Synthesis of enantiomerically pure (R,R)- and (S,S)-1,2-Bis(pentafluorophenyl)ethane-1,2-diamine and evaluation of the pK a value by ab initio calculations

Article abstract of DOI:10.1246/bcsj.77.1001

1,2-Bis(pentafluorophenyl)ethane-1,2-diamine (1) was synthesized by the imino pinacol coupling of 4-methoxy-N-(pentafluorobenzylidene)benzylamine using a Zn-Cu couple and p-TsOH·H₂O. The optical resolution of (±)-1 by means of chiral HPLC gave

Full text of DOI:10.1246/bcsj.77.1001

ꢀ 2004 The Chemical Society of Japan
Bull. Chem. Soc. Jpn., 77, 1001–1008 (2004) 1001
Synthesis of Enantiomerically Pure (R,R)- and (S,S)-1,2-
Bis(pentafluorophenyl)ethane-1,2-diamine and Evaluation
of the pKa Value by Ab Initio Calculations
ꢀ
Shinichi Minami, and Tadashi Ema
Takashi Sakai, Toshinobu Korenaga, Noriyuki Washio, Yuji Nishio,
Department of Applied Chemistry, Faculty of Engineering, Okayama University,
3-1-1 Tsushima-naka, Okayama 700-8530
Received September 24, 2003; E-mail: tsakai@cc.okayama-u.ac.jp
1,2-Bis(pentafluorophenyl)ethane-1,2-diamine (1) was synthesized by the imino pinacol coupling of 4-methoxy-N-
(pentafluorobenzylidene)benzylamine using a Zn–Cu couple and p-TsOH H2O. The optical resolution of (ꢂ)-1 by means
ꢁ
of chiral HPLC gave enantiomerically pure (R,R)- and (S,S)-1. The pKa value of 1 was estimated by a titration experiment
and ab initio calculations, showing that 1 has a basicity comparable to aniline derivatives.
Introduction of a pentafluorophenyl (C6F5) group to func-
tional compounds is now an attractive method to modulate
the potential,1 because the C6F5 group has the increased elec-
tron-withdrawing property and the interesting ability of stack-
ing with an electron-rich aromatic ring.2 Moreover, the C6F5–
heteroatom (O, N, halogen) interaction is also under active dis-
cussion,3 and we have recently explored a C6F5–oxygen
interaction by X-ray analysis.1d In these respects, we have re-
ported the preparation and structural properties of (1R,2S)-
and (1S,2R)-2-amino-1,2-bis(pentafluorophenyl)ethanol (A),1a
(1R,2S)-2-amino-1-(pentafluorophenyl)-2-phenylethanol (B),1d
and (1R,2R)- and (1S,2S)-bis(pentafluorophenyl)ethane-1,2-
diol (C)1c in optically pure forms (Fig. 1). We focus here on
the synthesis of (S,S)- and (R,R)-1,2-bis(pentafluorophenyl)-
ethane-1,2-diamine [(S,S)-1 and (R,R)-1] as the fluorinated an-
alogs of 1,2-diphenylethane-1,2-diamine [(S,S)-2 and (R,R)-2],
which are widely used as excellent ligands for asymmetric cat-
alysts.4 The pKa value of the diamine 1 is the important index
for its practical application to asymmetric synthesis as a chiral
ligand, and, therefore, it was evaluated both by a titration ex-
periment in H2O–EtOH and by using ab initio calculations.
Results and Discussion
We planned that the compound (ꢂ)-1 could be synthesized
via the imino pinacol coupling of 4-methoxy-N-(pentafluoro-
benzylidene)aniline (3a)5a or 4-methoxy-N-(pentafluorobenzy-
lidene)benzylamine (3b) according to the method for the non-
fluorinated analog 26 because Fujisawa and Shimizu had report-
ed the enantioselective imino pinacol coupling of N-benzyli-
dene-p-anisidine in the presence of a Zn–Cu couple and (þ)-
camphorsulfonic acid (CSA) leading to (R,R)-N,N-di-p-ani-
syl-1,2-diphenylethylenediamine with 97% ee as a mixture of
dl:meso (81:19) isomers in 63% yield. Alterations in the reac-
tivity and selectivity of the imines 3 by the influence of the
C6F5 group would give us a useful measure for designing the
reaction of a compound having a C6F5 group, and the novel
coupling products may have attractive features. Many other cat-
Fig. 1.
Published on the web May 6, 2004; DOI 10.1246/bcsj.77.1001

1002 Bull. Chem. Soc. Jpn., 77, No. 5 (2004)
1,2-Bis(pentafluorophenyl)ethane-1,2-diamine
Scheme 1.
Table 1. Iminopinacol Coupling of Imine 3a
Entry
Solvent
Acid
Time/h
Racemic:Mesoa)
4a/%b)
1
2
3
4
DMF
CH2Cl2
Et2O
(þ)-CSA
(þ)-CSA
(þ)-CSA
(þ)-CSA
30
6
6
—
44:56
—
complex mixture
trace
no reaction
57
THF
6
46:54
a) Determined by 19F NMR analysis. b) Isolated yield.
Table 2. Iminopinacol Coupling of Imine 3b
Entry
Acid
Time/h
Racemic:Mesoa)
4b/%b)
1
2
(þ)-CSA
3.5
1.0
50:50
51:49
14
27
p-TsOH H2O
ꢁ
a) Determined by 19F NMR analysis. b) Isolated yield.
alysts7 might be available for this coupling reaction; however,
we used only the Zn–Cu couple here because of its ease of han-
dling and treatment.
Imines 3a and 3b were prepared by the reaction of penta-
fluorobenzaldehyde with p-anisidine and 4-methoxybenzyl-
amine, respectively, in almost quantitative yields (Scheme 1)8
as E-isomers exclusively.5b The imino pinacol coupling of 3a
was carried out by using the Zn–Cu couple and (þ)-CSA at
room temperature (Scheme 1),6 giving N,N0-bis(4-methoxy-
ide 5a by treatment with SOCl2 (Scheme 1).9 In trans-5a, a
couple of doublets (ꢀ 5.92 and 6.35) due to the two non-equiv-
alent methine protons were observed, suggesting the dl-form of
4a. On the other hand, in cis-5a, a singlet (ꢀ 6.29) for the equiv-
alent methine protons appeared, indicating the meso-form of
4a. Unfortunately, no chiral induction was observed despite
the use of (þ)-CSA. Fujisawa and Shimizu6b suggested that
in their reaction with non-fluorinated imine, a sufficient basicity
of the nitrogen atom is essential for the formation of a transient
complex with (þ)-CSA, which affects the reactivity as well as
the diastereo- and enantioselectivity. In this aspect, imine 3a
with the electron-withdrawing C6F5 group is at a considerable
disadvantage for this reaction. Therefore, the obtained yield of
57% seems to be rather valuable. The imino pinacol coupling of
3b was then examined under similar conditions (Scheme 1,
Table 2), giving N,N0-bis(4-methoxybenzyl)-1,2-bis(penta-
phenyl)-1,2-bis(pentafluorophenyl)ethane-1,2-diamine
(4a)
(57% yield, dl:meso 46:54). The reaction was found to be high-
ly sensitive to the solvent (Table 1), with THF being the most
suitable among the examined solvents such as DMF, CH2Cl2,
and Et2O (Table 1, entries 1–3). The diastereomeric structures
1
of the dl- and meso-forms of 4a were determined by H NMR
after transformation into the corresponding thiadiazolidine ox-

T. Sakai et al.
Bull. Chem. Soc. Jpn., 77, No. 5 (2004) 1003
Scheme 2.
fluorophenyl)ethane-1,2-diamine (4b) in 14% yield as a mix-
ture of dl- and meso-4b without diastereo- and enantioselectiv-
ity (Scheme 1 and Table 2). The structures of dl- and meso-4b
were similarly determined by 1H NMR after transformation in-
to the corresponding trans-5b (ꢀ 5.01 and 5.67) and cis-5b
(ꢀ 5.46). Replacement of the (þ)-CSA additive with p-
purity. At present, the HPLC resolution of (ꢂ)-1 with a chiral
column (CHIRALCEL OD-H, hexane:2-propanol:diethyl-
amine = 70:20:0.1) is the better choice, giving (R,R)-1 (99%
ee) and (S,S)-1 (>99% ee) in high optical purity. Interestingly,
the HPLC resolution of (ꢂ)-1 can be performed more effective-
ly than that of non-fluorinated (ꢂ)-2, because a hundred mg of
both enantiomers is obtainable in one charge using a 4.6 mm (d)
ꢄ 25 cm (l) column. The absolute configurations of (R,R)-1 and
TsOH H2O also gave a mixture of (ꢂ)-4b and meso-4b with
ꢁ
a slightly improved yield of 27%. Despite much effort, the yield
could not be improved, and unidentified by-products were
always formed.
1
(S,S)-1 were determined by H NMR spectra after transforma-
tion into the corresponding mono MTPA (MTPA: ꢁ-meth-
oxy-ꢁ-(trifluoromethyl)phenylacetic acid) amides, (R,R)-6
and (S,S)-6,11 in which the methyl group in the methoxy moiety
of (S,S)-6 is observed at upper field (ꢀ 3.44) than that (ꢀ 3.49) of
(R,R)-6 due to the ring current effect12 of the pentafluorophenyl
group located on the same side, as shown in Scheme 3.
The pKa of the conjugate acid of 1 was estimated both by a
titration experiment and a computational method, because in-
formation on the basicity is requisite for predicting the stability
of the metal–amine complex13 for asymmetric catalysis. As the
pKa values reported for amines are commonly measured in wa-
ter, it is preferred that those of 1 and 2 are measured in water.
However, the solubility of the amines 1 and 2 is low even in
acidic water. This forced us to measure the pKa values in a
mixed solvent of H2O–EtOH (1:2) to obtain referential infor-
mation. Thus, these diamines were titrated with 0.5 M KOH
in a mixed solvent of aqueous nitric acid and EtOH (1:2) using
a potentiometric apparatus. The obtained pKa2 values of 1 and 2
in H2O–EtOH (1:2) were 5.8 and 8.3 (2.5 pK unit difference),
respectively.
Attempts for the removal of p-methoxyphenyl (PMP) and p-
methoxybenzyl (PMB) groups leading to compound 1 are
shown in Scheme 2. Diamine (ꢂ)-4a was treated with 0.5 molar
amounts of cerium(IV) ammonium nitrate (CAN), which gave
the starting aldehyde and p-anisidine via oxidative decomposi-
tion. meso-4a also had similar results. In contrast, the removal
of 4-methoxybenzyl groups from diamine (ꢂ)-4b was success-
fully accomplished with 10% Pd/C under 2 atm of H2 to give
(ꢂ)-1 in 86% yield. A similar treatment of meso-4b also gave
meso-1 in 38% yield.
The optical resolution of (ꢂ)-1 was then attempted using two
methods: a) salt formation with chiral acids, and b) HPLC sep-
aration with a chiral column. The chiral acids used in the former
method were (þ)-mandelic acid, (þ)-tartaric acid, (þ)-CSA,
(ꢃ)-O,O0-dibenzoyltartaric acid, (ꢃ)-menthoxyacetic acid,
and (þ)-naproxen.10 Among them, three-times recrystalliza-
tions of the salts prepared from (ꢂ)-1 and an equimolar amount
of (þ)-naproxen afforded (S,S)-1 with 96% ee in 17% overall
yield, although the additional recrystallizations of the (S,S)-1
(96% ee) were useless for further improvement of the optical
For an estimate of the pKa values of 1 and 2 in water, ab ini-

1004 Bull. Chem. Soc. Jpn., 77, No. 5 (2004)
1,2-Bis(pentafluorophenyl)ethane-1,2-diamine
Scheme 3.
tio calculations14 were carried out. A linear correlation between
the molecular electrostatic potential (MEP) minima (Vmin) in
the vicinities of the amino groups and the pKa values has pro-
ven to be effective for evaluating a wide range of pKa values of
amines,15 although chiral amines and 1,2-diamines are not in-
volved. For estimation of the pKa values of the 1,2-diamines
1 and 2, we revalued the linear correlation between the MEP
and the authentic experimental pKa values of the amines in-
volving ethylenediamine,16 (2R,3R)-2,3-diaminobutane,16 and
(R)-1-phenylethylamine. In particular, we employed the MEP
able for estimation of the pKa of diamines 1 and 2. The pKa2
values of 1 and 2 in water were thus estimated from Eq. 1 after
calculation of the corresponding VNRNH to give 6:1 ꢂ 0:2
2
(VNRNH ¼ ꢃ18:4002) and 8:9 ꢂ 0:2 (VNRNH ¼ ꢃ18:4196), re-
spectively, which are similar to those determined by titrations.
Noteworthy is that the pKa2 value of 1 was revealed to have a
stronger basicity than those of aniline derivatives involving
2-naphthylamine, which is known to form stable metal com-
plexes.22
2
2
at the nitrogen atom(s) of amines (VNRNH ) rather than those in
Conclusion
2
the vicinity of the amino group.17 The values of the MEP at
Enantiomerically pure 1,2-diamines bearing two pentafluo-
rophenyl groups, (R,R)-1 and (S,S)-1, were synthesized for
the first time by the imino pinacol coupling of the correspond-
ing imine, and the pKa2 of 1 and the non-fluorinated analog 2
were estimated both by the titration experiments in H2O–EtOH
(1:2) and by using ab initio calculations. The linear correlation
procedure in the calculation method afforded the pKa2 value (in
water) of 6.1 for 1 and 8.9 for 2. The difference of 2.8 pK units
between them is significant in the application to organic reac-
tions as a catalyst ligand. The catalytic abilities of (R,R)- and
(S,S)-1 as chiral ligands are now under examination.
the nitrogen atom(s) (VNRNH ) of primary amines (17 examples)
2
and p-substituted anilines (5 examples)18 were calculated at the
ꢀꢀ
B3LYP/6-311G level after optimization of the geometry of
ꢀꢀ
amines at the B3LYP/6-311G
level19 using the Gaussian
98W.20 As a result, the calculated values were found to be suf-
ficiently correlated with the experimental pKa values (in water)
for the corresponding conjugate acids of the amines21 (best fit
line: ðpKaÞ ¼ ꢃ145:498 ꢄ ðVNRNH Þ ꢃ 2671:12 (Eq. 1), r ¼
2
2
0:9958, RMS error = 0.16) (Table 3). The calculated pKa (or
pKa2) values of ethylenediamine, (2R,3R)-2,3-diaminobutane,
and (R)-1-phenylethylamine showed good accuracy, with the
differences between the experimental and the theoretical values
calculated from Eq. 1 being only 0.04, <0:01, and 0.18 pK
units, respectively. These results show that this method is suit-
Experimental
General. All reactions were carried out under a nitrogen at-
mosphere with dry and freshly distilled solvents under anhydrous

T. Sakai et al.
Bull. Chem. Soc. Jpn., 77, No. 5 (2004) 1005
Table 3. Correlation between Calculated VNRNH and Experimental pKa Values in Water
2
VNRNH
Exp.
pKa
Calc.
pKa
2
11
10
9
Amines
c)
k)
/au a)
i-PrNH2
EtNH2
MeNH2
−18.4329
−18.4314
−18.4312
−18.4269
−18.4270
−18.4285
−18.4264
−18.4260
−18.4225
−18.4200
−18.4166
−18.4179
−18.4084
−18.4060
−18.4013
−18.3996
−18.3959
−18.3960
−18.3907
−18.3868
−18.3848
−18.3757
10.63d)
10.63e)
10.62e)
10.13f)
10.00f)
9.97f)
9.92g)
9.7h)
10.82
10.60
10.57
9.95
10.00
10.20
9.88
9.82
9.31
8.94
8.44
8.64
7.26
6.94
6.22
5.97
5.43
5.40
4.69
4.11
3.83
2.50
(S)-PhCH(NH2)Me
(2S,3S)-[MeCH(NH2)-]2
meso-[MeCH(NH2)-]2
NH2CH2CH2NH2
CH2=CHNH2
PhCH2NH2
BrCH2CH2CH2NH2
Cl2CFCH2CH2NH2
CF3CH2CH2NH2
F2CHCH2NH2
CF3CH(F)CH2NH2
CF3CH2NH2
CF3CF2CH2NH2
Cl3CCH2NH2
p-MeO-C6H4NH2
p-F-C6H4NH2
b)
b)
8
1
b)
2
7
9.33h)
8.93i)
8.8i)
6
8.6i)
7.52i)
7.1i)
5
5.87i)
5.7i)
4
5.47i)
5.34h)
4.65j)
4.16h)
3.98g)
2.45j)
3
2-NpNH2
p-Cl-C6H4NH2
p-CF3-C6H4NH2
2
−18.44 −18.42 −18.4 −18.38
V
N
/au
∗∗
a) Calculation was performed at the B3LYP/6-311G
level
Best fit line (Eq. 1):
(pK ) = –145.498 × (V RNNH ) – 2671.12,
2
using Gaussian 98W. b) pKa2 (second dissociation constant)
values were estimated in case of diamine. c) pKa values of
the conjugate acids. d) Ref. 19a. e) Ref. 19b. f) Ref. 19c. g)
Ref. 19d. h) Ref. 19e. i) Ref. 19f. j) Ref. 19g. k) Calculation
from Eq. 1.
a
r2 = 0.9958, RMS error = 0.16.
1: V RNNH (–18.4002), pKa calc (6.1 0.2).
2
2: V RNNH (–18.4196), pKa calc (8.9 0.2).
2
conditions unless otherwise noted. Tetrahydrofuran (THF) was dis-
tilled from sodium, and dichloromethane (CH2Cl2) was distilled
1651, 2844, 2972, 3026 cmꢃ1
(E)-4-Methoxy-N-(pentafluorobenzylidene)benzylamine
.
from calcium hydride. Reactions were monitored by thin-layer
chromatography with precoated silica-gel plates (Merck 60 F254
(3b). Compound 3b was prepared from 4-methoxybenzylamine
(137 mg, 1.00 mmol) and pentafluorobenzaldehyde (196 mg,
1.00 mmol) in 100% yield (315 mg, 1.00 mmol) by the procedure
described for 3a.
Yellow solid, mp 80–81 ꢅC; 1H NMR (200 MHz, CDCl3) ꢀ 3.80
(s, 3H), 4.84 (s, 2H), 6.89 (d, J ¼ 8:4 Hz, 2H), 7.24 (d, J ¼ 8:4 Hz,
2H), 8.45 (s, 1H); 13C NMR (50 MHz, CDCl3 (except for C6F5 car-
bon)) ꢀ 55.2, 65.8, 114.0, 129.1, 130.0, 149.8, 159.4; 19F NMR
(188 MHz, CDCl3) ꢀ ꢃ163:2 to ꢃ162:9 (m, 2F), ꢃ152:2 (t, J ¼
21 Hz, 1F), ꢃ143:9 to ꢃ143:8 (m, 2F); IR (KBr) 1032, 1169,
1228, 1497, 1612, 1652, 2844, 2899, 3009 cmꢃ1. Anal. Calcd for
C15H10F5NO: C, 57.15; H, 3.20; N, 4.44%. Found: C, 57.00; H,
3.04; N, 4.52%.
,
plate length 40 mm). As a usual workup procedure, the reaction
mixture was extracted with ethyl acetate (EtOAc). The organic lay-
er was dried over MgSO4, filtered with suction, and concentrated
under reduced pressure. Preparative column chromatography was
carried out using silica gel (Fuji Silysia BW-127 ZH, 100–270
mesh). 1H NMR and 13C NMR spectra were measured at 200
MHz and 50 MHz, respectively, and chemical shifts are given rel-
ative to tetramethylsilane (TMS). 19F NMR spectra were measured
at 188 MHz, and chemical shifts are given relative to CCl3F using
C6F6 as secondary reference (ꢃ162:9 ppm).
(E)-4-Methoxy-N-(pentafluorobenzylidene)aniline (3a). To
a solution of pentafluorobenzaldehyde (196 mg, 1.00 mmol) in
dry CH2Cl2 (1.0 mL) was added p-anisidine (123 mg, 1.00 mmol)
in the presence of molecular sieves 4A. After stirring at room tem-
perature for 3 h, the mixture was filtered. The filtrate was concen-
trated to give a yellow solid. After purification by column chroma-
tography (SiO2, hexane/EtOAc (4:1)), compound 3a (295 mg,
0.979 mmol) was obtained in 98% yield.
N,N0-Bis(4-methoxyphenyl)-1,2-bis(pentafluorophenyl)eth-
ane-1,2-diamine ((ꢀ)-4a and meso-4a). A mixture of zinc pow-
der (2.58 g, 37.9 mmol) and Cu(OAc)2 H2O (141 mg, 0.710
ꢁ
mmol) in acetic acid (30 mL) was stirred at the reflux temperature
for 5 min. The resulting precipitate was filtered, washed with acetic
acid, and then with ether (ꢄ3). The obtained Zn–Cu couple was
dried in vacuo and then 10 mL of THF was added. To the Zn–
Cu suspension were added a solution of (þ)-CSA (697 mg, 3.00
mmol) in THF (2.0 mL) and then a solution of 3a (301 mg, 1.00
mmol) in dry THF (3.0 mL) subsequently at room temperature un-
der a N2 atmosphere. After stirring the mixture at room tempera-
ture for 6 h, saturated aqueous NaHCO3 (10 mL) was added at 0
ꢅC. The resulting mixture was filtered through a pad of Celite.
ꢅ
1
Yellow solid, mp 128–129 C; H NMR (200 MHz, CDCl3) ꢀ
3.85 (s, 3H), 6.96 (d, J ¼ 8:9 Hz, 2H), 7.28 (d, J ¼ 8:9 Hz, 2H),
8.59 (s, 1H); 13C NMR (50 MHz, CDCl3 (except for C6F5 carbon))
ꢀ 55.4, 114.4, 122.4, 144.0, 145.7, 159.4; 19F NMR (188 MHz,
CDCl3) ꢀ ꢃ163:1 to ꢃ162:9 (m, 2F), ꢃ151:7 (t, J ¼ 21 Hz, 1F),
ꢃ143:4 to ꢃ143:3 (m, 2F); IR (KBr) 835, 1036, 1251, 1494,

1006 Bull. Chem. Soc. Jpn., 77, No. 5 (2004)
1,2-Bis(pentafluorophenyl)ethane-1,2-diamine
4.43%. Found: C, 56.73; H, 3.48; N, 4.30%.
The filtrate was extracted with EtOAc (ꢄ3), and the combined ex-
tracts were washed with brine. The mixture was dried over anhy-
drous Na2SO4 and concentrated to give a crude product of a mix-
ture of meso-4a and (ꢂ)-4a, which was found to be separable by
the higher solubility of meso-4a in EtOH and by column chroma-
tography. The crude product was washed with EtOH and filtered to
give meso-4a (44 mg, 0.073 mmol, 15% yield) as a residue. Col-
umn chromatography (SiO2, hexane/EtOAc (15:1)) of the filtrate
afforded meso-4a (49 mg, 0.081 mmol, 16% yield) and a mixture
of meso- and (ꢂ)-4a, the latter of which was washed with EtOH
to give (ꢂ)-4a (79 mg, 0.13 mmol, 26% yield).
meso-4b: white solid; mp 159–161 ꢅC; 1H NMR (200 MHz,
CDCl3) ꢀ 1.83 (br, 2H), 3.35 (d, J ¼ 13:2 Hz, 2H), 3.61 (d, J ¼
13:2 Hz, 2H), 3.78 (s, 6H), 4.23 (s, 2H), 6.72 (d, J ¼ 8:5 Hz,
4H), 6.84 (d, J ¼ 8:7 Hz, 4H); 13C NMR (50 MHz, CDCl3 (except
for C6F5 carbon)) ꢀ 51.0, 55.2, 55.9, 113.5, 129.2, 130.9, 158.8;
19F NMR (188 MHz, CDCl3) ꢀ ꢃ162:3 to ꢃ162:0 (m, 4F),
ꢃ157:1 (t, J ¼ 20 Hz, 2F), ꢃ146:9 to ꢃ146:8 (m, 2F), ꢃ143:4
to ꢃ143:3 (m, 2F); IR (KBr) 853, 978, 1033, 1115, 1251, 1505,
1614, 2811, 2846, 2941, 3036, 3399 cmꢃ1. Anal. Calcd for
C30H22F10N2O2: C, 56.97; H, 3.51; N, 4.43%. Found: C, 56.97;
H, 3.36; N, 4.52%.
(ꢂ)-4a: white solid; mp 143–145 ꢅC; 1H NMR (200 MHz,
CDCl3) ꢀ 3.73 (s, 6H), 4.30 (br, 2H), 5.32 (s, 2H), 6.59 (d, J ¼
9:0 Hz, 4H), 6.77 (d, J ¼ 9:0 Hz, 4H); 13C NMR (50 MHz, CDCl3
(except for C6F5 carbon)) ꢀ 53.9, 55.6, 115.0, 115.1, 139.6, 153.5;
19F NMR (188 MHz, CDCl3) ꢀ ꢃ161:5 to ꢃ161:3 (m, 4F), ꢃ153:4
(t, J ¼ 21 Hz, 2F), ꢃ144:5 to ꢃ144:3 (m, 4F); IR (KBr) 822, 989,
1129, 1242, 1513, 1655, 2837, 2920, 2959, 3380, 3421 cmꢃ1. Anal.
Calcd for C28H18F10N2O2: C, 55.64; H, 3.00; N, 4.63%. Found: C,
55.59; H, 3.31; N, 4.47%.
2,5-Bis(4-methoxyphenyl)-trans-3,4-bis(pentafluorophenyl)-
1,2,5-thiadiazolidine 1-Oxide (trans-5a). To a CH2Cl2 (3.0 mL)
solution of (ꢂ)-4a (77 mg, 0.13 mmol) and triethylamine (71 mL,
0.51 mmol) was added a solution of distilled SOCl2 (14 mL, 0.19
ꢅ
mmol) in CH2Cl2 (1.0 mL) at 0 C under a N2 atmosphere. After
stirring the mixture at room temperature for 3 h, the reaction was
quenched by the addition of brine. The organic layer was treated
in the usual manner to give trans-5a (83 mg, 0.13 mmol) quantita-
tively.
White solid; mp 152–154 ꢅC; 1H NMR (200 MHz, CDCl3) ꢀ
3.76 (s, 3H), 3.77 (s, 3H), 5.89 (d, J ¼ 10:2 Hz, 1H), 6.36 (d, J ¼
10:2 Hz, 1H), 6.81–6.90 (m, 4H), 7.20–7.26 (m, 4H); 19F NMR
(188 MHz, CDCl3) ꢀ ꢃ161:2 to ꢃ160:9 (m, 4F), ꢃ151:7 (t, J ¼
21 Hz, 1F), ꢃ151:0 (t, J ¼ 21 Hz, 1F), ꢃ143:8 to ꢃ143:6 (m,
1F), ꢃ142:6 to ꢃ142:5 (m, 2F), ꢃ139:2 to ꢃ139:0 (m, 1F); IR
(KBr) 669, 951, 998, 1155, 1249, 1509, 1655, 2840, 2917, 2964,
3385 cmꢃ1. Anal. Calcd for C28H16F10N2O3S: C, 51.70; H, 2.48;
N, 4.31%. Found: C, 52.04; H, 2.78; N, 4.36%.
meso-4a: white solid; mp 170–173 ꢅC; 1H NMR (200 MHz,
CDCl3) ꢀ 3.69 (s, 6H), 3.96 (br, 2H), 5.27 (s, 2H), 6.54 (d, J ¼
9:0 Hz, 4H), 6.70 (d, J ¼ 9:0 Hz, 4H); 13C NMR (50 MHz, CDCl3
(except for C6F5 carbon)) ꢀ 53.9, 54.9, 114.3, 114.9, 138.3, 153.0;
19F NMR (188 MHz, CDCl3) ꢀ ꢃ162:2 to ꢃ162:1 (m, 4F), ꢃ154:8
(t, J ¼ 21 Hz, 2F), ꢃ147:7 to ꢃ147:5 (m, 2F), ꢃ144:3 to ꢃ144:0
(m, 2F); IR (KBr) 821, 982, 1038, 1116, 1248, 1412, 1523, 1655,
1744, 2843, 2915, 2961, 3015, 3368, 3413 cmꢃ1. Anal. Calcd for
C28H18F10N2O2: C, 55.64; H, 3.00; N, 4.63%. Found: C, 55.32;
H, 3.13; N, 4.73%.
N,N0-Bis(4-methoxybenzyl)-1,2-bis(pentafluorophenyl)eth-
ane-1,2-diamine ((ꢀ)-4b and meso-4b). To a solution of CuSO4
(1.50 g, 9.37 mmol) in water (10 mL) was added a solution of zinc
powder (13.1 g, 200 mmol) in water (32 mL) at room temperature.
After stirring at room temperature for 1 h, the resulting mixture
was filtered and washed with acetone (ꢄ3) and then with Et2O
(ꢄ3). The Zn–Cu couple was dried in vacuo. To the Zn–Cu suspen-
2,5-Bis(4-methoxyphenyl)-cis-3,4-bis(pentafluorophenyl)-
1,2,5-thiadiazolidine 1-Oxide (cis-5a). cis-5a was prepared from
meso-4a (71 mg, 0.12 mmol) and SOCl2 (13 mL, 0.18 mmol) in
81% yield (62 mg, 0.12 mmol) by a similar procedure to that de-
scribed for trans-5a.
White solid; mp 192–194 ꢅC; 1H NMR (200 MHz, CDCl3) ꢀ
3.76 (s, 6H), 6.26 (s, 2H), 6.84 (d, J ¼ 8:9 Hz, 4H), 7.16 (d, J ¼
8:9 Hz, 4H); 19F NMR (188 MHz, CDCl3) ꢀ ꢃ162:0 to ꢃ161:7
(m, 2F), ꢃ161:0 to ꢃ160:8 (m, 2F), ꢃ151:7 (t, J ¼ 21 Hz, 2F),
ꢃ143:2 (d, J ¼ 24 Hz, 2F), ꢃ139:8 (d, J ¼ 21 Hz, 2F); IR
(KBr) 985, 1254, 1360, 1505, 1609, 1654, 2841, 2922, 2968,
3364, 3507 cmꢃ1. Anal. Calcd for C28H16F10N2O3S: C, 51.70;
H, 2.48; N, 4.31%. Found: C, 51.97; H, 2.76; N, 4.14%.
2,5-Bis(4-methoxybenzyl)-trans-3,4-bis(pentafluorophenyl)-
1,2,5-thiadiazolidine 1-Oxide (trans-5b). trans-5b was prepared
from (ꢂ)-4b (10 mg, 0.010 mmol) and SOCl2 (1.4 mL, 0.020
mmol) in 93% yield (10 mg, 0.093 mmol) by the procedure de-
scribed above.
White solid; mp 172–173 ꢅC; 1H NMR (200 MHz, CDCl3) ꢀ
3.65 (d, J ¼ 13:2 Hz, 1H), 3.76 (s, 3H), 3.78 (s, 3H), 4.16 (d, J ¼
13:2 Hz, 1H), 4.23 (d, J ¼ 14:7 Hz, 1H), 4.35 (d, J ¼ 14:7 Hz,
1H), 5.01 (d, J ¼ 10:5 Hz, 1H), 5.67 (d, J ¼ 10:5 Hz, 1H), 6.74
(d, J ¼ 8:6 Hz, 2H), 6.81 (d, J ¼ 8:5 Hz, 2H), 7.07 (d, J ¼ 8:5
Hz, 2H), 7.21 (d, J ¼ 8:6 Hz, 2H); 19F NMR (188 MHz, CDCl3)
ꢀ ꢃ162:3 to ꢃ162:0 (m, 2F), ꢃ161:2 (m, 2F), ꢃ153:1 (t, J ¼ 21
Hz, 1F), ꢃ151:9 (t, J ¼ 21 Hz, 1F), ꢃ143:0 to ꢃ142:8 (m, 1F),
ꢃ142:0 to ꢃ141:9 (m, 2F), ꢃ138:6 to ꢃ138:5 (m, 1F); IR (KBr)
819, 940, 982, 1057, 1116, 1251, 1506, 1613, 1654, 2847, 2918,
3015 cmꢃ1. Anal. Calcd for C30H20F10N2O3S: C, 53.10; H, 2.97;
N, 4.13%. Found: C, 53.34; H, 3.36; N, 3.88%.
sion in THF (90 mL) was added a solution of p-TsOH H2O (38.1
ꢁ
g, 200 mmol) in THF (70 mL) at room temperature under a N2 at-
mosphere, and then a solution of 3b (31.5 g, 100 mmol) in dry THF
(90 mL) was added to the mixture at 0 ꢅC over 15 min. After stir-
ring at room temperature for 2 h, aqueous saturated NaHCO3 (200
mL) and then aqueous NaOH were added to adjust the pH to 7–8 at
ꢅ
0 C. The resulting mixture was filtered through a pad of Celite.
The filtrate was extracted with EtOAc (ꢄ3), and treated in the usu-
al manner to give a crude product. EtOH (200 mL) was added, and
the mixture was stirred for 1 h. Insoluble meso-4b (3.58 g, 5.66
mmol, 11% yield) was separated by filtration. After concentrating
the filtrate, the residue was purified by column chromatography
(SiO2, hexane/EtOAc (15:1)) to give pure meso-4b (0.592 g,
0.936 mmol, 2% yield) and a mixture of meso-4b and (ꢂ)-4b.
The latter mixture was washed with EtOH to obtain (ꢂ)-4b (4.42
g, 6.99 mmol, 14% yield).
(ꢂ)-4b: white solid; mp 140–141 ꢅC; 1H NMR (200 MHz,
CDCl3) ꢀ 2.43 (br, 2H), 3.61 (d, J ¼ 13:8 Hz, 2H), 3.69 (d, J ¼
13:8 Hz, 2H), 3.78 (s, 6H), 4.52 (s, 2H), 6.80 (d, J ¼ 8:7 Hz,
4H), 7.14 (d, J ¼ 8:7 Hz, 4H); 13C NMR (50 MHz, CDCl3 (except
for C6F5 carbon)) ꢀ 51.9, 55.3, 56.6, 113.7, 129.2, 131.2, 158.8;
19F NMR (188 MHz, CDCl3) ꢀ ꢃ162:6 to ꢃ162:4 (m, 4F),
ꢃ155:0 (t, J ¼ 21 Hz, 2F), ꢃ143:2 to ꢃ143:1 (m, 4F); IR (KBr)
768, 985, 1112, 1244, 1524, 1613, 1656, 2842, 2941, 3039, 3292
cmꢃ1. Anal. Calcd for C30H22F10N2O2: C, 56.97; H, 3.51; N,
2,5-Bis(4-methoxybenzyl)-cis-3,4-bis(pentafluorophenyl)-
1,2,5-thiadiazolidine 1-Oxide (cis-5b). cis-5b was prepared from

T. Sakai et al.
Bull. Chem. Soc. Jpn., 77, No. 5 (2004) 1007
meso-4b (10 mg, 0.010 mmol) and SOCl2 (1.4 mL, 0.020 mmol) in
93% yield (10 mg, 0.093 mmol) by the procedure described above.
White solid; mp 157–158 ꢅC; 1H NMR (200 MHz, CDCl3) ꢀ
3.78 (s, 6H), 4.04 (s, 4H), 5.46 (s, 2H), 6.81 (d, J ¼ 8:7 Hz, 4H),
7.24 (d, J ¼ 8:7 Hz, 4H); 19F NMR (188 MHz, CDCl3) ꢀ
ꢃ162:2 to ꢃ162:0 (m, 2F), ꢃ161:5 to ꢃ161:2 (m, 2F), ꢃ152:5
(t, J ¼ 21 Hz, 2F), ꢃ142:4 to ꢃ142:3 (m, 2F), ꢃ139:6 to
ꢃ139:5 (m, 2F); IR (KBr) 818, 899, 986, 1089, 1256, 1306,
1360, 1505, 1614, 1657, 2840, 2914, 3008, 3064 cmꢃ1. Anal.
Calcd for C30H20F10N2O3S: C, 53.10; H, 2.97; N, 4.13%. Found:
C, 53.05; H, 3.07; N, 4.16%.
phere. After stirring at room temperature for 3 h, the resulting mix-
ture was diluted with water and extracted with Et2O. The usual
treatment of the mixture gave a colorless oil. After purification
by column chromatography (SiO2, hexane/EtOAc (2:1)), (R)-
MTPA amide was obtained in 80% yield (24.7 mg, 0.0406 mmol):
Colorless oil; 1H NMR (200 MHz, CDCl3) ꢀ 2.14 (br, 2H), 3.49 (s,
1H), 4.70 (d, J ¼ 10:6 Hz, 1H), 5.63 (dd, J ¼ 10:6, 7.3 Hz, 1H),
7.34–7.41 (m, 5H), 7.91 (d, J ¼ 7:3 Hz, 1H); 19F NMR (188
MHz, CDCl3) ꢀ ꢃ161:6 to ꢃ161:1 (m, 4F), ꢃ153:6 (t, J ¼ 21
Hz, 1F), ꢃ153:3 (t, J ¼ 21 Hz, 1F), ꢃ143:9 (d, J ¼ 22:4 Hz,
2F), ꢃ143:4 (d, J ¼ 22:4 Hz, 2F), ꢃ69:9 (s, 3F).
(ꢀ)-1,2-Bis(pentafluorophenyl)ethane-1,2-diamine ((ꢀ)-1).
A mixture of 10% Pd/C (170 mg, 0.160 mmol) and (ꢂ)-4b (1.00
g, 1.58 mmol) in EtOAc (7.0 mL) was stirred at room temperature
for 8 h under 3 atm of H2. The resulting mixture was filtered with
Celite and concentrated in vacuo. The residue was purified by col-
umn chromatography (SiO2, hexane/EtOAc (0.8:1)) to give (ꢂ)-1
(530 mg, 1.35 mmol) in 86% yield.
White solid, mp 78–79 ꢅC; 1H NMR (200 MHz, CDCl3) ꢀ 2.01
(br, 4H), 4.50 (s, 2H); 13C NMR (50 MHz, CDCl3 (except for C6F5
carbon)) ꢀ 52.6; 19F NMR (188 MHz, CDCl3) ꢀ ꢃ162:0 to ꢃ161:8
(m, 4F), ꢃ155:1 (t, J ¼ 21 Hz, 2F), ꢃ143:9 to ꢃ143:8 (m, 4F); IR
(KBr) 829, 984, 1128, 1502, 1655, 2922, 2962, 3310 cmꢃ1; Anal.
Calcd for C14H6F10N2: C, 42.87; H, 1.54; N, 7.14%. Found: C,
43.21; H, 1.49; N, 7.09%.
Formation of (R)-MTPA Amide from (S,S)-1. (R)-MTPA
amide of (S,S)-1 was prepared from (S,S)-1 (23.5 mg, 0.0630
mmol) with (R)-MTPA (21.8 mg, 0.0930 mmol) in 67% yield
(25.7 mg, 0.0422 mmol) by the procedure described above: Color-
less oil; 1H NMR (200 MHz, CDCl3) ꢀ 2.10 (br, 2H), 3.44 (s, 1H),
4.70 (d, J ¼ 10:3 Hz, 1H), 5.64 (dd, J ¼ 10:3, 7.7 Hz, 1H), 7.43–
7.59 (m, 5H), 7.89 (d, J ¼ 7:7 Hz, 1H); 19F NMR (188 MHz,
CDCl3) ꢀ ꢃ161:5 to ꢃ161:0 (m, 4F), ꢃ153:9 (t, J ¼ 21 Hz, 1F),
ꢃ153:6 (t, J ¼ 21 Hz, 1F), ꢃ143:9 (d, J ¼ 22:1 Hz, 2F), ꢃ143:6
(d, J ¼ 22:4 Hz, 2F), ꢃ70:0 (s, 3F).
Titration Experiments. Solutions of diamines 1 and 2 (0.5 M)
in aqueous nitric acid (pH 2.5) and ethanol (1:2) were titrated with
aqueous 0.5 M KOH using a potentiometer. The isoelectric points
were observed at pH 5.8 and 8.3, respectively.
Optical Resolution of (ꢀ)-1,2-Bis(pentafluorophenyl)ethane-
1,2-diamine by Recrystallization with (S)-(þ)-Naproxen. Rac-
emic diamine (ꢂ)-1 (100 mg, 0.25 mmol) and (S)-(þ)-naproxen
(59 mg, 0.26 mmol) in EtOH (0.8 mL) were stirred at the reflux
temperature for 20 min. After cooling to room temperature, the
salts were separated by decantation from the filtrate. Recystallizai-
ton (3 times) of the salts from EtOH (0.7 mL) gave white crystals.
The crystals were treated with 1 M aqueous NaOH and extracted
with Et2O (3 times). The combined extracts were dried over anhy-
drous Na2SO4, and concentration under reduced pressure gave
(S,S)-1 (17 mg, 0.043 mmol, 96% ee) in 17% yield.
This work was partially supported by the Ministry of Educa-
tion, Culture, Sports, Science and Technology. We are grateful
to Dr. Shinichi Takeda in Osaka University for his kind assis-
tance in the potentiometric analysis of compounds 1 and 2.
We also thank the SC-NMR Laboratory of Okayama University
1
for H, 13C, and 19F NMR measurements.
References
1
Synthesis of chiral 1,2-diol or 2-amino alcohol bearing pen-
Optical Resolution of (ꢀ)-1,2-Bis(pentafluorophenyl)ethane-
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was resolved by chiral HPLC into (S,S)-1 (>99% ee, 107 mg) and
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26
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26
1.9, MeOH); ½ꢁꢆD for (R,R)-1 = þ50:7 (c 1.9, MeOH).
meso-1,2-Bis(pentafluorophenyl)ethane-1,2-diamine (meso-
1). meso-1 was prepared from meso-4b (683 mg, 1.08 mmol) un-
der 2 atm of H2 in 38% yield (159 mg, 0.405 mmol) following the
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3
4
White solid, mp 125–126 ꢅC; 1H NMR (200 MHz, CDCl3) ꢀ
1.68 (br, 4H), 4.51 (s, 2H); 13C NMR (50 MHz, CDCl3 (except
for C6F5 carbon)) ꢀ 53.2; 19F NMR (188 MHz, CDCl3) ꢀ ꢃ162:4
to ꢃ162:2 (m, 4F), ꢃ156:0 (t, J ¼ 20 Hz, 2F), ꢃ144:5 to
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43.20; H, 1.46; N, 7.12%.
5
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lution of (R)-ꢁ-methoxy-ꢁ-(trifluoromethyl)phenylacetic acid
7
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