Synthesis and characterization of fluorous (S)- and (R)-1-phenylethylamines that effect heat facilitated resolution of (±)-2-(8-carboxy-1-naphthylsulfinyl)benzoic acid via diastereomeric salt formation and study of their circular dichroism

Article abstract of DOI:10.1016/j.jfluchem.2006.05.011

Perfluoroalkyl- or nonafluoro-tert-butoxy-alkyl-substituted enantiopure amines having the structure PhCHCH₃(NR¹R²) [R¹ = H, CH₃; R² = (CH₂)₃C₈F₁₇

Full text of DOI:10.1016/j.jfluchem.2006.05.011

Journal of Fluorine Chemistry 127 (2006) 1405–1414
www.elsevier.com/locate/fluor
Synthesis and characterization of fluorous (S)- and
(R)-1-phenylethylamines that effect heat facilitated
resolution of (ꢀ)-2-(8-carboxy-1-naphthylsulfinyl)benzoic
acid via diastereomeric salt formation and study
of their circular dichroism
a
Denes Szabo , Aniko Nemes , Istvan Kovesdi ,
a
b
´
Viktor Farkas , Miklos Hollosi , Jozsef Rabai
´
´
´
´
´
¨
a
a
a,
*
´
´
a
¨
¨
´
Institute of Chemistry, Eotvos Lorand University, P.O. Box 32, H-1518, Budapest 112, Hungary
b EGIS Pharmaceuticals Ltd., P.O. Box 100, H-1475 Budapest, Hungary
Received 17 April 2006; received in revised form 5 May 2006; accepted 11 May 2006
Available online 20 May 2006
ˇ
Dedicated to Professor Boris Zemva for his creative work in noble gas chemistry.
Abstract
Perfluoroalkyl- or nonafluoro-tert-butoxy-alkyl-substituted enantiopure amines having the structure PhCHCH3(NR1R2) [R1 = H, CH3;
R2 = (CH2)3C8F17, (CH2)2OC(CF3)3; R1 = R2 = (CH2)3C8F17, (CH2)2OC(CF3)3] are obtained in high yields, when (S)-(ꢁ)-1-phenylethylamine
is reacted with readily accessible alkylating reagents or fluorous 28 amines (R1 = H; R2 = (CH2)3C8F17, (CH2)2OC(CF3)3) are methylated in a
Leuckart–Wallach reaction. The solubility patterns of these novel chiral amines and their hydrochlorides are qualitatively described for a broad
spectrum of solvents and the fluorous partition coefficients of the free bases are determined by GC. A novel method for the resolution of
enantiomers is disclosed here, which involves the use a half-equivalent of the selected resolving agent in solvent water that displays low solubility
for the crystalline diastereomeric salt(s) formed even at temperatures near to its boiling point. Compound (S)-(ꢁ)-PhCHCH3[NH(CH2)3C8F17] is
found to satisfy all the latter conditions and successfully used for the heat facilitated resolution of the title racemic acid. The circular dichroism
(CD) spectra of six novel fluorous (S)-(ꢁ)-1-phenylethylamine derivatives are measured in ethanol, trifluoroethanol and hexafluoropropan-2-ol and
discussed in detail.
# 2006 Elsevier B.V. All rights reserved.
Keywords: Alkylation; Chiral amines; Circular dichroism; Fluorine; Fluorophilicity; Optical resolution; Specific rotation; Synthesis
1. Introduction
Complexes of fluorous chiral amines with relatively stable
s-bonded metal centers, in particular those are bonded through
a M–C s-bond, are the subjects of a recent study for the
development of systems, that could provide an increased
stability with respect to metal leaching [6]. Although fluorous
cinchona derivatives have been prepared and used in
asymmetric organocatalysis to afford up to 40% enantiomeric
excesses in the Diels–Alder reaction of anthrone and N-
methylmaleimide [7], the potential of such chiral amines for
optical resolution has not been explored yet. The relative
frequencies (%) of the use of a selection of basic resolving
agents indicate that brucine (21%), quinine (16%) and (S)- and
(R)-1-phenylethylamine (12%) are the first three candidates if
Fluorous amines have been receiving increasing attention
because they are suitable precursors for the synthesis of
fluorous scavangers, reagents and recoverable catalyst pre-
cursor ligands [1]. With the use of chiral fluorous nitrogen
ligand–metal systems [2], asymmetric catalyses were estab-
lished for the cyclopropanation of styrenes [3], epoxidation of
olefins [4], hydrogen-transfer reduction of ketones [4] and
hydrolytic kinetic resolution of terminal epoxides [5].
* Corresponding author.
´
E-mail address: rabai@elte.hu (J. Rabai).
0022-1139/$ – see front matter # 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2006.05.011

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D. Szabo et al. / Journal of Fluorine Chemistry 127 (2006) 1405–1414
1406
the resolution of a racemic acid via diastereomeric salt
formation is considered [8]. For development of novel resolving
agents that allow effective fluorous recovery [8], we choose (S)-
and (R)-1-phenylethylamine, since both enantiomeric forms are
commercially available. The syntheses of fluorous amines are
well documented and rely on the access to appropriate
fluorinated building blocks [9,10].
(perfluoro-tert-butyloxy)ethyl]-(S)-PEA 4 were prepared by
using 2-(perfluoro-tert-butyloxy)ethyl tosylate (9) and -triflate
(10), respectively, as alkylating reagents. The Leuckart–
Wallach methylation [11] of 1 and 3 with formaldehyde and
formic acid afforded 38 amines 5 and 6, respectively, in
quantitative yields.
The chiral bases 1–6 synthesized here are colorless and
volatile liquids, which can easily be converted to their
storageable hydrochlorides 1–6*HCl, appearing as white
crystals, in quantitative yields (Scheme 1).
2. Results and discussion
1
All new compounds were characterized by H NMR, 13C
2.1. Synthesis of a series of N-fluoroalkylated (S)-(ꢁ)-PEA
NMR and 19F NMR, IR and MS spectroscopy, as described in
Section 4. The NMR properties showed numerous patterns, but
usually of a routine nature. For example, the NCH2CH2 13C
signals were grouped in ranges (28 amines 1,3 and 1,3*HCl
d = 43.5–46.6; 38 amines 2,4,5,6 and (2,5,6)*HCl d = 48.4–53.7)
such as for the CH2OC(CF3)3 13C signals (3,4,6 and (3,4,6)*HCl,
d = 60.7–69.6), always downfield of the CH2C8F17 signals (1,2,5
and (1,2,5)*HCl d = 28.2–28.8).
derivatives
The reaction of (S)-(ꢁ)-1-phenylethylamine ((S)-PEA)
with: (i) 3-(perfluorooctyl)propyl iodide (7), (ii) 3-(perfluor-
ooctyl)propanal (8)/NaBH(OAc)3/THF, (iii) 2-(perfluoro-tert-
butyloxy)ethyl tosylate (9) and (iv) 2-(perfluoro-tert-butylox-
y)ethyl triflate (10), respectively, afforded fluorous amines 1–
4 in good isolated yields (Scheme 1). The secondary N-[3-
(perfluorooctyl)propyl]-(S)-PEA 1 was prepared as reported
by Pozzi and co-workers [3], but isolated by vacuum
distillation. For the synthesis of N,N-bis[3-(perfluorooctyl)-
propyl]-(S)-PEA 2we applied a two-step N-alkylation method
developed by Gladysz and co-workers [9a]. The bulky N-[2-
(perfluoro-tert-butyloxy)ethyl]-(S)-PEA 3 and N,N-bis[2-
Some of these amine hydrochlorides in CDCl3 solution
displayed proton multiplets doubled according to a temporary
diastereomeric form which can be attributed to the hindered
nitrogen inversion on the protonated nitrogen or the appearance
of small intensity carbon signals of a higher energy
diastereomeric form (Section 4).
Scheme 1. Synthesis of selected 28 and 38 fluorous (S)-(ꢁ)-1-phenylethylamine derivatives. (i) C8F17(CH2)3I (7)/K2CO3/CH3CN, 80 8C; (ii) 1: C8F17(CH2)2CHO
(8)/THF, 2: NaBH(OAc)3, r.t.; (iii) (CF3)3CO(CH2)2OTs (9)/K2CO3/CH3CN, 90 8C; (iv) (CF3)3CO(CH2)2OSO2CF3 (10)/K2CO3/CH3CN, 90 8C; (v) CH2O/H2O/
HCO2H, 90 8C; (vi) HCl/THF.

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D. Szabo et al. / Journal of Fluorine Chemistry 127 (2006) 1405–1414
1407
Table 1
Solubility behavior of enantiomeric and racemic 1-phenyethylamine derivatives and their hydrochlorides at ambient temperature
Entry
Compound
BTF
CF3C6F11
n-Hexane
THF
Acetone
MeOH
CH2Cl2
CHCl3
Ether
CH3CN
1
2
(ꢀ)-1
++
++
ꢁ
++
++
ꢁ
++
++
+
++
++
+
++
++
+
++
++
++
++
++
++
++
++
++
++
++
++
++
++
++
++
++
++
++
++
+
++
++
++
++
++
++
++
++
++
++
++
++
++
++
++
++
++
++
++
++
ꢁ
++
++
ꢁ
(ꢁ)-1
3
(ꢀ)-1*HCl
(ꢁ)-1*HCl
(ꢀ)-2
4
ꢁ
ꢁ
+
++
++
++
+
++
++
++
++
++
+
++
++
++
++
++
+
ꢁ
ꢁ
5
++
++
++
++
ꢁ
++
++
ꢁ
++
++
ꢁ
++
++
ꢁ
++
++
ꢁ
6
(ꢁ)-2
7
(ꢁ)-2*HCl
(ꢁ)-3
8
++
ꢁ
++
ꢁ
++
+
++
ꢁ
++
ꢁ
9
(ꢀ)-3*HCl
(ꢁ)-3*HCl
(ꢁ)-4
10
11
12
13
14
15
16
17
18
ꢁ
ꢁ
ꢁ
+
+
+
ꢁ
ꢁ
++
++
++
++
ꢁ
++
ꢁ
++
ꢁ
++
++
++
++
ꢁ
++
++
++
++
+
++
++
++
++
++
++
++
++
++
ꢁ
++
+
(ꢁ)-4*HCl
(ꢀ)-5
++
++
ꢁ
++
++
ꢁ
++
++
ꢁ
++
++
ꢁ
(ꢁ)-5
(ꢀ)-5*HCl
(ꢁ)-5*HCl
(ꢁ)-6
ꢁ
ꢁ
ꢁ
ꢁ
+
ꢁ
+
++
ꢁ
++
ꢁ
++
ꢁ
++
ꢁ
++
+
++
ꢁ
++
+
(ꢁ)-6*HCl
(++), 1 volume or weight of sample dissolves in 3 volumes or weights of solvent; (+), 1 volume or weight of sample dissolves in 6–9 volumes or weights of solvent;
(ꢁ), 1 volume or weight of sample does not dissolve in 12 volumes or weights of solvent.
2.2. Phase properties of N-fluoroalkylated (S)-(ꢁ)-PEA
We thought that GC determination of fluorous partition
coefficients, Pexp, for (ꢁ)-PEA derivatives could be a probe
of their phase behavior (cf. Section 4). Indeed, the
experimentally determined partition coefficients were in
good agreement with expected trends. These values are
increased either by the number of fluorous ponytails (Table 2,
entries 1 and 2, 3 and 4) or the removal of the polar and
hydrogen-bond forming >NH groups with an N-methylation
reaction (Table 2, entries 1–5 and 3–6). To show that specific
fluorophilicity, fspec, correlates with cohesion parameter, dde
Wolf, the fluorous isotherm of the free amines was calculated
with a group contribution method [12,13]. Good linear fitting
was found as expected: the lower dde Wolf, the larger the fspec
is (Fig. 1).
derivatives
The liquid free amines 1–6 and their solid HCl salts
displayed good miscibility and/or solubilities in broad spectrum
organic solvents at ambient temperature, but all hydrochlorides
were found sparingly soluble or insoluble in ether and c-
CF3C6F11 (Table 1). Only the bis(perfluoroalkylalkyl)- and
bis(perfluoroalkoxyalkyl)-derivatives among the HCl salts
tested were found to be soluble in benzotrifluoride (Table 1,
entries 7 and 12). Methanol and chloroform displayed good
solvation power in all cases (Table 1, entries 1–18).
No differences were observed in the solubility character-
istics of the free bases either racemic or pure enantiomeric
forms were tested (Table 1, entries 1 and 2, 5 and 6, 13 and 14).
The (ꢀ)-1*HCl and the enantiopure (ꢁ)-1*HCl samples
appeared to have different solubilities in THF, acetone and
CH2Cl2. This property could be used for enantiomeric
enrichment of a partially resolved sample, since the salt of
the pure enantiomer has higher solubility than the correspond-
ing racemate (Table 1, entries 3 and 4). On the other hand the
(ꢀ)-3*HCl and (ꢁ)-3*HCl, as well as the (ꢀ)-5*HCl and (ꢁ)-
5*HCl pairs showed similar solubility patterns (Table 1, entries
9 and 10, 13 and 14). These qualitative data disclosed the rather
complex nature of structure–solubility correlation.
2.3. Resolution via diastereomeric salt formation under
optimal conditions
Optical resolution of racemates via diastereomeric salt
formation is regarded to one of the most powerful tools for the
production of the pure enantiomers [8]. The separation of the
formed p- and n-salts is generally carried out by fractional
crystallization. Effective processes can be elaborated in two
stage optimization starting with the selection of the resolving
agent, followed by the setting of the process paramaters
Table 2
Calculated specific fluorophilicity values and cohesion parameters of fluorous (ꢁ)-PEA derivatives
Compound
Structure
Vm (cm3 molꢁ1
)
dde Wolf (MPa1/2
)
Pexp
fspec
1
2
3
4
5
6
PhCHMe(NH(CH2)3C8F17
)
373
625
290
393
457
310
14.88
13.73
15.67
14.78
14.39
15.13
0.290
4.860
0.154
1.010
0.401
0.165
ꢁ0.651
0.496
PhCHMe(N((CH2)3C8F17)2)
PhCHMe(NH(CH2)2OC(CF3)3)
PhCHMe(N((CH2)2OC(CF3)3)2)
ꢁ1.268
0.0035
ꢁ0.392
ꢁ1.141
PhCHMe(NMe(CH2)3C8F17
)
PhCHMe(NMe(CH2)2OC(CF3)3)

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D. Szabo et al. / Journal of Fluorine Chemistry 127 (2006) 1405–1414
1408
between the organic melt and the bulk water phases until a
composition finally crystallized.
Indeed, the reaction of the racemic sulfoxide dicarboxylic
acid (ꢀ)-SO with one of the seven chiral bases tested (Table 3),
resulted in the formation of a crystalline precipitate ((+)-
{1*SO*1}) and partial resolution of (ꢀ)-SO (Scheme 2). The
pure (S)-(+)- and (R)-(ꢁ)-SO enantiomers were obtained with
selective precipitation of the racemic portion with dioxane as
reported [14,15]. It should be added, that no crystalline
diastereomers were formed with this (ꢀ)-SO, when its
resolution has been attempted with cinchona and other
alkaloids [14].
Selective reactions of nonracemic enantiomer mixtures
provide valuable tools for obtaining pure enantiomers from
partially resolved samples [16]. Unlike to this heat facilitated
optical resolution procedure the general practice applies
cooling instead of heating to effect diastereomeric salt
crystallizations [8,17].
Fig. 1. Fluorous isotherm of (ꢁ)-PEA derivatives calculated from de Wolf
increments.
including stoichiometry of the resolving agent, selection and
volume of the solvent, and the temperature regime.
Our procedure combines the advantages of the methods of
Pope and Peachey [18], and that of Kantor and Hauser who first
reported that prolonged heating of the initially precipitated
diastereomeric salts with insufficient amount of solvent could
improve separation efficacy [19]. The scope and limitations of
this novel non-conventional resolution method are being
investigated and further results will be published later [17].
Based on simplified models (cf. ‘‘resolution equations (a),
(b) and (c)’’ in ref. [14]) and literature data [8], we thought to
devise an ideal process. Water is the solvent of choice and half-
equivalent of the resolving agent is used here at a temperature,
which effects the crystallization of the higher melting
diastereomeric salt.
Our approach involves the mixing of two equivalents of
racemic acid (ꢀ)-HA with one equivalent of the enantiopure
chiral base (ꢁ)-B and one equivalent of NaOH. This treatment
leads to the formation of two diastereomeric salts, (ꢁ,ꢁ)-BHA
(p-salt) and (ꢁ,+)-BHA (n-salt), besides the sodium salts of the
enantiomeric acids, (ꢁ)-NaA and (+)-NaA. If the resolving
agent, (ꢁ)-B, was selected to afford either the p- or the n-salt
with higher melting point then the set temperature of solvent
water, then the first phase separated melt of the mixed
diastereomeric salts could change its composition on prolonged
heating and stirring due to exchange of enantiomeric anions
2.4. Circular dichroism spectra of the fluorous (S)-(ꢁ)-
PEA derivatives
The circular dichroism (CD) spectra of 1-phenylethylamine
(PEA) and its derivatives have been discussed in detail [20,21].
We measured the far-UV (195–250 nm, 1Bb and 1La transitions)
1
and near-UV (240–330 nm, Lb transition) CD spectrum of
fluorous derivatives of (S)-PEA in different solvents. In ethanol
in the spectrum of (S)-PEA-perchlorate two minima were
observed at 209 and at 213 nm. The intensity of these two peaks
Table 3
Preliminary experiments for the selection of the appropriate resolving agent (cf. Section 4.10)
Conditions PEA*HCl 1*HCl 2*HCl 3*HCl
4*HCl
5*HCl
6*HCl
SO + 1/2B; 90 ! 20 8C Clear solution Crystalline precipitate Sticky precipitate Sticky precipitate Sticky precipitate Sticky precipitate Sticky precipitate
SOfrom H O: [a]578 (DMF)
0
ꢁ260a
Corresponds to 51% enantiomeric excess (cf. ref. [15]).
0
ꢁ2.5
+2.1
ꢁ3.0
0
2
a
Scheme 2. Heat facilitated resolution of (ꢀ)-2-(8-carboxy-1-naphthylsulfinyl)benzoic acid ((ꢀ)-SO).

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D. Szabo et al. / Journal of Fluorine Chemistry 127 (2006) 1405–1414
1409
Fig. 3. Far-UV CD spectra of compound 4*HCl in ethanol ( ), in TFE ( ) and
in HFP ( ).
Fig. 2. Far-UV CD spectra of compounds 1*HCl ( ), 2*HCl ( ), 3*HCl ( ),
5*HCl ( ) and 6*HCl ( ) in ethanol.
Fig. 4. Near-UV CD spectra of compound 2*HCl (a) and compound 4*HCl (b) in ethanol ( ), in TFE ( ) and in HFP ( ).
increased and red shifted with fluorinated alkyl substitution of
the amino group (Fig. 2). However, in the case of the tertiary
amine with two identical perfluoroalkyl substituents 2*HCl,
two positive bands also appeared in the far-UV region. In the
CD spectrum of 4*HCl only positive peaks can be seen in
ethanol (Fig. 2).
the case of 4*HCl the solvent effect is most significant: in HFIP
the vibrational peaks became negative (Fig. 4b).
The quadrant sector rule as applied to a-substituted
phenylethane may be depicted as shown in Scheme 3a [22].
In Scheme 3a, the signs refer to the rotatory contributions of
groups lying above the phenyl ring plane. The sign of the
rotational perturbation of a group lying in a particular sector was
deduced empirically [22]. It was concluded that an alkyl group is
not capable of a rotationally significant interaction with the
phenyl chromophore. Thus, it is the protonated amino group
The replacement of ethanol by trifluoroethanol (TFE) or
1,1,1,3,3,3-hexafluoropropan-2-ol (HFP) increased the inten-
sity of the negative bands in the far-UV spectra of 1*HCl,
2*HCl, 3*HCl, 5*HCl and 6*HCl. The effect of TFE is more
expressed in the case of molecules which have one linear
fluorinated alkyl groups. However, in the fluorinated solvents
TFE and HFP the spectra of 4*HCl are dominated by a negative
band at 214 and 213 nm, respectively (Fig. 3). We suppose that
these unexpected spectral differences are caused by the bulky
fluorinated alkyl groups which considerably influence the
conformation.
1
the position of which determines the sign of the Lb band. In
Scheme 3b, the prevailing conformer of compounds (1–6)*HCl
of (S)-configuration can be seen. The NH3+ group is located in a
positive quadrant. In agreement with this, the sign of the1Lb band
is positive. The only exception is the CD spectrum of 4*HCl in
HFP that suggest a drastic conformational change.
In the near-UV CD spectrum the Cotton effects associated
with the 1Lb transition of the benzene ring were observed
between 240 and 275 nm for all molecules and in different
solvents. We observed four or five vibrational bands out of the
six theoretical bands. The same effects were found as in the far-
UV spectrum: the intensity of the vibrational peaks in TFE was
increased and appeared with some red shift (see e.g. Fig. 4a). In
Scheme 3. The quadrant sector rule of the substituted benzene ring [22].

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D. Szabo et al. / Journal of Fluorine Chemistry 127 (2006) 1405–1414
1410
The optical activity of the HCl salts of N-polyfluoroundecyl-
(ppm) relative to TMS (1H, d = 0), CDCl3 (13C, d = 77.0) or for
19F (CFCl3, d = 0) on the d scale. Coupling constants J were
given in Hz. Mass spectrometric experiments were performed on
a Bruker Esquire 3000plus ion trap mass spectrometer, equipped
with electrospray ionization source. Spectra were acquired in
positive ionization mode, in the 15–2000 m/z range. Samples
were dissolved in methanol. Identification of molecular weights
was performed by electrospray ionization mass spectrometry
(ESI-MS). All compounds displayed intensive protonated
molecular ion ([M + H]+) in the mass spectra. CD spectra were
recorded on a Jasco J-810 dichrograph (calibrated with
ammonium d-10-camphor-sulfonate) at room temperature using
0.1 cm cell for measurements between 195 and 250 nm and 1 cm
between 240 and 330 nm. Ethanol (Uvasol), 2,2,2-trifluoroetha-
nol (Aldrich, 99%+) and 1,1,1,3,3,3-hexafluoropropan-2-ol
(Uvasol) were used as solvents and the concentration was
1 mM dmꢁ3. Optical rotations were determined on a Carl Zeiss
Polamat A polarimeter with a 1 dm cell and DMF or MeOH
sample solutions at 25 8C. Melting points were determined on a
Boetius micro-melting point apparatus and are uncorrected. All
reactions were monitored by GC (Hewlett-Packard 5890 Series
II, PONA [cross-linked methylsilicone gum] 50 m ꢂ 0.2 mm
ꢂ 0.5 mm column, H2 carrier gas, FID detection). Fluorous
partitioncoefficients(Pexp)weredeterminedbyGCasfollows:in
a 2 ml volumetric flask the given compounds (10 mg) were
extracted in a 1.00 ml to 1.00 ml mixture of pre-equilibrated c-
CF3C6F11 and toluene. The closed vessel was first immersed in a
water bath (50 8C) for 30 min with frequent shaking, and then
allowed to cool to 25 8C. After standing overnight at this
temperature 300 ꢀ 3 ml aliquots of the separated upper and
lower phases were withdrawn and diluted with 300 ꢀ 3 ml
C6H5CF3, which served as an internal standard for GC analysis.
An average of 7–11 injections for each entry resulted in listed
values (Table 1).
PEA derivatives is determined by the aromatic chromophore
perturbed by the ꢁCH3 and ꢁNH(+)< groups. Comparison of
the far-UV region of the CD spectra in ethanol and TFE of
compounds 1*HCl, 3*HCl, 5*HCl and 6*HCl led to the
conclusion that the relative amount of conformers is similar.
The CH3 group attached to N in 5*HCl stabilizes the dominant
conformer. The presence of two polyfluoroundecyl groups in
1
2*HCl does not affect the sign of the La band at 215 nm in
ethanol or TFE, but gives rise to a positive long-wavelength
band at 225 nm and a positive band in the 1Bb region (at
199 nm). It is 4*HCl the spectrum of which in ethanol features
only positive bands between 195 and 240 nm. The attached two
(perfluoro-tert-butyloxy)ethyl groups appears to influence the
conformational equilibrium but an interaction between the
phenyl ring and the (perfluoro-tert-butyloxy)ethyl group(s)
cannot be excluded either.
The sign of the Cotton effects in the region 240–275 nm
can be predicted based on a quadrant sector rule [22] (Scheme
3). The 1Lb band region of 4*HCl with the typical vibrational
fine structure shows an expressed solvent sensitivity. While
all the splitted bands of 1*HCl, 2*HCl, 3*HCl, 5*HCl and
6*HCl in ethanol and TFE are positive similarly to the
spectrum of PEA, the near-UV region shows a negative band
pattern in HFP and an averaged, almost zero spectrum in TFE
(Fig. 4b). It is compound 4*HCl which differs in both CD
spectral and conformational behavior from all the other
members of the family of 1*HCl, 2*HCl, 3*HCl, 5*HCl and
6*HCl.
3. Conclusions
In conclusion, a series of light fluorous (S)-(ꢁ)-1-
phenylethylamine derivatives was synthesized by the alkylation
of (S)-(ꢁ)-PEA, that may be used for the production of high
value enantiomerically pure acids in this novel half-equivalent
resolution method involving hot water as the solvent of choice
for diastereomeric salt crystallizations. Amines 1–6 could
supplement the inventory of fluorine containing chiral a-
phenylethylamines, which became accessible on laboratory
through to industrial scales via asymmetric syntheses devel-
oped at Central Glass [23].
4.2. General procedure for the syntheses of amine
hydrochlorides (1–6*HCl)
Amines 1–6 (0.20 g) were dissolved in THF (5 ml) and
cooled to 0 8C, and then two to three drops of 12 M HCl was
added. The mixtures were evaporated under vacuum and dried
to afford the title salts in quantitative yields.
4. Experimental
4.3. N-(4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11-
heptadecafluoroundecyl)-(1S)-1-phenylethylamine (1) and
hydrochloride (1*HCl)
4.1. General description of methods and materials
FC-72 and c-CF3C6F11 were purchased from Fluorochem,
while fluorous reagents 7 [9j], 8 [9a] and 9 [10] were prepared
as reported. The other reagents and solvents were Aldrich,
Fluka or Uvasol products. Fourier-transformed infrared spectra
were recorded neat, as a film on a Bruker Equinox FTIR
spectrophotometer, nmax in cmꢁ1. The intensity of the bands is
characterized as broad (br), strong (s), medium (m) or weak
(w). 1H NMR, 13C NMR and 19F NMR spectra were recorded
on Varian INOVA 500 (500 MHz for 1H) spectrometer at 25 8C.
Data were expressed as chemical shifts in part per million
Slightly modified procedure to that reported in ref. [3]. A
mixture of (S)-(ꢁ)-PEA (1.23 g, 10 mmol), 7 (5.87 g,
10 mmol), K2CO3 (3.45 g, 25 mmol) and acetonitrile
(30 ml) was sealed in a 100 ml glass ampoule and stirred at
80 8C for 96 h. Then, the ampoule was opened at r.t. and the
mixture partitioned between water (25 ml) and ether
(3 ꢂ 20 ml). The ether layer was separated, dried (Na2SO4)
and compound 1 was isolated by fractional distillation. Yield:
4.43 g (76%) colorless liquid, bp = 150–155 8C/0.5 mmHg;
[a]546 = ꢁ18.3 (c = 1, MeOH); with agreeable (1H, 13C, 19F)

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D. Szabo et al. / Journal of Fluorine Chemistry 127 (2006) 1405–1414
1411
1
NMR spectra to that reported [3]. H NMR (CDCl3): d 1.35
2JCF = 22.0 Hz, CH2CF2), 48.8; 49.6 (NCH2), 64.3 (CH), 130.2
(C(Ar.), p-CH), 128.8 (C(Ar.), o-CH), 129.6 (C(Ar.), m-CH),
134.1 (C(Ar.), g-CH). 19F NMR (CDCl3): d ꢁ81.4 (3F, t,
J = 9.9 Hz, F-8, CF3), ꢁ114.0 (2F, m, F-1, CF2), ꢁ122.5 (6F, m,
F-2, 3, 6, CF2), ꢁ123.3 (2F, m, F-5, CF2), ꢁ123.8 (2F, m, F-4,
CF2), ꢁ126.7 (2F, m, F-7, CF2). Prochirality of carbons in the
chains can be seen on some signals due to hindered nitrogen
inversion. IR (KBr) n, cmꢁ1: 3431 (br), 2948 (w), 1241 (vs),
1205 (vs), 1149 (s). ESI-MS: m/z = 1042.2 [M + H]+; calcd. for
[C30H22F34N]+ 1042.2.
(3H, d, J = 6.6 Hz, CH3), 3.75 (1H, q, J = 6.6 Hz, CH), 2.60;
2.47 (2H, m, NCH2), 2.12 (2H, m, CH2CF2), 1.72 (2H, m,
CH2CH2CH2), 7.35–7.22 (5H, m, H(Ar.). 13C NMR (CDCl3): d
2
21.0 (CH3), 24.4 (CH2CH2CH2), 28.8 (t, JCF = 22.5 Hz,
CH2CF2), 46.6 (NCH2), 58.3 (CH), 126.5 (C(Ar.), o-CH),
127.0 (C(Ar.), p-CH), 128.5 (C(Ar.), m-CH), 145.6 (C(Ar.), g-
CH). 19F NMR (CDCl3): d ꢁ81.3 (3F, t, J = 9.9 Hz, F-8, CF3),
ꢁ114.4 (2F, m, F-1, CF2), ꢁ122.4 (6F, m, F-2, 3, 6, CF2),
ꢁ123.2 (2F, m, F-5, CF2), ꢁ124.0 (2F, m, F-4, CF2), ꢁ126.6
(2F, m, F-7, CF2).
1*HCl: mp 185 8C, [a]546 = ꢁ11.2 (c = 1, MeOH). 1H NMR
(CDCl3): d 1.92 (3H, d, J = 6.7 Hz, CH3), 4.26 (1H, m, CH),
2.82; 2.73 (2H, m, NCH2), 2.31 (2H, m, CH2CF2), 2.10 (2H, m,
CH2CH2CH2), 7.64–7.38 (5H, m, H(Ar.)), 10.4; 10.1 (2H,
N+H2). 13C NMR (CDCl3): d 17.4 (CH3), 20.5 (CH2CH2CH2),
4.5. N-{2-[1,1-bis(trifluoromethyl)-2,2,2-
trifluoroethoxy]ethyl)}-(1S)-1-phenylethylamine (3) and
hydrochloride (3*HCl)
A stirred mixture of (S)-PEA (2.42 g, 20 mmol), tosylate 9
(6.68 g, 20 mmol) and K2CO3 (6.9 g, 50 mmol) in dry
acetonitrile was heated at 90 8C under an argon atmosphere
for 60 h. The insoluble salts were filtered off and the solvent
was removed under vacuum, then the crude product distilled to
afford the title amine 5. Yield: 3.9 g (51%) colorless liquid, bp
108–110 8C/15 mmHg, [a]546 = ꢁ24.2 (c = 1, MeOH). 1H
NMR (CDCl3): d 1.35 (3H, d, J = 6.6 Hz, CH3), 3.79 (1H, q,
J = 6.6 Hz, CH), 4.07 (2H, m, OCH2), 2.80; 2.67 (2H, m,
NCH2), 7.34–7.22 (5H, m, H(Ar.)). 13C NMR (CDCl3): d 24.5
(CH3), 46.6 (NCH2), 58.0 (CH), 69.6 (OCH2), 120.3 (q,
J = 292.5, CF3), 126.5 (C(Ar.), o-CH), 127.0 (C(Ar.), p-CH),
128.5 (C(Ar.), m-CH), 145.2 (C(Ar.), g-CH). 19F NMR
(CDCl3): d ꢁ70.9 (CF3). IR (neat) n, cmꢁ1: 2970 (w), 1269
(vs), 1253 (vs), 1161 (s) and 972 (s).
2
28.3 (t, JCF = 22.5 Hz, CH2CF2), 45.0 (NCH2), 59.5 (CH),
127.8 (C(Ar.), o-CH), 129.5 (C(Ar.), p-CH), 129.6 (C(Ar.), m-
CH), 135.6 (C(Ar.), g-CH). 19F NMR (CDCl3): d ꢁ81.4 (3F, t,
J = 9.9 Hz, F-8, CF3), ꢁ114.9 (2F, m, F-1, CF2), ꢁ122.5 (6F, m,
F-2, 3, 6, CF2), ꢁ123.4 (2F, m, F-5, CF2), ꢁ124.0 (2F, m, F-4,
CF2), ꢁ126.8 (2F, m, F-7, CF2). IR (KBr) n, cmꢁ1: 3437 (br),
2770 (m), 1242 (vs), 1206 (vs), 1150 (vs). ESI-MS: m/z = 582.1
[M + H]+; calcd. for [C19H17F17N]+ 582.1.
4.4. N,N-bis(4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11-
heptadecafluoroundecyl)-(1S)-1-phenylethylamine (2) and
hydrochloride (2*HCl)
To a solution of aldehyde 8 (2.14 g, 4.5 mmol) in dry THF
(30 ml) was added (S)-PEA (0.23 g, 1.86 mmol) and stirred at
r.t. for 10 min. After the addition of NaBH(OAc)3 (1.19 g,
5.62 mmol) the mixture was stirred for 20 h. Then, 1N NaOH
(20 ml) was added and the mixture extracted with ether
(3 ꢂ 50 ml). The organic layers were separated and dried
(Na2SO4) and the solvent removed under vacuum. The crude
product was purified by column chromatography (silica gel,
hexane/ether, 9:1) to afford the title compound 2. Yield:
1.93 g (56%) colorless liquid, [a]546 = ꢁ2.82 (c = 1, MeOH).
1H NMR (CDCl3): d 1.34 (3H, d, J = 6.8 Hz, CH3), 3.90 (1H,
q, J = 6.8 Hz, CH), 2.57; 2.40 (4H, m, NCH2), 2.08; 1.91 (4H,
m, CH2CF2), 1.68 (4H, m, CH2CH2CH2), 7.33–7.22 (5H, m,
H(Ar.)). 13C NMR (CDCl3): d, 18.6 (CH3), 13.8
3*HCl: mp 205–209 8C, [a]546 = ꢁ11.2 (c = 1, MeOH). 1H
NMR (CDCl3): d 1.85 (3H, d, J = 7.0 Hz, CH3), 4.33 (1H, q,
J = 7.0 Hz, CH), 4.69; 4.39 (2H, m, OCH2), 3.05 (2H, m,
NCH2), 7.34–7.22 (5H, m, H(Ar.)), 10.6; 10.2 (2H, N+H2). 13
C
NMR (CDCl3): d 20.4; [18.4] (CH3), 43.5 (NCH2), 59.3; [58.2]
(CH), 65.1 (OCH2), 120.0 (q, J = 292.0, CF3), 127.7 (C(Ar.), o-
CH), 129.6 (C(Ar.), p-CH), 129.6 (C(Ar.), m-CH), 135.4
(C(Ar.), g-CH). 19F NMR (CDCl3): d ꢁ70.7 (CF3). Small
intensity carbon signals (for carbons CH and CH3 in square
brackets) of a higher energy temporary diastereomeric form
appear. Note the nontypical nonequivalency of N+H2 hydrogens
in the proton spectrum as well. IR (KBr) n, cmꢁ1: 3436 (br),
2745 (m), 1267 (vs), 1168 (m), 973 (m). ESI-MS: m/z = 384.1
[M + H]+; calcd. for [C14H15F9NO]+ 384.1.
2
(CH2CH2CH2), 28.5 (t, JCF = 22.0 Hz, CH2CF2), 48.4
(NCH2), 57.7 (CH), 127.0 (C(Ar.), p-CH), 127.8 (C(Ar.),
o-CH), 128.1 (C(Ar.), m-CH), 142.9 (C(Ar.), g-CH). 19F
NMR (CDCl3): d ꢁ81.4 (3F, t, J = 9.9 Hz, F-8, CF3), ꢁ114.9
(2F, m, F-1, CF2), ꢁ122.5 (6F, m, F-2, 3, 6, CF2), ꢁ123.3 (2F,
m, F-5, CF2), ꢁ124.4 (2F, m, F-4, CF2), ꢁ126.7 (2F, m, F-7,
CF2). Prochirality of carbons in the chains are averaged out
due to fast nitrogen inversion. IR (neat) n, cmꢁ1: 2977 (w),
1242 (vs), 1208 (vs), 1152 (s).
4.6. N,N-bis{2-[1,1-bis(trifluoromethyl)-2,2,2-
trifluoroethoxy]ethyl)}-(1S)-1-phenylethylamine (4) and
hydrochloride (4*HCl)
A stirred mixture of (S)-PEA (0.48 g, 4.0 mmol), triflate 10
(3.5 g, 8.6 mmol) and K2CO3 (2.36 g, 17.1 mmol) in dry
acetonitrile (13 ml) was heated at 90 8C under argon atmo-
sphere for 72 h. Water (20 ml) and ether (20 ml) was added to
the mixture, then the aqueous phase was separated and
extracted with ether (2 ꢂ 10 ml). The ether layers were
combined and dried (Na2SO4), and then the solvent was
removed. The crude product was purified by vacuum
1
2*HCl: mp 102–104 8C, [a]546 = ꢁ2.8 (c = 1, MeOH). H
NMR (CDCl3): d 1.93 (3H, d, J = 6.4 Hz, CH3), 4.41 (1H, m,
CH), 3.4–2.8 (4H, m, NCH2), 2.5–1.95, (8H, m, CH2CF2,
CH2CH2CH2), 7.7–7.5 (5H, m, H(Ar.)), 12.7 (1H, N+H). 13C
NMR (CDCl3): d 17.7 (CH3), 15.1; 15.5 (CH2CH2CH2), 28.2 (t,

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D. Szabo et al. / Journal of Fluorine Chemistry 127 (2006) 1405–1414
1412
distillation to afford the title amine 4. Yield: 1.53 g (60%)
colorless liquid, bp 114–118 8C/0.5 mmHg, [a]546 = ꢁ5.8
1217 (vs), 1146 (vs). ESI-MS: m/z = 596.1 [M + H]+; calcd. for
[C20H19F17N]+ 596.1.
1
(c = 1, MeOH). H NMR (CDCl3): d 1.37 (3H, d, J = 6.8 Hz,
CH3), 3.90 (1H, q, J = 6.8 Hz, CH), 3.94 (4H, m, OCH2), 2.92–
2.76 (4H, m, NCH2), 7.34-7.22 (5H, m, H(Ar.)). 13C NMR
(CDCl3): d 16.19 (CH3), 50.9 (NCH2), 69.3 (CH), 60.7 (OCH2),
120.4 (q, J = 293.0, CF3), 127.5 (C(Ar.), o-CH), 127.1 (C(Ar.),
p-CH), 128.3 (C(Ar.), m-CH), 143.3 (C(Ar.), g-CH). 19F NMR
(CDCl3): d ꢁ71.0 (CF3). IR (neat) n, cmꢁ1: 2977 (w), 1307 (vs),
1248 (vs), 1154 (vs) and 972 (vs).
4*HCl: mp 141–144 8C, [a]546 = ꢁ8.0 (c = 1, MeOH). 19F
NMR (CDCl3): d ꢁ70.6 (CF3). Because of conformational
motions at room temperature the proton and carbon NMR
spectra contain many diffuse non-characteristic signals, only
the fluorine data is given. IR (KBr) n, cmꢁ1: 3438 (br), 1267
(vs), 1257 (vs), 1154 (s) and 973 (s). ESI-MS: m/z = 646.1
[M + H]+; calcd. for [C20H18F18NO2]+ 646.1.
4.8. N-methyl-N-{2-[1,1-bis(trifluoromethyl)-2,2,2-
trifluoroethoxy]ethyl)}-(1S)-1-phenylethylamine (6) and
hydrochloride (6*HCl)
A stirred solution of amine 3 (1.49 g, 3.9 mmol), formic
acid (1.3 ml) and formaldehyde (1.3 ml 37% in H2O) was
heated at 90 8C for 2 h. Then, the mixture was cooled,
treated with 1 M NaOH (15 ml) and extracted with ether
(3 ꢂ 10 ml). Then, the organic phase was separated, dried
(Na2SO4) and evaporated. The residue was distilled to afford
the title amine 6. Yield: 1.11 g (72%) colorless liquid, bp
1
114 8C/15 mmHg, [a]546 = ꢁ14.5 (c = 1, MeOH). H NMR
(CDCl3): d 1.35 (3H, d, J = 6.8 Hz, CHCH3), 3.61 (1H, q,
J = 6.8 Hz, CH), 2.27 (3H, NCH3), 4.02 (2H, m, OCH2),
2.75; 2.60 (2H, m, NCH2), 7.33–7.21 (5H, m, H(Ar.)). 13C
NMR (CDCl3): d 18.4 (CHCH3), 39.6 (NCH3), 53.2 (NCH2),
63.7 (CH), 68.5 (OCH2), 120.4 (q, J = 293.9, CF3), 127.5
(C(Ar.), o-CH), 126.9 (C(Ar.), p-CH), 128.2 (C(Ar.), m-CH),
143.9 (C(Ar.), g-CH). 19F NMR (CDCl3): d ꢁ70.9 (CF3). IR
(neat) n, cmꢁ1: 2978 (w), 1268 (vs), 1252 (vs), 1156 (s) and
971 (s).
4.7. Methyl N-(4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11-
heptadecafluoroundecyl)-(1S)-1-phenylethylamine (5) and
hydrochloride (5*HCl)
A stirred solution of 28 amine 1 (1.74 g, 3 mmol), formic
acid (1 ml) and formaldehyde (1 ml, 37% in H2O) was heated
at 90 8C for 2 h. Then, the mixture was cooled, treated with
1 M NaOH (10 ml) and extracted with ether (3 ꢂ 5 ml). Then,
the organic phase was separated, dried (Na2SO4) and
evaporated. The residue was distilled to afford the title
amine 7. Yield: 1.02 g (57%) colorless liquid, bp 164–169 8C/
15 mmHg), [a]546 = ꢁ11.0 (c = 1, MeOH). 1H NMR
(CDCl3): d 1.34 (3H, d, J = 6.8 Hz, CH3), 3.55 (1H, q,
J = 6.8 Hz, CH), 2.44; 2.33 (2H, m, NCH2), 2.18 (3H, CH3),
2.05 (2H, m, CH2CF2), 1.71 (2H, m, CH2CH2CH2), 7.33–7.21
(5H, m, H(Ar.)). 13C NMR (CDCl3): d 18.1 (CHCH3), 18.0
6*HCl: mp 160–165 8C, [a]546 = ꢁ11.3 (c = 1, MeOH). 1H
NMR (CDCl3): d 1.89; 1.90 (3H, d, J = 6.8 Hz, CHCH3), 4.80;
4.93 (1H, CH), 2.66; 2.90 (3H, NCH3), 4.41; 4.55 (2H, m,
OCH2), 3.85–3.0 (2H, m, NCH2), 7.72–7.40 (5H, m, H(Ar.)),
12.9; 13.0 (1H, N+H). 13C NMR (CDCl3): d 17.0; 17.2
(CHCH3), 36.5; 38.9 (NCH3), 51.9; 53.7 (NCH2), 64.6; 64.7
(CH), 66.0; 66.6 (OCH2), 119.9 (q, J = 292.5, CF3), 128.7;
129.0 (C(Ar.), o-CH), 130.0; 130.2 (C(Ar.), p-CH), 129.4;
129.5 (C(Ar.), m-CH), 133.9; 133.2 (C(Ar.), g-CH). 19F NMR
(CDCl3): d ꢁ70.6 (CF3). Each carbon signals and most of the
proton multiplets doubled according to a temporary diaster-
eomeric form due to hindered nitrogen inversion on the
protonated nitrogen. Note the doubling of N+H signal in the
proton spectrum, as well. IR (KBr) d, cmꢁ1: 3431 (br), 2921
(w), 1268 (vs), 1155 (s) and 972 (s). ESI-MS calculated:
397.1 m/z, measured: 397.1 m/z. ESI-MS: m/z = 398.1
[M + H]+; calcd. for [C15H17F9NO]+ 398.1.
2
(CH2CH2CH2), 28.6 (t, JCF = 22.5 Hz, CH2CF2), 38.0
(NCH3), 52.8 (NCH2), 63.5 (CH), 127.6 (C(Ar.), o-CH),
126.9 (C(Ar.), p-CH), 128.1 (C(Ar.), m-CH), 143.9(C(Ar.), g-
CH). 19F NMR (CDCl3): d ꢁ81.3 (3F, t, J = 9.9, F-8, CF3),
ꢁ114.7 (2F, m, F-1, CF2), ꢁ122.3 (6F, m, F-2, 3, 6, CF2),
ꢁ123.2 (2F, m, F-5, CF2), ꢁ124.0 (2F, m, F-4, CF2), ꢁ126.6
(2F, m, F-7, CF2). IR (neat) n, cmꢁ1: 2978 (w), 1242 (vs),
1209 (vs) and 1152 (vs).
5*HCl: mp 133–155 8C, [a]546 = ꢁ10.4 (c = 1, MeOH). 1H
NMR (CDCl3): d 1.91; 1.92 (3H, CH3), 4.32; 4.47 (1H, CH),
2.86; 2.65 (3H, CH3), 3.4–1.8 (6H, m, NCH2CH2CH2CF2),
7.66–7.42 (5H, m, H(Ar.)), 12.6; 10.2 (1H, N+H). 13C NMR
(CDCl3): d 17.0; 17.4 (CHCH3), 15.4; 15.6 (CH2CH2CH2),
28.3; 28.5 (CH2CF2), 35.3; 38.6 (NCH3), 51.3; 53.6 (NCH2),
64.9; 66.4 (CH), 128.7; 129.2 (C(Ar.), o-CH), 130.0; 130.2
(C(Ar.), p-CH), 129.4; 129.5 (C(Ar.), m-CH), 132.9; 133.9
(C(Ar.), g-CH). 19F NMR (CDCl3): d ꢁ81.3 (3F, t, J = 9.2, F-8,
CF3), ꢁ114.2 (2F, m, F-1, CF2), ꢁ122.4 (6F, m, F-2, 3, 6, CF2),
ꢁ123.2 (2F, m, F-5, CF2), ꢁ123.8 (2F, m, F-4, CF2) and ꢁ126.6
(2F, m, F-7, CF2). Each carbon signals and most of the proton
multiplets doubled according to a temporary diastereomeric
form due to hindered nitrogen inversion on the protonated
nitrogen. IR (KBr) n, cmꢁ1: 3435 (br), 2925 (w), 1244 (vs) and
4.9. 2-[1,1-Bis(trifluoromethyl)-2,2,2-trifluoroethoxy]ethyl
trifluoromethanesulfonate (10)
The solution of trifluoromethanesulfonic anhydride (10.0 g,
35.4 mmol) in dichloromethane (60 ml) was cooled to ꢁ20 8C
and a solution of 2-(nonafluoro-tert-butoxy)ethyl alcohol 9
(10 g, 35.4 mmol) and dry pyridine (2.8 g, 35.4 mmol) in
dioxane (20 ml) was added. The mixture was then stirred at
0 8C for 1 h. Salts were filtered off and the solvents were
removed by evaporation. The residue was purified by
distillation to afford triflate 10. Yield: 6.0 g (47%) colorless
1
liquid, bp 107–115 8C/15 mmHg. H NMR (CDCl3): d 4.68
(2H, t, J = 4.4 Hz), 4.35 (2H, t, J = 4.4 Hz). 13C NMR (CDCl3):
d 120.1 (3C, q, J = 292 Hz), 118.6 (1C, q, J = 292 Hz), 79.9
(1C, m), 73.3 (1C, s), 66.5 (1C, s). 19F NMR (CDCl3): d ꢁ71.2

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D. Szabo et al. / Journal of Fluorine Chemistry 127 (2006) 1405–1414
1413
(9F, s), ꢁ75.6 (3F, s). IR (neat) n, cmꢁ1: 1271 (vs), 1253 (vs),
´
Horvath (Eds.), Handbook of Fluorous Chemistry, Wiley-VCH, Wein-
heim, 2004, pp. 236–246.
1168 (s), 1146 (s) and 974 (s).
[2] (a) G. Pozzi, M. Cavazzini, S. Quici, D. Maillard, D. Sinou, J. Mol. Catal.
A 182–183 (2002) 455–461;
4.10. General procedure of the selection of the resolving
agent
(b) G. Pozzi, I. Shepperson, Coord. Chem. Rev. 242 (2003) 115–124.
[3] I. Shepperson, S. Quici, G. Pozzi, M. Nicoletti, D. O’Hagan, Eur. J. Org.
Chem. (2004) 4545–4551.
[4] J. Bayardon, D. Sinou, O. Holcznecht, L. Mercs, G. Pozzi, Tetrahedron:
Asymmetry 16 (2005) 2319–2327.
The racemic acid (ꢀ)-SO*H2O (35.9 mg, 0.10 mmol) was
first dissolved in 0.10 M aq-NaOH (2.00 ml) at 100 8C, then the
clear solution obtained treated with a half-equivalent of the
chiral base selected from the (ꢁ)-EPA*HCl and (ꢁ)-1–6*HCl
family. The mixtures were heated at 90 8C for 6 h and then
cooled to r.t. One of the seven bases, 1*HCl, effected
crystallization (Table 3). This salt was filtered out, then the
clear aqueous phase acidified with 1 M H2SO4 to pH 2 at 0 8C.
The precipitated SO*H2O was filtered and washed with water,
then dried (i.v. P2O5).
[5] I. Shepperson, M. Cavazzini, G. Pozzi, S. Quici, J. Fluorine Chem. 125
(2004) 175–180.
[6] (a) H. Kleijn, A.W. Kleij, J.J.M. de Pater, M. Lutz, A. Spek, J.T.B.H.
Jastrzebski, B.-J. Deelman, G. van Koten, Inorg. Chim. Acta 359 (2005)
2674–2682;
(b) I.P. Beletskaya, A.V. Cheprakov, J. Organometal. Chem. 689 (2004)
4055–4082;
(c) J. Dupont, C.S. Consorti, J. Spencer, Chem. Rev. 105 (2005) 2527–
2571.
[7] F. Fache, O. Piva, Tetrahedron Lett. 42 (2001) 5655–5657.
[8] (a) J. Jaques, A. Collet, S.H. Wilen, Enantiomers, Racemates, and
Resolutions, Wiley, New York, 1981, pp. 251–368;
(b) D. Kozma (Ed.), CRC Handbook of Optical Resolutions via Diaster-
eomeric Salt Formation, CRC Press, Boca Raton, 2000;
(c) F. Faigl, D. Kozma, in: F. Toda (Ed.), Enantiomer Separation: Funda-
mentals and Practical Methods, Kluwer Academic Press, Dordrecht, 2004
(Chapter 9).
4.11. Optical resolution of (ꢀ)-2-(8-carboxy-1-
naphthylsulfinyl)benzoic acid
The racemic acid (ꢀ)-SO*H2O (0.359 g, 1.00 mmol) was
dissolved in 0.1 M NaOH (20 ml) and heated to 100 8C.
Then, 1*HCl (0.62 g, 1.00 mmol) was added and the mixture
was stirred at 90 8C for 6 h. After cooling to r.t. the crystals
were filtered off, washed with water and dried to give the
diastereomeric salt with (+)-rotation {(+)-SO*((ꢁ)-1)2}
(0.61 g, mp 90.5–91.5 8C, [a]578 = +77, c = 0.5, DMF). To
liberate the (+)-acid the latter salt was dissolved in CHCl3
(10 ml) and treated with 1 M Na2CO3 (3 ꢂ 3 ml). The
alkaline phase was acidified with 1 M H2SO4 to pH 2. The
precipitate was filtered, washed with water and dried to yield
(+)-SO*H2O (0.117 g, [a]578 = +343, ee = 68%, c = 0.5,
DMF). The resolving agent amine (S)-(ꢁ)-1 (0.46 g, 79%)
was recovered by the evaporation of the CHCl3 phase. The
clear aqueous filtrate of the (+)-diastereomeric salt {(+)-
SO*((ꢁ)-1)2} was acidified with 1 M H2SO4 to pH 2 and the
precipitated (ꢁ)-acid was filtered off, washed with water and
dried to give the partially resolved acid (ꢁ)-SO*H2O
(0.18 g, [a]578 = ꢁ259.5, ee = 51%, c = 0.5, DMF). These
partially resolved (+)- and (ꢁ)-acid samples showed
identical properties and spectral data to that reported in
ref. [15].
[9] (a) C. Rocaboy, W. Bauer, J.A. Gladysz, Eur. J. Org. Chem. 14 (2000)
2621–2628;
´
(b) Z. Szlavik, G. Tarkanyi, A. Gomory, G. Tarczay, J. Rabai, J. Fluorine
´
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¨
Chem. 108 (2001) 7–14;
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´
´
(c) J. Rabai, A. Abulikemu, D. Szabo, in: J.A. Gladysz, I.T. Horvath, D.P.
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(i) J.-M. Vincent, D. Lastecoueres, M. Contel, M. Laguna, R.H. Fish,
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(j) J.-M. Vincent, R.H. Fish, in: J.A. Gladysz, I.T. Horvath, D.P. Curran
(Eds.), Handbook of Fluorous Chemistry, Wiley/VCH, Weinheim, 2004 ,
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´ ´ ´
[10] D. Szabo, J. Mohl, A.-M. Balint, A. Bodor, J. Rabai, J. Fluorine Chem., in
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We acknowledge the Hungarian Scientific Research
Foundation (OTKA T43738 and T049792). We also thank
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Drs. Elemer Vass and Gitta Schlosser for providing us with
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[13] D. Szabo, A.-M. Bonto, I. Kovesdi, A. Gomory, J. Rabai, J. Fluorine
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[14] J. Rabai, Angew. Chem. Int. Ed. Engl. 31 (1992) 1631–1633;
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FTIR and MS spectra and Mrs. Ana-Maria Balint for
calculating fluorous isotherms.
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J. Rabai, Angew. Chem. 104 (1992) 1648–1650.
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