A rare case of facial selectivity inversion for Sharpless asymmetric dihydroxylation in a series of structurally homogeneous substrates: Synthesis of non-racemic 3-(nitrophenoxy)-propane-1,2-diols

Article abstract of DOI:10.1016/j.tetasy.2014.05.008

Asymmetric dihydroxylation of mono nitrophenyl allyl ethers leads to the corresponding non-racemic 3-(nitrophenoxy)-propane-1,2-diols 1a-c. As this takes place, regardless of the reagent used (AD-mix-α or AD-mix-β), the configuration of the predominant enantiomer for the para- and meta-nitrosubstituted products is opposite to the configuration of the ortho-nitrophenyl derivative. A correlation between the melting points and vibrational spectra of the racemic and enantiopure diols 1a-c allowed us to establish that all of the chiral substances investigated formed stable racemic compounds in the solid phase.

Full text of DOI:10.1016/j.tetasy.2014.05.008

Tetrahedron: Asymmetry 25 (2014) 1015–1021
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A rare case of facial selectivity inversion for Sharpless asymmetric
dihydroxylation in a series of structurally homogeneous substrates:
synthesis of non-racemic 3-(nitrophenoxy)-propane-1,2-diols
Zemfira A. Bredikhina, Alexey V. Kurenkov, Olga A. Antonovich, Alexander V. Pashagin,
⇑
Alexander A. Bredikhin
A.E. Arbuzov Institute of Organic and Physical Chemistry of Kazan Scientific Center of 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 6 May 2014
Accepted 27 May 2014
Asymmetric dihydroxylation of mono nitrophenyl allyl ethers leads to the corresponding non-racemic
3-(nitrophenoxy)-propane-1,2-diols 1a–c. As this takes place, regardless of the reagent used (AD-mix-
a
or AD-mix-b), the configuration of the predominant enantiomer for the para- and meta-nitrosubstituted
products is opposite to the configuration of the ortho-nitrophenyl derivative. A correlation between the
melting points and vibrational spectra of the racemic and enantiopure diols 1a–c allowed us to establish
that all of the chiral substances investigated formed stable racemic compounds in the solid phase.
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
affect the crystallization process for racemic as well as for enantio-
pure TAGE.
Terminal aromatic glycerol ethers Ar-OCH2CH(OH)CH2OH
(TAGE) are a popular class of organic compounds and include reg-
istered drugs such as chlorphenesin, guaifenesin, and mephene-
sin.1 The compounds of this series can act as precursors in the
synthesis of other registered drugs.2,3 The ability of the TAGE’s
glycerol moiety to produce intermolecular hydrogen bonds in a
liquid medium has led to thermotropic liquid crystals,4,5 while also
allowing them to act as low molecular weight supramolecular gel-
ling agents.5–7
Many, if not all, of the aforementioned TAGE properties depend
upon the chirality of the system. In some cases, we were able to
relate these features with the type of crystal packing of the com-
pounds investigated.7,8 In turn, the crystal packing of aromatic
glycerol ethers by itself is extremely sensitive to the position and
nature of the substituents within the aromatic moiety of the mol-
ecule.7,9 This mutual influence in one form or another was studied
for alkyl7,8,10 and alkoxy11 substituents, halogens,12,13 and cyano
groups.12,14 Within the overall strategy of this investigation the
mononitro phenyl glycerol ethers 1a–c (see Scheme 1) are of
obvious interest.
Analysis of the available literature showed that nitrosubstituted
aromatic ethers of glycerol represented are of general chemical
interest. To date, they have found application in the synthesis of
imidazoles useful as antifungal and antibacterial agents,15 and in
the synthesis of substituted sulfonamide derivatives for the
preparation of pharmaceuticals.16 Furthermore, a nitro group can
be easily reduced, and used in the synthesis of polymeric acetoace-
tanilide azo colorants,17 and in the synthesis of polyesters exhibit-
ing holographic optical properties.18 It is reasonable to expect that
in all of these cases, the use of enantiomeric starting materials will
lead to useful changes in the targeted product properties.
Available information with regard to obtaining non-racemic
(scalemic) nitrophenoxy-1,2-propanediols is extremely scarce,
with only the meta-diol (R)-1b being described.19 The biocatalytic
kinetic resolution of para- and ortho-nitrophenyl glycidol ethers
is also mentioned, with the corresponding diols being obtained in
yields of 6% and 38% and enantiomeric excesses of 20% and 28%; no
properties of the products are cited.20
It is known that scal-aryloxypropane-1,2-diols can be prepared
from the corresponding allyloxybenzenes using the Sharpless
asymmetric dihydroxylation reactions.21,22 Earlier, using methyl-,
methoxy-, chloro-, and cyanosubstituted allyloxybenzenes as an
example, Wang et al. found that dihydroxylation of the
para-substituted phenyl allyl ethers proceeded with satisfactory
enantioselectivity (products ee 89–95%). At the same time for
Since the nitro group is a strong electron acceptor, it can bring
about its own specificity into the intermolecular crystal formative
interactions (hydrogen bonding,
p–p interactions, etc.), and thus
the
ortho-substituted
allyloxybenzenes,
the
asymmetric
⇑
Corresponding author. Tel.: +7 843 2727393; fax: +7 843 2731872.
E-mail address: baa@iopc.ru (A.A. Bredikhin).
dihydroxylation enantioselectivity decreases, and the products
http://dx.doi.org/10.1016/j.tetasy.2014.05.008
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

1016
Z. A. Bredikhina et al. / Tetrahedron: Asymmetry 25 (2014) 1015–1021
OH
OH
OH
O
OH
OH
O
OH
O
NO2
O2N
NO2
1a
1c
1b
Scheme 1. Mononitrophenyl glycerol ethers.
were obtained with 28–63% ee.23 It was also found that the use of
AD-mix-b as a reagent led to a product with an (S)-configuration at
C2, and vice versa, (R)-TAGEs were obtained by using AD-mix-a.
This rule was confirmed for a series of para-alkylphenyl allyl
ethers.5
The asymmetric dihydroxylation of nitro phenyl allyl ethers has
not been conducted before. In this regard, our initial aim was to
expand upon the asymmetric dihydroxylation procedure to nitro-
substituted phenyl allyl ethers. We aimed to obtain a set of
mononitro substituted phenyl glycerol ethers 1a–c in racemic
and non-racemic (scalemic) forms with satisfactory chemical yield
and a necessary degree of enantiomeric purity. We expected that
the analysis of the physicochemical characteristics of the com-
pounds obtained would provide preliminary information on the
phase behavior of this family during crystallization.
2. Results and discussion
2.1. Chemistry
Figure 1. HPLC chromatograms of 3-(2-nitrophenoxy)-propane-1,2-diol 1a. Green
curve—rac-1a; blue curve—diol 1a obtained by dihydroxylation of nitrophenyl allyl
ether 3a using AD-mix-b; red curve—(R)-1a; black curve—diol 1a obtained by
The main method of analysis for the asymmetric dihydroxylation
enantioselectivity is ‘chiral’ HPLC. To obtain reliable results, this
method needs a pre-selection of experimental conditions using
racemic samples of the test compounds. Racemic nitrophenoxy-
1,2-propanediols, rac-1, can be obtained by reaction of the corre-
sponding phenols with rac-glycidol,17,24 by hydrolysis of racemic
arylglycidyl ethers,15,16,18 and by reaction of the corresponding phe-
nolates with rac-3-chloropropane-1,2-diol.25,26 The latter approach
seems preferable because 3-chloropropane-1,2-diol is available in
racemic and enantiopure forms. However, using the protocols cited
in the literature the desired products are obtained in low yield. Thus,
rac-1c was obtained in 28% yield by a reaction in acetonitrile in the
presenceof K2CO3.25 Racemic1b has beenobtained from meta-nitro-
phenol in ethanol in the presence of KOH with a yield of 26%.19 We
have found thatthe yield ofthe desired products canbe substantially
improved upon if the reaction of nitrosubstituted sodium phenolate
with a slight excess of chloropropanediol is carried out in toluene
with the addition of 0.1 equiv of 15-crown-5 as a phase transfer cat-
alyst (see Scheme 2).
dihydroxylation of nitrophenyl allyl ether 3a using AD-mix-a.
With samples of racemic diols 1a and 1c in hand, we chose the
conditions under which the individual enantiomers were suffi-
ciently separated on the chromatograms that quantitative analysis
could be performed (green curves in Figs. 1 and 2).
Figure 2. HPLC chromatograms of 3-(4-nitrophenoxy)-propane-1,2-diol 1c. Green
curve: rac-1c; blue curve: 1c diol obtained by using AD-mix-b; red curve: (R)-1c.
However, we were unable to achieve good separation of the
enantiomers of meta-derivative 1b, so we treated diol 1b with a
slight excess of thionyl chloride. The mixture of cis- and trans-
diastereomers of the cyclic sulfites was formed quantitatively; each
of the diastereomers is represented by two enantiomers, the relative
amount of which coincides with that of the initial 1b (see Scheme 3).
Figure 3 shows a chromatogram of the mixture of cyclic sulfites
obtained by derivatization of rac-1b (green curves). As indicated in
the picture, the peaks of all four stereoisomers are well separated;
the peak areas of the diastereomeric pairs do not coincide with
each other, but the peak areas of the individual enantiomers within
every diastereomeric pair are identical (provided that the starting
diol is racemic).
With the method of analysis in hand, we next studied the asym-
metric dihydroxylation of nitrophenyl allyl ethers 3a–c (Scheme 4).
The use of AD-mix-b as a reagent led to inconsistent results. If the
major product of the reaction of ortho-nitrophenyl derivative
(Fig. 1a, blue curve) was enantiomer of 1a with a shorter retention
time, then for the para-nitro analogue (Fig. 2, blue curve) the enan-
tiomer 1c with a longer retention time dominates among the prod-
ucts. In the case of the meta-derivative, the cyclic sulfites obtained
from the major enantiomer 1b change the output order, depending
on the type of diastereomer (Fig. 3, blue curve).

Z. A. Bredikhina et al. / Tetrahedron: Asymmetry 25 (2014) 1015–1021
1017
O2N
O2N
K2CO3
O2N
O
OH
+
2a-c
Br
3a-c
AD-mix-α
3a
O
OH
β
H
OH
AD-mix-
3b,c
(S)-1a-c
AD-mix-β
AD-mix-α
O2N
3a
O
OH
OH
3b,c
H
(R)-1a-c
2-NO2 a, 3-NO2 b, 4-NO2
Scheme 4. Asymmetric dihydroxylation of aryl allyl ethers 3a–c.
c
In order to resolve this problem, we prepared samples of pure
diols (R)-1a–c from (R)-3-chloropropane-1,2-diol (98% ee) as
shown in Scheme 2. From our experience we know that this reac-
tion is accompanied by virtually no racemization and proceeds
with retention of the original configuration of the stereogenic cen-
ter. We have previously reported on the synthesis of non-racemic
ortho-, meta-, and para-substituted cyanophenyl glycerol ethers
from non-racemic chloropropanediol and have shown that the
enantiomeric purity of the products is close to the enantiomeric
purity of the starting material.12 The absolute configuration of
the so obtained cyanosubstituted TAGEs was determined by
X-ray diffraction using a Flack parameter approach.14 In all cases,
the initial configuration of chloropropanediol was retained in the
products. Similar results were obtained for ortho-, meta-, and
para-methylphenyl ethers of glycerol.6,8
Figure 3. HPLC chromatograms of cyclic sulfites obtained on the basis of 3-(3-
nitrophenoxy)-propane-1,2-diols 1b (see Scheme 3). Green curves: rac-1b was used
as the starting material; blue curves: diol 1b, obtained by using AD-mix-b, was used
as the starting material; red curves: sulfites from (R)-1b.
We can attribute these results (restricting ourselves to the
ortho- and para-derivatives at this stage) to one of two reasons.
The first possibility is that changing the position of the nitro group
changes the relative order of output from the chromatographic col-
umn for the enantiomers with the same configuration. The second
possibility is that a change in substitution pattern of the aromatic
moiety qualitatively alters the reaction selectivity, leading to a pre-
dominance of the different enantiomers among the products in the
case of 1a and 1c. Both situations are unusual and have not previ-
ously been described for structurally similar compounds.
OH
ONa
O2N
O2N
i
a
b
c
2-NO2 ; 3-NO2 ; 4-NO2
2a-c
OH
ONa
O2N
O2N
ii
Cl
OH
O
OH
+
OH
rac-1a-c
Scheme 2. Reagents and conditions: (i) Na, EtOH; (ii) toluene, 15-crown-5 (0.1 equiv), 90–95 °C, ꢀ30–40 h; isolated yield 60–75%.
O
O
S
S
HO
H
O
O
O
O
O
OH
+
( )
S
H
H
(
R
)
CH2OC6H4NO2-m
m-O2NC6H4OH2C
-1b
(S)
trans
SOCl2
NO2
+
+
O
O
O
S
S
H
OH
O
O
O
OH
O
+
(R)
H
(S)
H
m-O2NC6H4OH2C
CH2OC6H4NO2-m
-1b
(R)
cis
NO2
Scheme 3. Cyclic sulfite derivatives obtained from 3-(3-nitrophenoxy)-propane-1,2-diol.

1018
Z. A. Bredikhina et al. / Tetrahedron: Asymmetry 25 (2014) 1015–1021
Chromatograms of the pure enantiomers (R)-1a,c (and of the
A comparison of the melting points of racemic and enantioen-
riched samples of the same chiral compound provides valuable
information with regard to the nature of its crystallization.
Appreciable excess of the melting point of a racemate over the
melting point of enantiopure 1b strongly suggests that a racemic
compound is formed by the enantiomers of this substance in the
solid phase. The relationship of the melting temperatures for rac-
1a,c and scal-1a,c allows us to exclude, for both compounds, the
formation of a normal conglomerate, but leaves the possibility of
the formation of continuous or partial solid solutions during crys-
tallization. It is possible to prove or disprove such a possibility by
comparison of the IR spectra of crystalline samples for racemic and
enantiopure chiral compound. The similarity of the IR spectra is
indicative of the similarity of the crystal structure for these sam-
ples, and in its turn may indicate that the test substance crystal-
lizes as a conglomerate or a solid solution. In contrast, the IR
spectra of the racemic compounds are typically different from
those of the corresponding enantiomers.27,28
Experimental IR spectra for crystalline samples of 1a–c in KBr
tablets, and Pearson correlation coefficients for each pair of ‘race-
mate–scalemate’ are shown in Figure 4. Details of the quantitative
comparison of the spectra have been described in our previous
papers.5,12
Both a visual comparison of the spectra and the correlation
coefficients between them allow us to establish substantial differ-
ences for all rac. versus scal pairs of 1a–c. Without going into a
detailed analysis, we can see that the main differences between
the spectra are concentrated in the region of stretching vibrations
corresponding sulfites in the case of (R)-1b) are shown in Figures
1–3 (red curves). Comparison of these data with the chromato-
grams of the dihydroxylation products indicates that for
para- and meta-nitro allyloxybenzenes the ‘normal’ stereoselectiv-
ity of the reaction (which was described in the literature23,5), in
which engagement with AD-mix-b leads predominantly to the
(S)-enantiomers of the products, is retained. The situation changes
for ortho-nitro derivatives, when the major product of the same
reaction is (R)-1a (Fig. 1a; the enantiomeric excess of the product
is only 22%). To the best of our knowledge, this is the first example
of an inversion of the product configuration during an asymmetric
dihydroxylation reaction when applying a common reagent to
uniformly organized series of arylallyl ethers.
To confirm the disclosed regularity, we carried out the asym-
metric dihydroxylation of allyl ethers 3a–c using AD-mix-
a as
the reagent. The general scheme of the process is illustrated in
Scheme 4, and the quantitative characteristics are shown in
Table 1; the chromatogram of the ‘abnormal’ reaction products
for ortho-nitro derivative is shown in Figure 1 (black curve).
The problem of interpreting and predicting the facial selectivity
for asymmetric dihydroxylation reactions remains. Significant pro-
gress has been made in the study of the transition state of the reac-
tion, and rules have been developed (‘The Mnemonic Device’),
linking the stereoselectivity with the relative size of the substitu-
ents arranged an oxidizing ethylene moiety.21,22 Unfortunately,
such models are inefficient with respect to monosubstituted ethyl-
enes, which include all aryl allyl ethers. It is difficult to imagine
that a change in the position of the substituent in the aromatic
ring, which is located at a sufficient distance from the ethylene
unit, distorts the steric requirements leading to a reverse in the
stereoselectivity. Apparently, a nitro group in the ortho-position
of a benzene ring takes part in some directional interactions
(dipole–dipole, intermolecular hydrogen bond, etc.) with the
reagent in the activated complex. However, the proof of this
hypothesis is beyond the scope of our work.
mOH. Therefore, for the newly obtained TAGEs, one might expect
that a significant difference exists in the system of intermolecular
hydrogen bonding in crystals of racemic and enantiomerically pure
compounds. Differences in the spectra are also a reliable indication
of the formation of stable in solid phase racemic compounds.
A binary melting phase diagram for chiral compounds forming a
normal racemic compound in the solid phase is characterized by
two eutectics located on the composition axis symmetrical relative
to the racemate.27,28 The eutectic position on the phase diagram is
of considerable practical interest. When samples whose composi-
tion lies between eutectics are crystallized, the enantiomeric pur-
ity of the crystalline crop drops to ee = 0 inclusive. Conversely,
samples with an enantiomeric composition, that lies within the
interval between the eutectic and the closest pure enantiomer,
through the crystallization sequence can be obtained with the
2.2. Preliminary solid phase inspection of the mono nitro TAGEs
investigated
Table 2 shows some experimental characteristics of the racemic
and enantiopure samples of 1a–c obtained from rac- and
(R)-3-chloropropane-1,2-diol respectively.
Table 1
Yield, enantiomeric excess, and some physicochemical characteristics of the products of asymmetric dihydroxylation of allyl ethers 3a–c
Diol
AD-mix-
a
AD-mix-b
20
20
Yield (%)
Configuration, ee (%)
[
a
]
(c 1, EtOH)
Yield (%)
Configuration, ee (%)
[
a
]
(c 1, EtOH)
436
436
1a
1b
1c
66
49
65
(S) 42 (38)a
+1.7
61
45
66
(R) 22 (15)a
(S) 94b (94)a,b
(S) 92 (>99)a
À1.1
(R) 89b (90)a,b
(R) 89 (>99)a
À26.8
+29.2
+31.6
À34.0
a
Ee of diols scal-1a–c after recrystallization from benzene.
Ee was determined after derivatization with thionyl chloride.
b
Table 2
Yield and some physicochemical characteristics for rac- and (R)-1a–c
Diol
rac-diol
(R)-diol
D
Tfr,s
20
Yield (%)
mp (°C)
Yield (%)
mp (°C)
[a
]
(c 1, EtOH)
ee (%)
D
1a
1b
1c
61
68
75
45–46
93–94
70–71
73
63
70
54–55
66–67
71–72
À0.5 (À4.2)a
99.2
99.2b
>99
À9
27
À1
À15.0 (À31.1)a
À17.4 (À37.2)a
a
20
Value of [
a
]
436
(c 1, EtOH).
b
Ee was determined after derivatization with thionyl chloride.

Z. A. Bredikhina et al. / Tetrahedron: Asymmetry 25 (2014) 1015–1021
1019
that all of the examined chiral substances formed stable racemic
compounds in the solid phase.
4. Experimental
4.1. General
The NMR spectra were recorded on a Bruker Avance-400 spec-
trometer (399.9 MHz for 1H and 100.5 MHz for 13C) in CDCl3 or
(CD3)2C@O with TMS or the signals of the solvent as the internal
standard. The IR spectra of the polycrystalline samples of rac-
and (S)-diols 1a–c under investigations in KBr pellets were
recorded on a Bruker Tensor 27 spectrometer. Optical rotations
were measured on a Perkin–Elmer model 341 polarimeter (concen-
tration c is given as g/100 mL). Melting points for general purposes
were determined using a Boëtius apparatus and are uncorrected.
The elemental compositions were determined using a EuroVector
EA3000 CHN analyzer. Thin-layer chromatography was performed
on Silufol UV-254 plates using EtOAc–hexane (4:6) as eluent; TLC
plates were visualized under UV light or by treatment with iodine
vapor. HPLC analyses were performed on a Shimadzu LC-20AD sys-
tem controller, UV monitor 275 nm were used as detectors. The
columns used, from Daicel, Inc., were Chiralcel OD (0.46 Â 25 cm)
or Chiralpak AD (0.46 Â 25 cm); column temperature 21–23 °C;
flow rate: 1.0 mL/min. For the determination of enantiomeric com-
positions, the columns were calibrated against the corresponding
racemic diols 1a–c.
4.2. Compounds
Racemic 3-chloropropane-1,2-diol (99+%) was purchased from
Acros Organics; allyl bromide (99%), 2-nitrophenol (98%),
3-nitrophenol (98+%), 4-nitrophenol (99%), and (R)-3-chloropro-
pane-1,2-diol (97%, 98% ee) were purchased from Alfa Aesar.
Figure 4. IR spectra of samples of racemic (red curves) and enantiopure (blue
curves) 1a–c and coefficients of correlation between them.
highest enantiomeric purity. It is possible to estimate approxi-
mately the eutectic position for compounds 1a–c from recrystalli-
zation results for the products obtained by the asymmetric
dihydroxylation (Table 1, columns 3 and 6). As can be seen from
the above data, the enantiomeric purity of the samples 1a and 1b
varies little during the recrystallization. This means that for
diol 1a, the eutectics are obtained with eeeu ꢁ 45%, and for 1b
eeeu ꢁ 90%. In contrast, a single recrystallization significantly
increases the enantiomeric purity of the sample 1c, and gives a diol
with eeeu <85%.
AD-mix-a and AD-mix-b were purchased from Aldrich.
4.2.1. General procedure for the synthesis of aryl allyl ethers 3a–c
Aryl allyl ethers were prepared by analogy with published pro-
cedures.5,29 A stirred suspension of the appropriate phenol 2a–c
(6 mmol), allyl bromide (0.8 g, 6.6 mmol), and ground water-free
K2CO3 (0.91 g, 6.6 mmol) in anhydrous acetone (10 mL) was
refluxed for 12–14 h; the progress of the reaction was monitored
by TLC analysis. The reaction mixture was diluted with water
(30 mL) and extracted with Et2O (3 Â 40 mL). The collected organic
phases were washed with 1 M NaOH (15 mL) and dried over
MgSO4. After removal of the solvent, the residual oil 3 was distilled
under reduced pressure.
3. Conclusion
A series of enantiomeric and racemic terminal mononitrophe-
nyl ethers of glycerol 1a has been synthesized by the asymmetric
dihydroxylation of mononitrophenyl allyl ethers and by the
reaction of the corresponding nitrophenols with racemic and
(R)-3-chloropropane-1,2-diol. In the case of para- and meta-nitro-
phenyl allyl ethers, the asymmetric dihydroxylation reaction
proceeds with good enantioselectivity, and, in accordance with
previously known results for different aryl allyl ethers, leads to
(S)-nitrophenoxypropane-1,2-diols, (S)-1b,c if AD-mix-b is used
as the reagent. Using the same reagent during dihydroxylation of
ortho-nitrophenyl allyl ethers, alongside with a lowering of the
reaction enantioselectivity, there is an inversion of facial selectiv-
ity, that is, (R)-3-(2-nitrophenoxy)-propane-1,2-diol (R)-1a is
obtained. This inversion of the asymmetric dihydroxylation facial
selectivity in the ranks of closely-related substrates has not previ-
ously been observed.
4.2.1.1. 1-(Allyloxy)-2-nitrobenzene, 3a. Yield: 61%, yellow oil
[lit.30,31 yellow oil]; bp 152–153 °C (10 Torr), nD
1.5525;
25
Rf = 0.62. 1H NMR (CDCl3) d 4.71 (ddd, J = 1.5, 5.1 Hz; 2H, OCH2),
5.36 (ddt, J = 1.5, 1.5, 10.6 Hz; 1H, CH2), 5.51 (ddt, J = 1.5, 1.5,
17.3 Hz; 1H, CH2), 6.07 (ddt, J = 5.1, 10.6, 17.3 Hz; 1H, CH), 7.05
(ddd, J = 1.1, 7.4, 7.7 Hz, 1H, C4ArH), 7.10 (d, J = 8.4 Hz, 1H, C6ArH),
7.53 (ddd, J = 1.7, 7.4, 8.4 Hz; 1H, C5ArH), 7.86 (dd, J = 1.7, 7.7 Hz;
1H, C3ArH).
4.2.1.2. 1-(Allyloxy)-3-nitrobenzene, 3b. Yield: 61%, yellow oil,
which crystallizes upon standing; bp 90–92 °C (0.4 Torr), mp
30–31.5 °C (EtOH), Rf = 0.72. [lit.32 bright yellow oil; lit.33 bp
92.2–92.3 °C (0.6 Torr), mp 32–33 °C]. 1H NMR (CDCl3) d 4.65 (d,
J = 5.3 Hz; 2H, OCH2), 5.37 (dd, J = 1.3, 10.5 Hz; 1H, CH2), 5.48
(dd, J = 1.3, 17.3 Hz; 1H, CH2), 6.08 (ddt, J = 5.3, 10.5, 17.3 Hz; 1H,
CH), 7.26 (d, J = 2.2 Hz, 1H, C6ArH), 7.45 (t, J = 8.1 Hz; 1H, C5ArH),
7.77 (t, J = 2.2 Hz; 1H, C2ArH), 7.85 (dd, J = 1.2, 8.1 Hz; 1H, C4ArH).
Comparison of melting points and vibrational spectra of the
racemic and enantiopure nitrophenylpropanediols 1a–c revealed

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Z. A. Bredikhina et al. / Tetrahedron: Asymmetry 25 (2014) 1015–1021
4.2.1.3. 1-(Allyloxy)-4-nitrobenzene, 3c. Yield: 57.5%, colorless
4.2.3.3. rac-3-(3-Nitrophenoxy)-1,2-propanediol rac-1b. Yield:
68%, mp 93–94 °C (hexane/CH2Cl2). 1H NMR (acetone-D6) d:
3.66–3.76 (m, 2H, CH2OH), 3.82 (t, J = 5.8 Hz, OH, the signal disap-
pears when adding D2O), 4.02–4.09 (m, 1H, CHOH), 4.15 (dd,
J = 6.1, 9.8 Hz, 1H, OCH2), 4.20 (d, J = 5.2 Hz, OH, the signal disap-
pears when adding D2O), 4.27 (dd, J = 4.3, 9.8 Hz, 1H, OCH2), 7.43
(ddd, J = 0.9, 2.4, 8.3 Hz, 1H, C6ArH), 7.59 (dd, J = 8.3, 8.3 Hz, 1H,
C5ArH), 7.79 (dd, J = 2.4, 2.4 Hz, 1H, C2ArH), 7.84 (ddd, J = 0.9, 2.4,
8.3 Hz, 1H, C4ArH). 13C NMR (acetone-D6) d: 63.5 (CH2OH), 70.8
(CHO), 70.9 (CH2O), 109.4 (C2Ar), 115.8 (C6Ar), 122.0 (C4Ar), 130.8
(C5Ar), 149.8 (C3Ar), 160.3 (C1Ar). Anal. Calcd for C9H11NO5: C,
50.71; H, 5.20; N, 6.57. Found: C, 51.32; H, 4.98; N, 6.09.
oil [lit.29 colorless oil]; bp 107–108 °C (0.5 Torr) [lit.33 bp 105–
106 °C (0.4 Torr), lit.29 bp 126–129 °C (3 Torr)]; nD
1.5775;
25
Rf = 0.68. 1H NMR (CDCl3) d 4.67 (ddd, J = 1.5, 5.3 Hz; 2H, OCH2),
5.38 (ddt, J = 1.5, 1.5, 10.5 Hz; 1H, CH2), 5.46 (ddt, J = 1.5, 1.5,
17.3 Hz; 1H, CH2), 6.07 (ddt, J = 5.3, 10.5, 17.3 Hz; 1H, CH),
6.98–7.02 (m, 2H, C2,6ArH), 8.21–8.25 (m, 2H, C3,5ArH).
4.2.2. General procedure for the asymmetric dihydroxylation
process
Sharpless asymmetric dihydroxylation reactions were carried
out according to the literature procedure.23 A stirred solution of
AD-mix (1.4 g) in t-BuOH (5 mL) and water (5 mL) was cooled to
0 °C. To the suspension, the corresponding aryl allyl ether 3a–c
(1 mmol) was added and then the reaction mixture was stirred
intensively at 0 °C for 24–28 h. Next, Na2SO3 (1.5 g) was added
and stirred at room temperature for 30 min. The t-BuOH layer
was separated and the aqueous layer was extracted with EtOAc
(3 Â 30 mL). The combined organic layers were washed with brine
(20 mL), dried over MgSO4, and concentrated under reduced pres-
sure to give the product as crystals or an oil. When necessary, the
crude product was purified by column chromatography (silica gel,
eluent: EtOAc/hexane = 2:1). Yields, configuration, and enantio-
meric excess of scal-1a–c are shown in Table 1.
4.2.3.4. (R)-3-(3-Nitrophenoxy)-1,2-propanediol (R)-1b. Yield:
63%, mp 66–67 °C (hexane/CH2Cl2); [
a
]
20 = À15.0 (c 1, EtOH);
20
[a]
436 = À31.1 (c 1, EtOH); {lit.19
[a]
20 = ÀD12.3 (c 1, EtOH)}; 99.2%
D
ee [For reliable ee determination the crude diol was transformed
into
a diastereomeric mixture of cyclic sulfites via reaction
between scal-1b (1 equiv) and SOCl2 (1.1 equiv) in CH2Cl2 at 0 °C.
Chiral HPLC analysis of the reaction mixture: Daicel Chiralcel OD
column; eluent 2-propanol/hexane = 1:4; tR = 16.0 min (minor),
tR = 17.1 min (major); tR = 23.4 min (major), tR = 27.2 min (minor)].
NMR spectra were identical with those cited above for rac-1b. Anal.
Calcd for C9H11NO5: C, 50.71; H, 5.20; N, 6.57. Found: C, 51.18; H,
5.33; N, 6.33.
4.2.3. General procedure for the synthesis of 3-(nitrophenoxy)-
propane-1,2-diols 1a–c from 3-chloro-1,2-propanediol
4.2.3.5. rac-3-(4-Nitrophenoxy)-1,2-propanediol rac-1c. Yield:
75%, mp 70–71 °C (hexane) (lit.25 mp 64 °C; lit.26 mp 58 °C). 1H
NMR (acetone-D6) d: 3.66–3.75 (m, 2H, CH2OH), 3.85 (br s, OH),
4.03–4.09 (m, 1H, CHOH), 4.18 (dd, J = 6.1, 9.8 Hz, 1H, OCH2),
4.23 (d, J = 4.9 Hz, OH), 4.29 (dd, J = 4.3, 9.8 Hz, 1H, OCH2),
7.16–7.20 (m, 2H, C2,6ArH), 8.21–8.25 (m, 2H, C3,5ArH). 13C NMR
(acetone-D6) d: 63.4 (CH2OH), 70.7 (CHO), 70.9 (CH2O), 115.3
(C2,6Ar), 126.1 (C3,5Ar), 141.9 (C4Ar), 164.9 (C1Ar). Anal. Calcd for
C9H11NO5: C, 50.71; H, 5.20; N, 6.57. Found: C, 50.85; H, 5.24; N,
6.58.
Sodium metal (0.23 g, 10 mmol) was dissolved in 4 mL of abso-
lute ethanol and an appropriate nitrophenol 2a–c (1.39 g,
10 mmol) in 2 mL of EtOH was added to the resulting solution.
The resulting mixture was stirred at room temperature for
30 min, and then the ethanol was removed in vacuo to dryness.
Racemic or scalemic 3-chloro-1,2-propanediol 3 (1.44 g, 13 mmol),
15-crown-5 (0.2 g, 0.9 mmol), and toluene (10 mL) were then
added to the residue. The resulting mixture was heated with stir-
ring at 90 5 °C for 30–40 h. The reaction was monitored by TLC.
Next, toluene was distilled off in vacuo to dryness, after which
15 mL of water were added and extracted with CH2Cl2
(5 Â 30 mL). The organic phase was dried over MgSO4. The solution
was then filtered and concentrated on a rotary evaporator to give
an oil (75–90%), which was dissolved in refluxing benzene; nitrodi-
ols 1a–c (60–75%) precipitated as crystals upon cooling. Analyti-
cally pure samples were obtained by recrystallization from
hexane or hexane/CH2Cl2. The characteristics of the diols are
shown below.
4.2.3.6. (R)-3-(4-Nitrophenoxy)-1,2-propanediol (R)-1c. Yield:
20
70%, mp 71–72 °C (hexane); [
a]
20 = À17.4 (c 1, EtOH); [
a]
=
D
436
À37.2 (c 1, EtOH); >99% ee [chiral HPLC analysis; Chiralpak AD col-
umn; eluent: hexane/2-propanol = 9:1; tR = 37.1 min (major),
tR = 40.6 min (minor)]. NMR spectra were identical with those cited
above for rac-1c. Anal. Calcd for C9H11NO5: C, 50.71; H, 5.20; N,
6.57. Found: C, 50.14; H, 5.32; N, 6.30.
Acknowledgment
4.2.3.1. rac-3-(2-Nitrophenoxy)-1,2-propanediol rac-1a. Yield:
61%, mp 45–46 °C (hexane) (lit.26 mp 45 °C; lit.34 mp 96 °C). 1H
NMR (CDCl3) d: 2.56 (t, J = 5.9 Hz, 1H, OH), 3.24 (d, J = 5.0 Hz, 1H,
OH), 3.80–3.94 (m, 2H, CH2OH), 4.12–4.18 (m, 1H, CHOH), 4.22
(dd, J = 5.8, 9.2 Hz, 1H, OCH2), 4.28 (dd, J = 4.1, 9.2 Hz, 1H, OCH2),
7.09 (ddd, J = 1.0, 7.8, 7.8 Hz, 1H, C4ArH), 7.13 (dd, J = 1.0, 7.8 Hz,
1H, C6ArH), 7.57 (ddd, J = 1.7, 7.8, 7.8 Hz, 1H, C5ArH), 7.91 (dd,
J = 1.7, 7.8 Hz, 1H, C3ArH). 13C NMR (CDCl3) d: 63.7 (CH2OH), 70.2
(CHO), 71.8 (CH2O), 115.4 (C6Ar), 121.5 (C4Ar), 126.4 (C3Ar), 135.1
(C5Ar), 140.1 (C2Ar), 152.6 (C1Ar). Anal. Calcd for C9H11NO5: C,
50.71; H, 5.20; N, 6.57. Found: C, 50.41; H, 5.57; N, 6.79.
The authors thank Dr. D.V. Zakharychev for valuable technical
assistance.
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