First synthesis of 2-aminosubstituted-2-perfluoroalkyl-3,6-dihydro-2H-thiopyrans by hetero-Diels-Alder reactions of fluorinated thioamides under microwave heating

Article abstract of DOI:10.1016/j.tetlet.2009.12.064

This Letter presents the first examples of hetero-Diels-Alder reactions of polyfluoroalkanethiocarboxylic acid amides and 2,3-dimethylbutadiene under microwave heating. Cycloaddition reactions proved to be dependent on the nature of perfluoroalkyl chain a

Full text of DOI:10.1016/j.tetlet.2009.12.064

Tetrahedron Letters 51 (2010) 990–993
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Tetrahedron Letters
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First synthesis of 2-aminosubstituted-2-perfluoroalkyl-3,6-dihydro-2H-thio-
pyrans by hetero-Diels–Alder reactions of fluorinated thioamides under
microwave heating
c
b,
Sergey S. Mikhailichenko a,b, Jean-Philippe Bouillon a, , Thierry Besson , Yuri. G. Shermolovich
*
*
a Université de Rouen, EA 3233 & FR 3038—S.M.S., I.R.C.O.F., rue Tesnière, F-76821 Mont-Saint-Aignan Cedex, France
b Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 5, Murmanska, 02094, Kiev, Ukraine
c Université de Rouen, UMR CNRS 6014 & FR 3038—C.O.B.R.A., I.R.C.O.F., rue Tesnière, F-76131 Mont Saint-Aignan Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
This Letter presents the first examples of hetero-Diels–Alder reactions of polyfluoroalkanethiocarboxylic
acid amides and 2,3-dimethylbutadiene under microwave heating. Cycloaddition reactions proved to be
dependent on the nature of perfluoroalkyl chain and on the substituents attached to the nitrogen atom.
Formation of ammonium salts was also performed by simple treatment of the corresponding cycload-
ducts with trifluoromethanesulfonic acid. In the case of octafluorobutyl-substituted derivative, one spon-
taneous desamination reaction took place leading to new 2H-thiopyran.
Received 27 October 2009
Revised 10 December 2009
Accepted 14 December 2009
Available online 16 December 2009
Letter dedicated to the memory of Professor
Heinz G. Viehe
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Fluorine
Sulfur
2H-Thiopyran
Hetero-Diels–Alder reaction
Thioamide
Microwaves
1. Introduction
would allow obtaining fluorinated thiopyran derivatives bearing
a basic amino group.
Addition of perfluoroalkyl substituents to a thiocarbonyl group
substantially rises its dienophilic character in hetero-Diels–Alder
reactions with electron-rich 1,3-dienes giving the possibility to
synthesize fluorine-containing thiopyrane derivatives. Fluorine-
containing thioaldehydes,1–4 thioketones,3,5–7 halogenides of poly-
fluoroalkanethioncarboxylic acids5,8,9 and dithiocarboxylic acid
esters10–14 are used as such dienophiles. At the same time, polyfluo-
roalkanethioncarboxylic acid amides are inert in the reactions with
1,3-dienes. The only successful example of such cycloaddition
reaction was described by Viehe and co-workers for N-methyl-N-
acetyl-trifluorothioacetamide and was explained by the electron-
withdrawing influence of amide substituents on the thiocarbonyl
group (Scheme 1).12
2. Results and discussion
The first attempt was performed using thioamide 1a and 2,3-
dimethylbutadiene (10 equiv) under standard conditions (Scheme
2, Table 1, entry 1). Unfortunately, at room temperature, no con-
version of 1a into 3,6-dihydro-2H-thiopyran 2a was observed (by
19F NMR) in the reaction mixture after 24 h.
Then, we turned our attention to more drastic conditions. First
of all, a mixture of thioamide 1a and 2,3-dimethylbutadiene
(10 equiv) was heated in a sealed tube, at 200 °C and for 20 h,
In this Letter, we present the pioneering examples of hetero-
Diels–Alder reactions between fluorinated aliphatic thioamides
and electron-rich 1,3-dienes. Implementation of such reactions
S
CF3
CH3
rt, 2h
CH3
N
+
F3C
N
S
CH2Cl2
COCH3
COCH3
* Corresponding author.
98%
E-mail addresses: jean-philippe.bouillon@univ-rouen.fr (J.-P. Bouillon), sher-
m@ioch.kiev.ua (Yuri. G. Shermolovich).
Scheme 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.064

S. S. Mikhailichenko et al. / Tetrahedron Letters 51 (2010) 990–993
991
S
CF3
NHRR'
CF3
CF3
N
Reagents and
CF3SO3H
n-hexane
NRR'
+
F3C
N
S
S
2a,c,e
S
conditions (Table 1)
CF3SO3
O
O
3a: R,R' = (CH2)2O(CH2)2 : 92%
3c: R = H, R' = p-Tol: 89%
3e: R,R' = H: 96%
1a (1 equiv.)
2a
(10 equiv.)
Scheme 2.
Scheme 4. Ref. 22.
Table 1
Reaction of thioamide 1a with 2,3-dimethylbutadiene under various conditions
solvents (e.g., DMSO and DMF) in lots of pharmaceutical applica-
tions under microwaves and it may be eliminated by simple
extraction with water during the work up.
Entry
Reagents and conditions
Conversiona (%)
1
2
3
4
5
Neat, 25 °C, 24 h
0
In a second step, careful optimization of microwave conditions
was undertaken. Investigating various parameters (time, tempera-
ture, and power input) we observed that longer heating (>3 h) of
the reaction mixture decreased the yield of cycloadduct 2a. In
addition, several other minor fluorinated by-products appeared.
This result could be explained by possible retro-Diels–Alder reac-
tion or polymerization of 2,3-dimethylbutadiene under these con-
ditions. We also observed that the pressure in the vials was very
close to the security values (near 15–16 bars) and that lower quan-
tities of starting reactants allowed working under more acceptable
conditions. Because we also estimated that an excess of 2,3-
dimethylbutadiene was necessary for the success of the synthesis,
we decided to conduct the reaction stepwise, adding new portions
of 2,3-dimethylbutadiene to the reaction mixture every 30 min of
heating. The butadiene derivative was rapidly introduced via a syr-
inge without opening the vial, avoiding release of chemicals into
atmosphere. The overall reaction time was 2.5 h and the global
quantity of 2,3-dimethylbutadiene reached 12.5 equiv. Under
these optimized conditions (Scheme 3),20 a 77% conversion of 1a
into heterocycle 2a was estimated in accordance to 19F NMR spec-
troscopy data of the crude reaction mixture. Cycloadduct 2a21 was
purified by silica gel column chromatography affording a 43% yield
of a thermally stable liquid (Table 2).
The scope of this new hetero-Diels–Alder reaction was then ex-
tended to other perfluorinated thioamides 1b–e bearing different
types of substituents on the amino group (primary and secondary
thioamides) and various perfluoroalkyl chains (n-C3F7, (CF2)4H).
Applying the conditions described above, novel 3,6-dihydro-2H-
thiopyrans 2b–e were synthesized for the first time in low to mod-
erate yields (Table 2, 15–35%).
The basicity of amino group in compounds 2 may be sufficient
for expecting formation of the corresponding ammonium salts in
the presence of a strong acid. Thus, reaction of 2a,c,e with trifluo-
romethanesulfonic acid gave salts 3a,c,e in almost quantitative
yields (Scheme 4).22 Compounds 3a23 and 3e are viscous water sol-
uble liquids, while 3c is a crystalline product. The basic property of
heterocycles 2a,c,e is very important for further biological applica-
tions, especially in order to increase water solubility and biodi-
sponibility of possible active compounds. Indeed, we have earlier
shown that some fluorine-containing dihydrothiopyran derivatives
possess a high inotropic activity.24
Neat, sealed tube, 200 °C, 20 h
High pressure (16 kbar), 25 °C, 24 h
NMP, sealed tube, 180 °C, 16 h
NMP, microwave (400 W), Weflon™, 180 °C, 3 h
<5
<5
<5
50
a
Conversion of 1a into 2a was measured by 19F NMR in the reaction mixture.
S
RF
N
Δ
R
R
+
RF
N
microwaves
S
R`
(400W, WeflonTM
)
R'
1a-e
2a-e
Scheme 3. Ref. 20.
leading to very low conversion (Table 1, entry 2). Activation using
high pressure apparatus (16 kbar, 25 °C, 24 h) or heating in N-
methylpyrrolidone (NMP) at 180 °C for 16 h, was also used without
success (Table 1, entries 3 and 4).
The last method consists in the use of microwave irradiation
and its capacity to heat rapidly reaction mixtures as described in
various examples.15,16 Despite rate enhancement, higher product
yields and easier handling of reaction mixtures are the main ben-
efits usually described for this methodology.17
After experimental design, we found that thioamide 1a reacted
for 3 h with an excess (10 equiv) of 2,3-dimethylbutadiene in NMP
in a sealed tube under microwave irradiation18 at 180°C (400 W),
in the presence of Weflon™ (Teflon™ filled with graphite). This
material is heated by the microwave field and subsequently trans-
fers this heat to the reaction mixture (the same heating effect may
be obtained with graphite but in the case of Weflon™ dispersion of
the powder and dangerous hot-spots are suppressed). Analysis of
the reaction mixture showed 50% conversion of the starting thio-
amide into 2-morpholino-2-trifluoromethyl-3,6-dihydro-2H-thio-
pyrane 2a (Table 1, entry 5). The choice of NMP as the solvent
was justified by its efficiency to transform electromagnetic energy
into thermal energy.19 This polar aprotic solvent allows to work
until 200 °C without troublesome with vapor and high pressure
in the tubes. It is now a common replacement for more sensitive
Table 2
Reactions of thioamides 1a–e with 2,3-dimethylbutadiene under microwaves20
Entry
Thioamide
R
R0
Rf
T (°C)
Conv. (%)
Cycloadducta (%)
1
2
3
4
5
1a
1b
1c
1d
1e
(CH2)2O(CH2)2
(CH2)2O(CH2)2
H
H
H
CF3
(CF2)2CF3
CF3
(CF2)4H
CF3
185
180
125
145
85
77
50
54
50
57
2a: 43
2b: 28
2c: 26
2d: 15b
2e: 35
p-Tol
p-Tol
H
a
Isolated yields. All pure cycloadducts were obtained after purification by silica gel column chromatography.
Desamination of cycloadduct 2d took place during heating the reaction mixture under microwave irradiation.
b

992
S. S. Mikhailichenko et al. / Tetrahedron Letters 51 (2010) 990–993
S
S
(CF2)4H
CF3SO3H
n-Hexane
- CF3SO3 H3N(p-Tol)
2d
(CF2)4H
NH2(p-Tol)
H
4
30%
CF3SO3
3d
Scheme 5. Ref. 25.
13. Bouillon, J. P.; Shermolovich, Y. G.; Portella, C. Tetrahedron Lett. 2001, 42, 2133–
2135.
14. Pfund, E.; Lequeux, T.; Vazeux, M.; Masson, S. Tetrahedron Lett. 2002, 43, 2033–
2036.
15. For a recent book see: Microwaves in Organic Synthesis; Loupy, A., Ed.; Whiley-
VCH Gmbh: KGaA, Weinhein, 2006.
Compared to its congeners, the behavior of compound 2d bear-
ing a longer perfluoroalkyl substituent was slightly different.
Under analogous conditions, 2d afforded first the corresponding
salt 3d which underwent spontaneous desamination into 2H-thio-
pyran 4 (Scheme 5).25 Influence of ammonium and octafluorobutyl
substituents (which is more electron-withdrawing than trifluoro-
methyl one) would probably facilitate deprotonation of intermedi-
ate 3d. To the best of our knowledge, compound 4 is one of the first
examples of the 6-perfluoroalkyl-2H-thiopyrans. Only one highly
fluorinated compound of this type was already described in the
literature using a complex thermal rearrangement of 2,3-diaza-
bicyclo[3.2.0]heptadiene.26
16. For recent reviews see: (a) Caddick, S.; Fitzmaurice, R. Tetrahedron 2009, 65,
3325–3355; (b) Kappe, C. O.; Dallinger, D. Mol. Div. 2009, 13, 71–193; (c) De la
Hoz, A.; Diaz-Ortiz, A.; Moreno, A. Chem. Soc. Rev. 2005, 34, 164–178.
17. Complete description of instrument and methodology was published in:
Ferguson, J. D. Mol. Div. 2003, 7, 281–286.
18. Focused microwave irradiations were carried in pressurized (0–20 bar) sealed
vials (0–20 bar, tubes of 10 mL, sealed with a septum) with a CEM Discover™
focused microwave reactor (monomode system).17 Power input (0–400 W)
was monitored by computer as infrared measurement and continuous
feedback temperature control. The experiments were performed using
stirring option whereby the contents of a vessel are stirred by means of a
rotating plate located below the floor of the microwave cavity and a Teflon-
coated magnetic stir bar in the vessel. In all experiments a target temperature
was selected together with a power. The target temperature was reached with
a ramp of 2 min and the chosen microwave power stay constant to hold the
mixture at this temperature. The time of the reaction does not include the
ramp period.
3. Conclusion
In conclusion, we have described the first microwave-assisted
hetero-Diels–Alder reactions of perfluoroalkanethioamides 1a–e
with 2,3-dimethylbutadiene affording new 3,6-dihydro-2H-thio-
pyrans 2a–e. The use of rapid and controlled microwave heating
in sealed vials allowed good conditions of work and reproducibil-
ity. We also observed that the nature of perfluoroalkyl chains
and substituents on the nitrogen atom of thioamides have a signif-
icant influence on the yields of 2. Treatment of cycloadducts 2a,c,e
with trifluoromethanesulfonic acid gave the corresponding
ammonium salts 3a,c,e in almost quantitative yields, except for
2-octafluorobutyl-substituted derivative 3d which underwent a
spontaneous desamination reaction. Investigation of the scope
and limitations of these novel hetero-Diels–Alder reactions in the
presence of various thioamides and other electron-rich 1,3-dienes
(symmetrical and unsymmetrical) is actually in course in our
laboratories.
19. For recent examples of the use of NMP under microwaves see: (a) Lamazzi, C.;
Dreau, A.; Bufferne, C.; Flouzat, C.; Patrick Carlier, P.; ter Halle, R.; Besson, T.
Tetrahedron Lett. 2009, 50, 5402–5405; (b) Pereira, M.; De, F.; Thiéry, V.;
Besson, T. Tetrahedron Lett. 2007, 48, 7657–7659.
20. Typical procedure for the preparation of cycloadduct 2a:
a mixture of
perfluorothioamide 1a (1.0 mmol) and 2,3-dimethylbutadiene (2.5 mmol) in
N-methylpyrrolidone (5 mL) in the presence of pieces of Weflon™ (Weflon™ is
Teflon™ filled with graphite) was heated 30 min at 180 °C under irradiation
(400 W) in a microwave oven. After 30 min of heating, 2,3-dimethylbutadiene
(2.5 mmol) was added to the cooled reaction mixture, then the mixture was
again heated for 30 min. This procedure was repeated three times (total
heating time: 2.5 h, 1,3-diene: 12.5 equiv). After cooling, the reaction mixture
was poured into water (50 mL) and extracted three times with
dichloromethane (3 ꢀ 30 mL). The combined organic phases were washed
with water (30 mL), dried over MgSO4, filtered, and evaporated under reduced
pressure. The residue was purified by flash column chromatography on silica
gel, eluting with a mixture (9:1) of petroleum ether and ethyl acetate affording
121 mg (yield: 43%) of cycloadduct 2a (Scheme 3, Table 2).
21. Spectral data of 4-(4,5-dimethyl-2-trifluoromethyl-3,6-dihydro-2H-thiopyran-
2-yl)morpholine (2a). Oil. Rf (petroleum ether/ethyl acetate (9:1)) = 0.37 (TLC-
development: ethanolic phosphomolybdic acid solution). 1H NMR (CDCl3, d
Acknowledgments
2
ppm): 1.71 (s, 3H, Me), 1.75 (s, 3H, Me), 2.44 (d, JH,H = 17.5 Hz, 1H, CHAHB),
2.69 (m, 2H, NCH2), 2.79 (d, 2JH,H = 16.4 Hz, 1H, SCHAHB), 2.83 (d, 2JH,H = 17.5 Hz,
The authors thank Institut Normand de Chimie Moléculaire,
Médicinale et Macromoléculaire (INC3M, FR 3038) and Ambassade
de France at Kiev (S.S.M.) for financial support.
2
1H, CHAHB), 3.13 (m, 2H, NCH2), 3.23 (d, JH,H = 16.4 Hz, 1H, SCHAHB), 3.59 (m,
4H, O(CH2)2). 19F NMR (CDCl3, d ppm): ꢁ71.3 (s, 3F, CF3). 13C NMR (CDCl3, d
ppm): 18.9 (s, CH3), 20.0 (s, CH3), 30.4 (s, CH2S), 35.2 (q, 3JC,F = 1.1 Hz, CH2), 47.2
2
(s, CH2N), 68.1 (s, CH2O), 71.0 (q, JC,F = 24.9 Hz, CCF3), 122.5 (s, Cq), 123.9 (s,
1
Cq), 126.6 (q, JC,F = 293.1 Hz, CF3). GC–MS: m/z = 281 [M+]. HRMS (ESI+): calcd
References and notes
for C12H18F3KNOS m/z 320.0698, found 320.0692.
22. Typical procedure for the preparation of ammonium salt 3a:
a mixture of
compound 2a (1.0 mmol) and trifluoromethanesulfonic acid (1.0 mmol) in n-
hexane (15 mL) was stirred for 16 h at room temperature. After completion of
the reaction, the solution was decanted and the product was dried in vacuo
affording 0.40 g (yield: 92%) of ammonium salt 3a (Scheme 4).
1. Shermolovich, Y. G.; Slyusarenko, E. I.; Markovski, L. N. Zh. Org. Khim. (Russ.)
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702.
23. Spectral data of (4,5-dimethyl-2-trifluoromethyl-3,6-dihydro-2H-thiopyran-2-
yl)morpholinium trifluoromethane sulfonate (3a). Oil. 1H NMR (CDCl3, d ppm):
2
1.84 (s, 3H, Me), 1.87 (s, 3H, Me), 2.76 (d, JH,H = 14.5 Hz, 1H, CHAHB), 2.95 (d,
2
2JH,H = 15.5 Hz, 1H, SCHAHB), 3.00 (d, JH,H = 14.5 Hz, 1H, CHAHB), 3.58 (d,
2JH,H = 15.5 Hz, 1H, SCHAHB), 3.44 (m, 2H, NHCH2), 3.80 (m, 2H, NHCH2), 4.13
(m, 4H, O(CH2)2). 19F NMR (CDCl3, d ppm): ꢁ67.9 (s, 3F, CF3), ꢁ79.1 (s, 3F,
CF3SO 3ꢁ). Anal. Calcd for C13H19F6NO4S2: C, 36.19; H, 4.44; N, 3.25; S, 14.87.
Found3: C, 35.94; H, 4.65; N, 3.38; S, 17.92.
24. Markovski, L. N.; Shermolovich, Yu. G.; Slusarenko, E. I.; Timoshenko, V. M.
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25. Spectral data of 3,4-dimethyl-6-(1,1,2,2,3,3,4,4-octafluorobutyl)-2H-thiopyran
(4). This compound was purified by flash column chromatography on silica gel
(eluent: petroleum ether). Rf (petroleum ether) = 0.51. Oil. 1H NMR (CDCl3, d
ppm): 1.84 (s, 3H, Me), 1.92 (s, 3H, Me), 3.22 (s, 2H, SCH2), 6.08 (tt,
12. Laduron, F.; Nyns, C.; Janousek, Z.; Viehe, H. G. J. Prakt. Chem/Chem-Ztg. 1997,
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3
2JH,F = 52.2 Hz, JH,F = 5.6 Hz, 1H, HCF2), 6.50 (s, 1H, CH@). 19F NMR (CDCl3, d

S. S. Mikhailichenko et al. / Tetrahedron Letters 51 (2010) 990–993
993
3
ppm): ꢁ111.9 (m, 2F, CF2), ꢁ124.6 (m, 2F, CF2), ꢁ130.7 (m, 2F, CF2), ꢁ138.2
(dm, 2JF,H = 52.2 Hz, 2F, HCF2). 13C NMR (CD3COCD3, d ppm): 17.5 (s, CH3), 19.3
4JC,F = 2.2 Hz, CH3–C–CH@), 127.3 (s, CH3–C–CH2), 133.1 (t, JC,F = 8.5 Hz,
@CH). MS (ESI+): m/z = 327 [M+H]. Anal. Calcd for C11H10F8S: C, 40.50; H,
3.09; S, 9.83. Found: C, 40.12; H, 2.87; S, 9.85.
1
(s, CH3), 31.8 (s, CH2), 104–122 (m, 3 ꢀ CF2), 115.7 (tt, JC,F = 254.4 Hz,
2JC,F = 31.2 Hz, HCF2), 121.4 (t, 2JC,F = 24.7 Hz, C–(CF2)4H), 126.4 (t,
26. Laganis, E. D.; Lemal, D. M. J. Am. Chem. Soc. 1980, 102, 6634–6636.