Chalcogenide-Lewis acid mediated reactions of electron-deficient alkynes with aldehydes

Article abstract of DOI:10.1002/chem.200390169

Reactions of but-3-yn-2-one (2) with aldehydes 1 in the presence of a Lewis acid and dimethyl sulfide (3a) predominantly gave (E)-α-(halomethylene)aldols 4-5 in high yields, while reactions of methyl propiolate (6a) mainly afforded (Z)-3-halogeno-2-(hydro

Full text of DOI:10.1002/chem.200390169

FULL PAPER
Chalcogenide-Lewis Acid Mediated Reactions of Electron-Deficient Alkynes
with Aldehydes
Sayaka Kinoshita, Hironori Kinoshita, Tatsunori Iwamura, Shin-ichi Watanabe, and
Tadashi Kataoka*[a]
Abstract: Reactions of but-3-yn-2-one
(2) with aldehydes 1 in the presence of a
Lewis acid and dimethyl sulfide (3a)
predominantly gave (E)-a-(halomethy-
lene)aldols 4 5 in high yields, while
reactions of methyl propiolate (6a)
mainly afforded (Z)-3-halogeno-2-(hy-
droxymethyl)acrylates 7 8 in low to
moderate yields.A reaction of dimethyl
acetylenedicarboxylate (10) with 1a in
the presence of TiCl4 and 1,1,3,3-tetra-
methylthiourea (3c) produced maleate
(E)-11 (40%) and butenolide 12 (40%).
When a reaction of 6a with 1a was
carried out in the presence of TiBr4 and
3a (0.2 equiv) at À208C for 60 h,
3-(methylthio)-2-(hydroxyalkyl)acrylate
9a was obtained in an 8% yield.Experi-
ments were conducted in order to eluci-
date the formation mechanism of 9a,
and it was made clear that 9a was
formed via the processes of the Michael
addition of sulfide 3a to alkynoate 6a
and an aldol reaction with 1a and
demethylation.
Keywords: aldol reaction ¥ alkynes
À
¥ C C coupling ¥ ketones ¥ Michael
addition
reaction of active alkynes as shown in Scheme 1: A complex
formed from TiCl4 and a chalcogenide reacts with an alkyne to
form titanium chloroallenolate, which undergoes an aldol
reaction with an aldehyde to afford an a-halomethylene aldol.
It has been reported that a-acetylenic ketones and esters
underwent amine-promoted dimerization[8] and the Michael
addition of triethylammonium salts.[9] Recently, Nair et al.
examined the reaction of dimethyl acetylenedicarboxylate
(DMAD) with aromatic aldehydes in the presence of pyridine
and obtained 2-oxo-3-benzylidenesuccinates.[10] On the other
hand, the phosphine-catalized reactions of DMAD with
activated carbonyl compounds produced highly functional-
ized butenolides.[11]
Introduction
We have developed the chalcogeno-Baylis Hillman reaction
catalyzed by a system using a Lewis acid and a chalcogenide.[1]
The reaction mechanism does not involve the addition of the
chalcogenide to an enone but involves processes in which a
halogenide ion derived from the Lewis acid undergoes the
Michael addition to an enone and the resulting enolate reacts
with an aldehyde to give an a-halomethyl aldol.[2] The
halomethyl aldol product can be converted into an a-
methylene aldol (the Morita Baylis Hillman adduct) by
preparative TLC on silica gel or by treatment with a base.This
reaction proceeded quickly, and we thus overcame the
drawback of the slow rate of the Morita Baylis Hillman
reaction.[3] Therefore, this reaction can be used instead of the
Morita Baylis Hillman reaction.It has been reported that
reactions of thioesters or a-keto esters can proceed smoothly
a-Hydroxyalkyl- or a-aminoalkyl-acrylates are usually
15]
prepared from a-metallated acrylates and aldehydes[12
or
imines.[13c] The Michael addition of an iodide ion and the
subsequent aldol reaction of an aldehyde have been reported
7]
18]
only under the reaction conditions we used.[4
by some research groups.[16
The phosphine-catalyzed
Since the Morita Baylis Hillman reaction involves the b-
elimination or the retro-Michael reaction in the last step, the
Morita Baylis Hillman reaction of active alkynes would not
proceed.However, since the reaction we developed goes
through the Michael and aldol reactions, we can anticipate the
addition of imides, sulfonamide and carboxylates to alky-
noates has been also reported.[19]
We now report the chalcogenide-TiCl4-mediated reactions
of alkynyl ketones and alkynoates.[20] Recently, Li et al.
reported the TiCl4-catalyzed reactions of alkynyl ketones
with aldehydes, but the reactions of methyl propiolate or
DMAD did not proceed under their conditions.[21]
[a] Prof.Dr.T.Kataoka, S.Kinoshita, H.Kinoshita, Dr.T.Iwamura,
Dr.S-.i.Watanabe
Gifu Pharmaceutical University
6-1 Mitahora-higashi 5-chome, Gifu 502-8585 (Japan)
Fax : (‡81)58-237-5979
Results and Discussion
E-mail: kataoka@gifu-pu.ac.jp
We first conducted reactions of but-3-yn-2-one (2) with p-
nitrobenzaldehyde (1a).The results are shown in Table 1.
Supporting information for this article is available on the WWW under
http://www.chemeurj.org or from the author.
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1496 1502
Reactions of aldehydes with an
Ch TiCl3
O
Ch TiCl3
O
electron-withdrawing
group
Cl
Cl
1b d gave only E isomers of
4b d in high yields, but reac-
tions of benzaldehyde (1e) and
p-tolualdehyde (1 f) produced a
diastereomixture of the E and
Z isomers of 4e f.Hydrocin-
namaldehyde (1g) reacted with
2 to give adduct 4g in an 84%
yield as a mixture of diaster-
eoisomers (E/Z 20:1).
or
R1
R1
Cl
OTiCl3
R1
H
OTiCl3
R1
Cl Ch
TiCl4
TiCl4
Ch
or
Ch
Cl
TiCl3
H
Cl
Ch: chalcogenide
Cl3
Ti
R2CHO
O
O
R2
R1
The diastereoisomers of the
products were separated by
preparative TLC on silica gel
using CH2Cl2/EtOAc or recy-
cling preparative HPLC on pol-
ystyrene gels using CHCl3.
Cl
Scheme 1.Application of chalcogeno-Baylis Hillman reaction to alkynes.
Table 1.Reaction of but-3-yn-2-one ( 2) with aldehydes 1.
Their stereostructure was determined by the NOE experi-
ments between the vinyl proton and the methyl group for the
E isomers and between the vinyl proton and the benzylic
proton for the Z isomers.The major isomer of 4a [(E)-4a]
ˆ
showed a 9% NOE enhancement between CH and COMe,
and the minor Z isomer [(Z)-4a] showed a 5% NOE
ˆ
enhancement between CH and CHAr.
Next, we examined the reactions of acetylenic monoesters 6
with aldehydes 1.The results are summarized in Table 2.
When reactions of 3 equiv of methyl propiolate (6a) with
1 equiv of p-nitrobenzaldehyde (1a) were conducted in the
presence of 1 equiv of TiCl4 and 0.1 equiv of 3a at room
temperature for 24 h, product 7a was formed in a 53% yield
as a mixture of diastereoisomers (E/Z 1:4) (entry 1).The
prolonged reaction time increased the yields up to a 75%
yield (entries 2 and 3).The use of 1 equiv of 3a lowered the
yield and diastereoselectivity (entry 4).When 3a was not used
but only titanium Lewis acid was used, the reaction did not
proceed at all (entries 5 and 6).This finding indicates that a
sulfide plays an important role in the tandem Michael aldol
reaction of acetylenic esters with aldehydes.A small amount
of b-(methylthio)acrylate 9a was obtained from the reactions
using 3a and TiBr4 (entries 7 9).This implies that a sulfide
can cause the Michael addition to an active alkene or alkyne;
therefore, this subject will be discussed below.Reactions with
other aldehydes 1b and 1d under the same conditions as those
in entry 3 gave adducts 7b (36%) and 7d (47%), respectively
(entries 10 and 11).A b-substituted alkynoate, methyl
2-butynoate (6b), reacted with 1a to give adduct 7h in a
25% yield (entry 12).
The reaction of DMAD (10) with 1a afforded adduct 11
(30%) and methyl 4-chloro-2-(4-nitrophenyl)-5-oxo-2,5-dihy-
drofuran-3-carboxylate (12) (10%) (Table 3, entry 1).When
1,1,3,3-tetramethyl-thiourea (3c) was used instead of 3a, the
yields of both 11 and 12 were increased to a 40% yield
(entry 2).The geometry of 11 was determined to be E from
the 1H NMR spectrum showing a singlet at d ˆ 6.06 due to the
benzylic proton, which is very close to that of (E)-7a (d ˆ
6.05). Incidentally, the benzylic proton of (Z)-7a appeared at
d ˆ 5.61. Furthermore, it is known that (Z)-2-(hydroxyme-
thyl)but-2-enedioic esters readily cyclize to furanone deriva-
Entry
R
Catalyst
Product
Yield [%]
E/Z ratio
1
2[a]
3
4
5
6
7
8
9
p-NO2C6H4 (1a)
p-NO2C6H4 (1a)
p-NO2C6H4 (1a)
p-NO2C6H4 (1a)
p-CF3C6H4 (1b)
p-FC6H4 (1c)
p-ClC6H4 (1d)
C6H5 (1e)
p-CH3C6H4 (1 f)
PhCH2CH2 (1g)
3a/TiCl4
3b/TiCl4
TiCl4
4a
4a
4a
5a
4b
4c
4d
4e
4 f
4g
86
89
84
49
73
89
73
84
86
84
E only
E only
1:1
E only
E only
E only
E only
20:1
TiBr4
3a/TiCl4
3a/TiCl4
3a/TiCl4
3a/TiCl4
3a/TiCl4
3a/TiCl4
15:1
20:1
10
[a] The condition was conducted at RT for 5 h.
The reaction of 3 equiv of 2 with 1 equiv of 1a proceeded in
the presence of 1 equiv of TiCl4 and 0.1 equiv of dimethyl
sulfide (3a) at 08C for 2 h to give (E)-a-chloromethylene
aldol 4a in an 86% yield (entry 1).On changing 3a into 2,6-
diphenylselenopyran-4-one (3b), the reaction was slow and
continued at room temperature for 5 h (entry 2).The reaction
using only TiCl4 (without 3a) gave a mixture of the E and Z
isomers in a ratio of 1:1 (entry 3).Li×s group obtained only the
E isomer from the reaction using TiCl4 at room temperature
for 2 h.[21] The differences between Li×s findings and ours
will be discussed later.The reaction using TiBr became
complex and afforded (E)-5a in a 49% yield (entry 4).
4
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T.Kataoka et al.
FULL PAPER
Table 2.Reaction of alkyne carboxylic ester 6 with aldehydes 2.
OMe
O
O
OH
O
X
OH
X
O
OH
O
3a (0.1 equiv)
R1
H
R1
OMe
R1
OMe R1
OMe
SMe
dry CH2Cl2, Conditions
Lewis acid (1 equiv)
R2
R2
R2
(1 equiv)
(3 equiv)
Z-7: X = Cl
Z-8: X = Br
E-7: X = Cl
Z-8: X = Br
9
1
6
Entry
R1
R2
Conditions
Catalyst
Products
Yield [%]
E/Z ratio
1
2
3
4[a]
5
p-NO2C6H4 (1a)
p-NO2C6H4 (1a)
p-NO2C6H4 (1a)
p-NO2C6H4 (1a)
p-NO2C6H4 (1a)
p-NO2C6H4 (1a)
p-NO2C6H4 (1a)
H (6a)
H (6a)
H (6a)
H (6a)
H (6a)
H (6a)
H (6a)
RT, 24 h
RT, 41 h
RT, 50 h
RT, 50 h
RT, 50 h
RT, 50 h
RT, 50 h
3a/TiCl4
3a/TiCl4
3a/TiCl4
3a/TiCl4
TiCl4
7a
7a
7a
7a
53
70
75
34
1:4
1:6
1:7
1:3
no reaction
no reaction
37
trace
9
6
7
TiBr4
3a/TiBr4
8a
9a
8a
9a
8a
9a
7b
7d
7h
1:2
8[b]
9[b]
p-NO2C6H4 (1a)
p-NO2C6H4 (1a)
H (6a)
H (6a)
À 208C, 60 h
À 408C, 60 h
3a/TiBr4
3a/TiBr4
1:1.
3
8
trace
5
36
47
25
10
11
12
p-CF3C6H4 (1b)
p-ClC6H4 (1d)
p-NO2C6H4 (1a)
H (6a)
H (6a)
CH3 (6b)
RT, 50 h
RT, 50 h
RT, 50 h
3a/TiCl4
3a/TiCl4
3a/TiCl4
1:6
1:7
1:1
[a] 3a (1 equiv) was used.[b] 3a (0.2 equiv) was used.
Table 3.Reaction of dimethyl acetylene dicarboxylate ( 10) with p-nitro-
benzaldehyde (2).
R1
H
OH
O
TiCl3
O
R2
R1
3a or (Me2N)2C=S
O
R2
3c
O
CO2Me
H
Cl
Cl
(0.1 equiv)
H
TiCl4 (1 equiv)
H
15 Z isomer
13
dry CH2Cl2, RT, 50 h
kinetically preferred process
O2N
CO2Me
Z isomer > E isomer
1
10
R1
H
OH
O
H
MeO2C
Cl
TiCl3
OH
O
O
R2
R1
O
R2
Cl
OMe
O
O
H
Cl
O2N
Cl
(E)-11
CO2Me
16 E isomer
O2N
14
themodynamically preferred process
12
E isomer >> Z isomer
Entry
Chalcogenide
Products (Yield [%])
Scheme 2.Mechanism for formation of a-(chloromethylene)aldols 15 and
16.
1
2
3a
3c
(E)-11 (30), 12 (10)
(E)-11 (40), 12 (40)
stable than 15 and is produced from 14 via the thermodynami-
cally preferred process.Our findings that reactions of but-3-
yn-2-one predominantly formed (E)-a-halomethylene aldol
and reactions of alkynoates preferentially produced (Z)-
acrylates are in good agreement with Taniguchi×s findings.[16]
The ratio of the Z isomers increased in the reactions of
alkynyl ketone 2 with aldehydes possessing a formyl group-
stabilizing substituent 1e g (entries 8 10 in Table 1) or of
alkynyl esters 6a b (Table 2), probably because these
reactions were slower than those of 2 with aldehydes bearing
an electron-withdrawing group 1a d and were governed by
the kinetically controlled process.
tives,[11, 22] some of which exert specific and strong pharmaco-
logical and agrochemical activities.[23]
The mechanism for the formation of E and Z isomers of a-
halomethylene aldols is shown in Scheme 2.
An allenolate is formed by the addition of a chloride ion to
an ynone as shown in Scheme 1 and reacts with an aldehyde
via the cyclic transition state 13 or 14.[16] The transition state
13 has no steric repulsion between the hydrogen of the
allenolate and the R2 substituent of the aldehyde, while the
transition state 14 has a steric hindrance between the chlorine
atom and the R2 group.Therefore, 13 is more stable than 14,
and Z isomer 15 is formed from 13 via the kinetically
preferred process.On the other hand, E isomer 16 is more
Next, we discuss the formation of a-(methylthiomethyle-
ne)aldol 9a obtained from the reaction of 6a with p-nitro-
benzylaldehyde (1a) (entries 7 9 in Table 2).Possible
formation mechanisms for 9a are shown in Scheme 3.
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Chalcogenide-Lewis Acid Mediated Reactions
1496 1502
Mechanism 1)
an acid-sensitive triphenyl-
methyl moiety.Then the result-
ing 22 would be hydrolyzed to
give 23 when the reaction is
worked up.In order to confirm
this hypothesis, we prepared an
authentic sample of 24 in a 73%
yield by the reaction of 22 with
sodium methanethiolate and
then treated it with TiBr4 under
the same conditions as those of
the reaction of 22, 3a and TiBr4.
Compound 24 was converted
into 23 in a 17% yield, but the
unreacted 24 was recovered in a
59% yield.From these findings,
it was revealed that the Lewis
acid 17 was not generated in
situ and aldol 19 was not
formed via mechanism 1).
TiX4
Me2S
MeS-TiX3
MeX
S
TiX4
17
O
X3
Ti
R1
O
O
H
OTiX3
R1
MeS
OTiX3
R1
R2CHO
R2
R1
SMe
MeS
H
19
18
Mechanism 2)
20
TiX3
X
X
H
OTiX3
R1
O
Me2S
H
OTiX3
R1
Me2S
R1
Me2S
X
X3
Ti
X3
Ti
R2CHO
O
X
O
O
O
Since the intramolecular Mi-
chael addition reaction of a
sulfide group to an enone moi-
ety in an acidic medium is
known,[25, 26] it might be difficult
but possible to cause the Mi-
chael addition of dimethyl sul-
R2
R1
SMe2
R2
R1
SMe
MeX
19
21
Scheme 3.Possible mechanism for formation of a-(methylthiomethylene)aldol 19.
fide to an electron-deficient alkyne.Sulfonium salts bearing
an alkyl group undergo dealkylation with halide ions.[27] Based
on these reports, sulfide 19 should be formed via mechanism 2).
In order to examine the reactivity of sulfide 9a and
sulfonium salt 25, we prepared them and conducted their
reactions shown in Scheme 5.
Sulfide 9a was derived with the retained configuration by
the reaction of (Z)-b-chloroacrylate (Z)-7a with sodium
methanethiolate via the addition and elimination processes.[28]
The methylation of sulfide 9a with the Meerwein reagent gave
a-formylcinnamate 26 in an 85% yield, which would be
formed via the following processes: addition of water to the a-
carbon of sulfonium salt 25, elimination of dimethyl sulfide
(3a), ketonization and elimination of water.Attempts to
It is known that a Lewis acid TiX4 and a sulfide form a
complex.[24] If the complex formed from TiX4 and dimethyl
sulfide (3a) releases MeX to generate a new Lewis acid, MeS-
TiX3 17 in mechanism 1), 17 reacts with an alkynoate to afford
g-(methylthio)allenolate 18.The reaction of the allenolate 18
with an aldehyde gives an aldol product 19.On the other
hand, mechanism 2) involves the Michael addition of dimeth-
yl sulfide (3a) to an alkynoate by activation with TiX4.The
resulting g-(dimethylsulfonio)allenolate 20 reacts with an
aldehyde to form a-(dimethylsulfoniomethylene)aldol 21,
which changes into an aldol product 19 accompanied by
demethylation.
If the reaction proceeds via mechanism 1), the Lewis acid
17 generated in situ works as an equivalent of MeSÀ.We
selected 9-phenylthioxanthyli-
um salt (22) as an acceptor of
MeSÀ and conducted the reac-
tions shown in Scheme 4.
1. 3a (0.2 equiv),
TiBr4 (1 equiv)
dry CH2Cl2
Ph
Ph OH
A reaction of 22 (1 equiv)
with 3a (0.2 equiv) and TiBr4
(1 equiv) was conducted in di-
chloromethane at À208C for
3 d.The product was not
9-(methylthio)-9-phenylthioxan-
thene (24) but 9-phenyl-thioxan-
thenol (23) in a 75% yield.
Product 23 would be formed by
the hydrolysis of 22, but it is
possible that the desired product
24 would be first produced and
transformed into 22 in an acidic
reaction medium because 24 has
-20°C, 3 d
2. sat. NaHCO3
S
S
ClO4
23 (75%)
22
Ph SMe
NaSMe (3 equiv)
dry CH2Cl2, RT, 1 h
3a (0.2 equiv)
23 (17%)
24 (59%)
TiBr4 (1 equiv)
-20°C, 3 d
S
24 (73%)
Scheme 4.Attempt to trap methanethiolate ion.
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1499

T.Kataoka et al.
FULL PAPER
standard (d ˆ 77.0). Mass spectra were
recorded on a JEOL JMS-SX102A
spectrometer with a direct-insertion
probe at 70 eV.Elemental analyses of
new compounds were performed by
Yanaco CHN Corder MT-5.All chro-
matographic isolations were accom-
plished with BW-350 (Fuji Silysia) for
column chromatography or with Kie-
selgel 60 PF254 containing gypsum
OH
O
OH
O
Me3OBF4
RT, 1 h
MeSNa
MeOH
OMe
OMe
SMe
O2N
Cl
O2N
Z-7a
9a
O
OH
O
OH
O
H2O
OMe
OMe
SMe2
OMe
SMe2
(Merck) for preparative TLC.CH Cl2
CHO
2
O2N
O2N
O2N
HO
BF4
was washed with water, dried over
CaCl2, and freshly distilled from
P4O10.The recycling preparative
HPLC was performed by LC-918 liq-
uid chromatography (Japan Analytical
Industry Co., Ltd.) equipped with
JAIGEL-1H and -2H columns (poly-
styrene gels).
26 (85 %)
25
SMe
O
TiCl4 (0.25 equiv)
RT, 72 h
TiCl4 (1 equiv)
Z-7a
1a
OMe
SMe
27 (33%)
Z-7a (21%)
25
(47%)
0°C, 0.5 h
O2N
General: For data of compounds 4a,
c
g, 5a and 7a, b, d, h, see Supporting
Scheme 5.Reaction of vinylsulfonium salt 25.
Information.
A typical reaction of but-3-yn-2-one
(2) with an aldehyde: p-Trifluorome-
thylbenzaldehyde (1b, 87 mg, 0.5 mmol) and dimethyl sulfide (3a) (3 mg,
0.05 mmol) were added to a solution of but-3-yn-2-one (2) (102 mg,
1.5 mmol) in dry dichloromethane (1.5 mL). TiCl4 (55 mL, 0.5 mmol) was
added dropwise at 08C.The mixture was stirred for 2 h and then quenched
by adding saturated aqueous NaHCO3 solution (1.5 mL). The inorganic
precipitate was removed by filtration through Celite, and the filtrate was
dried over MgSO4 and concentrated under reduced pressure.The residue
was purified by preparative TLC on silica gel with hexane/ethyl acetate
(2:1) to give (E)-4-chloro-3-[1-hydroxy-1-(4-trifluoromethylphenyl)-meth-
yl]but-3-en-2-one [(E)-4b] in a 73% yield.
isolate sulfonium salt 25 were unsuccessful because of its
lability.When sulfonium salt 25 was prepared in situ and then
treated with 0.25 equiv of TiCl4, (Z)-b-chloroacrylate (Z)-7a
was obtained in a 21% yield.When 1 equiv of TiCl 4 was used,
methyl 3-methylthio-2-[1-methylthio-1-(p-nitrophenyl)me-
thyl]acrylate 27(33%) as a mixture of E and Z isomers, (Z)-
7a (6%) and 1a (47%) were obtained.The bis(methylthio)
derivative 27 would be formed from the substitution reac-
tion of the hydroxy group of 9a for a methanethiolate ion
that is generated by the retro-aldol reaction of 9a under
acidic reaction conditions.The chloride ( Z)-7a would be
formed via the addition of a chloride ion and the succes-
sive elimination of dimethyl sulfide (3a) with the reten-
tion of the configuration,[29] although a pathway via the
reaction of aldehyde 1a with methyl propiolate (6a) result-
ing from the retro-aldol reaction of 9a could not be
completely excluded.The aldehyde 1a would be given
from the retro-aldol reaction of 26 which occurred during
(E)-4-Chloro-3-[1-hydroxy-1-(4-trifluoromethylphenyl)methyl]but-3-en-2-
one [(E)-4b]: white powder (from AcOEt/hexane); m.p. 61 648C (m.p.
68 708C[21]); 1H NMR (400 MHz, CDCl3): d ˆ 2.33 (s, 3H; Me), 4.43 (d,
J ˆ 11 Hz, 1H; OH), 5.98 (d, J ˆ 11 Hz, 1H; benzylic H), 7.48 7.52 (m, 3H;
ArH, olefinic H), 7.58 7.60 (m, 2H; ArH); 13C NMR (100 MHz, CDCl3):
d ˆ 27.0 (q), 70.3 (d), 125.39 (d), 125.43 (d), 129.5 (s), 129.8 (s), 136.5 (d),
142.7 (s), 145.5 (s), 198.1 (s); IR (KBr) nÄ ˆ 3510 (OH), 1669 cmÀ1 (C O);
ˆ
‡
MS (EI): m/z (%): 278 (4) [M ], 127 (100); elemental analysis calcd (%)
for C12H10ClF3O2: C 51.72, H 3.62; found: C 51.74, H 3.62.
Reaction of methyl propiolate (6a) with aldehyde 1a: p-Nitrobenzalde-
hyde (1a) (76 mg, 0.5 mmol) and dimethyl sulfide (3a) (6 mg, 0.1 mmol)
were added to a solution of methyl propiolate (6a) (126 mg, 1.5 mmol) in
dry dichloromethane (1.5 mL). TiBr4 (184 mg, 0.5 mmol) was added to the
mixture at À208C.The whole mixture was stirred for 60 h at the same
temperature and then quenched by the addition of saturated aqueous
NaHCO3 solution (1.5 mL). The inorganic precipitate was removed by
1
purification of the raw product because the H NMR spec-
trum of the raw product had exhibited signals due to 26.The
reaction of sulfonium salt 25 with trimethylsulfoxonium
iodide did not give a b-iodoacrylate but gave a complex
mixture.
filtration through Celite.The filtrate was dried over MgSO and concen-
4
trated under reduced pressure.The residue was purified by preparative
In conclusion, we developed chalcogenide-TiCl4-mediated
reactions of a-acetylenic ketones and esters with aldehydes
giving (E)-a-(halomethylene)aldols and (Z)-3-halogeno-2-
(hydroxylmethyl)acrylates.Since the products have trans-
formable functional groups, we could utilize them as useful
intermediates for the synthesis of biologically active com-
pounds.
TLC on silica gel with hexane/ethyl acetate (2:1) to give 8a and 9a.
Methyl (E)-3-bromo-2-[1-hydroxy-1-(4-nitrophenyl)methyl]acrylate [(E)-
8a]: yellow powder (from AcOEt/hexane); m.p. 70 718C; 1H NMR
(400 MHz, CDCl3): d ˆ 3.75 (s, 3H; OMe), 4.25 (d, J ˆ 11 Hz, 1H; OH),
6.03 (d, J ˆ 11 Hz, 1H; benzylic H), 7.86 (s, 1H; olefinic H), 7.60 and 8.21
(each d, J ˆ 9 Hz, 2H; ArH); 13C NMR (100 MHz, CDCl3): d ˆ 52.7 (q),
71.6 (d), 123.7 (d), 126.0 (d), 126.1 (d), 136.9 (s), 147.4 (s), 148.5 (s), 164.4
À1
ˆ
(s); IR (KBr) nÄ ˆ 3486 (OH), 1708 (C O), 1523 (NO2), 1349 cm (NO2);
‡
MS (EI): m/z (%): 203 (100); [M ], m/z 315 or 317, was not observed;
elemental analysis calcd (%) for C11H10BrNO5: C 41.76, H 3.19, N 4.43;
found: C 42.01, H 3.35, N 4.33.
Experimental Section
Methyl (Z)-3-bromo-2-[1-hydroxy-1-(4-nitrophenyl)methyl]acrylate [(Z)-
8a]: yellow powder (from AcOEt/hexane); m.p. 125 1268C; 1H NMR
(400 MHz, CDCl3): d ˆ 3.38 (d, J ˆ 6.0 Hz, 1H; OH), 3.75 (s, 3H; OMe),
5.62 (d, J ˆ 6.0 Hz, 1H; benzylic H), 7.05 (s, 1H; olefinic H), 7.55, 8.21 (d,
J ˆ 8.8 Hz, each 2H; ArH); 13C NMR (100 MHz, CDCl3): d ˆ 52.3 (q), 74.4
(d), 116.7 (d), 123.8 (d), 127.3 (d), 138.6 (s), 147.4 (s), 147.7 (s), 165.6 (s); IR
Melting points were obtained with a Yanagimoto micro-melting-point
apparatus and are uncorrected.IR spectra of solids (KBr) and liquids
(NaCl) were recorded on
a JASCO FT/IR-230 spectrophotometer.
1H NMR spectra were recorded on a JEOL EX-400 (400 MHz) spectrom-
eter with tetramethylsilane as an internal standard. 13C NMR spectra were
obtained on a JEOL EX-400 spectrometer with CDCl3 as an internal
(KBr) nÄ ˆ 3480 (OH), 1707 (C O), 1522 (NO2), 1346 cmÀ1 (NO2); MS (EI):
ˆ
1500
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Chem. Eur. J. 2003, 9, No. 7

Chalcogenide-Lewis Acid Mediated Reactions
1496 1502
‡
m/z (%): 203 (100); [M ], m/z 315 or 317, was not observed; elemental
temperature.The mixture was stirred at the same temperature for 1 h and
then poured into water and extracted with dichloromethane.The extracts
were combined, dried over MgSO4 and concentrated under reduced
pressure.The residue was purified by preparative TLC on silica gel with
CH2Cl2/AcOEt (100:1) to give 24 in a 73% yield.
analysis calcd (%) for C11H10BrNO5: C 41.76, H 3.19, N 4.43; found: C
42.00, H 3.29, N 4.34.
Methyl (Z)-2-[1-hydroxy-1-(4-nitrophenyl)methyl]3-methyl-sulfanyl acryl-
ate [(Z)-9a]: yellow powder (from AcOEt/hexane); m.p. 102 1038C;
1H NMR (400 MHz, CDCl3): d ˆ 2.40 (s, 3H; SMe), 3.08 (d, J ˆ 5.5 Hz, 1H;
OH), 3.75 (s, 3H; OMe), 5.62 (d, J ˆ 5.5 Hz, 1H; benzylic H), 7.20 (s, 1H;
olefinic H), 7.56, 8.20 (d, J ˆ 8.8 Hz, each 2H; ArH); 13C NMR (100 MHz,
CDCl3): d ˆ 19.6 (q), 51.7 (q), 73.3 (d), 123.6 (d), 125.2 (s), 127.1 (d), 147.3
9-Methylthio-9-phenylthioxanthene (24): colorless prisms (from AcOEt/
hexane); m.p. 109 1108C; 1H NMR (400 MHz, CDCl3): d ˆ 1.75 (s, 3H;
SMe), 7.07 7.09 (m, 4H; ArH), 7.18 7.20 (m, 2H; ArH), 7.33 7.38 (m,
5H; ArH), 7.46 7.47 (m, 2H; ArH); 13C NMR (100 MHz, CDCl3): d ˆ 15.3
(q), 62.1 (s), 125.6 (d), 126.0 (d), 127.0 (d), 127.2 (d), 128.0 (d), 130.3 (d),
131.0 (d), 132.2 (s), 136.7 (s), 137.1 (s), 142.5 (s); MS (EI) m/z (%): 320 (1)
ˆ
(s), 149.5 (s), 151.0 (d), 166.1 (s); IR (KBr) nÄ ˆ 3503 (OH), 1671 (C O),
1517 (NO2), 1344 cmÀ1 (NO2); MS (EI): m/z (%): 283 (22) [M ], 236 (100);
‡
‡
[M ], 273 (100); elemental analysis calcd (%) for C20H16S2: C 74.96, H 5.03;
elemental analysis calcd (%) for C12H13NO5S: C 50.88, H 4.63, N 4.94;
found: C 50.72, H 4.61, N 4.92.
found: C 75.03, H 5.05.
Synthesis of methyl 2-[1-hydroxy-1-(4-nitrophenyl)methyl]3-methylsulfan-
yl acrylate (9a): A 15% aqueous solution of sodium methanethiolate
(1.40 g, 3.0 mmol) was added to a solution of (Z)-7a (543 mg, 2.0 mmol) in
MeOH (2.0 mL) at room temperature. The mixture was stirred at the same
temperature for 10 min and then poured into water and extracted with
Methyl (E)-2-[1-hydroxy-1-(4-nitrophenyl)methyl]3-methyl-sulfanyl acryl-
ate [(E)-9a]: yellow powder (from AcOEt/hexane); m.p. 113 1148C;
1H NMR (400 MHz, CDCl3): d ˆ 2.53 (s, 3H; SMe), 3.71 (s, 3H; OMe), 4.25
(brs, 1H; OH), 5.71 (brs, 1H; benzylic H), 7.77 (s, 1H; olefinic H), 7.60 and
8.18 (d, J ˆ 8.5 Hz, each 2H; ArH); 13C NMR (100 MHz, CDCl3): d ˆ 18.0
dichloromethane.The extracts were combined, dried over MgSO and
(q), 51.9 (q), 70.4 (d), 123.4 (d), 126.2 (s), 126.2 (d), 147.0 (s), 148.8 (d), 149.7
4
À1
ˆ
concentrated under reduced pressure.The residue was purified by
preparative TLC on silica gel using hexane/AcOEt (5:1) to give 9a in a
78% yield.The product was identical with a sample obtained from the
reaction of methyl propiolate with 1a in Table 2.
(s), 165.0 (s); IR (KBr) nÄ ˆ 3486 (OH), 1673 (C O), 1515 (NO2), 1350 cm
‡
(NO2); MS (EI): m/z (%): 283 (22) [M ], 236 (100); elemental analysis
calcd (%) for C12H13NO5S: C 50.88, H 4.63, N 4.94; found: C 50.75, H 4.69,
N 4.93.
Methylation of sulfide 9a: Me3OBF4 (177 mg, 1.2 mmol) was added to a
solution of 9a (283 mg, 1.0 mmol) in dry dichloromethane (2.0 mL) at 08C.
The mixture was stirred at room temperature for 1 h, and then the solvent
was evaporated under reduced pressure.The residue was washed with Et 2O
to give methyl (E)-2-formyl-3-(4-nitrophenyl)propenoate (26) in an 85%
yield.
Reaction of dimethyl acetylenedicarboxylate (10) with p-nitrobenzalde-
hyde (1a): p-Nitrobenzaldehyde (1a) (76 mg, 0.5 mmol) and 1,1,3,3-
tetramethyl-2-thiourea (3c) (6 mg, 0.05 mmol) were added to a solution
of 10 (213 mg, 1.5 mmol) in dry dichloromethane (1.5 mL). TiCl4 (55 mL,
0.5 mmol) was added dropwise at room temperature. The mixture was
stirred for 50 h and then quenched by adding saturated aqueous NaHCO3
solution (2 mL).The inorganic precipitate was removed by filtration
through Celite, and the filtrate was dried over MgSO4 and concentrated
under reduced pressure.The residue was purified by column chromatog-
raphy on silica gel eluting with hexane/ethyl acetate (1:1) to give a mixture
of (E)-2-chloro-3-[1-hydroxy-1-(4-nitrophenyl)methyl]but-2-enedioic di-
methyl ester [(E)-11] and 4-chloro-2-(4-nitro-phenyl)-5-oxo-2,5-dihydro-
furan-3-carboxylic methyl ester (12).The mixture was separated by
recycling preparative HPLC eluting with chloroform.
Methyl (E)-formyl-3-(4-nitrophenyl)propenoate (26): pale yellow needles
(from AcOEt/hexane); m.p. 131 1328C; 1H NMR (400 MHz, CDCl3): d ˆ
3.88 (s, 3H; SMe), 7.58 (s, 1H; olefinic H), 7.68, 8.28 (d, J ˆ 8.8 Hz, each 2H;
ArH), 9.72 (s, 1H; CHO); 13C NMR (100 MHz, CDCl3): d ˆ 52.9 (q), 124.0
(d), 130.6 (d), 136.2 (s), 138.6 (s), 146.2 (d), 148.9 (s), 165.1 (s), 188.7 (d); IR
À1
ˆ
ˆ
(KBr): nÄ ˆ 1738 (C O), 1675 (C O), 1516 (NO2), 1350 cm (NO2); MS
‡
(EI): m/z (%): 235 (10) [M ], 203 (100); HRMS (EI) calcd for C11H9NO5:
‡
235.0481; found: 235.0486 [M ].
(E)-2-Chloro-3-[1-hydroxy-1-(4-nitrophenyl)methyl]but-2-enedioic
di-
Reaction of sulfonium salt 25 with TiCl4: a) Me3OBF4 (18 mg, 0.12 mmol)
was added to a solution of 9a (28 mg, 0.1 mmol) in dry dichloromethane
(0.5 mL) at 08C.The mixture was stirred at room temperature for 1 h
followed by the addition of TiCl4 (3 mL, 0.03 mmol) and stirred for 3 days.
The reaction mixture was quenched by the addition of saturated aqueous
NaHCO3 solution, and the inorganic precipitate was removed by filtration
through Celite.The filtrate was dried over MgSO 4 and concentrated under
reduced pressure.The residue was purified by preparative TLC on silica gel
with ethyl acetate/hexane (3:10) to give methyl (Z)-3-chloro-2-[1-hydroxy-
1-(4-nitrophenyl)methyl]acrylate (7a) in a 21% yield.The product was
identical with an authentic Z isomer obtained from the reaction of 6a with
1a.
methyl ester [(E)-11]:colorless needles (from hexane/chloroform); m.p.
1648C; 1H NMR (400 MHz, CDCl3): d ˆ 3.48 (d, J ˆ 7 Hz, 1H; OH), 3.76,
3.87 (each 3H, s; CO2Me), 6.06 (d, J ˆ 7 Hz, 1H; benzylic H), 7.66, 8.23
(each d, J ˆ 8 Hz, 2H; ArH); 13C NMR (100 MHz, CDCl3): d ˆ 53.2 (q),
53.8 (q), 71.3 (d), 123.8 (d), 127.1 (d), 129.4 (s), 140.0 (s), 146.3 (s), 147.8 (s),
ˆ
162.1 (s), 164.9 (s); IR (KBr): nÄ ˆ 3481 (OH), 1716 (C O), 1523 (NO2),
‡
1342 cmÀ1 (NO2); MS (EI): m/z (%): 329 (1) [M ], 147 (100); elemental
analysis calcd (%) for C13H12ClNO7: C 47.36, H 3.67, N 4.25; found: C 47.15,
H 3.65, 4.31.
4-Chloro-2-(4-nitrophenyl)-5-oxo-2,5-dihydrofuran-3-carboxylic
methyl
ester (12): yellow oil; 1H NMR (400 MHz, CDCl3): d ˆ 3.83 (s, 3H;
CO2Me), 6.24 (s, 1H; benzylic H), 7.52, 8.27(each d, J ˆ 9 Hz, 2H; ArH);
13C NMR (100 MHz, CDCl3): d ˆ 53.2 (q), 80.8 (d), 124.1 (d), 128.4 (d),
b) Me3OBF4 (35 mg, 0.24 mmol) was added to a solution of 9a (57 mg,
0.2 mmol) in dichloromethane (1.0 mL) at 08C.The mixture was stirred at
room temperature for 1 h followed by the addition of TiCl4 (22 mL,
0.2 mmol) and stirred for 30 minutes. The reaction mixture was quenched
by the addition of saturated aqueous NaHCO3 solution, and the inorganic
precipitate was removed by filtration through Celite.The filtrate was dried
over MgSO4 and concentrated under reduced pressure.The residue was
purified by preparative TLC on silica gel with ethyl acetate/hexane (3:10)
to give acrylate 27 as a mixture of the E and Z isomers (E/Z 2:5) and (Z)-7a
in 38% and 6% yields, respectively.
130.7 (s), 139.6 (s), 145.3 (s), 148.8 (s), 159.8 (s), 166.0 (s); IR (KBr): nÄ ˆ
À1
ˆ
ˆ
3349 (OH), 1791 (C O), 1732 (C O), 1523 (NO2), 1351 cm (NO2); MS
‡
(EI): m/z (%): 297 (22)[M ], 268 (100); HRMS (EI): calcd for
‡
C13H8ClNO6: 297.0040; found: 297.0034 [M ].
Reaction of 9-phenylthioxanthylium perchlorate (22) with TiBr4 and
dimethyl sulfide (3a): TiBr4 (184 mg, 0.5 mmol) was added to a stirred
solution of 9-phenylthioxanthylium perchlorate[30] (22) (186 mg, 0.5 mmol)
and dimethyl sulfide (3a) (6 mg, 0.1 mmol) in dry dichloromethane
(1.5 mL) at À208C.The mixture was stirred at the same temperature for
3 days and then quenched by the addition of saturated aqueous NaHCO3
solution (1.5 mL). The inorganic precipitate was removed by filtration
through Celite, and the filtrate was dried over MgSO4 and concentrated
under reduced pressure.The residue was purified by preparative TLC on
silica gel with CH2Cl2/AcOEt (100:1) to give 9-phenylthioxanthen-9-ol (23)
in a 75% yield.Product 23 was identical with an authentic sample prepared
from thioxanthone and phenylmagnesium bromide.[30]
Methyl (E)-3-methylthio-2-[1-methylthio-1-(4-nitrophenyl)methyl]acry-
late [(E)-27]: Yellow oil; 1H NMR (400 MHz, CDCl3): d ˆ 2.04 (s, 3H;
SMe), 2.46 (s, 3H; SMe), 3.71 (s, 3H; OMe), 5.05 (s, 1H; benzylic H), 7.48
(d, J ˆ 8.8 Hz, 2H; ArH), 7.51 (s, 1H; olefinic H), 8.16 (d, J ˆ 8.8 Hz, 2H;
ArH); 13C NMR (100 MHz, CDCl3): d ˆ 16.2 (q), 19.8 (q), 51.3 (d), 51.8 (q),
122.1(s), 123.8 (d), 128.9 (d), 147.0 (s), 148.0 (s), 151.5 (d), 166.0 (s); IR
(NaCl) nÄ ˆ 1705 (C O), 1520 (NO2), 1347 cmÀ1 (NO2); MS (EI): m/z (%):
ˆ
‡
313 (10) [M ], 266 (100); HRMS (EI) calcd for C13H15O4NS2: 313.0442;
‡
found: 313.0434 [M ].
Synthesis of 9-methylthio-9-phenylthioxanthene (24): A 15% aqueous
sodium methanethiolate solution (700 mg, 1.5 mmol) was added to a
solution of 22 (186 mg, 0.5 mmol) in dichloromethane (1.5 mL) at room
Methyl (Z)-3-methylthio-2-[1-methylthio-1-(4-nitrophenyl)methyl]acry-
late [(Z)-27]: yellow oil; 1H NMR (400 MHz, CDCl3): d ˆ 2.17 (s, 3H;
Chem. Eur. J. 2003, 9, No. 7
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/03/0907-1501 $ 20.00+.50/0
1501

T.Kataoka et al.
FULL PAPER
SMe), 2.47 (s, 3H; SMe), 3.70 (s, 3H; OMe), 5.18 (s, 1H; benzylic H), 7.68
(d, J ˆ 8.5 Hz, 2H; ArH), 7.77 (s, 1H; olefinic H), 8.16 (d, J ˆ 8.5 Hz, 2H;
ArH); 13C NMR (100 MHz, CDCl3): d ˆ 16.4 (q), 18.8 (q), 49.4 (d), 52.0 (q),
[17] C.Zhang, X.Lu, Synthesis 1996, 586 588.
[18] G.Li, H-.X.Wei, B.S.Phelps, S.H.Kim,
H-.X.Wei, J.J.Gao, G.Li, P.W.Pare
5677 5680.
Org. Lett. 2001, 3, 823 826;
, Tetrahedron Lett. 2002, 43,
¬
123.4 (d), 125.3 (s), 129.0 (d), 146.6 (s), 146.9 (s), 148.3 (d), 164.6 (s); IR
À1
ˆ
(NaCl) nÄ ˆ 1704 (C O), 1520 (NO2), 1346 cm (NO2); MS (EI) m/z (%):
[19] a) B.M.Trost, G.R.Dake, J. Am. Chem. Soc. 1997, 119, 7595 7596;
‡
¬
313 (15) [M ], 266 (100); HRMS (EI) calcd for C13H15O4NS2 313.0442;
b) C.A.Ibarra, A.G.Csa ky», C.G.Oliva, Tetrahedron Lett. 1999, 40,
‡
found: 313.0446 [M ].
8465 8467.
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Iwamura, S.Watanabe, Angew. Chem. 2000, 112, 2448 2450; Angew.
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Tetrahedron Lett.
This work was supported in part by a Grant-in-Aid for Scientific Research
(C) (No.12672056) and JSPS Fellows (No.3824) from Japan Society for the
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