New synthesis of polyfluoroalkyl racemic α-amino acids

Article abstract of DOI:10.1016/j.jfluchem.2005.07.013

We describe here a new synthesis of racemic α-amino acids containing polyfluorinated aliphatic long chain R_F(CH₂)₃Y (R_F = C₂F₅, C₆F₁₃, C ₈F₁₇) (Y = CH(NH₂)COOH) based on So?rensen's method. The radical addition of perfluoroalkyl iodides R _FI (R_F = C₂F₅, C₆F ₁₃, C₈F₁₇) at room temperature to ethyl-2-carbetoxy-2-phthalimido-pent-4-enoate 3 was first initiated by Et ₃B/O₂. Then, the reduction of adducts 4a-c using Et ₃B/O₂/Bu₃SnH leads to ethyl-2-carbetoxy-2- phthalimido-5-perfluoroalkyl-pentanoate 5a-c under mild conditions. Experimental conditions for optimisation of the iodoperfluoroalkylation step using Et ₃B/O₂ were studied. Finally, deprotection of 5a-c gave the desired products 6a-c in good yields.

Full text of DOI:10.1016/j.jfluchem.2005.07.013

Journal of Fluorine Chemistry 126 (2005) 1487–1492
www.elsevier.com/locate/fluor
New synthesis of polyfluoroalkyl racemic a-amino acids
*
L. Delon, P. Laurent, H. Blancou
Laboratoire Organisation Mol e´ culaire, Evolution et Mat e´ riaux Fluor e´ s, UMR CNRS 5073, Universit e´ Montpellier II,
CC17, Place E. Bataillon, F34095 Montpellier Cedex 05, France
Received 22 June 2005; received in revised form 29 July 2005; accepted 29 July 2005
Available online 4 November 2005
Abstract
We describe here a new synthesis of racemic a-amino acids containing polyfluorinated aliphatic long chain R
17) (Y = CH(NH I (R
)COOH) based on S o¨ rensen’s method. The radical addition of perfluoroalkyl iodides R
room temperature to ethyl-2-carbetoxy-2-phthalimido-pent-4-enoate 3 was first initiated by Et B/O . Then, the reduction of adducts 4a–c
using Et B/O /Bu SnH leads to ethyl-2-carbetoxy-2-phthalimido-5-perfluoroalkyl-pentanoate 5a–c under mild conditions. Experimental
F
(CH
2
)
3
Y (R
F
2
= C F
5
, C
6 13
F ,
C
8
F
2
F
F
= C
F
2 5
6 8
, C F13, C F17) at
3
2
3
2
3
3 2
conditions for optimisation of the iodoperfluoroalkylation step using Et B/O were studied. Finally, deprotection of 5a–c gave the desired
products 6a–c in good yields.
#
2005 Elsevier B.V. All rights reserved.
Keywords: Fluorinated amino acids; Perfluoroalkyl iodide; Radical initiation; Triethylborane; Tributyltin hydride
1
. Introduction
synthesis of these compounds starting from diethyl
phthalimidomalonate 2 according to S o¨ rensen’s amino acid
synthesis pathway [26,27] (Scheme 1).
The increased importance of fluorinated compounds in
medicine and engineering applications such as artificial
blood, antipsychotics, anticancer drugs and insecticides has
stimulated the study of fluorine chemistry. Modification of
bioactive compounds by the introduction of fluorine and
fluoroalkyl groups is an area of current interest [1–4].
Fluorine containing amino acids have found a wide range
of applications in enzymology and pharmaceutical, medic-
inal and agricultural chemistry as a consequence of their
utility in biochemical processes and modifying biological
activity [5–10]. For example, a-trifluoroalanine is an
important compound of this class of fluorinated amino
acids [11–13] and it is known to act as a suicide inhibitor for
a number of pyridoxal enzymes [14–16]. Whereas the
literature is rich in methodologies for the preparation of
mono- or di-fluorinated a-amino acids [17–19], few
examples of synthetic routes leading to a-amino acids
containing highly fluorinated n-alkyl chains have been
reported [20–25]. We describe here a new and efficient
2. Results and discussion
Some years ago we reported on the synthesis of racemic
a-amino acids of general formula R (CH )
Y
(Y = CH(NH )COOH) (R = C F , C F ; n = 3 and 10)
F
2 nꢀ1
2
F
6
13
8 17
starting from the corresponding carboxylic acid [28]. A
general method to synthesise different carboxylic acids
containing a perfluoroalkyl group was thus developed [29].
Because of the inevitable loss of material in this process, it
seemed better to introduce the perfluoroalkyl group towards
the end of the reaction sequence.
Free radical addition of perfluoroalkyl iodide (R I) on
F
unsaturated compounds such as an olefin using a radical
initiator is one of the best methods for the introduction of the
perfluoroalkyl segment in organic compounds [30,31].
Several chemical sources such as peroxides, azonitriles,
redox systems, metals or transition metal complexes,
currently used to efficiently generate perfluoroalkyl radicals
*
Corresponding author. Tel.: +33 4 67 14 39 19; fax: +33 4 67 63 10 46.
E-mail address: hubert.blancou@univ-montp2.fr (H. Blancou).
starting from R I, have been reviewed [32,33]. Thus, a large
F
0022-1139/$ – see front matter # 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2005.07.013

1488
L. Delon et al. / Journal of Fluorine Chemistry 126 (2005) 1487–1492
Scheme 1.
Scheme 2.
variety of unsaturated molecules containing functional
groups can undergo iodoperfluoroalkylation involving a
radical pathway. In this context, olefinic aminomalonate 3
derived from diethyl phthalimidomalonate 2 appeared to be
an attractive precursor since it has a protected a-amino acid
group [34]. We were able to prepare 3 in 55% overall yield
starting from diethyl malonate (Scheme 2).
Thus, we focused on addition of R I to olefin 3 using a
radical initiator followed by reduction of adducts 4a–c with
a reducing agent.
F
We successfully explored triethylborane in this reaction,
which is known to give free alkyl radicals upon treatment
with oxygen [35]. In fact, Et B/O has the advantage over
3
2
classical initiators of being efficient even at low temperature
(ꢀ78 8C). Utimoto and Oshima were the first to apply the
reaction of triethylborane with oxygen to initiate such
radical reactions [36]. Since they revealed shortly afterwards
that Et B/O induces iodoperfluoroalkylation on unsaturated
The synthesis of protected highly fluorinated a-amino
acids 5a–c was performed by perfluoroalkylation of 3 using
R I as perfluoroalkyl radical source. In the retrosynthetic
F
pathway described above, step b was essential (Scheme 1).
3
2
Scheme 3.

L. Delon et al. / Journal of Fluorine Chemistry 126 (2005) 1487–1492
1489
Table 1
Addition of perfluoroalkyl iodide to 3 using Et
3
B/O
2
a
b
Tansformation (%)
ꢀ1 a
[C] (mol L )
R
F
[ET
3
F
B]/[R I]
Solvent
C
6
C
6
C
6
C
8
C
6
C
8
C
6
C
8
C
6
C
8
C
6
C
8
C
2
C
6
C
8
F
13
13
13
17
13
17
13
17
13
17
13
17
5
0.1 (1 M hexane)
0.2 (1 M hexane)
0.1 (1 M THF)
0.1 (1 M THF)
0.2 (1 M THF)
0.2 (1 M THF)
0.2 (1 M THF)
0.2 (1 M THF)
0.1 (1 M hexane)
0.1 (1 M hexane)
0.2 (1 M hexane)
0.2 (1 M hexane)
0.2 (1 M hexane)
0.2 (1 M hexane)
0.2 (1 M hexane)
DMF
DMF
65
69
72
69
78
75
63
60
80
80
95
95
90
100
100
2.9
2.9
5.8
5.8
5.8
5.8
4.8
4.8
2.9
2.9
2.9
2.9
2.9
—
F
F
F
F
F
F
F
F
F
F
F
F
F
F
Toluene
Toluene
Toluene
Toluene
THF
THF
1,2-Dichloroethane
1,2-Dichloroethane
1,2-Dichloroethane
1,2-Dichloroethane
1,2-Dichloroethane
No solvent
13
17
No solvent
—
a
In a typical experimental procedure, reactions were performed at a given concentration of 3 in solvent with a stoichiometric amount of R
F
I. Introduction of
Et
3
b
B (1 M solution in hexane or THF) via a syringe at 25 8C under vigorous stirring led to an instantaneous and exothermic reaction.
1
Conversions were determined by H NMR spectroscopy by the relative integration of the allylic protons signals of compound 3 compared with that of the
phthalimide proton signal in the crude product.
molecules under mild conditions [37], the use of Et B/O in
3
[37–42]. However, in our case, compound 3 showed very
poor solubility in such solvents. Consequently, we per-
formed the reaction at room temperature in other organic
solvents in which 3 was soluble in order to optimise yields
(Table 1).
2
the chemistry of perfluoroalkyl radicals was investigated
38–40] even for perfluoroalkylation of olefins containing
polymers [41,42]. The proposed mechanism for the radical
[
addition of R I on 3 initiated by autoxidation of
F
trietylborane is described in Scheme 3.
In this study, 1,2-dichloroethane was a good alternative
solvent to hexane or pentane. In other solvents such as DMF,
toluene or THF, the reaction was incomplete even after a
prolonged time. The [R I]/[Et B] ratio was also adjusted to
In these reactions, the choice of solvent is critical to
mediate iodoperfluoroalkylation in high yields. The most
ideal solvents are apolar solvents such as hexane or pentane
F
3
Scheme 4.
Scheme 5.

1490
L. Delon et al. / Journal of Fluorine Chemistry 126 (2005) 1487–1492
determinate the minimal initiator level required. We found
that 20% molar ratio was necessary to give 95%
spectrometer. Melting points were recorded on a Stuart
SMP3 instrument.
(
R = C F , C F ) and 90% (R = C F ) transformation
F 6 13 8 17 F 2 5
under optimal conditions (solvent and concentration).
Moreover, it appeared that when the reaction was
performed without solvent, this lead to a quantitative
addition of non-volatile R I (R = C F , C F ) on 3.
4.2. Synthesis of diethyl bromomalonate (1)
A mixture of diethylmalonate (480 g, 3 mol) and CCl4
(450 mL) was placed in a flask equipped with a magnetic
stirring bar, reflux condenser and an additional funnel
containing Br (498 g, 3 mol). Several millilitres of Br were
F
F
6
13
8 17
Then, the in situ deiodination of adducts 4a–c in 1,2-
dichloroethane using tributyltin hydride was initiated by a
residual amount of triethylborane present in media [36],
2
2
added to the flask which then irradiated with a Tensor lamp.
As the red colour disappeared, more Br was added drop
1
9
leading to 5a–c in quantitative yield (observed by
NMR spectroscopy of the crude product). KF treatment
36] and recrystallization are however required to obtain
F
2
wise to maintain a gentle reflux. After complete addition, the
solution was heated at reflux for 1 h, then cooled and diluted
with additional CCl . The solution was washed with 5%
[
5
a–c in high purity (Scheme 4).
Finally, deprotection of the resulting protected a-amino
4
Na CO (2 mL ꢁ 300 mL), dried over Na SO filtered, and
2
3
2
4
acids 5a–c, performed by hydrazinolysis of phthalimide
group as described in the classical Gabriel method [43]
followed by saponification and then decarboxylation of
diester function, gave racemic a-amino acids 6a–c in good
yields (Scheme 5).
distilled over reduced pressure to give 1 (691 g, 96%) as a
colorless liquid which is identified with literature [34].
1
H NMR (CDCl ) d (ppm): 1.32 (t, 6H, J = 7.2 Hz); 4.31
3
(q, 4H, J = 7.2 Hz); 4.84 (s, 1H).
1
3
C NMR (CDCl ) d (ppm): 13.2 (s, CH CH O); 41.8 (s,
3
3
2
BrCH (CO Et) ); 62.1 (CH CH O s); 163.8 (s, CO Et).
2
2
3
2
2
3
. Conclusion
4.3. Synthesis of diethyl phthalimidomalonate (2)
In summary we have developed a new and efficient
Diethyl bromomalonate (720 g, 3 mol) was added to
potassium phthalimide (555 g, 3 mol) in 200 mL of
anhydrous MeCN. Reaction was very exothermic and the
mixture was stirred at room temperature during 1 h and then
1 h at reflux. After cooling, solvent was distilled under
method for the synthesis of highly fluorinated racemic a-
amino acids starting from diethyl malonate. In this case,
Et B/O and Bu SnH were used to induce perfluoroalkyla-
3
2
3
tion of 3 at room temperature. Optimisation of the
iodoperfluoroalkylation step was executed in order to obtain
adducts 4a–c in good yields. Thus, we have demonstrated
that a wide range of fluorinated chains can be introduced into
amino acid side chains.
reduced pressure and residual solid was washed with H O
2
(1 L) and filtered. Product was dissolved in CH Cl (4 L)
2
2
and washed twice with H O (2 L ꢁ 0.5 L). Organic layer
2
was dried on Na SO and distilled under reduced pressure.
2
4
The method is reproducible and each step proceeds in
better that 60% yield with only one chromatographic
purification required (step b, Scheme 1, R = C F ). All the
The crude product was purified by crystallization from
EtOH to give pure product 2 (720 g, 78%) as a white powder.
1
mp: 78 8C (ref. [34] 75–76 8C). H NMR (CDCl ) d
F
2
5
3
steps in the synthetic pathway can be performed on a
multigram scale to produce 6a–c in large quantities.
(ppm): 1.31 (t, 6H, J = 7.1 Hz); 4.32 (q, 4H, J = 7.2 Hz);
1
3
5.49 (s, 1H); 7.76–7.89 (m, 4H). C NMR (CDCl ) d (ppm):
3
1
3.6 (s, CH3 CH O); 57.7 (CH(CO Et) ); 62.2 (s,
2 2 2
CH CH O); 123.1 (s, CH ); 131.0 (s, CH ); 133.8 (s,
3
2
Ar
Ar
4
. Experimental
CH ); 163.7 (s, C O); 165.8 (s, C O). I.R (KBr) n
Ar max
ꢀ
1
cm ): 1733 (nC O) 2987 (nCH) 3029 (nCHAr). MS (FAB+)
(
m/z: 306 (M + H) , 215, 214, 197, 123.
+
4
.1. General experimental procedures
0
Bromine, diethylmalonate, potassium phthalimide, allyl
4.4. Synthesis of ethyl-2-carbetoxy-2 -phthalimidopent-
4-enoate (3)
bromine, triethylborane and tributyltin hydride were
purchassed from Aldrich. Different perfluoroalkyl iodides
were purchased from Elf Atochem.
A solution of KOH (62.5 g, 1.1 mol) in 35 mL of H O
2
1
19
13
The products were characterised by H F and C NMR
spectroscopy, all at room temperature and recorded in
CDCl3 and [(CD ) SO)] on a Brucker AVANCE 300
was completed with EtOH (100 mL) and added to a mixture
of diethyl phthalimidomalonate (338 g, 1.1 mol) in EtOH
(2 L). A yellow solid was formed instantaneously, filtered,
washed with anhydrous ether (3mL ꢁ 100 mL) and dried
under reduced pressure. Potassium phthalimidomalonate
salt (340 g, 1 mol) was obtained, dissolved in anhydrous
DMF (340 mL) and allyl bromide (121 g, 1 mol) was added
drop wise. The mixture was kept at 100 8C under stirring
3 2
spectrometer. All chemical shifts are reported in parts per
million (ppm) downfield of the standard (TMS and CCl F).
3
Infrared spectra were recorded on a Brucker IFS 25
instrument in the transmitance mode. Frequencies are given
ꢀ
1
in cm . Mass spectra were recorded on a Jeol SX 102

L. Delon et al. / Journal of Fluorine Chemistry 126 (2005) 1487–1492
1491
during 1 h, then cooled at room temperature and product was
isolated by precipitation in H O (2 L). A white solid was
ꢀ114.3 (t, 2F, J = 14.1 Hz); ꢀ121.9 (s, 2F); ꢀ122.9 (s, 2F);
1
3
ꢀ123.7 (s, 2F); ꢀ126.2 (m, 2F). C NMR (CDCl ) d (ppm):
2
3
filtrate, dissolved in Et O (1 L), washed with H O (100 mL)
2
13.7 (s, CH CH O); 15.6 (s, CH CH CH ); 30.5–31,0 (t,
2
3
2
2
2
2
and dried over Na SO . The organic layer was then filtered
2
CH CF , J = 22.6 Hz); 32,6 (s, CH CH –N); 62.8 (s,
2 2 2 2
4
and solvent distilled under reduced pressure to give 3 (280 g,
overall yield: 74%) as a white solid.
CH CH O); 67.5 (s, CH C(CO Et) ); 110.2–121.9 (m,
3 2 2 2 2
C F ); 123.5 (s, CH ); 131.6 (s, CH ); 134.2 (s, CH );
6
13
Ar
Ar
Ar
ꢀ1
1
mp: 62 8C. H NMR (CDCl ) d (ppm): 1.25 (t, 6H,
166.1 (s, C O); 167.4 (s, C O). IR (KBr) nmax (cm ):
1000–1200 (n ) 1727 (n O) 3024 (nCHAr). MS (FAB+) m/
+
z: (M + H) (666) 546, 518. HRMS: calculated for
3
J = 7.1 Hz); 3.15 (d, 2H, J = 7.2 Hz); 4.25 (q, 4H,
J = 7.2 Hz); 4.90 (m, 2H); 5.95 (m, 1H); 7.70 (m, 4H).
CF
C
1
3
C NMR (CDCl ) d (ppm): 13.2 (s, CH CH O); 37.2 (s,
C H F NO : 666.1161; found: 666.1157
24 21 13
3
3
2
6
1
CH CH CH); 62.0 (CH CH O s); 67.0 (s, C(CO Et) );
5c (R = C F ): mp: 65 8C. H NMR (CDCl ) d (ppm):
2
3
2
2
2
F
8
17
3
1
19.1 (s, CH2 CH); 122.8 (s, CH ); 130.8 (s, CH ), 132.1
1.20 (t, 6H, J = 7.1 Hz); 1.63–1.77 (m, 2H); 1.95–2.16 (m,
2H); 2.51 (m, 2H); 4.23 (q, 4H, J = 7.1 Hz); 7.64–7.82 (m;
Ar
Ar
(
s, CH2 CH); 133.7 (s, CH ); 165.3 (s, C O); 166.4 (s,
Ar
ꢀ1
19
C O). IR (KBr) nmax (cm ): 1736 (nC O) 2986 (nCH). MS
FABꢀ) m/z: 345 (Mꢀ), 305, 270, 231, 199, 146. HRMS:
calculated for C H O N: 345.1212; found: 345.1231.
4H). F NMR (CDCl ) d (ppm): ꢀ81.0 (t, 3F, J = 11.3 Hz);
3
(
ꢀ114.4 (t, 2F, J = 14.1 Hz); ꢀ122.9 (s, 2F), ꢀ122.1(s, 4F);
1
3
ꢀ122.9 (s, 2F); ꢀ123.7 (s, 2F); ꢀ126.3 (s, 2F). C NMR
1
8 19 6
(CDCl )
3
d
(ppm): 13.0 (s, CH CH O); 14.9 (s,
3 2
4.5. Synthesis of ethyl-2-carbetoxy-2-phthalimido-5-
perfluoroalkyl-pentanoate (5a–c) (R = C F , C F ,
CH CH CH ); 29.8–30.4 (t, CH CF , J = 22.6 Hz); 31.9
2 2 2 2 2
(s, CH CH –N); 62.1 (s, CH CH O); 66.7 (s,
F
2
5
6
13
2
2
3
2
C F )
8 17
CH C(CO Et) ); 106.1–122.3 (m, C F ) 122.9 (s, CH );
2 2 2 8 17 Ar
1
30.7 (s, CH ); 133.8 (s, CH ); 165.4 (s, C O); 166.6 (s,
Ar Ar
ꢀ
C O). IR (KBr) nmax (cm ): 1000–1200 (n ) 1724 (n O)
CF C
1
Triethylborane (1.0 M hexane solution, 4.35 mL,
ꢀ
3
+
4
3
1
.35 ꢁ 10 mol) was added to a solution of 3 (10 g,
2988 (nCH) 3103 (nCHAr). MS (FAB+) m/z: (M + H) (766)
692, 646, 618. HRMS: calculated for C H F NO :
766.1097; found: 766.1093.
ꢀ2
ꢀ2
.0 ꢁ 10 mol) and R I (3.0 ꢁ 10 mol, 7.1 g R = C F ,
F
F
2
5
26 21 17
6
2.9 g R = C F , 15.8 g R = C F ) in 1,2-dichloroethane
F
6
13
F
8 17
(
10 mL) at 25 8C. The resultant mixture was stirred at 25 8C
ꢀ2
during 0.5 h. Bu SnH (8.4 g, 7.8 mL, 3.0 ꢁ 10 mol) was
4.6. Synthesis of 2-amino-5-perfuoroalkyl-pentano ¨ı c
acids (6a–c) (R = C F , C F C F )
3
added via a syringe and the mixture was stirred at 25 8C
during 2 h. Solvent was distilled under reduce pressure, the
F
2
5
6
13,
8 17
ꢀ
3
crude product was dissolved in Et O (60 mL) and KF (6.9 g,
2
Hydrazine hydrate (98%) (0.450 g, 9.6 ꢁ 10 mol) was
ꢀ
F 2 5
3
0
.12 mol) was added to the solution. The mixture was stirred
added to a solution of 5a–c (7.5 ꢁ 10 mol, R = C F :
F 6 13 F 8 17
at room temperature during 24 h and filtered. Solvent was
distilled under reduced pressure. 5a was purified by column
chromatography on silica gel (petroleum ether/diethyl
ether = 80/20) to give a colorless oil (10.8 g, 80%). 5b
was crystallized from heptane to give pure product (14.6 g,
3.5 g, R = C F : 5 g, R = C F : 5.7 g) in EtOH (15 mL).
The mixture was kept at reflux and stirred during 24 h.
Phtalyl hydrazide was filtered and organic layer was distilled
under reduced pressure. Resultant product was dissolved in
ꢀ
2
EtOH (20 mL), a solution of KOH (1.05 g, 1.8 ꢁ 10 mol)
76%) as a white powder. 5c was crystallized by precipitation
in a petroleum ether–diethyl ether mixture to give pure
in H O (3 mL) was added and the mixture kept at reflux
2
under stirring during 5 h. EtOH was then distilled under
reduced pressure, HCl aq. 32% (40 mL) was added and the
mixture was kept at reflux and stirred during 24 h. HCl
solution was distilled under reduced pressure, the remained
product (16.6 g, 75%) as a white powder.
1
5
J = 7.1 Hz); 1.68 (m, 2H); 1.92–2.10 (m, 2H); 2.49 (m, 2H);
a (R = C F ): H NMR (CDCl ) d (ppm): 1.21 (t, 6H,
F
2
5
3
1
.25 (q, 4H, J = 7.2 Hz); 7.68–7.81 (m; 4H). F NMR
9
4
product was dissolved in H O (20 mL) and the mixture was
2
(
J = 19.7 Hz).
CDCl ) d (ppm): ꢀ85.5 (s, 3F); ꢀ118.26 (t, 2F,
adjusted at pH 6 using KOH solution (0.75 M). Precipitated
amino acid was filtered and washed with water (10 mL).
Products were crystallized from a H O/EtOH mixture to
3
1
3
C NMR (CDCl ) d (ppm): 13.1 (s,
3
CH CH O); 15.0 (s, CH CH CH ); 29.9 (t, CH CF ,
3
2
2
2
2
2
2
2
J = 21.9 Hz); 31.9 (s, CH CH –N); 62.1 (s, CH CH O);
give pure products 6a–c [6(a), R = C F , 1.25 g (60%);
2
2
3
2
F
2 5
6
6.7 (s, CH C(CO Et) ); 111.8–120.8 (m, C F ); 123.3 (s,
6(b), R = C F , 2.5 g (70%); 6(c), R = C F , 3.16 g
F 6 13 F 8 17
2
2
2
2
5
CH ); 130.7 (s, CH ); 133.8 (s, CH ); 165.5 (s, C O);
(73%)].
6a (R = C F ) H NMR [(CD ) SO + CF CO H] d
(ppm): 1.68 (m, 2H); 1.92 (m, 2H); 2.30 (m, 2H); 3.98 (s,
Ar
Ar
Ar
ꢀ
1
66.7 (s, C O). IR (KBr) nmax (cm ): 1000–1200 (n )
1
1
1
3
4
CF
F
2
5
3 2
3
2
+
725 (nC O) 3030 (nCHAr). MS (FAB+) m/z: (M + H) (466)
1
9
92, 346, 318. HRMS: calculated for C H F NO :
2
1H); 8.50 (s, 3H). F NMR [(CD ) SO + CF CO H] d
3 2
0
21
5
6
3
3
2
1
66.1289; found: 466.1287.
b (R = C F ): mp: 96 8C. H NMR (CDCl ) d (ppm):
.28 (t, 6H, J = 6.9 Hz); 1.74–1.85 (m, 2H); 2.05–2.25(m,
(ppm): ꢀ85.8 (s, 3F); ꢀ118.3 (s, 2F).
C NMR
[(CD ) SO + CF CO H] d (ppm): 15.89 (s, CH CH CH ),
3 2 3 2 2 2 2
1
5
F
6
13
3
1
2
4
28.8 (t, CH CH CF , J = 21.1 Hz), 29.1 (s, CH CH CH),
2 2 2 2 2
H); 2.60 (m, 2H); 4.32 (q, 4H, J = 7.2 Hz); 7.74–7.91 (m;
9
51.5 (s, CH CH(NH )COOH), 112.4–120.7 (m, C F );
2
2
2 5
1
+
H). F NMR (CDCl ) d (ppm): ꢀ81.1 (t, 3F, J = 11.2 Hz);
170.8 (s, CO H). MS (FAB+) m/z: (M + H) (236) 154, 136.
2
3

1492
L. Delon et al. / Journal of Fluorine Chemistry 126 (2005) 1487–1492
[
11] T. Sakai, F. Yan, S. Kashino, K. Uneyama, Tetrahedron 52 (1996) 233–
44.
HRMS: calculated for C H F NO : 236.0710; found:
5
7
11
2
2
2
36.0751.
b (R = C F ) H NMR [(CD ) SO + CF CO H] d
ppm): 1.68 (m, 2H); 1.92 (m, 2H); 2.28 (m, 2H); 3.98 (s,
[
[
12] V.A. Soloshonok, V.P. Kukhar, Tetrahedron 53 (1997) 8307–8314.
13] N. Lebouvier, C. Laroche, F. Huguenot, T. Brigaud, Tetrahedron Letts.
1
6
F
6
13
3 2
3
2
(
4
3 (2002) 2827–2830.
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46–347.
[15] W. Faraci, C. Walsh, Biochemistry 28 (1989) 431–437.
1
9
1
H); 8.45 (s, 3H). F NMR [(CD ) SO + CF CO H] d
3 2 3 2
3
(
ppm): ꢀ80.6 (s, 3F); ꢀ113.5 (s, 2F); ꢀ121.9 (s, 2F);
1
3
ꢀ
122.9 (s, 2F); ꢀ123.3 (s, 2F); ꢀ126.1 (s, 2F). C NMR
[
[
16] E. Wang, C. Walsh, Biochemistry 20 (1981) 7539–7546.
17] X. Qiu, W. Meng, F. Qing, Tetrahedron 60 (2004) 6711–6745.
[
(CD ) SO + CF CO H] d (ppm): 15.7 (s, CH CH CH );
3 2 3 2 2 2 2
2
5
1
9.0 (s, CH CH CH), 29.2 (t, CF CH CH , J = 21.9 Hz);
2 2 2 2 2
[18] M. Mae, H. Amii, K. Uneyama, Tetrahedron Lett. 41 (2000) 7893–
7896.
1.5 (s, CH CH(NH )COOH); 110.2–122.1 (m, C F );
2
2
6 13
+
[
19] T. Tsushima, K. Kawada, S. Ishihara, N. Ushida, O. Shiratori, J.
Higaki, M. Hirata, Tetrahedron 44 (1988) 5375.
70.7 (s, COOH). MS (FAB+) m/z: (M + H) (436) 390.
HRMS: calculated for C H F NO : 436.0582; found:
1
1
11 13
2
[
[
20] N.O. Brace, J. Org. Chem. 32 (1967) 430–434.
4
36.0567.
c (R = C F ) H NMR [(CD ) SO + CF CO H] d
ppm): 1.68 (m, 2H); 1.89 (m, 2H); 2.26 (m, 2H); 3.98 (s,
21] K. Uneyama, J. Hao, H. Amii, Tetrahedron Lett. 39 (1998) 4079–4082.
1
6
F
8
17
3 2
3
2
[22] H. Watanabe, Y. Hashizume, K. Uneyama, Tetrahedron Lett. 33 (1992)
4333–4336.
(
1
9
[
[
[
23] J.G. Riess, C. Blaignon, M. Leblanc, French Patent 1987/2620445.
24] V.P. Kukhar, J. Fluorine Chem. 69 (1994) 199–205.
1
H); 8.38 (s, 3H). F NMR [(CD ) SO + CF CO H] d
3 2 3 2
(
ppm): ꢀ80.9 (s, 3F); ꢀ113.7 (m, 2F); ꢀ121.9 (s, 2F);
25] V.A. Soloshonok, D.V. Avilov, V.P. Kukhar, L.V. Meervelt, N. Mis-
chenko, Tetrahedron Lett. 38 (1997) 4671–4674.
ꢀ
122.1 (s, 3F); ꢀ122.9 (s, 2F); ꢀ123.4 (s, 2F); ꢀ126.3 (s,
1
3
2
F). C NMR [(CD ) SO + CF CO H] d (ppm): 16.3 (s,
3 2 3 2
[26] C.S. Marvel, M. Palmer Stoddard, J. Org. Chem. 3 (1938) 198–203.
[27] D. Cabaret, S.A. Adediran, M.J. Garcia Gonzalez, R.F. Pratt, M.
Wakselman, J. Org. Chem. 64 (1999) 713–720.
CH CH CH ); 29.5 (s, CH CH CH), 29.7 (t, CF CH CH ,
J = 21.9 Hz); 52.0 (s, CH CH(NH )COOH); 106.8–122.8
2
2
2
2
2
2
2
2
2
2
+
[28] D. Tra Anh, H. Blancou, A. Commeyras, J. Fluorine Chem. 94 (1999)
(
m, C F ); 171.3 (s, COOH). MS (FAB+) m/z: (M + H)
8 17
5
7–60.
29] N. Requirand, H. Blancou, A. Commeyras, Bull. Soc. Chim. Fr. 130
1993) 798–806.
(536) 490. HRMS: calculated for C H F NO : 536.0518;
13 11 17 2
found: 536.0515.
[
(
[
[
[
[
[
30] W.R. Dolbier, Chem. Rev. 96 (1996) 1557–1584.
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33] N.O. Brace, J. Fluorine Chem. 93 (1999) 1–25.
34] K.J. Martinkus, C.H. Tann, S.J. Could, Tetrahedron 39 (1983) 3493–
3505.
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