2H),
7.25e7.80 (m, 9H), 8.17e8.19 (m, 1H); 13C NMR (100 MHz, CDCl3)
4.2.17. (E)-2-[Hydroxy(4-methoxyphenyl)methyl]-3-iodo-4-(me-
d 56.2, 69.9, 70.4, 95.6, 100.9, 122.7, 125.1, 125.4, 125.7, 126.5, 128.2,
thoxymethoxy)-1-phenylbut-2-en-1-one (E-5c).18a Orange semi-
128.8, 129.0, 129.5, 130.3, 133.3, 133.6, 133.8, 135.0, 151.1, 197.1; IR
(neat): 3433, 3066, 3012, 2935, 2892, 1667, 1596, 1511, 1449, 1315,
1275, 1241, 1216, 1150, 1104, 1062, 1029, 986, 936, 927, 799,
755 cmꢁ1; HRMS (EI) calcd for C23H22IO4 (MþH)þ 489.0563, found
489.0530.
solid; 1H NMR (400 MHz, CDCl3)
d
3.02 (d, J¼5.9 Hz, 1H), 3.08 (s,
3H), 3.74 (s, 3H), 4.05 (d, J¼13.1 Hz, 1H), 4.09 (d, J¼13.1 Hz, 1H), 4.36
(d, J¼6.9 Hz, 1H), 4.38 (d, J¼6.9 Hz, 1H), 5.86 (d, J¼5.9 Hz, 1H),
6.76e6.79 (m, 2H), 7.34e7.42 (m, 4H), 7.48e7.52 (m, 1H), 7.72e7.74
(m, 2H); 13C NMR (100 MHz, CDCl3)
d 55.2, 55.5, 72.6, 80.9, 95.8,
105.8, 113.7, 127.7, 128.5, 129.4, 132.4, 133.8, 136.4, 147.7, 159.3,
195.6; IR (neat) 3451, 3007, 2938, 1673, 1611, 1510, 1452, 1377, 1247,
4.2.23. (E)-2-[Hydroxy(thiophen-2-yl)methyl]-3-iodo-4-(methox-
ymethoxy)-1-phenylbut-2-en-1-one (E-5f).18a Yellow oil. 1H NMR
Please cite this article in press as: Yashiro, K.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.09.020

K. Yashiro et al. / Tetrahedron xxx (2016) 1e11
9
(500 MHz, CDCl3)
d
3.10 (s, 3H), 3.39 (br s, 1H), 4.07 (d, J¼12.8 Hz,
759 cmꢁ1; HRMS (EI) calcd for C17H17IO4SeC2H5O (M)þ 398.9552,
found 398.9536.
1H), 4.11 (d, J¼12.8 Hz, 1H), 4.37 (s, 2H), 6.11 (s, 1H), 6.88e6.90 (m,
1H), 7.16e7.17 (m, 2H), 7.37e7.40 (m, 2H), 7.51e7.54 (m, 1H),
7.77e7.79 (m, 2H); 13C NMR (126 MHz, CDCl3)
d
55.6, 72.6, 78.3,
4.2.29. (E)-3-[Hydroxy(phenyl)methyl]-4-iodo-5-(methoxymethoxy)
95.7, 106.7, 125.3, 125.3, 126.7, 128.5, 129.4, 133.9, 136.5, 143.7, 146.8,
195.1; IR (neat): 3450, 3011, 2937, 2885, 1667, 1622, 1595, 1582,
1449, 1375, 1315, 1242, 1216, 1179, 1151, 1105, 1049, 1004, 932,
755 cmꢁ1; HRMS (EI) calcd for C17H17IO4S (M)þ 443.9892, found
443.9891.
pent-3-en-2-one (E-5i).18a Yellow oil; 1H NMR (500 MHz, CDCl3)
d
2.01 (s, 3H), 3.07 (d, J¼5.5 Hz, 1H), 3.38 (s, 3H), 4.32 (d, J¼13.4 Hz,
1H), 4.37 (d, J¼13.4 Hz, 1H), 4.62 (s, 2H), 5.83 (d, J¼5.5 Hz, 1H),
7.27e7.32 (m, 1H), 7.35e7.38 (m, 2H), 7.41e7.49 (m, 2H); 13C NMR
(100 MHz, CDCl3)
d 32.2, 56.0, 72.5, 80.2, 95.6, 106.6, 125.7, 128.0,
128.6, 139.7, 151.1, 202.9; IR (neat) 3434, 3060, 3029, 2997, 2946,
2886, 1698, 1605, 1494, 1449, 1352, 1213, 1149, 1104, 1044, 920, 759,
705 cmꢁ1; HRMS (EI) calcd for C14H17IO4eHO (M)þ 359.0144, found
359.0145.
4.2.24. (Z)-2-[Hydroxy(thiophen-2-yl)methyl]-3-iodo-4-(methox-
ymethoxy)-1-phenylbut-2-en-1-one (Z-5f).18a Yellow semisolid; 1H
NMR (500 MHz, CDCl3)
d
3.47 (s, 3H), 3.65 (d, J¼6.1 Hz, 1H), 4.58 (d,
J¼12.8 Hz, 1H), 4.61 (d, J¼12.8 Hz, 1H), 4.74 (d, J¼6.7 Hz, 1H), 4.77
(d, J¼6.7 Hz, 1H), 6.14 (d, J¼6.1 Hz, 1H), 6.87e6.90 (m, 1H),
7.03e7.04 (m, 1H), 7.17e7.19 (m, 1H), 7.40e7.43 (m, 2H), 7.53e7.56
4.2.30. (Z)-3-[Hydroxy(phenyl)methyl]-4-iodo-5-(methoxymethoxy)
pent-3-en-2-one (Z-5i).18a Yellow oil; 1H NMR (400 MHz, CDCl3)
(m, 1H), 7.87e7.89 (m, 2H); 13C NMR (126 MHz, CDCl3)
d
56.1, 69.5,
d
2.09 (s, 3H), 3.45 (s, 3H), 3.53 (d, J¼5.5 Hz, 1H), 4.48 (d, J¼13.3 Hz,
70.6, 95.5, 101.6, 125.4, 125.6, 126.9, 128.6, 129.9, 133.7, 134.2, 144.0,
150.5, 196.9; IR (neat) 3411, 2019, 1667, 1596, 1450, 1316, 1260, 1216,
1150, 1103, 1041, 926, 764 cmꢁ1; HRMS (EI) calcd for C17H17IO4S
(M)þ 443.9892, found 443.9873.
1H), 4.58 (d, J¼13.3 Hz, 1H), 4.71 (d, J¼6.9 Hz, 1H), 4.75 (d, J¼6.9 Hz,
1H), 5.89 (d, J¼5.5 Hz, 1H), 7.27e7.40 (m, 5H); 13C NMR (126 MHz,
CDCl3)
d 30.1, 56.1, 70.0, 71.6, 95.5, 97.9, 125.9, 128.1, 128.7, 139.6,
154.1, 204.9; IR (neat) 3397, 3010, 2932, 2891, 1700, 1626, 1494,
1450, 1350, 1215, 1149, 1109, 1050, 919, 757, 700 cmꢁ1; HRMS (EI)
calcd for C14H17IO4eI (M)þ 249.1127, found 249.1126.
4.2.25. (E)-3-Hydroxy-2-[1-iodo-2-(methoxymethoxy)-ethylidene]-
1-phenyloctan-1-one (E-5g).18a Orange oil; 1H NMR (400 MHz,
CDCl3)
d
0.88 (t, J¼6.9 Hz, 3H),1.24e1.80 (m, 8H), 2.26 (br s,1H), 3.11
4.3. The iodo-Mannich reaction
(s, 3H), 4.05 (d, J¼13.3 Hz, 1H), 4.09 (d, J¼13.3 Hz, 1H), 4.40 (s, 2H),
4.63e4.67 (m, 1H), 7.46e7.50 (m, 2H), 7.57e7.61 (m, 1H), 7.94e7.96
4.3.1. Ethyl (E)-3-benzoyl-5,5-diethoxy-4-iodo-2-[(4-
methoxyphenyl)amino]pent-3-enoate (E-8). To a suspension of TiI4
(m, 2H); 13C NMR (100 MHz, CDCl3)
d 14.0, 22.5, 25.5, 31.3, 35.5,
55.5, 72.6, 79.7, 95.7, 103.4, 128.7, 129.5, 133.9, 136.5, 149.2, 195.4; IR
(neat) 3478, 3066, 2954, 2931, 2854, 1667, 1622, 1596, 1581, 1449,
1375, 1315, 1256, 1179, 1151, 1105, 1033, 938, 923, 754 cmꢁ1; HRMS
(ESI) calcd for C18H26IO4 (MþH)þ 433.0876, found 433.0847.
(100 mg, 0.18 mmol) in CH2Cl2 (1.0 mL) was added a mixture of g-
diethoxyalkynyl ketone 1a (34.8 mg, 0.15 mmol) and imino ester 7
(37.3 mg, 0.18 mmol) in CH2Cl2 (2.0 mL) at ꢁ40 ꢀC under an argon
atmosphere. The mixture was stirred at ꢁ40 ꢀC for 1.5 h. The re-
action mixture was quenched with saturated aqueous NaHCO3, and
EtOAc and 10% aqueous NaHSO3 were added successively. The
mixture was filtered through a Celite pad, and extracted with
EtOAc. The combined organic extracts were dried over Na2SO4 and
concentrated in vacuo. The residue was purified by buffered pre-
parative silica gel TLC (n-hexane/EtOAc/toluene¼3/1/1 as an elu-
ent) to give the iodo-Mannich products E-8 (34.8 mg, 41%). Yellow
4.2.26. (Z)-3-Hydroxy-2-[1-iodo-2-(methoxymethoxy)-ethylidene]-
1-phenyloctan-1-one (Z-5g).18a Light yellow semisolid; 1H NMR
(400 MHz, CDCl3)
d
0.86 (t, J¼6.9 Hz, 3H), 1.22e1.40 (m, 4H),
1.43e1.53 (m, 1H), 1.57e1.66 (m, 3H), 2.70 (d, J¼4.6 Hz, 1H), 3.49 (s,
3H), 4.52 (d, J¼12.9 Hz, 1H), 4.61 (d, J¼12.9 Hz, 1H), 4.75e4.83 (m,
3H), 7.47e7.51 (m, 2H), 7.59e7.63 (m, 1H), 8.01e8.04 (m, 2H); 13C
oil; 1H NMR (400 MHz, CDCl3)
d
0.98 (dd, J¼6.9, 7.3 Hz, 3H) 1.06 (t,
NMR (100 MHz, CDCl3) d 14.0, 22.5, 25.6, 31.4, 36.4, 56.2, 70.0, 71.4,
95.4, 100.0, 128.8, 130.0, 133.8, 134.4, 152.9, 197.2; IR (neat): 3451,
3060, 3004, 2954, 2932, 2854, 1665, 1596, 1580, 1449, 1314, 1259,
1152, 1103, 1039, 938, 757 cmꢁ1; HRMS (ESI) calcd for C18H26IO4
(MþH)þ 433.0876, found 433.0847.
J¼6.9 Hz, 3H), 1.32 (t, J¼7.1 Hz, 3H), 3.00 (dq, J¼6.9, 9.7 Hz, 1H), 3.26
(q, J¼6.9 Hz, 2H), 3.47 (dq, J¼7.3, 9.7 Hz, 1H), 3.74 (s, 3H), 4.08 (s,
1H), 4.21e4.35 (m, 2H), 4.54 (d, J¼5.5 Hz,1H), 5.32 (d, J¼5.5 Hz,1H),
6.58e6.62 (m, 2H), 6.73e6.77 (m, 2H), 7.26e7.30 (m, 2H), 7.44e7.48
(m, 1H), 7.72e7.75 (m, 2H); 13C NMR (100 MHz, CDCl3)
d 13.9, 14.6,
4.2.27. (E)-2-[Hydroxy(phenyl)methyl]-3-iodo-4-(methox-
14.6, 55.7, 61.7, 62.3, 62.4, 67.3,100.0,114.8,115.4,115.5,128.3,129.2,
133.8, 136.2, 140.1, 145.1, 152.8, 169.5, 194.6; IR (neat) 3374, 3065,
2978, 2932, 2907, 2831, 1739, 1661, 1595, 1515, 1449, 1369, 1290,
1238, 1156, 1113, 1063, 1031, 822, 736, 690 cmꢁ1; HRMS (EI) calcd
for C25H30INO6eI (M)þ 440.2073, found 440.2068.
ymethoxy)-1-(thiophen-2-yl)but-2-en-1-one (E-5h).18a Yellow oil;
1H NMR (400 MHz, CDCl3)
d 3.17 (s, 3H), 3.19 (br s, 1H), 4.16 (d,
J¼13.1 Hz,1H), 4.21 (d, J¼13.1 Hz,1H), 4.45 (d, J¼6.8 Hz,1H), 4.48 (d,
J¼6.8 Hz, 1H), 5.94 (d, J¼6.0 Hz, 1H), 6.93e6.95 (m, 1H), 7.17e7.29
(m, 4H), 7.45e7.47 (m, 2H), 7.61e7.62 (m, 1H); 13C NMR (100 MHz,
CDCl3) d 55.5, 72.7, 80.8, 95.8, 107.3, 125.8, 127.8, 128.0, 128.1, 135.8,
4.3.2. Ethyl (E)-3-benzoyl-4-iodo-5-(methoxymethoxy)-2-[(4-
139.7, 143.4, 147.5, 187.0; IR (neat): 3449, 3016, 2936, 1638, 1516,
1453, 1409, 1355, 1214, 1153, 1108, 1048, 918, 856, 755 cmꢁ1; HRMS
(EI) calcd for C17H17IO4SeI (M)þ 317.0848, found 317.0857.
methoxyphenyl)amino]pent-3-enoate (E-9). To a suspension of TiI4
(100 mg, 0.18 mmol) in CH2Cl2 (1.0 mL) was added a mixture of g-
methoxymethoxyalkynyl ketone 1b (36.8 mg, 0.18 mmol) and im-
ino ester 7 (31.1 mg, 0.15 mmol) in CH2Cl2 (2.0 mL) at ꢁ50 ꢀC under
an argon atmosphere. The mixture was stirred at ꢁ50 ꢀC for 1.5 h.
The reaction mixture was quenched with saturated aqueous
NaHCO3, and EtOAc and 10% aqueous NaHSO3 were added succes-
sively. The mixture was filtered through a Celite pad, and extracted
with EtOAc. The combined organic extracts were dried over Na2SO4
and concentrated in vacuo. The residue was purified by buffered
preparative silica gel TLC (n-hexane/EtOAc/CH2Cl2¼4/1/1 as an el-
uent) to give the iodo-Mannich products E-9 (41.9 mg, 52%) and Z-9
4.2.28. (Z)-2-[Hydroxy(phenyl)methyl]-3-iodo-4-(methox-
ymethoxy)-1-(thiophen-2-yl)but-2-en-1-one (Z-5h).18a Yellow oil;
1H NMR (400 MHz, CDCl3)
d 3.47 (s, 3H), 3.55 (br s, 1H), 4.61 (s, 2H),
4.74 (d, J¼6.8 Hz, 1H), 4.77 (d, J¼6.8 Hz, 1H), 5.96 (d, J¼6.0 Hz, 1H),
6.95e6.99 (m, 1H), 7.17e7.26 (m, 3H), 7.36e7.47 (m, 3H), 7.62e7.63
(m, 1H); 13C NMR (126 MHz, CDCl3)
d 56.2, 70.4, 72.6, 95.3, 101.8,
126.2, 128.0, 128.2, 128.5, 135.5, 135.7, 140.1, 151.9, 189.5; IR (neat)
3444, 3020, 2941, 1642, 1515, 1411, 1354, 1214, 1150, 1051, 922,
Please cite this article in press as: Yashiro, K.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.09.020

10
K. Yashiro et al. / Tetrahedron xxx (2016) 1e11
(22.6 mg, 28%); Yellow oil; 1H NMR (400 MHz, CDCl3)
d
1.32 (t,
1228, 1174, 1127, 1086, 1054, 1027, 902, 767 cmꢁ1; HRMS (EI) calcd
for C29H28O4 (M)þ 440.1988, found 440.1991.
J¼7.1 Hz, 3H), 3.12 (s, 3H), 3.75 (s, 3H), 4.08 (s, 2H), 4.25e4.33 (m,
2H), 4.36 (d, J¼6.9 Hz, 1H), 4.41 (d, J¼6.9 Hz, 1H), 4.56 (d, J¼5.5 Hz,
1H), 5.21 (d, J¼5.5 Hz, 1H), 6.58e6.62 (m, 2H), 6.74e6.78 (m, 2H),
7.27e7.31 (m, 2H), 7.44e7.49 (m, 1H), 7.69e7.71 (m, 2H); 13C NMR
4.4.3. 4-Benzoyl-2-benzyl-5-phenylfuran-3-carbaldehyde
(12).18a Yellow oil; 1H NMR (400 MHz, CDCl3)
d
4.43 (s, 2H),
7.24e7.53 (m, 13 H), 7.85e7.87 (m, 2H), 9.89 (s, 1H); 13C NMR
(100 MHz, CDCl3) 33.5, 119.3, 123.3, 126.6, 127.3, 128.5, 128.6,
(100 MHz, CDCl3) d 14.0, 55.5, 55.7, 62.3, 67.7, 72.2, 95.3,110.2,114.8,
115.3, 128.5, 129.0, 133.7, 136.4, 140.2, 144.9, 152.8, 169.6, 193.9; IR
(neat) 3376, 3060, 2991, 2943, 2904, 2831, 1741, 1663, 1595, 1511,
1450, 1285, 1240, 1204, 1151, 1105, 1031, 942, 822, 755 cmꢁ1; HRMS
(EI) calcd for C23H26INO6 (M)þ 539.0805, found 539.0807.
d
128.7, 128.8, 128.9, 129.1, 129.6, 133.7, 135.9, 137.2, 152.3, 161.2,
184.8, 191.9; IR (neat) 3020, 1684, 1559, 1495, 1448, 1216, 1024, 900,
757 cmꢁ1; HRMS (EI) calcd for C25H18O3eC6H5 (M)þ 289.0865,
found 289.0860.
4.3.3. Ethyl (Z)-3-benzoyl-4-iodo-5-(methoxymethoxy)-2-[(4-
methoxyphenyl)amino]pent-3-enoate (Z-9). Yellow oil; 1H NMR
4.4.4. {5-Benzyl-4-[(methoxymethoxy)methyl]-2-phenylfuran-3-
yl}(phenyl)methanone (13).18a A mixture of PdCl2(PPh3)2 (33.8 mg,
0.0482 mmol), CuI (36.6 mg, 0.192 mmol), phenyl acetylene
(197 mg, 1.93 mmol), Et3N (1.0 mL), and the iodide E-5a (416 mg,
0.949 mmol) in DMF (1.0 mL) was heated at 90 ꢀC under an argon
atmosphere for 6 days. The reaction mixture was cooled to room
temperature and quenched with saturated NH4Cl and EtOAc. The
layers were separated, and the aqueous layer was extracted with
EtOAc. The combined extracts were dried over Na2SO4, and con-
centrated in vacuo. The crude product was purified by preparative
TLC on silica gel (n-hexane/EtOAc¼4/1 as an eluent, developed
twice) to give the furan 13 (191 mg, 49%). Yellow oil; 1H NMR
(400 MHz, CDCl3)
d
1.27 (t, J¼7.1 Hz, 3H), 3.53 (s, 3H), 3.74 (s, 3H),
4.16e4.30 (m, 2H), 4.44 (br s, 1H), 4.45 (d, J¼13.5 Hz, 1H), 4.83 (d,
J¼6.9 Hz, 1H), 4.85 (d, J¼6.9 Hz, 1H), 4.87 (d, J¼13.5 Hz, 1H), 5.30 (s,
1H), 6.58e6.62 (m, 2H), 6.71e6.75 (m, 2H), 7.29e7.33 (m, 2H),
7.45e7.50 (m, 1H), 7.79e7.82 (m, 2H); 13C NMR (100 MHz, CDCl3)
d
14.0, 55.7, 56.2, 59.3, 62.5, 70.3, 95.7, 103.0, 114.8, 115.1, 128.4,
129.7, 133.5, 134.2, 139.9, 145.6, 153.0, 169.2, 196.3; IR (neat) 3377,
3060, 2992, 2945, 2898, 2830, 1740, 1664, 1596, 1511, 1449, 1239,
1208, 1151, 1105, 1034, 944, 822, 755 cmꢁ1; HRMS (EI) calcd for
C
23H26INO6 (M)þ 539.0805, found 539.0807.
(500 MHz, CDCl3)
7.16e7.19 (m, 3H), 7.29e7.38 (m, 9H), 7.43e7.47 (m, 1H), 7.82e7.83
(m, 2H); 13C NMR (100 MHz, CDCl3)
32.4, 55.2, 59.0, 95.6, 119.0,
d 3.23 (s, 3H), 4.13 (s, 2H), 4.47 (s, 2H), 4.47 (s, 2H),
4.4. Synthesis of tetra-substituted furans
d
4.4.1. (Z)-3-(Diethoxymethyl)-2-[hydroxy(phenyl)methyl]-1,5-di-
121.1, 126.6, 126.8, 128.2, 128.3, 128.6, 128.6, 129.6, 129.7, 133.1,
137.4, 147.5, 152.1, 152.5, 193.1; IR (neat) 3061, 3027, 2933, 2879,
2823, 1657, 1597, 1580, 1560, 1495, 1448, 1401, 1320, 1224, 1148,
1100, 1036, 971, 906 cmꢁ1; HRMS (EI) calcd for C27H24O4 (M)þ
412.1675, found 412.1655.
phenylpent-2-en-4-yn-1-one (10).18a
A mixture of PdCl2(PPh3)2
(3.5 mg, 0.0050 mmol), CuI (3.8 mg, 0.020 mmol), phenyl acetylene
(20.5 mg, 0.201 mmol), Et3N (0.5 mL), and the iodide E-3a (46.6 mg,
0.0999 mmol) in DMF (0.5 mL) was heated at 90 ꢀC under an argon
atmosphere for 20 h. The reaction mixture was cooled to room
temperature and quenched with H2O, 2 M HCl, and EtOAc. The
layers were separated, and the aqueous layer was extracted with
EtOAc. The combined extracts were washed with saturated aqueous
NaHCO3 and brine, dried over Na2SO4, and concentrated in vacuo.
The crude product was purified by preparative TLC on silica gel (n-
hexane/EtOAc¼5/1 as an eluent) to give the enynol 10 (32.1 mg,
Acknowledgements
This work was supported by Japan Society for the Promotion of
Science (JSPS) KAKENHI Grant Number JP16H01143 in Middle
Molecular Strategy and JP25410114.
73%); Yellow oil; 1H NMR (400 MHz, CDCl3)
d
0.98 (t, J¼6.9 Hz, 3H),
1.01 (t, J¼6.9 Hz, 3H), 3.14e3.28 (m, 2H), 3.41e3.58 (m, 3H), 4.82 (s,
Appendix A. Supplementary data
1H), 6.35 (d, J¼5.9 Hz, 1H), 7.13e7.53 (m, 13H), 7.64e7.66 (m, 2H);
13C NMR (100 MHz, CDCl3)
d 14.6, 14.7, 61.8, 62.1, 74.7, 84.2, 99.2,
Supplementary data (1H and 13C NMR spectra and Cartesian
coordinates) associated with this article can be found in the online
version, at http://dx.doi.org/10.1016/j.tet.2016.09.020.
99.4, 122.6, 123.9, 125.9, 127.7, 128.1, 128.3, 128.4, 128.9, 129.1, 131.8,
133.1, 137.5, 141.1, 147.6, 197.2; IR (neat): 3433, 3022, 2929, 1649,
1214, 1050, 747 cmꢁ1; HRMS (EI) calcd for C29H28O4eC2H5O (M)þ
395.1647, found 395.1646.
References and notes
4.4.2. [5-Benzyl-4-(diethoxymethyl)-2-phenylfuran-3-yl](phenyl)
methanone (11).18a
A
mixture of PdCl2(CH3CN)2 (3.6 mg,
1. (a) Jessen, H. J.; Schumacher, A.; Schmid, F.; Phaltz, A.; Gademann, K. Org. Lett.
2011, 13, 4368e4370; (b) Clausen, D. J.; Wan, S.; Floreancig, P. E. Angew. Chem.
2011, 123, 5284e5287 Angew. Chem. Int. Ed. 2011, 50, 5178e5181; (c) Franc¸ ais,
0.0138 mmol) and the enynol 10 (32.0 mg, 0.726 mmol) in THF
(0.5 mL) was heated at reflux under an argon atmosphere for 2 h.
The reaction mixture was cooled to room temperature and
quenched with saturated NH4Cl and EtOAc. The layers were sepa-
rated, and the aqueous layer was extracted with EtOAc. The com-
bined extracts were dried over Na2SO4, and concentrated in vacuo.
The crude product was purified by preparative TLC on silica gel (n-
hexane/EtOAc¼4/1 as an eluent, developed twice) to give the fu-
rans 11 (5.9 mg, 18%) and 12 (9.7 mg, 36%); Yellow oil; 1H NMR
ꢁ
~
A.; Leyva-Perez, A.; Etxebarria-Jardi, G.; Pena, J.; Ley, S. V. Chem.dEur. J. 2011, 17,
329e343; (d) Franc¸ ais, A.; Leyva, A.; Etxebarria-Jardi, G.; Ley, S. V. Org. Lett.
€
€
2010, 12, 340e343; (e) Pospísil, J.; Muller, C.; Furstner, A. Chem.dEur. J. 2009, 15,
5956e5968; (f) Jackson, K. L.; Henderson, J. A.; Motoyoshi, H.; Phillips, A. J.
Angew. Chem. 2009, 121, 2382e2386 Angew. Chem. Int. Ed. 2009, 48,
2346e2350; (g) Tortosa, M.; Yakelis, N. A.; Roush, W. R. J. Org. Chem. 2008, 73,
9657e9667; (h) Dounay, A. B.; Humphreys, P. G.; Overman, L. E.; Wrobleski, A.
D. J. Am. Chem. Soc. 2008, 130, 5368e5377; (i) Lee, S.; Hwang, G.-S.; Shin, S. C.;
Lee, T. G.; Jo, R. H.; Ryu, D. H. Org. Lett. 2007, 9, 5087e5089; (j) Maezaki, N.;
Kojima, N.; Sakamoto, A.; Tominaga, H.; Iwata, C.; Tanaka, T.; Monden, M.;
Damdinsuren, B.; Nakatomi, S. Chem.dEur. J. 2003, 9, 389e399; (k) Kadota, I.;
Takamura, H.; Ohno, A.; Matsuda, K.; Satake, M.; Yamamoto, Y. J. Am. Chem. Soc.
2003, 125, 11893e11899; (l) Trost, B. M.; Gunzner, J. L.; Dirat, O.; Rhee, T. H. J.
Am. Chem. Soc. 2002, 124, 10396e10415; (m) Longbottom, D. A.; Morrison, A. J.;
Dixon, D. J.; Ley, S. V. Angew. Chem. 2002, 114, 2910e2914 Angew. Chem. Int. Ed.
2002, 41, 2786e2790.
(400 MHz, CDCl3)
d
1.00 (t, J¼6.9 Hz, 6H), 3.38 (dq, J¼6.9, 9.2 Hz,
2H), 3.52 (dq, J¼6.9, 9.2 Hz, 2H), 4.25 (s, 2H), 5.56 (s, 1H), 7.13e7.25
(m, 4H), 7.30e7.40 (m, 8H), 7.46e7.50 (m, 1H), 7.86e7.89 (m, 2H);
13C NMR (100 MHz, CDCl3)
d 14.8, 33.3, 61.2, 97.0, 120.6,120.7, 126.0,
126.3, 128.0, 128.4, 128.4, 128.8, 129.7, 133.1, 127.7, 128.3, 150.2,
151.5, 193.6; IR (neat): 3062, 3029, 2976, 2928, 2892, 2882, 1667,
1598, 1582, 1560, 1493, 1448, 1415, 1390, 1340, 1315, 1285, 1257,
2. (a) Taniguchi, M.; Kobayashi, S.; Nakagawa, M. Tetrahedron Lett. 1986, 27,
4763e4766; (b) Taniguchi, M.; Hino, T.; Kishi, Y. Tetrahedron Lett. 1986, 27,
4767e4770.
Please cite this article in press as: Yashiro, K.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.09.020

K. Yashiro et al. / Tetrahedron xxx (2016) 1e11
11
3. (a) Timmons, C.; Kattuboina, A.; Banerjee, S.; Li, G. Tetrahedron 2006, 62,
7151e7154; (b) Kattuboina, A.; Kaur, P.; Timmons, C.; Li, G. Org. Lett. 2006, 8,
2771e2774.
19. Patel, C.; Sunoj, R. B. J. Org. Chem. 2010, 75, 359e367.
20. (a) Shinisha, C. B.; Sunoj, R. B. J. Am. Chem. Soc. 2010, 132, 12319e12330; (b)
Sreenithya, A.; Sunoj, R. B. Org. Lett. 2012, 14, 752e755.
4. Li, Q.; Shi, M.; Lyte, J. M.; Li, G. Tetrahedron Lett. 2006, 47, 7699e7702.
5. (a) Zhang, C.; Lu, X. Synthesis 1996, 586e588; (b) Lim, H. N.; Ji, S. H.; Lee, K. J.
Synthesis 2007, 2454e2460.
21. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Na-
katsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino,, J.; Zheng,,
G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery,
J. A., Jr; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K.
N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.;
Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.;
Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.;
Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.;
Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dan-
6. Wei, H.-X.; Gao, J. J.; Li, G.; ParØ, P. W. Tetrahedron Lett. 2002, 43, 5677e5680.
ꢁ
7. (a) Wei, H. X.; Timmons, C.; Farag, M. A.; Pare, P. W.; Li, G. Org. Biomol. Chem.
ꢁ
2004, 2, 2893e2896; (b) Deng, G.-H.; Hu, H.; Wei, H.-X.; Pare, P. W. Helv. Chim.
Acta 2003, 86, 3510e3515.
8. Alcaide, B.; Almendros, P.; Aragoncillo, C.; Rodríguez-Acebes, R. J. Org. Chem.
2004, 69, 826e831.
9. Yadav, J. S.; Reddy, B. V. S.; Gupta, M. K.; Eeshwaraiah, B. Synthesis 2005, 57e60.
10. Yadav, J. S.; Reddy, B. V. S.; Gupta, M. K.; Pandey, S. K. J. Mol. Catal. A 2007, 264,
309e312.
€
nenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, O.; Foresman, J. B.; Ortiz, J. V.;
11. (a) Senapati, B. K.; Hwang, G.-S.; Lee, S.; Ryu, D. H. Angew. Chem. 2009, 121,
4462e4465 Angew. Chem. Int. Ed. 2009, 48, 4398e4401; (b) Chen, D.; Guo, L.;
Kotti, S. R. S. S.; Li, G. Tetrahedron: Asymmetry 2005, 16, 1757e1762; (c) Chen, D.;
Timmons, C.; Liu, J.; Headley, A.; Li, G. Eur. J. Org. Chem. 2004, 3330e3335; (d) Li,
G.; Wei, H.-X.; Phelps, B. S.; Purkiss, D. W.; Kim, S. H. Org. Lett. 2001, 3, 823e826.
12. (a) Wei, H.-X.; Chen, D.; Xu, X.; Li, G.; ParØ, P. W. Tetrahedron: Asymmetry 2003,
14, 971e974; (b) Xu, X.; Chen, D.; Wei, H. X.; Li, G.; Xiao, T. L.; Armstrong, D. W.
Chirality 2003, 15, 139e142.
13. For examples of the intramolecular cyclization, see: (a) Ciesielski, J.; Cariou, K.;
Frontier, A. J. Org. Lett. 2012, 14, 4082e4085; (b) Sloman, D. L.; Bacon, J. W.;
Porco, J. A., Jr. J. Am. Chem. Soc. 2011, 133, 9952e9955; (c) Ciesielski, J.; Can-
terbury, D. P.; Frontier, A. J. Org. Lett. 2009, 11, 4374e4377; (d) Douelle, F.; Capes,
A. S.; Greaney, M. F. Org. Lett. 2007, 9, 1931e1934 For an example of the dia-
stereoselective intermolecular iodo-aldol reaction of internal alkynyl esters,
see; (e) Bugarin, A.; Connell, B. T. Tetrahedron Lett. 2015, 56, 3285e3287.
14. Shimizu, M.; Toyoda, T.; Baba, T. Synlett 2005, 2516e2518.
15. Shimizu, M.; Baba, T.; Toudou, S.; Hachiya, I. Chem. Lett. 2007, 36, 12e13.
16. Hachiya, I.; Minami, Y.; Shimizu, M. Heterocycles 2009, 79, 365e371.
17. Shimizu, M.; Okura, K.; Arai, T.; Hachiya, I. Chem. Lett. 2010, 39, 1052e1054.
18. (a) Hachiya, I.; Ito, S.; Kayaki, S.; Shimizu, M. Asian J. Org. Chem. 2013, 2,
931e934 See Supplementary material; (b) Hachiya, I.; Shimizu, M. Tetrahedron
Lett. 2014, 55, 2781e2788.
Cioslowski, J.; Fox, D. J. Gaussian 09, Revision D.01; Gaussian: Wallingford CT,
2009.
22. Dennington, R.; Keith, T.; Millam, J. GaussView, Version 5; Semichem: Shawnee
Mission, KS, 2009.
23. (a) Becke, A. D. Phys. Rev. A 1988, 38, 3098e3100; (b) Lee, C.; Yang, W.; Parr, R.
G. Phys. Rev. B 1988, 37, 785e789.
24. Becke, A. D. J. Chem. Phys. 1993, 98, 5648e5652.
25. (a) Hay, P. J.; Wadt, W. R. J. Chem. Phys. 1985, 82, 270e283; (b) Hay, P. J.; Wadt,
W. R. J. Chem. Phys. 1985, 82, 284e298; (c) Hay, P. J.; Wadt, W. R. J. Chem. Phys.
1985, 82, 299e310.
26. (a) Mejuch, T.; Gilboa, N.; Gayon, E.; Wang, H.; Houk, K. N.; Marek, I. Acc. Chem.
}
Res. 2013, 46, 1659e1669; (b) Arnason, I.; Gudnason, P. I.; Bjornsson, R.;
Oberhammer, H. J. Phys. Chem. A 2011, 115, 10000e10008.
27. Chan, Z.; Huang, G.; Jiang, H.; Huang, H.; Pan, X. J. Org. Chem. 2011, 76,
1134e1139.
28. (a) Schneider, C. C.; Caldeira, H.; Gay, B. M.; Back, D. F.; Zeni, G. Org. Lett. 2010,
12, 936e939; (b) Liu, F.; Ma, D. J. Org. Chem. 2007, 72, 4844e4850; (c) Fukuda,
Y.; Shiragami, H.; Utimoto, K.; Nozaki, H. J. Org. Chem. 1991, 56, 5816e5819.
29. Obrecht, D.; Weiss, B. Helv. Chim. Acta 1989, 72, 117e122.
30. Obrecht, D. Helv. Chim. Acta 1989, 72, 447e456.
Please cite this article in press as: Yashiro, K.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.09.020