Oxidation and chlorination reactions of perfluoroketene-N,S-acetals

Article abstract of DOI:10.1016/j.jfluchem.2009.06.019

The paper presents the results of the investigation of oxidation and chlorination reactions of perfluoroketene-N,S-acetals. Oxidation reactions of perfluoroketene-N,S-acetals proved to be dependent on the nature of oxidizing agent and led to the formation

Full text of DOI:10.1016/j.jfluchem.2009.06.019

Journal of Fluorine Chemistry 130 (2009) 878–885
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Oxidation and chlorination reactions of perfluoroketene-N,S-acetals
Sergiy S. Mykhaylychenko a,b, Jean-Philippe Bouillon b, Yuriy G. Shermolovich a,
*
a Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 5, Murmanska, 02094 Kiev, Ukraine
b Laboratoire Sciences et Me´thodes Se´paratives (SMS), EA 3233, Universite´ de Rouen, IRCOF, F-76821 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:
The paper presents the results of the investigation of oxidation and chlorination reactions of
perfluoroketene-N,S-acetals. Oxidation reactions of perfluoroketene-N,S-acetals proved to be dependent
on the nature of oxidizing agent and led to the formation of corresponding sulfone in the case of m-
Received 24 April 2009
Received in revised form 25 June 2009
Accepted 28 June 2009
Available online 5 July 2009
chloroperbenzoic acid or amides of
hydroperoxide or hydrogen peroxide. Reaction of 1-tert-butylsulfanyl-2,3,3,4,4,4-hexafluoro-1-[N-
methyl,N-((S)- -methylbenzyl)amino]-but-1-ene with sulfuryl chloride demonstrated the chlorination
a-H-perfluoroalkane carboxylic acids in the case of tert-butyl
a
Keywords:
of perfluoroketene-N,S-acetals as a new approach in the synthesis of chiral
carboxylic acid amides.
a-chloro perfluoroalkane
Fluorine
Sulfur
ß 2009 Elsevier B.V. All rights reserved.
Oxidation
Ketene-N,S-acetal
Perfluoroalkane carboxylic acid derivative
Chiral induction
1. Introduction
2. Results and discussion
Perfluoroketene dithioacetals were shown to be a versatile
synthons in the synthesis of fluorinated products, especially
heterocycles [1]. The main disadvantage of this strategy consists
in low availability and expensiveness of fluorinated aldehydes,
which are used for the preparation of perfluoroketene dithioa-
cetals [2]. That is why the search for cheaper reagents, offering a
favorable alternative to perfluoroketene dithioacetals, is of
current interest.
Recently, we have shown that perfluoroketene dithioacetal
analogues, such as perfluoroketene-N,S-acetals 2, can be easily
obtained in good yields by the reaction of accessible polyfluor-
oalkanethioncarboxylic acid N,N-dialkylamides 1 with organo-
lithium reagents [3] (Scheme 1).
The present paper deals with the investigation of perfluor-
oketene-N,S-acetals 2 chemical properties, as for a new type of
fluorinated compounds, which have not been studied before. We
focused our work on N,S-acetals containing S-tert-butyl group for
its unique properties. Starting from classical aspects, such as steric
hindrance and stability of the corresponding carbocation, the
compounds bearing S-tert-butyl group are widely used in synthetic
organic chemistry [4].
The methodology based on the substitution of vinylic fluorine
atom of perfluoroketene dithioacetals by potassium enolate of
acetone is
a valuable tool for the synthesis of fluorinated
heterocycles [5]. We examined the possibility of the substitution
of vinylic fluorine atom of perfluoroketene-N,S-acetals 4a,b by this
reagent (Scheme 2). However, we have found that N,S-acetals 4a,b
did not react with potassium enolate of acetone using the same
conditions as for perfluoroketene dithioacetals (at 0 8C) [5] or
under reflux in THF (Scheme 2).
The mobility of vinylic fluorine atom can be reinforced by the
increase of electron-withdrawing property of the substituents at
the carbon atoms of the C55C bond. In our case, this possibility
appears by sulfur atom oxidation into powerful electron-with-
drawing sulfonyl group.
For this purpose we have studied reactions of N,S-acetals 4a,b
with different oxidizers. To the best of our knowledge, oxidation
reactions of fluorinated N,S-acetals were not described in the
literature. In non-fluorinated series only one example of N,S-acetal
oxidation has been reported so far [6]. Lead tetraacetate was used
as oxidizing agent but this reaction proceeds without changes of
sulfur oxidation state.
We have found that the nature of the oxidizer strongly
influences the oxidation reaction of 4a,b. Thus, vinylsulfone 5
was obtained as a mixture of two geometric isomers (the ratio is
3:1 according to 19F NMR) by simple treatment of perfluoroketene-
N,S-acetal 4a with m-chloroperbenzoic acid (MCPBA) in dichlor-
omethane at room temperature (Scheme 3).
* Corresponding author. Tel.: +38 044 2928312; fax: +38 044 5732643.
E-mail address: sherm@ioch.kiev.ua (Y.G. Shermolovich).
0022-1139/$ – see front matter ß 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2009.06.019

S.S. Mykhaylychenko et al. / Journal of Fluorine Chemistry 130 (2009) 878–885
879
Scheme 1.
Scheme 4.
Unfortunately, sulfone 5 did not react with potassium ketone
enolate, the starting material was recovered quantitatively.
Probably, electron-donating influence of N,N-dialkylamino group
prevents the nucleophilic attack on the sp2 carbon atom bonded to
fluorine.
The reactions of perfluoroketene-N,S-acetals with well-known
and widely used oxidizers such as hydrogen peroxide and tert-
butyl hydroperoxide led to the desulfurization products. Treat-
ment of N,S-acetals 4a,b with tert-butyl hydroperoxide (98%) in
dichloromethane under reflux gave amide 6 in moderate yields
(Scheme 4).
acetals acidic hydrolysis leading to the formation of thioesters 13
[2].
It should be noted that to the best of our knowledge there is
only one example of non-fluorinated ketene-N,S-acetals acidic
hydrolysis leading to the formation of corresponding thioesters [9].
The compound 6 contains asymmetric carbon atom and it was
interesting to check the application of chiral induction concept in
order to obtain optically active hexafluorobutyric acid derivatives.
For this purpose, a chiral center should be presented in the starting
molecule of N,S-acetal, which can influence the stereochemistry of
the oxidation reaction with tert-butyl hydroperoxide. Thus, we
have used chiral amine 14 [10] for the preparation of perfluor-
oketene-N,S-acetal 17 (Scheme 7).
Reaction of N,S-acetal 4a with hydrogen peroxide (30% aq.)
proceeded less cleanly. Nevertheless, it also led to the formation of
amide 6, which was identified in the reaction mixture by means of
19F NMR.
The mechanism of such transformations is not clear yet. It may
be supposed that amide 6 results from the intermediately formed
sulfone 5 under the action of tert-butyl hydroperoxide. But
independent experiment has shown that sulfone 5 did not undergo
transformations during several hours of reflux in dichloromethane
in the presence of tert-butyl hydroperoxide.
We have found that sulfone 5 was transformed into amide 6
only under harder conditions: by the reaction with concentrated
hydrochloric acid in boiling dioxane (Scheme 5).
Reaction of 17 with tert-butyl hydroperoxide resulted in the
formation of amide 18 which was obtained as a mixture of
diastereomers (the ratio is 2:1 according to 1H NMR, d.e. = 33%) in
43% yield after purification on silica gel (Scheme 8). Diastereomers
of 18 were not separated by column chromatography.
In order to obtain optically active 2,3,3,4,4,4-hexafluorobutyric
acid 20, we carried out acidic hydrolysis of amide 18 using
concentrated (98%) sulfuric acid (1 h at 100 8C). However, instead
of the desired acid, we obtained amide 19 resulted from the
In this case the first step of the reaction could be the
protonation of nitrogen atom of 5 leading to intermediates 7
and 8. It is known that protonation of enamine proceeds at the
nitrogen atom with the following transfer of the proton to carbon
[7,8]. Subsequent addition of water to intermediate 8 accompanied
with elimination of tert-butylsulfinic acid from 9 gave amide 6.
In opposite to sulfone 5, treatment of perfluoroketene-N,S-
acetal 4a with concentrated hydrochloric acid in dioxane afforded
cleavage of a-(methyl)benzyl group (Scheme 9). Obviously, this
reaction proceeded in the same way as acid catalyzed debenzyla-
tion of amides [11]. At this stage we observed the complete
racemization of the amide 19.
Another approach to the synthesis of chiral polyfluoroalkane
carboxylic acid derivatives was based on our results of the
perfluoroketene-N,S-acetals chlorination. We have found that
treatment of N,S-acetal 4a with sulfuryl chloride in dichloro-
a
-hydroperfluoroalkylthioamide 10 (Scheme 6). This fact is in
methane led to the formation of
a-chloroamide 24 in 36% yield
striking contrast with the results of the perfluoroketene-S,S-
(Scheme 10). The formation of compound 24 could be explained by
Scheme 2.
Scheme 3.

880
S.S. Mykhaylychenko et al. / Journal of Fluorine Chemistry 130 (2009) 878–885
Scheme 5.
Scheme 6.
Scheme 7.

S.S. Mykhaylychenko et al. / Journal of Fluorine Chemistry 130 (2009) 878–885
881
Scheme 8.
Scheme 9.
Scheme 10.
the initial attack of sulfuryl chloride on sulfur atom of N,S-acetal 4a
with the formation of S-chlorosulfonium ion 21 (Scheme 10). Then,
fragmentation of 21 took place giving sulfenyl chloride 22. This
process was facilitated by the release of isobutylene.
In order to enforce our proposed mechanism, three published
experimental results have to be taken into account. Firstly, it was
reported that chlorination of 2-cyano-1,3,3,3-tetrafluoro-1-(tert-
butylsulfanyl)propene proceeded in a similar way giving corre-
sponding sulfenyl chloride which was a useful precursor of
thiazole derivative [12].
(Scheme 10). This chlorotropy phenomenon in the triad C–C–S was
already described in the literature for perfluoro-2-methyl-2-pent-
3-ensulfenylchloride [13].
Finally, thioamide 23 was oxidized with sulfuryl chloride to
amide 24 (Scheme 10). Oxidative property of sulfuryl chloride was
already exemplified by oxidation of sulfides to sulfoxides [14].
Nevertheless, to confirm our hypothesis, we performed quantita-
tive oxidation of thioamide 25 to amide 26 using sulfuryl chloride
in dichloromethane at room temperature (Scheme 11).
Reaction of perfluoroketene-N,S-acetal 17, which contains
one asymmetric center, with sulfuryl chloride did not lead to
the formation of the diastereomers of amide 27. From the reaction
Secondly,
a-chloroamide 24 was obtained by 1,3-migration of
chlorine atom from sulfur of 22 to C atom via intermediate 23
b

882
S.S. Mykhaylychenko et al. / Journal of Fluorine Chemistry 130 (2009) 878–885
group. Oxidation reactions of perfluoroketene-N,S-acetals 4a,b
proved to be dependent on the nature of oxidizing agents and lead
to the formation of corresponding sulfone in the case of MCPBA or
a
-H-perfluoroalkane carboxylic acid amides in the case of tert-
butyl hydroperoxide or hydrogen peroxide. Chlorination of chiral
N,S-acetal 17 with sulfuryl chloride demonstrated a new approach
to the synthesis of chiral
derivatives.
a-chloro perfluoroalkane carboxylic acid
Scheme 11.
3. Experimental
The 1H, 13C and 19F NMR spectra were recorded on a Varian-
VXR-300 instrument at 299.9, 75.4 and 282.2 MHz respectively.
Chemical shifts are given in ppm referenced to signals of CHCl3
mixture, the N-methylamide 28 was isolated in 32% yield (Scheme
12). 1-Chloro-1-phenylethane was detected by GC–MS in the crude
mixture.
(dH = 7.26 ppm, d
C = 77.16 ppm) for 1H and 13C NMR spectra and
Compound 28 proved to be optically active in accordance with
20
F = ꢂ162.9 ppm) as internal standard for 19F NMR
½
aꢀD
¼ þ2ꢁ (c = 0.75, CHCl3) measurements. A 50% enantiomeric
from C6F6 (d
excess was determined by means of 19F NMR experiments using
lanthanoid shift reagent, such as europium tris[3-(heptafluoro-
propylhydrohymethylene) (+)-camphorate], on the basis of
relative intensity measurement of two parts of AB-system of CF2
group signals of at ꢂ118.3 and ꢂ120.2 ppm (2JFAFB = 276.4 Hz)
spectra. MS data was obtained on ADSI MS, Agilent 1100\DAD\MSD
VL G1965 instrument.
Tetrahydrofuran (THF) was dried by distillation over sodium
and benzophenone. The progress of all reactions was monitored by
19F NMR spectroscopy. Silica gel Merck 60 (40–63
mm) was used
of major enantiomer and at ꢂ117.9 and ꢂ124.4 ppm (2JFAFB
=
for column chromatography. Elemental analysis was performed in
Analytical Laboratory of the Institute of Organic chemistry, NAS of
Ukraine.
284.1 Hz) of minor one, respectively (see Section 3). This result
let us propose that presence of chiral substituent in ketene-N,S-
acetal 17 can induce the chiral induction during the chlorination
reaction.
3.1. Preparation of thioamides (3, 16, 25)
Compound 28 is the first example of optically active
a-chloro
perfluoroalkane acids derivatives. Obviously, in this case, com-
pound 28 was not formed with a big enantiomeric excess. Further
improvements are under investigation.
In conclusion, oxidation, chlorination and nucleophilic sub-
stitution reactions of perfluoroketene-N,S-acetals were investi-
gated. Perfluoroketene-N,S-acetal 4a and its sulfonyl derivative 5
did not react with nucleophiles such as ketone enolates, probably
because of electron-donating properties of N,N-dialkylamino
The slightly modified method of thioamides synthesis
described in Ref. [15] was used.
Phosphorus pentasulfide (11.11 g, 25.00 mmol, 0.6 eq.) was
added to a suspension of amide (40.00 mmol, 1.0 eq.) in a solution
of hexamethyldisiloxane (HMDSO) (12.99 g, 80.00 mmol, 2.0 eq.)
in toluene (100 ml). The reaction mixture was stirred at 80 8C; the
reaction was followed by 19F NMR, monitoring the disappearance
of starting amide peaks. The mixture was cooled to room
Scheme 12.

S.S. Mykhaylychenko et al. / Journal of Fluorine Chemistry 130 (2009) 878–885
883
temperature. Solid material was filtered off and washed with 50 ml
3.3. General procedure for the preparation of perfluoroketene-N,S-
acetals (4a,b and 17) [3]
of diethyl ether. Solvents and excess of HMDSO were removed in
vacuo (10–15 mm Hg) up to 1/2 of volume and residue was diluted
with 50 ml of diethyl ether. Organic phase was successively
washed with saturated aqueous NaHCO3 solution (4ꢃ 50 ml),
saturated aqueous NaCl solution (2ꢃ 100 ml) and water (2ꢃ
100 ml). Aqueous phase was additionally extracted with diethyl
ether (2ꢃ 100 ml). Combined ethereal extracts were dried over
Na2SO4 and solvents were removed in vacuo. The residue was
distilled under reduced pressure.
t-BuLi (8.40 mmol, 1.2 eq., 1.7 M solution in pentane) or n-BuLi
(8.40 mmol, 1.2 eq., 1.6 M solution in hexane) was added dropwise
to a solution of corresponding thioamide (7.00 mmol, 1.0 eq.) in
THF (20 ml) at ꢂ70 8C under argon atmosphere. The reaction
mixture was stirred ꢂ70 8C for 0.5 h and allowed to warm to room
temperature for 5 h. MeOH (2 ml) was added to the reaction
mixture. Solvents were removed in vacuo at room temperature and
petroleum ether (30 ml) was added to the residue. After filtration,
the solvent was evaporated in vacuo to give the products (4a,b
and 17).
N-morpholino-2,2,3,3,4,4,4-heptafluorobutanethioamide (3).
Yield: 80%. Yellow liquid. bp 100–101 8C (10 mm Hg). 1H NMR
(CDCl3,
d d
ppm): 3.7–4.4 (m, 8H, morpholino). 19F NMR (CDCl3,
ppm): ꢂ81.1 (m, 3F, CF3), ꢂ98.7 (m, 2F, CF2CF2CS), ꢂ124.0 (m, 2F,
CF2CS). Anal. Calcd. for C8H8F7NOS: C, 32.1; H, 2.7; N, 4.7; S, 10.7.
Found: C, 32.2; H, 2.8; N, 4.7; S, 10.8.
1-tert-Butylsulfanyl-2,3,3,4,4,4-hexafluoro-1-morpholino-but-
1-ene (4a). Yield: 86%. Oil. Mixture of isomers (the ratio is 2/1
according to 19F NMR). Major isomer: 1H NMR (CDCl3,
d ppm): 1.41
N-methyl-N-((S)-
a
-methylbenzyl)-2,2,3,3,4,4,4-heptafluoro-
(s, 9H, t-Bu), 2.81 (m, 4H, 2ꢃ NCH2), 3.70 (m, 4H, 2ꢃ OCH2). 19F
butanethioamide (16). Yield: 92%. Liquid. Mixture of rotamers (the
NMR (CDCl3,
d
ppm): ꢂ84.1 (m, 3F, CF3), ꢂ114.5 (m, 2F, CF2),
20
ratio is 2/1 according to 19F NMR). ½a D
ꢀ
¼ ꢂ255ꢁ (c = 1, CHCl3).
ꢂ124.3 (m, 1F, CF). Selected data for minor isomer: 1H NMR (CDCl3,
3
Major isomer: 1H NMR (CDCl3,
d
ppm): 1.62 (d, JH,H = 6.9 Hz, 3H,
d
ppm): 1.36 (s, 9H, t-Bu). 19F NMR (CDCl3,
d
ppm): ꢂ83.7 (m, 3F,
CH–Me), 2.98 (s, 3H, N–Me), 7.10 (q, 3JH,H = 6.9 Hz, 1H, CH–N), 7.2–
CF3), ꢂ110.1 (m, 2F, CF2), ꢂ133.6 (m, 1F, CF). MS: m/z = 338 [M+1].
Anal. Calcd. for C12H17F6NOS: C, 42.7; H, 5.1; N, 4.2; S, 9.5. Found: C,
42.6; H, 5.3; N, 4.3; S, 9.6.
7.4 (m, 5H, Ph). 19F NMR (CDCl3,
d
ppm): ꢂ81.3 (t, 3JF,F = 10.5 Hz, 3F,
2
CF3), ꢂ98.1 (dm, JF,F = 269.2 Hz, 1F, CFAFBCF2CS), ꢂ101.1 (dm,
2JF,F = 269.2 Hz, 1F, CFAFBCF2CS), ꢂ122.9 (m, 2F, CF2CS). Selected
1-n-Butylsulfanyl-2,3,3,4,4,4-hexafluoro-1-morpholino-but-1-
ene (4b). Yield: 89%. Oil. Mixture of isomers (the ratio is 6/1
data for minor isomer: 1H NMR (CDCl3,
d ppm): 1.72 (d,
3JH,H = 6.9 Hz, 3H, CH–Me), 3.08 (s, 3H, N–Me), 5.78 (q,
3JH,H = 6.9 Hz, 1H, CH–N). 19F NMR (CDCl3,
according to 19F NMR). Major isomer: 1H NMR (CDCl3,
d
ppm): 0.92
3
d
ppm): ꢂ80.9 (t,
(t, JHH = 7.2 Hz, 3H, CH3), 1.50 (m, 4H, CH3CH2CH2), 2.83 (t,
3JH,H = 7.2 Hz, 2H, CH2–S), 2.89 (m, 4H, 2ꢃ NCH2), 3.69 (m, 4H, 2ꢃ
3JF,F = 10.5 Hz, 3F, CF3), ꢂ96.9 (dm, 2JF,F = 275.8 Hz, 1F, CFAFBCF2CS),
ꢂ98.9 (dm, 2JF,F = 275.8 Hz, 1F, CFAFBCF2CS), ꢂ123.1 (m, 2F, CF2CS).
Anal. Calcd. for C13H12F7NS: C, 45.0; H, 3.5; N, 4.0; S, 9.2. Found: C,
44.9; H, 3.6; N, 4.0; S, 9.3.
OCH2). 19F NMR (CDCl3,
d
ppm):
d
ꢂ84.5 (m, 3F, CF3), ꢂ115.1 (m, 2F,
CF2), ꢂ135.4 (m, 1F, CF). Selected data for minor isomer: 19F NMR
(CDCl3,
d
ppm): ꢂ84.7 (m, 3F, CF3), ꢂ110.9 (m, 2F, CF2), ꢂ139.3 (m,
N-Piperidino-2,2,3,3-tetrafluoropropanethioamide (25). Yield:
1F, CF). MS: m/z = 338 [M+1]. Anal. Calcd. for C12H17F6NOS: C, 42.7;
H, 5.1; N, 4.2; S, 9.5. Found: C, 42.6; H, 5.3; N, 4.1; S, 9.6.
1-tert-Butylsulfanyl-2,3,3,4,4,4-hexafluoro-1-[N-methyl,N-
83%. Yellow liquid. bp 114–116 8C (15 mm Hg). 1H NMR (CDCl3,
d
ppm): 1.76 (m, 6H, piperidino), 3.95 (m, 2H, piperidino), 4.16 (m,
2H, piperidino), 6.80 (tt, 2JH,F = 53.4 Hz, 3JH,F = 5.6 Hz, 1H, HCF2). 19
F
((S)-a-methylbenzyl)amino]-but-1-ene (17). Yield: 93%. Oil. Mix-
20
NMR (CDCl3,
d
ppm): ꢂ114.6 (m, 2F, CF2CS), ꢂ136.9 (dm,
ture of isomers (the ratio is 2.5/1 according to 19F NMR). ½a D
ꢀ
¼
2JF,H = 53.4 Hz, 2F, HCF2). Anal. Calcd. for C8H11F4NS: C, 41.9; H,
ꢂ5ꢁ (c = 1, CHCl3). Major isomer: 1H NMR (CDCl3,
d ppm): 1.33 (d,
4.8; N, 6.1; S, 14.0. Found: C, 42.0; H, 4.9; N, 6.0; S, 14.1.
3JH,H = 6.7 Hz, 3H, CH–Me), 1.45 (s, 9H, t-Bu), 2.39 (s, 3H, N–Me),
4.29 (q, JH,H = 6.7 Hz, 1H, CH–Me), 7.2-7.4 (m, 5H, Ph). 19F NMR
3
2
3.2. Preparation of amide (15)
(CDCl3,
d
ppm): ꢂ83.9 (m, 3F, CF3), ꢂ113.9 (dd, JF,F = 284.4 Hz,
3JF,F = 8.9 Hz, 1F, CFAFB), ꢂ115.2 (dd, JF,F = 284.4 Hz, JF,F = 8.9 Hz,
2
3
To a solution of heptafluorobutyryl chloride (8.37 g, 36 mmol,
1 eq.) in diethyl ether (40 ml), a solution of (S)-N-methyl-1-
phenylethylamine [10] (4.86 g, 36 mmol, 1 eq.) and triethyla-
mine (3.64 g, 36 mmol, 1 eq.) in diethyl ether (40 ml) was added
dropwise at ꢂ10 8C under argon atmosphere. Reaction mixture
1F, CFAFB), ꢂ127.9 (m, 1F, CF). Selected data for minor isomer: 1H
NMR (CDCl3,
d
ppm): 1.38 (s, 9H, t-Bu), 1.55 (d, 3JH,H = 7.2 Hz, 3H,
CH–Me), 2.68 (s, 3H, N–Me), 5.20 (q, 3JH,H = 7.2 Hz, 1H, CH–Me). 19
F
NMR (CDCl3,
d
ppm): ꢂ84.4 (m, 3F, CF3), ꢂ109.7 (d, 2JF,F = 274.8 Hz,
1F, CFAFB), ꢂ122.6 (d, 2JF,F = 274.8 Hz, 1F, CFAFB), ꢂ130.6 (m, 1F, CF).
MS: m/z = 385 [M+1]. Anal. Calcd. for C17H21F6NS: C, 53.0; H, 5.5; N,
3.6; S, 8.3. Found: C, 52.9; H, 5.7; N, 3.7; S, 8.5.
was then stirred at ꢂ5 8C for 1 h and
1 night at room
temperature. The precipitate was filtered off and the filtrate
was washed with water (2ꢃ 40 ml). The organic layer was
separated, dried over Na2SO4 and concentrated in vacuo, giving
3.4. Oxidation reaction of perfluoroketene-N,S-acetal (4a)
N-methyl-N-((S)-
tanamide.
a
-methylbenzyl)-2,2,3,3,4,4,4-heptafluorobu-
with MCPBA
N-methyl-N-((S)-
a
-methylbenzyl)-2,2,3,3,4,4,4-heptafluoro-
To a solution of perfluoroketene-N,S-acetal (4a) (2.36 g,
butanamide (15). Yield: 87%. Liquid. Mixture of rotamers (the ratio
7.00 mmol, 1.0 eq.) in dichloromethane (25 ml), a solution of
MCPBA (3.62 g, 21.00 mmol, 3.0 eq.) in dichloromethane (10 ml)
was added at room temperature. The mixture was stirred for 4 h at
this temperature. The precipitate of m-chlorobenzoic acid was
filtered off and a half of filtrate was evaporated in vacuo. After
cooling at 4 8C for 4 h, the new precipitate was again filtered and
the filtrate was evaporated in vacuo. Finally, the product (5) was
crystallized from hexane as colorless solid. Analytical sample was
obtained after recrystallization from hexane.
20
is 2/1 according to 19F NMR). ½a D
ꢀ
¼ ꢂ115ꢁ (c = 1, CHCl3). Major
isomer: 1H NMR (CDCl3,
d
ppm): 1.56 (d, 3JH,H = 7.5 Hz, 3H, CH–Me),
3
2.80 (s, 3H, N–Me), 5.99 (q, JH,H = 7.5 Hz, 1H, CH–N), 7.2–7.4 (m,
5H, Ph). 19F NMR (CDCl3,
d
ppm): ꢂ80.8 (t, JF,F = 8.8 Hz, 3F, CF3),
3
ꢂ113.3 (m, 2F, CF2), ꢂ126.3 (m, 2F, CF2CO). Selected data for minor
isomer: 1H NMR (CDCl3,
d
ppm): 1.66 (d, 3JH,H = 6.6 Hz, 3H, CH–Me),
2.69 (s, 3H, N–Me), 5.43 (q, JH,H = 6.6 Hz, 1H, CH–N). 19F NMR
3
(CDCl3,
d
ppm): ꢂ80.4 (t, 3JF,F = 8.7 Hz, 3F, CF3), ꢂ115.5 (m, 2F, CF2),
ꢂ126.1 (m, 2F, CF2CO). Anal. Calcd. for C13H12F7NO: C, 47.1; H, 3.7;
N, 4.2. Found: C, 47.0; H, 3.8; N, 4.2.
1-tert-Butylsulfonyl-2,3,3,4,4,4-hexafluoro-1-morpholino-but-
1-ene (5). Yield: 76%. Solid. mp 78 8C. Mixture of isomers (the ratio
is 3/1 according to 19F NMR). Major isomer: 1H NMR (CDCl3,
d
Preparation of starting amides for the synthesis of (3) and (25)
was performed according to the method described in Ref. [16].
ppm): 1.43 (s, 9H, t-Bu), 2.78 (m, 2H, CH2 morpholino), 3.5–3.9 (m,

884
S.S. Mykhaylychenko et al. / Journal of Fluorine Chemistry 130 (2009) 878–885
6H, morpholino). 19F NMR (CDCl3,
d
ppm): ꢂ84.2 (m, 3F, CF3),
hydroperoxide. Yield: 43%. Oil. Diastereomeric ratio: ꢄ2/1
20
ꢂ111.8 (m, 1F, CF), ꢂ117.3 (m, 2F, CF2). 13C NMR (CDCl3,
d
ppm):
(according to 1H NMR data). ½a D
ꢀ
¼ ꢂ65ꢁ (c = 1, CHCl3). Major
23.9 (s, (CH3)3C), 51.8 (s, CH2–N), 63.5 (s, CH2–O), 66.5 (s, (CH3)3C–
isomer: 1H NMR (CDCl3, ppm): 1.56 (d, 3JH,H = 7.2 Hz, 3H, CH–Me),
d
2
2
3
SO2), 109.3 (m, CF2), 116.6 (m, CF3), 136.8 (dm, JC,F = 20.1 Hz,
2.72 (s, 3H, N–Me), 5.58 (ddd, JH,F = 47.6 Hz, JH,F = 17.7 Hz,
1
2
3
C55CF), 151.5 (dt, JC,F = 285.2 Hz, JC,F = 25.5 Hz, CF55). Selected
data for minor isomer: 19F NMR (CDCl3,
ppm): ꢂ110.9 (m, 1F, CF),
ꢂ120.8 (m, 2F, CF2). MS: m/z = 370 [M+1]. Anal. Calcd. for
12H17F6NO3S: C, 39.0; H, 4.6; N, 3.8; S, 8.7. Found: C, 38.9; H,
3JH,F = 4.4 Hz, 1H, CHF), 6.05 (q, JH,H = 7.2 Hz, 1H, CH–Me), 7.3–
d
7.4 (m, 5H, Ph). 19F NMR (CDCl3,
d
ppm): ꢂ83.8 (dd, 3JF,FA = 10.2 Hz,
3JF,FB = 1.5 Hz, 3F, CF3), ꢂ123.3 (dm, JF,F = 287.6 Hz, 1F, CFAFB),
2
C
ꢂ128.6 (dm, 2JF,F = 287.6 Hz, 1F, CFAFB), ꢂ201.1 (dm, 2JH,F = 47.6 Hz,
4.8; N, 4.0; S, 8.8.
1F, CHF). Selected data for minor isomer: 1H NMR (CDCl3,
d
ppm):
1.54 (d, JH,H = 7.2 Hz, 3H, CH–Me), 6.00 (q, 3JH,H = 7.2 Hz, 1H, CH–
3
3.5. Hydrolysis reaction of perfluoroketene-N,S-acetal (4a)
Me). 19F NMR (CDCl3,
2JH,F = 47.6 Hz, 1F, CHF). MS: m/z = 314 [M+1]. Anal. Calcd. for
13H13F6NO: C, 49.9; H, 4.2; N, 4.5. Found: C, 49.8; H, 4.3; N, 4.4.
d
ppm): ꢂ83.7 (m, 3F, CF3), ꢂ200.5 (dm,
To
a
solution of perfluoroketene-N,S-acetal (4a) (1.01 g,
C
3.00 mmol, 1.0 eq.) in dioxane (10 ml) a few drops of concentrated
hydrochloric acid was added. The reaction mixture was refluxed
for 7 h, and then solvent was evaporated in vacuo. The residue was
dissolved in chloroform (15 ml) and washed with water (2ꢃ
10 ml). The organic layer was separated, dried over MgSO4 and
concentrated in vacuo. Thioamide (10) was obtained as pure
compound.
3.8. Reaction of
a-hydroamide (18) with concentrated sulfuric acid
Amide (18) (0.78 g, 2.50 mmol, 1 eq.) was dissolved in
concentrated (98%) sulfuric acid (5 ml) and the reaction mixture
was heated at 100 8C for 1 h. After cooling, it was poured into a
mixture of ice and water (10 ml), and then extracted with ether
(3ꢃ 15 ml). The organic layer was separated, dried over MgSO4 and
concentrated in vacuo. Amide (19) was purified by sublimation in
vacuo (0.07 mm Hg) at 120 8C.
N-morpholino-2,3,3,4,4,4-hexafluorobutanethioamide (10).
Yield: 67%. Oil. 1H NMR (CDCl3,
d ppm): 3.7–4.0, 4.2–4.4 (m, 8H,
2
3
morpholino), 6.24 (ddd, JH,F = 47.8 Hz, JH,F = 20.7 Hz,
3JH,F = 4.7 Hz, 1H, CHF). 19F NMR (CDCl3,
d
ppm): ꢂ83.6 (dd,
N-methyl-2,3,3,4,4,4-hexafluorobutaneamide (19). Yield: 48%.
3JF,FA = 12.4 Hz, 3JF,FB = 1.5 Hz, 3F, CF3), ꢂ119.3 (dm, 2JF,F = 280.0 Hz,
Solid. mp 64 8C. 1H NMR (CDCl3,
d ppm): 2.94 (s, 3H, NH–Me), 5.23
2
2
3
3
1F, CFAFB), ꢂ127.8 (dm, JF,F = 280.0 Hz, 1F, CFAFB), ꢂ180.0 (dm,
(ddd, JH,F = 46.1 Hz, JH,F = 16.8 Hz, JH,F = 4.8 Hz, 1H, CHF), 7.02
2JH,F = 47.8 Hz, 1F, CHF). MS: m/z = 282 [M+1]. Anal. Calcd. for
C8H9F6NOS: C, 34.2; H, 3.2; N, 5.0; S, 11.4. Found: C, 34.1; H, 3.4; N,
5.0; S, 11.5.
(brs, 1H, NH). 19F NMR (CDCl3,
d
ppm): ꢂ82.9 (dd, 3JF,FA = 12.0 Hz,
3JF,FB = 1.5 Hz 3F, CF3), ꢂ122.9 (dm, JF,F = 284.3 Hz, 1F, CFAFB),
ꢂ127.7 (dm, 2JF,F = 284.3 Hz, 1F, CFAFB), ꢂ205.8 (dm, 2JH,F = 46.1 Hz,
1F, CHF). MS: m/z = 210 [M+1]. Anal. Calcd. for C5H5F6NO: C, 28.7;
H, 2.4; N, 6.7. Found: C, 28.8; H, 2.5; N, 6.6.
2
3.6. Hydrolysis reaction of sulfone (5)
To a solution of sulfone (5) (1.11 g, 3.00 mmol, 1.0 eq.) in
dioxane (10 ml) few drops of concentrated hydrochloric acid were
added. The reaction mixture was refluxed for 7 h. Then solvent was
evaporated in vacuo, the residue was dissolved in chloroform
(15 ml) and washed with water (2ꢃ 10 ml). The organic layer was
separated, dried over MgSO4 and concentrated in vacuo. The crude
product was purified by silica gel column chromatography
(eluent:mixture (90:10) of petroleum ether and ethyl acetate) to
give the amide (6).
3.9. General procedure for the chlorination reaction of
perfluoroketene-N,S-acetals (4a, 17) with sulfuryl chloride
Mixture of perfluoroketene-N,S-acetal (4a or 17) (2.50 mmol,
1.0 eq.) and sulfuryl chloride (5.00 mmol, 2.0 eq.) in dichloro-
methane (10 ml) (for 4a) or in chloroform (10 ml) (for 17) was
stirred 16 h at room temperature (for 4a) or was heated at 50 8C for
30 min (for 17). After the completion of the reaction (checked by
19F NMR of the crude mixture), the solvent was evaporated in vacuo
and the crude product was purified by fractional distillation to give
the desired amide (24 or 28).
N-morpholino-2,3,3,4,4,4-hexafluorobutaneamide (6). Yield:
2
55%. Oil. 1H NMR (CDCl3,
d
ppm): 5.54 (ddd, JH,F = 46.5 Hz,
3JH,F = 18.6 Hz, JH,F = 4.8 Hz, 1H, CHF), 3.6–3.8 (m, 8H, morpho-
N-morpholino-2-chloro-2,3,3,4,4,4-hexafluorobutaneamide
(24). Yield: 36%. Liquid. bp 65 8C/ 0.07 mm Hg. 1H NMR (CDCl3,
d
3
3
lino). 19F NMR (CDCl3,
d
ppm): ꢂ83.5 (dd, JF,FA = 10.5 Hz,
3JF,FB = 1.5 Hz, 3F, CF3), ꢂ123.7 (dm, JF,F = 283.9 Hz, 1F, CFAFB),
ꢂ128.5 (dm, 2JF,F = 283.9 Hz, 1F, CFAFB), ꢂ200.3 (dm, 2JH,F = 46.5 Hz,
1F, CHF). MS: m/z = 266 [M+1]. Anal. Calcd. for C8H9F6NO2: C, 36.2;
H, 3.4; N, 5.3. Found: C, 36.4; H, 3.5; N, 5.3.
ppm): 3.6–4.0 (m, 8H, morpholino). 19F NMR (CDCl3,
d
ppm): ꢂ77.6
2
3
3
(dd, JF,FA = 11.3 Hz, JF,FB = 1.5 Hz, 3F, CF3), ꢂ116.9 (dm,
2JF,F = 276.6 Hz, 1F, CFAFB), ꢂ127.7 (dm, 2JF,F = 276.6 Hz, 1F, CFAFB),
ꢂ126.9 (m, 1F, CFCl). 13C NMR (CDCl3, 50 8C,
d ppm): 43.7 (s, NCH2),
66.7 (s, OCH2), 101.9 (dt, JC,F = 272.8 Hz, JC,F = 27.3 Hz, CFCl),
109.8 (m, CF2), 118.6 (qt, 1JC,F = 288.1 Hz, 2JC,F = 34.7 Hz, CF3), 158.7
1
2
3.7. General procedure for the oxidation reaction of perfluoroketene-
2
N,S-acetals (4a,b and 17) with tert-butyl hydroperoxide
(d, JC,F = 21.5 Hz, CO). MS: m/z = 302 [M+1], 300 [M+1]. Anal.
Calcd. for C8H8ClF6NO2: C, 32.1; H, 2.7; Cl, 11.8; N, 4.7. Found: C,
32.0; H, 2.8; Cl, 12.0; N, 4.5.
The mixture of perfluoroketene-N,S-acetal (4a,b or 17)
(0.80 mmol, 1.0 eq.) and tert-butyl hydroperoxide (1.60 mmol,
2.0 eq.) in dichloromethane (10 ml) was refluxed for 5 h. After the
completion of the reaction (checked by 19F NMR of the crude
mixture), the solvent was evaporated in vacuo. The crude product
was purified by silica gel column chromatography (eluent:mixture
(90:10) of petroleum ether and ethyl acetate) to give the
corresponding amide (6 or 18).
N-methyl-2-chloro-2,3,3,4,4,4-hexafluorobutaneamide (28).
20
Yield: 32%. Liquid. bp 120 8C. ½a D
ꢀ
¼ þ2ꢁ (c = 0.75, CHCl3),
e.e. = 50%. 1H NMR (CDCl3,
d
ppm): 3.46 (s, 3H, NH–Me). 19F
NMR (CDCl3,
d
ppm): ꢂ79.3 (dd, 3JF,FA = 14.5 Hz, 3JF,FB = 1.5 Hz, 3F,
2
CF3), ꢂ118.3 (dm, JF,F = 274.7 Hz, 1F, CFAFB), ꢂ120.2 (dm,
2JF,F = 274.7 Hz, 1F, CFAFB), ꢂ121.0 (m, 1F, CFCl). Selected 19F
NMR spectrum data of the mixture of compound 28 with europium
tris[3-(heptafluoropropylhydrohymethylene) (+)-camphorate].
Major enantiomer:
N-morpholino-2,3,3,4,4,4-hexafluorobutaneamide (6). Yield:
57% (obtained from 4a). Yield: 61% (obtained from 4b).
N-methyl,N-((S)-
neamide (18). General procedure was used but the reaction
mixture was refluxed for 18 h after addition of 3.0 eq. of tert-butyl
a
-methylbenzyl)-2,3,3,4,4,4-hexafluorobuta-
ꢂ118.3 (dm, 2JF,F = 276.4 Hz, 1F, CFAFB), ꢂ120.2 (dm,
2JF,F = 276.4 Hz, 1F, CFAFB). Minor enantiomer: ꢂ117.9 (dm,
2JF,F = 284.1 Hz, 1F, CFAFB), ꢂ124.4 (dm, 2JF,F = 284.1 Hz, 1F, CFAFB).

S.S. Mykhaylychenko et al. / Journal of Fluorine Chemistry 130 (2009) 878–885
885
13C NMR (CDCl3,
d
ppm): 29.6 (s, NH–Me), 102.2 (dt,
(June 2008) and to ‘‘Le Ministere de l’Education et de la Recherche’’
for its ‘‘Mobility grant’’ (September 2007 to February 2008),
respectively.
`
2
1JC,F = 260.2 Hz, JC,F = 27.7 Hz, CFCl), 109.5 (m, CF2), 117.9
1
2
2
(qt, JC,F = 286.9 Hz, JC,F = 34.4 Hz, CF3), 161.4 (d, JC,F = 21.5 Hz,
CO). MS: m/z = 246 [M+1], 244 [M+1]. Anal. Calcd. for C5H4ClF6NO:
C, 24.7; H, 1.7; Cl, 14.6; N, 5.8. Found C, 24.5; H, 1.8; Cl, 14.7;
N 5.9.
References
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911, vol. 12, Oxford University Press/American Chemical Society, Washington DC,
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3.10. Reaction of thioamide (25) with sulfuryl chloride
(b) C. Portella, M. Muzard, J.-P. Bouillon, C. Brule´, F. Grellepois, Y.G. Shermolovich,
V.M. Timoshenko, A.N. Chernega, E. Sotoca-Usina, M. Parra, S. Gil, Heteroatom
Chem. 18 (2007) 500–508.
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sulfuryl chloride (2.70 g, 20.00 mmol, 2.0 eq.) in dichloromethane
(50 ml) was stirred 16 h at room temperature. After the completion
of the reaction (checked by 19F NMR of the crude mixture), the
solvent was evaporated in vacuo and the crude product was
purified by fractional distillation to give amide (26).
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1034.
N-piperidino-2,2,3,3-tetrafluoropropanamide (26). Yield: 87%.
Yellow liquid. bp 33–34 8C (0.05 mm Hg). 1H NMR (CDCl3,
d
ppm):
1.68 (m, 6H, piperidino), 3.60 (m, 4H, piperidino), 6.29 (tt,
3
2JH,F = 52.2 Hz, JH,F = 6.0 Hz, 1H, HCF2). 19F NMR (CDCl3,
d ppm):
ꢂ119.9 (m, 2F, CF2CS), ꢂ136.9 (dm, 2JF,H = 52.2 Hz, 2F, HCF2). Anal.
Calcd. for C8H11F4NO: C, 45.1; H, 5.2; N, 6.6. Found: C, 45.0; H, 5.3;
N, 6.6.
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Acknowledgments
Yuriy G. Shermolovich and Sergiy Mykhaylychenko are deeply
indebted to University of Rouen for associated professor position