A novel effective electrophile: β-trifluoroacetylketene diphenyldithioacetal S,S-tetroxide

Article abstract of DOI:10.1016/j.tetlet.2003.12.022

A synthesis of a novel electrophilic reagent - β- trifluoroacetylketene diphenyldithioacetal S,S-tetroxide 3 is described. The reaction of 3 with various electron-rich aromatics such as 1,3-dimethoxybenzene, 2-methylthiophene, N-methylpyrrole, and 2-methylindole was investigated. In the course of these reactions an unusual migration of a phenylsulfonyl group takes place. An easy and ready for scale-up procedure for the synthesis of previously unknown β-aryl, α-phenylsulphonyl substituted α,β-unsaturated trifluoromethyl ketones is reported.

Full text of DOI:10.1016/j.tetlet.2003.12.022

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1129–1132
A novel effective electrophile:
b-trifluoroacetylketene diphenyldithioacetal S,S-tetroxide
Arkady L. Krasovsky, Sergej V. Druzhinin, Valentine G. Nenajdenko*
and Elizabeth S. Balenkova
Department of Chemistry, Moscow State University, 119992 Moscow, Russia
Received 15 October 2003; revised 24 November 2003; accepted 5 December 2003
Abstract—A synthesis of a novel electrophilic reagent––b-trifluoroacetylketene diphenyldithioacetal S,S-tetroxide 3 is described.
The reaction of 3 with various electron-rich aromatics such as 1,3-dimethoxybenzene, 2-methylthiophene, N-methylpyrrole, and
2-methylindole was investigated. In the course of these reactions an unusual migration of a phenylsulfonyl group takes place. An
easy and ready for scale-up procedure for the synthesis of previously unknown b-aryl, a-phenylsulphonyl substituted a,b-unsatu-
rated trifluoromethyl ketones is reported.
Ó 2003 Elsevier Ltd. All rights reserved.
Introduction of fluorine into organic compounds often
leads to enhanced physiological activity.1;2 During our
studies on nucleophilic substitution at olefinic carbon
atoms, it was found that b-trifluoroacetylvinylsulfones
react readily with various N-,3 S-,4 and C-nucleophiles5
to give b-substituted trifluoromethylketones in high
yields. Moreover it was shown that b-trifluoroacetyl-
vinylsulfones are excellent bielectrophiles6 and dieno-
philes.7 Introduction of an additional phenylsulfonyl
group at the a-position of b-trifluoroacetylvinylsulfones
leads to an increase in their electrophilicity and the
presence of a phenylsulfonyl group in products. More-
over, the presence of an RSO2-group enlarges the range
of further possible modifications of products. These
facts prompted us to develop a convenient synthetic
method for b-trifluoroacetylketene diphenyldithioacetal
tetroxide starting from b-trifluoroacetylketene S,S-ace-
tal,8 which was expected to be an excellent electrophile.
Trifluoroacetylketene diphenyldithioacetal tetroxide
could serve as a versatile building block for the con-
struction of functionalized heterocycles bearing trifluoro-
methyl groups.
readily available triphenyl trithioorthoacetate. The next
task was the oxidation of 1 to the corresponding
tetroxide 3. Earlier we found trifluoroperacetic acid in
non-aqueous media to be an excellent oxidant for elec-
tron-deficient sulfur atoms in alkenes containing several
strongly electron-withdrawing groups.4;9 The use of tri-
fluoroacetic acid or its anhydride and aqueous hydrogen
peroxide for this purpose had been previously reported10
and its higher oxidative ability over that of commonly
used m-CPBA was demonstrated. However, oxidation
of 1 in aqueous trifluoroacetic acid yielded bis(phenyl-
sulfonyl)methane 2. We believe that water easily adds to
the electron-deficient double bond even in strongly
€
acidic media, followed by retro-Knovenagel reaction
(Scheme 1). We found that the preparation of tri-
fluoroacetylketene diphenyldithioacetal tetroxide
3
demands water-free conditions11 using CF3CO3H pre-
pared by cautious addition of trifluoroacetic anhydride
to ice-cold 98–99% hydrogen peroxide.12 It should also
be noted that the ketenedithioacetal tetroxide 3 is an
extremely reactive electrophile and easily reacted with
water to form bis(phenylsulfonyl)methane 2.
We prepared the b-trifluoroacetylketene S,S-acetal 1
We found that trifluoroacetylketene diphenyldithio-
acetal tetroxide 3 being a highly reactive electrophile
easily reacts at room temperature with 1,3-dimethoxy-
benzene and 2-methylthiophene to form ketones 4, 5 in
high yields (Scheme 2).13 It was found that the reaction
of 3 with electron-rich aromatics proceeds in an unusual
way to form 1,1,1-trifluoro-4-aryl-3-(phenylsulfonyl)-
but-3-en-2-ones that could be important structural units
using the Hojo procedure8 by the trifluoroacetylation of
Keywords: Electrophile; b-Trifluoroacetylketene dithioacetal S,S-
tetroxide; Alkene; Aromatic substitution.
* Corresponding author. Tel.: +7-095-939-2276; fax: +7-095-932-8846;
e-mail: nen@acylium.chem.msu.ru
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.12.022

1130
A. L. Krasovsky et al. / Tetrahedron Letters 45 (2004) 1129–1132
CF
CF
3
3
O
PhSO2
PhSO2
PhSO2
PhSO2
PhS
PhS
O
(CF3CO)2O
H2O2 (98%)
CF3CO2H
H2O2 (50%)
3, 95%
2, 80%
1
H2O
- CF3COCHO
Scheme 1.
O
O
O
O
O
+
COCF3
SO2Ph
SO2Ph
COCF3
CH2Cl2, 20 °C
76%
CF3
O
PhSO2
PhSO2
O
4b
4a
4a / 4b - 7 / 1
3
S
COCF3
SO2Ph
S
CH2Cl2, 20 °C
81%
5
Scheme 2.
for the synthesis of fluorine containing biologically
active compounds. It should be noted that this type of
compound was previously unknown. This is obviously
due to the absence of appropriate methods for the
synthesis of unsaturated CF3 ketones.
It is interesting that in the case of reaction of tetroxide 3
with more electron-rich compounds such as 2-methyl-
indole and N-methylpyrrole, elimination of a sulphonyl
group at room temperature does not take place. Satu-
rated adducts 6, 8 with a migrated phenylsulfonyl group
were obtained as a mixture of diastereomers. The reac-
tions proceed stereoselectively under very mild condi-
tions. The phenylsulfonyl group could be easily
eliminated from the adduct with N-methylpyrrole 6 by
reflux in dichloromethane with the formation of corre-
sponding unsaturated ketone 7, whereas 2-methylindole
substituted ketone 9 could be obtained only using tri-
ethylamine-promoted elimination, prolonged refluxing
in dichloromethane did not lead to the elimination of the
phenylsulfonyl group. In both cases, only elimination of
b-phenylsulfonyl group occurred due to deprotonation
of the more acidic a-hydrogen between the two electron-
withdrawing groups (Scheme 3).
The structure of 4a was unambiguously established by
X-ray crystallography14 (Fig. 1). It was found that a
migration of a phenylsulfonyl group had taken place
and the adduct 4a has the E-configuration. We believe
that the predominance of E-isomer 4a and the absence
of Z-isomer in the case of reaction with 2-methylthio-
phene is connected to the size of the trifluoroacetyl
group in comparison with a phenylsulfonyl group.
In conclusion, we have prepared a new highly active
electrophile-b-trifluoroacetylketene diphenyldithioacetal
tetroxide 3. We have investigated tetroxide 3 in Michael
reactions with electron rich aromatics, which permits
access to various previously unknown 1,1,1-trifluoro-4-
aryl-3-(phenylsulfonyl)but-3-en-2-ones in good yields.
Tetroxide 3 was proved to be a good synthetic equiva-
lent of a 1,1,1-trifluoro-3-(phenylsulfonyl) but-3-en-2-
one cation in reactions with electron-rich aromatics
(Scheme 4). The procedure is extremely simple and can
be easily scaled up. These results allow us to expect that
it can be extended to the synthesis of a variety of
b-substituted a-sulfonyl vinyl trifluoromethyl ketones.
Figure 1. ORTEP molecular structure of 4a.

A. L. Krasovsky et al. / Tetrahedron Letters 45 (2004) 1129–1132
1131
N
CH2Cl2
N
N
COCF3
SO2Ph
COCF3
SO2Ph
CH2Cl2, 0 °C
74%
∆, 24h
PhSO2
77%
CF3
6
7
O
PhSO2
PhSO2
mixture of diastereomers 4.3 / 1
H
N
H
N
3
N
H
COCF3
Et3N
COCF3
SO2Ph
CH2Cl2, 0 °C
89%
rt, 2h
93%
PhSO2
SO2Ph
8
9
mixture of diastereomers 6.7 / 1
Scheme 3.
10. Pouzet, P.; Erdelmeier, I.; Ginderow, D.; Mornon, J.-P.;
Dansette, P.; Mansuy, D. J. Chem. Soc., Chem. Commun.
1995, 473; Pouzet, P.; Erdelmeier, I.; Ginderow, D.;
Mornon, J.-P.; Dansette, P.; Mansuy, D. J. Heterocycl.
Chem. 1997, 34, 1567; Ho, M. T.; Treiber, A.; Dansette, P.
Tetrahedron Lett. 1998, 39, 5049–5052; Lu, Y.; Lemal, D.
M.; Jasinski, J. P. J. Am. Chem. Soc. 2000, 122, 2440–
2445.
CF3
CF3
O
PhSO2
PhSO2
O
+
SO2Ph
Scheme 4.
11. Preparation of b-trifluoroacetylketene diphenyldithioacetal
tetroxide 3: To a solution of the b-trifluoroacetylketene
S,S-acetal 18 (10 mmol) in TFA (15 mL), a mixture of
trifluoroacetic anhydride (10 mL) and 98–99% hydrogen
peroxide (60 mmol) was added at 0 °C. The solution was
stirred at 0 °C for 3 h. Removal of the solvent under
reduced pressure at 0 °C afforded the product as the light-
brown oil that was used for the further reactions without
This work is in progress in our laboratory and the
results will be reported in due course.
Acknowledgements
The research described in this publication was supported
by the Russian Fundamental Investigation Foundation
(Grant 03-03-32024-a).
1
additional purification. H NMR (400 MHz, CDCl3) 7.52
(m, 4H, m-Ph), 7.62 (m, 2H, p-Ph), 7.81 (m, 4H, o-Ph),
8.01 (s, 1H, @CAH). 13C NMR (400 MHz, CDCl3) 114.6
(q, CF3, J 290.3 Hz), 129.7, 130.1, 135.9, 136.2, 137.5,
138.1, 142.2, 153.4, 182.7 (q, C@O, J 40.9 Hz). Found: C,
47.07; H, 2.41; Anal. Calcd for C16H11F3O5S2: C, 47.52%;
H, 2.74%.
References and notes
12. Highly concentrated H2O2 was obtained according to:
Giguere, P. A. Bull. Chem. Soc. Fr. 1954, 720.
1. Chemistry of Organic Fluorine Compounds: An Update;
Hudlicky, M.; Pavlath A. E., Eds.; ACS Monograph
Series N 187; American Chemical Society: Washington,
DC, 1995.
2. Filler, A.; Kobayashi, Y. Biomedical Aspects of Fluorine
Chemistry; Kodansha Ltd.: Tokyo, 1981.
3. Krasovsky, A. L.; Nenajdenko, V. G.; Balenkova, E. S.
Russ. Chem. Bull. 2001, 8, 1329–1333.
4. Krasovsky, A. L.; Nenajdenko, V. G.; Balenkova, E. S.
Russ. Chem. Bull. 2002, 11, 1925–1930.
13. General procedure for the reaction of b-trifluoroacetyl-
ketene diphenyldithioacetal tetroxide 3 with aromatics: To
a solution of 3 (5 mmol) in dichloromethane (20 mL) the
aromatic compound (6 mmol) in dichloromethane (20 mL)
was added at rt (in the case of 2-methylindole and N-
methylpyrrole at 0 °C). Then the reaction mixture was
stirred at rt for the appropriate time (TLC control). The
organic solvents were removed in vacuo. The products
were purified by column chromatography (silica gel,
hexane).
5. Nenajdenko, V. G.; Krasovsky, A. L.; Lebedev, M. V.;
Balenkova, E. S. Synlett 1997, 12, 1349.
Selected spectra E-4a: yellow crystals, mp 147–150 °C
(dec.) 1H NMR (400 MHz, CDCl3) 3.63 (s, 3H, CH3); 3.85
(s, 3H, CH3); 6.38 (br s, 1H); 6.55 (br d, 1H, J 8.8 Hz); 7.33
(br d, 1H, J 8.8 Hz); 7.53 (br t, 2H, J 7.5 Hz); 7.62 (br t,
1H, J 7.3 Hz); 7.90 (br d, 2H, J 7.3 Hz); 8.12 (br s, 1H,
@CH). Found: C, 53.73; H, 3.61; Anal. Calcd for
C18H15F3O5S: C, 54.00%; H, 3.78%.
6. Krasovsky, A. L.; Hartulyari, A. S.; Nenajdenko, V. G.;
Balenkova, E. S. Synthesis 2002, 1, 133–137; Krasovsky,
A. L.; Moiseev, A. M.; Nenajdenko, V. G.; Balenkova,
E. S. Synthesis 2002, 7, 901–905; Krasovsky, A. L.;
Nenajdenko, V. G.; Balenkova, E. S. Synthesis 2002,
1379–1384; Arcady, L.; Krasovsky, A. L.; Moiseev, A. M.;
Nenajdenko, V. G.; Balenkova, E. S. Khem. Get. Soed.
2002, 2, 253–256.
7. Krasovsky, A. L.; Nenajdenko, V. G.; Balenkova, E. S.
Tetrahedron 2001, 57, 201–209.
8. Hojo, M.; Masuda, R. J. Org. Chem. 1975, 40, 963–965.
9. Krasovsky, A. L.; Pissarev, S. A.; Nenajdenko, V. G.;
Balenkova, E. S. J. Chem. Soc., Perkin Trans. 1 2002,
2554–2560.
8 white crystals, mixture of diastereomers a/b 6.7/1, mp
1
123–124 °C H NMR (CDCl3) 2.51 (s, 3H, a+b); 5.36 (d,
1H, J 11.9 Hz, a); 5.42 (d, 1H, J 11.7 Hz, b); 5.73 (d, 1H, J
11.7 Hz, b); 5.86 (d, 1H, J 11.9 Hz, a); 6.57 (br t, 1H, J
7.6 Hz, a); 6.65–7.30 (m, 9H, Ph+indole, a+b), 7.62 (br t,
2H, J 7.7 Hz, Ph, a+b); 7.71 (br t, 1H, J 7.4 Hz, Ph, a+b);
7.93 (br s, 1H, NH, b); 8.04 (d, 1H, J 7.5 Hz, Ph, b); 8.09
(d, 1H, J 7.5 Hz, Ph, a); 8.38 (br s, 1H, NH, a). Found: C,

1132
A. L. Krasovsky et al. / Tetrahedron Letters 45 (2004) 1129–1132
55.82; H, 3.64; Anal. Calcd for C25H20F3NO5S2: C,
56.07%; H, 3.76%.
14. Crystallographic data (excluding structure factors) for the
structures in this paper, have been deposited with the
Cambridge Crystallographic Data Centre as supplemen-
tary publication number CCDC 161708. The structure is
refined from the 1589 independent reflections to the values
RF ¼ 0.0370, wRF ¼ 0.0990. Monoclinic, space group
P21/n, Z ¼ 4, a ¼ 19:879ð4Þ, b ¼ 11:510ð2Þ, c ¼ 8:181ð2Þ,
b ¼ 101:33ð3Þ.