Practical and scalable syntheses of substituted ketene dithioacetal monoxides

Article abstract of DOI:10.1246/bcsj.20130148

Practical syntheses of substituted ketene dithioacetal monoxides (KDMs) from the corresponding aldehydes or ethyl trifluoroacetate are described. Newly developed procedures are scalable and versatile to provide aryl-, alkyl-, and trifluoromethyl-substitut

Full text of DOI:10.1246/bcsj.20130148

Short Articles
Bull. Chem. Soc. Jpn. Vol. 86, No. 10, 1193-1195 (2013) 1193
Table 1. Scope of Synthesis of KDMs
(Method A: Ref. 1a)
Practical and Scalable Syntheses
of Substituted Ketene
Dithioacetal Monoxides#
O
O
OH O
Triton-B
THF
SMe
SMe
SMe
via
+
R–CHO
R
R
SMe
SMe
SMe
1
A
(Method B)
(1) BuLi
(2) R–CHO
(3) Ac2O
Kei Murakami,1 Hideki Yorimitsu,*1,2
and Atsuhiro Osuka1
O
OAc O
O
t-BuOK
SMe
SMe
SMe
R
R
t-BuOH
Toluene
One-pot
SMe
SMe
SMe
1Department of Chemistry, Graduate School of Science,
Kyoto University, Sakyo-ku, Kyoto 606-8502
1
Yield/%
Entry
R
1
2ACT-C, Japan Science and Technology Agency (JST),
Method Aa)
Method Bb)
Sakyo-ku, Kyoto 606-8502
1
2
3
4
5
6
7
8
9
Ph
1a
1b
1c
1d
1e
1f
1g
1h
1i
91 (3.9 g)c),d)
89 (1.1 g)d)
79 (0.96 g)d)
94 (1.0 g)d)
72 (0.95 g)d)
21 (0.33 g)d)
25 (0.34 g)d)
0
®
®
4-ClC6H4
4-MeOC6H4
3-thienyl
1-naphthyl
9-anthryl
4-CF3C6H4
4-TBSOC6H4
Me
Received May 28, 2013
E-mail: yori@kuchem.kyoto-u.ac.jp
®
®
®
15 (0.72 g)d)
42 (1.7 g)e)
70 (5.4 g)f),g)
69 (1.6 g)h)
29 (0.96 g)i)
38 (1.7 g)j)
Practical syntheses of substituted ketene dithioacetal
monoxides (KDMs) from the corresponding aldehydes or
ethyl trifluoroacetate are described. Newly developed proce-
dures are scalable and versatile to provide aryl-, alkyl-,
and trifluoromethyl-substituted KDMs in gram scales.
®
10
11
c-hex
C6F5
1j
1k
0
0
a) Starting from 5.0 mmol of FAMSO. b) Starting from
15 mmol of FAMSO. c) Starting from 20 mmol of FAMSO.
d) E/Z > 99/1. e) E/Z = 3/1. f) Starting from 22 mmol
of FAMSO. g) E/Z = 4/1. h) E/Z = 9/1. i) E/Z = 1.5/1.
j) E/Z = 1/1.
Ketene dithioacetal monoxides (KDMs) are ketene equiv-
alents and have been employed as useful precursors of ester
derivatives.1 Although KDMs are potentially attractive building
blocks, general use of KDMs has been limited to the synthesis
of esters. Recently, we have developed new transformations
from KDMs to multisubstituted carbonyl compounds2 and
polycyclic aromatic compounds3 through extended Pummerer
reactions.4 In the course of our studies, we naturally required
sufficient amounts of various KDMs as starting materials.
Generally, KDMs have been prepared from methyl meth-
ylsulfinylmethyl sulfide (FAMSO)5 and aromatic aldehydes
under basic conditions.1a,1b Although the synthesis is easy and
scalable, the scope is limited to electronically neutral or rich
aromatic aldehydes. Herein, we report versatile and scalable
protocols for the preparation of KDMs.
First, we evaluated the scope of Method A that was
developed by Ogura1a,1b (Table 1, upper). Treatment of benzal-
dehyde with FAMSO in the presence of a catalytic amount
of Triton-B afforded 1a in 91% yield (Entry 1). The reactions
by Method A were stereoselective to give thermodynamically
stable E-isomers exclusively. Although the reactions of elec-
tronically neutral or rich aromatic aldehydes resulted in high
yields, a bulky 9-anthryl group and an electron-withdrawing
trifluoromethyl group retarded the reactions (Entries 1-5 vs.
Entries 6 and 7). Albeit the low yields of 1f and 1g, Method A
is still efficient since it is a stereoselective one-step process.
A siloxy group was not tolerated under the conditions
of Method A and 4-hydroxybenzaldehyde was recovered
(Entry 8). We thus developed an alternative two-pot procedure
(Method B). Treatment of FAMSO with butyllithium afforded
lithiated FAMSO, which reacted with an aldehyde to provide
the corresponding lithium alkoxide. Addition of acetic anhy-
dride to the solution gave the corresponding acetate in one pot.
Subsequent elimination with potassium tert-butoxide yielded
the corresponding KDM. Method B was scalable and 5.4 g
of 1h was obtained from 22 mmol of FAMSO in 70% overall
yield (Entry 8). Not only aryl- but also alkyl-substituted KDMs
were synthesized from the corresponding aliphatic aldehydes.
The reaction with acetaldehyde afforded 1i in 69% overall
yield (Entry 9). Method B realized a gram-scale synthesis
of bulky cyclohexyl-substituted KDM 1j while 1j was not
accessible by Method A (Entry 10). Electron-deficient KDM
1k was also easily prepared by Method B (Entry 11). The reac-
tion of pentafluorobenzaldehyde by Method A did not proceed
to give 1k because the electron-withdrawing group increased
the acidity of the hydroxy group to prevent the E1cB reaction
from intermediate A.
Method B is not applicable to prepare trifluoromethyl-
substituted KDM 6 because trifluoroacetaldehyde is not avail-
able.6 We thus invented a scalable synthetic route from ethyl
trifluoroacetate (Scheme 1). The reaction of ethyl trifluoro-
acetate with lithiated bis(methylthio)methane (2) afforded the
corresponding ketone 3. The ketone moiety was reduced by
LAH and then the hydroxy group was acetylated with acetic
anhydride to give 4. Oxidation of one of the sulfanyl groups by
mCPBA provided 5. Elimination with potassium tert-butoxide
furnished 4.7 g of CF3-substituted KDM 6 in 46% overall yield
from 2. Notably, the overall transformation necessitated puri-
fication only once in the last step to yield 6.
Published on the web July 20, 2013; doi:10.1246/bcsj.20130148

1194 Bull. Chem. Soc. Jpn. Vol. 86, No. 10 (2013)
© 2013 The Chemical Society of Japan
BuLi
(1) LAH
O
OAc
(15 mL) was added. After extraction with ethyl acetate (20
mL © 3), the combined organic part was dried over Na2SO4
and concentrated. The crude mixture was purified on silica gel
(hexane/ethyl acetate 2:1 mixture as an eluent) to afford 1h in
70% (5.4 g, 16 mmol, E/Z = 4:1) overall yield.
SMe CF3CO2Et
(2) Ac2O, Et3N
SMe
SMe
SMe
F3C
F3C
SMe
THF
[a]
SMe
[b]
2
3
4
O
OAc O
SMe
mCPBA
t-BuOK
SMe
F3C
46% (4.7 g)
(E/Z = 4/1)
50 mmol scale
Method C:
[a] Bis(methylthio)methane (2) (5.1 mL,
F3C
t-BuOH/Toluene
SMe
50 mmol) and THF (50 mL) were added to a 100-mL flask. The
mixture was cooled to ¹20 °C. Butyllithium (34 mL, 55 mmol,
1.6 M solution in hexane) was then added to the flask and the
resulting mixture was stirred for 1 h at ¹20 °C. The solution
was cannulated to a THF (100 mL) solution of ethyl trifluoro-
acetate (12 mL, 100 mmol) in a 300-mL flask at ¹78 °C. The
mixture was gradually warmed to 25 °C over 2 h and stirred for
an additional 12 h. An addition of water (50 mL) was followed
by extraction with ethyl acetate (40 mL © 3). The combined
organic layer was dried over Na2SO4 and concentrated in vacuo
to give the corresponding ketone 3 as white solids. [b] Ketone
3 and THF (100 mL) were placed in a 300-mL flask and
the solution was cooled to ¹78 °C. LAH (1.9 g, 50 mmol) was
added to the solution. The mixture was warmed to 25 °C over
1 h and stirred for an additional 3 h. The reaction was quenched
with EtOAc (25 mL) and then aq. HCl (1 M, 50 mL). The
organic compounds were extracted with ether (40 mL) three
times. The combined organic part was washed with brine, dried
over Na2SO4, and concentrated to give the corresponding
alcohol. The alcohol was diluted with dichloromethane (100
mL). 4-Dimethylaminopyridine (0.61 g, 5.0 mmol) and tri-
ethylamine (8.4 mL, 60 mmol) were added to the solution. The
mixture was cooled to 0 °C and acetic anhydride (5.7 mL, 60
mmol) was added subsequently. The mixture was warmed to
25 °C and stirred for 12 h. The crude mixture was then filtered
through a pad of silica gel and concentrated under reduced
pressure to yield the corresponding ester 4. [c] A dichloro-
methane (300 mL) solution of 4 was cooled to ¹20 °C. mCPBA
(2.8 g, 13 mmol) was added to the solution and the resulting
mixture was stirred at ¹20 °C for 30 min. The procedure
(addition/30-min stirring) was repeated 4 times to add overall
11 g (50 mmol) of mCPBA. The portionwise additions of
mCPBA at the low-temperature are the key to prevent over
oxidation. After the last addition, the mixture was stirred at
0 °C for 2 h and then at 25 °C for an additional 2 h. The reac-
tion was quenched with aq. Na2S2O3 (40 mL). The product
was partitioned with ethyl acetate (30 mL © 3). The combined
organic layer was washed with brine and then dried over
Na2SO4 and concentrated in vacuo to afford 5. [d] Sulfoxide 5,
t-BuOH (25 mL), and toluene (45 mL) were placed in a 100-mL
flask. The mixture was cooled to 0 °C. t-BuOK (5.6 g, 50
mmol) was added to the flask portionwise and the resulting
mixture was then stirred for 30 min. The reaction was quenched
with H2O (50 mL). The organic compounds were extracted with
ethyl acetate (40 mL) three times. The combined organic part
was dried over Na2SO4 and concentrated in vacuo. Chromato-
graphic purification on silica gel (hexane/ethyl acetate = 1:1)
afforded 6 in 46% (4.7 g, 23 mmol, E/Z = 4:1) overall yield
from 2.
SMe
[c]
[d]
5
6
Scheme 1. Synthesis of CF3-substituted KDM 6 (Method C).
Experimental
General. 1H NMR (600 MHz), 19F NMR (565 MHz), and
13C NMR (151 MHz) spectra were taken on a JEOL ECA-600
spectrometer and were recorded in CDCl3. Chemical shifts (¤)
are in parts per million relative to chloroform at 7.26 ppm
1
for H and relative to CDCl3 at 77.2 ppm for 13C. Hexafluoro-
benzene was used as the external reference for 19F (¤ = ¹162.9
ppm). IR spectra were determined on a JASCO IR-810. Mass
spectra were determined on a Bruker micrOTOF II spectrom-
eter. TLC analyses were performed on commercial glass plates
bearing a 0.25-mm layer of Merck Silica gel 60F254. Silica gel
(Wakogel 300 mesh) was used for column chromatography.
Unless otherwise noted, materials obtained from commercial
suppliers were used without further purification. FAMSO
and bis(methylthio)methane were purchased from Wako Pure
Chemical Industries, Ltd. Triton-B was purchased from TCI
Co., Ltd. Anhydrous THF was purchased from Wako Pure
Chemical Industries, Ltd. and stored under nitrogen atmos-
phere. All reactions were carried out under nitrogen.
Synthetic Procedures.
Method A:
Synthesis of 1a
is representative. FAMSO (2.1 mL, 20 mmol), benzaldehyde
(3.0 mL, 30 mmol), and THF (5 mL) were added to a 20-mL
two-necked flask. Triton-B (2 mL, 4.4 mmol, 40% solution in
methanol) was added to the solution and the resulting mixture
was heated to 60 °C for 6 h. The mixture was cooled to 25 °C,
filtered through a pad of silica gel, and then concentrated
in vacuo. The crude mixture was purified by silica gel column
chromatography (hexane/ethyl acetate 1:1 mixture as an elu-
ent) to afford 1a in 91% (3.9 g, 18 mmol) yield.
Method B:
Synthesis of 1h is representative. FAMSO
(2.3 mL, 22 mmol) and THF (15 mL) were added to a 100-mL
two-necked flask. At ¹40 °C, butyllithium (15 mL, 25 mmol,
1.6 M solution in hexane) was slowly added to the solution and
the resulting mixture was stirred for 30 min. 4-(tert-Butyldi-
methylsiloxy)benzaldehyde (5.8 g, 25 mmol) in THF (15 mL)
was added to the solution at the same temperature and stirring
continued for 30 min. The mixture was gradually warmed to
0 °C and acetic anhydride (3.1 mL, 34 mmol) was then added.
The mixture was warmed to 25 °C and stirred for an addi-
tional 1 h. A saturated solution of NH4Cl (15 mL) was added.
The organic compounds were extracted with ethyl acetate (20
mL © 3). The combined organic part was dried over Na2SO4
and concentrated in vacuo. The crude mixture was diluted with
toluene (22 mL) and t-BuOH (22 mL). The solution was cooled
to 0 °C and t-BuOK (2.5 g, 22 mmol) was added to the solu-
tion. The mixture was gradually warmed to 25 °C over 1 h and
stirred for an additional 1 h. A saturated solution of NH4Cl
Characterization Data. Products 1a,1b 1b,1b 1c,1b 1e,7 and
1i8 are known compounds and showed identical spectra
according to the literature. Although the two stereoisomers of
KDMs were not completely separable, the major E-isomers can

K. Murakami et al.
Bull. Chem. Soc. Jpn. Vol. 86, No. 10 (2013) 1195
be isolated in analytically pure forms after extensive purifica-
tion by silica gel column chromatography.
7.44 (s, 1H). 19F NMR: ¤ ¹162.70 (m, 2F), ¹154.15 (m, 1F),
¹138.45 (m, 2F). HRMS (APCI) Found: m/z 302.9941. Calcd
for C10H8OF5S2 [M + H]+: 302.9931. (Z)-Isomer: 1H NMR:
¤ 2.56 (s, 3H), 2.81 (s, 3H), 6.27 (s, 1H).
(E)-1-Methylsulfanyl-1-methylsulfinyl-2-(3-thienyl)-
ethene (1d): Oil. IR (neat): 1592, 1417, 1288, 1159, 1056,
1
856, 781 cm¹1. H NMR: ¤ 2.34 (s, 3H), 2.74 (s, 3H), 7.36-
(E)-2-Trifluoromethy-1-methylsulfanyl-1-methylsulfinyl-
7.37 (m, 1H), 7.66 (s, 1H), 7.77-7.78 (s, 1H), 7.92-7.93 (m,
1H). 13C NMR: ¤ 18.44, 40.45, 126.15, 128.46, 129.11, 131.06,
135.38, 138.49. HRMS (ESI) Found: m/z 240.9789. Calcd for
C8H10OS3Na [M + Na]+: 240.9786.
lethene (6): Oil. IR (neat): 1606, 1296, 1114, 1068, 938, 750
¹1
cm
.
1H NMR: ¤ 2.45 (s, 3H), 2.81 (s, 3H), 6.86 (q, J =
7.8 Hz, 1H). 19F NMR: ¤ ¹59.39. 13C NMR: ¤ 17.27, 40.69,
122.23 (q, J = 37 Hz), 122.44 (q, J = 270 Hz), 157.18. HRMS
(APCI) Found: m/z 204.9971. Calcd for C5H7OF3S2 [M]+:
(E)-2-(9-Anthryl)-1-methylsulfanyl-1-methylsulfinyl-
ethene (1f): Solid. Mp: 136.3-137.5 °C. IR (neat): 1522,
1
204.9963. (Z)-Isomer: H NMR: ¤ 2.38 (s, 3H), 2.84 (s, 3H),
1
1419, 1261, 1145, 1070, 748 cm¹1. H NMR: ¤ 1.81 (s, 3H),
5.45 (q, J = 8.6 Hz, 1H).
3.05 (s, 3H), 7.50-7.51 (m, 4H), 7.97-7.98 (m, 2H), 8.04-8.05
(m, 2H), 8.46 (s, 1H), 8.49 (s, 1H). 13C NMR: ¤ 17.39, 41.18,
125.52, 125.62, 126.33, 128.02, 128.22, 129.10, 129.18,
131.38, 134.01, 147.54. HRMS (ESI) Found: m/z 335.0543.
Calcd for C18H16OS2Na [M + Na]+: 335.0535. Crystallo-
graphic data have been deposited with Cambridge Crystallo-
graphic Data Centre: Deposition number CCDC-947652 for
compound 1f. Copies of the data can be obtained free of charge
via http://www.ccdc.cam.ac.uk/conts/retrieving.html (or from
the Cambridge Crystallographic Data Centre, 12, Union Road,
Cambridge, CB2 1EZ, U.K.; Fax: +44 1223 336033; e-mail:
deposit@ccdc.cam.ac.uk).
This work was supported by Grants-in-Aid from MEXT
(No. 24106721 “Reaction Integration”) and from JSPS
(Nos. 24685007 and 23655037). K.M. acknowledges JSPS
Fellowship for Young Scientists.
References
#
Dedicated to Professor Teruaki Mukaiyama in celebration
of the 40th anniversary of the Mukaiyama aldol reaction.
a) K. Ogura, G.-i. Tsuchihashi, Tetrahedron Lett. 1972, 13,
1
1383. b) K. Ogura, Y. Ito, G.-i. Tsuchihashi, Bull. Chem. Soc. Jpn.
1979, 52, 2013. c) P. Garner, W. B. Ho, H. Shin, J. Am. Chem. Soc.
1993, 115, 10742. d) K. Krohn, S. Cludius-Brandt, Synthesis 2010,
2616. e) K. Ogura, K. Arai, G.-i. Tsuchihashi, Bull. Chem. Soc.
Jpn. 1982, 55, 3669.
(E)-2-(4-Trifluoromethylphenyl)-1-methylsulfanyl-1-
methylsulfinylethene (1g): Oil. IR (neat): 1616, 1319, 1164,
1
1110, 1064, 831 cm¹1. H NMR: ¤ 2.32 (s, 3H), 2.79 (s, 3H),
7.65 (s, 1H), 7.66-7.67 (m, 2H), 7.95-7.96 (m, 2H). 19F NMR:
¤ ¹63.97. 13C NMR: ¤ 18.17, 40.54, 124.00 (q, J = 271 Hz),
125.69 (d, J = 4.3 Hz), 130.12, 131.12 (q, J = 33 Hz), 134.08,
137.11, 144.17. HRMS (ESI) Found: m/z 303.0105. Calcd for
2
a) S. Yoshida, H. Yorimitsu, K. Oshima, Org. Lett. 2009,
11, 2185. b) T. Kobatake, S. Yoshida, H. Yorimitsu, K. Oshima,
Angew. Chem., Int. Ed. 2010, 49, 2340. c) K. Murakami, J. Imoto,
H. Matsubara, S. Yoshida, H. Yorimitsu, K. Oshima, Chem.®Eur.
J. 2013, 19, 5625. d) H. Yorimitsu, J. Synth. Org. Chem., Jpn.
2013, 71, 341.
1
C11H11F3OS2Na [M + Na]+: 303.0096. (Z)-Isomer: H NMR:
¤ 2.54 (s, 3H), 2.76 (s, 3H), 6.85 (s, 1H), 7.39-7.40 (m, 2H),
7.62-7.64 (m, 2H).
3
a) S. Yoshida, H. Yorimitsu, K. Oshima, Chem. Lett. 2008,
(E)-2-[4-(tert-Butyldimethylsiloxy)phenyl]-1-methylsul-
37, 786. b) S. Yoshida, H. Yorimitsu, K. Oshima, Org. Lett. 2007,
9, 5573. c) T. Kobatake, D. Fujino, S. Yoshida, H. Yorimitsu, K.
Oshima, J. Am. Chem. Soc. 2010, 132, 11838. d) Y. Ookubo, A.
Wakamiya, H. Yorimitsu, A. Osuka, Chem.®Eur. J. 2012, 18,
12690.
fanyl-1-methylsulfinylethene (1h):
Oil. IR (neat): 1733,
1599, 1504, 1261, 1170, 1064, 988, 835, 781 cm¹1. 1H NMR: ¤
0.23 (s, 6H), 0.99 (s, 9H), 2.32 (s, 3H), 2.73 (s, 3H), 6.86-6.88
(m, 2H), 7.54 (s, 1H), 7.85-7.86 (m, 2H). 13C NMR: ¤ ¹4.18,
18.42, 19.64, 25.79, 40.43, 120.39, 131.91, 136.34, 137.23,
138.58, 157.36. HRMS (ESI) Found: m/z 343.1231. Calcd
4
Recent examples of extended Pummerer reactions: a) S.
Akai, K. Kakiguchi, Y. Nakamura, I. Kuriwaki, T. Dohi, S. Harada,
O. Kubo, N. Morita, Y. Kita, Angew. Chem., Int. Ed. 2007, 46,
7458. b) K. S. Feldman, M. D. Fodor, J. Org. Chem. 2009, 74,
3449. c) A. Padwa, S. Nara, Q. Wang, Tetrahedron Lett. 2006, 47,
595. d) X. Huang, N. Maulide, J. Am. Chem. Soc. 2011, 133, 8510.
e) A. J. Eberhart, J. E. Imbriglio, D. J. Procter, Org. Lett. 2011, 13,
5882. f) K. Haraguchi, H. Matsui, S. Takami, H. Tanaka, J. Org.
Chem. 2009, 74, 2616. g) A. J. Eberhart, D. J. Procter, Angew.
Chem., Int. Ed. 2013, 52, 4008. h) X. Huang, M. Patil, C. Farès, W.
Thiel, N. Maulide, J. Am. Chem. Soc. 2013, 135, 7312.
1
for C16H27O2S2Si [M + H]+: 343.1216. (Z)-Isomer: H NMR:
¤ 0.21 (s, 6H), 0.99 (s, 9H), 2.54 (s, 3H), 2.75 (s, 3H), 6.82-
6.83 (m, 2H), 7.07 (s, 1H), 7.18-7.19 (m, 2H).
(E)-2-Cyclohexyl-1-methylsulfanyl-1-methylsulfinyl-
ethene (1j): Solid. Mp: 58.8-60.8 °C. IR (neat): 1602, 1448,
1419, 1261, 1147, 1061, 966, 750 cm¹1. 1H NMR: ¤ 1.22-1.37
(m, 6H), 1.62-1.78 (m, 4H), 2.31 (s, 3H), 2.67 (s, 3H), 2.84-
2.86 (m, 1H), 6.75 (d, 1H, J = 9.8 Hz). 13C NMR: ¤ 19.82,
25.66 (2C), 25.90, 32.34, 32.39, 38.95, 40.44, 139.17, 148.26.
HRMS (ESI) Found: m/z 219.0870. Calcd for C10H19OS2
5
Preparation of FAMSO: K. Ogura, G.-i. Tsuchihashi, Bull.
Chem. Soc. Jpn. 1972, 45, 2203.
Trials for the reaction of trifluoroacetaldehyde ethyl hemi-
acetal with FAMSO in the presence of Triton-B failed.
F. Sandrinelli, G. Fontaine, S. Perrio, P. Beslin, J. Org.
Chem. 2004, 69, 6916.
1
[M + H]+: 219.0872. (Z)-Isomer: H NMR: ¤ 1.13-1.32 (m,
6
6H), 1.67-1.82 (m, 4H), 2.43 (s, 3H), 2.68 (s, 3H), 2.74-2.82
(m, 1H), 6.06 (d, 1H, J = 10 Hz).
7
(E)-2-Pentafluorophenyl-1-methylsulfanyl-1-methylsulfi-
nylethene (1k): Oil. IR (neat): 1517, 1492, 1425, 1261, 1132,
8
Y. Kitahara, M. Mochii, M. Mori, A. Kubo, Tetrahedron
1
1065, 1004, 962 cm¹1. H NMR: ¤ 2.33 (s, 3H), 2.87 (s, 3H),
2003, 59, 2885.