Spontaneous resolution amongst chiral ortho-cyanophenyl glycerol derivatives: an effective preferential crystallization approach to a single enantiomer of the β-adrenoblocker bunitrolol

Article abstract of DOI:10.1016/j.tetasy.2008.05.025

The β-adrenoblocker bunitrolol 1 as well as intermediate cyclic sulfate 6 and glycidyl ether 8 have been prepared in enantiopure form by starting from enantiopure o-cyanophenyl glycerol ether 2 by an entrainment resolution procedure. Thermal investigations reveal that 1·HCl forms a moderately stable racemic compound, whereas 2, 6 and 8 are conglomerate forming substances potentially capable of entrainment resolution. Some chemical and chiroptical characteristics for bunitrolol and possible intermediates in its synthesis were corrected, and configurations were verified with the configuration of 1·HCl.

Full text of DOI:10.1016/j.tetasy.2008.05.025

Tetrahedron: Asymmetry 19 (2008) 1430–1435
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Tetrahedron: Asymmetry
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Spontaneous resolution amongst chiral ortho-cyanophenyl glycerol
derivatives: an effective preferential crystallization approach to a single
enantiomer of the b-adrenoblocker bunitrolol
*
Zemfira A. Bredikhina, Flyura S. Akhatova, Dmitry V. Zakharychev, Alexander A. Bredikhin
A.E. Arbuzov Institute of Organic and Physical Chemistry, Russian Academy of Sciences, Arbuzov St., 8, Kazan 420088, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 March 2008
Accepted 23 May 2008
The b-adrenoblocker bunitrolol 1 as well as intermediate cyclic sulfate 6 and glycidyl ether 8 have been
prepared in enantiopure form by starting from enantiopure o-cyanophenyl glycerol ether 2 by an entrain-
ment resolution procedure. Thermal investigations reveal that 1ꢀHCl forms a moderately stable racemic
compound, whereas 2, 6 and 8 are conglomerate forming substances potentially capable of entrainment
resolution. Some chemical and chiroptical characteristics for bunitrolol and possible intermediates in its
synthesis were corrected, and configurations were verified with the configuration of 1ꢀHCl.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
the key chiral substances studied. We share the opinion that the
binary melting phase diagram is a ‘roadmap’ for those concerned
For the family of b-adrenergic blockers with general formula
ArOCH2CH(OH)CH2NHAlk, it has been shown that (S)-enantiomers
are eutomer components of the racemic drug, whereas (R)-
enantiomers (distomers) usually display other (often undesirable)
activities.1 The b-adrenoblocker bunitrolol, 1-(2-cyanophenoxy)-
2-hydroxy-3-tert-butylaminopropane 1 is no exception. Its enanti-
omers demonstrate different activities2 and different rates of met-
abolic oxidation3 in specially organized in vitro experiments.
Bunitrolol is registered as a racemate.4 Bearing in mind a general
tendency for the replacement of racemic drugs by their single
enantiomer analogues,5 we wanted to report herein the synthesis
and properties of scalemic 1, as well as of some valuable interme-
diates and related compounds.
with chiral substance resolution and/or purification. Thus, we have
tried to reconstruct the phase diagrams for bunitrolol (as its hydro-
chloride) and for its main precursors.
2. Results and discussion
Many approaches to non-racemic b-adrenoblocker compounds
have been described in the literature,7 one of which starts from
the scalemic aryl glycerol ethers. In the case of bunitrolol, the start-
ing material would be 3-(2-cyanophenoxy)-propane-1,2-diol 2.
Compound (S)-2 was obtained through a Sharpless asymmetric
dihydroxylation of the corresponding aryl allyl ether by Wang
et al.8 The synthesis was repeated by Sayyed et al.9 For obtaining
this intermediate in racemic and scalemic forms we have used
the reaction of 2-cyanophenol 3 and rac- or scal-3-chloro-1,2-pro-
panediol 4.
Our interest in this problem was for several reasons. First of all
we were hopeful of finding a new application of the spontaneous
resolution in obtaining practically important products.
The second reason is less general. During the progress of this
work, we have found that an essential part of published physical
and chiroptical properties for bunitrolol itself and for the main
intermediates are discrepant or erroneous. Recently, we estab-
lished the absolute configuration of bunitrolol hydrochloride by a
direct Bijvoet method,6 meaning that we had a reliable reference
point for the chiroptical correlations. The chemical transformations
studied in this work are outlined by Scheme 1.
At this point, discrepancies between the published and our ob-
served characteristics began. For a sample of 28% ee, Wang et al. re-
ported the value of ½a D20
ꢁ
¼ þ9:4 (c 0.5, EtOH).8 The value of
½
a 2D0
ꢁ
¼ þ21:8 (c 0.5, EtOH) for the sample of 65% ee was reported
by Sayyed et al.9 It can be seen that these numbers correspond to
one another and should be in compliance with the value of
½
a 2D0
ꢁ
¼ þ33:6 for the enantiopure sample (9.4:28 = 21.8:65 =
33.6:100). The last work also reports the melting point 140–
142 °C for the same sample. For the very pure sample of (S)-2
(overall purity was higher than 99.2% by differential scanning
calorimetry, enantiomeric purity was higher than 99.4% by
The final part of our work is devoted to thermochemical analy-
sis of the melting (and hence the crystallization) peculiarities of
chiral HPLC) we have found mp 72–74 °C and ½a D20
¼ þ3:1 (c 1.0,
ꢁ
* Corresponding author. Tel.: +7 843 2727392; fax: +7 843 2731872.
E-mail address: baa@iopc.knc.ru (A. A. Bredikhin).
EtOH).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.05.025

Z. A. Bredikhina et al. / Tetrahedron: Asymmetry 19 (2008) 1430–1435
1431
t
O
NH Bu
2
OH
H
O
O
S
OSO
2
O
Cl
OH
OH
HO
(S)-4
NC
NC
O
O
H
NC
x
vi
iii
vi
(S)-1
(S)-1·HCl
i
(S)-2
ii
(2RS,4R)-5
9
iv
v
t
Bu
O
t
NH Bu
NH
OH
OH
OH
2
O
S
O
OSO
3
O
H
O
NC
O
NC
OH
NC
O
NC
OH
NC
O
x
i
ix
vi
+
OH
(S)-1·HCl
rac-2
Cl
rac-4
3
(R)-6
vii
(S )-1
10
ii
OH
H
Br
O
H
H
OH
OH
Cl
OH
OH
H
NC
O
NC
O
NC
O
x
viii
vi
(R)-4
(S)-1*HCl
(S)-1
i
(R)-2
(R)-7
(S)-8
Scheme 1. Reagents and conditions: (i) NaOH, EtOH, reflux; (ii) spontaneous resolution; (iii) SOCl2, CH2Cl2, 0 °C; (iv) NaIO4, RuCl3ꢀH2O, CH3CN; (v) SO2Cl2, AcOEt, NEt3, 0 °C;
(vi) ButNH2; (vii) LiBr, THF; (viii) K2CO3, MeOH; (ix) (a) H2SO4; (b) NaOH; (x) HCl.
From the results of Wang et al. it follows that aryl allyl ethers
bearing ortho-substituents are unsuitable substrates for Sharpless
asymmetric dihydroxylation, and the corresponding diols are ob-
tainable with poor enantiomeric excesses.8 Conversely, it was
shown that some phenyl glycerol ethers bearing ortho-substituents
demonstrate the ability for spontaneous resolution.10,11 This group
contains o-Cl-, o-Br- and o-I-phenyl glycerol ethers;12 the com-
pounds which closely resemble the o-CN-phenyl glycerol ether 2.
Bearing this in mind, we quantitatively investigated the melting
properties of chiral compound 2 by means of differential scanning
calorimetry (d.s.c.).
glomerates. The near zero positive value for D
G0 also points to the
same peculiarity for chiral 2.13 From all this information it follows
that the chiral diol 2 displays a property of spontaneous resolution
and could be potentially resolved by direct methods.
Direct methods of racemate resolution, especially operating an
entrainment effect, that is, the preferential crystallization of an
enantioenriched crop induced by seeding with enantiopure crys-
tals a supersaturated solution of a conglomerate forming (almost)
racemic chiral compound, is a gratifying labour for synthetic chem-
ists, since in the event of success, it allows us to obtain both enan-
tiomers easily without resorting to any enantiopure auxiliaries.
Even in the case of conglomerate forming substances it is not
always easy to use the benefits of spontaneous resolution. Coque-
rel is of opinion that almost half of conglomerate forming com-
pounds would demonstrate poor entrainment characteristics.15,16
As evident from Section 4, racemic diol 2 is a member of the
better part of the conglomerate family: for this compound we were
able to demonstrate an entrainment effect, which is the preferen-
tial crystallization of an enantioenriched crop induced by seeding
with enantiopure crystals of the oversaturated racemate solution.
Six runs (three cycles) were sufficient enough to resolve about
4 g of the racemate, obtaining the (R)- and (S)-2 samples of about
2 g each. The quality of both specimens is good enough, and mak-
The results obtained for the temperature and the enthalpy of
fusion of the pure enantiomer and the pure racemate of diol 2, as
well as the calculated13 values of the entropy of enantiomer mixing
for liquid racemate,
compound in the solid state,
D
Sml , and free energy of formation of racemic
D
G0, are presented in Table 1. From
the d.s.c. data, the idealized melting temperatures against the com-
position diagram for compound 2 were reconstructed and are
shown in Figure 1a. The binary phase diagram for the compound
has an obvious single eutectic V-shape typical of a racemic con-
glomerate.14 The entropy of mixing for the enantiomers of 2 in
the liquid state is equal to 5.56 J Kꢂ1 molꢂ1, which is slightly less
but very close to the ideal value of 5.75 J Kꢂ1molꢂ1 (Rln2) for con-
Table 1
D.s.c. measured melting point and enthalpy of fusion of racemic (low index R) and enantiopure (low index A) compounds 1, 2, 6 and 8 and calculated thermodynamic
characteristics for these substances
Compound
TfA (°C)
TfR (°C)
D
HfA (kJ molꢂ1
)
D
HfR (kJ molꢂ1
)
D
Sml (J Kꢂ1 molꢂ1
)
D
G0 (J molꢂ1
)
2
6
8
72.6
118.6
90.5
51.1
87.4
65.7
27.7
26.3
27.7
41.6
36.9
22.2
25.4
40.1
5.56
5.33
5.32
4.50
19.2
15.2
ꢂ68.4
1ꢀHCl
184.5
162.6
ꢂ516

1432
Z. A. Bredikhina et al. / Tetrahedron: Asymmetry 19 (2008) 1430–1435
in Table 1. Reconstructed from the d.s.c. data, the idealized binary
phase diagram for compound 6 is depicted in Figure 1b. Once again
the phase diagram and calculated thermodynamic parameters are
close to those typical for a racemic conglomerate.
In the work reported by Sayyed et al.,9 sulfate (R)-6 [depicted in
the original work as the compound 5d and mistakenly named as
(2R)-1-(2-cyanophenoxy)-1,3,2-dioxathiolane-2,2-dioxide]
has
been described as a gum, ½a D20
¼ þ8:6 (c 2.0, EtOH). In reality it is
ꢁ
a very crystalline solid, melting at 118–120 °C, ½a D20
¼ þ17:0 (c
ꢁ
0.6, EtOH). The phase diagram (Fig. 1b) shows that even a sample
with an enantiomeric purity of 50.6% (100 ꢃ 8.6/17.0) must fuse
between 88 °C (eutectic line) and 107 °C (liquidus line).
The conglomerate forming abilities of sulfate 6 give rise to the
potential possibility of using this intermediate in a symmetry brak-
ing step. Demonstration experiments performed by us have shown
that racemic 6 could be resolved to enantiomers through an
entrainment procedure. After optimization and scaling-up of this
stage, racemic cyclic sulfate 6 could be a promising starting mate-
rial in the single enantiomer bunitrilol production. If that is the
case, it is desirable to change the usual two-step sequence of sulfite
formation/ruthenium oxidation, comfortable for laboratory pur-
poses, to another one, which is shorter, less expensive and which
features a simpler work-up, and does not require the use of envi-
ronmentally unfriendly heavy metals. An alternative approach
consists in direct action of sulfuryl chloride on the corresponding
diol 2. Recently Alonso and Riera have drawn attention to this scar-
cely used synthetic route.18 Following the general recommenda-
tions of this work, we were able to obtain rac- as well as scal-6
with moderate to good yields by the direct procedure.
Both sulfites 5 and sulfates 6 react with tert-butylamine, and al-
low us to obtain the target bunitrolol 1 with moderate (sulfites) to
low (sulfates) yield. The main difference between these starting
materials consists of the intermediate betaines stability. The inter-
mediate internal salt of alkylsulfurous acid 9 is quite labile and
easily destroyed by excess amine present. Hence the ‘sulfite route’
to the target bunitrolol 1 could be organized as a one-pot process.
At the same time the intermediate internal salt of alkylsulfuric acid
10 is sufficiently stable and could be destroyed only in more drastic
conditions.
Figure 1. Experimental (circles) points and calculated (solid lines) binary melting
phase diagrams for compounds 2 (a), 6 (b), 8 (c) and 1ꢀHCl (d).
ing sure that the compound
2 is amenable to preferential
crystallization we made no attempts to improve the crop
enantiopurity or to optimize experimental conditions for the
resolution.
Some years ago Bittman et al. reported a highly effective meth-
od of transformation of a cyclic sulfate to an epoxide.19 Following
this approach, sulfate 6 was opened by LiBr in THF to provide vic-
inal bromohydrin 7. Subsequent cyclization of 7 in methanolic
K2CO3 solution led to glycidol ether 8 (Scheme 1).
The thermochemistry of chiral epoxide 8 obtained by an alter-
native route was studied earlier,6 and for the sake of completeness
we reproduce the thermodynamic properties and phase diagram of
this compound in Table 1 and Figure 1c. As was established in our
previous work, chiral epoxide 8 is a conglomerate forming com-
pound with poor entrainment abilities.6
The so-established availability of both enantiomers of diol 2
allowed us to compare different routes to free enantiomeric forms
of bunitrolol hydrochloride 1ꢀHCl and free 1. The general approach
to obtain a vicinal amino alcohol starting from a vicinal diol moiety
involves the formation of an intermediate cyclic fragment easily
capable of subsequent opening with an amine. The most frequently
used cyclic moieties, namely sulfite, sulfate and oxirane, could be
obtained from one another in this sequence. Scheme 1 shows such
a transformation, as applied to diol 2. Special attention must be
given to formal change of the configurational descriptor(s), while
the real configuration of the central carbon atom remains constant.
Cyclic sulfites 5 are obtainable through the reaction of 2 with
thionyl chloride with quantitative yield. Due to the appearance of
an additional chiral sulfur atom, cyclic sulfites 5 were obtained
from enantiopure (S)-2 as an epimer mixture (cis/trans ratio of
about 2:3) with an (R)-configuration at the carbon centre. The
mixture was used in all the next steps without separation of the
individual diastereomers. For this reason, sulfites 5 were not inves-
tigated by d.s.c.
The enantiomeric glycidol ether (S)-8 has been obtained by two
groups. Nicola et al. described this compound as a solid mp 88–
89 °C, with a positive sign for its specific rotation in ethanol,
½
a 2D5
ꢁ
¼ þ17:7 (c 1, EtOH).20 Sayyed et al. declared that (S)-8 is a
gum with a positive sign for specific rotation, but in chloroform,
½
a 2D5
ꢁ
¼ þ2:3 (c 2.3, CHCl3).9 The sample of 8 obtained from sulfate
(R)-6 (Scheme 1) was a white solid, mp 90–91 °C, ½a D20
¼ þ18:5 (c
ꢁ
0.5, EtOH). We have found that epoxide 8 (as well as diol 2) belongs
to an uncommon group of compounds whose specific rotation sign
can change with a change of solvent. The sample of enantiomeric 8
with ½a 2D0
ꢁ
¼ þ18:1 (c 1.0, EtOH) manifests ½a D20
¼ ꢂ5:0 (c 1.0,
ꢁ
In this work, the cyclic sulfates 6 were obtained firstly through
the well known Sharpless ruthenium-catalyzed oxidation of the
sulfite to sulfate with periodate.17 We have investigated the chiral
sulfate 6 thermochemically. D.s.c. measured as well as calculated
thermodynamic characteristics for this compound are presented
CHCl3) or ½a 2D0
¼ ꢂ14:5 (c 0.65, CCl4).
ꢁ
To establish the absolute configuration for glycidol ethers 8, we
transformed both enantiomers of the compound into b-blocker
bunitrolol 1 (Scheme 1). Levorotary (in ethanol) bunitrolol hydro-
chloride (ꢂ)-1ꢀHCl was obtained from the dextrorotary (in ethanol)

Z. A. Bredikhina et al. / Tetrahedron: Asymmetry 19 (2008) 1430–1435
1433
epoxide, as well as dextrorotary (+)-1ꢀHCl derivatives from levoro-
4.2. Synthesis
tary 8. For the (+)-1ꢀHCl the (R)-configuration was established
unambiguously by the Bijvoet method.6 The epoxide opening by
simple amines is known to be stereospecific and proceeds with a
retention of configuration for the carbon stereogenic centre. Thus,
the epoxide with an (S)-absolute configuration, (S)-8, must display
a positive specific rotation in ethanol and negative one in chloro-
form and carbon tetrachloride.
Racemic epichlorohydrin (99%) was purchased from Alfa Ae-
sarÒ; rac-3-chloropropane-1,2-diol (99+%) and 2-cyanophenol
(99%) were purchased from Acros OrganicsÒ; methyl-tert-butyl
ether (MTBE, 99.5%) was from Fisher Scientific. (R)- and (S)-3-
chloro-1,2-propanediol, (R)-4 and (S)-4 were prepared through Jac-
obsen kinetic hydrolytic resolution of rac-epichlorohydrin without
modifications.21
Non-racemic bunitrolol (S)-1 as a free base is low melting,
poorly soluble in water compound, characterized by a solvent
dependable specific rotation {mp 30–32 °C; ½a D20
ꢁ
¼ ꢂ9:0 (c 0.8,
4.2.1. rac-3-(2-Cyanophenoxy)-propane-1,2-diol rac-2
EtOH); ½a 2D0
ꢁ
¼ þ12:3 (c 0.38, H2O)}. In no part does it resemble
Compound rac-2 was synthesized by analogy with our early
works.10,11 To a solution of 2-cyanophenol 3 (6.5 g, 0.055 mol) in
ethanol (37 ml), a solution of NaOH (3.1 g, 0.077 mol) in water
(12 ml) was added and the resulting mixture was stirred and heated
at reflux for 30 min. Then a solution of racemic 3-chloropropane-
1,2-diol rac-4 (7.3 g, 0.066 mol) in ethanol (6 ml) was added within
30 min, and the mixture was further stirred and heated at reflux for
3 h. After cooling, the volume of the resulting mixture was reduced
to about one third followed by the addition water (40 ml) and
extraction with CH2Cl2 (3 ꢃ 60 ml). The combined organic layers
were dried over anhydrous Na2SO4 and the solvent was removed.
The crude diol rac-2 was purified by distillation (bp 154–160 °C at
0.05 mm Hg). Yield 9.1 g (86%); viscous oil, crystallizing upon
standing. White solid was washed with ether. Mp 50–52 °C (hex-
ane/EtOAc). 1H NMR (600 MHz, CDCl3) d 2.20 (dd, J = 5.9, 6.6 Hz,
1H, IH), 2.90 (d, J = 4.4 Hz, 1H, IH), 3.83 (dd, J = 11.2, 5.0 Hz, 1H,
OCH2), 3.90 (dd, J = 11.2, 3.5 Hz, 1H, OCH2), 4.15–4.22 (m, 3H,
CHO, CH2O), 7.01 (d, J = 8.6 Hz, 1H, Ar), 7.05 (t, J = 7.6 Hz, 1H, Ar),
7.53–7.56 (m, 2H, Ar). Anal. Calcd for C10H11NO3: C, 62.17; H,
5.73; N, 7.25. Found: C, 62.31; H, 5.77; N, 7.42.
its description in the Sayyed et al. paper {(S)-bunitrolol: mp 162
°C; ½a 2D0
ꢁ
¼ ꢂ10:0 (c 1.4, H2O), 60% ee}.9 The low melting point pre-
cludes an ordinary d.s.c. investigations of the bunitrolol base.
On the other hand, hydrochloride 1ꢀHCl is quite suitable for
these purposes. D.s.c. measured as well as calculated thermo-
dynamic characteristics for this compound is presented in Table
1. Reconstructed from the d.s.c. data the idealized binary phase
diagram for 1ꢀHCl is depicted in Figure 1d. This time the phase
diagram is typical for a racemic compound forming substance,
and the calculated substantial negative Gibbs free energy,
D
G0, is
in agreement with a moderate stability of such a solid state race-
mic compound.
3. Conclusion
In conclusion, we have modified the known synthetic route to a
single enantiomer b-adrenoblocker bunitrolol using the spontane-
ous resolution of rac-3-(2-cyanophenoxy)-propane-1,2-diol, rac-2
as a symmetry breaking step. During the progress of this work
we have corrected an essential part of published physical and chir-
optical properties for bunitrolol itself and for main intermediates
en-route for this compound.
We have shown thermochemically also that not only diol rac-2,
but also its reactive cyclic sulfate 6 and epoxide 8 derivatives man-
ifests the same property of spontaneous resolution in racemic
form. Thus, other symmetry breaking points based upon this qual-
ity are possible in the same synthetic sequence. At least, all of the
mentioned intermediates could be enantioenriched to a desirable
degree by simple recrystallization. As for the bunitrolol itself, it
could also be enantioenriched by crystallization in the hydrochlo-
ride form, starting from samples with a rather low ee P 14% (bin-
ary phase diagram eutectic point).
4.2.2. (R)-3-(2-Cyanophenoxy)-propane-1,2-diol (R)-2
Compound (R)-2 was prepared from (R)-3-chloro-1,2-propane-
diol (R)-4 {0.73 g, 6.6 mmol; ½a D20
¼ ꢂ6:4 (c 5, H2O)} and 2-cyano-
ꢁ
phenol 3 (0.65 g, 5.5 mmol) as described for rac-2. Crude diol (R)-2
(0.93 g, 89%) was crystallized from a mixture of light petroleum/
EtOAc 1:1 to give (R)-2 (0.64 g, 61%); mp 72–74 °C; ½a D20
¼ ꢂ3:0
ꢁ
(c 0.9, EtOH); ½a D20
¼ þ9:5 (c 1.0, MTBE); 99.9% ee [chiral HPLC
ꢁ
analysis of the diacetate derivative; column temperature 27 °C;
eluent: hexane/isopropanol = 95/5; tR = 23.3 min (major)] IR (KBr,
cmꢂ1): 3262 (broad, O–H), 2227 (CN), 1599, 1496 (Ar). 1H NMR
(600 MHz, CDCl3) d 2.90 (br s, 2H, IH), 3.83 (dd, J = 11.0, 4.7 Hz,
1H, OCH2), 3.90 (dd, J = 11.0, 2.9 Hz, 1H, OCH2), 4.14–4.20 (m, 3H,
CHO, CH2O), 7.01 (d, J = 8.9 Hz, 1H, Ar), 7.04 (t, J = 7.3 Hz, 1H, Ar),
7.53–7.56 (m, 2H, Ar). 13C NMR (150.864 MHz, CDCl3) d 63.3
(CH2IH), 70.0 (CH), 70.2 (OCH2), 102.1 (C2Ar), 112.5 ðCA6rÞ, 116.5
(CN), 121.3 ðCA4rÞ, 133.6 ðCA3rÞ, 134.5 ðCA5rÞ, 160.3 ðCA1rÞ. Anal. Calcd
for C10H11NO3: C, 62.17; H, 5.73; N, 7.25. Found: C, 62.05; H,
5.69; N, 7.14.
4. Experimental
4.1. General
The NMR spectra were recorded on a Bruker Avance-600
spectrometer in CDCl3 or DMSO-d6 with TMS or the signals of the
solvent as the internal standard. The IR spectra were recorded on
a Bruker IFS-66v Fourier-transform spectrometer. Optical rota-
tions were measured on a Perkin–Elmer model 341 polarimeter
(concentration c is given as g/100 ml). Melting points for general
purposes were determined using a Boëtius apparatus and are
uncorrected.
The melting curves were measured on a Perkin–Elmer Diamond
DSC differential scanning calorimeter in aluminium pans with the
rate of heating of 10 °C minꢂ1. The mass of the samples amounted
to approximately 2.5 mg. Temperature scale and heat flux were
calibrated against the data for indium, phenol and naphthalene.
HPLC analyses were performed on a Shimadzu LC-20AD system
controller, and UV monitor 275 nm was used as a detector. The col-
umn used, from Daicel, Inc., was Chiralcel OD (0.46 ꢃ 25 cm).
4.2.3. (S)-3-(2-Cyanophenoxy)-propane-1,2-diol (S)-2
Compound (S)-2 was synthesized analogously from the (S)-3-
chloropropane-1,2-diol (S)-4 {0.73 g, 6.6 mmol; ½a D20
¼ þ6:1 (c 4.8,
ꢁ
H2O)}. Yield: 0.68 g (65%). Mp 72–74 °C; ½a D20
¼ þ3:1 (c 1.0, EtOH);
ꢁ
½
a 2D0
ꢁ
¼ þ14:3 (c 0.5, H2O); ½a D20
¼ ꢂ9:5 (c 1.0, MTBE); 99.4% ee [chi-
ꢁ
ral HPLC analysis of the diacetate derivative; column temperature
27 °C; eluent: hexane/isopropanol = 95:5; tR = 21.1 min (major)]
{cf. lit.9 mp 140–142 °C; ½a 2D0
¼ þ21:8 (c 0.5, EtOH) for 65% ee;
ꢁ
lit.8
½
a 2D0
ꢁ
¼ þ9:4 (c 0.5, EtOH) for 28% ee}. NMR spectra were close
to above-described for the (R)-enantiomer and racemate.
4.2.4. Resolution of racemic 3-(2-cyanophenoxy)-1,2-prop-
anediol, rac-2 by preferential crystallization (entrainment)
Racemic 2 (5.8 g) and (R)-2 (0.6 g) were dissolved in 85 ml of
MTBE at 40 °C. The solution was cooled to 12 °C and seeded with

1434
Z. A. Bredikhina et al. / Tetrahedron: Asymmetry 19 (2008) 1430–1435
finely-pulverized (R)-2 (16 mg, 99% ee). During 45 min of stirring
the temperature was lowered to 8 °C; after stirring the mixture
for 80 min at 8–9 °C, precipitated (R)-2 was collected by filtration
½
a 2D0
ꢁ
¼ þ17:0 (c 0.6, EtOH); 99.9% ee [chiral HPLC; column temper-
ature 29 °C; eluent: hexane/isopropanol = 60:40; tR = 13.0 min
(major), tR = 14.6 min (minor).] Cf. lit.9 gum, ½a D20
¼ þ8:6 (c 2.0,
ꢁ
{1.04 g after drying; ½a D20
ꢁ
¼ þ8:3 (c 0.65, MTBE), 87% ee}. The extra
EtOH). IR (KBr, cmꢂ1): 3074, 3044 (CAr–H); 2947 (C–H); 2233
(CN); 1581, 1600, 1494 (Ar); 1375, 1206 [S(@O)2]; 1060, 977,
834, 756 (S–O–C). 1H NMR (600 MHz, CDCl3) d 4.39 (dd, J = 10.2,
6.8 Hz; 1H, OCH2), 4.48 (dd, J = 10.2, 5.0 Hz; 1H, OCH2), 4.82 (dd,
J = 9.0, 5.7 Hz; 1H, CH2IS), 4.93 (dd, J = 9.0, 6.4 Hz; 1H, CH2OS)
portion of rac-2 (1.02 g) was then dissolved in the mother liquor at
40 °C; the resulting solution was cooled to 10 °C. After the addition
to a solution of (S)-2 (16 mg, 99% ee) as seed crystals, and stirring
the mixture for 85 min at 7–8 °C, (S)-2 {0.80 g after drying;
½
a 2D0
ꢁ
¼ ꢂ7:9 (c 0.7, MTBE), 83% ee} was collected by filtration. Fur-
5.29–5.33 (m, 1H, CHOS), 7.02 (d, J = 8.32 Hz, 1H, C6ArH), 7.13 (dd,
3;5
Ar
ther resolution was carried out at 7–8 °C by adding amended
amounts of rac-2 to the filtrate in a manner similar to that de-
J = 7.4, 7.6 Hz; 1H, C4ArH), 7.6 (m, 2H,
C
H). 13C NMR
(150.864 MHz, CDCl3) d 66.8 (CH2OS), 69.7 (OCH2), 77.8 (CHOS),
102.9 ðC2ArÞ, 113.0 ðCA6rÞ, 115.5 (CN), 122.7 ðC4ArÞ, 134.0 ðCA3rÞ, 134.6
ðC5ArÞ, 158.8 ðCA1rÞ. Anal. Calcd for C10H9NSO5: C, 47.05; H, 3.55; N,
5.48; S, 12.55. Found: C, 47.14; H, 3.48; N, 5.56; S, 12.54.
scribed above. After a second cycle, 0.66 g of (R)-2 {½a D20
¼ þ8:2
ꢁ
(c 0.6, MTBE), 86% ee} and 0.60 g of (S)-2 {½a D20
¼ ꢂ7:9 (c 1.0,
ꢁ
MTBE), 84% ee} were collected. After third cycle, 0.58 g of (R)-2
{½a 2D0
ꢁ
¼ þ8:2 (c 0.6, MTBE), 87% ee} and 0.62 g of (S)-2 {½a D20
¼
ꢁ
ꢂ7:5 (c 1.1, MTBE), 80% ee} were collected. A high degree of enan-
tiomeric purity of collected diols can be achieved by simple recrys-
tallization from MTBE. For example, a portion of (R)-2 (1.04 g, 87%
ee) was dissolved in boiling MTBE (45 ml). After cooling the
solution to 0–5 °C for 24 h the crystallized (R)-2 was collected by
4.2.6.2. Method B. Sulfate (R)-6 was obtained from diol (S)-2 and
SO2Cl2 following a slightly modified published procedure.18 Diol
(S)-2 (0.58 g, 3 mmol) was dissolved in AcOEt under a nitrogen
atmosphere. NEt3 (4.8 ml, 36 mmol) was then added and the mix-
ture cooled to 0–2 °C. SO2Cl2 (1.2 ml, 15 mmol) in AcOEt (1 ml) was
added dropwise over a period of 3 h. The reaction mixture was stir-
red at this temperature for 30 min. Water (45 ml) was added and
the layers separated and the organic one was washed twice with
water and brine. After drying over MgSO4, the solution was filtered
through a small pad of silica gel. The filtrate was then concentrated
by rotary evaporation (i-PrOH was used to remove the residual
H2O) and further dried under vacuum, washed with ether to yield
0.67 g of a crude solid (R)-6 (87% yield), which was crystallized
filtration {yield 0.87 g; ½a D20
¼ þ9:5 (c 0.8, MTBE), >99% ee}.
ꢁ
4.2.5. (2RS,4R)-4-(2-Cyanophenoxymethyl)-1,3,2-dioxathi-
olane-2-oxide, (2RS,4R)-5
To a stirred and cooled (0 °C) solution of (S)-3-(2-cyanophen-
oxy)-propane-1,2-diol (S)-2 (1.93 g, 0.01 mol) in CH2Cl2 (25 ml) a
solution of SOCl2 (1.31 g, 0.011 mol) in CH2Cl2 (10 ml) was added
dropwise. The reaction mixture was stirred for an extra 1 h, and
the volatile material was removed under reduced pressure to
afford a viscous oil, which crystallized upon standing. The mixture
of cis and trans isomers, (2R,4R)-5 and (2S,4R)-5, (38:62) was used
in the next step without further purification; quantitative yield,
from CCl4 to give a pure (R)-6; mp 118–120 °C (CCl4); ½a D20
¼
ꢁ
þ16:5 (c 0.6, EtOH).
4.2.7. (S)-4-(2-Cyanophenoxymethyl)-1,3,2-dioxathiolane-2,2-
dioxide, (S)-6
Compound (S)-6 was obtained from (R)-2 and SO2Cl2 following
the above-mentioned procedure (method B); mp 118–120 °C,
mp 70–80 °C, ½a 2D0
ꢁ
¼ þ24:3 (c 1.0, CH2Cl2)}. 1H NMR (600 MHz,
CDCl3) d 4.15 (dd, J = 10.0, 6.3 Hz; 1H, CH2OS-trans,); 4.28 (dd,
J = 10.0, 4.2 Hz; 1H, CH2OS-trans), 4.39 (dd,J = 9.1, 7.6 Hz; 0.6H,
CH2OS–cis), 4.54 (dd, J = 9.1, 5.2 Hz; 0.6H, CH2OS-cis), 4.63 (dd,
J = 8.9, 4.4 Hz; 1.0H, CH2OAr-trans), 4.76 (d, J = 6.8 Hz, 1.2 H,
CH2OAr-cis), 4.90 (dd, J = 8.9, 6.5 Hz; 1.0H, CH2OAr-trans), 4.97–
5.02 (m, 0.6H, CHOS-cis), 5.30–5.33 (m, 1.0H, CHOS-trans), 7.00
(d, J = 8.6 Hz, 1.0H, C6ArH-trans), 7.03 (d, J = 8.6 Hz, 0.6H, CA6rH-cis),
7.09–7.12 (m, 1.6H, C4ArH-cis=trans), 7.56–7.60 (m, 3.2H,
C5ArH-cis=trans, C3ArH-cis=trans). 13C NMR (150.864 MHz, CDCl3) d
67.28 (CH2OAr-trans); 68.69 (CH2OS-trans); 69.43 (CH2OAr-cis);
70.20 (CH2OS-cis); 77.32 (CHOS-trans); 79.06 (CHOS-cis); 102.51,
102.71 ðC2ArÞ, 112.74, 112.82 ðCA6rÞ; 115.76, 115.90 (CN), 122.12,
122.20 ðC4ArÞ; 133.90, 134.00 ðCA3rÞ; 134.51, 134.58 ðCA5rÞ; 159.40
ðC1ArÞ.
½
a 2D0
ꢁ
¼ ꢂ16:9 (c 0.5, EtOH).
4.2.8. rac-4-(2-Cyanophenoxymethyl)-1,3,2-dioxathiolane-2,2-
dioxide, rac-6
Compound rac-6 was synthesized by two-step sequence of sul-
fite formation/ruthenium oxidation analogously with the above-
described (Sections 4.2.5 and 4.2.6.1) methods from the rac-3-(2-
cyanophenoxy)-propane-1,2-diol, rac-2 (1.5 g, 7.8 mmol). Yield:
1.69 g (85%); white solid; mp 87–89 °C (CCl4); Anal. Calcd for
C
10H9NSO5: C, 47.05; H, 3.55; N, 5.48; S, 12.55. Found: C, 47.38;
H, 3.44; N, 5.40; S, 12.41. Other portion of rac-6, 0.56 g from
0.58 g of rac-2 and 2.4 g SO2Cl2 were obtained analogously with
Section 4.2.6.2; mp 86–88 °C.
4.2.6. (R)-4-(2-Cyanophenoxymethyl)-1,3,2-dioxathiolane-2,2-
dioxide, (R)-6
4.2.9. Resolution of rac-4-(2-cyanophenoxymethyl)-1,3,2-
dioxathiolane-2,2-dioxide, rac-6 by preferential crystallization
(entrainment)
4.2.6.1. Method A. Sulfate 6 was obtained by ruthenium-cata-
lyzed oxidation of sulfites 5 by analogy with the published proce-
dures.17,19 To the crude mixture of (2RS,4R)-5, obtained from 1.93 g
(0.01 mol) of diol (S)-2, CCl4 (30 ml) was added and the resulting
solution was refluxed for 30 min to remove the traces of gaseous
HCl. After evaporation of solvent under reduced pressure and cool-
ing to 0 °C, the mixture of CH3CN (11 ml) and H2O (1.3 ml), NaIO4
(3.2 g, 0.015 mol) and RuCl3ꢀH2O (4 mg, 0.017 mmol) was added to
the residue. The resulting mixture was stirred for 5–6 h (monitored
by TLC). After the reaction was completed, the solvent was evapo-
rated under reduced pressure, and residue was diluted with AcOEt
(70 ml) and H2O (2 ml). The organic layer was washed with water
(4 ml), saturated aqueous NaHCO3 (2 ꢃ 2 ml), and brine (4 ml).
After drying over MgSO4, the solution was filtered through a small
pad of silica gel. The filtrate was then concentrated to afford (R)-6
Racemic 6 (660 mg) and (R)-6 (34 mg) were dissolved in 19 ml
of EtOH at 50 °C. The solution was cooled to 15 °C and seeded with
finely-pulverized (R)-6 (2 mg). After stirring the mixture for 60 min
at 11–12 °C, precipitated (R)-6 was collected by filtration {52 mg
after drying; ½a D20
¼ þ14:5 (c 0.5, EtOH), 84% op}. The extra portion
ꢁ
of rac-6 (50 mg) was then dissolved in the mother liquor at 50 °C;
the resulting solution was cooled to 15 °C. After the addition to a
solution of (S)-6 (2 mg) as seed crystals, and stirring the mixture
for 85 min at 10–11 °C, (S)-6 {40 mg after drying; ½a D20
¼ ꢂ11:6 (c
ꢁ
0.5, EtOH), 67% op} was collected by filtration.
4.2.10. (S)-1,2-Epoxy-3-(2-cyanophenoxy)-propane, (S)-8
Compound (S)-8 was obtained by analogy with a published pro-
cedure.19 To a solution of 0.63 g (2.5 mmol) of cyclic sulfate (R)-6 in
as
a white solid. Yield: 2.2 g (86%); mp 118–120 °C (CCl4);

Z. A. Bredikhina et al. / Tetrahedron: Asymmetry 19 (2008) 1430–1435
1435
15 ml of dry THF was added 1.04 g (12 mmol) of anhydrous LiBr.
The suspension was stirred at room temperature for 2–3 h (moni-
tored by TLC for the disappearance of cyclic sulfate). After the sol-
vent was removed under vacuum, in the resulting residue, 25 ml of
ether and 25 ml of 20% aqueous H2SO4 were added. The hetero-
geneous solution was stirred at 25 °C overnight. After completion
of the reaction, the two layers were separated, and the aqueous
layer was extracted with diethyl ether (3 ꢃ 15 ml). The combined
ether layer was washed with saturated NaHCO3, water and brine,
dried over Na2SO4 and concentrated to give 0.62 g of (R)-3-
(2-cyanophenoxy)-1-bromo-2-propanol, (R)-7, as a slightly yellow
oil. To a solution of crude bromoalcohol (R)-7 in 20 ml of MeOH
anhydrous K2CO3 (1.10 g, 8 mmol) was added at 0 °C. The hetero-
geneous solution was stirred at this temperature for 2 h (moni-
tored by TLC), and then 10 ml of saturated NH4Cl aqueous
solution was added, followed by extraction with CH2Cl2 (4 ꢃ
15 ml). The extracts were washed with water and brine, dried
over Na2SO4 and concentrated to give 0.38 g (86% on the basic of
6) of crude (S)-1,2-epoxy-3-(2-cyanophenoxy)-propane, (S)-8, as
4.2.11.3. Method C. (S)-1,2-Epoxy-3-(2-cyanophenoxy)-propane,
(S)-8 (0.38 g, 2.15 mmol) and 2.3 ml (21 mmol) of ButNH2 were
heated at reflux for 5–7 h. The reaction was monitored by TLC.
After the disappearance of the starting epoxide the mixture was
evaporated to dryness and the residual viscous oil was crystallized
upon standing giving (S)-1-(2-cyanophenoxy)-2-hydroxy-3-tert-
butylaminopropane; (S)-bunitrolol (S)-1 as a free base. Mp 30–
32 °C; ½a 2D0
ꢁ
¼ ꢂ9:0 (c 0.8, EtOH); ½a D20
ꢁ
¼ þ12:3 (c 0.38, H2O) [cf.
lit.9 for (S)-bunitrolol: mp 162 °C; ½a 2D0
ꢁ ¼ ꢂ10:0 (c 1.4, H2O), 60%
ee]. 1H NMR (600 MHz, CDCl3) d 1.13 (s, 9H, CH3), 2.49 (br s, 2H,
OH, NH), 2.79 (dd, J = 12.1, 6.6 Hz; 1H, CH2N), 2.93 (dd, J = 12.1,
4.4 Hz; 1H, CH2N), 3.97–4.01 (m, 1H, CH), 4.12 (d, J = 4.8 Hz, 2H,
CH2O), 7.00–7.02 (m, 2H, Ar), 7.51–7.56 (m, 2H, Ar). 13C NMR
(150.864 MHz, CDCl3): d 30.54 (CH3), 45.75 (NCH2), 51.97 (CMe3),
69.40 (CHOH), 73.22 (OCH2), 103.75 ðC2ArÞ, 114.04 ðCA6rÞ, 117.80
(CN), 122.55 ðCA4rÞ, 135.12 ðCA3rÞ, 135.77 ðC5ArÞ, 162.03 ðCA1rÞ [cf.
lit.9]. The thus obtained (S)-1 was dissolved in ether, and dry HCl
was passed through the solution until saturation was achieved.
The solid hydrochloride was filtered out (yield 87%); after two suc-
cessive crystallizations from EtOH, (S)-1ꢀHCl was isolated in a yield
a white solid; mp 90–91 °C (diethyl ether/methanol), ½a D20
¼
ꢁ
þ18:5 (c 0.5, EtOH), ½a D20
ꢁ
¼ ꢂ5:0 (c 1.0, CHCl3) {lit.20 mp 88–
of 66%; mp 184–186 °C, ½a D20
ꢁ
¼ ꢂ29:6 (c 0.9, EtOH); ½a D20
¼ ꢂ14:7 (c
ꢁ
89 °C, ½a 2D5
ꢁ
¼ þ17:7 (c 1, EtOH); lit.9 gum, ½a D25
ꢁ
¼ þ2:3 (c 2.3,
0.8, H2O).
CHCl3)}.
(R)-1ꢀHCl was obtained from (R)-8 and ButNH2 following the
above-mentioned procedure. (R)-1ꢀHCl: mp 187–189 °C,
½
a 2D0
ꢁ
¼ þ29:2 (c 0.7, EtOH).
4.2.11. (S)-1-(2-Cyanophenoxy)-2-hydroxy-3-tert-butylamino-
propane hydrochloride; (S)-bunitrolol hydrochloride; (S)-1ꢀHCl
4.2.11.1. Method A. A solution of dioxathiolane (2RS,4R)-5 (0.9 g,
3.8 mmol) and ButNH2 (2.8 g, 38 mmol) in DMF (5 ml) was heated
at 60–70 °C for 45 h. After this period, excess amine and DMF were
removed in vacuo, 40 ml of a 1 M solution of NaOH was added, the
mixture was extracted with AcOEt (3 ꢃ 40 ml), and extract was
dried over Na2SO4. After removal of the solvent in vacuo, the resi-
due was dissolved in 15 ml of ether and gaseous HCl was passed
through the resulting solution to give 0.59 g (55%) (S)-1ꢀHCl, mp
Acknowledgements
The authors are indebted to Dr. A.V. Pashagin for chiral chroma-
tography measurements. The authors thank the Russian Fund of
Basic Research for financial support (Grant Nos. 06-03-32508 and
07-03-12070).
References
184–186 °C (EtOH); ½a D20
ꢁ
¼ ꢂ29:7 (c 0.6, EtOH). IR (KBr, cmꢂ1):
1. Mehvar, R.; Brocks, D. R. J. Pharm. Pharm. Sci. 2001, 4, 185–200.
2. Nathanson, J. A. J. Pharmacol. Exp. Ther. 1988, 245, 94–101.
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5. Murakami, H. Top. Curr. Chem. 2007, 269, 273–299.
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3260 (br, OH); 2927, 2874 ðNH2þÞ; 2227 (CN); 1599, 1580, 1496
(Ar). 1H NMR (600 MHz, CDCl3): d 1.54 (s, 9H, CH3), 3.29 (dd,
J = 18.5, 9.5 Hz; 1H, CH2N), 3.40 (dd, J = 18.5, 8.6 Hz; 1H, CH2N),
4.25 (dd, J = 9.5, 5.1 Hz, 1H, CH2O), 4.29 (dd, J = 9.5, 4.0 Hz, 1H,
1CH2O), 4.72 (m, 1H, CH), 5.50 (s, 1H, OH), 7.03–7.06 (m, C4ArH,
C6ArH), 7.53–7.56 (m, C3ArH, CA5rH), 8.29 (s, 1H, NH), 9.62 (s, 1H,
NH). 13C NMR (150.864 MHz, CDCl3):
d 25.91 (CH3), 45.28
(NCH2), 58.01 (CMe3), 65.58 (CHOH), 70.82 (OCH2), 102.36 ðC2 Þ,
113.04 ðC6ArÞ, 116.27 (CN), 121.50 ðCA4rÞ, 133.43 ðC3ArÞ, 134.50 ðCA5ArrÞ,
160.14 ðC1ArÞ. Anal. Calcd for C14H21ClN2O2: C, 59.89; H, 7.49; N,
9.98; Cl, 12.48. Found: C, 60.07; H, 7.74; N, 9.76; Cl, 12.8.
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4.2.11.2. Method B. The cyclic sulfate opening with tert-butyl
amine was conducted by analogy with a published procedure.22
A solution of cyclic sulfate (R)-6 (255 mg, 1.0 mmol) and ButNH2
(0.11 g, 0.16 ml, 1.5 mmol) in 5 ml THF was stirred at room tem-
perature for 24 h until the disappearance of 6 (TLC). The solution
was then concentrated, and the residue was stirred with 20% aque-
ous H2SO4 (9 ml) and ether (20 ml) for 12 h. Sodium hydroxide pel-
lets were added to the ice-cooled reaction mixture slowly until the
pH >12 was reached. The layers were separated, and the aqueous
layer was extracted with three more portions of AcOEt (30 ml
each) and combined extract was dried over Na2SO4. After the
removal of solvent, the residue was dissolved in PriOH (minimal
amount), and 0.2 ml of concd aqueous HCl was added. White
crystals slowly precipitate during standing. After filtering off and
ether rinsing out 71 mg (25%) of (S)-bunitrolol hydrochloride,
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Tetrahedron 2005, 61, 2831–2838.
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22. Tomalia, D. A.; Falk, J. C. J. Heterocycl. Chem. 1972, 9, 891–894.
(S)-1ꢀHCl was collected. Mp 184–186 °C (EtOH), ½a D20
¼ ꢂ29:1 (c
ꢁ
0.9, EtOH).