Synthesis of new 3-(1-ethylsulfanyl-2-perfluoroalkyl)-5-hydroxy-5-methyl (or 5-phenyl)-1,5-dihydro-pyrrol-2-ones Starting from γ-Keto thioesters and amines

Article abstract of DOI:10.1055/s-2004-815970

γ-Keto thioesters were easily transformed into α,β- unsaturated lactams using a two-step process (via furans) or by a one-pot reaction. This methodology is general and efficient leading to a varied substitution pattern. The structures of all new heterocycles were assigned using 2D NMR experiments, computer-assisted elucidation, and X-ray diffraction analyses.

Full text of DOI:10.1055/s-2004-815970

PAPER
711
Synthesis of New 3-(1-Ethylsulfanyl-2-perfluoroalkyl)-5-hydroxy-5-methyl
(or 5-phenyl)-1,5-dihydro-pyrrol-2-ones Starting from g-Keto Thioesters and
Amines
F
luorinate
e
d 1,5-Dihyd
a
ro-pyrrol-2
n
-ones -Philippe Bouillon,*a Bernard Tinant,b Jean-Marc Nuzillard,c Charles Portellaa
a
Laboratoire ‘Réactions Sélectives et Applications’, UMR CNRS 6519, Université de Reims, Faculté des Sciences B.P. 1039,
51687 Reims Cedex 2, France
Fax +33(3)26913166; E-mail: jp.bouillon@univ-reims.fr
b
c
Université Catholique de Louvain, Laboratoire de Chimie Physique et de Cristallographie, 1 Place Louis Pasteur, 1348 Louvain-la-
Neuve, Belgium
Laboratoire de Pharmacognoise, UMR CNRS 6013, Université de Reims, Faculté des Sciences, Batiment 18, Moulin de las Housse B.
P. 1039, 51687 Reims Cedex 2, France
Received 17 November 2003; revised 12 January 2004
O
Abstract: g-Keto thioesters were easily transformed into a,b-unsat-
urated lactams using a two-step process (via furans) or by a one-pot
reaction. This methodology is general and efficient leading to a var-
ied substitution pattern. The structures of all new heterocycles were
assigned using 2D NMR experiments, computer-assisted elucida-
tion, and X-ray diffraction analyses.
R2
F3C
N
N
RF=CF3
Ref. 6
R1
RF
O
RF
SEt
SEt
SEt
O
F
O
Key words: fluorine, nitrogen heterocycles, lactam, pyrrol-3-one
R1
Y
RF=CF3 : 1
RF=C2F5 : 2
RF=CF3, R1=Me, Ar: 3
RF=C2F5, R1=Me: 4
RF=C2F5
R1=Me
Ref. 7
Me
CF3
X
Perfluoroketene dithioacetals 1 and 2 are versatile build-
ing blocks owing to the ease at which vinylic fluoride un-
dergoes nucleophilic substitution and to the presence of a
masked carboxylic function.1–3 We have recently reported
the convenient conversion of perfluoroketene dithioace-
X=O, NR2
Y=NHR2, SEt
Scheme 1
tals into their corresponding g-keto thioesters 3 and 4 reaction in order to lead to a preparative one-pot method-
(Scheme 1).2,3 The increasing interest in trifluoromethyl- ology for a,b-unsaturated lactams.
ated heterocycles4,5 and the need for new fluorinated
Besides some specialized methodologies,8 the majority of
building blocks for parallel synthesis prompted us to in-
vestigate the applications of the bifunctionalized interme-
5-hydroxy-1,5-dihydro-pyrrol-2-ones syntheses (which
we simply call a,b-unsaturated lactams) are based on cy-
diates 3, 4 towards the synthesis of a large variety of
clization reactions of a,b-unsaturated keto-amides9 or on
heterocycles. The g-keto thioester 3 (RF = CF3, R1 = Me,
Ar) was shown to be an excellent precursor for the prepa-
ration of trifluoromethyl g-lactones,2 g-lactams,3 py-
ridazin-3-ones,6 and pyridazines6 (Scheme 1). The higher
homolog 4 (RF = C2F5, R1 = Me) offered further opportu-
nities, since an additional HF elimination easily occurred
under basic conditions. Indeed, when 4 was treated with
primary amines (which are basic as well as nucleophilic
reagents), trifluoromethylated furans and pyrroles were
obtained in good yields (Scheme 1).7
amination reactions of the corresponding g-lactones.10 No
example of a 1,5-dihydro-pyrrol-2-one bearing a fluori-
nated substituent has been reported so far.
The g-keto thioesters 4, 12, 13 were prepared according to
our reported procedure:2,3 nucleophilic substitution of the
vinylic fluoride of the starting perfluoroketene dithioace-
O
NHBn
As previously reported,7 the reaction of g-keto thioester 4
with non-nucleophilic diisopropylamine led exclusively
to the furan thioester 5. Surprisingly, when pure furan 5
was treated with benzylamine, the new heterocyclic com-
pound 7 was isolated as a mixture (47:53) of diastereo-
mers, instead of the expected furan 6 (Scheme 2). The
present paper reports on the full investigation of this new
Me
CF3
O
O
6
Y
(i)
CF3
Me
CF3
X
SEt
5
H
X=O, Y=SEt
Me
HO
O
N
Bn
7 (84%, dr 47:53)
SYNTHESIS 2004, No. 5, pp 0711–0721
x
x
.
x
x
.2
0
0
4
Advanced online publication: 12.02.2004
DOI: 10.1055/s-2004-815970; Art ID: Z16403SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 2 Reagents and conditions: (i) BnNH2, Et2O, r.t., 16 h

712
J.-P. Bouillon et al.
PAPER
tals 2 or 8 by potassium enolates of ketones, followed by assigned using 2D NMR experiments such as 1H-1H (CO-
acid hydrolysis of intermediates 9–11 (Scheme 3). This SY) and 1H-13C (HMQC, HMBC) correlations and X-ray
methodology allowed us to introduce structural diversity diffraction analysis (vide infra). Then the reaction was
at the initial step (using various perfluoroalkyl-substituted successfully extended to the g-keto thioesters bearing var-
aldehydes) as well as at the vinylic substitution step (both ious RF and R1 substituents. The yield of lactam 18 was
aliphatic and aromatic enolates worked well).
good but compound 19 (yield: 49%) was accompanied by
the unsaturated derivative 20 as a single stereoisomer
(Scheme 5). The full determination of the structure of 20
will be discussed later.
RF
EtS
CF2H
F
SEt
O
EtS
RF
H
R1
Me
HO
(i)
O
O
R1
N
N
HO
O
Bn
Bn
RF = CF3, R1 = Me : 5
RF = CF3, R1 = Ph : 14
RF = (CF2)2H, R1 = Me :15
7 (84%, dr 47:53)
18 (86%, dr 40:60)
19 (49%, dr 45:55)
20 (21%)
Scheme 5 Reagents and conditions: (i) BnNH2, Et2O, r.t., 16h.
Scheme 3 Reagents and conditions: (i) EtSH, TiCl4, CH2Cl2, –20 to
25 °C, 16 h; (ii) KOHaq, Bu4NBr, CH2Cl2, 25 °C, 12h; (iii) R1COMe,
KH, THF, 0–25 °C, 10 h; (iv) TFA, H2O, reflux, 10 h
In order to increase the overall yield of our procedure, we
tried to perform a one-pot reaction starting from g-keto
thioesters. Compound 4 was first treated with 2 equiva-
lents of diisopropylamine in diethyl ether at room temper-
ature for 24 hours then benzylamine (1.2 equiv) was
added to the resulting mixture. After stirring for 16 hours
at the same temperature and usual work-up (see experi-
mental section), the corresponding lactam 7 was isolated,
after flash chromatography on silica gel, in 68% yield
(Scheme 6, Table 1), a higher yield compared to the two-
step procedure (Schemes 4 and 5; 5, 7). The reaction was
general and worked well (yields: 55–80%) with a wide va-
riety of primary amines: linear and branched aliphatic
amines (entries 1–3), aromatic and heteroaromatic deriv-
atives (entries 4,5), and functionalized amines bearing one
hydroxyl or one ester group (entries 6,7, and 9). It is worth
noting that the reactions with 2-aminoethanol and phe-
nylglycinol were chemoselective. Interestingly, the result-
ing compounds 25 and 26 bear an additional hydroxyl
group, which could be used for further cyclisations. Un-
fortunately, these reactions were not selective: we ob-
tained an almost equal mixture of both diastereomers. The
diastereoselectivity was assigned using 19F chemical
shifts. It was generally impossible to separate the dia-
stereomers except for lactam 26 which could be separated
by preparative HPLC. All pure diastereomers of 26 are
oils.
We then prepared the 2-perfluoroalkyl furans 5, 14, and
15 by treatment of g-keto thioesters 4, 12, 13 with diiso-
propylamine in diethyl ether. We used our reported
procedure7 (Scheme 4, Method 1) for compounds 4 and
13, while the phenyl-substituted derivative 12 required
stronger conditions – 3 equivalents of diisopropylamine in
boiling diethyl ether for 22 hours (Scheme 4, Method 2).
Except for 14, the reactions led to mixtures of furan and
its tautomer, in moderate to good yields. Although we
have not studied this issue further, we assume that the re-
action occurs under thermodynamic control owing to the
+
acidic-basic medium (i-Pr2NH2 /i-Pr2NH). The conjugat-
ed methylene derivatives 16 and 17 would have a reso-
nance energy only slightly lower than that of the
corresponding furans 5 and 15, respectively.7
RFCF2
O
O
O
EtS
RF
EtS
(i) or
(ii)
SEt
+
R1
O
RF
O
O
R1
RF = CF3, R1 = Me : 4
RF = CF3, R1 = Ph : 12
RF = (CF2)2H, R1 = Me : 13
5 (52%)
14 (58%)
15 (51%)
16 (16%)
17 (7%)
Scheme 4 Reagents and conditions: Method 1: 57 and 15: i-Pr2NH
(2 equiv.), Et2O, r.t., 24 h; Method 2: 14: i-Pr2NH (3 equiv), Et2O, re-
flux, 22 h.
F3C
SEt
CF3CF2
O
H
1) (i)
Me
HO
SEt
O
In the first experiment, furan 5 was treated with a slight
excess of benzylamine (1.2 equiv) under mild conditions
(Et2O, r.t., 16 h) to give the new a,b-unsaturated lactam 7
(yield: 84%) as a mixture of diastereomers (Scheme 5, de
19F NMR). The structure 1,5-dihydro-pyrrol-2-one was
N
2) (ii)
O
Me
R2
4
7, 21-28
Scheme 6 Reagents and conditions: (i) Method 1: i-Pr2NH (2
equiv), Et2O, r.t., 24 h; (ii) R2NH2, r.t., 16 h.
Synthesis 2004, No. 5, 711–721 © Thieme Stuttgart · New York

PAPER
Fluorinated 1,5-Dihydro-pyrrol-2-ones
713
Table 1 One-pot Synthesis of a,b-Unsaturated Lactams 7, 21–28
F3C
SEt
CF3CF2
O
Entry
R2
Lactam (%) Diastereoselectivityb
H
1) (i)
Ph
SEt
1
2
3
4
5
6
7
8
9
Bn
7 (68)
21 (68)
22 (80)
23 (76)
24 (31)a
25 (60)
26 (56)
27 (55)
28 (67)
(47:53)
O
N
2) (ii)
HO
O
Ph
R2
nC5H11
iPr
(47:53)
R2=Bn: 18 53% (40/60)
R2=Ph: 29 47% (50/50)
12
(55:45)
Ph
(50:50)
Scheme 7 Reagents and conditions: (i) Method 2: i-Pr2NH (3
equiv), Et2O, reflux, 22 h; (ii) R2NH2, r.t., 16 h.
C5H4N
(CH2)2OH
CHPhCH2OH
(CH2)3NMe2
CH2CO2Me
(48:52)
(50:50)
tion analysis, the X-ray structure obtained is shown in
Figure 1 and shows a relative of 5R*,14S*.
(50:28:20:traces)
(55:45)
Then, in order to optimise the yield of lactam 19
(Scheme 5), g-keto thioester 13 was submitted to the one-
pot procedure. Surprisingly we did not obtain the expect-
ed lactam 19 but the unsaturated derivative 20, which was
isolated in an overall yield of 48%. This compound was
previously obtained in low yield (21%) as a by-product
(Scheme 5). Compound 20 which was isolated as one ste-
reoisomer, exhibited a characteristic 19F NMR spectra: a
vinylic fluorine at –113.3 ppm as a triplet of doublets
(44:56)
a Lactam 24 was accompanied with the furan 5 (yield: 10%).
b The diastereoselectivity was assigned using 19F chemical shifts.
Compound 22 was unambiguously given a planar formula
using the available knowledge about its synthetic origin
and information collected from 1D and 2D NMR spectra.
The 55:45 mixture of diastereomers was submitted to
analysis, but the signals were easily paired by chemical
shift value and/or coupling pattern similarity. The identi-
fication of S-Et, C-CF3, and N-iPr groups, the presence of
12 carbon atoms in the 13C NMR spectrum, the observa-
tion of a carbonyl group (d = 166 ppm) and a molecular
mass of 297 led to the formula C12H18F3NO2S, which is in
good agreement with combustion data. The construction
of the planar formula was achieved using the LSD
program11 (www.univ-reims.fr/LSD). All the hydrogen
atoms except one are attached to carbon atoms, and the
exchangeable one is bound either to an oxygen or to a ni-
trogen atom. This results in two LSD data sets. The pro-
cessing of the identified molecular fragments, and of
HMQC and HMBC data provided a single solution, the
one proposed for 22, when the presence of an OH group
was assumed. No structure was produced in the hypothe-
sis of an NH group, thus eliminating other alternative
structures. The presence of the 1,5-dihydro-pyrrol-2-one
nucleus in a,b-unsaturated lactams is fully supported by
the X-ray diffraction analysis of 18a, and by the solution
NMR study of 22.
(3JF,F = 22.0, JF,H = 16.3 Hz) and a difluoromethylene
3
group at –123.3 ppm as a doublet of doublets (2JF,H = 52.5,
3JF,F = 22.0 Hz). Similarly the phenyl-substituted deriva-
tive 30 was obtained in 40% yield, after silica gel chroma-
tography (Scheme 8). Again, only one stereoisomer was
characterised even in the crude mixture (19F and 1H NMR
spectra). Such unsaturated derivatives have not been re-
ported in the literature even in a non-fluorinated series.
An important problem was to determine the stereochem-
istry of the newly created double bond as 19F, H or 13C
1
NMR spectra were devoid of any useful information. For-
tunately, compound 30 slowly crystallised in hexane–
EtOAc allowing X-ray diffraction analysis. The X-ray
clearly showed a cis-relationship between the ethylsulfa-
nyl and difluoromethylene groups (Figure 2). This was
Then, to assess the scope and limitations of our methodol-
ogy, the one-pot reaction was extended to phenyl-substi-
tuted g-keto thioester. Compound 12 was first reacted
with diisopropylamine using Method 2 then benzylamine
or aniline was added to the resulting mixture to afford the
new a,b-unsaturated lactam 18 or 29 in moderate yield as
a mixture of diastereomers (Scheme 7). Both diastereo-
mers of 18, obtained as white solids, were completely sep-
arated by preparative TLC using hexane–EtOAc (85:15)
as eluent.
After slow evaporation of hexane–CHCl3 crystals of the
major diastereomer 18a were obtained for X-ray diffrac-
Figure 1 View and atom labelling of 18a.12
Synthesis 2004, No. 5, 711–721 © Thieme Stuttgart · New York

714
J.-P. Bouillon et al.
PAPER
EtS
CF2H
F
H(CF2)3
O
1) (i)
Me
HO
SEt
O
N
2) (ii)
O
R2
Me
R2=Bn: 20 48%
R2=Ph: 30 40%
13
Scheme 8 Reagents and conditions: (i) Method 1: i-Pr2NH, Et2O,
r.t., 24 h; (ii) R2NH2, r.t., 16 h.
probably the result of steric interaction between the carbo-
nyl oxygen (O6) and the fluorine atom (F12). The dihy-
dropyrrole and the vinylic substituents are not co-planar
and the observed torsion angle C2-C3-C7-C11 is 43°. The
poor conjugation in the solid state is confirmed by the en-
docyclic bond length values, which are very similar to
those observed for 18a.
Figure 2 View and atom labelling of 30.12
substituent and the amide function. Furan 31 could react
as a Michael acceptor with thiol released in the medium,
to give the dihydro derivative 32. Such an intermediate
might undergo ring opening followed by a 1,3-proton mi-
gration to afford the g-keto amide 33. Finally 33 could cy-
clise into the desired a,b-unsaturated lactam 7, 19, 20, 22–
30 (Scheme 10). This hypothesis is supported by the fol-
lowing feature: non-fluorinated analogues of 33 were al-
ready used as key intermediates in 1,5-dihydro-pyrrol-2-
one syntheses.9 Nevertheless we cannot exclude the alter-
native sequence ring opening of 32 – cyclisation of the
amide on the ketone function – 1,3-proton migration to
give the final lactam.
As it was previously assumed (Scheme 5), the derivative
20 could result from HF elimination from lactam 19 ow-
ing to the basic medium. This hypothesis was confirmed
by treating pure 19 with a slight excess of TBAF (2 equiv)
in THF solution (Scheme 9). The same stereoisomer of 20
was isolated in 62% yield after flash chromatography.
H(CF2)2
EtS
CF2H
F
SEt
H
TBAF, Et2O
Me
HO
Me
HO
In conclusion, this study extends the field of synthetic ap-
plications of perfluoroketene dithioacetals. The synthons
2 and 8 are easily converted into the corresponding furans
5, 14, and 15, which behave as key intermediates for the
preparation of 5-hydroxy-1,5-dihydro-pyrrol-2-ones. The
a,b-unsaturated lactams 7 and 18–30 were prepared in
moderate to good yields from g-keto thioesters using a
two-step sequence (via isolated furans) or using a one-pot
reaction. The scope of our methodology was exemplified
by the syntheses of new lactams bearing a large variety of
substituents [RF = CF3, (CF2)2H; R1 = Me, Ph;
R2 = Alkyl, Ar, Hetar]. An efficient synthesis of unsatur-
ated lactams 20 and 30 was also performed starting from
the tetrafluoroethyl-substituted g-keto thioester 13. The
O
N
O
N
Bn
Bn
19
20
62%
Scheme 9
The formation of a,b-unsaturated lactams 7, 19, 20, 22–30
may be explained by the mechanism depicted in
Scheme 10. Owing to the enhanced nucleophilicity of the
primary amine, the first step could be a substitution reac-
tion of ethylsulfanyl group leading to the corresponding
furan 31. This compound exhibits an interesting conjugat-
ed system, which is activated by both the trifluoromethyl
O
O
O
H
R2HN
RF
EtS
R2HN
R2NH2
R1
R1
RF
EtS
R1
RF
O
O
O
EtSH
5, 14, 15
31
32
RF
RF
SEt
SEt
H
H
R1
O
O
O
N
R1 NH
R2
33
HO
R2
7, 19, 20, 22-30
Scheme 10
Synthesis 2004, No. 5, 711–721 © Thieme Stuttgart · New York

PAPER
Fluorinated 1,5-Dihydro-pyrrol-2-ones
715
1H NMR (CDCl3): d = 1.24 (t, 3JH,H = 7.3 Hz, 3 H), 1.44 (s, 3 H), 2.5
(br s, 1 H, OH), 2.62 (q, 3JH,H = 7.3 Hz, 2 H), 4.54 (d, 2JH,H = 15.4
structure of lactams 7 and 18–30 were confirmed by 2-D
NMR experiments, X-ray diffraction analyses (for 18a
and 30) and computer-assisted structural elucidation (for
22). The a,b-unsaturated lactams exibit interesting fea-
tures: a conjugated amide system and a hemiaminal func-
tion which could be a precursor of an iminium salt. These
new aspects of synthetic applications are under investiga-
tion.
2
Hz, 1 H), 4.66 (d, JH,H = 15.4 Hz, 1 H), 7.00 (s, 1 H), 7.01 (td,
2JH,F = 52.5, 3JH,F = 16.3 Hz, 1 H), 7.3–7.4 (m, 5 H).
13 C NMR (CDCl3): d = 14.6 (s, CH3), 23.5 (s, CH3), 27.4 (s, CH2),
42.1 (s, CH2), 88.2 (s, C4), 107.0 (td, 1JC,F = 238.0, 2JC,F = 25.8 Hz,
CF2H), 112.8 (m, C4), 127.4 (s, CH), 128.0 (s, 2 × CH), 128.6 (s,
2 × CH), 131.0 (s, C4), 138.1 (s, C4), 149.3 (s, CH), 152.4 (dt,
1JC,F = 283.2, 2JC,F = 23.4 Hz, CF), 165.7 (s, CO).
19F NMR (CDCl3): d = –113.3 (td, 3JF,F = 22.0, 3JF,H = 16.3 Hz, 1 F),
–123.3 (dd, 2JF,H = 52.5, 3JF,F = 22.0 Hz, 2 F).
For information on instruments used see ref.13 Compounds 2,81, 9–
112 and 4, 12, 133,7 were prepared according to reported procedures.
MS: m/z (%) = 358 [M+ + 1], 357 [M+], 340, 328, 324 (100), 106.
1,1-Bis(ethylthio)-2,3,3,4,4,5,5-heptafluoropentene (8)
Yield: 74% (23.4 g); oil; bp 105–107 °C/6 mbar.
IR (film): 2977, 1604, 1452, 1264, 1162 cm–1.
Preparation of a,b-Unsaturated Lactams 7, 20–28, 30; General
One-Pot Procedure (Schemes 6, 8)
i-Pr2NH (10.0 mmol, 2 equiv) was added to a solution of g-keto
thioester 4 or 13 (5.0 mmol, 1 equiv) in Et2O (30 mL). The mixture
was stirred for 24 h at r.t. Primary amine (6.0 mmol, 1.2 equiv) was
added to the resulting solution, and the stirring continued for a fur-
ther 16 h at r.t. After the usual work-up, the residue was chromato-
graphed on silica gel (PE–EtOAc or hexane–EtOAc) to give the
corresponding lactam 7, 20–28 or 30 (Table 4).
3
1H NMR (CDCl3): d = 1.24 (t, JH,H = 7.3 Hz, 3 H), 1.26 (t,
3
3JH,H = 7.3 Hz, 3 H), 2.81 (q, JH,H = 7.3 Hz, 2 H), 2.89 (qd,
3JH,H = 7.3, 5JH,F = 1.0 Hz, 2 H), 6.04 (tt, 2JH,F = 52.2, 3JH,F = 5.5 Hz,
1 H).
13C NMR (Selected signals, CDCl3): d = 14.2 (s, CH3), 14.6 (s,
4
CH3), 27.2 (d, JC,F = 4.3 Hz, CH2), 28.0 (s, CH2), 107.8 (tt,
1JC,F = 253.1, 2JC,F = 31.2 Hz, CF2 H), 126.4 (d, 2JC,F = 19.9 Hz, C4),
3-(1-Ethylthio-2,3,3-trifluoroprop-1-en-1-yl)-5-hydroxy-5-me-
thyl-1-phenyl-1,5-dihydro-2H-pyrrol-2-one (30)
145.4 (dt, 1JC,F = 263.8, 2JC,F = 26.3 Hz, CF).
19F NMR (CDCl3): d = –100.3 (m, 1 F), –111.3 (m, 2 F), –131.0 (m,
2 F), –137.5 (d, 2JF,H = 52.2 Hz, 2 F, CF2H).
Yield: 40% (0.69 g); yellow solid; mp 101–103 °C.
IR (KBr): 3346, 2976, 1686, 1663, 1601, 1504 cm–1.
GC-MS: m/z (%) = 316 [M+], 287, 215, 125 (100).
3
1H NMR (CDCl3): d = 1.28 (t, JH,H = 7.4 Hz, 3 H), 1.58 (s, 3 H),
3
2.70 (q, JH,H = 7.4 Hz, 2 H), 2.8 (br s, 1 H, OH), 7.05 (td,
2JH,F = 53.0, 3JH,F = 16.2 Hz, 1 H), 7.12 (s, 1 H), 7.3–7.4 (m, 1 H),
Furans 5, 15 and Tautomers 16, 17; General Procedure
(Scheme 4, Method 1)
7.45 (dd, 3JH,H = 8.2, 3JH,H = 7.4 Hz, 2 H), 7.55 (d, 3JH,H = 8.2 Hz, 2
i-Pr2NH (15.0 mmol, 2.0 equiv) was added to a solution of g-keto
thioester 4 or 13 (7.5 mmol, 1.0 equiv) in Et2O (100 mL). A white
solid precipitated immediately. The mixture was stirred for 24 h at
r.t., then diluted with Et2O (50 mL) and washed with brine (50 mL).
The aq phase was extracted with Et2O (4 × 50 mL). The combined
organic phases were dried over MgSO4, filtered and concentrated in
vacuo. The residue was chromatographed on silica gel (hexane–
EtOAc) to give the furan 57 or 15 and the corresponding tautomer
167 or 17 (Table 2).
H).
13 C NMR (CDCl3): d = 14.5 (s, CH3), 23.2 (s, CH3), 27.3 (s, CH2),
89.4 (s, CH2), 107.0 (td, 1JC,F = 238.0, 2JC,F = 25.8 Hz, CF2H), 112.7
2
3
(dt, JC,F = 14.5, JC,F = 7.5 Hz, C4), 126.5 (s, 2 × CH), 127.1 (s,
CH), 128.9 (s, 2 × CH), 130.8 (s, C4), 135.0 (s, C4), 149.4 (s, CH),
152.3 (dt, 1JC,F = 283.2, 2JC,F = 23.4 Hz, CF), 165.0 (s, CO).
19F NMR (CDCl3): d = –112.5 (td, 3JF,F = 22.4, 3JF,H = 16.2 Hz, 1 F),
–123.4 (dd, 2JF,H = 53.0, 3JF,F = 22.4 Hz, 2 F).
GC-MS: m/z (%) = 344 [M+ + 1], 343 [M+], 314, 310 (100), 106.
Reaction of g-Keto Thioester 12 with Diisopropylamine
(Scheme 4, Method 2)
Preparation of a,b-Unsaturated Lactams 18, 29; General One-
Pot Procedure (Scheme 7)
i-Pr2NH (3 equiv, 1.35 mL, 9.63 mmol) was added to a solution of
g-ketothioester 12 (1.09 g, 3.21 mmol) in Et2O (30 mL), and the
mixture refluxed for 22 h. The same work-up was applied as for
method 1, the residue was chromatographed on silica gel (n-hex-
ane–EtOAc, 97:3) to give the furan 14 (0.56 g, yield: 58%). The
spectroscopic data of 14 are collected in Table 3.
i-Pr2NH (9.0 mmol, 3 equiv) was added to a solution of g-keto
thioester 12 (3.0 mmol, 1 equiv) in Et2O (20 mL) and refluxed for
22 h. The crude mixture was chromatographed on silica gel (n-hex-
ane–EtOAc) to give the lactam 18 or 29 as mixture of diastereomers
(Table 4).
Reaction of Lactam 19 with TBAF (Scheme 9)
Reactions of Furans 5, 14, 15 with Benzylamine; General Proce-
dure (Scheme 5)
A solution of TBAF in THF (0.56 mL, 0.56 mmol, 2 equiv) was
added to a solution of lactam 19 (0.11 g, 0.28 mmol) in Et2O (2 mL).
The mixture was stirred for 5 h at r.t., then diluted with Et2O (5 mL)
and washed with H2O (7 mL). The aq phase was extracted with Et2O
(2 × 5 mL). The combined organic phases were dried over MgSO4,
filtered and concentrated in vacuo. The residue was chromato-
graphed on silica gel (PE–EtOAc, 70:30) to give compound 20 as a
single stereoisomer (62 mg, yield: 62%).
A mixture of furan 5, 14 or 15 (5.0 mmol, 1 equiv) and benzylamine
(6.0 mmol, 1.2 equiv) in Et2O (10 mL) was stirred for 16 h at r.t. The
crude was then diluted with Et2O (30 mL) and washed with brine
(30 mL). The aq phase was extracted with Et2O (4 × 30 mL). The
combined organic phases were dried over MgSO4, filtered and con-
centrated in vacuo. The residue was chromatographed on silica gel
(PE–EtOAc or hexane–EtOAc) to give the corresponding lactam 7,
18 or 19 and the compound 20.
X-Ray Crystal Structure Determination of Compounds 18a, 30
(Figures 1 and 2)
Compound 18a
C21H20F3NO2S, Mr = 407.44, monoclinic, C2/c (Nr 15)
a = 41.117(2), b = 5.873(1), c = 17.242(2) Å, b = 109.93(1)°,
1-Benzyl-3-(1-ethylthio-2,3,3-trifluoroprop-1-en-1-yl)-5-hy-
droxy-5-methyl-1,5-dihydro-2H-pyrrol-2-one (20)
Yield: 48% (1.72 g); oil.
IR (film): 3346, 2929, 1689, 1621, 1363 cm–1.
Synthesis 2004, No. 5, 711–721 © Thieme Stuttgart · New York

716
J.-P. Bouillon et al.
PAPER
Table 2 Spectroscopic Data of Ketene Dithioacetals 10 and 11 and g-Keto Thioesters 12 and 13
Com- Sol-
IR
GC-MS
m/z
19F NMRc
d, J (Hz)
1H NMRc
d, J (Hz)
13 C NMRc
d, J (Hz)
pda
ventsb
(cm–1)
10
PE–
EtOAc
(96:4)
2926,
1695,
1449,
1213
384[M+], –83.2 (m, 3 F),
326, 279, –107.4 (m, 2 F)
105
1.20 (t, 3JH,H = 7.3, 3 H), 1.36 (t,
3JH,H = 7.3, 3 H), 2.84 (q,
3JH,H = 7.3, 2 H), 2.89 (q,
14.5 (s, CH3), 14.7 (s, CH3), 28.1 (s,
CH2), 29.3 (s, CH2), 42.5 (t,
3JC,F = 3.8, CH2), 113.2 (tq,
1
3JH,H = 7.3, 2 H), 4.35 (t, 3JH,F = 1.6, JC,F = 256.8, 2JC,F = 38.7, CF2), 119.2
2 H), 7.50 (m, 2 H), 7.6-7.7 (m, 1
H), 8.00 (m, 2 H)
(qt, 1JC,F = 288.0, 2JC,F = 39.5, CF3),
127.7 (t, 2JC,F = 20.4, C4), 128.0 (s,
CH), 128.6 (s, CH), 133.2 (s, CH),
136.0 (s, C4), 148.3 (t, 3JC,F = 3.2, C4),
193.8 (s, CO)
11
hexane– 2930,
354[M+], –104.8 (m, 2 F),
311, 221, –129.4 (m, 2 F),
1.22 (t, 3JH,H = 7.3, 3 H), 1.30 (t,
14.5 (s, CH3), 14.7 (s, CH3), 28.2 (s,
EtOAc
(92:8)
1726,
1261,
1136
3JH,H = 7.3, 3 H), 2.21 (s, 3 H), 2.84 CH2), 29.2 (s, CH3), 29.3 (s, CH2),
(q, 3JH,H = 7.3, 4 H), 3.76 (m, 2 H), 47.3 (t, 3JC,F = 4.4, CH2), 107.8 (tt,
75
–137.4 (d,
2JF,H = 52.2, 2 F) 6.11 (tt, 2JH,F = 52.2, 3JH,F = 5.8, 1
1JC,F = 252.8, 2JC,F = 30.8, CF2 H),
110.9 (t, 1JC,F = 261.0, CF2), 115.7 (tt,
1JC,F = 256.0, 2JC,F = 32.2, CF2), 128.3
(t, 2JC,F = 20.9, C4), 147.8 (t,
H)
3JC,F = 3.7, C4), 202.7 (s, CO)
12d
PE
2928,
1687,
1594,
1449
341[M+], –82.4 (m, 3 F),
327, 279, –114.8 (dd,
1.27 (t, 3JH,H = 7.4, 3 H), 2.96 (m, 2 14.0 (s, CH3), 24.3 (s, CH2), 35.2 (s,
H), 3.40 (dd, 2JH,H = 18.1,
CH2), 49.7 (t, 2JC,F = 20.7, CH), 113.6
(tq, 1JC,F = 259.5, 2JC,F = 37.9, CF2),
259
2JF,F = 273.3,
3JH,H = 2.9, 1 H), 3.91 (dd,
3JF,H = 14.7, 1 F), JH,H = 18.1, 3JH,H = 10.1, 1 H), 4.16 118.7 (qt, 1JC,F = 287.1, 2JC,F = 36.2,
2
–116.8 (dd,
(m, 1 H), 7.48 (m, 2 H), 7.63 (m, 1 CF3), 128.1 (s, CH), 128.7 (s, CH),
2JF,F = 273.3,
3JF,H = 14.7, 1 F)
H), 7.98 (m, 2 H)
133.9 (s, CH), 135.5 (s, C4), 193.1 (t,
3JC,F = 2.6, COS), 194.7 (s, CO)
13
PE–
EtOAc
(88:12) 1683,
1154
2937,
1725,
328 [M + –113.2 (m, 2 F),
18], 311 –128.8 (m, 2 F),
[M + 1], –137.7 (d,
1.27 (t, 3JH,H = 7.4, 3 H), 2.21 (s, 3 13.9 (s, CH3), 24.1 (s, CH2), 29.5 (s,
H), 2.8–3.1 (m, 3 H), 3.28 (dd,
CH3), 39.4 (m, CH2), 49.2 (t,
2JH,H = 18.4, 3JH,H = 9.9, 1 H) 3.9–
2JC,F = 20.9, CH), 107.6 (tt,
268, 248e JF,H = 52.2, 2 F) 4.1 (m, 1 H), 6.03 (tt, 2JH,F = 52.2,
3JH,F = 5.7, 1 H)
1JC,F = 253.7, 2JC,F = 31.0, CF2 H),
105-115 (m, CF2), 115.8 (tt,
2
1JC,F = 257.8, 2JC,F = 32.4, CF2), 193.2
(t, 3JC,F = 3.2, COS), 203.1 (s, CO)
a Oils. Satisfactory microanalyses obtained.
b Solvent used for chromatographic separation.
c NMR solvent: CDCl3.
d Compound 12 was distilled under reduced pressure (102–106°C/0.05 mbar) then was recrystallised from petroleum ether; mp 35–36 °C
e CI (NH3).
V = 3914.1(3) Å3, Z = 8, Dx = 1.38 gcm–3. A total of 13856 reflec-
tions were collected using a Brucker CCD detector and Cu Ka radi-
ation (l = 1.54178 Å), 2822 independent reflections (Rint = 0.17).
The structure was solved by direct methods with SHELXS-9714 and
refined by least square using F2 values and anisotropic thermal pa-
rameters for non-hydrogen atoms with SHELXL-97.14 The H atoms
were calculated and included in the refinement with a common iso-
tropic temperature factor. The ethyl group is disordered: two posi-
tions were refined with site occupation factors of 0.5. The data have
been deposit with the Cambridge Crystallographic Data Centre (Nr
CCDC219335). Selected bond lengths (Å): N(1)-C(2) = 1.351(5),
C(2)-C(3) = 1.500(6), C(3)-C(4) = 1.323(6), C(4)-C(5) = 1.516(6),
N(1)-C(5) = 1.474(5).
Compound 30
C16H16F3NO2S, Mr = 343.36, orthorhombic, Pbca (Nr 61)
a = 10.421(4), b = 24.666(8), c = 12.687(4) Å, V = 3261(2) Å3,
Z = 8, Dx = 1.40 gcm–3. A total of 8746 reflections were collected
using a MAR345 image plate detector and Mo Ka radiation
(l = 0.71069 Å), 1696 independent reflections (Rint = 0.077). The
structure was solved by direct methods with SHELXS-9714 and re-
fined by least square using F2 values and anisotropic thermal param-
eters for non-hydrogen atoms with SHELXL-97.14 The H atoms
were calculated and included in the refinement with a common iso-
tropic temperature factor. The data have been deposit with the Cam-
bridge Crystallographic Data Centre (Nr CCDC 219336). Selected
bond lengths (Å): N(1)-C(2) = 1.362(4), C(2)-C(3) = 1.498(5),
C(3)-C(4) = 1.322(5), C(4)-C(5) = 1.496(5), N(1)-C(5) = 1.477(5),
C(3)-C(7) = 1.473(5), C(7)-C(11) = 1.319(5).
Synthesis 2004, No. 5, 711–721 © Thieme Stuttgart · New York

PAPER
Fluorinated 1,5-Dihydro-pyrrol-2-ones
717
Table 3 Spectroscopic Data of Furans 14, 15 and Compound 17
Com- Sol-
IR
GC-MS
m/z
19F NMRc
d, J (Hz)
1H NMRc
d, J (Hz)
13 C NMRc
d, J (Hz)
pda
ventsb
(cm–1)
14d
hexane– 2928,
300 [M+], –58.8 (d, 5JF,H = 2.6)
267, 239,
105
1.25 (t, 3JH,H = 7.4, 3 H), 3.04 14.1 (s, CH3), 28.8 (q, 6JC,F = 2.8,
(q, 3JH,H = 7.4, 2 H), 6.63 (m, 1 CH2), 101.0 (q, 4JC,F = 4.1, CH), 122.6
EtOAc
(97:3)
1767,
1450,
1148
H), 7.35 (m, 3 H), 7.62 (m, 2
H)
(q, 1JC,F = 276.7, CF3), 125.5 (s,
2 × CH), 127.2 (s, C4), 127.8 (q,
3JC,F = 2.8, C4), 128.9 (s, 2 × CH),
131.0 (s, CH), 135.1 (q, 2JC,F = 33.1,
C4), 155.5 (q, 4JC,F = 2.3, C4), 164.9 (s,
COS)
15
17
hexane– 2933,
270 [M+], –112.9 (m, 2 F), –136.2 1.26 (t, 3JH,H = 7.4, 3 H), 2.18 14.0 (s, CH3), 14.5 (s, CH3), 30.6 (s,
237, 209, (dt, 2JF,H = 53.4, (s, 3 H), 3.05 (q, 3JH,H = 7.4, 2 CH2), 104.3 (t, 4JC,F = 6.7, CH), 109.6
69
3JF,F = 8.1, 2 F)
EtOAc
(94:6)
1769,
1638,
1114
H), 6.13 (m, 1 H), 6.14 (tt,
(tt, 1JC,F = 253.0, 2JC,F = 36.6, CF2H),
115.3 (tt, 1JC,F = 253.5, 2JC,F = 28.5,
CF2), 132.0 (m, C4), 133.6 (t,
2JC,F = 23.5, C4), 157.8 (t, 4JC,F = 3.2,
C4), 164.4 (s, COS)
2JH,F = 53.4, 3JH,F = 4.5, 1 H)
hexane– 2933,
270 [M+], –118.7 (m, 2 F), –135.3 1.29 (t, 3JH,H = 7.4, 3 H), 2.6– 14.0 (s, CH3), 27.1 (s, CH2), 39.6 (t,
EtOAc
(92:8)
1775,
1654,
1112
210, 190, (dd, 2JF,F = 300.7,
120
2.8 (m, 2 H), 4.18 (m, 1 H),
2JC,F = 23.6, CH), 99.5 (s, CH2), 109.1
2JF,H = 53.9, 1 F),
–140.5 (ddt,
5.02 (d, 2JH,H = 2.6, 1 H), 5.34 (t, 1JC,F = 253.6, CF2H), 116.4 (t,
(d, 2JH,H = 2.6, 1 H) 6.24 (t,
1JC,F = 253.6, CF2), 128.7 (s, C4),
2JF,F = 300.7,
2JF,H = 53.9, 3JF,F = 8.1,
1 F)
2JH,F = 53.9, 1 H), 7.39 (s, 1 H) 138.8 (s, CH), 153.3 (s, C4), 168.5 (s,
COS)
a Satisfactory microanalyses obtained.
b Solvent used for chromatographic separation.
c NMR solvent: CDCl3.
d Recrystallisation in PE–EtOAc; mp 92–93 °C
Table 4 Spectroscopic Data of Lactams 7, 18, 19 and 21–29
Com- Sol-
IR
GC-MSc 19F NMRd
m/z d, J (Hz)
1H NMRd
d, J (Hz)
13 C NMRd
d, J (Hz)
pda
ventsb
(cm–1)c
7a
PE–
EtOAc
(80:20) 1686,
1648
3347,
2932,
346 [M + –69.1 (d, 3JF,H = 7.7)
1], 328,
285, 106
1.35 (t,3JH,H = 7.4, 3 H), 1.41
(s, 3 H), 2.22 (br s, 1 H, OH),
2.7–2.9 (m, 2 H), 4.28 (q,
14.1 (s, CH3), 23.2 (s, CH3), 27.9 (s,
CH2), 41.2 (q, 2JC,F = 32.5, CH), 42.1
(s, CH2), 88.7 (s, C4) 125.77 (q,
1
3JH,F = 7.7, 1 H), 4.63 (m, 2 H), JC,F = 278.6, CF3), 127.3 (s, CH),
6.86 (m, 1 H), 7.3–7.4 (m, 5 H) 127.9 (s, 2 × CH), 128.5 (s, 2 × CH),
131.1 (s, C4), 137.8 (s, C4), 145.0 (s,
C4), 167.0 (s, CO)
7be
–68.9 (d, 3JF,H = 7.7)
1.34 (t, 3JH,H = 7.4, 3 H), 1.44 27.6 (s, CH2), 88.9 (s, C4), 125.84 (q,
(s, 3 H), 2.15 (br s, 1 H, OH),
1JC,F = 278.6, CF3)
4.30 (q, 3JH,F = 7.7, 1 H)
18af
hexane– 3346,
408 [M + –69.2 (d, 3JF,H = 8.6)
1], 347,
240, 106
1.34 (t, 3JH,H = 7.4, 3 H), 2.72 14.09 (s, CH3), 27.9 (s, CH2), 41.2 (q,
(br s, 1 H, OH), 2.8–2.9 (m, 2 2JC,F = 31.7, CH), 43.2 (s, CH2), 91.3
H), 3.98 (d, 2JH,H = 15.0, 1 H), (s, C4), 122.1 (q, 1JC,F = 279.5, CF3),
4.37 (q, 3JH,F = 8.6, 1 H), 4.68 125.86 (s, 2 × CH), 127.18 (s, CH),
(d, 2JH,H = 15.0, 1 H), 6.86 (s, 1 128.27 (s, 2 × CH), 128.5 (s,
EtOAc
2931,
(85:15) 1686,
1645
H), 7.21 (m, 5 H), 7.3–7.4 (m, 2 × CH), 128.72 (s, 2 × CH), 128.78
5 H)
(s, CH), 130.8 (s, C4), 135.6 (s, C4),
137.31 (s, C4), 145.5 (s, CH), 167.8 (s,
CO)
Synthesis 2004, No. 5, 711–721 © Thieme Stuttgart · New York

718
J.-P. Bouillon et al.
PAPER
Table 4 Spectroscopic Data of Lactams 7, 18, 19 and 21–29 (continued)
Com- Sol-
IR
GC-MSc 19F NMRd
1H NMRd
d, J (Hz)
13 C NMRd
d, J (Hz)
pda
ventsb
(cm–1)c
m/z
d, J (Hz)
18bf
–68.8 (d, 3JF,H = 8.6)
1.34 (t, 3JH,H = 7.4, 3 H), 2.57 14.05 (s, CH3), 27.6 (s, CH2), 41.4 (q,
(br s, 1 H, OH), 2.7–3.0 (m, 2 2JC,F = 31.7, CH), 43.3 (s, CH2), 91.5
H), 3.95 (d, 2JH,H = 15.0, 1 H), (s, C4), 122.7 (q, 1JC,F = 279.5, CF3),
4.33 (q, 2JH,F = 8.6, 1 H), 4.73 125.91 (s, 2 × CH), 127.23 (s, CH),
(d, 2JH,H = 15.0, 1 H), 6.83 (s, 1 128.31 (s, 2 × CH), 128.6 (s,
H), 7.24 (m, 5 H), 7.36 (m, 5 H) 2 × CH), 128.74 (s, 2 × CH), 128.80
(s, CH), 130.5 (s, C4), 135.8 (s, C4),
137.34 (s, C4), 145.0 (s, CH), 167.9 (s,
CO)
19af
hexane– 3350,
378 [M + –117.8 (ddd,
1], 317,
2JF,F = 266.6,
1.30 (t, 3JH,H = 7.4, 3 H), 1.40 14.2 (s, CH3), 23.3 (s, CH3), 27.5 (s,
EtOAc
2931,
(s, 3 H), 2.27 (br s, 1 H, OH),
CH2), 39.2 (t, 3JC,F = 23.7, CH), 42.1
(86:14) 1686,
1644
216, 106 3JF,H = 18.8, 3JF,F = 8.1, 2.7–2.9 (m, 2 H), 4.22 (m, 1 H) (s, CH2), 88.8 (s, C4), 110–120 (m,
1 F), –119.9 (d,
2JF,F = 266.6, 1 F),
–135.0 (ddd,
4.54 (d, 2JH,H = 15.5, 1 H), 4.70 CF2H, CF2), 127.3 (s, CH), 127.8 (s,
(d, 2JH,H = 15.5, 1 H), 6.21 (m, 2 × CH), 128.6 (s, 2 × CH), 131.7 (s,
1 H), 6.88 (m, 1 H), 7.2–7.4 (m, C4), 137.9 (s, C4), 145.5 (s, CH),
2JF,F = 300.3,
5 H)
167.3 (s, CO)
2JF,H = 53.9, 3JF,F = 8.1,
1 F), –139.7 (ddt,
2JF,F = 300.3,
2JF,H = 53.9, 3JF,F = 8.1,
1 F)
19bf
–119.0 (m, 2 F), –135.5 1.22 (t, 3JH,H = 7.4, 3 H), 1.35 14.2 (s, CH3), 23.2 (s, CH3), 27.1 (s,
(dd, 2JF,F = 298.9,
2JF,H = 53.9, 1 F),
–140.3 (ddt,
(s, 3 H), 2.43 (br s, 1 H, OH),
2.6–2.8 (m, 2 H), 4.15 (t,
3JH,F = 16.2, 1 H), 4.47 (d,
CH2), 39.2 (t, 3JC,F = 23.6, CH), 42.1
(s, CH2), 88.9 (s, C4), 109.2 (tt,
1JC,F = 250.9, 2JC,F = 32.8, CF2H),
110–120 (m, CF2), 127.4 (s, CH),
127.9 (s, 2 × CH), 128.6 (s, 2 × CH),
131.6 (s, C4), 138.0 (s, C4), 145.5 (s,
2JF,F = 298.9,
2JH,H = 15.5, 1 H), 4.57 (d,
2
2JF,H = 53.9, 3JF,F = 8.5, JH,H = 15.5, 1 H), 6.17 (tdd,
1 F)
2JH,F = 53.9, 3JH,F = 6.0,
3JH,F = 4.0, 1 H), 6.81 (m, 1 H), CH), 167.3 (s, CO)
7.2–7.3 (m, 5 H)
21a
PE–
EtOAc
3342,
2934,
326 [M + –69.2 (d, 3JF,H = 7.6)
1 ], 325
0.91 (t, 3JH,H = 6.7, 3 H), 1.2– 13.9 (s, CH3), 14.0 (s, CH3), 22.2 (s,
1.4 (m, 7 H), 1.55 (s, 3 H), 1.6– CH2), 22.81 (s, CH3), 27.4 (s, CH2),
(83:17) 1686,
1649
[M], 308,
265, 196
1.8 (m, 2 H), 2.31 (br s, 1 H,
28.6 (s, CH2), 29.3 (s, CH2), 38.9 (s,
OH), 2.7–2.9 (m, 2 H), 3.2–3.3 CH2), 41.0 (q, 2JC,F = 31.5, CH), 88.5
(m, 1 H), 3.4–3.5 (m, 1 H), 4.1– (s, C4), 125.7 (q, 1JC,F = 278.6, CF3),
4.3 (m, 1 H), 6.82 (s, 1 H)
131.0 (s, C4), 144.7 (s, CH), 166.7 (s,
CO)
21be
22ag
–68.9 (d, 3JF,H = 7.6)
1.54 (s, 3 H), 2.30 (br s, 1 H,
OH)
22.75 (s, CH3), 27.7 (s, CH2), 88.6 (s,
C4), 125.8 (q, 1JC,F = 278.6, CF3),
144.6 (s, CH), 166.6 (s, CO)
PE–
EtOAc
(82:18) 1692,
1653
3369,
3019,
298 [M + –68.9 (d, 3JF,H = 11.4)
1.27 (t, 3JH,H = 7.4, 3 H), 1.39 14.03 (s, CH3), 20.2 (s, CH3), 20.7 (s,
1], 297
[M], 280,
237
(d, 3JH,H = 6.9, 3 H), 1.41 (d,
CH3), 22.8 (s, CH3), 27.8 (s, CH2),
3JH,H = 6.9, 3 H), 1.51 (s, 3 H), 40.8 (q, 2JC,F = 31.7, CH), 43.72 (s,
2.65–2.85 (m, 2 H), 3.25 (br s, CH), 88.89 (s, C4), 125.8 (q,
1 H, OH), 3.80 (sept,
1JC,F = 278.7, CF3), 131.9 (s, C4),
144.0 (s, CH), 165.87 (s, CO)
3JH,H = 6.9, 1 H), 4.13 (q,
3JH,F = 11.4, 1 H), 6.72 (s, 1 H)
22be,g
–69.2 (d, 3JF,H = 11.4)
1.26 (t, 3JH,H = 7.4, 3 H), 1.40 14.00 (s, CH3), 20.3 (s, CH3), 20.6 (s,
(d, 3JH,H = 6.9, 3 H), 1.42 (d,
CH3), 22.9 (s, CH3), 27.4 (s, CH2),
3JH,H = 6.9, 3 H), 1.52 (s, 3 H), 43.74 (s, CH), 89.04 (s, C4), 125.9 (q,
3.29 (br s, 1 H, OH), 4.15 (q,
1JC,F = 278.6, CF3), 131.8 (s, C4),
3JH,F = 11.4, 1 H), 6.73 (s, 1 H) 144.2 (s, C4), 165.89 (s, CO)
23a
PE–
EtOAc
(88:12) 1654,
1603,
3369,
1695,
332 [M + –68.9 (d, 3JF,H = 7.6)
1], 331
[M], 314,
271, 253
1.32 (t, 3JH,H = 7.3, 3 H), 1.50 14.1 (s, CH3), 22.9 (s, CH3), 28.1 (s,
(s, 3 H), 2.7–2.9 (m, 2 H), 4.32 CH2), 41.2 (q, 2JC,F = 31.3, CH), 90.0
(q, 3JH,F = 7.6, 1 H), 6.94 (s, 1 (s, C4), 115.4 (s, CH), 125.87 (q,
H), 7.31 (m, 1 H), 7.43 (dd,
3JH,H = 8.0, 3JH,H = 7.2, 2 H),
7.53 (d, 3JH,H = 7.6, 2 H)
1JC,F = 276.8, CF3), 126.1 (s, CH),
128.9 (s, CH), 131.1 (s, C4), 135.0 (s,
C4), 144.4 (s, CH), 166.2 (s, CO)
1500
Synthesis 2004, No. 5, 711–721 © Thieme Stuttgart · New York

PAPER
Fluorinated 1,5-Dihydro-pyrrol-2-ones
719
Table 4 Spectroscopic Data of Lactams 7, 18, 19 and 21–29 (continued)
Com- Sol-
IR
GC-MSc 19F NMRd
1H NMRd
d, J (Hz)
13 C NMRd
d, J (Hz)
pda
ventsb
(cm–1)c
m/z
d, J (Hz)
23be
–69.1 (d, 3JF,H = 7.6)
1.33 (t, 3JH,H = 7.3, 3 H), 1.53 27.7 (s, CH2), 41.1 (q, 2JC,F = 31.3,
(s, 3 H), 4.29 (q, 3JH,F = 7.6, 1 CH), 90.1 (s, C4), 119.0 (s, CH),
H), 6.70 (d, 3JH,H = 7.6, 2 H),
125.79 (q, 1JC,F = 276.8, CF3), 127.0
6.78 (t, 3JH,H = 7.4, 1 H), 6.97 (s, CH), 129.2 (s, CH), 145.0 (s, CH)
(s, 1 H), 7.17 (dd, 3JH,H = 8.0,
3JH,H = 7.2, 2 H)
24ag
PE–
EtOAc
(93:7)
3373,
2931,
1713,
1660,
1596
333
–68.8 (d, 3JF,H = 8.5)
1.30 (t, 3JH,H = 7.4, 3 H), 1.826 13.98 (s, CH3), 25.3 (s, CH3), 26.9 (s,
(s, 3 H), 2.7-2.9 (m, 2 H), 4.31 CH2), 41.1 (q, 2JC,F = 31.9, CH), 91.2
(q, 3JH,F = 8.5, 1 H), 6.9 (br s, 1 (s, C4), 115.3 (s, CH), 119.7 (s, CH),
H, OH), 7.08 (s, 1 H), 7.11 (m, 125.8 (q, 1JC,F = 278.6, CF3), 130.9 (s,
[M + 1],
255, 95,
80h
1 H), 7.79 (ddd, 3JH,H = 7.9,
3JH,H = 7.6, 4JH,H = 1.2, 1 H),
C4), 138.84 (s, CH), 146.37 (s, CH),
146.43 (s, CH), 151.16 (s, C4), 166.01
8.31 (d, 3JH,H = 8.5, 1 H), 8.34 (s, CO)
(d, 3JH,H = 4.1, 1 H)
24be,g
–68.7 (d, 3JF,H = 8.5)
1.34 (t, 3JH,H = 7.4, 3 H), 1.833 14.11 (s, CH3), 27.6 (s, CH2), 41.2 (q,
(s, 3 H), 7.07 (s, 1 H)
2JC,F = 31.9, CH), 91.3 (s, C4), 115.4
(s, CH), 119.6 (s, CH), 131.0 (s, C4),
138.82 (s, CH), 145.9 (s, CH), 146.41
(s, CH), 151.23 (s, C4), 165.98 (s, CO)
25a
PE–
EtOAc
(30:70) 1686,
1649
3354,
2935,
300 [M + –69.1 (d, 3JF,H = 7.6)
1.30 (t, 3JH,H = 7.5, 3 H), 1.56 13.9 (s, CH3), 22.6 (s, CH3), 27.26 (s,
(s, 3 H), 1.74 (br s, 1 H, OH),
CH2), 41.03 (q, 2JC,F = 31.5, CH),
1], 282,
239, 221h
2.7–2.8 (m, 2 H), 3.3–3.4 (m, 1 41.5 (s, CH2), 61.1 (s, CH2), 88.1 (s,
H), 3.8–4.0 (m, 2 H), 4.1–4.4
(m, 2 H), 6.90 (s, 1 H)
C4), 125.69 (q, 1JC,F = 278.5, CF3),
130.1 (s, C4), 145.81 (s, CH), 167.69
(s, CO)
25be
26ai
–68.9 (d, 3JF,H = 7.6)
1.31 (t, 3JH,H = 7.5, 3 H)
27.34 (s, CH2), 41.09 (q, 2JC,F = 32.5,
CH), 88.2 (s, C4), 125.76 (q,
1JC,F = 278.5, CF3), 130.2 (s, C4),
145.85 (s, CH), 167.75 (s, CO)
PE–
EtOAc
(60:40) 1685,
1651
3362,
2934,
376
–68.93 (d, 3JF,H = 7.6)
1.25 (t, 3JH,H = 7.4, 3 H), 1.43 14.1 (s, CH3), 23.4 (s, CH3), 27.5 (s,
[M + 1],
375 [M],
344, 106
(s, 3 H), 2.59 (br s, OH, 1 H),
2.6-2.9 (m, 2 H), 3.30 (br s,
OH, 1 H), 4.02 (dd,
CH2), 41.1 (q, 3JC,F = 31.5, CH),
57.54 (s, CH), 63.0 (s, CH2), 89.9 (s,
C4), 125.78 (q, 1JC,F = 276.8, CF3),
2JH,H = 11.7, 3JH,H = 4.0, 1 H), 127.3 (s, CH), 127.7 (s, 2 × CH),
4.19 (q, 3JH,F = 7.6, 1 H), 4.41, 128.5 (s, 2 × CH), 130.69 (s, C4),
(m, 1 H), 4.80 (dd, 3JH,H = 7.4, 138.17 (s, C4), 145.6 (s, CH), 167.8 (s,
3JH,H = 4.0, 1 H), 6.77 (s, 1 H), CO)
7.2–7.4 (m, 5 H)
26be
–69.10 (d, 3JF,H = 7.6)
1.31 (t, 3JH,H = 7.4, 3 H), 1.44 27.7 (s, CH2), 57.51 (s, CH), 62.9 (s,
(s, 3 H), 2.7-2.9 (m, 2 H), 3.46 CH2), 89.8 (s, C4), 125.72 (q,
(br s, 2 H, 2 × OH), 4.07 (m, 1 1JC,F = 276.8, CF3), 127.6 (s,
H), 4.24 (m, 1 H), 4.48 (m, 1
2 × CH), 128.6 (s, 2 × CH), 130.75
H), 4.94 (m, 1 H), 6.81 (s, 1 H), (s, C4), 138.25 (s, C4), 145.5 (s, CH),
7.2–7.4 (m, 5 H)
167.7 (s, CO)
26ce,i
–69.01 (d, 3JF,H = 7.6)
1.33 (s, 3 H), 1.34 (t,
27.4 (s, CH2), 58.1 (s, CH), 89.0 (s,
3JH,H = 7.4, 3 H), 2.7–2.9 (m, 2 C4), 125.83 (q, 1JC,F = 276.8, CF3),
H), 3.93 (dd, 2JH,H = 10.7,
3JH,H = 4.1, 1 H), 4.26 (q,
3JH,F = 7.6, 1 H), 4.65 (m, 1 H),
4.79 (dd, 2JH,H = 10.7,
130.9 (s, C4), 145.9 (s, CH), 167.6 (s,
CO)
3JH,H = 4.1, 1 H), 6.91 (s, 1 H),
7.3–7.4 (m, 5 H)
26de
–68.81 (d, 3JF,H = 7.6)
3.84 (m, 1 H), 4.58 (m, 1 H),
4.73 (m, 1 H), 6.88 (s, 1 H)
29.6 (s, CH2), 58.2 (s, CH), 88.9 (s,
C4)
Synthesis 2004, No. 5, 711–721 © Thieme Stuttgart · New York

720
J.-P. Bouillon et al.
PAPER
Table 4 Spectroscopic Data of Lactams 7, 18, 19 and 21–29 (continued)
Com- Sol-
IR
GC-MSc 19F NMRd
m/z d, J (Hz)
1H NMRd
d, J (Hz)
13 C NMRd
d, J (Hz)
pda
ventsb
(cm–1)c
j
27a
3322,
2933,
1697,
1647
341 [M + –68.5 (d, 3JF,H = 7.6)
1], 340
[M], 325,
261
1.29 (t, 3JH,H = 7.3, 3 H), 1.45 14.0 (s, CH3), 23.3 (s, CH3), 23.4 (s,
(s, 3 H), 2.12 (s, 6 H), 2.2–2.6 CH2), 27.0 (s, CH2), 37.47 (s, CH2),
(m, 4 H), 2.7–2.9 (m, 2 H), 3.17 40.9 (q, 2JC,F = 31.7, CH), 43.8 (s,
(m, 1 H), 3.79 (m, 1 H), 4.1–4.3 2 × CH3), 57.76 (s, CH2), 87.9 (s, C4),
(m, 1 H), 6.87 (s, 1 H)
125.8 (q, 1JC,F = 278.5, CF3), 129.0 (s,
C4), 147.2 (s, CH), 166.8 (s, CO)
27be
–68.8 (d, 3JF,H = 7.6)
1.30 (t, 3JH,H = 7.3, 3 H), 1.46 13.9 (s, CH3), 23.2 (s, CH3), 27.1 (s,
(s, 3 H), 6.93 (s, 1 H)
CH2), 37.52 (s, CH2), 40.6 (q,
2JC,F = 31.7, CH), 43.5 (s, 2 × CH3),
57.70 (s, CH2), 88.2 (s, C4), 125.9 (q,
1JC,F = 278.5, CF3), 129.3 (s, C4),
148.1 (s, CH), 166.7 (s, CO)
28ag
PE–
EtOAc
(70:30) 1761,
1694,
3250,
2931,
328 [M + –69.1 (d, 3JF,H = 11.4)
1], 310,
249, 189
1.31 (t, 3JH,H = 7.3, 3 H), 1.509 14.1 (s, CH3), 22.1 (s, CH3), 27.5 (s,
(s, 3 H), 2.7–2.9 (m, 2 H), 3.18 CH2), 39.7 (s, CH2), 41.1 (q,
(br s, OH), 3.78 (s, 3 H), 3.94
2JC,F = 31.9, CH), 52.7 (s, CH3), 88.2
(d, 2JH,H = 17.9, 1 H), 4.21 (q, (s, C4), 125.7 (q, 1JC,F = 278.5, CF3),
1646
3JH,F = 8.9, 1 H), 4.409 (d,
130.7 (s, C4), 146.2 (s, CH), 167.2 (s,
2JH,H = 17,9, 1 H), 6.96 (s, 1 H) CON), 170.7 (s, COO)
28be,g
–68.9 (d, 3JF,H = 11.4)
1.30 (t, 3JH,H = 7.3, 3 H), 1.514 41.2 (q, 2JC,F = 31.9, CH), 88.3 (s, C4),
(s, 3 H), 3.11 (br s, 1 H, OH),
125.8 (q, 1JC,F = 278.5, CF3), 130.6 (s,
3.92 (d, 2JH,H = 17.9, 1 H), 4.22 C4), 145.8 (s, CH), 167.3 (s, CON)
(q, 3JH,F = 8.9, 1 H), 4.402 (d,
2JH,H = 17.9, 1 H), 6.94 (s, 1 H)
29a
hexane– 3346,
393 [M], –69.1 (d, 3JF,H = 8.5)
301, 241,
105
1.27 (t, 3JH,H = 7.1, 3 H), 2.7– 14.05 (s, CH3), 27.6 (s, CH2), 41.3 (q,
EtOAc
2931,
2.9 (m, 2 H), 3.25 (br s, 1 H,
2JC,F = 32.0, CH), 92.42 (s, C4), 124.1
(85:15)k 1693,
1601,
OH), 4.32 (q, 3JH,F = 8.5, 1 H), (s, CH), 125.82 (s, CH), 125.86 (q,
1
6.85 (s, 1 H), 7.0–7.5 (m, 10H) JC,F = 278.3, CF3), 125.9 (s, CH),
1501
128.6 (s, CH), 128.66 (s, CH), 128.72
(s, CH), 130.1 (s, C4), 135.51 (s, C4),
136.4 (s, C4), 145.1 (s, CH), 167.35 (s,
CO)
29be
–68.7 (d, 3JF,H = 8.5)
1.30 (t, 3JH,H = 7.1, 3 H), 3.39 14.13 (s, CH3), 28.0 (s, CH2), 41.2 (q,
(br s, 1 H, OH), 4.34 (q,
2JC,F = 32.0, CH), 92.38 (s, C4), 124.4
3JH,F = 8.5, 1 H), 6.87 (s, 1 H) (s, CH), 125.76 (q, 1JC,F = 278.3,
CF3), 125.77 (s, CH), 126.0 (s, CH),
130.4 (s, C4), 135.46 (s, C4), 136.2 (s,
C4), 145.4 (s, CH), 167.26 (s, CO)
a Oil. Satisfactory microanalyses obtained. The compounds were obtained as a mixture of diastereomers (major diastereomers are recognised
by the letter a).
b Solvent used for chromatographic separation.
c IR and GC-MS spectra were recorded on the mixture of diastereomers.
d NMR solvent: CDCl3.
e Selected spectroscopic data of minor diastereomers.
f Diastereomers were separated by preparative TLC using hexane–EtOAc (85:15) as eluent.
g 1H NMR spectra (500 MHz), 13C NMR spectra (125 MHz).
h CI (NH3).
i Pure diastereomers were obtained by preparative HPLC using hexane–EtOAc (70:30) as eluent.
j Crude product obtained without purification.
k Purification by preparative TLC.
Acknowledgment
References
We thank Dr. V. M. Timoshenko for the preparation of compound
8, Prof. L. Van Meervelt (Katholieke Universiteit Leuven, Belgi-
um) for the X ray analyses of compound 18a. H. Baillia and S. Lan-
thony are thanked for NMR spectra, HPLC and microanalyses.
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Synthesis 2004, No. 5, 711–721 © Thieme Stuttgart · New York