Nucleophilic chain substitution on perfluoroketene dithioacetals by ethyl 2-trimethysilyl acetate. Application to the synthesis of 2-trifluoromethyl succinic acid derivatives

Article abstract of DOI:10.1016/j.tet.2004.08.040

A highly efficient substitution of the vinyl fluoride of perfluoroketene dithioacetals was achieved using trimethylsilylacetate to give 2-perfluoroalkyl succinic acid derivatives and 2-trifluoromethyl succinimides. This chain process was initiated by a catalytic amount of fluoride salt, whereas reaction failed with the corresponding lithium enolate. Graphical Abstract

Full text of DOI:10.1016/j.tet.2004.08.040

Tetrahedron 60 (2004) 9849–9855
Nucleophilic chain substitution on perfluoroketene dithioacetals
by ethyl 2-trimethysilyl acetate. Application to the synthesis of
2-trifluoromethyl succinic acid derivatives*
†
*
´
´
Cedric Brule, Jean-Philippe Bouillon and Charles Portella
´ ´ ´
UMR 6519 “Reactions Selectives et Applications”. CNRS—Universite de Reims Champagne—Ardenne, BP 1039,
51687 Reims Cedex 2, France
Received 29 July 2004; accepted 18 August 2004
Abstract—A highly efficient substitution of the vinyl fluoride of perfluoroketene dithioacetals was achieved using trimethylsilylacetate to
give 2-perfluoroalkyl succinic acid derivatives and 2-trifluoromethyl succinimides. This chain process was initiated by a catalytic amount of
fluoride salt, whereas reaction failed with the corresponding lithium enolate.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
the synthesis of trifluoromethyl lactones,3 lactams,4 pyri-
dazines,5 furanes and pyrroles.6 The first step in all these
syntheses consists of the reaction of 1 with a ketone enolate.
Within the framework of our studies on new methods for the
synthesis of multifunctional organofluorine compounds, we
have developed perfluoroketene dithiocetals 1 as versatile
building blocks. Compounds 1 are synthetic equivalents of
2-hydroperfluorocarboxylic derivatives.1 Their umpolung
reactivity, associated to the vinyl fluorine substitution,
significantly extends their applications. The substitution by
alkoxide or simple organometallic reagents has previously
been observed for the difluoromethylene analogues.2 The
reaction of 1 with functionalized nucleophiles offers a
greater potential because of possible subsequent hetero-
cyclization (Scheme 1). We have reported applications in
To diversify the synthetic applications of 1, we wished to
extend these reactions to other nucleophilic species, in
particular ester enolates. Surprisingly, in contrast to lithium
enediolates,7 various attempts with lithium ethyl acetate
enolate (from AcOEt and LDA) failed whatever the reaction
conditions (Scheme 2). Instead of the expected product 2,
the only isolated product resulted from the displacement of
the vinyl fluoride by the ethoxide group, the latter being
produced by a Claisen condensation which eventually
occurred after a long reaction time. We wish to describe a
chain reaction with ethyl 2-trimethylsilyl acetate which
enabled us to overcome this failure and to apply our
synthetic method to the synthesis of 2-trifluoromethylsuc-
cinic acid derivatives.
Scheme 1.
* Perfluoroketene dithioacetals. Part 12. For part 11, see Ref. 7
Scheme 2.
Keywords: Vinyl fluorine substitution; Silyl nucleophile; Succinic acid
derivatives; Trifluoromethyl succinimides.
2. Results and discussion
* Corresponding author. Tel.: C33-3-26913234; fax: C33-3-26913166;
e-mail: charles.portella@univ-reims.fr
†
Silylated nucleophiles often behave differently than their
metallated analogues, due to their stabilized nature. Several
´ ´ ´
Current address: Sciences et Methodes Separatives EA 2659, Universite
de Rouen. IRCOF. F-76821 Mont-Saint-Aignan Cedex, France.
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.08.040

´
C. Brule et al. / Tetrahedron 60 (2004) 9849–9855
9850
Scheme 3.
significant examples can be cited: trifluoromethytrimethyl-
silane is a nucleophilic trifluoromethylating reagent of
choice whereas main metal analogues decompose into
difluorocarbenes.8 2-Trimethylsilyldithiolane acts, under
fluoride activation, as an efficient nucleophile whereas the
2-lithio analogue decomposes via ethylene elimination.9
Compound 3a was initially chosen as a model to explore the
reactivity of the dicarboxylic derivatives. A high chemical
resistance of the ester moiety was observed in the reaction
of 3a with methylhydrazine which gave the monoconden-
sation product with the thiolester group instead of the
expected dihydropyridazinedione. On the other hand, 2a
was easily saponified to give the intermediate ketene-
dithioacetal 4 in almost quantitative yield. This product was
then converted in high yield to the acid thiolester 5 by a
stronger acid treatment (Scheme 4). Compound 4 was also
prepared in one step by reacting 1a with the lithium dianion
of acetic acid.7
A stabilized hypervalent intermediate is the key form of
nucleophile donor. If the nucleophilic reaction releases a
silicophilic nucleofugal group, the transformation can
proceed by a mild chain mechanism. The chain transfer
step is often a silicon transfer to an alkoxide, as in the case
of nucleophilic additions on carbonyl compounds. Owing to
the strength of the Si–F bond, the chain transfer is
particularly efficient in reactions involving fluoride elimi-
nation, as shown in the conversion of acylsilane into
difluoroenol silyl ethers using trifluoromethyl–trimethyl-
silane.10 This led us to consider the substitution reaction of
the vinyl fluoride of 1 with ethyl 2-trimethylsilyl acetate
following the chain reaction depicted in Scheme 3.
In contrast to 3a, 5 behaved as a bis(electrophilic) species,
Reaction conditions were optimized regarding the fluoride
initiator and the solvent used. With cesium fluoride in DME
or the usual tetrabutylammonium fluoride in THF, diffi-
culties were encountered in reaching a total conversion and
interesting yields. Tetramethylammonium fluoride (TMAF)
in THF proved to be the best initiator. This fluoride salt is
easily dehydrated by simple heating under vacuum without
the decomposition encountered with TBAF. Unfortunately
the very clean reaction observed was initially counter-
balanced by an incomplete conversion. As in any chain
process, the efficiency of the chain transfer step is crucial in
bringing the reaction to completion. Finally, a total
conversion with excellent yields of products 2 was achieved
using 5% of TMAF in THF, provided that the initiator was
added portionwise (see Experimental). The dithioacetal
moiety was hydrolyzed under the usual conditions to give
the 2-perfluoroalkyl dicarboxylic derivatives 3, bearing two
differentiated carboxyl functions (Scheme 4).
Scheme 4.

´
C. Brule et al. / Tetrahedron 60 (2004) 9849–9855
9851
the physico-chemical and biological properties of organic
substrates.13 2-Trifluoromethyl succinimides, and more
generally 2-trifluoromethyl succinic acid derivatives are
undoubtedly very interesting building blocks open to a wide
range of potential transformations. Several compounds
comprising the 2-trifluoromethyl succinic or succinimide
framework have been described,14,15 most of them being
obtained from 2-trifluoromethylmaleimide or maleic acid.15
To our knowledge, there is one report on the direct synthesis
of 2-trifluoromethyl succinimides, and this in poor yield.16
The reaction sequence presented here is thus the first general
preparation of N-alkyl or N-aryl 2-trifluoromethyl succini-
mides of practical value and transposable to a multigram
scale.
3. Conclusions
In summary, we have developed a preparative access to
2-trifluoromethyl and 2-pentafluoroethyl succinic acid
derivatives in various forms, particularly in the 2-trifluoro-
methyl imide series. This is the result of the combination of
the starting perfluoroketene dithioacetal functionality and
the specific behavior of the silylated precursor of ethyl
acetate enolate. Applications in the pentafluoroethyl series
are under investigation and will be reported in due course.
4. Experimental
Scheme 5.
4.1. Materials and general methods
giving some unexpected results. Reaction with aliphatic
primary amines under standard conditions first gave the
opened acid-amide 6a–d (Scheme 5, path a). Cyclodehy-
dration then gave 2-trifluoromethyl succinimides 7a–d by
heating the corresponding 6a–d to 200 8C (Scheme 5). The
reaction of 5 with aromatic primary amines directly
provided the corresponding N-aryl succinimides 7e–g
(Scheme 5, path b). Hydrazine and methylhydrazine reacted
similarly giving the corresponding N-aminosuccinimides
7h,7i in moderate yields. In contrast phenylhydrazine gave
7e, a condensation product with the loss of one nitrogen.
Similar cleavage of the nitrogen–nitrogen bond has
already been observed.11 In the same way, reaction with
N,N0-dimethylhydrazine gave N-methyl-2-trifluoromethyl
succinimide 7j (Scheme 6).
Melting points are uncorrected FT-IR spectra were recorded
on a MIDAC Corporation Spectrafile IR apparatus. 1H, 13
C
and 19F spectra were recorded on a Bruker AC-250 or
AC-500 spectrometer with CDCl3 as the solvent. Tetra-
methylsilane (dZ0.00 ppm) or CHCl3 (dZ7.27 ppm) were
used as internal standards for 1H, CDCl3 (dZ77.23 ppm) for
13C NMR spectra, and CFCl3 (dZ0.0 ppm) for 19F NMR
spectra. GCMS spectra were obtained on Trace MS
Thermoquest apparatus (70 eV) in electron impact mode.
Elemental analyses were performed with a Perkin–Elmer
CHN 2400 apparatus. High Resolution Mass Spectra
(HRMS) were performed on Q-TOF Micromass in positive
ESI mode (CVZ30 V). All reactions were monitored by
TLC (Merck F 254 silica gel) or by 19F NMR. All anhydrous
reactions were carried out under dry argon. THF was dried
and distilled from sodium/benzophenone. Ethyl 2-trimethyl-
silyl acetate was distillated before use. Tetramethylam-
monium fluoride (TMAF) was dried by heating at 200 8C,
under reduced pressure, during 4–5 h. Perfluoroketene
dithioacetals 1a,b were prepared according to our reported
method.1 Products were separated by chromatography on
silica gel using a mixture of petroleum ether and ethyl
acetate.
4.2. Typical procedure for the preparation of
compounds (2a,b) (Scheme 4)
Scheme 6.
Succinimides constitute an important class of organic
compounds, both as synthetic intermediates and for their
biological properties.12 The introduction of fluorine and in
particular of a trifluoromethyl substituent greatly modifies
To a suspension of TMAF (100 mg, 1.0 mmol, 0.025 equiv)
in dry THF (100 mL), under argon atmosphere, was added
1a (10.1 g, 43.0 mmol, 1 equiv). Ethyl 2-trimethylsilyl
acetate (9.4 mL, 51.0 mmol, 1.2 equiv) was then added

´
C. Brule et al. / Tetrahedron 60 (2004) 9849–9855
9852
3
dropwise to the resulting suspension. The mixture was
stirred at room temperature under argon (4–5 h). Each hour
a new portion of TMAF (50 mg, 0.5 mmol) was added until
total conversion of the starting dithioacetal 1a (4–5!). The
crude mixture was washed with brine (60 mL). After
separation, the aqueous phase was extracted twice with
ether (2!50 mL). The combined organic phases were dried
over MgSO4, filtered and concentrated in vacuo. The
residue was chromatographed on silica gel using a mixture
of petroleum ether–EtOAc (99/1) to give the ketene
dithioacetal 2a (12.2 g, 94%).
CDCl3) d 1.25 (t, JH,HZ7.1 Hz, 3H, OCH2CH3), 1.27 (t,
3JH,HZ7.4 Hz, 3H, SCH2CH3), 2.73 (dd, JH,HZ17.2,
2
3JH,HZ4.0 Hz, 1H, H-2), 2.97 (qd, JH,HZ7.4, JZ1.5 Hz,
3
2H, SCH2CH3), 3.08 (dd, 2JH,HZ17.2, 3JH,HZ10.3 Hz, 1H,
3
3
3
H-2), 3.82 (dqd, JH,HZ10.3, JH,FZ8.5, JH,HZ4.0 Hz,
1H, H-3), 4.15 (q, JH,HZ7.1 Hz, 2H, OCH2CH3); 13C
NMR (62.9 MHz, CDCl3) d 14.0 (s, SCH2CH3 or
OCH2CH3), 14.1 (s, SCH2CH3 or OCH2CH3), 24.2 (s,
3
3
2
SCH2CH3), 31.0 (q, JC,FZ2.5 Hz, C-2), 52.7 (q, JC,F
27.0 Hz, C-3), 61.4 (s, OCH2CH3), 123.6 (q, JC,F
Z
Z
1
3
280.8 Hz, CF3), 169.4 (s, C-1), 192.4 (q, JC,FZ2.1 Hz,
COS); 19F NMR (235.4 MHz, CDCl3) d K68.2 (d, JF,H
Z
3
8.5 Hz); IR (film) 2984, 2937, 1742, 1686, 1306, 1259,
1170, 1123 cmK1; GCMS (EI) m/e (%) 259 (MC1), 213,
197 (100), 169, 149, 121, 101. Anal. Calcd for C9H13F3O3S:
C, 41.86; H, 5.07. Found: C, 42.06; H, 5.08.
4.2.1. Ethyl 4,4-bis(ethylsulfanyl)-3-trifluoromethylbut-
3-enoate (2a). Yield: 94%; oil; 1H NMR (250 MHz, CDCl3)
3
3
d 1.23 (t, JH,HZ7.3 Hz, 3H, SCH2CH3), 1.25 (t, JH,H
Z
3
7.1 Hz, 3H, OCH2CH3), 1.27 (t, JH,HZ7.3 Hz, 3H,
SCH2CH3), 2.84 (q, JH,HZ7.3 Hz, 2H, SCH2CH3), 2.86
3
3
(q, JH,HZ7.3 Hz, 2H, SCH2CH3), 3.74 (s, 2H, H-2), 4.16
4.3.2. Ethyl 3-(ethylsulfanylcarbonyl)-4,4,5,5,5-penta-
(q, JH,HZ7.1 Hz, 2H, OCH2CH3); 13C NMR (62.9 MHz,
CDCl3) d 14.0 (s, OCH2CH3), 14.6 and 15.0 (s, 2!
3
fluoropentanoate (3b). Yield: 84%; oil; 1H NMR
3
(250 MHz, CDCl3) d 1.26 (t, JH,HZ7.1 Hz, 3H,
3
SCH2CH3), 27.9 and 28.8 (s, 2!SCH2CH3), 37.5 (q,
Z
OCH2CH3 or SCH2CH3), 1.27 (t, JH,HZ7.4 Hz, 3H,
1
3JC,FZ2.8 Hz, C-2), 61.2 (s, OCH2CH3), 122.7 (q, JC,F
2
3
OCH2CH3 or SCH2CH3), 2.80 (dd, JH,HZ17.2, JH,H
3.6 Hz, 1H, H-2), 2.9–3.2 (m, 3H, SCH2CH3 and H-2), 3.84
Z
2
275.6 Hz, CF3), 130.2 (q, JC,FZ29.0 Hz, C-3), 146.0 (q,
3JC,FZ3.1 Hz, C-4), 169.3 (s, C-1); 19F NMR (235.4 MHz,
CDCl3) d K57.0 (s); IR (film) 2981, 2930, 1740, 1302,
1159, 1132 cmK1; GCMS (EI) m/e (%) 302 (MC), 274, 253,
229, 139 (100), 75. Anal. Calcd for C11H17F3O2S2: C,
43.69; H, 5.67. Found: C, 43.37; H, 5.95.
(m, 1H, H-3), 4.17 (q, JH,HZ7.1 Hz, 2H, OCH2CH3); 13C
NMR (62.9 MHz, CDCl3) d 13.87 and 13.92 (s, SCH2CH3
3
and OCH2CH3), 24.2 (s, SCH2CH3), 30.7 (m, C-2), 50.5 (t,
2JC,FZ20.7 Hz, C-3), 61.4 (s, OCH2CH3), 113.1 (tq, 1JC,F
Z
2
1
257.5, JC,FZ37.9 Hz, CF2), 118.5 (qt, JC,FZ287.1,
2JC,FZ37.8 Hz, CF3), 169.3 (s, C-1), 192.4 (m, COS); 19F
NMR (235.4 MHz, CDCl3) d K82.6 (m, 3F, CF3), K115.6
4.2.2. Ethyl 4,4-bis(ethylsulfanyl)-3-pentafluoroethylbut-
3-enoate (2b). Yield: 91%; oil; 1H NMR (250 MHz, CDCl3)
2
3
(dd, JF,FZ274.1, JF,HZ13.8 Hz, 1F, CF2), K117.5 (dd,
3
3
2JF,FZ274.1, JF,HZ13.8 Hz, 1F, CF2); IR (film) 2983,
d 1.22 and 1.25 and 1.26 (t, JH,HZ7.2 Hz, 9H, 2!
3
2936, 1743, 1686, 1276, 1210 cmK1; GCMS (EI) m/e (%)
309 (MC1), 263, 247, 219, 199 (100), 151, 77.
SCH2CH3COCH2CH3), 2.84 and 2.86 (q, JH,HZ7.2 Hz,
3
4H, 2!SCH2CH3), 3.66 (s, 2H, H-2), 4.15 (q, JH,H
Z
7.2 Hz, 2H, OCH2CH3); 13C NMR (62.9 MHz, CDCl3) d
14.0 and 14.6 and 14.8 (s, 2!SCH2CH3COCH2CH3), 28.3
3
4.3.3. 3-(Ethylsulfanylcarbonyl)-4,4,4-trifluorobutanoic
acid (5). Yield: 87%; oil; H NMR (250 MHz, CDCl3) d
and 29.3 (s, 2!SCH2CH3), 38.1 (t, JC,FZ4.3 Hz, C-2),
1
1
2
61.2 (s, OCH2CH3), 113.3 (tq, JC,FZ257.4, JC,F
Z
3
2
1
2
1.27 (t, JH,HZ7.4 Hz, 3H, SCH2CH3), 2.80 (dd, JH,H
Z
39.0 Hz, CF2), 119.2 (qt, JC,FZ288.0, JC,FZ39.0 Hz,
17.8, 3JH,HZ3.9 Hz, 1H, H-2), 2.97 (q, 3JH,HZ7.4 Hz, 2H,
SCH2CH3), 3.16 (dd, JH,HZ17.8, JH,HZ10.1 Hz, 1H,
H-2), 3.80 (m, 1H, H-3), 11.3 (brs, 1H, OH); 13C NMR
(62.9 MHz, CDCl3) d 14.0 (s, SCH2CH3), 24.3 (s,
2
3
CF3), 127.2 (t, JC,FZ20.7 Hz, C-3), 148.8 (t, JC,F
Z
2
3
3.2 Hz, C-4), 169.3 (s, C-1); 19F NMR (235.4 MHz, CDCl3)
d K107.1 (m, 2F, CF2), K83.3 (m, 3F, CF3); IR (film)
2982, 2931, 1741, 1197, 1130 cmK1; GCMS (EI) m/e (%)
352 (MC), 323, 303, 279 (100), 189, 75.
3
2
SCH2CH3), 30.7 (q, JC,FZ2.0 Hz, C-2), 52.4 (q, JC,F
Z
1
27.4 Hz, C-3), 123.5 (q, JC,FZ280.8 Hz, CF3), 175.8 (s,
C-1), 192.2 (q, 3JC,FZ1.5 Hz, COS); 19F NMR (235.4 MHz,
4.3. Typical procedure for acid hydrolysis of compounds
(2a,b and 4) (Scheme 4)
3
CDCl3) d K68.1 (d, JF,HZ8.6 Hz); IR (film) 3053, 2971,
2937, 1720, 1684, 1260, 1171, 1124 cmK1; GCMS (EI) m/e
(%) 231 (MC1), 169, 149, 121, 101, 95, 62 (100); HRMS
(ESI) calcd for C7H9F3O3NaS m/eZ253.0122; found
253.0122.
To a solution of ketene dithioacetal 2a (6.64 g, 22.0 mmol,
1 equiv) in trifluoroacetic acid (15 mL, 0.2 mol, 9 equiv)
was added water (1.2 mL, 66.0 mmol, 3 equiv). The mixture
was refluxed until complete conversion of 2a (10 h). After
cooling, water (30 mL) was added and the medium was
basified using a saturated aqueous solution of NaHCO3
(20 mL). The resulting aqueous phase was extracted twice
with CH2Cl2 (2!40 mL). The combined organic layer was
dried over MgSO4, filtered and concentrated in vacuo. The
residue was chromatographed on silica gel using a mixture
of petroleum ether–EtOAC (95/5) to give the compound 3a
(4.71 g, 83%).
4.4. Preparation of compound (4) (Scheme 4)
To a solution of compound 2a (9.97 g, 33.0 mmol) in EtOH
(50 mL) was added an aqueous solution of KOH 3 M
(50 mL). The mixture was heated at 80 8C for 3 h. After
cooling at 0 8C and acidification with hydrochloric acid 1 M
(30 mL) until pHZ1, the mixture was extracted with ether
(3!100 mL). The combined organic phase was dried over
MgSO4, filtered and concentrated in vacuo. The residue was
recrystallized using a mixture of petroleum ether–EtOAc to
give the compound 4 (8.9 g, 98%).
4.3.1. Ethyl 3-(ethylsulfanylcarbonyl)-4,4,4-trifluoro-
butyrate (3a). Yield: 83%; oil; 1H NMR (250 MHz,

´
C. Brule et al. / Tetrahedron 60 (2004) 9849–9855
9853
4.4.1. 4,4-Bis(ethylsulfanyl)-3-trifluoromethylbut-3-
enoic acid (4). Solid: mp 79–80 8C; H NMR (250 MHz,
4.5.3. 1-(n-Pentyl)-3-trifluoromethyl-pyrrolidine-2,5-
dione (7b). Yield: 71%; oil; H NMR (250 MHz, CDCl3)
1
1
3
3
CDCl3) d 1.23 (t, JH,HZ7.2 Hz, 3H, SCH2CH3), 1.26 (t,
d 0.88 (t, JH,HZ6.9 Hz, 3H, CH3), 1.3 (m, 4H, 2!CH2),
3JH,HZ7.2 Hz, 3H, SCH2CH3), 2.84 (q, 3JH,HZ7.2 Hz, 2H,
SCH2CH3), 2.87 (q, 3JH,HZ7.2 Hz, 2H, SCH2CH3), 3.79 (s,
2H, H-2), 11.5 (s, 1H, OH); 13C NMR (62.9 MHz, CDCl3)
d 14.6 and 14.9 (s, 2!SCH2CH3), 28.0 and 28.9 (s,
SCH2CH3), 37.3 (m, C-2), 122.7 (q, 1JC,FZ275.6 Hz, CF3),
1.6 (m, 2H, NCH2CH2), 2.83 (dd, JH,HZ18.5, JH,HZ
2
3
5.2 Hz, 1H, H-4), 2.98 (dd, 2JH,HZ18.5, 3JH,HZ9.4 Hz, 1H,
3
H-4), 3.54 (t, JH,HZ7.4 Hz, 2H, NCH2), 3.5–3.6 (m, 1H,
H-3); 13C NMR (62.9 MHz, CDCl3) d 13.8 (s, CH3), 22.1 (s,
CH2), 27.0 (s, CH2), 28.7 (s, CH2), 29.4 (m, C-4), 39.5 (s,
2
2
1
129.1 (q, JC,FZ29.4 Hz, C-3), 147.0 (m, C-4), 176.2 (s,
NCH2), 44.3 (q, JC,FZ29.9 Hz, C-3), 123.7 (q, JC,FZ
C-1); 19F NMR (235.4 MHz, CDCl3) d K57.0 (s); IR (KBr)
3100, 2965, 1697, 1570, 1411 cmK1; HRMS (ESI) calcd for
C9H14F3O2S2 m/eZ275.0387; found 275.0374.
278.5 Hz, CF3), 169.6 (q, JC,FZ3.0 Hz, C-2), 173.4 (s,
3
3
C-5); 19F NMR (235.4 MHz, CDCl3) d K69.4 (d, JF,H
Z
8.6 Hz); IR (film) 2960, 2874, 1716, 1405, 1353, 1256,
1186 cmK1; GCMS (EI) m/e (%) 238 (MC1), 237 (MC),
181, 168 (100), 41; HRMS (ESI) calcd for C10H15F3NO2
m/eZ238.1055; found 238.1064.
4.5. Typical procedure for preparation of succinimides
(7a–d) (Scheme 5, path a)
4.5.4. 1-Isopropyl-3-trifluoromethyl-pyrrolidine-2,5-
dione (7c). Yield: 56%; oil; H NMR (250 MHz, CDCl3)
d 1.38 (d, JH,HZ6.9 Hz, 6H, CH3), 2.78 (dd, JH,HZ18.5,
To a solution of g-carboxy-thioester 5 (0.23 g, 1.00 mmol,
1.00 equiv) in toluene (6 mL) was added benzylamine
(0.11 g, 1.04 mmol, 1.05 equiv). The mixture was heated
first at 110 8C for 2 h (formation of intermediate 6a). After
evaporation of toluene, the residue was heated to 200 8C for
1–3 h. After cooling, the crude mixture was diluted with
ether (8 mL) and washed with brine (5 mL). After
separation, the aqueous phase was extracted with ether
(3!5 mL). The combined organic phase was dried over
MgSO4, filtered and concentrated in vacuo. The residue was
chromatographed on silica gel using a mixture of petroleum
ether/EtOAc (85/15) to give the succinimide 7a (0.19 g,
73%).
1
3
2
2
3
3JH,HZ5.1 Hz, 1H, H-4), 2.93 (dd, JH,HZ18.5, JH,H
Z
Z
3
9.5 Hz, 1H, H-4), 3.5 (m, 1H, H-3), 4.40 (sept, JH,H
6.9 Hz, 1H, NCH); 13C NMR (62.9 MHz, CDCl3) d 18.9 (s,
CH3), 29.3 (q, 3JC,FZ1.8 Hz, C-4), 44.0 (q, 2JC,FZ29.5 Hz,
C-3), 44.7 (s, NCH), 123.8 (q, 1JC,FZ278.7 Hz, CF3), 169.5
(m, C-2), 173.4 (s, C-5); 19F NMR (235.4 MHz, CDCl3) d
3
K69.6 (d, JF,HZ9.5 Hz); IR (film) 2982, 1785, 1716,
1404, 1369 cmK1; GCMS (EI) m/e (%) 210 (MC1), 209
(MC), 194, 168 (100), 123, 95, 44; HRMS (ESI) calcd for
C8H11F3NO2 m/eZ210.0742; found 210.0740.
4.5.5. 1-(10-Phenylethyl)-3-trifluoromethyl-pyrrolidine-
2,5-dione (7d). Yield: 76%; mixture (50/50) of diastereo-
4.5.1. 3-Benzylcarbamoyl-4,4,4-trifluoro-butanoic acid
(6a). Yield: 68%; Solid: mp 167–169 8C; 1H NMR
1
mers; oil; H NMR (250 MHz, CDCl3) d 1.82 (d, JH,H
3
Z
2
3
2
(250 MHz, CD3OD) d 2.75 (dd, JH,HZ17.2, JH,H
Z
7.3 Hz, 3HC3H, CH3), 2.78 and 2.79 (dd, JH,HZ18.5,
2
3
2
3JH,HZ5.0 Hz, 1HC1H, H-4), 2.90 and 2.92 (dd, JH,H
Z
3.4 Hz, 1H, H-2), 3.09 (dd, JH,HZ17.2, JH,HZ11.1 Hz,
1H, H-2), 3.7 (m, 1H, H-3), 4.4 (m, 2H, NHCH2), 7.3 (m,
5H, Ph), NH and OH not visible; 13C NMR (62.9 MHz,
18.5, 3JH,HZ9.5 Hz, 1HC1H, H-4), 3.5 (m, 1HC1H, H-3),
3
5.45 and 5.46 (q, JH,HZ7.3 Hz, 1HC1H, NCH), 7.2–7.5
CD3OD) d 31.1 (m, C-2), 44.4 (s, NHCH2), 47.7 (q, 2JC,F
Z
(m, 5HC5H, Ph); 13C NMR (62.9 MHz, CDCl3) d 16.1 and
1
16.4 (s, CH3), 29.3 (m, C-4), 44.0 (q, 2JC,FZ29.9 Hz, C-3),
26.7 Hz, C-3), 126.5 (q, JC,FZ279.2 Hz, CF3), 128.2 (s,
CH Ph), 128.4 (s, 2!CH Ph), 129.5 (s, 2!CH Ph), 139.3 (s,
Cq Ph), 167.6 (m, CON), 173.2 (s, C-1); 19F NMR
1
51.0 and 51.2 (s, NCH), 123.7 and 123.8 (q, JC,F
Z
278.8 Hz, CF3), 127.3 and 127.5 (s, 2!CH Ph), 128.0 and
128.1 (s, CH Ph), 128.5 (s, 2!CH Ph), 138.5 and 138.7 (s,
3
(235.4 MHz, CD3OD) d K68.2 (d, JF,HZ8.6 Hz); IR
Cq Ph), 169.3 (m, C-2), 173.1 and 173.2 (s, C-5); 19F NMR
(KBr) 3297, 3098, 2971, 2941, 1710, 1656, 1242,
1169 cmK1; MS (ESI) m/e (%) 314 (MCK)C, 298 (MC
Na)C, 276 ((MCH)C, 100). Anal. Calcd for C12H12F3NO3:
C, 52.37; H, 4.39; N, 5.09. Found: C, 51.82; H, 4.24;
N, 4.94.
3
(235.4 MHz, CDCl3) d K69.5 and K69.4 (d, JF,H
Z
.
9.5 Hz); IR (film) 2981, 1713, 1606, 1505, 1455, 1385 cmK1
4.6. General procedure for preparation of succinimides
(7e–i) (Scheme 5, path b)
4.5.2. 1-Benzyl-3-trifluoromethyl-pyrrolidine-2,5-dione
(7a). Yield: 73%; oil; H NMR (250 MHz, CDCl3) d 2.86
1
The same procedure as described for path a (Scheme 5),
except that the mixture was heated at 110 8C for 2 h, gave
after work-up and purification by silica gel chromatography
(mixture of petroleum ether–ethyl acetate) the succinimides
7e–i.
2
3
(dd, JH,HZ18.5, JH,HZ5.4 Hz, 1H, H-4), 2.99 (dd,
3
2JH,HZ18.5, JH,HZ9.4 Hz, 1H, H-4), 3.6 (m, 1H, H-3),
2
2
4.68 (d, JH,HZ17.2 Hz, 1H, NCH2), 4.73 (d, JH,H
Z
17.2 Hz, 1H, NCH2), 7.3 (m, 5H, Ph); 13C NMR (62.9 MHz,
CDCl3) d 29.4 (q, 3JC,FZ1.7 Hz, C-4), 43.1 (s, NCH2), 44.4
(q, JC,FZ30.0 Hz, C-3), 123.7 (q, JC,FZ278.5 Hz, CF3),
128.3 (s, CH Ph), 128.7 (s, 2!CH Ph), 128.8 (s, 2!CH Ph),
2
1
4.6.1. 1-Phenyl-3-trifluoromethyl-pyrrolidine-2,5-dione
(7e). Yield: 81%; solid: mp 117 8C; H NMR (250 MHz,
1
3
2
3
134.8 (s, Cq Ph), 169.3 (q, JC,FZ2.6 Hz, C-2), 173.0 (s,
CDCl3) d 2.86 (dd, JH,HZ18.6, JH,HZ5.5 Hz, 1H, H-4),
2.99 (dd, 2JH,HZ18.6, 3JH,HZ9.5 Hz, 1H, H-4), 3.6 (m, 1H,
H-3), 7.1 (dm, 3JH,HZ7.5 Hz, 2H, 2!CH Ph), 7.4 (m, 3H,
C-5); 19F NMR (235.4 MHz, CDCl3) d K69.3 (d, JF,H
Z
3
9.5 Hz); IR (film) 3036, 2954, 1789, 1716, 1456,
1402 cmK1; GCMS (EI) m/e (%) 258 (MC1), 257 (MC),
160, 104, 95, 77 (100), 51; HRMS (ESI) calcd for
C12H11F3NO2 m/eZ258.0742; found 258.0736.
3!CH Ph); 13C NMR (62.9 MHz, CDCl3) d 29.4 (q, 3JC,F
Z
2
2.0 Hz, C-4), 44.4 (q, JC,FZ29.9 Hz, C-3), 123.7 (q,
1JC,FZ278.5 Hz, CF3), 126.3 (s, 2!CH Ph), 129.2 (s, CH

´
C. Brule et al. / Tetrahedron 60 (2004) 9849–9855
9854
3
Ph), 129.3 (s, 2!CH Ph), 131.0 (s, Cq Ph), 168.7 (q, 3JC,F
Z
K69.5 (d, JF,HZ9.5 Hz); IR (film) 3497, 3303, 2944,
1717, 1361, 1259, 1178 cmK1; GCMS (EI) m/e (%) 197
(MC1), 168, 95, 77, 69 (100); HRMS (ESI) calcd for
C6H8F3N2O2 m/eZ197.0538; found 197.0543.
2.7 Hz, C-2), 172.5 (s, C-5); 19F NMR (235.4 MHz, CDCl3)
3
d K69.2 (d, JF,HZ9.5 Hz); IR (KBr) 3074, 2960, 1717,
1406, 1212 cmK1; GCMS (EI) m/e (%) 243 (MC), 174, 120,
95, 91 (100), 77. Anal. Calcd for C11H8F3NO2: C, 54.33; H,
3.32; N, 5.76. Found: C, 54.56; H, 3.13; N, 5.72.
4.7. Preparation of the succinimide (7j) (Scheme 6)
4.6.2. 1-(p-Methoxyphenyl)-3-trifluoromethyl-pyrroli-
dine-2,5-dione (7f). Yield: 81%; solid: mp 148–150 8C;
To a suspension of sodium ethoxide (68 mg, 1.00 mmo0l,
2.00 equiv) in dry toluene (3 mL) was added N,N -
dimethylhydrazine dihydrochloride (69 mg, 0.52 mmol,
1.05 equiv). The mixture was stirred at room temperature
for 1 h. The g-carboxy thioester 5 (0.12 g, 0.50 mmol,
1.00 equiv) was then added. The resulting mixture was
heated at 110 8C for 2 h and gave after work-up and
purification by silica gel chromatography (mixture of
petroleum ether–EtOAc (80/20)) the succinimide 7j
(27 mg, 30%).
2
1H NMR (250 MHz, CDCl3) d 2.95 (dd, JH,HZ18.6,
2
3
3JH,HZ5.3 Hz, 1H, H-4), 3.09 (dd, JH,HZ18.6, JH,H
Z
9.6 Hz, 1H, H-4), 3.6 (m, 1H, H-3), 3.82 (s, 3H, CH3), 6.98
(d, 3JH,HZ8.6 Hz, 2H, 2!CH Ar), 7.15 (d, 3JH,HZ8.6 Hz,
2H, 2!CH Ar); 13C NMR (62.9 MHz, CDCl3) d 29.4 (q,
2
3JC,FZ2.0 Hz, C-4), 44.3 (q, JC,FZ30.1 Hz, C-3), 55.4 (s,
CH3), 114.5 (s, 2!CH Ar), 123.5 (s, NCq Ar), 123.7 (q,
1JC,FZ279.1 Hz, CF3), 127.5 (s, 2!CH Ar), 159.8 (s, OCq
Ar), 169.0 (q, 3JC,FZ3.2 Hz, C-2), 172.8 (s, C-5); 19F NMR
3
(235.4 MHz, CDCl3) d K69.3 (d, JF,HZ8.6); IR (KBr)
4.7.1. 1-Methyl-3-trifluoromethyl-pyrrolidine-2,5-dione
Z
3020, 2955, 1714, 1609, 1445, 1411 cmK1; GCMS (EI) m/e
(%) 273 (MC, 100), 204, 122. Anal. Calcd for
C12H10F3NO3: C, 52.75; H, 3.69; N, 5.13. Found: C,
52.89; H, 3.63; N, 4.80.
1
2
(7j). Oil; H NMR (250 MHz, CDCl3) d 2.87 (dd, JH,H
3
2
18.5, JH,HZ5.3 Hz, 1H, H-4), 3.01 (dd, JH,HZ18.5,
3JH,HZ9.5 Hz, 1H, H-4), 3.07 (s, 3H, NCH3), 3.6 (m, 1H,
H-3); 19F NMR (235.4 MHz, CDCl3) d K69.3 (d, JF,H
Z
3
8.6 Hz); GCMS (EI) m/e (%) 182 (MC1), 181 (MC), 124,
96 (100).
4.6.3. 1-(Pyridin-2-yl)-3-trifluoromethyl-pyrrolidine-2,5-
dione (7g). Yield: 31%; oil; 1H NMR (250 MHz, CDCl3) d
2
3
3.04 (dd, JH,3HZ18.6, JH,HZ5.4 Hz, 1H, H-4), 3.20 (dd,
2JH,HZ18.6, JH,HZ9.7 Hz, 1H, H-4), 3.8 (m, 1H, H-3),
7.30 (dd, 3JH3,HZ7.9, 4JH,4HZ0.9 Hz, 1H, CH Ar), 7.41 (ddd,
3JH,HZ7.9, JH,HZ4.9, JH,HZ0.9 Hz, 1H, CH Ar), 7.89
Acknowledgements
The authors are grateful to ANRT and CEREP company for
a grant (C.B.) and financial support. They thank Dr. Eric
Nicolaı (CEREP) for helpful discussions, Sylvie Lanthony,
Henri Baillia and Dominique Harakat for their contribution
to the analytical work and Dr. Karen Ple for english
correction.
3
3
4
(ddd, JH,HZ7.9, JH,HZ7.9, JH,HZ1.8 Hz, 1H, CH Ar),
3
8.65 (dm, JH,HZ4.9 Hz, 1H, CH Ar); 13C NMR
¨
2
(62.9 MHz, CDCl3) d 29.8 (m, C-4), 44.7 (q, JC,F
Z
30.1 Hz, C-3), 122.2 (s, CH Ar), 123.7 (q, 1JC,FZ278.8 Hz,
CF3), 124.6 (s, CH Ar), 138.7 (s, CH Ar), 145.3 (s, Cq Ar),
149.9 (s, CH Ar), 168.2 (m, C-2), 171.9 (s, C-5); 19F NMR
(235.4 MHz, CDCl3) d K69.0 (d, 3JF,HZ9.5 Hz); IR (film)
3064, 2930, 1798, 1736, 1594, 1472, 1439, 1387 cmK1
;
HRMS (ESI) calcd for C10H8F3N2O2 m/eZ245.0538; found
245.0534.
References and notes
4.6.4. 1-Amino-3-trifluoromethyl-pyrrolidine-2,5-dione
1. Muzard, M.; Portella, C. J. Org. Chem. 1993, 58, 29–31.
2. (a) Tanaka, K.; Nakai, T.; Ishikawa, N. Chem. Lett. 1979,
175–178. (b) Purrington, S. T.; Somaha, N. F. J. Fluorine
Chem. 1989, 43, 229–234.
(7h). Yield: 45%; oil; 1H NMR (250 MHz, CD3OD) d
2
3
2.86 (dd, JH,3HZ18.3, JH,HZ4.8 Hz, 1H, H-4), 3.09 (dd,
3
2JH,HZ18.3, JH,HZ9.5 Hz, 1H, H-4), 3.97 (qdd, JH,F
Z
3
3
9.5, JH,HZ9.5, JH,HZ4.8 Hz, 1H, H-3), NH2 not visible;
3. Huot, J. F.; Muzard, M.; Portella, C. Synlett 1995, 247–248.
´
4. Henin, B.; Huot, J. F.; Portella, C. J. Fluorine Chem. 2001,
107, 281–283.
13C NMR (62.9 MHz, CD3OD) d 29.5 (q, JC,FZ2.1 Hz,
3
2
1
C-4), 44.8 (q, JC,FZ29.9 Hz, C-3), 126.5 (q, JC,F
Z
3
277.4 Hz, CF3), 170.8 (q, JC,FZ3.2 Hz, C-2), 174.7 (s,
´
¨
5. Brule, C.; Bouillon, J. P.; Nicolaı, E.; Portella, C. Synthesis
C-5); 19F NMR (235.4 MHz, CD3OD) d K68.7 (d, 3JF,H
Z
2003, 436–442.
6. Bouillon, J. P.; Henin, B.; Huot, J. F.; Portella, C. Eur. J. Org.
9.5 Hz); GCMS (EI) m/e (%) 183 (MC1), 156, 123, 95
(100), 77, 69; HRMS (ESI) calcd for C5H6F3N2O2 m/eZ
183.0381; found 183.0376.
´
Chem. 2002, 1556–1561.
7. Sotoca, E.; Bouillon, J.-P.; Gil, S.; Parra, M.; Portella, C.,
Tetrahedron Lett., accepted for publication.
4.6.5. 1-Methylamino-3-trifluoromethyl-pyrrolidine-2,5-
dione (7i). Yield: 47%; oil; H NMR (250 MHz, CDCl3) d
8. (a) Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97,
757–786. (b) Singh, R. P.; Shreeve, J. M. Tetrahedron 2000,
56, 7613–7632.
1
3
2
2.71 (d, JH,HZ5.2 Hz, 3H, CH3), 2.83 (dd, JH,HZ18.6,
2
3
3JH,HZ4.8 Hz, 1H, H-4), 3.00 (dd, JH,HZ18.6, JH,H
Z
9. Degl’Innocenti, A.; Capperucci, A.; Nocentini, T. Tetrahedron
Lett. 2001, 42, 4557–4559.
9.5 Hz, 1H, H-4), 3.6 (m, 1H, H-3), 4.73 (q, 3JH,HZ5.2 Hz,
1H, NH); 13C NMR (62.9 MHz, CDCl3) d 27.8 (q, JC,F
Z
10. (a) Brigaud, T.; Doussot, P.; Portella, C. J. Chem. Soc., Chem.
Commun. 1994, 2117–2118. (b) Portella, C.; Brigaud, T.;
Plantier-Royon, R. J. Fluorine Chem. 2000, 101, 193–198 and
references therein.
3
2
2.1 Hz, C-4), 37.5 (s, CH3), 42.7 (q, JC,FZ30.1 Hz, C-3),
1
3
123.5 (q, JC,FZ279.0 Hz, CF3), 167.0 (q, JC,FZ3.2 Hz,
C-2), 170.9 (s, C-5); 19F NMR (235.4 MHz, CDCl3) d

´
C. Brule et al. / Tetrahedron 60 (2004) 9849–9855
9855
11. Eltamany, E. H.; Mourad, A.-F. E. Pol. J. Chem. 1987,
425–432.
ACS Symposium series, 639. (c) Hiyama, T. Organofluorine
compounds Chemistry and Applications; Springer: Berlin,
2000.
12. Anticonvulsive activity: (a) Kornet, M. J.; Crider, A. M.;
Magarian, E. O. J. Med. Chem. 1977, 20, 405–412. (b) Kornet,
M. J.; Crider, A. M. J. Med. Chem. 1977, 20, 1210–1213.
(c) Stratford, E. S.; Curley, R. W. J. Med. Chem. 1983, 26,
1463–1469. Tranquilizing activity: New, J. S.; Yevich, J. P.;
Eison, M. S.; Taylor, D. P.; Eison, A. S.; Riblet, L. A.;
VanderMaelen, C. P.; Temple, D. L. J. Med. Chem. 1986, 29,
1476–1482.
14. (a) Sewald, N.; Riede, J.; Bissinger, P.; Burger, K. J. Chem.
Soc. Perkin Trans. 1 1992, 267–273. (b) Pustovit, Yu. M.;
Ogojko, P. I.; Nazaretian, V. P.; Faryat’eva, L. B. J. Fluorine
Chem. 1994, 69, 225–229.
15. (a) Burdon, J.; Smith, T. J.; Tatlow, J. C. J. Chem. Soc. 1961,
4519–4521. (b) Gusinskaya, V. A.; Borisova, Z. V. Izvestiya
Akademii Nauk SSSR, Seriya Khimicheskaya 1965,
1907–1908. Chem. Abstr. 1966, 64, 11000.
13. (a) Welch, J. T.; Eswarakrishnan, S. Fluorine in Bioorganic
Chemistry; Wiley: New York, 1991. (b) Ojima, I.; McCarthy,
J. R.; Welch, J. T. Biomedical Frontiers of Fluorine Chemistry
16. Hoberg, H.; Guhl, D. J. Organomet. Chem. 1989, 378,
279–292.