Synthesis and chiral recognition ability of O-phenyl ethylphosphonothioic acid with a conformationally flexible phenoxy group for CH/π interaction

Article abstract of DOI:10.1016/j.tetasy.2006.03.009

Enantiopure O-phenyl ethylphosphonothioic acid 1 was easily obtained by the enantioseparation of racemic 1, which was prepared from commercially available phosphorothioic trichloride in four steps. Enantiopure 1 was found to show an excellent chiral recognition ability for various 1-arylethylamine derivatives during the diastereomeric salt formation. In particular, enantiopure 1 was able to recognize the chirality of o- and m-substituted 1-arylethylamine derivatives, of which the chirality is generally difficult to establish by conventional resolving agents. X-ray crystallographic analyses of the less-soluble diastereomeric salts revealed that the conformation of the phenoxy group in enantiopure 1 could change in the diastereomeric salt crystals and that the excellent chiral recognition ability of enantiopure 1 resulted from the effective CH/π interaction of the phenoxy phenyl group.

Full text of DOI:10.1016/j.tetasy.2006.03.009

Tetrahedron: Asymmetry 17 (2006) 967–974
Synthesis and chiral recognition ability of O-phenyl
ethylphosphonothioic acid with a conformationally flexible
phenoxy group for CH/p interaction
Yuka Kobayashi,* Jin Maeda, Fumi Morisawa and Kazuhiko Saigo*
Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, Hongo,
Bunkyo-ku, Tokyo 113-8656, Japan
Received 3 February 2006; accepted 10 March 2006
Available online 12 April 2006
Abstract—Enantiopure O-phenyl ethylphosphonothioic acid 1 was easily obtained by the enantioseparation of racemic 1, which was pre-
pared from commercially available phosphorothioic trichloride in four steps. Enantiopure 1 was found to show an excellent chiral rec-
ognition ability for various 1-arylethylamine derivatives during the diastereomeric salt formation. In particular, enantiopure 1 was able
to recognize the chirality of o- and m-substituted 1-arylethylamine derivatives, of which the chirality is generally difficult to establish by
conventional resolving agents. X-ray crystallographic analyses of the less-soluble diastereomeric salts revealed that the conformation of
the phenoxy group in enantiopure 1 could change in the diastereomeric salt crystals and that the excellent chiral recognition ability of
enantiopure 1 resulted from the effective CH/p interaction of the phenoxy phenyl group.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
amines with O-alkyl phenylphosphonothioic acids, there
were two obviously different mechanisms from the view-
point of hydrogen-bonding networks constructed in the
less-soluble diastereomeric salts; chiral recognitions
through the formation of a cluster-like hydrogen-bonding
network and a columnar hydrogen-bonding network.
Moreover, the phenyl group of O-alkyl phenylphosphono-
thioic acids was found to play an important role in chiral
recognition of the racemic primary amines to cause a
dramatic change of the chiral recognition mechanism.
These results gave valuable information for the elucida-
tion of the mechanism of chiral recognition by P-chiral
compounds, not only in the crystalline state, but also in
solutions.
Chiral phosphorus (P-chiral) compounds have been
attracting increasing interest due to their unique proper-
ties arising from the coordinative/functional group itself
being chiral. Some enantiopure phosphorus compounds
have been widely used as chiral solvating agents1 and
chiral ligands2 in solution, and chiral recognition and
induction mechanisms have been discussed on the basis
of 1H NMR data. However, to date there is only one
report for the study on the mechanism of chiral recogni-
tion by P-chiral compounds in solution, inferred from
the results of X-ray crystallographic analyses.3 On the
other hand, we have previously reported that P-chiral
compounds could recognize the chirality of substrates in
the crystalline state, as well as in solution; O-alkyl phen-
ylphosphonothioic acids showed a superior chiral recogni-
tion ability for various racemic primary amines during
diastereomeric salt formation.4 X-ray crystallographic
studies on the less- and more-soluble diastereomeric salts
revealed that for the chiral recognition of racemic primary
This first success in chiral recognition by O-alkyl phen-
ylphosphonothioic acids during diastereomeric salt forma-
tion prompted us to develop another new chiral
phosphonothioic acid, which could recognize the chirality
of a wide variety of racemic primary amines. We designed
enantiopure O-phenyl ethylphosphonothioic acid with the
expectation that the phenoxy group, which is conforma-
tionally flexible, would change its conformation depending
on the shape of target 1-phenylethylamine derivatives to
realize close packing of the component molecules in diaste-
reomeric salt crystals with the aid of the efficient CH/p
*
Corresponding authors. Tel.: +81 3 5841 7266; fax: +81 3 5802 3348
(K.S.); e-mail addresses: yuka@chiral.t.u-tokyo.ac.jp; saigo@chiral.t.
u-tokyo.ac.jp; saigo@k.u-tokyo.ac.jp
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.03.009

968
Y. Kobayashi et al. / Tetrahedron: Asymmetry 17 (2006) 967–974
interaction(s) between the phenoxy phenyl group and the
phenyl group in the target amines.
The enantioseparation of racemic 1 was attempted by using
commercially available resolving agents such as enantio-
pure 1-phenylethylamine (PEA), erythro-2-amino-1,2-diph-
enylethanol (ADPE), and norephedrine (NE). The results
are summarized in Table 1. Among the resolving agents
examined, PEA was found to be the most suitable for the
enantioseparation of racemic 1 from the viewpoints of yield
of the diastereomeric salt and the enantiomeric excess of 1
incorporated in the salt. Then, we adopted enantiopure
PEA for the enantioseparation of 1 on a large scale. As a
result, enantiopure (Rp)-1 was obtained in 53% yield (based
on a half amount of racemic 1 used), when (R)-PEA was
used as the resolving agent in the first stage (Scheme 2).
The absolute configuration of 1 in the diastereomerically
pure salt thus obtained was determined to be Rp in relation
to that of (R)-PEA on the basis of the X-ray crystallo-
graphic analysis of the salt (Fig. 1). The antipode, (Sp)-1,
was obtained in 73% by the enantioseparation of (Sp)-en-
riched 1, recovered from the mother liquor, with (S)-PEA.
Herein, we report the synthesis and chiral recognition abil-
ity of enantiopure O-phenyl ethylphosphonothioic acid,
as well as a chiral recognition mechanism on the basis of
X-ray crystallographic analyses.
2. Results and discussion
2.1. Synthesis of enantiopure O-phenyl ethylphosphonothioic
acid 1
Racemic O-phenyl ethylphosphonothioic acid 1 was syn-
thesized from commercially available phosphorothioic tri-
chloride in four steps, according to the procedures
described for the synthesis of nucleic acid derivatives5
(Scheme 1). Phosphorothioic trichloride was allowed to
react with 0.5 equiv of ethylaluminum dichloride in hexane
at reflux to give crude ethylphosphonothioic dichloride in
79% yield based on the ethylaluminum dichloride used
(40% yield based on phosphorothioic trichloride used).
However, the distillation of crude ethylphosphonothioic
dichloride resulted in a very low yield (20%), due to its ther-
mal instability. Therefore, crude ethylphosphonothioic
dichloride was used for the following step without further
purification. The reaction of crude ethylphosphonothioic
dichloride with 2.5 equiv of phenol in the presence of tri-
ethylamine (2.5 equiv) at room temperature afforded crude
O,O0-diphenyl ethylphosphonothioate in quantitative
yield, which was hydrolyzed by treatment with 4 M aque-
ous KOH solution in dioxane at 50 ꢁC to give crude
racemic 1 with satisfactory purity for the following
enantioseparation; chemically pure 1 was easily obtained
upon crystallizing the salt with dibenzylamine, followed
by treatment of the salt with hydrochloric acid.
2.2. Chiral recognition ability of enantiopure O-phenyl
ethylphosphonothioic acid 1
The chiral recognition ability of enantiopure O-phenyl eth-
ylphosphonothioic acid 1 was examined for various race-
mic 1-phenylethylamine derivatives. As shown in Table 2,
enantiopure 1 showed excellent chiral recognition ability
for most of the racemic amines examined; only upon crys-
tallizing the diastereomeric salts, the enantiomeric excesses
of the amines incorporated in the corresponding diastereo-
meric salts and the efficiencies (the yield of the diastereo-
meric salt · the enantiomeric excess of the amine)
exceeded 85% and 0.63, respectively, except in the case of
amine 2f (entry 6). However, the efficiency (0.53) for 2f
was even acceptable from the general viewpoint of chiral
recognition during diastereomeric salt formation. It is
noteworthy that enantiopure 1 effectively recognized the
S
S
P
S
P
S
P
Phenol (2.5 eq)
Et3N (2.5 eq)
1) KOH aq (5 eq)
Dioxane, 50 ˚C
2) HCl aq
HCl aq
EtAlCl2 (0.5 eq)
Hexane
O-•+H2NBn2
Et
OH
PSCl3
Et
P
Cl
Cl
Et
OPh
Et
CH2Cl2
rt
reflux
OPh
OPh
79%
OPh
3) Bn2NH (1 eq)
79%
quant.
quant.
racemic 1
Scheme 1. Synthesis of racemic 1.
Table 1. Enantioseparation of racemic 1 with basic resolving agents
Entry
Resolving agent
Amount of solventa (mL) AcOEt/hexane
Temperature (ꢁC)
Yield (%)b
ee (%)c
1
2
3
4
(R)-PEAd
1.0/0.0
0.8/0.2
1.0/1.5
1.2/2.6
rt
rt
rt
ꢀ10
47
62
41
37
>99 (Rp)
98 (Rp)
64 (Rp)
95 (Sp)
(R)-PEAd
(1R,2S)-ADPEe
(1S,2R)-NEf
a Amount of the solvent normalized to a 1 mmol scale.
b Yield of the crystallized diastereomeric salt based on a half amount of the racemic amine.
c Enantiomeric excess (ee) of the liberated amine, which was determined by a HPLC analysis.
d 1-Phenylethylamine.
e 2-Amino-1,2-diphenylethanol.
f Norephedrine.

Y. Kobayashi et al. / Tetrahedron: Asymmetry 17 (2006) 967–974
969
S
P
1) recryst. x 2
1) (R)-PEA
AcOEt/hexane
AcOEt/hexane
(Rp)-1•(R)-PEA salt
(Rp)-1
Et
OH
2) HClaq
53% yield
>99%ee
OPh
+
1) HCl aq
2) (S)-PEA
3) recryst. x 1
AcOEt/hexane
4) HCl aq
1
crude racemic 1
(Sp)-1•(R)-PEA enriched salt
recovered from the mother liquor
(Sp)-1
73% yield
>99%ee
Scheme 2. Synthesis of enantiopure 1.
Figure 1. Crystal structure of the less-soluble (Rp)-1Æ(R)-2a salt: (a) top view and (b) side view. The gray circles indicate hydrogen-bonding networks. The
dotted lines, black arrows, and green arrows show hydrogen bonds, inter-columnar T-shaped CH(sp2)/p interactions, and intra-columnar CH(sp3)/p
interaction, respectively. The bond distances are in Angstroms.
Table 2. Enantioseparation of 1-phenylethylamine derivatives with enantiopure 1
S
2a: R = H
2f: R = p-Me
2g: R = p-Br
2h: R = p-Cl
2i: R = p-F
2j: R = p-Et
2b: R = o-Me
2c: R = o-Br
2d: R = m-Me
2e: R = m-Br
NH2
Et
P
OH
OPh
R
1
2
Entry
Racemic amine
Amount of solventa (mL) AcOEt/hexane
Yield (%)b
ee (%)c
Efficiencyd
1e
2g
3g
4e
2a
2b
2c
2d
2e
2f
0.4/0.1
3.9/0
5.0/0
1.2/7.3
1.9/4.8
0.6/0.9
0.5/0
4.6/1.3
0.5/0
82
84
80
76
65
79
86
75
69
91
97 (R)f
97 (S)
>99 (S)
96 (R)
97 (S)
67 (R)
88 (S)
87 (R)
94 (S)
85 (S)
0.80
0.82
0.80
0.73
0.63
0.53
0.76
0.65
0.65
0.78
5g
6e
7g
8e
9g
10g
2g
2h
2i
2j
0.6/5.6
a Amount of the solvent normalized to a 1 mmol scale.
b Yield of the crystallized diastereomeric salt based on a half amount of the racemic amine.
c Enantiomeric excess (ee) of the liberated amine, which was determined by a HPLC analysis.
d Efficiency is the product of the yield and the ee.
e (Rp)-1 was used.
f Absolute configuration of the major enantiomer, which was determined by an X-ray crystallographic analysis and/or deduced on the basis of the elution
order in the HPLC analysis.
g (Sp)-1 was used.
chirality of o- and m-substituted amines 2b–e (entries 2–5),
which is usually difficult to distinguish by conventional
carboxylic acid-type resolving agents due to the steric
repulsion between the substituent and columnar
a

970
Y. Kobayashi et al. / Tetrahedron: Asymmetry 17 (2006) 967–974
hydrogen-bonding network consisting of ammonium
cations and carboxylate anions.6 It should be also noted
that in all cases the absolute configurations of the amines
2a–j majorly incorporated in the less-soluble diastereo-
meric salts are the same with respect to the absolute config-
uration of enantiopure 1 used, indicating that the chirality
of amines 2a–j was recognized by enantiopure 1 through
the same mechanism.
performed the X-ray crystallographic analyses of the less-
soluble diastereomeric salts. Single crystals of the less-solu-
ble diastereomeric salts of (R)-PEA 2a, (S)-1-(2-methylphen-
yl)ethylamine 2b, and (S)-1-(4-fluorophenyl)ethylamine 2i
with (Rp)- or (Sp)-1 suitable for X-ray crystallographic
analyses were obtained. The crystal structures are shown
in Figures 1–3, respectively.
In all of the diastereomeric salt crystals, a columnar hydro-
gen-bonding network with a 2-fold screw axis in the center
(21 column), which consists of the ammonium cations and
phosphonothioate anions, is commonly formed. The bond
lengths and angles are close to each other in the three salt
crystals. Moreover, the networks are very similar to those
2.3. Mechanism of chiral recognition by enantiopure
O-phenyl ethylphosphonothioic acid 1
In order to clarify the chiral recognition mechanism by
enantiopure O-phenyl ethylphosphonothioic acid 1, we
Figure 2. Crystal structure of the less-soluble (Sp)-1Æ(S)-2b salt: (a) top view and (b) side view. The gray circles indicate hydrogen-bonding networks. The
dotted lines, black arrows, and green arrows show hydrogen bonds, inter-columnar CH(sp3)/p interaction, and intra-columnar CH(sp3)/p interaction,
respectively. The bond distances are in Angstroms.
Figure 3. Crystal structure of the less-soluble (Sp)-1Æ(S)-2e salt: (a) top view and (b) side view. The gray circles indicate hydrogen-bonding networks. The
dotted lines and green arrows show hydrogen bonds and intra-columnar CH(sp3)/p interactions, respectively. The bond distances are in Angstroms.

Y. Kobayashi et al. / Tetrahedron: Asymmetry 17 (2006) 967–974
971
in the salt crystals of chiral primary amines with O-ethyl
phenylphosphonothioic acids4a and with mandelic acid
derivatives.6 However, the packing modes of the 21 col-
umns for the three salt crystals are slightly different from
each other and are inevitably different from those for the
salt crystals with O-ethyl phenylphosphonothioic acid
and with mandelic acid derivatives from the viewpoint of
CH/p interaction.
meric (Sp)-1Æ(S)-2e salt crystal as shown in Figure 3a. This
phenomenon would arise from the relatively long molecu-
lar length of (S)-2e, compared to those of 2a and 2b, and
is consistent with the general tendency that a large differ-
ence in molecular length between a resolving agent and a
target molecule is disadvantageous for the packing of col-
umns or sheets in a diastereomeric salt crystal.8 However,
in the (Sp)-1Æ(S)-2e salt crystal, there is only one highly
effective CH(sp3)/p interaction between the methyl group
at the a-position of the 2e molecule and the phenyl group
of the 2e molecule in the neighboring unit cell along the b-
The packing of 21 columns in the less-soluble diastereo-
meric (Rp)-1Æ(R)-2a salt crystal is quite effective, because
three kinds of T-shaped inter-columnar CH(sp2)/p interac-
tions exist; one column contacts with the neighboring col-
umns by six kinds of CH(sp2)/p interactions (Fig. 1a).
The side view of the columns indicates that intra-columnar
CH(sp3)/p interaction also exists between the methyl group
at the a-position of the 2a molecule and the phenyl group
of the 2a molecule in the neighboring unit cell along the b-
axis (Fig. 1b). The distances for the inter-columnar
CH(sp2)/p interactions and the intra-columnar CH(sp3)/p
˚
axis at a very short distance of 3.33 A, which is almost the
same as those for CH(sp2)/p interactions, to stabilize the
column. Such short intra-columnar CH(sp3)/p interac-
tions have never been reported for the crystals of the
less-soluble diastereomeric salts with enantiopure phos-
phonothioic acids and with enantiopure carboxylic acids,
as far as we know.9 The formation of the strong intra-
columnar CH(sp3)/p interaction would arise from the con-
formational flexibility of the phenoxy group in enantio-
pure 1.
˚
interaction are relatively short; 3.56–3.72 and 3.34 A,
respectively. The angles for the inter-columnar CH(sp2)/p
interactions are between 85ꢁ and 91ꢁ to achieve almost
complete T-shaped contacts, which have been suggested
to be energetically favorable.7 Thus, the crystal structure
of the less-soluble diastereomeric (Rp)-1Æ(R)-2a salt
strongly indicates that the salt crystal is effectively stabi-
lized not only by the formation of a helical hydrogen-bond-
ing network but also by multiple CH/p interactions.
A less effective packing of columns might result in lower
efficiency of the enantioseparation of the p-substituted
amines (entries 6–10), compared with that of the o- and
m-substituted amines. However, moderate to excellent
chiral recognition by enantiopure 1 in a range of 67–
94% enantiomeric excesses was achieved as a result of
the formation of strong intra-columnar CH(sp3)/p interac-
tion, to reinforce the hydrogen-bonded column in the
crystals.
The packing mode of 21 columns in the less-soluble diaste-
reomeric (Sp)-1Æ(S)-2b salt crystal is obviously less favor-
able, compared with that in the (Rp)-1Æ(R)-2a salt crystal.
As shown in Figure 2a, there is only one inter-columnar
CH(sp3)/p interaction in the salt crystal. The top view of
the columns shows that the conformation of the phenyl
group of (S)-2b in the (Sp)-1Æ(S)-2b salt crystal is largely
different from that in the (Rp)-1Æ(R)-2a salt crystal; the phen-
yl group of (S)-2b is located perpendicular to the neigh-
boring phenyl group of the (Sp)-1 molecules to avoid
repulsion between the methyl group at the o-position in
the (S)-2b molecule and the phenyl group of the (Sp)-1
molecule. On the other hand, intra-columnar CH(sp3)/p
interaction increases in number (Fig. 2b), compared with
that in the (Rp)-1Æ(R)-2a salt crystal. The methylene group
of the (Sp)-1 molecule interacts with the perpendicularly lo-
cated phenyl group of the (S)-2b molecule at a general dis-
3. Conclusion
A novel resolving agent, enantiopure O-phenyl ethyl-
phosphonothioic acid 1, was synthesized by a method
applicable to a large-scale preparation. The chiral recogni-
tion ability of enantiopure 1 was moderate to excellent for
various 1-phenylethylamine derivatives; the efficiencies
were in a range of 0.53–0.82. The X-ray crystallographic
analyses of the less-soluble diastereomeric salts revealed
that the high performance of enantiopure 1 in the enantio-
separation resulted from the formation of inter-columnar
CH(sp2)/p, inter-columnar CH(sp3)/p and/or intra-colum-
nar CH(sp3)/p interaction. The CH/p interaction site of
enantiopure 1, which can easily change its conformation
in salt crystals, played an important role in decreasing
the dependency on the shape of target amines and made
the chiral recognition ability of enantiopure 1 moderate
to excellent for a variety of racemic 1-phenylethylamine
derivatives.
˚
tance of 3.86 A. Moreover, the methyl group of the (S)-2b
molecule interacts with the neighboring phenyl group of
the (Sp)-1 molecule at a relatively short distance of
˚
3.63 A. The formation of these interactions results from
the tunability of the conformation of the phenoxy group
in (Sp)-1 owing to the freely rotatable C–O–P bond. Thus,
the crystal structure of the less-soluble (Sp)-1Æ(S)-2b salt
crystal revealed that (Sp)-1 can flexibly change its confor-
mation, depending on a target amine, to stabilize the salt
crystal more effectively through the formation of intra-
columnar CH(sp3)/p interactions instead of inter-columnar
CH/p interaction(s).
4. Experimental
4.1. General
Solvents were purified, dried, and stored according to stan-
dard procedures. TLC analyses were performed using
Merck pre-coated silica gel plates (Art. 5715). Column
chromatography was carried out using silica gel 60
Different from the above two cases, there exists no inter-
columnar CH/p interaction in the less-soluble diastereo-

972
Y. Kobayashi et al. / Tetrahedron: Asymmetry 17 (2006) 967–974
(0.063–0.200 mm). Phosphorothioic trichloride was pur-
chased from Aldrich Co. Melting points were measured
using a Laboratory Devices Mel-Temp and are uncor-
rected. IR spectra were recorded on a JASCO FT/IR-480
Plus spectrophotometer. Optical rotations were recorded
4.4. Racemic O-phenyl ethylphosphonothioic acid racemic 1
A solution of crude O,O0-diphenyl ethylphosphonothioate
(8.78 g, 32 mmol) in a mixture of 4 M aqueous KOH
solution (40 mL) and 1,4-dioxane (180 mL) was stirred at
50 ꢁC for 6 h. The solution was concentrated under reduced
pressure to remove 1,4-dioxane and then extracted
with dichloromethane (2 · 150 mL). The aqueous layer
was neutralized with 3 M aqueous HCl solution and
extracted with dichloromethane (8 · 150 mL). The aque-
ous layer was then acidified with 3 M aqueous HCl
solution (30 mL) and extracted with dichloromethane
(9 · 100 mL). The combined extracts were dried over anhy-
drous Na2SO4, filtered, and concentrated under reduced
pressure to give crude racemic 1 (6.49 g, 32 mmol, quant.)
with satisfactory purity for the following enantioseparation
as a colorless oil. For the isolation of the chemically pure 1,
an aliquot of the crude product was purified by the
formation of the salt with dibenzylamine. A mixture of
crude racemic 1 (643 mg, 3.2 mmol) and dibenzylamine
(622 mg, 3.2 mmol) was allowed to crystallize from
AcOEt/hexane (3.5 mL/10.5 mL) to give the corresponding
salt, which was decomposed upon treatment with 1 M
aqueous HCl solution (20 mL) to afford pure racemic 1
(506 mg, 2.5 mmol, 79%) as a colorless oil. IR (NaCl): m
3000–2900, 2880, 1590, 1485, 1455, 1200, 1160, 920,
1
on a JASCO DIP-360 in a 1-cm cell. H (300 MHz) and
31P NMR (121 MHz) spectra were measured on a Varian
MERCURY 300 instrument. Chemical shifts (d) are re-
ported as parts per million relative to internal tetrameth-
1
ylsilane for H NMR and to external 85% H3PO4 for 31P
NMR; the coupling constants are in Hertz. HPLC analyses
were performed on a Daicel CHIRALCEL OJ-H for 2b
and OD-H for 2d, and Daicel CROWNPAK CR (+) for
2a, 2c, and 2e–j. Intensity data for the X-ray crystallo-
graphic analyses were collected by an imaging plate (IP)
instrument using a Mo X-ray source.
4.2. Ethylphosphonothioic dichloride
To a solution of phosphorothioic trichloride (10 mL,
100 mmol) in dry hexane (10 mL), 1 M ethylaluminum
dichloride in dry hexane (50 mL, 50 mmol) was added at
0 ꢁC under an argon atmosphere. After being refluxed for
8 h, the reaction mixture was cooled to 0 ꢁC, and H2O/
1,4-dioxane (5 mL/15 mL) and H2O (80 mL) were succes-
sively added to the mixture. The organic layer was sepa-
rated, successively washed with H2O (2 · 150 mL) and
brine (150 mL), dried over anhydrous Na2SO4, filtered,
and concentrated under reduced pressure to give crude
ethylphosphonothioic dichloride (6.47 g, 39.6 mmol, 79%)
with satisfactory purity for the following reaction as a
colorless oil. IR (NaCl): m 3000–2850, 1720, 1455, 1380,
1
780, 685 cmꢀ1. H NMR (300 MHz, CDCl3): d 1.32 (dt,
JP–H = 23 Hz, JH–H = 8 Hz, 3H), 2.20 (dq, JP–H = 16 Hz,
JH–H = 8 Hz, 2H), 7.17–7.22 (m, 3H), 7.32–7.37 (m, 2H).
31P NMR (121 MHz, CDCl3): d 94.62.
4.5. (Rp)-O-Phenyl ethylphosphonothioic acid (Rp)-1
1
1030, 1010, 775, 745, 675, 645 cmꢀ1. H NMR (300 MHz,
CDCl3): d 1.41 (dt, JP–H = 32 Hz, JH–H = 8 Hz, 3H),
2.81 (dq, JP–H = 12 Hz, JH–H = 8 Hz, 2H). 31P NMR
(121 MHz, CDCl3): d 95.13.
To a solution of crude racemic 1 (3.73 g, 18.5 mmol) in a
mixture of ethyl acetate/hexane (7 mL/1.75 mL), (R)-1-
phenylethylamine (PEA; 2.24 g, 18.5 mmol) was added,
after which the mixture was stirred at reflux for 30 min.
The mixture was cooled to rt with stirring and then left
for standing at ꢀ10 ꢁC for 12 h. The deposited salt was col-
lected by filtration using a membrane filter (T050A047A,
ADVANTEC). The salt, which was obtained, was recrys-
tallized twice from ethyl acetate/hexane (15 mL/2 mL and
then 15 mL/2.4 mL) to afford diastereopure (Rp)-1Æ(R)-
PEA salt (1.59 g, 4.9 mmol, 53% based on a half amount
of racemic 1 used). Mp: 142.5–145.5 ꢁC. IR (KBr): m
3000–2900, 1588, 1523, 1484, 1205, 1082, 911, 884, 777,
4.3. O,O0-Diphenyl ethylphosphonothioate
To a solution of crude ethylphosphonothioic dichloride
(4.98 g, 31 mmol) in dichloromethane (15 mL) was added
dropwise a mixture of phenol (7.19 g, 76 mmol) and trieth-
ylamine (11 mL, 76 mmol) in dichloromethane (25 mL) at
0 ꢁC under an argon atmosphere, and the mixture was stir-
red at rt for 3 h. After removal of unreacted triethylamine
and dichloromethane under reduced pressure, dichloro-
methane (80 mL) was added to the residue. The resultant
solution was successively washed with H2O (3 · 80 mL)
and brine (80 mL). The organic layer was dried over anhy-
drous Na2SO4, filtered, and concentrated under reduced
pressure to give crude O,O0-diphenyl ethylphosphonothio-
ate (8.57 g, 31 mmol, quant.) with satisfactory purity for
the following reaction as a colorless oil.
761, 711, 596, 505 cmꢀ1 1H NMR (300 MHz, CDCl3):
.
d 1.32 (dt, JP–H = 23 Hz, JH–H = 8 Hz, 3H), 2.20 (dq,
JP–H = 16 Hz, JH–H = 8 Hz, 2H), 7.17–7.22 (m, 3H),
7.32–7.37 (m, 2H). 31P NMR (121 MHz, CDCl3): d 82.61.
To the diastereomeric salt thus obtained was added 1 M
aqueous KOH solution (80 mL), and the solution was ex-
tracted with dichloromethane (5 · 80 mL). The aqueous
layer was acidified with 3 M aqueous HCl solution
(50 mL) and then extracted with dichloromethane
(6 · 90 mL). The combined extracts were dried over anhy-
drous Na2SO4, filtered, and concentrated under reduced
pressure to afford enantiopure (Rp)-1 (992 mg, 4.9 mmol,
53% based on a half amount of racemic PEA used) as a yel-
low oil. The enantiomeric excess of (Rp)-1 thus obtained
was determined by HPLC analysis (Daicel CHIRALCEL
For an elemental analysis, an aliquot of the crude product
was purified by silica gel chromatography. IR (NaCl): m
2979, 2939, 1592, 1489, 1455, 1211, 1189, 1161, 918, 798,
1
688 cmꢀ1. H NMR (300 MHz, CDCl3): d 1.41 (dt, JP–
H = 23 Hz, JH–H = 8 Hz, 3H), 2.36 (dq, JP–H = 15 Hz,
JH–H = 8 Hz, 2H), 7.11–7.36 (m, 10H). 31P NMR
(121 MHz, CDCl3): d 98.62. HRMS (EI): m/z calcd for
C14H15O2PS 278.0530, found 278.0538.

Y. Kobayashi et al. / Tetrahedron: Asymmetry 17 (2006) 967–974
973
OJ-RH; eluent, HClO4 (pH 2)/CH3CN = 8:2; flow rate,
4.8. General procedure for the enantioseparation of
1-phenylethylamine derivatives with enantiopure 1
0.5 mL/min; t1 (Rp-isomer) = 24 min, t2 (Sp-isomer) =
20
34 min; enantiomeric excess, >99%). ½aꢁD ¼ ꢀ9:9 (c 1.23,
MeOH). IR (NaCl): m 3000–2850, 1592, 1490, 1456, 1200,
To a solution of enantiopure 1 in a mixture of ethyl ace-
tate/hexane (composition, see Tables 1 and 2), 1 equiv of
a racemic amine were added. The mixture was stirred under
reflux for 2 h, slowly cooled to rt with stirring, and then
stirred for 3 h at rt. The precipitated crystalline powder
was collected by filtration using a membrane filter
(T050A047A, ADVANTEC) and dried under reduced
pressure.
1
1163, 919, 779, 689 cmꢀ1. H NMR (300 MHz, CDCl3): d
1.32 (dt, JP–H = 23 Hz, JH–H = 8 Hz, 3H), 2.19 (dq,
JP–H = 16 Hz, JH–H = 8 Hz, 2H), 7.17–7.22 (m, 3H),
7.32–7.37 (m, 2H). 31P NMR (121 MHz, CDCl3): d
94.62. Anal. Calcd for C8H11O2PS: C, 47.52; H, 5.48.
Found: C, 47.28; H, 5.70.
4.6. (Sp)-O-Phenyl ethylphosphonothioic acid (Sp)-1
4.9. Preparation of single crystals for X-ray crystallography
After concentration of the mother liquor of the initial crys-
tallization in the above procedure, 1 M aqueous KOH
solution (50 mL) was added to the residue, and the solution
extracted with dichloromethane (3 · 50 mL). The aqueous
layer was acidified (pH = 1) with 3 M aqueous HCl
4.9.1. General procedure for the preparation of single
crystals. Single crystals for X-ray crystallographic analy-
ses were prepared by the slow evaporation of the solvents
from saturated ethyl acetate/hexane solutions.
solution
and
then
extracted
with
dichloro-
methane (3 · 50 mL). The combined extracts were dried
4.9.2. Crystal data for (Rp)-1Æ(R)-2a salt. FW = 323.39,
over anhydrous Na2SO4, filtered, and concentrated under
monoclinic, space group P21, a = 11.094(11), b = 6.785(5),
3
˚
˚
reduced pressure to afford (Sp)-enriched
1
(2.47 g,
c = 12.011(2) A, b = 102.921(8), V = 881.2(2) A , Z = 2,
R = 0.0460, Rw = 0.0620. (CCDC 294558). Mp: 142.5–
145.5 ꢁC (decomp.).
12.2 mmol). To a solution of (Sp)-enriched 1 thus obtained
in a mixture of ethyl acetate/hexane (12 mL/2 mL),
(S)-PEA (1.48 g, 12.2 mmol) was added, and the mixture
stirred at reflux for 2 h. After being slowly cooled to rt,
the mixture was stirred overnight at rt, and the precipitated
crystalline powder collected by filtration. The obtained
salt was recrystallized once from ethyl acetate/hexane
(22.5 mL/3.8 mL) to afford diastereopure (Sp)-1Æ(S)-PEA
salt (2.11 g, 6.5 mmol, 71% based on a half amount of race-
mic 1 initially used) (mp: 142.5–145.5 ꢁC). To the diastereo-
meric salt thus obtained, 1 M aqueous KOH solution
(80 mL) was added, and the solution was extracted with
dichloromethane (4 · 100 mL). The aqueous layer was
acidified with 3 M aqueous HCl solution (70 mL) and then
extracted with dichloromethane (5 · 100 mL). The com-
bined extracts were dried over anhydrous Na2SO4, filtered,
and concentrated under reduced pressure to afford enantio-
4.9.3. Crystal data for (Sp)-1Æ(S)-2b salt. FW = 337.42,
orthorhombic, space group P212121, a = 7.573(2), b =
3
˚
˚
10.790(5), c = 21.930(13) A, V = 1792.0(1) A , Z = 4, R =
0.0480, Rw = 0.0610. (CCDC 294559). Mp: 167.0–
171.5 ꢁC (decomp.).
4.9.4. Crystal data for (Sp)-1Æ(S)-2e salt. FW = 341.38,
monoclinic, space group P21, a = 11.591(10), b = 6.683(5),
3
˚
˚
c = 24.156(3) A, b = 104.550(4), V = 1811.2(3) A , Z = 4,
R = 0.0470, Rw = 0.0550. (CCDC 294560). Mp: 143.0–
146.0 ꢁC (decomp.).
References
pure (Sp)-1 (1.32 g, 6.5 mmol, 71% based on a half amount
19
of racemic PEA initially used) as a yellow oil. ½aꢁD ¼ þ9:4
1. (a) Li, K. Y.; Zhou, Z. H.; Chan, A. S. C.; Tang, C. C.
Heteroatom Chem. 2002, 1, 93; (b) Lacour, J.; Vial, L.;
Bernardinelli, G. Org. Lett. 2002, 14, 2309; (c) Omelaficzuk,
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2687.
1
(c 2.40, MeOH). The IR, H NMR, and 31P NMR were
identical with those of enantiopure (Rp)-1.
4.7. Preparation of racemic amines
2. (a) Shi, M.; Zhang, W. Tetrahedron: Asymmetry 2004, 15,
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metry 1999, 10, 4701.
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Racemic amines were prepared by the reductive amination
of the corresponding ketones according to the procedures
described in the literature.10 To a solution of ketone
(30 mmol) in methanol (50 mL), ammonium acetate
(300 mmol) and sodium cyanoborohydride (30 mmol) were
added at rt. After being stirred for 1 week, 3 M aqueous
HCl solution (50 mL) was added dropwise to the reaction
mixture. The resulting mixture was concentrated to remove
methanol and washed with dichloromethane (3 · 80 mL),
and then the aqueous solution was basified (pH = 12) with
3 M aqueous KOH solution (70 mL). The liberated amine
was extracted with dichloromethane (3 · 80 mL), and the
combined organic extracts were dried over anhydrous
Na2SO4. After removal of the solvent under reduced pres-
sure, the crude product was purified by distillation under
reduced pressure.
5. (a) Mikolajczyk, M.; Midura, W. H.; Schmutzler, R.;
Schiebel, H.-M.; Schulze, P. New J. Chem. 2001, 25, 1073;
(b) Maier, L. Helv. Chim. Acta 1964, 47, 27.

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