Synthesis of (2,2,2-trifluoroethyl) substituted pyridazin-3(2H)-ones and 1,5-dihydropyrrol-2-ones from α,β-unsaturated γ-lactones and hydrazines

Article abstract of DOI:10.1016/j.jfluchem.2009.01.008

This paper presents the transformation of α,β-unsaturated γ-lactones into 2,2,2-trifluoroethyl substituted pyridazin-3(2H)-ones and 1,5-dihydropyrrol-2-ones starting from various hydrazines. The influence of the γ-lactone substitution (sulfanyl versus sul

Full text of DOI:10.1016/j.jfluchem.2009.01.008

Journal of Fluorine Chemistry 130 (2009) 418–427
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Journal of Fluorine Chemistry
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Synthesis of (2,2,2-trifluoroethyl) substituted pyridazin-3(2H)-ones and
1,5-dihydropyrrol-2-ones from
a,b-unsaturated g-lactones and hydrazines
Sergiy Mykhaylychenko a,b, Dominique Harakat c, Georges Dupas d,
Yuriy G. Shermolovich b, Jean-Philippe Bouillon a,
*
a
´
´
´
Laboratoire Sciences et Methodes Separatives (SMS), EA 3233, Universite de Rouen, IRCOF, F-76821 Mont-Saint-Aignan Cedex, France
b Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 5, Murmanska, 02094 Kiev, Ukraine
c Institut de Chimie Mole´culaire de Reims, CNRS UMR 6229, Universite´ de Reims Champagne-Ardenne, UFR Sciences Exactes et Naturelles, BP 1039, F-51687 Reims Cedex 2, France
d Laboratoire de Chimie Organique Fine et He´te´rocyclique, UMR 6014 COBRA, IRCOF, INSA de Rouen, 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 paper presents the transformation of
a,b-unsaturated g-lactones into 2,2,2-trifluoroethyl
Received 10 November 2008
Received in revised form 23 January 2009
Accepted 27 January 2009
Available online 5 February 2009
substituted pyridazin-3(2H)-ones and 1,5-dihydropyrrol-2-ones starting from various hydrazines.
The influence of the -lactone substitution (sulfanyl versus sulfonyl moiety) and the nature of the
g
hydrazines (unsubstituted, alkyl- or aryl-substituted) on the outcome of the reaction were studied. All
new heterocycles were characterized using 1D NMR, IR, MS and their data was compared with those of
two reported X-ray diffraction structures. The two possible competitive pathways leading to pyridazin-
3(2H)-ones and/or 1,5-dihydropyrrol-2-ones are discussed. Ab initio DFT calculations were also
performed in order to rationalize several experimental results.
Keywords:
Fluorine
Heterocycle
ß 2009 Elsevier B.V. All rights reserved.
Pyridazin-3(2H)-one
1,5-Dihydropyrrol-2-one
g
-Lactone
1. Introduction
chemicalpropertiesinordertoimprovetheir biologicalactivity. This
strategy is widely used in the search of new drugs. The increasing
The pyridazine and pyridazin-3-one family have attracted a
great deal of attention due to the wide spectrum of their
pharmaceutical and agrochemical activities. For example, 3-
(alkylamino)pyridazine derivatives are well documented and
exhibit anti-hypertensive or anti-depressant properties [1,2].
Pyridazin-3(2H)-ones also possess interesting synthetic versatility
(precursors of 3-(alkylamino)pyridazines) and possible binding
sites for interaction with various receptors. Therefore, these
molecules have been used as positive inotropic agents for the
treatment of congestive heart failure, potassium channel activa-
tors, antiasthmatics, an antihistaminic agent (Azelastine) and a
phosphodiesterase inhibitor (Zordoverine) [3,4].
interest in fluorinated heterocycles (especially trifluoromethylated
ones) [8–11] and the continuous need of new scaffolds for library
syntheses prompted us to develop a general method for the
preparation of new fluorine containing pyridazine and pyridazin-3-
one derivatives, based on a building block strategy.
There are few syntheses of fluorinated pyridazin-3-ones
reported so far, being mainly devoted to the preparation of 4-
perfluoroalkyl substituted derivatives. Indeed, the general
approach to 4-trifluoromethyl pyridazin-3(2H)-ones 1 (R2 = CF3)
is based on a building block strategy starting from 4,4,4-trifluoro-
1-phenylbut-2-en-1-one 2 [2], 2-trifluoromethyl g-keto thioesters
3 [12], or more recently from 3,3,3-trifluoropyruvate 4 [13] and
hydrazines (Scheme 1: Path A). Nevertheless, these methods suffer
from several limitations such as multi-step sequences starting
from commercially unavailable compounds (2, 3), low-overall
yields (2), substrate dependency (3) or incompatibility with
additional functional groups reactive toward hydrazine (4).
The number of 4-perfluoroalkyl pyridazine-3(2H)-ones (longer
than CF3 group) are limited to the synthesis of 4-(1,2,2,2-
tetrafluoroethyl)pyridazin-3(2H)-ones 1 (R2 = CH(F)CF3) [12], or
4-(1-ethylthio-2,2,2-trifluorethyl) derivatives 1 (R2 = CH(SEt)CF3)
obtained by the sequence of a furan ring opening/ring closure of
Pyridazin-3(2H)-ones have generally been prepared from
g-
keto derivatives (acid or corresponding chloride, ester) [5], and
various substituted hydrazines via dihydro intermediates, using
multi-step sequence.
g-Lactones (saturated or a,b-unsaturated)
have also been used as starting materials [6,7].
The introduction of fluorine-containing substituents into organic
compounds is a very useful tool for changing their physical and
* Corresponding author. Tel.: +33 235522422; fax: +33 235522959.
E-mail address: jean-philippe.bouillon@univ-rouen.fr (J.-P. Bouillon).
acylic g-ketosemicarbazide [14] (Scheme 1: Path B).
0022-1139/$ – see front matter ß 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2009.01.008

S. Mykhaylychenko et al. / Journal of Fluorine Chemistry 130 (2009) 418–427
419
Scheme 1.
In order to increase structural diversity on the pyridazin-3-one
nucleus, we were interested in preparing new 4-(2,2,2-trifluor-
oethyl) substituted derivatives 1 (R2 = CH2CF3) starting from
unsaturated -lactones 6a,b and hydrazines (Scheme 1: Path C).
The proposed strategy is based on a few results in the non-
fluorinated -lactone series [15–17] as well as on our recent
straightforward transformation of -lactones 6a,b into -lactams 7
(Scheme 2) [18]. Furthermore, this method has the advantage of
introducing either a phenylsulfanyl or a phenylsulfonyl group
useful for further interesting transformations. To the best of our
knowledge, there are no examples of a pyridazin-3(2H)-one
bearing such substituents in the literature.
2. Results and discussion
a
,b
-
In the first experiment, compound 6a was treated with
5.0 equiv. of hydrazine hydrate in THF, for 16 h, at room
temperature (Scheme 3: Method 1). The crude mixture was
checked by 19F NMR to confirm complete conversion of the starting
material. At the end of the reaction, the solvent was evaporated in
vacuo and the residue was purified by silica gel column
chromatography affording the new pyridazin-3(2H)-one 9a (yield:
g
g
g
g
21%) and g-lactam 10a (yield: 33%) (Table 1: entry 1).
The transformation was then extended to various substituted
hydrazines (R1 = Me, Ph) or hydrazinium salts (R1 = Et, p-MeC6H4)
in order to study the influence of the R1 substituent on the
selectivity of the reaction. When hydrazinium derivatives were
used, triethylamine was added as a base (Scheme 3: Method 2).
The reactions of 6a with methylhydrazine (Method 1) and
ethylhydrazinium oxalate (Method 2) proceeded smoothly pro-
viding only pyridazin-3(2H)-ones 9b and 9c in 61% and 57% yields,
g
-Ketothioester 8 was prepared according to our reported
procedure [19] starting from the corresponding perfluoroketene
dithioacetal [20,21]. The treatment of 8 with non-nucleophilic
diisopropylamine in diethyl ether led to
a,b-unsaturated g-
lactone 6a as a mixture of stereomers [19]. This compound was
then easily transformed into sulfonyl derivative 6b by oxidation
with meta-chloroperbenzo¨ıc acid (MCPBA). Finaly,
were efficiently converted into 3-(2,2,2-trifluoroethyl)
(yields: 41–87%) in the presence of various substituted amines
(Scheme 2) [18].
In this paper, we would like to report on a thorough investigation
of heterocyclizations of compounds 6a,b with hydrazines in order to
preparenewpyridazin-3(2H)-ones.Inparticular, theinfluenceofthe
lactone substitution (X = S, SO2) and the nature of hydrazines on the
outcome of the reaction were studied.
g
-lactones 6a,b
-lactams 7
respectively (Scheme 3, Table 1: entries 2 and 3). In contrast, g-
g
lactone 6a did not react with phenylhydrazine; only a very low
conversion was observed by 19F NMR of the crude mixture, even
after reflux for 24 h (Table 1: entry 4). The carbonyl group seemed
less reactive toward the poorly nucleophilic phenylhydrazine. A
similar observation has been already done for the reaction of 6a
with aniline [18].
In order to increase the electrophilicity of the carbonyl function,
the same transformations were performed with phenysulfonyl
Scheme 2. Reagents and conditions: (i) iPr2NH, Et2O, rt; (ii) MCPBA, CH2Cl2, rt; (iii) RNH2, Et2O or THF, rt.

420
S. Mykhaylychenko et al. / Journal of Fluorine Chemistry 130 (2009) 418–427
Scheme 3. Reagents and conditions: (i) Method 1: R1NHNH2 (2–5 equiv.), THF, rt, 16 h or Method 2: R1NHNH2ꢁ2HX (2 equiv.), Et3N (4 equiv.), THF, rt, 16 h.
lactone 6b. Indeed, we have already demonstrated that vinylogous
conjugation with an electron-withdrawing substituent activates
the carbonyl group thus facilitating the addition of less nucleo-
philic amines [18]. Reactions of hydrazine hydrate (R1 = H, entry 5)
or alkylhydrazines (R1 = Me, Et: entries 6, 7) proceeded in the same
manner affording new pyridazin-3(2H)-ones 9d–f in moderate to
good yields (Scheme 3, Table 1).
We then turned our attention to aryl substituted hydrazines.
Reactions of the sulfonyl lactone 6b with phenyl- and p-
tolylhydrazines were selective providing
g-lactams 10c and 10d
(Scheme 3, Table 1). Unfortunately, yields remained quite low
(26–51%). It is worth noting that the reaction of 6b with
p-tolylhydrazine (entry 9) was accompanied by the formation of
lactam 12 (ꢀ10%) (Fig. 1), probably due to N-N bond cleavage of
lactam 10d. This type of cleavage has been already observed in the
literature in non-fluorinated heterocyclic chemistry [22] and also
The behaviour of hydrazine hydrate with g-lactone 6b (Table 1:
entry 5) was slightly different than it with sulfanyl analogue 6a
(entry 1). Indeed, the major reaction product of 6b with hydrazine
was the intermediate 11a (Fig. 1) which appeared to be unstable
and was decomposed into a complex mixture of products during its
purification on silica gel column chromatography. Intermediate
11a was characterized in the crude mixture by means of MS
spectra and 19F, 1H and 13C NMR. Nevertheless, pyridazin-3-one 9d
was isolated as pure compound in 22% yield. In order to increase
the yield, we attempted performing a mild in situ dehydration of
11a by addition of a dehydrating agent to the reaction mixture.
However, magnesium sulphate or p-toluenesulfonic acid did not
work (no conversion) whereas sulphuric acid or simple heating led
to complete decomposition of 11a.
during the reaction of an
with phenylhydrazine [23]. In order to confirm its structure,
-lactam 12 (Fig. 1) was unambiguously prepared in 71% yield
a-pentafluoroethyl g-carboxythioester
g
from compound 6b and an aqueous solution of ammonia in THF at
room temperature, according to our reported procedure [18].
This transformation was also applied to N,N-dimethylhydrazine
in order to confirm the
observed for -lactone 6a whereas reaction of 6b led exclusively to
-lactam 10e in 64% yield (Scheme 4). Again, these two
heterocyclizations highlighted the strong reactivity difference
between sulfanyl (X = S) and sulfonyl (X = SO2) -lactones.
An important part of this work was to characterize the structure
of the new pyridazin-3(2H)-ones 9a–f and -lactams 10a–e. First
g-lactam structure. No reaction was
g
g
g
g
of all, NMR spectra (19F, 1H, 13C), IR, MS and elemental analyses
were in good agreement with the proposed structures. Never-
theless, this data was not sufficient to unambiguously confirm the
precise skeleton of 9 and 10. Therefore, we compared carefully
selected NMR (d19F
compounds 9 and 10 (Table 2) with those of 13 (for pyridazin-
3(2H)-ones) and those of 14 (for -lactams) for which X-ray
diffraction analyses were already obtained (Fig. 2) [14,18].
As shown in Table 2, the fluorine ( 19F), olefinic proton (dH-5/H-4
C-2 to C-6) chemical shifts of pyridazin-3(2H)-ones 9
-lactams 10 and 14 are very similar respectively.
, dH-5/H-4, dC-2 to C-6) and IR data (nCO) of
g
d
)
and carbon (
d
and 13 and
g
Fig. 1.
Furthermore, infrared absorptions of the carbonyl group (nC O) are
characteristic of a cyclic amide function. Therefore, we may
reasonably assume that the structures 9, 13 and 10, 14 are very
similar.
Table 1
Reactions of
g-lactones 6a,b with hydrazines.
Reactions of lactones 6a,b with substituted hydrazines
appeared to be quite selective: alkylhydrazines gave mainly
Entry Substrate
X
Methoda R1
Pyridazin-3-oneb
g
-Lactamb
pyridazin-3-ones 9b,c,e,f whereas arylhydrazines provided
lactams 10c,d. To explain this selectivity, we proposed the
mechanism depicted in Scheme 5.
g-
1
2
3
4
6a
6a
6a
6a
S
S
S
S
1
1
2
1
H
9a: 21%
9b: 61%
9c: 57%
–
10a: 33%
Me
Et
Phc
–
–
–
5
6
7
8
9
6b
6b
6b
6b
6b
SO2
SO2
SO2
SO2
SO2
1
1
2
1
2
Hd
9d: 22%
9e: 58%
9f: 66%
–
–
Me
–
Et
10b: 7%
10c: 51%
10d: 26%e
Ph
p-MeC6H4
–
a
Method 1: hydrazine (2–5 equiv.), THF, rt, 16 h; Method 2: hydrazinium salt
(2 equiv.), Et3N (4 equiv.), THF, rt, 16 h.
b
Isolated yields.
c
Very low conversion was obtained even at reflux for 24 h.
d
The crude showed intermediate 11a as the major product but it partially
decomposed during silica gel chromatography.
e
Lactam 10d was accompanied by lactam 12 (ꢀ10%).
Scheme 4. Reagents and conditions: Method 1: Me2NNH2, THF, rt, 16 h.

S. Mykhaylychenko et al. / Journal of Fluorine Chemistry 130 (2009) 418–427
421
Table 2
Selected NMR and IR data for pyridazin-3-ones 9a–f, 13 and
g-lactams 10a–e, 14.
.
Entry
X
R1/R2
Cpda
d19F (ppm)
dH-5/H-4 (ppm)
dC-2 (ppm)
dC-3 (ppm)
dC-4 (ppm)
dC-5 (ppm)
dC-6 (ppm)
IR (n )
CO, cmꢂ1
1
2
3
4
5
6
7
S
H
9a
9b
9c
ꢂ64.8
ꢂ64.8
ꢂ64.8
ꢂ62.9
ꢂ64.8
ꢂ64.8
ꢂ68.1
7.44
–
–
–
–
–
–
–
161.0
159.6
159.0
160.3
159.5
159.0
158.5
132.9
132.0
132.0
131.8
131.9
132.1
135.3
127.5
127.0
127.4
134.6
132.4
132.1
130.1
145.5
1667
1657
1652
1667
1656
1670
1652
S
Me
Et
H
7.2–7.4
7.1–7.3
7.43
143.6
S
143.5
SO2
SO2
SO2
–
9db
9e
137.2 or 138.1
137.5
Me
Et
–
7.38
9f
13c
7.42
135.7
7.20
143.9
8
9
S
NH2
10ad
10b
10c
10d
10e
14c
ꢂ64.3
ꢂ65.1
ꢂ65.1
ꢂ65.0
ꢂ65.1
ꢂ65.2
6.79
169.4
167.2
167.6
167.5
165.9
168.3
129.7
146.3
143.2
145.3
143.7
142.2
144.7
91.4
86.7
87.6
86.9
86.6
87.4
–
–
–
–
–
–
1651
–
e
SO2
SO2
SO2
SO2
–
NHEt
NHPh
NHpMeC6H4
NMe2
–
7.10
e
10
11
12
13
7.2–7.3
7.30
1656
1652
1652
1682
128.6
129.2
128.7
7.09
7.33
a
NMR solvent: CDCl3.
b
c
NMR solvent: DMSO-d6.
Structures determined by X-ray diffraction analysis [14,18].
NMR solvent: CD3COCD3.
d
e
Not visible.
Substituted hydrazines (R1NHNH2) possess two different
g-lactams 10a–e. Such reactions were observed for phenyl- and
reaction sites. Therefore, two competitive pathways can operate
depending on the more nucleophilic centre of hydrazine. In the
case of alkylhydrazines, the nitrogen atom bearing an alkyl group is
more nucleophilic and attacks the carbonyl group of 6a,b to give
the acyclic intermediates 15 (Scheme 5: N-1 attack). Further
cyclization of 15 followed by dehydration of 11 provides pyridazin-
3-ones 9a–f. It is worth noting that intermediates 11a (R1 = H) and
11b (Scheme 6) were detected and characterized in the crude
mixture. These reactions were observed for methyl- and ethylhy-
drazines; their selectivity was around 90% or higher (Table 1:
entries 2, 3, 6, 7).
p-tolylhydrazines (Table 1: entries 8 and 9).
According to the proposed mechanism, the behaviour of
hydrazine hydrate with 6a,b (Table 1: entries 1 and 5) remains
difficult to explain. Indeed, pyridazin-3-ones 9a,d and/or g-lactam
10a were obtained depending on substrate substitution (sulfanyl
versus sulfonyl moiety).
We then tried to rationalize the experimental results using ab
initio DFT calculations at the B3LYP 6–31G(d) theory level. It has
already been mentioned that the energy of the LUMO is significantly
lower in lactone 6b compared to 6a [18]. The first attack of any
hydrazine derivative could occur either on C2 (carbonyl lactone) or
C5. This is especially true in the case of 6b where the strong electron
withdrawing effect of the sulfone would decrease the electronic
density on C5, thus reinforcing its Michae¨l acceptor character. The
charges and orbital coefficients in the LUMOs of 6a,b were then
In the case of arylhydrazines, the unsubstituted amino group is
more nucleophilic and attacks the carbonyl group of 6a,b leading to
acyclic intermediates 16 (Scheme 5: N-2 attack).
g-Ketosemicar-
bazides 16 then undergo cyclization into the corresponding
Fig. 2. X-ray diffraction analyses of compounds 13 and 14.

422
S. Mykhaylychenko et al. / Journal of Fluorine Chemistry 130 (2009) 418–427
Scheme 5. Proposed mechanism for the formation of compounds 9a–f and 10a–e.
Scheme 6. Reagents and conditions: Method 2: MeNHNHMeꢁ2HCl, Et3N, THF, rt, 16 h.

S. Mykhaylychenko et al. / Journal of Fluorine Chemistry 130 (2009) 418–427
423
Table 3
Charges and MO coefficients in the LUMO on C2 and C5 of lactones 6a,b.
.
Lactone
Charge on C2
Charge on C5
MO coeff.a C2
MO coeff.a C5
6a (X = S)
0.58
0.59
0.42
0.47
0.27
0.26
0.21
0.22
6b (X = SO2)
a
The reported values take into account the 2p and 3p MO coefficients.
In order to better elucidate the proposed mechanism, the
reaction of 6b with symmetrical N,N0-dimethylhydrazine was
performed under the same conditions (Scheme 6). Compound 11b
was unambiguously characterized in the crude mixture (this
observation confirms our hypothesis concerning the selectivity of
alkylhydrazines) but appeared to be not stable for a long reaction
time or during purification. Nevertheless, NMR and MS (HRMS)
data were in good agreement with the proposed structure.
Characteristic signals of a 1,6-dihydropyridazin-3-one skeleton
were observed in 13C NMR (quaternary C-6 carbon at 84.7 ppm,
olefinic CH-5 carbon at 134.2 ppm and carbonyl function at
161.3 ppm) and in the 1H NMR spectra (olefinic H-5 proton at
6.26 ppm). During chromatography on silica gel, 1,6-dihydropyr-
idazin-3-one 11b underwent spontaneous transformation into its
dehydrated derivatives containing exocyclic double bonds. Com-
pounds 19 and 20 were isolated as a (ꢀ50/50) mixture, in 47%
overall yield (Scheme 6). It was not possible to separate them by
usual column chromatography. Their structures were in good
Fig. 3. Intermediate species 17 with a hydrogen bond.
studied. The differences (Table 3) are in favour of an attack on C2 in
both cases assuming that the primary attack of the hydrazine
derivative involves either a charge or an orbital control.
The most striking experimental result concerned the exclusive
formation of the g-lactam 10e when 6a,b were reacted with N,N-
dimethylhydrazine (Scheme 4). Calculations on the postulated
intermediate species 17 (Fig. 3) clearly revealed the formation of a
hydrogen bond between an oxygen atom of the sulfone and the
hydrogen atom of the Me2NNH moiety. The H–O distance (around
210 pm) and the linear arrangement N–H–O observed are in good
agreement with a strong hydrogen bond. This hydrogen bond
would favour the proximity of the nitrogen atom connected to the
carbonyl group and the other carbonyl (distance around 320 pm)
and also increase the stability of intermediate 17. Moreover,
calculations performed on 18 (Fig. 4) showed longer S–H distance
(around 430 pm) which is not in accordance with the formation of
a hydrogen bond. Because both intermediates 17 and 18 are similar
for an electronic point of view, this hydrogen bond could explain
the transformation of 6b into 10e in a good yield whereas no
agreement with IR, MS and NMR data, especially 19F NMR spectra
3
show a CF3 group (
d
= ꢂ65.0 ppm, JF,H = 10.5 Hz) identified as a
triplet for 19 whereas the CF3 group of 20 (
d
= ꢂ58.3 ppm,
3JF,H = 9.4 Hz) appeared as a doublet. It is worth noting that
compounds 19 and 20 were isolated as single isomers. Never-
theless, due to complicated 1H spectra and several overlaps of 1H
signals, it was not possible to determine the configuration of their
exocyclic double bonds by NOE experiments.
In conclusion, a new general synthesis of 2,2,2-trifluoroethyl
pyridazin-3(2H)-ones 9 and 1,5-dihydropyrrol-2-ones 10 has been
developed starting from
a,b-unsaturated g-lactones 6a,b and
hydrazines. Reaction selectivity depends on the nature of the
conversion for 6a into the corresponding
g-lactam was observed.
When -lactones 6a,b were reacted with other hydrazines, the
g
Table 4
experimental results obtained were more difficult to explain.
Competition, however, between intermediates 15 and 16 could be
envisioned (Scheme 5). While formation of 16 would be favoured
by the above-mentioned hydrogen bond, ease of ring closure might
depend on the nature of the substituents connected to the terminal
nitrogen atom. Calculation of the formation enthalpies of
intermediates 15 and 16 shows that 16 is more stable than 15
when a sulfonyl group (X = SO2) is present (a difference of
2.5 kcal molꢂ1 for R1 = Me and 10 kcal molꢂ1 for R1 = Ph). The
stability difference between 15 and 16 is less pronounced in the
case of a sulfanyl group (X = S) (only 0.46 kcal molꢂ1 for R1 = Me
and 0.65 kcal molꢂ1 for R1 = Ph). The observed hydrogen bond in
any intermediate 16 may explain this stability difference.
Charges on the nitrogen atoms of postulated intermediates 15–18.
.
Entry
Postulated intermediates
Charge on
Charge
on NH2
Charge on
NR1R2
The charge densities on the nitrogen atoms of intermediates
15–18 were then calculated. When the electronic density on the
terminal nitrogen atom of 15 is large enough (Table 4: entries 1 and
2), ring closure occurs through this intermediate and leads to the
pyridazinone derivatives 9. Alternatively, when this density is less
important (Table 4: entry 3), ring closure involves the more stable
N–C
O
1
2
3
4
5
15: X = S, R1 = Me
15: X = SO2, R1 = Me
16: X = SO2, R1 = H, R2 = Ph
17: X = SO2, R1 = R2 = Me
18: X = S, R1 = R2 = Me
ꢂ0.31
ꢂ0.31
ꢂ0.53
ꢂ0.51
ꢂ0.47
ꢂ0.57
–
ꢂ0.57
–
–
–
–
ꢂ0.50
ꢂ0.25
ꢂ0.25
intermediate 16 and leads to the g-lactam derivatives 10.

424
S. Mykhaylychenko et al. / Journal of Fluorine Chemistry 130 (2009) 418–427
phenylhydrazine: 2 equiv.) in THF (5 mL) was stirred for 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 residue was purified by silica gel column
chromatography (eluent: mixture of petroleum ether and ethyl
acetate) to give the corresponding pyridazin-3(2H)-ones 9a,b,d,e
and/or g-lactams 10a,c,e (Schemes 3 and 4, Table 1). For lactams
10a,c, pure analytical samples were obtained by recrystallization
from a mixture of pentane and ethyl acetate.
3.2. Typical procedure for the reactions of lactones 6a,b and
hydrazinium salts (Method 2)
Triethylamine (0.90 g, 8.8 mmol) was added to a solution of
ethylhydrazinium oxalate (0.26 g, 4.4 mmol) in THF (8 mL). After
15 min stirring, a solution of lactone 6a (0.63 g, 2.2 mmol) in THF
(2 mL) was added. The reaction mixture was then stirred for 16 h at
room temperature. After the completion of the reaction (checked
by 19F NMR of the crude mixture), the precipitate was filtered off
and the filtrate was concentrated in vacuo. The residue was purified
by silica gel column chromatography (eluent: mixture (90:10) of
petroleum ether and ethyl acetate) giving 0.41 g (yield: 57%) of
pure pyridazin-3(2H)-one 9c (Scheme 3, Table 1: entry 3).
3.3. Reaction of lactone 6a with hydrazine (Scheme 3, Table 1:
entry 1, Method 1)
Fig. 4. Intermediate species 18 without a hydrogen bond.
6-(Phenylsulfanylmethyl)-4-(2,2,2-trifluoroethyl)-pyridazin-
3(2H)-one (9a). It was purified on silica gel, eluting with a mixture
(60:40) of petroleum ether and ethyl acetate. Yield: 21%. Oil. 1H
hydrazine substituent: alkylhydrazines (R1 = Me, Et) afforded
mainly pyridazin-3-ones 9 whereas arylhydrazines (R1 = Ph, p-
3
4
MeC6H4) provided
g
-lactams 10. Further transformations of these
NMR (CDCl3,
CH2CF3), 3.99 (s, 2H, CH2S), 7.2–7.4 (m, 5H, Ph), 7.44 (m, 1H, CH),
11.4 (brm, 1H, NH). 19F NMR (CDCl3,
ppm): ꢂ64.8 (t,
3JF,H = 10.5 Hz). 13C NMR (CDCl3,
ppm): 32.5 (q, JC,F = 31.2 Hz,
d ppm): 3.44 (qd, JH,F = 10.5, JH,H = 1.0 Hz, 2H,
new heterocycles 9 and 10 are under investigation.
d
2
d
3. Experimental
CH2CF3), 37.6 (s, CH2S), 125.1 (q, 1JC,F = 277.0 Hz, CF3), 127.5 (s, CH),
129.2 (s, 2 ꢃ CH Ph), 131.1 (s, 2 ꢃ CH Ph), 132.8 (s, CH), 132.9 (q,
3JC,F = 2.9 Hz, CCH2CF3), 133.2 (s, Cq Ph), 145.5 (s, Cq, C N), 161.0 (s,
IR spectra were recorded on a FT-IR PerkinElmer PARAGON 500.
1H NMR (250 MHz), 19F NMR (235 MHz) and 13C NMR (63 MHz)
spectra were recorded, in CDCl3 as a solvent unless otherwise
specified, on a Bruker AC250 Instrument spectrometer. Tetra-
C
O). IR (film, cmꢂ1): 3227, 2924, 1667, 1613. MS (ESI): m/z = 301
[M+1], 283 [M+1ꢂH2O]. HRMS (ESI): calcd. for C13H12F3N2OS m/z
301.0622, found 301.0615.
methylsilane (1H NMR:
= 7.27 ppm; 13C NMR:
= 0.00 ppm) were used as internal standards for 1H, 13C or 19F
d
d
= 0.00 ppm) or CHCl3 (1H NMR:
d
d
= 77.00 ppm) or CFCl3
(
19F NMR:
1-(N-Amino)-3-(2,2,2-trifluoroethyl)-5-hydroxy-5-(phenylsul-
fanylmethyl)-1,5-dihydropyrrol-2-one (10a). It was purified by
chromatography on silica gel, eluting with a mixture (60:40) of
petroleum ether and ethyl acetate. Recrystallization from a
mixture of pentane and ethyl acetate. Yield: 33%. Solid. m.p.
spectra. The abbreviations for the multiplicity of the proton and
carbon signals are as follows: s singlet, d doublet, t triplet, q
quartet, m multiplet, Cq quaternary carbon. Column chromato-
graphy was performed with silica gel (63–200 mesh, Normasil
Prolabo, Fontenay-sous-bois, France). Mass spectra (MS) were
recorded on a Thermo Finnigan, LCQ Advantage Max, Electrospray
Ionisation, Source heater T = 220 8C, cone voltage = 33 V. High-
Resolution Mass Spectra (HRMS) were recorded with a Q-TOF
Micromass Instrument in the positive ESI (CV = 30 V) mode.
Melting points were recorded on a Bu¨cchi apparatus and are
uncorrected. DFT calculations were carried out with the Gaussian-
03 suite of programs [24] implemented on a P575 IBM cluster. We
used the three parameters hybrid function of Becke [25] and the
correlation function of Lee et al. (B3LYP) [26] with the 6–31G(d)
basis set for any element. Formation enthalpies have been
calculated after a frequency calculation in order to be sure that
the geometry found corresponds to a stationary point and to
achieve the zero point correction.
139 8C. 1H NMR (CD3COCD3,
CHAHBCF3), 3.19 (qm, JH,F = 10.4 Hz, 1H, CHAHBCF3), 3.56 (m, 2H,
d
ppm): 3.12 (qm, 3JH,F = 10.4 Hz, 1H,
3
CH2S), 3.98 (brs, 2H, NH2), 5.6 (brm, 1H, OH), 6.79 (s, 1H, CH), 7.2–
7.4 (m, 5H, Ph). 19F NMR (CD3COCD3,
d
ppm): ꢂ64.3 (t,
2
3JF,H = 10.4 Hz). 13C NMR (CD3OD,
d ppm): 30.5 (q, JC,F = 31.6 Hz,
CH2CF3), 39.7 (s, CH2S), 91.4 (s, Cq, COH), 126.7 (q, 1JC,F = 275.9 Hz,
3
CF3), 127.9 (s, CH Ph), 129.7 (q, JC,F = 2.9 Hz, CCH2CF3), 130.1 (s,
2 ꢃ CH Ph), 131.4 (s, 2 ꢃ CH Ph), 137.0 (s, Cq Ph), 146.3 (s, CH),
169.4 (s, CO). IR (KBr, cmꢂ1): 3311, 2935, 1698, 1651, 1617. MS
(ESI): m/z = 301 [M+1ꢂH2O]. HRMS (ESI): calcd. for
C13H13F3N2NaO2S m/z 341.0548, found 341.0559.
3.4. Reaction of lactone 6a with methylhydrazine (Scheme 3, Table 1:
entry 2, Method 1)
6-(Phenylsulfanylmethyl)-4-(2,2,2-trifluoroethyl)-2-methyl-
pyridazin-3(2H)-one (9b). It was purified by chromatography on
silica gel, eluting with a mixture (60:40) of petroleum ether and
3.1. General procedure for the reactions of lactones 6a,b and
hydrazines (Method 1)
ethyl acetate. Yield: 61%. Oil. 1H NMR (CDCl3,
d ppm): 3.42 (qd,
4
The mixture of lactone 6a or 6b (1.0 mmol) and hydrazine
(hydrazine hydrate: 5 equiv., N-methyl-, N,N-dimethyl- or N-
3JH,F = 10.6, JH,H = 1.0 Hz, 2H, CH2CF3), 3.66 (s, 3H, NCH3), 3.95 (s,
2H, CH2S), 7.2–7.4 (m, 6H, Ph + CH). 19F NMR (CDCl3,
d ppm):

S. Mykhaylychenko et al. / Journal of Fluorine Chemistry 130 (2009) 418–427
425
3
ꢂ64.8 (t, JF,H = 10.6 Hz). 13C NMR (CDCl3,
d
ppm): 32.9 (q,
7.75 (dm, 3JH,H = 8.3 Hz, 2H Ph). 19F NMR (CDCl3,
3JF,H = 10.5 Hz). 13C NMR (CDCl3,
d
ppm): ꢂ64.8 (t,
2JC,F = 31.0 Hz, CH2CF3), 37.8 (s, CH2S), 40.3 (s, NCH3), 125.2 (q,
1JC,F = 277.2 Hz, CF3), 127.0 (s, CH), 129.0 (s, 2 ꢃ CH Ph), 131.2 (s,
2 ꢃ CH Ph), 131.3 (s, CH), 132.0 (q, 3JC,F = 2.7 Hz, CCH2CF3), 133.4 (s,
Cq Ph), 143.6 (s, C N), 159.6 (s, C O). IR (film, cmꢂ1): 3444, 2927,
1657, 1613, 1487. MS (ESI): m/z = 315 [M+1], 206 [M+1-SPh].
d
ppm): 33.0 (q, JC,F = 31.2 Hz,
2
CH2CF3), 40.6 (s, NCH3), 60.9 (s, CH2SO2), 125.0 (q, 1JC,F = 277.3 Hz,
CF3), 128.4 (s, 2 ꢃ CH Ph), 129.3 (s, 2 ꢃ CH Ph), 131.9 (q,
4
3JC,F = 2.7 Hz, CCH2CF3), 132.4 (q, JC,F = 1.5 Hz, CH ), 134.3 (s,
CH Ph), 135.6 (s, Cq), 137.5 (s, Cq), 159.5 (s, C O). IR (KBr, cmꢂ1):
2974, 2928, 1656, 1611, 1537, 1446. MS (ESI): m/z = 347 [M+1],
315. HRMS (ESI): calcd. for C14H14F3N2O3S m/z 347.0677, found
347.0668.
HRMS (ESI): calcd. for
315.0781.
C14H14F3N2OS m/z 315.0779, found
3.5. Reaction of lactone 6a with ethylhydrazine (Scheme 3, Table 1:
entry 3, Method 2)
3.8. Reaction of lactone 6b with ethylhydrazine (Scheme 3, Table 1:
entry 7, Method 2)
6-(Phenylsulfanylmethyl)-4-(2,2,2-trifluoroethyl)-2-ethylpyri-
dazin-3(2H)-one (9c). Method 2 was used but the reaction mixture
was refluxed for 60 h. The compound was purified by chromato-
graphy on silica gel, eluting with a mixture (90:10) of petroleum
6-(Phenylsulfonylmethyl)-4-(2,2,2-trifluoroethyl)-2-ethyl-
pyridazin-3(2H)-one (9f). It was purified by chromatography on
silica gel, eluting with a mixture (50:50) of petroleum ether and
ethyl acetate and recristallization from pentane/CH2Cl2. Yield:
ether and ethyl acetate. Yield: 57%. Oil. 1H NMR (CDCl3,
d ppm):
1.14 (t, 3JH,H = 7.2 Hz, 3H, CH3), 3.37 (q, 3JH,F = 10.6 Hz, 2H, CH2CF3),
66%. Solid. m.p. 133 8C. 1H NMR (CDCl3,
d
ppm): 1.08 (t,
3.90 (s, 2H, SCH2), 4.01 (q, 3JH,H = 7.2 Hz, 2H, NCH2), 7.1–7.3 (m, 6H,
3JH,H = 7.2 Hz, 3H, CH3), 3.47 (q, JH,F = 10.5 Hz, 2H, CH2CF3),
3
3
Ph + CH). 19F NMR (CDCl3,
d
ppm): ꢂ64.8 (t, JF,H = 10.6 Hz). 13C
3.99 (q, 3JH,H = 7.2 Hz, 2H, NCH2), 4.32 (s, 2H, CH2SO2), 7.42 (s, 1H,
3
3
NMR (CDCl3,
d
ppm): 13.3 (s, CH3), 32.9 (q, 2JC,F = 31.1 Hz, CH2CF3),
CH), 7.53 (dd, JH,H = 7.4, JH,H = 7.2 Hz, 2H, Ph), 7.66 (tm,
37.8 (s, CH2S), 47.1 (s, NCH2), 125.2 (q, 1JC,F = 277.2 Hz, CF3), 127.4
(s, CH), 129.0 (s, 2 ꢃ CH Ph), 131.0 (s, CH), 131.3 (s, 2 ꢃ CH Ph),
132.0 (q, 3JC,F = 2.6 Hz, CCH2CF3), 133.3 (s, Cq Ph), 143.5 (s, Cq C N),
159.0 (s, C O). IR (film, cmꢂ1): 2980, 2937, 1660, 1652, 1614, 1538,
1440. MS (ESI): m/z = 351 [M+Na], 329 [M+1]. HRMS (ESI): calcd.
for C15H16F3N2OS m/z 329.0935, found 329.0930.
3JH,H = 7.4 Hz, 1H, Ph), 7.73 (dm, JH,H = 7.2 Hz, 2H, Ph). 19F NMR
3
(CDCl3,
d
ppm): ꢂ64.8 (t, 3JF,H = 10.5 Hz). 13C NMR (CDCl3,
d ppm):
13.1 (s, CH3), 33.0 (q, 2JC,F = 31.3 Hz, CH2CF3), 47.4 (s, NCH2), 60.9
1
(s, CH2SO2), 125.1 (q, JC,F = 277.4 Hz, CF3), 128.4 (s, 2 ꢃ CH Ph),
129.3 (s, 2 ꢃ CH Ph), 132.1 (m, CH + CCH2CF3), 134.2 (s, CH Ph),
135.7 (s, Cq), 137.3 (s, Cq), 159.0 (s, C O). IR (KBr, cmꢂ1): 2989,
2928, 1670, 1613, 1584, 1529, 1449. MS (ESI): m/z = 383 [M+Na],
361 [M+1]. HRMS (ESI): calcd. for C15H16F3N2O3S m/z 361.0834,
found 361.0837.
3.6. Reaction of lactone 6b with hydrazine (Scheme 3, Table 1:
entry 5, Method 1)
1-(N-Ethylamino)-3-(2,2,2-trifluoroethyl)-5-hydroxy-5-(phe-
nylsulfonylmethyl)-1,5-dihydro-pyrrol-2-one (10b). Yield: 7%.
This compound was partly purified by chromatography on silica
gel, eluting with a mixture (50:50) of petroleum ether and ethyl
6-(Phenylsulfonylmethyl)-4-(2,2,2-trifluoroethyl)-pyridazin-
3(2H)-one (9d). It was purified by chromatography on silica gel,
eluting with a mixture (30:70) of petroleum ether and ethyl
acetate. Yield: 22%. Solid. m.p. 264 8C. 1H NMR (DMSO-d6,
d
ppm):
acetate giving a mixture (90:10) of pyridazinone 9f and
g-lactam
3
3.56 (q, JH,F = 10.9 Hz, 2H, CH2CF3), 4.72 (s, 2H, CH2SO2), 7.43 (s,
1H, CH), 7.6–7.8 (m, 5H, Ph), 13.3 (brs, 1H, NH). 19F NMR (DMSO-
10b. Selected 1H NMR data (CDCl3,
d
ppm): 3.0–3.2 (m, 4H,
3
NHCH2 + CH2CF3), 7.10 (s, 1H, CH), 7.91 (dm, JH,H = 7.2 Hz, 2H,
3
d6,
d
ppm): ꢂ62.9 (t, JF,H = 10.9 Hz). 13C NMR (DMSO-d6,
d
ppm):
Ph). 19F NMR (CDCl3,
NMR data (CDCl3,
d
ppm): ꢂ65.1 (t, 3JF,H = 10.5 Hz). Selected 13
C
2
2
31.9 (q, JC,F = 29.9 Hz, CH2CF3), 59.7 (s, CH2SO2), 125.8 (q,
1JC,F = 277.0 Hz, CF3), 128.0 (s, 2 ꢃ CH Ph), 129.4 (s, 2 ꢃ CH Ph),
131.8 (q, 3JC,F = 2.9 Hz, CCH2CF3), 134.6 (s, 2C, CH Ph + CH ), 137.2
(s, Cq), 138.1 (s, Cq), 160.3 (s, C O). IR (KBr, cmꢂ1): 3222, 2994,
2904, 1667, 1610, 1416, 1366. MS (ESI): m/z = 333 [M+1]. HRMS
(ESI): calcd. for C13H12F3N2O3S m/z 333.0521, found 333.0525.
6-(Phenylsulfonylmethyl)-4-(2,2,2-trifluoroethyl)-6-hydroxy-
1,6-dihydropyridazin-3(2H)-one (11a). The compound 11a was
characterized in the crude mixture but it decomposed partly
during silica gel chromatography. Selected 1H NMR data (DMSO-
d
ppm): 13.3 (s, CH3), 30.3 (q, JC,F = 31.3 Hz,
CH2CF3), 46.1 (s, NHCH2), 60.0 (s, CH2SO2), 86.7 (s, Cq, COH), 127.9
(s, 2 ꢃ CH Ph), 129.3 (s, 2 ꢃ CH Ph), 139.7 (s, Cq Ph), 143.2 (s, CH),
167.2 (s, C O).
3.9. Reaction of lactone 6b with phenylhydrazine (Scheme 3, Table 1:
entry 8, Method 1)
1-(N-Phenylamino)-3-(2,2,2-trifluoroethyl)-5-hydroxy-5-
(phenylsulfonylmethyl)-1,5-dihydro-pyrrol-2-one (10c). It was
purified by chromatography on silica gel, eluting with a mixture
(60:40) of petroleum ether and ethyl acetate. Recrystallization
d6, d ppm): 3.96 (m, 2H, CH2CF3), 4.05 (m, 1H, CHAHBSO2), 4.13 (m,
1H, CHAHBSO2), 6.99 (s, 1H, CH), 7.7–8.1 (m, 5H, Ph). 19F NMR
(DMSO-d6,
(DMSO-d6,
d
d
ppm): ꢂ63.1 (t, 3JF,H = 11.1 Hz). Selected 13C NMR data
from a mixture of pentane and ethyl acetate. Yield: 51%. Solid. m.p.
2
3
ppm): 32.7 (q, JC,F = 28.6 Hz, CH2CF3), 59.3 (s,
172 8C. 1H NMR (CDCl3,
d
ppm): 3.17 (qm, JH,F = 10.4 Hz, 2H,
2
CH2SO2), 87.2 (s, Cq, COH), 126.9 (s, 2 ꢃ CH Ph), 127.6 (s, CH
Ph), 129.4 (s, 2 ꢃ CH Ph), 133.6 (s, CH ), 134.2 (s, Cq Ph), 171.0 (s,
CH2CF3), 3.55 (d, JH,H = 14.2 Hz, 1H, CHAHBSO2), 3.88 (d,
2JH,H = 14.2 Hz, 1H, CHAHBSO2), 4.05 (brs, 1H, OH or NH), 5.95
3
C
O). IR (KBr, cmꢂ1): 1667, 1610. MS (ESI): m/z = 445 [M+THF+Na],
(brs, 1H, NH or OH), 6.86 (dm, JH,H = 7.8 Hz, 2H Ph), 6.93 (t,
423 [M+THF+1].
3JH,H = 7.4 Hz, 1H Ph), 7.2–7.3 (m, 3H, 2H Ph + CH), 7.61 (dd,
3JH,H = 7.8, 3JH,H = 7.3 Hz, 2H Ph), 7.72 (t, 3JH,H = 7.4 Hz, 1H Ph), 7.92
3
3.7. Reaction of lactone 6b with methylhydrazine (Scheme 3, Table 1:
entry 6, Method 1)
(d, JH,H = 7.4 Hz, 2H Ph). 19F NMR (CDCl3,
d
ppm): ꢂ65.1 (t,
3JF,H = 10.4 Hz). 13C NMR (CD3COCD3,
d
ppm): 30.2 (q,
2JC,F = 31.3 Hz, CH2CF3), 60.6 (s, CH2SO2), 87.6 (s, Cq, COH), 114.3
(s, CH Ph), 121.0 (s, CH Ph), 126.8 (q, 1JC,F = 275.9 Hz, CF3), 129.0 (s,
2 ꢃ CH Ph), 129.5 (s, 2 ꢃ CH Ph), 130.0 (s, 2 ꢃ CH Ph), 134.6 (s,
2 ꢃ CH Ph), 141.7 (s, Cq Ph), 145.3 (s, CH), 149.0 (s, Cq Ph), 167.6
(s, CO). IR (KBr, cmꢂ1): 3320, 1690, 1656, 1499. MS (ESI): m/z = 449
[M+Na], 427 [M+1], 409 [M+1ꢂH2O]. HRMS (ESI): calcd. for
6-(Phenylsulfonylmethyl)-4-(2,2,2-trifluoroethyl)-2-methyl-
pyridazin-3(2H)-one (9e). It was purified by chromatography on
silica gel, eluting with a mixture (40:60) of petroleum ether and
ethyl acetate. Yield: 58%. Solid. m.p. 146 8C. 1H NMR (CDCl3,
d
ppm): 3.46 (q, 3JH,F = 10.5 Hz, 2H, CH2CF3), 3.60 (s, 3H, NCH3), 4.30
(s, 2H, CH2SO2), 7.38 (s, 1H, CH), 7.53 (m, 2H Ph), 7.67 (m, 1H Ph),
C19H17F3N2NaO4S m/z 449.0759, found 449.0760.

426
S. Mykhaylychenko et al. / Journal of Fluorine Chemistry 130 (2009) 418–427
3.10. Reaction of lactone 6b with p-tolylhydrazine (Scheme 3, Table 1:
entry 9, Method 2)
361 [M+1ꢂH2O]. HRMS (ESI): calcd. for C15H18F3N2O4S m/z
379.0939, found 379.0934.
1-(N-(p-Tolyl)amino)-3-(2,2,2-trifluoroethyl)-5-hydroxy-5-
(phenylsulfonylmethyl)-1,5-dihydropyrrol-2-one (10d). It was
purified by chromatography on silica gel, eluting with a mixture
(20:80) of petroleum ether and ethyl acetate. Lactam 10d was
accompanied by lactam 12 (ꢀ10%). Yield: 26%. Oil. 1H NMR (CDCl3,
3.12. Reaction of lactone 6b with N,N0-dimethylhydrazine
(Scheme 6, Method 2)
Reaction of 6b (0.22 mmol) with N,N0-dimethylhydrazine
dihydrochloride (2 equiv.) in the presence of triethylamine
(4 equiv.) gave the intermediate 11b which was slowly and
spontaneously dehydrated into a mixture (ꢀ50:50) of compounds
19 and 20.
d
ppm): 2.23 (s, 3H, CH3), 3.09 (q, 3JH,F = 10.0 Hz, 2H, CH2CF3), 3.54
2
2
(d, JH,H = 14.3 Hz, 1H, CHAHBSO2), 3.86 (d, JH,H = 14.3 Hz, 1H,
CHAHBSO2), 4.37 (brs, 1H, OH or NH), 5.98 (brs, 1H, NH or OH), 6.72
(d, 3JH,H = 8.0 Hz, 2H tolyl), 6.98 (d, 3JH,H = 8.0 Hz, 2H tolyl), 7.30 (s,
1H, CH), 7.5–7.6 (m, 2H Ph), 7.6–7.7 (m, 1H Ph), 7.88 (d,
6-(Phenylsulfonylmethyl)-4-(2,2,2-trifluoroethyl)-6-hydroxy-
1,2-dimethyl-1,6-dihydro-pyridazin-3-one (11b). This compound
3JH,H = 7.9 Hz, 2H Ph). 19F NMR (CDCl3,
3JF,H = 10.0 Hz). 13C NMR (CDCl3,
d
ppm): ꢂ65.0 (t,
was characterized in the crude mixture. Oil. 1H NMR (CDCl3,
d
d
ppm): 20.5 (s, CH3), 30.0 (q,
ppm): 2.54 (s, 3H, NMe), 2.76 (s, 3H, NMe), 3.32 (q, 3JH,F = 10.4 Hz,
2JC,F = 32.0 Hz, CH2CF3), 59.7 (s, CH2SO2), 86.9 (s, Cq, COH), 124.9 (q,
1JC,F = 275.3 Hz, CF3), 114.0 (s, 2 ꢃ CH Ar), 128.0 (s, 2 ꢃ CH Ar),
2H, CH2CF3), 3.37 (d, JH,H = 14.4 Hz, 1H, CHAHBSO2), 3.77 (d,
2
2JH,H = 14.4 Hz, 1H, CHAHBSO2), 6.26 (s, 1H, CH), 7.59 (ddm,
3JH,H = 7.5 Hz, 3JH,H = 7.5 Hz, 2H Ph), 7.69 (tm, 3JH,H = 7.4 Hz, 1H Ph),
3
128.6 (q, JC,F = 3.3 Hz, CCH2CF3), 129.5 (s, 2 ꢃ CH Ar), 129.7 (s,
2 ꢃ CH Ar), 131.2 (s, Cq Ar), 134.4 (s, CH Ph), 139.4 (s, Cq Ar), 143.7
(s, CH), 144.0 (s, Cq Ar), 167.5 (s, CO). IR (film, cmꢂ1): 3430, 2925,
2854, 1779, 1652, 1449. MS (ESI): m/z = 423 [M+1ꢂH2O]. HRMS
(ESI): calcd. for C20H18F3N2O3S (M+1ꢂH2O) m/z 423.0990, found
423.0986.
7.92 (dm, 3JH,H = 8.1 Hz, 2H Ph). 19F NMR (CDCl3,
d
ppm): ꢂ65.7 (t,
2
3JF,H = 10.4 Hz). 13C NMR (CDCl3,
d ppm): 32.5 (q, JC,F = 30.9 Hz,
CH2CF3), 32.8 (s, NMe), 33.8 (s, NMe), 58.0 (s, CH2SO2), 84.7 (s, Cq,
1
COH), 125.1 (q, JC,F = 275.0 Hz, CF3), 125.8 (s, CH Ph), 128.0 (s,
2 ꢃ CH Ph), 129.3 (s, 2 ꢃ CH Ph), CCH2CF3 not visible, 134.2 (s,
CH ), 140.6 (s, Cq Ph), 161.3 (s, CO). MS (ESI): m/z = 401 [M+Na],
379 [M+1], 361 [M+1ꢂH2O].
3-(2,2,2-Trifluoroethyl)-5-hydroxy-5-(phenylsulfonylmethyl)-
1,5-dihydropyrrol-2-one (12) (Fig. 1). The compound 12 was
obtained in small amounts (ꢀ10%) in the reaction of 6b and p-
tolylhydrazine. In order to confirm its structure, 12 was
unambiguously prepared (0.24 g, yield: 71%) from lactone 6b
(1.0 mmol) and NH4OH (1.2 mmol, 1.2 equiv.) in THF (4 mL) at
room temperature for 16 h, according to a previously reported
procedure [18]. The compound 12 was purified by chromatogra-
phy on silica gel, eluting with a mixture (20:80) of petroleum ether
and ethyl acetate. Recrystallization from a mixture of pentane and
The mixture (ꢀ50:50) of 19 and 20 was purified by
chromatography on silica gel eluting with ethyl acetate. It was
not possible to separate them. Yield: 47%. Oil. IR (film, cmꢂ1): 2923,
2853, 1732, 1633, 1532, 1463. MS (ESI): m/z = 383 [M+Na], 361
[M+1]. HRMS (ESI): calcd. for C15H16F3N2O3S m/z 361.0834, found
361.0842.
6-(Phenylsulfonylmethylidene)-4-(2,2,2-trifluoroethyl)-1,2-
dimethyl-1,6-dihydropyridazin-3-one (19) (selected data). 1H
ethyl acetate. Solid. m.p. 171 8C. 1H NMR (CD3COCD3,
d
ppm): 2.90
NMR (CDCl3,
d
ppm): 3.33 (s, 3H, NMe), 3.40 (q, JH,F = 10.5 Hz,
3
3
(brs, 1H, OH or NH), 3.18 (q, JH,F = 11.1 Hz, 2H, CH2CF3), 3.84 (d,
2H, CH2CF3), 3.47 (s, 3H, CONMe), 5.14 (s, 1H, CHSO2), 7.0–7.4 (m,
5H, Ph), 8.38 (s, 1H, CH). 19F NMR (CDCl3,
ppm): ꢂ65.0 (t,
3JF,H = 10.5 Hz). 13C NMR (CDCl3,
ppm): 33.2 (q, JC,F = 30.9 Hz,
2
2JH,H = 14.8 Hz, 1H, CHAHBSO2), 3.90 (d, JH,H = 14.8 Hz, 1H,
d
2
CHAHBSO2), 5.66 (brs, 1H, OH or NH), 7.16 (m, 1H, CH ), 7.63
d
3
3
(dd, JH,H = 7.8, JH,H = 7.5 Hz, 2H Ph), 7.71 (m, 1H, Ph), 7.96 (dm,
CH2CF3), 34.6 (s, NMe), 41.0 (s, CONMe), 95.6 (s, CHSO2), 129.8 (s,
CH ), 145.6 (s, Cq, C–N), 157.6 (s, CO).
6-(Phenylsulfonylmethyl)-4-(2,2,2-trifluoroethylidene)-1,2-
dimethyl-1,4-dihydropyridazin-3-one (20) (selected data). 1H
3JH,H = 7.1 Hz, 2H Ph). 19F NMR (CD3COCD3,
3JF,H = 11.1 Hz). 13C NMR (CD3COCD3,
d
ppm): ꢂ64.4 (t,
d
ppm): 29.6 (q,
2JC,F = 31.3 Hz, CH2CF3), 62.7 (s, CH2SO2), 85.4 (s, Cq, COH), 126.6
(q, 1JC,F = 275.9 Hz, CF3), 129.1 (s, 2 ꢃ CH Ph), 129.3 (q, 3JC,F = 3.3 Hz,
CCH2CF3), 129.8 (s, 2 ꢃ CH Ph), 134.4 (s, CH Ph), 142.2 (s, Cq Ph),
147.1 (s, CH), 169.8 (s, CO). IR (KBr, cmꢂ1): 3450, 3093, 2994,
2944, 1722, 1450. MS (ESIꢂ): m/z = 334 [Mꢂ1], 316 [Mꢂ1ꢂH2O].
HRMS (ESI+): calcd. for C13H12F3NNaO4S m/z 358.0337, found
358.0339.
NMR (CDCl3,
4.05 (s, 2H, CH2SO2), 5.83 (s, 1H, CH), 6.08 (q, JH,F = 9.4 Hz, 1H,
CHCF3), 7.0–7.4 (m, 5H, Ph). 19F NMR (CDCl3,
ppm): ꢂ58.3 (d,
3JF,H = 9.4 Hz). 13C NMR (CDCl3,
ppm): 34.2 (s, NMe), 40.4 (s,
d ppm): 3.06 (s, 3H, NMe), 3.28 (s, 3H, CONMe),
3
d
d
CONMe), 59.2 (s, CH2SO2), 107.6 (s, CH ), 109.6 (m, CHCF3) 137.6
(s, Cq, C–N), 158.7 (s, CO).
3.11. Reaction of lactone 6b with N,N-dimethylhydrazine
Acknowledgements
(Scheme 4, Method 1)
Yuriy G. Shermolovich and Sergiy Mykhaylychenko are deeply
indebted to University of Rouen for associated professor position
1-(N,N-Dimethylamino)-3-(2,2,2-trifluoroethyl)-5-hydroxy-5-
(phenylsulfonylmethyl)-1,5-dihydropyrrol-2-one (10e). It was
purified by chromatography on silica gel eluting with a mixture
(40:60) of petroleum ether and ethyl acetate. Yield: 64%. m.p.
`
(June 2008) and to ‘‘Le Ministere de l’Education et de la Recherche’’
for its ‘‘Mobility grant’’ (September 2007–February 2008), respec-
tively. The authors thank also the Centre de Ressources Informa-
tiques de Haute-Normandie (CRIHAN) for software optimization
132 8C. 1H NMR (CDCl3,
d ppm): 2.82 (s, 6H, NMe2), 3.04 (qd,
3JH,F = 10.6, 4JH,H = 1.5 Hz, 2H, CH2CF3), 3.27 (d, 2JH,H = 14.1 Hz, 1H,
´
and technical support, and Dr. K. Ple for English improvement.
2
CHAHBSO2), 4.00 (d, JH,H = 14.1 Hz, 1H, CHAHBSO2), 4.3 (brs, 1H,
3
References
OH), 7.09 (m, 1H, CH ), 7.59 (tm, JH,H = 7.5 Hz, 2H Ph), 7.70 (tm,
3
3JH,H = 7.5 Hz, 1H Ph), 7.94 (dm, JH,H = 7.1 Hz, 2H Ph). 19F NMR
(CDCl3,
d
ppm): ꢂ65.1 (t, 3JF,H = 10.6 Hz). 13C NMR (CDCl3,
d ppm):
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