1-(Trifluoromethyl)cyclopent-3-enecarboxylic acid derivatives: Platforms for bifunctional cyclic trifluoromethyl building blocks

Article abstract of DOI:10.1002/ejoc.201101321

We report herein the synthesis and applications of 1-(trifluoromethyl) cyclopent-3-ene-1-carboxylic acid and itsesters, promising new trifluoromethylated cyclic building blocks. Initially prepared starting from a pentafluorodithiopropanoic ester, a more convenient and effective approach has been developed starting from commercially available trifluoropropanoic acid or its methyl ester. The interest in these building blocks is exemplified by their use as platforms for a variety of difunctional trifluoromethylcyclopentane derivatives. We disclose herein a promising new building block, 1-(trifluoromethyl)cyclopent-3-enecarboxylic acid (and its esters), accessible in high yield from commercially available trifluoropropanoic acid derivatives. These building blocks exhibit high synthetic potential, given the reaction diversity offered by the double bond and thecarboxylic function. Copyright

Full text of DOI:10.1002/ejoc.201101321

FULL PAPER
DOI: 10.1002/ejoc.201101321
1-(Trifluoromethyl)cyclopent-3-enecarboxylic Acid Derivatives: Platforms for
Bifunctional Cyclic Trifluoromethyl Building Blocks
Fabienne Grellepois,*[a] Vincent Kikelj,[a] Nicolas Coia,[a] and Charles Portella*[a]
Keywords: Carbocycles / Allylation / Cyclization / Fluorine / Amino acids
We report herein the synthesis and applications of 1-(tri-
fluoromethyl)cyclopent-3-ene-1-carboxylic acid and its
esters, promising new trifluoromethylated cyclic building
blocks. Initially prepared starting from a pentafluorodithio-
propanoic ester, a more convenient and effective approach
has been developed starting from commercially available tri-
fluoropropanoic acid or its methyl ester. The interest in these
building blocks is exemplified by their use as platforms for a
variety of difunctional trifluoromethylcyclopentane deriva-
tives.
Their derivatization to yield various difunctionalized CF3-
cyclopentane compounds of interest (epoxy ester, γ-hy-
droxy, γ-keto and γ-amino acid derivatives) is also reported.
Introduction
1-(Trifluoromethyl)cyclopent-3-enecarboxylic acid and
its derivatives are uncommon compounds, yet this type of
five-membered carbocyclic structure is of great potential
interest (Figure 1). The hydrophobic, electron-withdrawing
and sterically demanding trifluoromethyl group and its abil-
ity to enhance metabolic stability may significantly modify
the chemical physical and biological properties of such
structures.[1,2] On the other hand, the presence of the endo-
cyclic double bond in addition to the carboxylic function
brings versatility due to possible further derivatization (Fig-
ure 1). For example, their non-trifluoromethylated counter-
parts have been used as intermediates in the synthesis of
carbocyclic nucleoside analogues.[3]
Results and Discussion
This work was initially inspired by our results on the
domino transformation of pentafluorodithiopropanoic es-
ters,[4] which, under reaction with allymagnesium halide,
were converted into the corresponding α,α-diallyl deriva-
tives.[5] This formal α-fluorine substitution is actually the
result of two successive three-step domino transformations:
thiophilic nucleophilic allylation, β-elimination of fluoride
and σ [3,3] rearrangement.[5] Thus, benzyl α,α-diallyl dithio-
ester 2 was prepared from benzyl pentafluorodithio-
propanoate (1) and its RCM reaction was investigated, a
task that may not be trivial due to the presence of sulfur.[6]
Grubbs’ I catalyst was indeed ineffective, but the cyclopen-
tene derivative 3 was obtained in high yield by using 10
(2ϫ5) mol-% Grubbs’ II catalyst (Scheme 1).
Figure 1. Properties of 1-(trifluoromethyl)cyclopentenecarboxylic
acid.
We report in this paper a new and effective methodology
for the preparation of this class of building block by the
ring-closing metathesis (RCM) of α,α-diallyl intermediates
and the development of an efficient synthesis of the latter.
[a] Université de Reims-Champagne-Ardenne, Institut de Chimie
Moléculaire de Reims, UMR CNRS 6229, UFR des Sciences
Exactes et Naturelles,
Scheme 1. Preparation of 1-(trifluoromethyl)cyclopent-3-ene-
carboxylic acid (4) from pentafluorodithiopropanoate (1).
BP 1039, 51687 Reims Cedex 2, France
Fax: +33-3-26913166
E-mail: fabienne.grellepois@univ-reims.fr
charles.portella@univ-reims.fr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101321.
The need for a relatively high amount of the expensive
Grubbs’ II catalyst and the lower interest in dithiocarbox-
ylic derivatives prompted us to consider the more versatile
Eur. J. Org. Chem. 2012, 509–517
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
509

F. Grellepois, V. Kikelj, N. Coia, C. Portella
FULL PAPER
carboxylic analogues. Although compound 3 may be con-
verted quantitatively into the corresponding acid 4 follow-
ing our reported procedure[7] (Scheme 1), we searched for a
more straightforward approach to this cyclopentanecarbox-
ylic acid derivative starting from the commercially available
3,3,3-trifluoropropanoic acid (5) and its methyl ester 6,
more precisely via their enolates.
The reactivity of α-CF3 enolates and, more generally, of
α-CF3 anions, is problematic due to the competitive β-elimi-
nation of fluoride.[8] Only mono-α-allyl-trifluoropropanoic
derivatives have been reported so far. 2-Allyl-3,3,3-tri-
fluoropropanoic acid was prepared by Nakai and co-
workers by Claisen rearrangement of the silyl ketene acetal
derived from allyl 3,3,3-trifluoropropanoate.[9] Any exten-
sion of the process to the synthesis of our target would need
a further multistep transformation such that the overall
process would not be convenient. Kitazume and co-workers
reported the α-allylation of ethyl 3,3,3-trifluoropropanoate
by using allyl carbonate as electrophile under palladium ca-
talysis.[10,11] Under these neutral conditions the ester enol-
ate is stabilized as a Pd ligand before the last reductive eli-
mination step releasing the allyl-enolate coupling prod-
uct.[10] As the authors mentioned that in some cases the
diallylated ester was formed as a byproduct, we expected
that the use of excess carbonate would lead to the targeted
α,α-diallyl-trifluoropropanoate. When methyl 3,3,3-tri-
fluoropropanoate (6) was heated with 3 equiv. of allyl car-
bonate and [Pd2(dba)3]·CHCl3 (2.5 mol-%) or Pd(OAc)2
(3.5 mol-%) at reflux in THF in the presence of bis(diphen-
ylphosphanyl)ethane (dppe; 3 equiv./catalyst), total conver-
sion to the desired diallyl-trifluoropropanoate 7 was
achieved (Scheme 2). However, isolation of solvent-free 7
proved to be difficult due to its high volatility.
Scheme 3. Pd-catalysed diallylation of the 3,3,3-trifluoropropanoic
acid derivatives 5, 6 and 10.
The diallyl derivatives 8 and 11 were submitted to RCM.
Both the acid and ester underwent cyclization in high yields
by using a small amount of Grubbs’ I catalyst (Table 1).
Thus, the acid 4 and its ester 12 were synthesized in two or
three effective experimental steps, respectively, from 3,3,3-
trifluoropropanoic acid (5) or its methyl ester 6.[13]
Table 1. RCM of diallyl derivatives 8 and 11.
Substrate
R
Cat. [mol-%]
Product
Yield [%]
8
11
H
Bn
5
0.5
4
12
88
99
To emphasize the versatility of these 1-(trifluoromethyl)-
cyclopent-3-enecarboxylic acid derivatives 4 and 12, we ex-
plored their potential as platforms for a variety of difunc-
tional cyclopentane compounds.
Scheme 2. Pd-catalysed diallylation of methyl 3,3,3-trifluoroprop-
anoate (6).
To circumvent this problem, α,α-diallyl ester 7 was hy-
Unsaturated ester 12 was epoxidized with m-CPBA to
drolysed in situ to give directly the corresponding α,α-diall- provide a 93:7 mixture of diastereomers. The pure epoxide
yl-trifluoropropanoic acid 8, which was isolated in 93% 13, the stereochemistry of which was ascribed by chemical
overall yield after a simple extraction under pH control correlation (see below), was isolated in 81% yield after
(Scheme 3). The diallylation could also be performed di- chromatography (Scheme 4). The reason for the good facial
rectly on the 3,3,3-trifluoropropionic acid (5). In this case, selectivity remains unclear. As the epoxidation of the corre-
the reaction occurred by only using [Pd2(dba)3]·CHCl3 sponding non-trifluoromethylated cyclopentenecarboxylic
(2 mol-%) as the palladium source and gave the correspond- ester led to an oxirane on the side opposite the carboxylic
ing allyl α,α-diallyl ester 9, which was hydrolysed in situ to group,[14] one could attribute the stereoselectivity observed
give the acid 8 in 71% yield (Scheme 3). Alternatively, the in our case to the steric hindrance resulting from the trifluo-
Tsuji–Trost diallylation reaction could be performed on the romethyl group.[2] A pure steric effect would also induce
non-volatile benzyl 3,3,3-trifluoropropanoate[12] (10; pre- stereoselectivity in other bond-forming transformations on
pared in 97% yield from the acid 5 by the classical DCC/ the cyclopentane ring, which was not the case (see below).
DMAP method) to give the diallylated adduct 11 in 87% Thus, stereoelectronic effects associated with the strong
yield (Scheme 3).
electron-withdrawing character of CF3 could be the reason,
510
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 509–517

Trifluoromethylcyclopentenecarboxylic Acid Derivatives
as was proposed to explain the similarly high stereoselec- control of the temperature was necessary to limit the forma-
tivity of the epoxidation of methyl 1-phenylsulfonyl-3-cyclo- tion of benzyl alcohol and a trifluoromethylated byproduct
pentene-1-carboxylate.[15]
(detected in the 19F NMR spectrum of the crude mixture
but not isolated) during the hydroboration process. Appar-
ently, the inductive effect of the trifluoromethyl group acti-
vates the ester reduction by BH3·Me2S, which competes
with the olefin hydroboration pathway.[17] Deprotection of
benzyl esters 15 by hydrogenolysis[18] led to the hydroxy ac-
ids 16 (76% yield). Acid-catalysed cyclodehydration was
then carried out on the mixture of hydroxy acids 16 to de-
termine the configuration of both isomers and to separate
them. Recovery of the minor isomer of the hydroxy acid 16
(30% yield) and isolation of lactone 17 (49% yield) allowed
a trans relationship between the carboxylic acid and the
alcohol functions to be ascribed to the minor diastereoiso-
mer of the hydroxy acid 16 and thus of ester 15. The major
c-16 isomer was in turn obtained in 87% yield by basic
hydrolysis of lactone 17. Lactone 17 was also prepared in
56% yield by acid-induced intramolecular addition in the
cyclopentenecarboxylic acid 4 (Scheme 5). Triflic acid gave
the best result for this purpose, with other acids being tot-
ally ineffective (acidic ion-exchange resin, formic or tri-
fluoroacetic acid) or giving a lower yield (35% in neat
H2SO4).
The γ-keto acid 18 was prepared by a Wacker-type oxi-
dation. Ishii and co-workers reported the conversion of cy-
clopentene into cyclopentanone under oxygen by using a
catalytic system consisting of Pd(OAc)2 and molybdo-
vanadophosphate.[19] Their use in the reaction with cyclo-
pentenecarboxylic acid 4 cleanly afforded the correspond-
ing keto acid 18 in 85% yield (Scheme 6). Unfortunately,
no reaction was observed starting from the cyclopentene
benzyl ester 12. The keto benzyl ester 19 was obtained
either by benzylation of keto acid 18 (95% yield) or by
Swern oxidation of the γ-hydroxy ester 15 (75% yield). Keto
acid 18 and ester 19 are key intermediates in the prepara-
tion of heterocyclic cyclopentyl-tetrahydroisoquinolines
patented as modulators of chemokine receptor activity and
our approach may be viewed as an attractive alternative to
the one reported from trifluoromethacrylic acid.[20]
Scheme 4. Synthesis of epoxide 13.
Iodolactonization[16] of the cyclopentenecarboxylic acid
4 afforded the iodolactone 14 in 60% isolated yield (moni-
toring of the reaction by 19F NMR in the presence of an
internal standard revealed the total conversion of 4 into 14,
but a significant amount of the starting material was always
recovered after workup). Iodolactone 14 is an interesting
intermediate for creating molecular diversity through ring-
opening with various nucleophilic species. Condensation of
14 with sodium benzylate afforded the epoxy ester 13 in
which the oxirane ring and the trifluoromethyl group are
necessarily in a trans relationship (Scheme 4).
Classical hydroboration/oxidation of unsaturated ester 12
afforded the corresponding γ-hydroxy ester 15 in 75% yield
as an inseparable 44:56 mixture of diastereomers (using
BH3·THF instead of BH3·Me2S or Et2O instead of THF
did not improve the stereoselectivity; Scheme 5). Careful
Scheme 5. Synthesis of hydroxy acids 16 and lactone 17.
Scheme 6. Synthesis of γ-keto acid 18 and benzyl ester 19.
Eur. J. Org. Chem. 2012, 509–517
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
511

F. Grellepois, V. Kikelj, N. Coia, C. Portella
FULL PAPER
We finally considered the cyclopentene acid 4 as an inter- with potassium tert-butoxide in a solution of DMSO con-
esting starting material for the preparation of α-trifluoro- taining water. The reductive benzylamination route allowed
methyl analogues of γ-aminocyclopentanecarboxylic acid the eventual preparation of both diastereomers.
derivatives (α-CF3-Acpa). γ-Aminocyclopentanecarboxylic
acids (Acpa)[21] are known as valuable scaffolds for antican-
cer and antiviral agents[22] and they can also be seen as
conformationally restricted analogues of γ-aminobutanoic
acid (GABA).[23] Moreover, γ-aminocyclopentanecarbox-
ylic acids have been used in the design and synthesis of
peptides with definite non-natural secondary structures[24]
and of self-assembling peptide nanotubes.[25]
The free amino acid 20 was prepared in one step from
keto acid 18 by reductive amination using ammonia as the
nitrogen source (Scheme 7).[26] Amino acid 20 was obtained
in 76% yield as a 35:65 mixture of diastereomers. With the
aim of determining the configuration of both isomers and
of separating them, the mixture of amino acids 20 was
treated with methanesulfonyl chloride in the presence of
NaHCO3.[27] Unfortunately, lactam 21 from the cyclocon-
densation of the major diastereomer c-20 (amino and carb-
oxy groups in a cis relationship) was the only product that
could be isolated (40% yield). A complex mixture was de-
tected in the aqueous layer by 19F NMR, which probably
results from the degradation of the amino acid t-20. Open-
ing of lactam 21 under acidic conditions afforded the pure
amino acid c-20 (Scheme 7).
Scheme 8. Synthesis and separation of N-benzyl γ-amino acids 24.
Conclusions
We have reported the high-yielding synthesis of a promis-
ing new building block, 1-(trifluoromethyl)cyclopent-3-en-
ecarboxylic acid (and its esters), from commercially avail-
able trifluoropropanoic derivatives. This building block ex-
hibits high synthetic potential due to the reaction diversity
offered by the double bond and the carboxylic function. It
was epoxidized in high yield and with good facial selectiv-
ity, giving the epoxide in a trans relationship with respect
to the trifluoromethyl group. The hydroboration/oxidation
Scheme 7. Synthesis of γ-amino acids 20.
and reductive amination reactions were poorly diastereo-
selective. The cis and trans isomers of the γ-hydroxy and γ-
amino acids were distinguished by preparing the corre-
sponding lactone and lactam, respectively. The latter are
themselves interesting intermediates for further chemical
transformations.
This exploratory study opens the way to non-natural,
conformationally restrained trifluoromethyl γ-amino acids,
We then considered the N-benzyl amino acid series in
order to have access to both isolated diastereomers. Direct
reductive amination of the keto acid 18 failed. The latter
was converted into its methyl ester 22 (81% yield), the re-
ductive amination[28] of which led to the corresponding N-
benzyl ester 23 (93% yield, 60:40 mixture of inseparable
diastereomers; Scheme 8). A similar methodology was
which are currently being studied.
adopted to attempt a separation by lactamization. Its appli-
cation to the amino ester 23 proved difficult.[29] Therefore
Experimental Section
23 was saponified (90% yield) and the resulting N-benzyl
General: THF was distilled from sodium benzophenone. DCM was
amino acid 24 was treated with thionyl chloride
distilled from CaH2. Benzyl alcohol was distilled from magnesium.
(Scheme 7).[30] The recovered major isomer t-24 (51% yield)
Benzyl 2,2-diallyl-3,3,3-trifluorodithiopropanoate (2) was prepared
and the N-benzyl lactam 25 (28% yield) were separated.
Hydrolysis of 25 under harsh acidic conditions or with con-
centrated aqueous sodium hydroxide failed. Finally, 25 was
as described previously.[5] 3,3,3-Trifluoropropionic acid (5) was pro-
duced by the Central Glass company. Benzyl 3,3,3-trifluoropro-
panoate (10) was prepared from 5 under classical conditions
converted into the N-benzyl amino acid c-24 by heating (BnOH in the presence of DCC and DMAP). Other reagents and
512
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 509–517

Trifluoromethylcyclopentenecarboxylic Acid Derivatives
solvents were obtained from common commercial sources and used
as received. Thin-layer chromatography using precoated alumin-
ium-backed plates (Merck Kieselgel 60F254) were visualized by
UV light and/or by a solution of potassium permanganate, phos-
phomolybdic acid or ninhydrin. Silica gel 70–230 μm (Merck) was
used for filtration. Silica gel 40–63 μm (Merck or Macherey–Nagel
GmbH & Co. KG) was used for flash chromatography. NMR spec-
tra were recorded with 250, 500 or 600 MHz spectrometers. Chemi-
= 30 °C). The solution of the diallyl allyl ester 9 in THF was then
added to a solution of 1 m KOH in EtOH (34 mL, 34.0 mmol,
5 equiv.) and the reaction was heated at reflux for 1 h 40 min. The
reaction mixture was cooled to room temp. and partially concen-
trated under reduced pressure. The residue was poured into water
and extracted twice with CH2Cl2. The aqueous layer was acidified
with 4 m HCl until pH = 1 and extracted twice with CH2Cl2. The
organic layer was dried (MgSO4), filtered and concentrated under
reduced pressure to afford the acid 8 (992 mg, 71%) as a colourless
1
cals shifts (δ) are reported in ppm relative to TMS for H and 13C
NMR spectra and relative to CFCl3 for 19F NMR spectra. In the
13C NMR spectroscopic data, reported signal multiplicities relate
to C–F coupling. The following abbreviations are used to indicate
the multiplicities: s (singlet), d (doublet), t (triplet), q (quartet),
quint. (quintet), m (multiplet), br. s (broad singlet). Diastereomeric
ratios (dr) were determined by 19F NMR spectroscopy. HRMS
were recorded with an ESI-Q-TOF mass spectrometer using an
electrospray source in positive or negative mode.
oil. IR (film): νmax = 3087, 2989, 1722, 1226, 1183, 1138, 926 cm–1.
˜
1
19F NMR (235 MHz, CDCl3): δ = –68.6 (s, CF3) ppm. H NMR
(250 MHz, CDCl3): δ = 2.63 (d, J = 7.5 Hz, 4 H), 5.17 (d, J =
9.5 Hz, 2 H), 5.21 (d, J = 17.0 Hz, 2 H), 5.78 (m, 2 H), 9.27 (br. s,
1 H) ppm. 13C NMR (63 MHz, CDCl3): δ = 36.1, 56.0 (q, J =
23.5 Hz), 119.8, 125.8 (q, J = 285.0 Hz), 131.2, 175.4 ppm. HRMS:
calcd. for C9H10O2F3 [M – H]– 207.0633; found 207.0640.
Benzyl 2-Allyl-2-trifluoromethylpent-4-enoate (11): A solution of
benzyl 3,3,3-trifluoropropanoate (10) (10.0 g, 45.8 mmol) and allyl
ethyl carbonate (18.2 mL, 137.5 mmol, 3 equiv.) in THF (450 mL)
Benzyl 1-Trifluoromethylcyclopent-3-enecarbodithiocarboxylate (3):
A solution of benzyl 2,2-diallyl-3,3,3-trifluorodithiopropanoate (2)
(1.93 g, 5.84 mmol) and Grubbs’ II catalyst (248 mg, 0.29 mmol, was added to
a solution of Pd(OAc)2 (411 mg, 1.8 mmol,
0.05 equiv.) in dichloromethane (19.5 mL) was stirred at reflux un-
der Ar for 45 min. An additional portion of Grubbs’ II catalyst
(248 mg, 0.29 mmol, 0.05 equiv.) was then added to the reaction
mixture. After stirring for 1 h 30 min, the reaction mixture was co-
oled to room temp. and then filtered through a pad of silica gel
(CH2Cl2). The filtrate was concentrated under reduced pressure
and the residue was purified by chromatography on silica gel (pen-
tane) to give the dithioester 3 (1.76 g, 100%) as an orange liquid.
0.04 equiv.) and 1,2-bis(diphenylphosphanyl)ethane (dppe; 2.2 g,
5.5 mmol, 0.12 equiv.) in THF (50 mL) heated at reflux under Ar.
After stirring for 16 h at reflux, the reaction mixture was cooled to
room temp. and concentrated under reduced pressure. Chromatog-
raphy of the residue on silica gel (PE/CH2Cl2, 4:1) afforded the
benzyl ester 11 (11.9 g, 87%) as a colourless oil. IR (film): ν
=
˜
max
1742, 1455, 1228, 1177, 696 cm–1. 19F NMR (235 MHz, CDCl3): δ
= –68.5 (s, CF3) ppm. 1H NMR (250 MHz, CDCl3): δ = 2.61 (d, J
19F NMR (235 MHz, CDCl3) δ = –73.8 (s, CF3) ppm. 1H NMR = 7.0 Hz, 4 H), 5.10 (d, J = 11.0 Hz, 2 H), 5.11 (d, J = 16.0 Hz, 2
(250 MHz, CDCl3): δ = 3.12 (dd, J = 2.0, 17.5 Hz, 2 H), 3.53 (d,
J = 16.0 Hz, 2 H), 4.42 (s, 2 H), 5.65 (s, 2 H), 7.32 (m, 5 H) ppm.
13C NMR (63 MHz, CDCl3): δ = 42.3 (d, J = 1.0 Hz), 43.2, 68.9
(q, J = 24.0 Hz), 125.6 (q, J = 285.0 Hz), 127.7, 127.9, 128.7, 129.3,
133.9, 232.5 ppm.
H), 5.20 (s, 2 H), 5.73 (m, 2 H), 7.36 (s, 5 H) ppm. 13C NMR
(63 MHz, CDCl3): δ = 36.2, 55.9 (q, J = 25.0 Hz), 67.4, 119.6,
126.0 (q, J = 284.5 Hz), 128.2, 128.3, 128.6, 128.7, 131.4, 135.0,
168.3 ppm. HRMS: calcd. for C16H17F3NaO2 [M + Na]+ 321.1078;
found 321.1089.
2-Allyl-2-trifluoromethylpent-4-enoic Acid (8)[31]
1-Trifluoromethylcyclopent-3-enecarboxylic Acid (4)
Preparation from Methyl 3,3,3-Trifluoropropanoate (6): A solution
of methyl 3,3,3-trifluoropropanoate (6) (2.2 g, 15.0 mmol) and allyl
ethyl carbonate (5.91 g, 45.0 mmol, 3 equiv.) in THF (90 mL) was
added to a solution of Pd(OAc)2 (137 mg, 0.6 mmol, 0.04 equiv.)
and 1,2-bis(diphenylphosphanyl)ethane (dppe; 718 mg, 1.8 mmol,
0.12 equiv.) in THF (60 mL) at reflux under Ar. After 2 h of stirring
at reflux (reaction monitored by 19F NMR), the reaction mixture
was cooled to room temp., filtered through a pad of silica gel (pen-
tane) and the pentane was carefully evaporated under reduced pres-
sure (600 mbar, Tbath = 30 °C). The solution of the diallyl methyl
ester in THF was then added to a 1 m solution of KOH in EtOH
(75 mL, 75.0 mmol, 5 equiv.) and the reaction was heated at reflux
for 24 h. The reaction mixture was then cooled to room temp. and
concentrated under reduced pressure. The residue was poured into
water and extracted twice with CH2Cl2. The aqueous layer was
acidified until pH = 1 with 1 m HCl and extracted twice with
CH2Cl2. The organic layer was dried (MgSO4), filtered and concen-
trated under reduced pressure to afford the acid 8 (2.9 g, 93%) as
a colourless oil.
Preparation from Dithioester 3: Hydrogen peroxide (35% aq. sol.,
500 μL) and sodium hydroxide (12.5% aq. sol., 500 μL) were added
dropwise to a solution of dithioester 3 (99 mg, 0.33 mmol) in meth-
anol (5 mL) at room temp. The reaction mixture was vigorously
stirred for 5 min before CH2Cl2 and H2O were added. The aqueous
layer was separated, extracted twice with CH2Cl2 and then acidified
with 10% HCl. The aqueous layer was extracted thrice with
CH2Cl2. These three organic layers were combined, dried (MgSO4),
filtered and concentrated under reduced pressure to afford the acid
4 (59 mg, 100%) as a colourless liquid.
Preparation by Ring-Closing Metathesis of Diallyl Acid 8: A solu-
tion of the diallyl acid 8 (587 mg, 2.82 mmol) and Grubbs’ I cata-
lyst (116 mg, 0.14 mmol, 0.05 equiv.) in dichloromethane (30 mL)
was stirred at room temp. under Ar for 2 h. The reaction mixture
was then diluted with CH2Cl2 and extracted with 1 m NaOH. The
aqueous layer was extracted with CH2Cl2, acidified with 2 m HCl
until pH = 1 and extracted twice with CH2Cl2. These organic layers
were combined, dried (MgSO4), filtered and concentrated under
reduced pressure to give the acid 4 (445 mg, 88%) as a colourless
Preparation from 3,3,3-Trifluoropropionic Acid (5): A solution of
3,3,3-trifluoropropionic acid (5) (865 mg, 6.76 mmol), allyl ethyl
carbonate (3.96 g, 30.4 mmol, 4.5 equiv.), [Pd2(dba)3]·CHCl3
(140 mg, 0.135 mmol, 0.02 equiv.) in THF (35 mL) was heated at
reflux for 15 h. The reaction mixture was then cooled to room
temp., filtered through a pad of silica gel (pentane) and the pentane
was carefully evaporated under reduced pressure (600 mbar, Tbath
liquid. IR (film): ν
= 3074, 2940, 1720, 1289, 1168 cm–1. 19F
max
˜
NMR (235 MHz, CDCl3): δ = –73.5 (s, CF3) ppm. 1H NMR
(250 MHz, CDCl3): δ = 2.91 (d, J = 16.0 Hz, 2 H), 3.08 (d, J =
15.0 Hz, 2 H), 5.66 (s, 2 H) ppm; the OH signal was not detected.
13C NMR (63 MHz, CDCl3): δ = 39.0 (d, J = 1.5 Hz), 56.9 (q, J =
26.5 Hz), 126.2 (q, J = 280.5 Hz), 127.6, 177.1 ppm. HRMS: calcd.
for C7H7F3NaO2 [M + Na]+ 203.0288; found 203.0296.
Eur. J. Org. Chem. 2012, 509–517
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
513

F. Grellepois, V. Kikelj, N. Coia, C. Portella
FULL PAPER
Benzyl 1-Trifluoromethylcyclopent-3-enecarboxylate (12): A solu-
tion of benzyl ester 11 (597 mg, 2.0 mmol) and Grubbs’ I catalyst
(8.3 mg, 0.01 mmol, 0.005 equiv.) in dichloromethane (20 mL) was
stirred at room temp. under Ar for 2 h. The reaction mixture was
then concentrated under reduced pressure and the residue was puri-
fied by chromatography on silica gel (PE/CH2Cl2, 11:1) to give the
HRMS: calcd. for C14H13F3NaO3 [M + Na]+ 309.0714; found
309.0721.
Benzyl 3-Hydroxy-1-(trifluoromethyl)cyclopentanecarboxylate (15):
BH3·Me2S (2 m sol. in THF, 2.59 mL, 5.17 mmol, 1.4 equiv.) was
added slowly at –78 °C under Ar to a solution of cyclopentene ester
12 (1.0 g, 3.69 mmol) in THF (20 mL). The reaction mixture was
stirred for 30 min at this temperature and then for 39 h at –10 °C.
The reaction mixture was then carefully hydrolysed with H2O
(4 mL) at 0 °C. After stirring for 5 min, 30% H2O2 (1.43 mL,
12.5 mmol, 3.4 equiv.) and 1 m NaOH (4.06 mL, 4.06 mmol,
1.1 equiv.) were added to the reaction mixture. After stirring for
10 min, the reaction mixture was extracted thrice with Et2O. The
organic layer was washed with brine, a satd. aq. sol. of sodium
thiosulfate (until no peroxides could be detected by the peroxide
test) and brine, dried (MgSO4), filtered and concentrated under
reduced pressure. Chromatography of the residue on silica gel (PE/
EtOAc, 9:1 containing 0.1% of Et3N) afforded the γ-hydroxy ester
15 (800 mg, 75%) as a colourless oil (44:56 mixture of dia-
ester 12 (541 mg, 99%) as a colourless liquid. IR (film): ν
=
˜
max
1743, 1274, 1173 cm–1. 19F NMR (235 MHz, CDCl3): δ = –73.2 (s,
1
CF3) ppm. H NMR (250 MHz, CDCl3): δ = 2.89 (d, J = 16.0 Hz,
2 H), 3.09 (d, J = 16.0 Hz, 2 H), 5.24 (s, 2 H), 5.65 (m, 2 H), 7.37
(m, 5 H) ppm. 13C NMR (63 MHz, CDCl3): δ = 38.7 (d, J =
1.5 Hz), 57.0 (q, J = 26.0 Hz), 67.5, 126.3 (q, J = 280.5 Hz), 127.6,
127.8, 128.3, 128.5, 135.2, 169.9 ppm. HRMS: calcd. for
C14H13F3NaO2 [M + Na]+ 293.0765; found 293.0757.
6-Iodo-4-trifluoromethyl-2-oxabicyclo[2.2.1]heptan-3-one (14):
A
solution of acid 4 (101 mg, 0.51 mmol) and sodium hydrogen carb-
onate (214 mg, 2.55 mmol, 5 equiv.) in a mixture of THF (3 mL)
and H2O (3 mL) was stirred for 5 min at room temp. Potassium
iodide (85 mg, 0.51 mmol, 1 equiv.) and iodine (777 mg, 3.06 mmol,
6 equiv.) were then added. After stirring for 72 h, the reaction mix-
ture was partitioned between Et2O and water. The aqueous layer
was separated, acidified with 4 m HCl and extracted twice with
CH2Cl2. This organic layer was washed with brine, dried (MgSO4),
filtered and concentrated under reduced pressure to afford the
starting acid 4 (23 mg, 23%). The ethereal layer was washed with
a satd. aq. sol. of Na2S2O3 and brine, dried (MgSO4), filtered and
concentrated under reduced pressure to give the iodolactone 14
(94 mg, 60%) as a pale-yellow amorphous solid; m.p. 95–96 °C. IR
stereomers according to 19F NMR). IR (film): ν
= 3384, 2958,
˜
max
1740, 1274, 1172 cm–1. 19F NMR (235 MHz, CDCl3): δ = –71.7
1
(s, CF3, minor), –72.3 (s, CF3, major) ppm. H NMR (500 MHz,
CDCl3): δ = 1.75 (m, 1 H, minor), 1.82 (m, 1 H, major), 1.90 (m,
1 H), 2.00 (dd, J = 5.0, 13.5 Hz, 1 H, minor), 2.15 (m, 1 H, major),
2.22 (dd, J = 5.0, 14.5 Hz, 1 H, major), 2.28 (m, 2 H, minor), 2.40
(d, J = 14.5 Hz, 1 H, major), 2.53 (dt, J = 8.5, 15.0 Hz, 1 H, major),
2.64 (dd, J = 6.5, 14.5 Hz, 1 H, minor), 4.39 (m, 1 H), 5.20 (s, 2
H, minor), 5.24 (s, 2 H, major), 7.37 (m, 5 H) ppm; the OH signal
was not detected. 13C NMR (126 MHz, CDCl3): δ = 29.3, 34.6
(minor), 34.9 (major), 40.1 (minor), 40.6 (major), 57.6 (q, J =
26.5 Hz, minor), 57.8 (q, J = 26.0 Hz, major), 67.7 (minor), 67.9
(major), 72.4 (minor), 73.0 (major), 126.1 (q, J = 280.5 Hz, minor),
126.6 (q, J = 281.0 Hz, major), 127.8, 128.3 (major), 128.4 (minor),
128.5 (major), 128.6 (minor), 135.0 (major), 135.1 (minor), 170.2
(d, J = 1.5 Hz, minor), 171.0 (d, J = 1.5 Hz, major) ppm. HRMS:
calcd. for C14H15F3NaO3 [M + Na]+ 311.0871; found 311.0878.
(KBr): ν
= 1797, 1383, 1204, 1176, 1052, 1022, 912 cm–1. 19F
˜
max
NMR (235 MHz, CDCl3): δ = –71.1 (s, CF3) ppm. 1H NMR
(250 MHz, CDCl3): δ = 2.59 (dd, J = 4.0, 14.0 Hz, 2 H), 2.79 (m,
2 H), 4.19 (br. s, 1 H), 5.01 (s, 1 H) ppm. 13C NMR (63 MHz,
CDCl3): δ = 13.6, 36.4, 37.7, 55.9 (q, J = 32.0 Hz), 83.5, 123.1 (q,
J = 276.0 Hz), 169.0 ppm. C7H6F3IO2 (306.02): calcd. C 27.47, H
1.98; found C 27.57, H 2.41.
Preparation of γ-Hydroxy Esters 16 and Lactone 17: A solution of
hydroxy ester 15 (86 mg, 0.30 mmol), 10% Pd/C (16 mg,
0.015 mmol, 0.05 equiv.) and 1,4-cyclohexadiene (282 μL,
2.98 mmol, 10 equiv.) in absolute ethanol (3 mL) was stirred at
room temp. under Ar for 16 h. The suspension was then filtered
through Celite and the filtrate was concentrated under reduced
pressure. The residue was then diluted with CH2Cl2 and washed
twice with a satd. aq. sol. of NaHCO3. The aqueous layer was
carefully acidified with 10% HCl until pH = 1 and extracted once
with CH2Cl2 (to remove impurities) and twice with AcOEt. The
AcOEt layers were collected, dried (MgSO4), filtered and concen-
trated under reduced pressure to give the hydroxy acid 16 (45 mg,
76%) as a white solid as a 41:59 mixture of diastereomers. 19F
NMR (235 MHz, CD3CN): δ = –72.6 (s, CF3, minor), –73.7 (s,
CF3, major) ppm.
Benzyl c-3,c-4-Epoxy-1-(trifluoromethyl)cyclopentane-r-1-carboxyl-
ate (13)
Preparation by Epoxidation of Cyclopentene 12: m-Chloroper-
benzoic acid (284 mg, 1.15 mmol, 1.4 equiv.) was added in two por-
tions over 1 h to a solution of cyclopentene 12 (223 mg, 0.82 mmol)
in dichloromethane (10 mL) at room temp. After stirring for 24 h,
the reaction mixture was diluted with CH2Cl2 and washed with
H2O, a satd. aq. sol. of NaHCO3 and H2O. The organic layer was
dried (MgSO4), filtered and concentrated under reduced pressure.
Chromatography of the residue on silica gel (PE/EtOAc, 9:1) af-
forded the epoxide 13 (192 mg, 81%) as a colourless oil.
Preparation by Ring-Opening of the Iodolactone 14: A solution of
sodium benzylate in benzyl alcohol, prepared by treating sodium
(6 mg, 0.258 mmol, 1.2 equiv.) with benzyl alcohol (2 mL), was
added at 0 °C under Ar to the iodolactone 14 (66 mg, 0.215 mmol).
After stirring for 5 h, the reaction mixture was diluted with CH2Cl2
and washed twice with satd. aq. NH4Cl. The organic layer was
extracted, dried (MgSO4), filtered and concentrated under reduced
pressure. The residue was purified twice by chromatography on sil-
ica gel (PE/CH2Cl2, 9:1) to afford the epoxide 13 (58 mg, 94%) as
A solution of hydroxy acid 16 (102 mg, 0.515 mmol) and p-tolu-
enesulfonic acid monohydrate (5 mg, 0.026 mmol, 0.05 equiv.) in
chloroform (5 mL) was heated at reflux with a Dean–Stark appara-
tus for 8 h. The reaction mixture was then cooled to room temp.,
diluted with CH2Cl2 and washed thrice with H2O. The aqueous
layer was acidified with 10% HCl until pH = 1 and extracted with
AcOEt. This organic layer was washed with brine, dried (MgSO4),
a colourless oil. IR (film): νmax = 1743, 1278, 1183, 1085 cm–1. 19
F
˜
NMR (235 MHz, CDCl3): δ = –70.6 (s, CF3) ppm. 1H NMR filtered and concentrated under reduced pressure to afford the hy-
(250 MHz, CDCl3): δ = 2.09 (d, J = 14.5 Hz, 2 H), 3.09 (d, J =
14.5 Hz, 2 H), 3.55 (s, 2 H), 5.22 (s, 2 H), 7.36 (s, 5 H) ppm. 13C
NMR (63 MHz, CDCl3): δ = 32.5, 54.5 (q, J = 27.0 Hz), 54.9,
67.9, 125.5 (q, J = 281.0 Hz), 127.8, 128.2, 128.4, 135.2, 168.3 ppm.
droxy acid t-16 (31 mg, 30%) as a colourless oil. The CH2Cl2 layer
was dried (MgSO4), filtered and concentrated under reduced pres-
sure. Chromatography of the residue on silica gel (PE/CH2Cl2 from
100:0 to 0:100) afforded the lactone 17 (45 mg, 49%) as a colourless
514
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 509–517

Trifluoromethylcyclopentenecarboxylic Acid Derivatives
oil. Compound 17 was also prepared by stirring a solution of acid
4 (164 mg, 0.827 mmol) and trifluoromethanesulfonic acid (18 μL,
0.207 mmol, 0.25 equiv.) in CH2Cl2 (2 mL) for 3 h 30 min at room
temp. under Ar. The reaction mixture was diluted with CH2Cl2,
washed with H2O, a satd. aq. sol. of NaHCO3 and brine, dried
(MgSO4), filtered and concentrated under reduced pressure.
Chromatography of the residue on silica gel (PE/CH2Cl2 from
100:0 to 0:100) afforded the lactone 17 (84 mg, 56%).
Benzyl 3-Oxo-1-(trifluoromethyl)cyclopentanecarboxylate (19)[31]
Preparation by Esterification of Acid 18: A solution of keto acid
18 (1 g, 5.1 mmol), benzyl bromide (671 μL, 5.6 mmol, 1.1 equiv.),
sodium iodide (38 mg, 0.25 mmol, 0.05 equiv.) and caesium car-
bonate (1.66 g, 5.1 mmol, 1 equiv.) in acetone (50 mL) was stirred
at room temp. for 24 h. After concentration of the reaction mixture
under reduced pressure the residue was purified by chromatography
on silica gel (PE/Et2O, 4:1) to afford the ester 19 (1.39 g, 95%) as
a colourless liquid.
A solution of lactone 17 (36 mg, 0.20 mmol) and lithium hydroxide
monohydrate (25 mg, 0.60 mmol, 3 equiv.) in a mixture of THF
(750 μL) and water (500 μL) was stirred for 2 h 30 min at room
temp. and the reaction mixture was concentrated under reduced
pressure. The residue was diluted with H2O, acidified with 10%
HCl until pH = 1 and extracted thrice with AcOEt. The organic
layers were dried (MgSO4), filtered and concentrated under re-
duced pressure to afford the hydroxy acid c-16 (34.4 mg, 87%) as
a white amorphous solid.
Preparation by Oxidation of Hydroxy Ester 15: DMSO (558 μL,
7.86 mmol, 6 equiv.) was added dropwise to a stirred solution of
oxalyl chloride (332 μL, 3.93 mmol, 3 equiv.) in dichloromethane
(6 mL) at –78 °C and under Ar. After being stirred for 15 min, a
solution of the hydroxy ester 15 (378 mg, 1.31 mmol) in dichloro-
methane (3 mL) was added dropwise to the reaction mixture. The
reaction was stirred at –78 °C for 1 h and triethylamine (1.22 mL,
13.1 mmol, 10 equiv.) was added. The reaction mixture was stirred
for 15 min before the cold bath was removed and the mixture was
left to warm to room temp. The mixture was poured into satd. aq.
NaHCO3 and extracted twice with CH2Cl2. The combined organic
layers were washed with water and brine, dried (MgSO4), filtered
and concentrated under reduced pressure. Chromatography of the
residue on silica gel (PE/CH2Cl2 from 3:2 to 1:1) afforded the keto
t-3-Hydroxy-1-(trifluoromethyl)cyclopentane-r-1-carboxylic Acid (t-
16): IR (KBr): ν
= 3474, 2990, 1722, 1153 cm–1. 19F NMR
˜
max
1
(235 MHz, CD3CN): δ = –72.6 (s, CF3) ppm. H NMR (250 MHz,
CD3CN): δ = 1.66 (m, 1 H), 1.86 (m, 2 H), 2.18 (t, J = 7.5 Hz, 2
H), 2.64 (dd, J = 6.0, 14.0 Hz, 1 H), 4.29 (quint., J = 5.5 Hz, 1 H),
5.20 (br. s, 1 H) ppm; the OH signal was not detected. 13C NMR
(63 MHz, CD3CN): δ = 30.1, 35.3, 40.8, 58.0 (q, J = 26.0 Hz), 72.7,
ester 19 (281 mg, 75%) as a colourless liquid. IR (film): ν
=
˜
max
1753, 1162 cm–1. 19F NMR (235 MHz, CDCl3): δ = –72.4 (s,
127.8 (q,
J = 279.5 Hz), 172.3 ppm. HRMS: calcd. for
1
CF3) ppm. H NMR (250 MHz, CDCl3): δ = 2.43 (m, 4 H), 2.63
C7H9F3NaO3 [M + Na]+ 221.0401; found 221.0410.
(d, J = 18.5 Hz, 1 H), 2.91 (d, J = 18.5 Hz, 1 H), 5.25 (s, 2 H),
7.29–7.42 (m, 5 H) ppm. 13C NMR (63 MHz, CDCl3): δ = 27.3 (q,
J = 2.0 Hz), 35.9, 42.3 (q, J = 1.0 Hz), 55.4 (q, J = 27.5 Hz), 68.2,
125.5 (q, J = 281.0 Hz), 127.8, 128.7, 134.4, 168.6, 212.1 ppm.
HRMS: calcd. for C14H13F3NaO3 [M + Na]+ 309.0713; found
309.0714.
4-Trifluoromethyl-2-oxabicyclo[2.2.1]heptan-3-one (17): IR (film): ν
˜
= 1793, 1386, 1153 cm–1. 19F NMR (235 MHz, CDCl3): δ = –71.3
(s, CF3) ppm. 1H NMR (250 MHz, CDCl3): δ = 1.94–2.25 (m, 5
H), 2.43 (dd, J = 2.0, 10.5 Hz, 1 H), 4.97 (s, 1 H) ppm. 13C NMR
(63 MHz, CDCl3): δ = 23.6, 29.0, 40.6, 54.9 (q, J = 31.5 Hz), 79.3,
124.3 (q,
J = 285.5 Hz), 170.7 ppm. HRMS: calcd. for
3-Amino-1-(trifluoromethyl)cyclopentanecarboxylic Acid Hydro-
chloride (20): Sodium cyanoborohydride (388 mg, 6.17 mmol,
3 equiv.) and 28% aq. NH3 (16 mL) were added to keto acid 18
(403 mg, 2.06 mmol) in a saturated solution of ammonium acetate
in EtOH (40 mL). The reaction mixture was stirred at reflux for
28 h, cooled to room temp. and then concentrated under reduced
pressure. The residue was dissolved in H2O, loaded onto Dowex
50WX8 H+ ion-exchange resin (40 g) and washed several times with
H2O to remove excess salt. The amine was then eluted with 15%
aq. NH3, concentrated under reduced pressure and lyophilized. The
residue was treated with 1 m HCl and lyophilized to afford the
amine hydrochloride 20 (364.5 mg, 76%) as a white amorphous
solid (35:65 mixture of two diastereomers according to 19F NMR).
C7H7F3NaO2 [M + Na]+ 203.0296; found 203.0293.
c-3-Hydroxy-1-(trifluoromethyl)cyclopentane-r-1-carboxylic Acid (c-
16): M.p. 118–119 °C. IR (KBr): ν
= 3450, 2969, 1715,
˜
max
1148 cm–1. 19F NMR (235 MHz, CD3CN): δ = –73.7 (s, CF3) ppm.
1H NMR (250 MHz, CD3CN): δ = 2.02 (m, 2 H), 2.23–2.55 (m, 3
H), 2.65 (m, 1 H), 4.42 (br. s, 2 H), 4.56 (br. s, 1 H) ppm. 13C NMR
(63 MHz, CD3CN): δ = 29.9, 35.5, 40.8, 58.2 (q, J = 25.5 Hz), 73.7,
128.1 (q,
J = 281.0 Hz), 171.8 ppm. HRMS: calcd. for
C7H9F3NaO3 [M + Na]+ 221.0401; found 221.0392.
3-Oxo-1-(trifluoromethyl)cyclopentanecarboxylic Acid (18):[31]
A
mixture of acid 4 (3.29 g, 18.3 mmol), molybdovanadophosphate
{NPMoV, 852 mg, 6.5ϫmTotal[Pd(OAc)2]}, methanesulfonic acid
(118 μL, 1.82 mmol, 0.10 equiv.) and Pd(OAc)2 (66 mg, 0.29 mmol,
0.016 equiv.) in MeCN (56 mL) and H2O (14 mL) was stirred at
50 °C under O2. After 8 h of reaction, an additional portion of
Pd(OAc)2 (66 mg, 0.29 mmol, 0.016 equiv.) was added to the reac-
tion mixture. After 8 h of additional stirring, the reaction mixture
was cooled to room temp., poured into 1 m HCl and extracted with
Et2O. The organic layer was dried (MgSO4), filtered and concen-
trated under reduced pressure. The residue was filtered through a
short pad of silica gel (CH2Cl2) to give the ketone 18 (3.06 g, 85%)
IR (KBr): ν
= 3026, 1721, 1161 cm–1. 19F NMR (235 MHz,
˜
max
1
CDCl3): δ = –72.7 (s, CF3, minor), –73.0 (s, CF3, major) ppm. H
NMR (500 MHz, D2O): δ = 1.92 (m, 1 H), 2.12 (dd, J = 9.0,
14.0 Hz, 1 H, minor), 2.20–2.45 (m, 4 H), 2.62 (dd, J = 8.0,
15.0 Hz, 1 H, major), 2.82 (dd, J = 7.5, 15.0 Hz, 1 H, major), 3.88
+
(quint., J = 7.5 Hz, 1 H) ppm; OH and NH3 were not detected.
13C NMR (63 MHz, D2O): δ = 29.8, 30.1, 30.6, 35.7 (minor), 35.8
(major), 51.3 (minor), 51.9 (major), 57.7 (q, J = 26.5 Hz), 126.5 (q,
J = 280.0 Hz, minor), 126.6 (q, J = 280.0 Hz, major), 173.6
(minor), 174.3 (major) ppm. HRMS: calcd. for C7H11F3NO2 [M +
H]+ 198.0742; found 198.0745.
as a pale-yellow oil. IR (film): ν
= 2938, 1747, 1169 cm–1. 19F
˜
max
NMR (235 MHz, CDCl3): δ = –72.8 (s, CF3) ppm. 1H NMR 4-(Trifluoromethyl)-2-azabicyclo[2.2.1]heptan-3-one (21): A suspen-
(250 MHz, CDCl3): δ = 2.50 (m, 4 H), 2.67 (d, J = 19.0 Hz, 1 H),
sion of sodium hydrogen carbonate (225 mg, 2.68 mmol, 5 equiv.)
in acetonitrile (5 mL) was heated for 10 min at 80 °C. Methanesulf-
2.93 (d, J = 19.0 Hz, 1 H), 7.55 (br. s, 1 H) ppm. 13C NMR
(63 MHz, CDCl3): δ = 27.2, 35.9, 42.3, 55.1 (q, J = 28.0 Hz), 125.3 onyl chloride (124 μL, 1.61 mmol, 3 equiv.) was then added fol-
(q, J = 281.0 Hz), 173.1, 213.8 ppm. HRMS: calcd. for C7H6F3O3
lowed by the portionwise addition of amino acid 20 (125 mg,
0.535 mmol). After stirring for 3 h at 80 °C, the reaction mixture
[M – H]– 195.0269; found 195.0275.
Eur. J. Org. Chem. 2012, 509–517
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
515

F. Grellepois, V. Kikelj, N. Coia, C. Portella
FULL PAPER
was cooled to room temp. and partitioned between CHCl3 and
H2O. The aqueous layer was extracted thrice with CHCl3. The or-
ganic layers were combined, dried (MgSO4), filtered and concen-
trated under reduced pressure. Chromatography of the residue on
silica gel (CH2Cl2/MeOH, 15:1) afforded the lactam 21 (38 mg,
(m, 1 H, minor), 1.84 (dd, J = 9.0, 13.5 Hz, 1 H, major), 1.96 (m,
1 H, minor), 2.06 (m, 2 H), 2.20 (dd, J = 6.0, 14.0 Hz, 1 H, minor),
2.27 (m, 1 H, major), 2.38 (dd, J = 4.5, 14.0 Hz, 1 H, minor), 2.57
(quint., J = 7.5 Hz, 1 H, minor), 2.66 (dd, J = 6.5, 13.5 Hz, 1 H,
major), 3.32 (m, 1 H), 3.70–3.82 (m, 5 H), 7.25–7.37 (m, 5 H) ppm;
the NH signal was not detected. 13C NMR (63 MHz, CDCl3): δ =
29.1 (minor), 29.4 (major), 32.3 (minor), 32.5 (major), 37.7 (minor),
40%) as a white amorphous solid; m.p. 95–96 °C. IR (KBr): ν
˜
max
= 3291, 1722, 1683, 1657, 1180, 1138, 1051 cm–1. 19F NMR
1
(235 MHz, CDCl3): δ = –70.9 (s, CF3) ppm. H NMR (250 MHz, 38.3 (major), 51.9 (minor), 52.6 (major), 52.9, 57.3 (q, J = 26.5 Hz),
CDCl3): δ = 1.65–1.90 (m, 3 H), 1.95–2.15 (m, 3 H), 3.93 (br. s, 1 58.3 (major), 58.4 (minor), 126.3 (q, J = 280.5 Hz, major), 126.6
H), 7.56 (br. s, 1 H) ppm. 13C NMR (63 MHz, CDCl3): δ = 24.1,
31.0, 42.0, 53.7, 56.7 (q, J = 30.0 Hz), 125.3 (q, J = 275.5 Hz),
174.3 ppm. HRMS: calcd. for C7H9F3NO [M + H]+ 180.0636;
found 180.0642.
(q, J = 281.0 Hz, minor), 126.85 (minor), 126.94 (major), 127.9
(minor), 128.0 (major), 128.28 (minor), 128.33 (major), 140.1
(major), 140.2 (minor), 170.9 ppm. HRMS: calcd. for
C15H19F3NO2 [M + H]+ 302.1368; found 302.1381.
Preparation of γ-N-Benzyl Amino Acid Hydrochlorides 24 and
Lactam 25: A solution of N-benzyl ester 23 (154.5 mg, 0.513 mmol)
and 1 m NaOH (2.6 mL, 2.6 mmol, 5 equiv.) in ethanol (6.5 mL)
was stirred for 5 min at 0 °C and for 15 h at room temp. The reac-
tion mixture was then acidified with 4 m HCl until pH = 1 and
concentrated under reduced pressure. The residue was dissolved in
H2O, loaded onto Dowex 50WX8 H+ ion-exchange resin (15 g) and
washed several times with H2O. The amine was then eluted with
15% aq. NH3, concentrated under reduced pressure and lyophi-
lized. The residue was treated with 1 m HCl and lyophilized to af-
ford the N-benzyl amino acid hydrochloride 24 (149 mg, 90%) as
a white amorphous solid as a 70:30 mixture of diastereomers. 19F
NMR (235 MHz, D2O): δ = –72.7 (s, CF3, major), –73.0 (s, CF3,
minor) ppm.
c-3-Amino-1-(trifluoromethyl)cyclopentane-r-1-carboxylic Acid Hy-
drochloride (c-20): A solution of lactam 21 (18.5 mg, 0.103 mmol)
in a mixture of THF (200 μL) and 4 m HCl (300 μL) was heated at
reflux for 18 h. The mixture was then cooled to room temp. and
concentrated under reduced pressure. The residue was dissolved in
H2O, loaded onto Dowex 50WX8 H+ ion-exchange resin (2 g) and
washed several times with H2O. The amino acid was then eluted
with 15% aq. NH3, concentrated under reduced pressure and lyo-
philized. The residue was treated with 1 m HCl and lyophilized to
afford the amino acid hydrochloride c-20 (20 mg, 83%) as a white
amorphous solid. IR (KBr): ν
= 3129, 3052, 2296, 1723,
˜
max
1405 cm–1. 19F NMR (235 MHz, D2O): δ = –73.0 (s, CF3) ppm. 1H
NMR (250 MHz, D2O): δ = 1.91 (m, 1 H), 2.15–2.45 (m, 4 H),
2.57 (dd, J = 8.0, 15.0 Hz, 1 H), 3.85 (quint., J = 7.5 Hz, 1 H) ppm;
+
OH and NH3 were not detected. 13C NMR (63 MHz, D2O): δ =
A suspension of N-benzyl amino acid 24 (125.4 mg, 0.387 mmol)
in thionyl chloride (3 mL) was heated at 50 °C for 15 h. After cool-
ing to room temp. CH2Cl2 was added to the reaction mixture and
the suspension was filtered to give a white solid. The filtrate was
diluted with CH2Cl2, washed with a satd. aq. sol. of NaHCO3 and
brine, dried (MgSO4), filtered and concentrated under reduced
pressure. Chromatography of the residue on silica gel (PE/Et2O,
1:1) afforded the N-benzyl lactam 25 (20 mg, 28%) as a colourless
oil. The white solid was dissolved in H2O, loaded onto Dowex
50WX8 H+ ion-exchange resin (5 g) and washed several times with
H2O. The amine was then eluted with 15% aq. NH3, concentrated
under reduced pressure and lyophilized. The residue was treated
with 1 m HCl and lyophilized to afford the N-benzyl amino acid
hydrochloride t-24 (44 mg, 51%) as a white amorphous solid.
30.5, 35.8, 51.9, 57.8 (q, J = 26.0 Hz), 126.6 (q, J = 280.0 Hz),
174.6 ppm. HRMS: calcd. for C7H11F3NO2 [M + H]+ 198.0742;
found 198.0739.
Methyl 3-Oxo-1-(trifluoromethyl)cyclopentanecarboxylate (22): A
solution of keto acid 18 (1.07 g, 5.48 mmol), methyl iodide (512 μL,
8.22 mmol, 1.5 equiv.) and caesium carbonate (1.25 g, 3.84 mmol,
0.7 equiv.) in acetone (20 mL) was stirred at room temp. for 5 h.
The suspension was then filtered through Celite and the filtrate was
concentrated under reduced pressure. Purification of the residue by
chromatography on silica gel (pentane/Et2O, 1:1) afforded the ester
22 (935 mg, 81%) as a colourless liquid. IR (film): ν
= 2964,
˜
max
1750, 1163 cm–1. 19F NMR (235 MHz, CDCl3): δ = –72.6 (s,
1
CF3) ppm. H NMR (250 MHz, CDCl3): δ = 2.41 (m, 4 H), 2.61
(d, J = 17.5 Hz, 1 H), 2.88 (d, J = 17.5 Hz, 1 H), 3.81 (s, 3 H) ppm.
13C NMR (63 MHz, CDCl3): δ = 27.2, 35.9, 42.3, 53.4, 55.2 (q, J
= 27.5 Hz), 125.6 (q, J = 281.0), 169.2, 212.2 ppm. HRMS: calcd.
for C8H9F3NaO3 [M + Na]+ 233.0401; found 233.0400.
A solution of N-benzyl lactam 25 (37 mg, 0.137 mmol) and potas-
sium tert-butoxide (92 mg, 0.822 mmol, 6 equiv.) in DMSO
(800 μL) containing water (5 μL, 0.275 mmol, 2 equiv.) was heated
at 100 °C for 18 h. After cooling to room temp., the reaction mix-
ture was diluted in H2O, acidified with 1 m HCl and the product
was loaded onto Dowex 50WX8 H+ ion-exchange resin (4 g). The
resin was washed several times with H2O and the amine was eluted
with 15% aq. NH3, concentrated under reduced pressure and lyo-
philized. The residue was treated with 1 m HCl and lyophilized to
afford the N-benzyl amino acid hydrochloride c-24 (22 mg, 50%)
as a white moss.
Methyl 3-Benzylamino-1-(trifluoromethyl)cyclopentanecarboxylate
(23): A solution of keto ester 22 (935 mg, 4.45 mmol) and benzyl-
amine (972 μL, 8.90 mmol, 2 equiv.) in a mixture of THF (15 mL)
and acetic acid (5 mL) was stirred at room temp. under Ar. After
stirring for 40 min, sodium acetoxyborohydride (2.07 g, 9.79 mmol,
2.2 equiv.) was added to the reaction mixture. After stirring for 2 h
45 min, the reaction was diluted with diethyl ether and hydrolysed
with a satd. aq. sol. of Na2CO3. The aqueous layer was extracted
twice with Et2O and the combined organic layers were washed with
brine, dried (MgSO4), filtered and concentrated under reduced
pressure. Purification of the residue by chromatography on silica
gel (PE/Et2O, 1:1, containing 0.1% of Et3N) afforded the N-benzyl
amino ester 23 (1.25 g, 93%) as a colourless liquid (60:40 mixture
t-3-Benzylamino-1-(trifluoromethyl)cyclopentane-r-1-carboxylic
Acid Hydrochloride (t-24): IR (KBr): νmax = 2956, 2815, 1731, 1287,
˜
1176 cm–1. 19F NMR (235 MHz, D2O): δ = –72.7 (s, CF3) ppm. 1H
NMR (250 MHz, D2O): δ = 1.89 (m, 1 H), 2.11 (dd, J = 10.0,
14.0 Hz, 1 H), 2.36 (m, 3 H), 2.83 (dd, J = 7.5, 14.0 Hz, 1 H), 3.83
+
(m, 1 H), 4.24 (s, 2 H), 7.45 (s, 5 H) ppm; NH2 and OH were not
of two diastereomers according to 19F NMR). IR (film): ν
=
detected. 13C NMR (151 MHz, [D]DMSO): δ = 27.9, 28.6, 34.0,
49.2, 56.3 (q, J = 26.0 Hz), 56.7, 126.4 (q, J = 279.5 Hz), 128.6,
128.9, 130.1, 132.2, 170.4 ppm. HRMS: calcd. for C14H17F3NO2
[M + H]+ 288.1211; found 288.1206.
˜
max
2957, 1740, 1287, 1172 cm–1. 19F NMR (235 MHz, CDCl3): δ =
–72.2 (s, CF3, major), –72.4 (s, CF3, minor) ppm. 1H NMR
(500 MHz, CDCl3): δ = 1.49 (br. s, 1 H), 1.58 (m, 1 H, major), 1.66
516
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 509–517

Trifluoromethylcyclopentenecarboxylic Acid Derivatives
[9] T. Yokozawa, T. Nakai, N. Ishikawa, Tetrahedron Lett. 1984,
25, 3991–3994.
2-Benzyl-4-(trifluoromethyl)-2-azabicyclo[2.2.1]heptan-3-one (25):
IR (film): ν
= 1711, 1165 cm–1. 19F NMR (235 MHz, CDCl3):
˜
max
[10] Y. Komatsu, T. Sakamoto, T. Kitazume, J. Org. Chem. 1999,
δ = –71.0 (s, CF3) ppm. 1H NMR (250 MHz, CDCl3): δ = 1.57 (m,
2 H), 1.78 (m, 2 H), 2.02 (m, 2 H), 3.68 (br. s, 1 H), 3.98 (d, J =
15.0 Hz, 1 H), 4.58 (d, J = 15.0 Hz, 1 H), 7.23 (m, 5 H) ppm. 13C
NMR (63 MHz, CDCl3): δ = 25.1, 28.2, 40.7, 44.7, 57.1, 57.3 (q,
J = 30.0 Hz), 125.2 (q, J = 276.0 Hz), 127.8, 128.1, 128.8, 136.3,
170.7 ppm. HRMS: calcd. for C14H15F3NO [M + H]+ 270.1106;
found 270.1105.
64, 8369–8374.
[11] E. I. Negishi, S. Y. Liou, in: Handbook of Organopalladium
Chemistry for Organic Synthesis (Ed.: E. I. Negishi), John
Wiley & Sons, 2002, pp. 1769–1793.
[12] S. Yanagida, Y. Noji, M. Okahara, Bull. Chem. Soc. Jpn. 1981,
54, 1151–1158.
[13] Bis(allylation) and RCM in a one-pot process under the condi-
tions reported by Poli failed, see: C. Kammerer, G. Prestat, T.
Gaillard, D. Madec, G. Poli, Org. Lett. 2008, 10, 405–408.
[14] E. Tamanini, M. Watkinson, M. H. Todd, Tetrahedron: Asym-
metry 2006, 17, 2235–2239, and references cited herein.
[15] J. D. Butler, M. B. Donald, Z. Ding, J. C. Fettinger, M. J.
Kurth, Tetrahedron Lett. 2009, 50, 5110–5112.
[16] H. O. House, J. L. Haack, W. C. McDaniel, D. V. VanDerveer,
J. Org. Chem. 1983, 48, 1643–1654.
[17] For the BH3·Me2S reduction of α-alkoxy esters, see: J. S. Panek,
F. Xu, J. Org. Chem. 1992, 57, 5288–5290.
[18] J. S. Bajwa, Tetrahedron Lett. 1992, 33, 2299–2302.
[19] A. Kishi, T. Higushino, S. Sakaguchi, Y. Ishii, Tetrahedron
Lett. 2000, 41, 99–102.
[20] a) G. Butora, S. D. Goble, A. Pastemak, L. Yang, C. Zhou,
C. R. Moyes, WO 2004094371, 2004 (CAN 141:410822); b) G.
Butora, S. D. Goble, A. Pastemak, L. Yang, C. Zhou, C. R.
Moyes, US 20080081803, 2008 (CAN 148:426870).
[21] M. Ordoneza, C. Cativiela, Tetrahedron: Asymmetry 2007, 18,
3–99.
c-3-Benzylamino-1-(trifluoromethyl)cyclopentane-r-1-carboxylic
Acid Hydrochloride (c-24): IR (KBr): ν
= 2958, 2826, 1739,
˜
max
1172 cm–1. 19F NMR (235 MHz, D2O): δ = –73.0 (s, CF3) ppm. 1H
NMR (600 MHz, D2O): δ = 1.97 (qd, J = 8.5, 13.0 Hz, 1 H), 2.22
(m, 1 H), 2.34 (dt, J = 7.0, 12.0 Hz, 1 H), 2.41 (m, 1 H), 2.50 (dd,
J = 7.0, 15.0 Hz, 1 H), 2.62 (dd, J = 8.0, 15.0 Hz, 1 H), 2.77 (d, J
= 50.5 Hz, 1 H), 3.84 (quint., J = 7.5 Hz, 1 H), 4.28 (m, 2 H), 7.50
(m, 5 H) ppm; NH and OH were not detected. 13C NMR
(151 MHz, D2O): δ = 29.0, 29.9, 34.1, 50.1, 57.4 (q, J = 25.5 Hz),
58.1, 126.4 (q, J = 279.5 Hz), 129.3, 129.6, 129.7, 130.7, 174.6 ppm.
HRMS: calcd. for C14H17F3NO2 [M + H]+ 288.1211; found
288.1207.
Supporting Information (see footnote on the first page of this arti-
cle): NMR spectra for all new compounds (including the mixtures
of diastereomers).
[22] a) X. F. Zhu, Nucleosides Nucleotides Nucleic Acids 2000, 19,
651–690; b) J. B. Rodriguez, M. J. Comin, Mini-Rev. Med.
Chem. 2003, 97, 95–114.
[23] J. R. Hanrahan, G. A. R. Johnston, Synthesis of γ-aminobutyric
acid analogs, in: Amino acids, Peptides and Proteins in Organic
Chemistry (Ed.: A. B. Hughes), Wiley-VCH, Weinheim, Ger-
many, 2009, pp. 573–689.
[24] M. G. Woll, J. R. Lai, I. A. Guzei, S. J. C. Taylor, M. E. B.
Smith, S. H. Gellman, J. Am. Chem. Soc. 2001, 123, 11077–
11078.
[25] R. J. Brea, M. Amorin, L. Castedo, J. R. Granja, Angew. Chem.
2005, 117, 5856; Angew. Chem. Int. Ed. 2005, 44, 5710–5713.
[26] E. M. Dangerfield, C. H. Plunkett, A. L. Win-Mason, B. L.
Stocker, M. S. M. Timmer, J. Org. Chem. 2010, 75, 5470–5477.
[27] G. V. Shustov, A. Rauk, Tetrahedron: Asymmetry 1996, 7, 699–
708.
Acknowledgments
This research was supported by Sanofi-Aventis Recherche, the Cen-
tre National de la Recherche Scientifique (CNRS) and the Univer-
sity of Reims. We are grateful to the Central Glass Company (Ka-
wagoe) for a generous gift of 3,3,3-trifluoropropanoic acid. We also
thank Sylvie Lanthony (HRMS, IR, elemental analysis), Agathe
Martinez (NMR) and Dominique Harakat (HRMS).
[1] a) K. Uneyama, in: Organofluorine Chemistry, Blackwell, Ox-
ford, 2006; b) J. P. Bégué, D. Bonnet-Delpon, in: Bioorganic
and Medicinal Chemistry of Fluorine, Wiley-VCH, Weinheim,
Germany, 2008.
[2] M. Zanda, New J. Chem. 2004, 28, 1401–1411.
[3] L. E. Martinez, W. A. Nugent, E. N. Jacobsen, J. Org. Chem.
1996, 61, 7963–7966.
[4] L. A. Badadzhanova, N. V. Kirij, Yu. L. Yagupolskii, J. Fluor-
ine Chem. 2004, 125, 1095–1098.
[5] F. Grellepois, V. M. Timoshenko, Y. G. Shermolovich, C. Port-
ella, Org. Lett. 2006, 8, 4323–4326.
[6] M. D. McReynolds, J. M. Dougherty, P. R. Hanson, Chem.
Rev. 2004, 104, 2239–2258.
[7] F. Grellepois, C. Portella, Synthesis 2008, 3443–3446.
[8] K. Uneyama, T. Katagiri, H. Amii, Acc. Chem. Res. 2008, 41,
817–829.
[28] A. F. Abdel-Magid, S. J. Mehrman, Org. Process Res. Dev.
2006, 10, 971–1031.
[29] Treatment of N-benzyl amino ester 23 with LiHMDS afforded
a mixture of the N-benzyl lactam 25 and the unreacted amino
ester t-23, which could not be separated by chromatography on
SiO2 (yield ca. 55%).
[30] S. Y. Sung, A. W. Frahm, Arch. Biochem. Biophys. 1996, 329,
291–300.
[31] The diallyl acid 8 (ref.[7]) and the γ-keto acid derivatives 18 and
19 (ref.[20]) have been prepared by a different methodology and
partially described elsewhere.
Received: September 9, 2011
Published Online: November 23, 2011
Eur. J. Org. Chem. 2012, 509–517
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
517