Preparation of (1R,1′R)-1,1′-(anthracene-9,10-diyl)bis(2,2,2-trifluoroethanamine): a chiral diamine with low basicity

Article abstract of DOI:10.1016/j.tet.2008.10.082

A new chiral diamine with low basicity was synthesized in enantiopure form. (1R,1′R)-1,1′-(Anthracene-9,10-diyl)bis(2,2,2-trifluoroethanamine) was obtained by means of several stereochemically controlled reactions. The structures of the title compound and several intermediates were studied.

Full text of DOI:10.1016/j.tet.2008.10.082

Tetrahedron 65 (2009) 171–176
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Preparation of (1R,10R)-1,10-(anthracene-9,10-diyl)bis(2,2,2-trifluoroethanamine):
a chiral diamine with low basicity
,
a
a
Carla Estivill a, Julen Mendizabal a, Albert Virgili a , Eva Monteagudo , Teresa Flor ,
*
a
b
b
´
Francisco Sanchez-Ferrando , Angel Alvarez-Larena , Juan F. Piniella
a
´
`
Departament de Quımica, Universitat Autonoma de Barcelona, 08193 Bellaterra, Barcelona, Spain
b Servei de Difraccio´ de Raigs X, Universitat Auto`noma de Barcelona, 08193 Bellaterra, Barcelona, Spain
a r t i c l e i n f o
a b s t r a c t
A new chiral diamine with low basicity was synthesized in enantiopure form. (1R,10R)-1,10-(Anthracene-
9,10-diyl)bis(2,2,2-trifluoroethanamine) was obtained by means of several stereochemically controlled
reactions. The structures of the title compound and several intermediates were studied.
Ó 2008 Elsevier Ltd. All rights reserved.
Article history:
Received 19 September 2008
Accepted 23 October 2008
Available online 29 October 2008
Keywords:
Diamines
Enantiorecognition
a
-Trifluoromethylamines
Anthracene
1. Introduction
center may participate in several simultaneous soft connections,
while in addition the hydroxyl groups can be advantageously used
Chiral compounds able to form non-covalent bonds with ap-
propriate substrates result in sets of association complexes, which
display the usual properties of diastereomeric stereoisomers. The
main advantage of these diastereomeric association complexes is
that they lack the rigidity of covalent bonds between their moieties.
This is the objective of preparing compounds with easy associative
properties that can be applied to enantiorecognition in a versatile
way.1 Additionally, the same compounds may also be used to form
covalent derivatives useful as chiral auxiliaries in stereoselective
synthesis.2
for building covalent stable intermediates under differential ster-
eocontrolled conditions. Other derivatives, also effective as CSAs,
can likewise be applied as effective auxiliaries in stereocontrolled
reactions.4 The formation of tweezer structures5 takes advantage of
these properties.
Besides the hydroxyl function, present in all cases discussed so
far, a complementary basic center to make the hydrogen bond
could be useful. We now present the preparation of a similar
molecule in which the OH groups were replaced by two amino
groups, namely (1R,10R)-1,10-(anthracene-9,10-diyl)bis(2,2,2-tri-
fluoroethanamine) (1), a diamino compound with basic properties
that should be capable of forming bonds with acidic centers (Fig. 1).
We wish to emphasize the low basic character of these amino
groups6 due to the electron withdrawing character of the tri-
fluoromethyl group. This implies that ionic ammonium salts de-
rived from a complete reaction with weak acids will not be easily
formed, since formation of associated species should be more
favorable.
Common chiral auxiliaries are donor–acceptor compounds that
can participate in hydrogen bonds or
previously described the chiral auxiliary capacity of enantiopure
0-(bistrifluoromethyl)-9,10-anthracenedimethanol.3 Some fea-
p interactions. We have
a,a
tures of its structure make this compound a very effective chiral
solvating agent (CSA): (i) the presence of two stereogenic centers,
(ii) two acidic groups (OH) that can give hydrogen bonds, (iii) two
C–H bonds with a strong
a withdrawing group such as tri-
fluoromethyl, and (iv) a large aromatic ring such as anthracene with
the corresponding stereo and anisotropic influence and that pro-
vides p-stacking stabilization forces. All substituents on each chiral
Much effort has been spent into asymmetric synthesis of a-tri-
fluoromethylamines, which has resulted in a diversity of method-
ologies: reduction of an enantiopure imine formed from a ketone
and an enantiopure amine;7 reduction of an imine or oxime using
an enantiopure catalyst;8 and imine reduction by a [1,3] proton shift
process.9 Finally, the trifluoromethylation of a carbon–nitrogen
double bond of an enantiopure molecule is the method10 used in
* Corresponding author.
E-mail address: albert.virgili@uab.es (A. Virgili).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.10.082

172
C. Estivill et al. / Tetrahedron 65 (2009) 171–176
CF
3 NH2
atoms. We measured the rotation energy around the C9–C11 bond of
CF
3 NH2
H
H
2 by means of 1H NMR at several temperatures. At the coalescence
temperature (350 K) we obtained k¼1219 sꢁ1 and
D
Gs¼15.9 kcal/
mole. This value is greater than the value obtained for the corre-
sponding alcohol derivative.22
We obtained single crystals of 2S and determined its structure
by X-ray diffraction. The crystal structure is monoclinic with P21 as
space group. The CF3 group is placed in an orthogonal position to
anthracene plane. Molecules are packed in a herring bone ar-
rangement (Fig. 3) forming stacks where anthracenes are parallel
and partially overlapped. This overlapping and the distance be-
H
H2N
CF3
1
2
Figure 1. Structure of target compounds 1 and 2.
the present work to obtain the homochiral enantiomers of
1,10-(anthracene-9,10-diyl)bis(2,2,2-trifluoroethanamine) (1). Both
steps, the preparation of an enantiopure sulfinamide11 and the
trifluoromethylation process have been extensively studied and
developed.12
tween anthracene planes, 3.547 Å, point out the existence of
p–p
interactions. Moreover, molecules are linked by N–H/N and N–
H/F three-center hydrogen bonds forming infinite chains. Weaker
CarH/F intermolecular hydrogen bonds are also present.
Although there is no precedent for the double formation
of disulfinamides, we used similar conditions to prepare
(E,E,SS,SS)-N,N0-(anthracene-9,10-diylbis(methan-1-yl-1-ylidene))-
bis(2-methylpropane-2-sulfinamide) 5SSSS (Fig. 4). The reaction
between anthracene-9,10-dicarbaldehyde and (SS)-tert-butane-
sulfinamide in the presence of anhydrous CuSO4 gave anthracene-
9,10-dicarbonitrile as the only product, although in a very slow
reaction even under heating. The best condensation conditions
with water elimination were achieved using Ti(OEt)4 in THF, which
afforded a high yield (90%) of 5SSSS. The mono-reacted compound
(6SS) was also observed.
Attempts to prepare the trifluoromethylated compound 5, car-
ried out using TMSCF3 and t-BuOK as initiator, were unsuccessful. In
all tested reaction conditions and for all concentrations of the re-
actants we observed the degradation to anthracene-9,10-dicarbo-
nitrile. The very high basicity of the initiator possibly induces this
decomposition to a much larger extent than for the monofunctional
compound 3.
2. Results and discussion
Enantiomers of the amine 1-(anthracen-9-yl)-2,2,2-tri-
fluoroethanamine (2) have been described only once, but as their
hydrochloride ammonium salts.13 Therefore, we began by pre-
paring and studying the monofunctional free amine 2. Attempted
condensation processes between 9-anthraldehyde and one of the
enantiomers of tert-butanesulfinamide14 in the presence of
MgSO415 or CuSO416 under heating resulted in decomposition of the
corresponding sulfinamide to anthracenenitrile.17 Only the reaction
with CuSO4, after 60 days at room temperature, gave an 85% yield.
On the other hand, the described18 condensation with Ti(OEt)4 was
very effective and, when used with (Ss)-tert-butanesulfinamide,
gave
(E,Rs)-N-(anthracen-9-ylmethylene)-tert-butane-2-sulfina-
mide (3SS) in high yield (95%). The 1H and 19F NMR spectra revealed
a single stereoisomer.
The trifluoromethylation of 3SS was carried out as described,
with trifluoromethyltrimethylsilane (TMSCF3) (Ruppert’s rea-
gent) using tetrabutylammonium triphenylsilyldifluorosilicate
(TBAT),13 t-BuOK19 or tetramethylammonium fluoride (TMAF)18,20
as initiators. Only the third initiator resulted in complete conver-
sion to N-((R,Ss)-1-(anthracen-9-yl)-2,2,2-trifluoroethyl)-tert-bu-
tane-2-sulfinamide (4RSS). Acid (HCl) hydrolysis in methanol
followed by neutralization furnished the free amine (R)-1-
(anthracen-9-yl)-2,2,2-trifluoroethanamine (2R) in high yield
(80%) and total selectivity. The selectivity was measured by chiral
HPLC on Welch-O1 column, which resulted in a single peak. This
confirms the enantioselectivity of the method. Using the variation
of chemical shift of several protons of 2R (in CD3OD) with pD and
using HypNMR21 computer program, we measured the pKa of the
ammonium salt as 3.21ꢀ0.02. The enantiomeric free amine (S)-1-
(anthracen-9-yl)-2,2,2-trifluoroethanamine (2S) was obtained
using (RS)-tert-butanesulfinamide.
We obtained monotrifluoromethylation of 5SSSS (i.e., derivative
7RSSSS) almost exclusively when TMSCF3 and TBAT were used as
a source of fluorine (Fig. 5). TBAT (6 equiv) was used to obtain
a quantitative yield of the intermediate compound (7RSSSS). A va-
riety of changes in the conditions did not achieve bistri-
fluoromethyl addition in a useful proportion. Moreover, after
isolation of 7RSSSS, further reaction under the same conditions
The structures of sulfinamide 4 and the free amine 2 were
studied using NMR. Both compounds exhibited conformations in
which the CF3 group was pointing away from the anthracene ring in
an almost orthogonal orientation (Fig. 2). Thus, rotation around the
C9–C11 bond is hindered by the interaction between the CF3 group
and the peri-hydrogen atoms H1 and H8. NMR spectra (both 1H and
13C) illustrate the lack of symmetry of the anthracene ring, showing
separate signals for each individual aromatic proton and carbon
R
CF3
H11
HN
H1
H8
H8
H1
NH
R
H11
CF3
Figure 2. Vertical view of the equilibrium between rotational conformers of com-
pounds 2 (R¼H) and 4 (R¼SO-tert-butyl).
Figure 3. Cell representation of X-ray structure of (S)-1-(anthracen-9-yl)-2,2,2-
trifluoroethanamine (2S).

C. Estivill et al. / Tetrahedron 65 (2009) 171–176
173
O
O
S
N
S
N
O
H
H
O
O
S
NH2
+
2
N
S
6SS
5SSSS
O
H
O
Figure 4. Preparation of (E,E,SS,SS)-N,N0-(anthracene-9,10-diylbis(methan-1-yl-1-ylidene))bis(2-methylpropane-2-sulfinamide) 5SSSS.
failed to promote the addition of a second CF3 group. The first
sulfinamide group of 5SSSS was more reactive than the second one,
and also more than that of monofunctionalized compound 4. The
maximum yield obtained when TBAT was used was 5%.
assigned the cisoid conformation on the basis of HMBC results.
Thus, the presence of the HMBC cross peaks HB4/C2B and H1B/C3B is only
compatible with a cisoid conformation.
Hydrolysis of 8RRSSSS (Fig. 9) was carried out in 4 M HCl in
methanol/dioxane. This furnished, after neutralization, the enan-
tiomer 1RR of the target molecule. In this case, the 1H NMR (Fig. 10)
shows the presence of the two conformers cisoid/transoid only after
Tetramethylammonium fluoride (TMAF) is a fluoride anion
source less sterically hindered than TBAT. Using TMAF in similar
conditions we could finally obtain the desired doubly reacted
compound. Both trifluoromethyl groups add to the si face of the
imine E-bonds, giving (SS,SS)-N,N0-(1R,10R)-1,10-(anthracene-9,10-
diyl)bis(2,2,2-trifluoroethane-1,1-diyl)bis(2-methylpropane-2-sul-
finamide) (8RRSSSS) as a single isomer, as shown by analysis using
NMR and chiral HPLC. Single crystal X-ray diffraction furnished the
structure shown in Figure 6 with the R,R absolute configuration in
the new stereogenic carbon atoms.
cooling at 250 K (Tc¼280 K, K¼47.0 sꢁ1
,
D
Gs¼14.2 kcal/mol). Sim-
ilar processes starting with 8SSRSRS yielded 1SS.
After assigning all 1H and 13C NMR signals, and considering the
presence of HA1/C3A and H4A/CA2 cross peaks in the HMBC spectrum
(only compatible with a cisoid situation) (Fig. 11), we assigned the
cisoid conformation to A signals. Consequently B resonances cor-
respond to the transoid conformation.
The crystal structure shows the two CF3 groups orthogonal to
the aromatic ring and on the same side of the anthracene plane.
They define a ‘cisoid’ conformation. Crystal structure is ortho-
rhombic with P212121 as space group of symmetry. Molecules are
linked by N–H/O]S hydrogen bonds forming layers.
The enantiomer (RS,RS)-N,N0-(1S,10S)-1,10-(anthracene-9,10-diyl)-
bis(2,2,2-trifluoroethane-1,1-diyl)bis(2-methylpropane-2-sulfina-
mide) (8SSRSRS) was obtained in the same way beginning with the
other enantiomer 5RSRS ((E,E,SS,SS)-N,N0-(anthracene-9,10-diyl-
bis(methan-1-yl-1-ylidene))bis(2-methylpropane-2-sulfinamide)).
Even at room temperature, solutions of 8 show the presence of
two conformers differing in the relative positions of both tri-
fluoromethyl groups with respect to the anthracene ring (Fig. 7),
either on the same face (cisoid isomer) or on opposite faces
(transoid isomer) of the aromatic plane. Proton NMR (Fig. 8) gave
two groups of signals, namely A and B, that could be assigned to the
transoid and cisoid conformers, respectively.
The two amino groups bear the electron withdrawing tri-
fluoromethyl group in the b position. This reduces the availability of
the nitrogen atom electron pair, thus decreasing the basicity of the
amine and increasing the acidity of the corresponding ammonium
salts. We measured the variation of the chemical shift of several
protons with the pD, and using computational methods (HypNMR)
we determined the pKa’s for the two deprotonation processes for
the double ammonium salt of 1RR. The resulting pKa values,
3.06ꢀ0.04 and 1.36ꢀ0.08, correspond to the deprotonation of the
monoprotic and diprotic ammonium salts (Fig. 12).
Preliminary studies of the behavior of 1RR as chiral solvating
agent have been carried out with ibuprofen, a chiral carboxylic
acid with a high industrial interest. The difference between the
chemical shift of two protons (H2 and H3) of ibuprofen enantio-
mers was plotted against the concentration of 1RR (Fig. 13). The
high solubility of 1RR allows the use of high CSA/substrate ratios.
As shown by the tendency of the data, the enantiodifferentiation
increases slowly but in a long range, achieving large values for
a ratio of 15:1.
Full analysis of the 1H NMR spectrum of 8 using NOE results (see
Supplementary data) allowed the individual assignment of all
protons for both conformers, A and B, as shown on experimental
part. From these data, HSQC, and HMBC spectra allowed the 13C
NMR assignment of all carbons for both conformers, also shown on
experimental part. Finally, taking into account the two different
types of C2 symmetry exhibited by both conformers, isomer B was
Possibly, the very low basicity of the diamine requires high ra-
tios to complex with the substrate. On the other hand, after use of
the CSA, recovery of both substrate and CSA is very easy. Simple
column chromatography of the contents of the NMR tube leads to
a complete separation of the components without loss of material.
O
S
NH
O
S
N
O
S
N
F3C
H
TMSCF3/TBAT
or
TMSCF3/TMAF
TMSCF3/TMAF
CF3
CF3
HN
S
N
S
HN
S
H
H
O
O
O
5SSSS
7RSSSS
Figure 5. Trifluoromethylation of sulfinamide 5.
8RRSSSS

174
C. Estivill et al. / Tetrahedron 65 (2009) 171–176
O
S
F3C
H
F3C
H
NH2
CF3
NH
1) HCl/dioxane
2) Neutralization
CF3
H2N
HN
H
H
8RRSSSS
1RR
S
O
Figure 9. Hydrolysis of disulfinamide 8RRSSSS.
3. Experimental section
3.1. General
Both enantiomers of compounds 3, 4 and of hydrochloride of 2
have been previously described. Free amines 2R and 2S are fully
described here for the first time and were stable at room temper-
ature. All compounds were completely characterized (Supple-
mentary data). The compounds partially reacted are also described
in Supplementary data.
Figure 6. X-ray structure of SS,SS,-N,N0-(1R,10R)-1,10-(anthracene-9,10-diyl)bis(2,2,2-
trifluoroethane-1,1-diyl)bis(2-methylpropane-2-sulfinamide) (8RRSSSS).
NMR spectra were recorded at 400 MHz and 500 MHz for
1H. The temperature was controlled to 0.1 ꢂC. The NMR sig-
nals were identified completely with the aid of several 1D
(NOE) and 2D (COSY, NOESY, HMQC, and HMB) spectra. HRMS
R
3 NH
1
R
NH
1
were obtained in
(70 eV).
a Micromass Autospec by EI ionization
F3C
CF
H
H
4
1
4
3
2
2
3
2
2
3
3
C2
3.2. (E,E,SS,SS)-N,N0-(Anthracene-9,10-diylbis(methan-1-yl-1-
ylidene))bis(2-methylpropane-2-sulfinamide) (5SSSS)
C2
4
1
4
CF3
H
NH
HN
R
H
F3C
Under nitrogen 705 mg (5.83 mmol) of (S)-(ꢁ)-2-methyl-prop-
ansulfinamide and 750 mg (3.20 mmol) of 9,10-anthracendi-
carboxaldehyde were dissolved in 15 mL of anhydrous THF in
a 250 mL round-bottom flask. After cooling at 0 ꢂC, 4.90 mL of
a freshlyprepared 0.5 M solution of Ti(OEt)4 was added (2.45 mmol).
It was raised to room temperature and after 15 h the mixture was
poured into ice-water (100 mL). After filtration, it was extracted
with AcOEt (3ꢃ50 mL) and the organic layer dried with MgSO4
anhydrous. After the solvent evaporated the crude was purified by
column chromatography (flash) with hexane/CH2Cl2 95:5 to obtain
1.10 g of 5SSSS (86% yield). Mp dec; IR (KBr) 2961, 2926, 2865,
R
Cisoid
Transoid
Figure 7. Equilibrium between rotational conformers of compound 8RRSSSS
(R¼SOC(CH3)3) and compound 1RR (R¼H). The numbering is shown for identifying
symmetry C2.
1584, 1523, 1444, 1361 (m), 1177, 1074, 758, 736 cmꢁ1
;
1H NMR
T=300K
B
H2A,H2B, H3A,H3
B
A
B
H4
H4
A
A
B
H1
H1
H11
H11
T=250K
9.15
9.05
8.50 8.40 8.30
ppm
7.65 7.55
6.30 6.20
Figure 8. 300 K NMR edited spectrum of 8SSRSRS where transoid and cisoid forms are
indicated as A and B, respectively.
Figure 10. Part of the 1H NMR (CDCl3) spectrum at two temperatures of 1RR. A and B
signals corresponds to cisoid and transoid conformers, respectively.

C. Estivill et al. / Tetrahedron 65 (2009) 171–176
175
(400 MHz, CDCl3)
d
9.86 (H11, s, 2H), 8.69 (H1, m, 4H), 7.65 (H2, m, 4H),
1.40 (H14, s, 9H); 13C NMR (100 MHz, CDCl3)
d 162.7 (C11),129.9 (C1a),
129.6 (C9), 127.4 (C2), 125.1 (C1), 58.0 (C13), 22.7 (C14); MS (ES) (m/z,
%): 465 ((MNaþ2)þ,11), 464 ((MNaþ1)þ, 27), 463 (MNaþ,100), 441.1
(MHþ, 6).
3.3. (SS,SS)-N,N0-(1R,10R)-1,10-(Anthracene-9,10-diyl)bis(2,2,2-
trifluoroethane-1,1-diyl)bis(2-methylpropane-2-sulfinamide)
(8RRSSSS)
Under nitrogen 686 mg (1.56 mmol) of (E,E,SS,SS)-N,N0-
(anthracene-9,10-diylbis(methan-1-yl-1-ylidene))bis(2-methylpro
pane-2-sulfinamide) (5SSSS) was dissolved in 30 mL of anhy-
drous THF in
a 250 mL round-bottom flask and 872 mg
(9.36 mmol) of tetramethylammonium fluoride (TMAF) were
added. After cooling at 195 K, 1.85 mL of a freshly prepared
solution of 0.35 M of TMSCF3 in anhydrous THF (12.51 mmol)
was added. After 4 h the reaction was quenched with NH4Cl
solution, raised to room temperature and extracted with AcOEt.
The dried organic phase was evaporated and purified by flash
Figure 11. Aromatic part of HMBC spectrum of compound 1RR at 250 K.
chromatography (hexane/CH2Cl2 70:30), which resulted in
25
796 mg (1.37 mmol, 88%) of 8RRSSSS. Mp dec; [
a
]
254
þ31.0 (c 3,
100
90
80
70
60
50
40
30
20
10
0
H4
CH3OH); IR (KBr) 3267, 2960, 2922, 2851, 1255, 1164, 1096,
H4
1054, 1008, 765, 739 cmꢁ1 1H NMR (500 MHz, CDCl3)
;
d
cisoid
8.5
8.62 (H4, m, 2H), 8.45 (H1, m, 2H), 7.69 (H2, m, 2H), 7.67 (H3, m,
H1
2H), 6.55 (H11, dq, J¼8.31, 2.97 Hz, 2H), 4.14 (NH, d, J¼2.98 Hz,
2H), 1.29 (H17, s, 18H);
d transoid 8.60 (H4, m, 2H), 8.43 (H1, m,
2 +
1RR-D2
8.0
7.5
7.0
6.5
2H), 7.72 (H2, m, 2H), 7.63 (H3, m, 2H), 6.58 (H11, dq, J¼8.58,
3.94 Hz, 2H), 4.22 (NH, d, J¼3.41 Hz, 2H), 1.31 (H17, s, 18H); 13C
NMR (125 MHz CDCl3)
d cisoid 131.5 (C4a), 129.5 (C1a), 128.5–
H2
128.6 (C9), 127.4 (C2), 126.5 (C3), 126.0 (C4), 125.5 (C13
J¼295.6 Hz), 124.4 (C1), 57.0 (C15), 56.1–56.2 (C11, q, J¼32.63 Hz),
22.4 (C17); transoid 129.9 (C4a), 131.1 (C1a), 128.5–128.6 (C9),
, q,
1RR
1RR-D+
d
127.7 (C2), 126.1 (C3), 126.4 (C4), 125.5 (C13, q, J¼295.6 Hz), 123.9
(C1), 57.2 (C15), 56.1–56.2 (C11, q, J¼32.63 Hz), 22.4 (C17); 19F
H11
NMR (235.37 MHz, CDCl3)
d
cisoid ꢁ69.11 (CF3, d, J¼8.6 Hz);
d
transoid ꢁ68.79 (CF3, d, J¼9.5 Hz).
1
3
5
7
9
pH
3.4. (1R,10R)-1,10-(Anthracene-9,10-diyl)bis(2,2,2-
trifluoroethanamine) (1RR)
Figure 12. Evolution of chemical shift of several protons of 1RR with pD (black lines).
Red, blue, and brown lines correspond to the speciation of free amine, monoprotic, and
diprotic ammonium salts, respectively.
In
a 250 mL round-bottom flask 796 mg (1.37 mmol) of
8RRSSSS solved in 60 mL of methanol and 15 mL of HCl (4 M in
1,4-dioxane) was added. After 3.5 h the solution was neutralized
and extracted with AcOEt. The organic phase was dried, concen-
trated, and purified by flash chromatography (hexane/CH2Cl2
0.04
H
COOH
H3C
2
3
0.035
0.03
0.025
0.02
0.015
0.01
0.005
0
85:15) obtaining 354 mg (70%) of the target compound 1RR. Mp
25
114–116 ꢂC; [
a
]
254
ꢁ37.0 (c 3, CH3OH); IR (KBr) 3346, 1255, 1155,
1107, 882, 756 cmꢁ1
9.07 (H4, d, 2H), 8.33 (H1, d, 2H), 7.62 (H2, H3, m, 4H), 6.17 (H11, q,
2H), 2.20 (NH2, s, 4H); transoid 9.14 (H4, m, 2H), 8.35 (H1, m, 2H),
7.62 (H2, H3, m, 4H), 6.22 (H11, q, 2H), 2.20 (NH2, s, 4H); 13C RMN
(125 MHz, CDCl3, 250 K) cisoid 132.1 (C4a), 130.3 (C1a), 130.0 (C9),
128.2 (C4), 127.3 (C2), 127.1 (C13, q, J¼283.7 Hz), 125.9 (C3), 124.2
transoid 131.1 (C4a), 131.3 (C1a),
; d cisoid
1H NMR (500 MHz, CDCl3, 250 K)
d
H2
H3
d
(C1), 53.8 (C11, q, J¼31.7 Hz);
d
129.8 (C9), 128.2 (C4), 127.0 (C2), 127.1 (C13, q, J¼283.7 Hz), 125.9
(C3), 124.5 (C1), 54.1 (C11, q, J¼30.7 Hz); 19F RMN (235.37 MHz,
CDCl3)
d
cisoid ꢁ71.2 (CF3, b),
d
transoid ꢁ71.4 (CF3, b); MS (ES)
(m/z, %): 396 ((MNaþ1)þ, 9), 395 (MNaþ, 43). HRMS (EI, 70 eV):
m/z calcd for C18H14N2F6 [Mþ]: 372.10589; found: 372.10612.
Acknowledgements
0
5
10
eq 1RR/eq ibup.
15
Financial support from CYCYT (BQU2003-01231 and CTQ2006-
´
˜
`
01080) from the Ministerio de Educacion y Ciencia de Espana is
Figure 13. Evolution of enantiodifferentiation of protons H2 and H3 of ibuprofen with
the ratio eq 1RR/eq ibuprofen.
`
gratefully acknowledged. The Servei de Ressonancia Mangnetica

176
C. Estivill et al. / Tetrahedron 65 (2009) 171–176
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Supplementary data
Characterization NMR data of described compounds 2, 3, 4 and
intermediates compounds 5, 6, and 7 (1D-NOE, NOESY, COSY, 13C
NMR, HSQC, HMBC, 1H DNMR, X-ray, and pKa). Some other edited
NMR spectra of compounds 8 and 1, X-ray data and the HypNMR
application. Numerical data for the enantiodifferentiation of
ibuprofen.
Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication nos.
CCDC-702798 (2S) and 702799 (8RRSsSs). Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK, (fax: þ44 (0)1223 336033 or e-mail:
deposit@ccdc.cam.ac.uk). Supplementary data associated with this
article can be found in the online version, at doi:10.1016/
j.tet.2008.10.082.
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14. For a review see: Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35,
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