2-(2,2,2-trifluoroethylidene)-1,3-dithiane monoxide as a trifluoromethylketene equivalent

Article abstract of DOI:10.1021/ol9004883

A method to prepare 2-(2,2,2-trifluoroethylidene)-1,3-dithiane monoxide has been developed, and its interesting reactivity under Pummerer-like conditions is disclosed. The products are useful synthetic intermediates for the synthesis of α-trifluoromethyl

Full text of DOI:10.1021/ol9004883

ORGANIC
LETTERS
2009
Vol. 11, No. 10
2185-2188
2-(2,2,2-Trifluoroethylidene)-1,3-dithiane
Monoxide as a Trifluoromethylketene
Equivalent
Suguru Yoshida, Hideki Yorimitsu,* and Koichiro Oshima*
Department of Material Chemistry, Graduate School of Engineering, Kyoto UniVersity,
Kyoto-daigaku Katsura, Nishikyo-ku, Kyoto 615-8510, Japan
yori@orgrxn.mbox.media.kyoto-u.ac.jp; oshima@orgrxn.mbox.media.kyoto-u.ac.jp
Received March 9, 2009
ABSTRACT
A method to prepare 2-(2,2,2-trifluoroethylidene)-1,3-dithiane monoxide has been developed, and its interesting reactivity under Pummerer-like
conditions is disclosed. The products are useful synthetic intermediates for the synthesis of r-trifluoromethyl ketones.
Trifluoromethylated compounds have attracted much atten-
tion because of their important applications as biologically
active agents and advanced organic materials that exhibit
specific biological and physical properties.1 Methods for
introducing a trifluoromethyl group into an organic com-
pound have thus been investigated extensively.2 However,
R-trifluoromethylation of carbonyl compounds has remained
difficult.3 Therefore, a novel trifluoromethylketene equivalent
should be a useful building block for the synthesis of
R-trifluoromethyl carbonyl compounds.4
Recently, we have been developing the synthetic utility
of ketene dithioacetal monoxides as ketene equivalents.5
Thus, we have been interested in the chemical behavior of
trifluoromethylketene dithioacetal monoxide, 2-(2,2,2-trif-
luoroethylidene)-1,3-dithiane monoxide (1a). We anticipated
that 1a would react with nucleophile at C1 under extended
Pummerer reaction conditions5c,6 to yield ketene dithioacetal
2, which might be a very attractive intermediate for further
transformation (Scheme 1). Hydrolysis of ketene dithioacetal
(1) (a) Uneyama, K. Organofluorine Chemistry; Blackwell: Oxford,
2006. (b) Hiyama T.; Kanie, K.; Kusumoto, T.; Morizawa, Y.; Shimizu,
M. Organofluorine Compounds; Springer-Verlag: Berlin, Heidelberg, 2000.
(c) Ramachandran, P. V. Asymmetric Fluoroorganic Chemistry: Synthesis,
Applications, and Future Directions; American Chemical Society: Wash-
ington, DC, 2000. (d) Soloshonok, V. A. Enantiocontrolled Synthesis of
Fluoro-Organic Compounds: Stereochemical Challenges and Biomedical
Targets; Wiley: Chichester, 1999. (e) Chambers, R. D. Organofluorine
Chemistry; Springer: Berlin, 1997. (f) Ojima, I.; McCarthy, J. R.; Welch,
J. T. Biomedical Frontiers of Fluorine Chemistry; American Chemical
Society: Washington, DC, 1996. (g) Banks, R. E.; Smart, B. E.; Tatlow,
J. C. Organofluorine Chemistry: Principles and Commercial Applications;
Plenum Press: New York, 1994. (h) Filler, R.; Kobayashi, Y; Yagupolskii,
L. M. Organofluorine Compounds in Medicinal Chemistry and Biomedical
Applications; Elsevier: Amsterdam, 1993. (i) Hudlicky, M. Chemistry of
Organic Fluorine Compounds, 2nd ed.; Ellis Horwood: Chichester, 1976.
(2) (a) Shimizu, M.; Hiyama, T. Angew. Chem., Int. Ed. 2005, 44, 214.
(b) Ma, J.-A.; Cahard, D. Chem. ReV. 2004, 104, 6149. (c) Mikami, K.;
Itoh, Y.; Yamanaka, M. Chem. ReV. 2004, 104, 1. (d) Iseki, K. Tetrahedron
1998, 54, 13887.
(3) Selected examples: (a) Miura, K.; Takeyama, Y.; Oshima, K.;
Utimoto, K. Bull. Chem. Soc. Jpn. 1991, 64, 1542. (b) Umemoto, T.; Adachi,
K. J. Org. Chem. 1994, 59, 5692. (c) Sato, K.; Omote, M.; Ando, A.;
Kumadaki, I. Org. Lett. 2004, 6, 4359. (d) Mikami, K.; Tomita, Y.; Ichikawa,
Y.; Amikura, K.; Itoh, Y. Org. Lett. 2006, 8, 4671. (e) Eisenberger, P.;
Gischig, S.; Togni, A. Chem.sEur. J. 2006, 12, 2579.
(4) (a) Solberg, J.; Benneche, T.; Undheim, K. Acta Chem. Scand. 1989,
43, 69. (b) Huot, J.-F.; Muzard, M.; Portella, C. Synlett 1995, 247. (c)
Hanamoto, T.; Anno, R.; Yamada, K.; Ryu, K. Tetrahedron Lett. 2007, 48,
3727.
(5) (a) Yoshida, S.; Yorimitsu, H.; Oshima, K. Synlett 2007, 1622. (b)
Yoshida, S.; Yorimitsu, H.; Oshima, K. Org. Lett. 2007, 9, 5573. (c)
Yoshida, S.; Yorimitsu, H.; Oshima, K. Chem. Lett. 2008, 37, 786. (d)
Yoshida, S.; Yorimitsu, H.; Oshima, K. Heterocycles 2008, 76, 679. (e)
Yoshida, S.; Yorimitsu, H.; Oshima, K. Chem. Lett. 2009, 38, 248. (f)
Yoshida, S.; Yorimitsu, H.; Oshima, K. Heterocycles, in press, DOI:
10.3987/COM-09-S(S)6.
10.1021/ol9004883 CCC: $40.75
Published on Web 04/16/2009
 2009 American Chemical Society

Scheme 1
.
Synthesis of R-Trifluoromethyl Ketone Using the
Trifluoromethylketene Equivalent 1a
Scheme 2. Synthesis of
2-(2,2,2-Trifluoroethylidene)-1,3-dithiane Monoxide (1a)
dithioacetal 9a in high yield (Table 1, entry 1). A mixture
of E and Z isomers of 1a (E/Z ) 2:3) reacted equally as
(E)-1a to afford 9a. Perfluoroalkylketene dithioacetal mon-
oxide (E)-1b also reacted with allylsilane 8a under the same
reaction conditions (entry 2). On the other hand, the reactions
of ethylidene and phenylmethylene 1,3-dithiane monoxide
(E)-1c and (E)-1d gave complex mixtures (entries 3 and 4).
Thus, the trifluoromethyl or perfluoroalkyl group played an
important role for the successful reaction.
2 could provide thiol ester 3, which should react with
nucleophile at C2 to give R-trifluoromethyl ketone 4.7
Alternatively, reduction of 2 could afford dithiane 5, which
can participate in the conventional dithiane chemistry.8 The
synthesis of 6 would provide another route to R-trifluoro-
methyl ketone. Here, we report the synthetic method for
2-(2,2,2-trifluoroethylidene)-1,3-dithiane monoxide (1a) and
its interesting reactivity in extended Pummerer reaction.
2-(2,2,2-Trifluoroethylidene)-1,3-dithiane monoxide (1a)
was prepared starting from 1,3-dithiane and ethyl trifluoro-
acetate as a stereoisomeric mixture (E/Z ) 4:1) (Scheme 2).
The method is facile and scalable. Trifluoroacetylation of
1,3-dithiane followed by reduction and tosylation afforded
dithiane 7. Oxidation of 7 to monoxide and subsequent
treatment with potassium tert-butoxide yielded 2-(2,2,2-
trifluoroethylidene)-1,3-dithiane monoxide (1a). The stere-
oisomers of 1a were separated from each other by column
chromatography on silica gel.
Table 1. Extended Pummerer Reaction of 1 with Allylsilane 8a
entry
R
1
9
yield/%a
1
2
3
4
CF3
n-C3F7
Me
1a
1b
1c
1d
9a
9b
9c
9d
86 (85)b
84
0
7
An interesting reactivity of 2-(2,2,2-trifluoroethylidene)-
1,3-dithiane monoxide (1a) was observed in an extended
Pummerer reaction with allylsilanes. Treatment of (E)-1a
with allyltrimethylsilane (8a) in the presence of trifluo-
romethanesulfonic anhydride and 2,6-di-tert-butylpyridine in
nitromethane provided the corresponding allylated ketene
Ph
a Isolated yields. b An E/Z mixture (2:3) was used instead of pure E
isomer.
Next we examined the scope and limitation using various
allylsilanes or allylstannane 8 (Table 2). The reactions with
allyl-tert-butyldimethylsilane (8b) and allyltriethoxylsilane
(8c) also proceeded effectively to give allylated ketene
dithioacetal 9a in good yields (entries 2 and 3). On the other
hand, allyltributylstannane (8d) failed to cause efficient
allylation and afforded 9a in only 29% yield (entry 4). The
reactions with ꢀ-methyl- and ꢀ-phenyl-substituted allylsilanes
8e and 8f afforded the corresponding products 9e and 9f,
respectively, in high yields (entries 5 and 6).
(6) Selected examples: (a) Craig, D.; Daniels, K. Tetrahedron 1993, 49,
11263. (b) Kita, Y.; Takeda, Y.; Matsugi, M.; Iio, K.; Gotanda, K.; Murata,
K.; Akai, S. Angew. Chem., Int. Ed. Engl. 1997, 36, 1529. (c) Padwa, A.;
Kuethe, J. T. J. Org. Chem. 1998, 63, 4256. (d) Akai, S.; Morita, N.; Iio,
K.; Nakamura, Y.; Kita, Y. Org. Lett. 2000, 2, 2279. (e) Feldman, K. S.;
Vidulova, D. B. Org. Lett. 2004, 6, 1869. (f) Akai, S.; Kawashita, N.; Satoh,
H.; Wada, Y.; Kakiguchi, K.; Kuriwaki, I.; Kita, Y. Org. Lett. 2004, 6,
3793. (g) Padwa, A.; Nara, S.; Wang, Q. Tetrahedron Lett. 2006, 47, 595.
(h) Feldman, K. S.; Karatjas, A. G. Org. Lett. 2006, 8, 4137. (i) Feldman,
K. S.; Skoumbourdis, A. P.; Fodor, M. D. J. Org. Chem. 2007, 72, 8076.
(7) Thiol esters are useful for synthesis of aldehydes or ketones. Selected
examples: (a) Fukuyama, T.; Lin, S.-C.; Li, L. J. Am. Chem. Soc. 1990,
112, 7050. (b) Kuniyasu, H.; Ogawa, A.; Sonoda, N. Tetrahedron Lett.
1993, 34, 2491. (c) Tokuyama, H.; Yokoshima, S.; Yamashita, T.;
Fukuyama, T. Tetrahedron Lett. 1998, 39, 3189. (d) Liebeskind, L. S.; Srogl,
J. J. Am. Chem. Soc. 2000, 122, 11260. (e) Ikeda, Z; Hirayama, H.;
Matsubara, S. Angew. Chem., Int. Ed. 2006, 45, 8200.
In the reactions with γ-substituted allylsilanes (entries
7-10), unusual regioselectivity was observed.9 γ-(2-Phe-
nylethyl)-substituted allylsilane 8g reacted with 1a to yield
(8) Seebach, D.; Corey, E. J. J. Org. Chem. 1975, 40, 231.
(9) Hosomi, A.; Endo, M.; Sakurai, H. Chem. Lett. 1976, 941.
Org. Lett., Vol. 11, No. 10, 2009
2186

Table 2. Reactions of 1a with Allylsilanes or Allylstannane 8 in
the Presence of Tf2O
Scheme 3. Plausible Reaction Mechanism
A.5b,c Allylsilane 8g or 8h then attacks the cationic sulfur
along with liberation of trimethylsilyl triflate to afford
sulfonium salt B.11 Sulfonium salt B then undergoes [3,3]-
sigmatropic rearrangement via a chairlike transition state,
followed by deprotonation, to afford 9g or 9h with exclusive
stereo- and regioselectivity.11c,12,13 Although the role of the
trifluoromethyl group is still unclear, the trifluoromethyl
group might prevent generation of unstable dicationic species
via cleavage of the S-OTf bond.5b,c
The products 9 are useful synthetic intermediates. We thus
demonstrate two different approaches to synthesize R-trif-
luoromethylketones from ketene dithioacetal 9.
Treatment of ketene dithioacetal 9a with aqueous hydro-
chloric acid in acetonitrile followed by methylation yielded
thiol ester 10, which is a good electrophile in the reactions
with various nucleophiles (Scheme 4).7 For instance, pal-
ladium-catalyzed cross-coupling reactions of thiol ester 10
with organozinc reagents afforded R-trifluoromethyl ketones
11a and 11b in good yields.
Scheme 4. Synthesis of R-Trifluoromethyl Ketones 11
a Isolated yields. b 2.0 equiv of 8 was used, and the reaction was
performed at 0 °C for 1 h. c CH2Cl2 was used as a solvent instead of
CH3NO2. d CH2Cl2/CH3NO2 (1:1) was used as a solvent.
ketene dithioacetal 9g stereo- and regioselectively (entry 7),
which was produced via carbon-carbon bond formation at
the R-position of 8g. γ-Heptyl-substituted allylsilane 8h also
reacted at the R-position exclusively (entry 8).10 Notably,
9g and 9h were formed with exclusive E selectivity.
However, the reaction with cinnamylsilane 8i gave a complex
mixture with no trace amount of the expected product 9i
(entry 9). γ,γ-Disubstituted allylsilane 8j was not a good
allylating agent (entry 10).
a 50 °C, 6 h. b 0 °C, 1 h.
Reduction of ketene dithioacetal 9a proceeded smoothly
in the presence of NaBH4 and hydrochloric acid to afford
(11) (a) Baraznenok, I. L.; Nenajdenko, V. G.; Balenkova, E. S.
Tetrahedron 2000, 56, 3077. (b) Nenajdenko, V. G.; Vertelezkij, P. V.;
Balenkova, E. S. Synthesis 1997, 351. (c) Harvey, J. N.; Viehe, H. G.
J. Chem. Soc., Chem. Commun. 1995, 2345.
A plausible reaction mechanism that rationalizes the stereo-
and regioselectivity is shown in Scheme 3. Treatment of 1a
with trifluoromethanesulfonic anhydride gives sulfonium salt
(12) Thio-Claisen rearrangement of allyl vinyl sulfonium ion has been
reported: (a) Bycroft, B. W.; Landon, W. J. Chem. Soc., Chem. Commun.
1970, 967. (b) Tomita, K.; Terada, A.; Tachikawa, R. Heterocycles 1976,
(10) Dichloromethane was used as a solvent instead of nitromethane.
In the case of nitromethane, 9h was obtained in low yield probably due to
the poor solubility of 8h.
4, 733
(13) The reaction of (phenylsulfinyl)ethene with allyltrimethylsilane
under the reaction conditions afforded a complex mixture
.
.
Org. Lett., Vol. 11, No. 10, 2009
2187

12 with butyllithium followed by addition of electrophiles
afforded dithianes 13a and 13b in good yields.
Scheme 5. Synthesis of Dithiane 13
In conclusion, we have synthesized 2-(2,2,2-trifluoroeth-
ylidene)-1,3-dithiane monoxide and disclosed its interesting
reactivity under Pummerer-like conditions. The trifluoro-
methyl group plays an important role for the extended
Pummerer reaction. The product should provide a new entry
to various trifluoromethylated compounds.
Acknowledgment. This work was supported by Grants-
in-Aid for Scientific Research and GCOE Research from
MEXT and JSPS. S.Y. acknowledges JSPS for financial
support.
Supporting Information Available: Experimental pro-
cedure and characterization data of 1, 7, 9, 10, 11, 12, and
13. This material is available free of charge via the Internet
at http://pubs.acs.org.
trifluoromethylated dithiane 12, which could be used further
as an acyl anion equivalent (Scheme 5). Deprotonation of
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