An Efficient Method for the Chemoselective Preparation of Benzoylated 1,2-Diols from Epoxides

Article abstract of DOI:10.1055/s-2003-42416

A very efficient and highly regioselective ring-opening reaction of epoxides with benzoic acid and its derivatives in the presence of cat. amount of tetrabutylammonium bromide (TBAB) in anhydrous acetonitrile has been developed. This effective method is useful for the preparation of selectively protected diols as precursor for many organic syntheses such as those of acyclic nucleosides and other synthetic purposes. The advantages of this method are efficiency, selectivity, low cost, and the applicability in large-scale synthesis of β-benzoyloxyalkanols.

Full text of DOI:10.1055/s-2003-42416

2552
PAPER
An Efficient Method for the Chemoselective Preparation of Benzoylated
1,2-Diols from Epoxides
Chemoselective
P
r
.
eparation of
K
Benzoylated1,2-D
h
iols alafi-Nezhad,* M. N. Soltani Rad, A. Khoshnood
Department of Chemistry, College of Science, Shiraz University, Shiraz 71454, Iran
Fax +98(711)2280926; E-mail: khalafi@chem.susc.ac.ir
Received 28 June 2003; revised 30 July 2003
Dedicated to Professor Habib Firouzabadi on the occasion of his 60th birthday.
Ce(OTf)4.11 Benzoic acid and its derivatives were found to
be the very useful carboxylic acids in ring opening reac-
tion of epoxides and are superior with respect to other car-
boxylic acids. This is due to the fact that mono-benzoate
Abstract: A very efficient and highly regioselective ring-opening
reaction of epoxides with benzoic acid and its derivatives in the
presence of cat. amount of tetrabutylammonium bromide (TBAB)
in anhydrous acetonitrile has been developed. This effective method
is useful for the preparation of selectively protected diols as precur- of 1,2-diols shows little tendency to isomerize as com-
sor for many organic syntheses such as those of acyclic nucleosides
pared to other mono-esters of 1,2-diols, especially mono-
acetate of 1,2-diols.12 Related to our interest in the synthe-
and other synthetic purposes. The advantages of this method are ef-
ficiency, selectivity, low cost, and the applicability in large-scale
sis of some novel acyclic nucleosides,13 we wish to report
synthesis of β-benzoyloxyalkanols.
the synthesis of -benzoyloxyalkanols as useful interme-
diates for organic synthesis. Herein we describe a very ef-
ficient and highly chemoselective synthesis of
Key words: benzoylated 1,2-diol, benzoic acid, epoxides, aceto-
nitrile, TBAB
benzoylated 1,2-diols using epoxides in the presence of
tetrabutylammonium bromide (TBAB) in anhydrous
Selective protection of hydroxyl groups in polyols is very
MeCN.
important in organic synthesis.1,2 There are miscellaneous
Benzoic acid and its derivatives were allowed to react
methods and reagents elaborated for the direct protection
with a set of terminal epoxides and the reaction afforded
of hydroxyl groups in a molecule.2–4 One way for the in-
the corresponding -benzoyloxy alkanols 1–19 (Tables 1
direct preparation of the titled compounds is the regio-
and 2) by using cat. amount of TBAB in anhydrous
selective ring opening of epoxides with removable
MeCN (Scheme 1). In most epoxide ring opening reac-
oxygen containing nucleophiles. They are usually exem-
tions, it is well demonstrated that both protic or Lewis ac-
plified for acid or base catalyzed alcoholysis of epoxides5
ids act as promoter for nucleophilic ring opening of
or ring opening reaction of epoxides with carboxylic ac-
epoxides. We have conducted some experiments to find
ids. Epoxides are well-known and fully established carbon
out the role of phase transfer catalysts (PTC) and solvents.
electrophiles capable of reacting with various nucleo-
The absence of TBAB in the reaction media gave no
philes. Their ability to undergo regioselective ring open-
yields after refluxing for 24 hours. This confirms the crit-
ing reactions contributes largely to their synthetic value.6
ical role of TBAB for this reaction.
Carboxylic acids are interesting because of low cost and
ease of handling and because their reaction with epoxides
provides a direct and appealing route to 1,2-diol mono-es-
ters.5g,i The reactions of epoxides with carboxylic acids
are generally limited to the reaction of HOAc catalyzed by
different Lewis acids.7 The use of NaOAc/HOAc5 and
benzoic acid/Co(salen)/i-Pr2NH8 were also reported.
-
Hydroxy esters were prepared by esterification of carbox-
ylic acid with vicinal epoxides by the use of FeCl3 as cat-
alyst in the presence of Et3N or N-methylmorpholine.9
Tetrabutylammonium chloride (TBAC) mediated ring
opening of 1-phenylthio-2,3-epoxypropane with benzoic
acid in anhydrous toluene was reported as the only exam-
ple for the synthesis of functionalized substituted , -un-
Scheme 1
We also examined the effect of other halides analogs of
TBAB including TBAF, TBAC and TBAI to understand
the generality of these PTC’s role in our reaction. For this
purpose, we selected the reaction of benzoic acid and ep-
ichlorohydrin (Table 1, entry 1) as a model reaction,
which was treated with cat. amount of tetrabutylammoni-
um halides (TBAX). Good yield (70%) was obtained by
using TBAC instead of TBAB. In the case of TBAF, we
expected higher yield due to the more basic properties of
F– ion. On the contrary, lower yield (43%) was ob-
saturated carbonyl compounds in low yield (18%).10
-
Carboxyalkanols were obtained by the ring opening of ep-
oxides with carboxylates in micellar media catalyzed by
SYNTHESIS 2003, No. 16, pp 2552–2558
x
x.
x
x
.
2
0
0
3
Advanced online publication: 29.09.2003
DOI: 10.1055/s-2003-42416; Art ID: Z09203SS.pdf
© Georg Thieme Verlag Stuttgart · New York

PAPER
Chemoselective Preparation of Benzoylated 1,2-Diols
2553
Table 1 Reaction of Epoxides with Benzoic acid and Catalytic Amount of TBAB in Anhydrous MeCN
Entry
1
Epoxides
Producta
Reaction time (h)
Yieldb (%)
O
O
O
O
O
O
O
O
O
Cl
O
O
O
O
O
O
O
O
Cl
Br
5
97
86
92
95
96
98
94
92
OH
OH
OH
OH
OH
OH
OH
OH
1
2
3
4
5
6
7
8
O
Br
2
3
4
5
6
7
8
5
4
6
5
5
6
5
O
O
O
CH3
CH3
OPh
OPh
C5H12
C5H12
O
O
O
O
O
O
O
O
CH3
CH3
O
O
O
O
Ph
9
5
4
ca. 100c
9b
10
O
O
10
98
O
OH
a Products were characterized by 1H NMR,13C NMR, IR spectroscopy.
b Yields of pure isolated products based on the starting epoxides.
c This compound gave two isomer products in ratio of (75:25).
Synthesis 2003, No. 16, 2552–2558 © Thieme Stuttgart · New York

2554
A. Khalafi-Nezhad et al.
PAPER
served.14 Use of TBAI has limitations because of the nu- oxide ring but is also followed by SN2 attack at carbon
cleophilic attack of I– ions at the epoxide ring. The containing halide moiety by the carboxylate anion. Under
formation of an iodohydrin as a side product is inevitable these conditions, SN2 attack at the leaving group cannot be
in this case; however, good yield was obtained (61%).
avoided but in our method the sole site of reaction was the
epoxide ring and the halide group was not attacked. This
was demonstrated in the case of epichlorohydrin and epi-
bromohydrin (Table 1, entries 1 and 2).
Several reactions were also carried out to understand the
effect of other solvents beside MeCN on the efficiency
and regioselectivity for product formation. A set of anhy-
drous aprotic solvents was used for the previously de- To explain the effects of miscellaneous PTC’s and sol-
scribed model reaction of benzoic acid, TBAB and vents (Table 2) on this reaction, we have proposed a ten-
epichlorohydrin. The results are depicted in Table 2.
tative mechanism (Scheme 2).
Table 2 Effect of Various Solvents on the Reaction of Epichlorohy-
drin with Benzoic Acid in the Presence of TBAB
Solvent
DMF
Reaction Time (h)
Yielda (%)
7
7
42
34
31
65
32
10
97
24
DMSO
HMPA
THF
9
7
Acetone
CH2Cl2
MeCN
PhMe
10
24
5
Scheme 2
In step (a) TBAX plays a significant role in establishing
equilibrium and dissociation of benzoic acid to give tetra-
butylammonium benzoate and in situ generated hydrogen
halide (HX). In step (b) HX is trapped by weakly basic
solvent MeCN. In step (c) the proton is exchanged with
epoxide to give protonated but loosely bound epoxide-ha-
lide ion pair. Exchange of tetrabutylammonium benzoate
and protonated epoxide-halide gives protonated and
loosely bound epoxide-benzoate ion pair in step (d). Fi-
nally in step (e) the collapse of protonated epoxide-ben-
zoate give -benzoyloxy alkanol. The efficiency of TBAF,
TBAC, TBAB and TBAI can be interpreted in terms of
acidic strengths of HF, HCl, HBr and HI, respectively.
The low efficiency of TBAF may be due to the weak acid-
ic strength of HF while others except HI (because of I– in-
terference) proved to be good catalysts for progress of the
reaction.
7
a Yield of pure isolated products based on the starting epoxides.
As Table 2 shows, there is no meaningful correlation be-
tween the efficiency of reaction and the dielectric constant
of the solvent since solvents with higher dielectric con-
stant compared to MeCN such as DMSO and DMF show
little selectivity in the ring opening reaction of epichloro-
hydrin. In contrast, solvent such as THF with lower di-
electric constant can be taken into account as the next
eligible solvent for the above-mentioned reaction. We
also studied the reaction trend of other benzoic acid deriv-
atives to realize the effect of both electron-donating and
electron-accepting substituents on the regioselectivity and
yield of reaction. The ability of these derivatives was in-
vestigated by using 2-(phenoxymethyl)oxirane as selected
model epoxide in the presence of TBAB in anhydrous
MeCN. The results are shown in Table 3.
It is important to emphasize that in particular mono-esters
of 1,2-diols are known to isomerize12 and such isomeriza-
tion is very fast in acidic15 or alkaline16 media. This be-
comes a serious drawback for chemoselective preparation
of mono-esters of 1,2-diols specially for 1,2-diols lacking
C2 symmetric centers. This happens often in direct protec-
tion of 1,2-diols using acylating agents catalyzed with ei-
ther base or Lewis acids. Under these conditions use of
quenching agent is essential for inhibition of isomeriza-
tion.17 A remarkable advantage of our method in compar-
ison with direct acylation of 1,2-diols is that neither base
nor acid was used to catalyze the reaction; therefore
isomerization is blocked during the course of reaction.
In addition, as shown in Table 3, satisfactory yields were
observed for benzoic acid derivatives with both electron-
accepting and electron-donating groups.
An interesting example on the selectivity of this method is
shown by the hydroxy benzoic acid derivatives (Table 3,
entries 14–16). In basic media, these benzoic acid deriva-
tives may act as ambident nucleophiles and therefore
complicated products are obtained because of the contri-
bution of phenolic OH in epoxides ring opening; however,
this problem was not seen in our method. The presence of
basic condition or alkali metal benzoate or the leaving
groups such as -Cl, -Br creates problems for epoxides ring
opening since the reaction is not only achieved at the ep-
In conclusion, we have developed an efficient method for
preparation of chemoselective benzoylated 1,2-diols from
epoxides. The reaction proceeds with various epoxides,
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PAPER
Chemoselective Preparation of Benzoylated 1,2-Diols
2555
Table 3 Reaction of Benzoic Acid Derivatives with 2-(Phenoxymethyl)oxirane Catalyzed by TBAB in Anhydrous MeCN
Entry
11
Acid
Product
Reaction Time (h)a
Yieldb (%)
62
O
O
OH
O
OPh
5
OH
O2N
O2N
11
O
O
OH
O
OPh
12
13
14
15
16
6
5
4
4
4
73
84
92
90
85
OH
Br
Br
12
O
O
O
O
O
O
OH
OH
OH
O
O
O
OPh
OPh
OPh
OH
OH
OH
Cl
Cl
13
HO
HO
HO
14
HO
15
OH
O
OH
O
OH
O
OPh
OH
16
O
O
OH
O
OPh
17
18
19
5
4
5
91
98
90
OH
H3C
H3C
17
O
O
OH
O
OPh
OH
MeO
MeO
18
O
O
OH
O
OPh
OH
N
N
19
a Products were characterized by 1H NMR,13C NMR, IR
b Yields of pure isolated products based on the starting epoxides.
benzoic acid or its derivatives in the presence of a catalyt-
ic amount of TBAB in anhydrous MeCN within 4–7
hours. Furthermore, this method is highly regioselective.
The chemicals were obtained from Fluka or Merck. Purification and
dehydration of solvents were done using the reported methods18 and
the anhydrous solvents were stored over molecular sieves. With
TLC using silica gel SILG/UV 254 plates the progress of the reac-
tion was followed. IR spectra were run on a Shimadzu FTIR-8300
Synthesis 2003, No. 16, 2552–2558 © Thieme Stuttgart · New York

2556
A. Khalafi-Nezhad et al.
PAPER
1
spectrophotometer. The H NMR and 13C NMR spectra were re-
corded on a Bruker Advanced DPX-250, FT-NMR spectrometer (
in ppm). Melting points were determined on a Büchi 510 in open
capillary tubes and are uncorrected. All yields refer to the isolated
products.
13C NMR (62.5 MHz, CDCl3): = 167.21, 159.20, 138.41, 130.90,
129.92,128.01, 123.62, 115.09, 115.04, 70.01, 69.92, 63.24.
2-Hydroxyoctyl Benzoate (5)17
Column chromatography purification on silica gel with n-hexane–
EtOAc (7:2) gave awhite crystals (2.40 g,96%); mp 48–50 ºC; Rf
0.81 (50% n-hexane–EtOAc).
Preparation of -Benzoyloxy Alkoanol; General Procedure
To a solution of epoxides (0.01 mol) in anhyd MeCN (40 mL) were
added benzoic acid (1.5 g, 0.012 mol) and cat. amount of TBAB
(0.1 g, 0.31 mmol), and the solution was refluxed for 4–7 h
(Tables 1 and 2). When TLC indicated disappearance of the starting
epoxides, the solvent was evaporated and the crude mixture was
suspended in 5% K2CO3 solution (50 mL) to remove unreacted ben-
zoic acid. The organic layer was extracted with CHCl3 (2 × 100
mL) and dried over Na2SO4 (20 g). Filtration and evaporation of the
solvent gave the crude product, which was purified with appropriate
methods described below.
IR (KBr): 3600–3160 (br), 3100, 2980, 1730(s), 1250 cm–1.
1H NMR (250 MHz, CDCl3): = 8.25–7.32 (m, 5 H, Ph), 4.53–
4.23(m, 2 H, PhCO2CH2), 4.19–3.86 (m, 1 H, HCOH), 2.45(s, 1 H,
OH, exchangeable with D2O), 1.75–1.25 [m, 10 H, (CH2)5], 1.00–
0.75 (t, J = 6.6 Hz, 3 H CH3).
13C NMR (62.5 MHz, CDCl3): = 167.24, 135.06, 130.09, 130.01,
127.68, 70.71, 69.11,35.06, 32.71, 30.04, 25.22, 24.54, 15.10.
2-Hydroxy-3-(methacryloyloxy)propyl Benzoate (6)
Column chromatography purification on silica gel with n-hexane–
EtOAc (5:3) gave a colorless oil (2.53 g, 98%); Rf 0.56 (50% n-hex-
ane–EtOAc).
3-Chloro-2-hydroxypropyl Benzoate (1)
Column chromatography purification on silica gel with n-hexane–
EtOAc (5:3) gave a colorless oil (2.00 g, 97%); Rf 0.75 (50% n-hex-
ane–EtOAc).
IR (liquid film): 3600–3150 (br), 3100, 2900, 1730 (s), 1280 cm–1.
1H NMR (250 MHz, CDCl3): = 8.22–7.26 (m, 5 H, Ph), 4.43–4.28
(dd, J = 2.1, 4.9 Hz, 2 H, PhCO2CH2), 4.21–4.00 (quint, J = 2.1 Hz,
1 H, HCOH), 3.61–3.52 (dd, J = 2.1, 4.8 Hz, 2 H, CH2Cl), 3.23 (br,
1 H, OH, exchangeable with D2O).
IR (liquid film): 3600–3150 (br), 3050, 2980, 1730, 1720 (two
bands), 1250, 1230 cm–1.
1H NMR (250 MHz, CDCl3): = 8.41–7.36 (m, 5 H, Ph), 6.21 (s, 1
H, =CHaHb), 5.63 (s, 1 H, =CHaHb), 4.64–4.50 (m, 2 H,
PhCO2CH2), 4.49–4.23 [m, 3 H, HCHOH, CH2=C(Me)CO2CH2],
3.33–3.01 (1 H, br, OH, exchangeable with D2O), 2.05 (3 H, s,
CH3).
13C NMR (62.5 MHz, CDCl3): = 167.01,134.21, 130.00, 129.97,
128.41, 70.00, 66.23, 57.31.
13C NMR (62.5 MHz, CDCl3): = 167.21, 166.32, 136.22, 135.09,
130.06, 128.51, 125.22, 69.90, 65.22, 65.09, 65.00, 20.31.
3-(Allyloxy)-2-hydroxypropyl Benzoate (7)11
Column chromatography purification on silica gel with n-hexane–
EtOAc (5:2) gave a colorless oil (2.21 g, 94%); Rf 0.60 (50% n-hex-
ane–EtOAc).
3-Bromo-2-hydroxypropyl Benzoate (2)
Column chromatography purification on silica gel with n-hexane–
EtOAc (5:3) gave a colorless foam (2.22 g, 86%); Rf 0.79 (50% n-
hexane–EtOAc).
IR (liquid film): 3600–3160 (br), 3100, 2950, 1730 (s), 1270 cm–1.
IR (liquid film): 3600–3150 (br), 3050, 2980,1735(s), 1250 cm–1.
1H NMR (250 MHz, CDCl3): = 8.21–7.25 (m, 5 H, Ph), 4.50–4.23
(dd, J = 1.0, 4.7 Hz, 2 H, PhCO2CH2), 4.21–4.05 (quint, J =4.7 Hz,
1 H, HCOH), 3.56–3.25 (dd, J = 1.2, 4.7 Hz, 2 H, CH2Br) 3.00–2.50
(br, 1 H, OH).
13C NMR (62.5 MHz, CDCl3): = 165.00, 132.24, 128.04, 127.64,
125.32, 67.61, 60.00, 39.02.
1H NMR (250 MHz, CDCl3): = 8.31–7.42 (m, 5 H, Ph), 6.00–5.72
(m, 1 H, =CHCH2), 5.23–4.89 (dd, J = 10.4, 7.7 Hz, 2 H, =CH2),
4.42–4.17(d, J = 4.4 Hz, 2 H, PhCO2CH2), 4.11–4.00 (m, 1 H,
HCOH), 4.00–3.81 (d, J = 5.5 Hz, 2 H, HCOHCH2O), 3.50–3.38
(m, 2 H, =CHCH2O), 2.76 (s, 1 H, OH, exchangeable with D2O).
13C NMR (62.5 MHz, CDCl3): = 167.22, 136.28, 135.01, 130.24,
1329.62, 117.31, 117.28, 74.41, 71.22, 69.32, 65.13.
2-Hydroxypropyl Benzoate (3)17,19a–c
Column chromatography purification on silica gel with n-hexane–
EtOAc (7:2) gave a colorless oil (1.64 g, 92%); Rf 0.54 (50% n-hex-
ane–EtOAc).
IR (liquid film): 3600–31500 (br), 3100, 2950, 1735 (s), 1265 cm–1.
1H NMR (250 MHz, CDCl3): = 8.20–7.31 (m, 5 H, Ph), 4.53–4.42
[m, 1 H, CH(OH)CH3], 4.42–4.21 (m, 2 H, PhCO2CH2), 2.34–1.85
(br, 1 H, OH), 1.38–1.22 (d, J = 5.9 Hz, 3 H, CH3).
13C NMR (62.5 MHz, CDCl3): = 135.01, 134.98, 130.00, 129.91,
127.63, 70.21, 66.20, 20.00.
2-Hydroxy-3-(iso-propyloxy)propyl Benzoate (8)
Column chromatography purification on silica gel with n-hexane–
EtOAc (5:2) gave a colorless oil (2.10 g, 92%); Rf 0.83 (50% n-hex-
ane–EtOAc).
IR (liquid film): 3600–3100 (br), 3050, 2980, 1735, 1265 cm–1.
1H NMR (250 MHz, CDCl3): = 8.24–7.28 (m, 5 H, Ph), 4.63–4.46
(dd, J = 2.6, 5.2 Hz, 2 H, PhCO2CH2), 4.26–4.00 (quint, J = 5.2, 1
H, HCOH), 3.76–3.44 [m, 3 H, (CH3)2CHO, CH2O (iso-Pr)], 3.33–
3.25 (br, 1 H, OH),1.35–1.00 (d, J = 6.0 Hz, 6 H, 2 CH3).
13C NMR (62.5 MHz, CDCl3): = 163.71, 134.32, 131.36, 131.02,
127.64, 74.81, 70.33, 70.02, 66.32, 22.23.
2-Hydroxy-3-phenoxypropyl Benzoate (4)
Column chromatography purification on silica gel with n-hexane–
EtOAc (5:3) gave white crystals (2.51 g, 95%); mp 65–67 ºC;
Rf 0.75 (50% n-hexane–EtOAc).
IR (KBr): 3600–3100 (br), 3150, 2980,1734 (s), 1275 cm–1.
1H NMR (250 MHz, CDCl3): = 8.43–6.79 (m, 10 H, PhCO2, PhO),
4.78–4.62 (dd, J = 2.0, 5.1 Hz, 2 H, PhCO2CH2), 4.56–4.39 (quint,
J = 5.1 Hz, 1 H, HCOH), 4.36–4.00 (dd, J = 2.1, 5.1 Hz, 2 H,
CH2OPh), 3.00 (s, 1 H, OH, exchangeable with D2O).
2-Hydroxy-2-phenylethyl Benzoate (9a)17,19
Column chromatography purification on silica gel elution with n-
hexane–EtOAc (7:3) gave pale yellow crystals (1.80 g, 75%); mp
64–66 ºC; Rf 0.85 (50% n-hexane–EtOAc); and oil (1.80 g, 75%);
Rf 0.68 (50% n-hexane–EtOAc).
IR (KBr): 3600–3200 (br), 3050, 2980, 1735(s), 1260 cm–1.
1H NMR (250 MHz, CDCl3): = 8.31–7.02 (m, 10 H, 2 Ph), 5.43–
5.26 (dd, J = 3.5, 7.9 Hz, 1 H, PhCHOH), 4.74–4.51 (dd, J = 3.5,
Synthesis 2003, No. 16, 2552–2558 © Thieme Stuttgart · New York

PAPER
Chemoselective Preparation of Benzoylated 1,2-Diols
2557
11.5 Hz, 1 H, PhCO2CHaHb), 4.51–4.32 (dd, J = 11.5, 8.0 Hz, 1 H
PhCO2CHaHb), 3.01–2.54 (br, 1 H, OH, exchangeable with D2O).
ClPhCO2CH2), 4.42–4.38 (quint, J = 4.9, 1 H, HCOH), 4.29–4.00
(dd, J = 4.9, 2.2 Hz, 2 H, CH2OPh), 2.50 (s, 1 H, OH).
13C NMR (62.5 MHz, CDCl3): = 167.34, 140.33, 134.99, 131.61,
130.03, 129.64, 129.53, 128.96, 127.36, 77.34, 70.29.
13C NMR (62.5 MHz, CDCl3): = 166.34, 158.24, 136.29, 132.67,
132.11, 130.44, 130.00, 126.68, 115.00, 69.36, 69.24, 65.98.
2-Hydroxy-1-phenylethyl Benzoate (9b)17,19
Column chromatography purification on silica gel with n-hexane–
EtOAc (7:3) gave a pale yellow oil (0.60 g, 25%); Rf 0.68 (50% n-
hexane–EtOAc).
2-Hydroxy-3-phenoxypropyl-4-hydroxy Benzoate (14)
Column chromatography purification on silica gel with n-hexane–
EtOAc (5:3) gave white crystals (2.60 g, 92%); mp 120–122 ºC; Rf
0.29 (50% n-hexane–EtOAc).
IR (liquid film): 3600–3200 (br), 3050, 2980, 1735 (s), 1265 cm–1.
IR (KBr): 3600–3140 (br), 3100, 2980, 1730(s), 1250 cm–1.
1H NMR (250 MHz, CDCl3): = 8.33–7.03 (m, 10 H, 2 Ph), 6.34–
6.02 (dd, J = 3.6, 7.1 Hz, 1 H, PhCO2CHPh), 4.34–3.85 (m, 2 H,
CH2OH), 2.31–2.00 (br s, 1 H, OH, exchangeable with D2O).
13C NMR (62.5 MHz, CDCl3): = 164.22, 138.22, 135.01, 131.24,
131.06, 129.64, 129.39, 126.83, 126.52, 79.61, 67.33.
1H NMR (250 MHz, DMSO-d6): = 11.24 (s, 1 H, HOPh, ex-
changeable with D2O), 7.91–7.83 (d, J = 8.6 Hz, 2 H, p-HOPh),
7.42–7.23 (d, J = 8.6 Hz, 2 H, p-HOPh), 7.00–7.83 (m, 5 H, Ph),
4.50–4.36 (dd, J = 4.9, 3.5 Hz, 2 H, p-HOPhCO2CH2), 4.25–4.21
(quint, J = 4.9 Hz, 1 H, HCOH), 4.20–4.00 (dd, J = 3.1, 4.9 Hz, 2
H, CH2OPh), 2.50–1.75 (br, 1 H, OH, exchangeable with D2O).
2-Hydroxycyclohexyl Benzoate (10)8,11,19d
Column chromatography purification on silica gel with n-hexane–
EtOAc (5:2) gave white crystals (2.13 g, 98%); mp 104–105 ºC;
Rf 0.73 (50% n-hexane–EtOAc).
13C NMR (62.5 MHz, DMSO-d6): = 167.24, 160.00, 156.24,
132.41, 132.56, 129.96, 123.69, 123.74,116.00, 70.00, 69.98,
65.31.
2-Hydroxy-3-phenoxypropyl-3-hydroxy benzoate (15)
Column chromatography purification on silica gel with n-hexane–
EtOAc (5:3) gave pale yellow crystals (2.40 g, 90%); mp 63–65 ºC;
Rf 0.53 (50% n-hexane–EtOAc).
IR (KBr): 3600–3100 (br), 3050, 2985, 1730(s), 1260 cm–1.
1H NMR (250 MHz, CDCl3): = 8.00–7.20 (m, 5 H, Ph), 4.80–4.76
(m, 1 H, PhCO2CH), 3.68–3.64 (m, 1 H, HCOH), 2.26 (s, 1 H, OH,
exchangeable with D2O), 2.10–1.26 [m, 8 H, (CH2)4].
13C NMR (62.5 MHz, CDCl3): = 165.84, 135.59, 132.80, 130.21,
128.96, 72.68, 68.73, 31.42, 29.82, 21.48, 21.39.
IR (KBr): 3600–3140 (br), 3100, 2980, 1730(s), 1250 cm–1.
1H NMR (250 MHz, CDCl3): = 7.86–6.93 (m, 9 H, m-HOPh, Ph),
4.63–4.50 (dd, J = 2.2, 4.9 Hz, 2 H m-HOPhCO2CH2), 4.50–4.32
(quint, J = 4.9, 1 H, HCOH), 4.29–4.00 (dd, J = 2.0, 4.9 Hz, 2 H,
CH2OPh), 4.00–3.00 (br, 1 H, HOPh, exchangeable with D2O), 2.50
(s, 1 H OH, exchangeable with D2O).
13C NMR (62.5 MHz, CDCl3): = 167.33, 159.23, 156.31, 131.32,
130.29, 130.02, 123.62, 123.02, 122.07, 116.24, 115.00, 69.68,
69.41, 66.32.
2-Hydroxy-3-phenoxypropyl-4-nitro Benzoate (11)
Column chromatography purification on silica gel with n-hexane–
EtOAc (5:3) gave pale yellow crystals (1.90 g, 62%); mp 85–87 ºC;
Rf 0.73 (50% n-hexane–EtOAc).
IR (KBr): 3600–3150 (br), 3100, 2985, 1735(s), 1550 (s), 1350,
1250 cm–1.
1H NMR (250 MHz, CDCl3): = 8.41–8.00 (2 d, J = 8.8 Hz, 4 H, p-
O2NPh,), 7.45–7.30 (m, 2 H, Ph), 7.00–6.60 (m, 3 H, Ph), 4.63–
4.51(dd, J = 5.1, 1.9 Hz, 2 H, p-O2NPhCO2CH2), 4.49–4.26 (quint,
J = 5.1 Hz, 1 H, HCOH), 4.19–3.96 (dd, J = 5.1, 2.3 Hz, 2 H,
CH2OPh), 2.51–2.00 (br, 1 H, OH).
13C NMR (62.5 MHz, CDCl3): = 168.29, 160.32, 140.41, 130.91,
130.22, 128.05, 124.01, 115.06, 115.02, 70.06, 70.00, 63.11.
2-Hydroxy-3-phenoxypropyl salcylate (16)
Column chromatography purification on silica gel with n-hexane–
EtOAc (5:2) gave a colorless oil (2.44 g, 85%); Rf 0.79 (50% n-hex-
ane–EtOAc).
IR (liquid film): 3600–3150 (br), 3100, 2985, 1728(s), 1250 cm–1.
1H NMR (250 MHz, CDCl3): = 10.68 (s, 1 H, HOPh, exchange-
able with D2O), 8.01–6.55(m, 9 H, o-HOPh, Ph), 4.58–4.50 (dd,
J = 1.9, 5.1 Hz, 2 H, o-HOPhCO2CH2), 4.48–4.36 (quint, J = 5.1 Hz,
1 H, HCOH), 4.00–3.79 (dd, J = 2.2, 5.1 Hz, 2 H, CH2OPh), 2.50–
2.00 (br, 1 H, OH, exchangeable with D2O).
13C NMR (62.5 MHz, CDCl3) : = 167.54, 160.16, 156.34, 136.24,
131.42, 130.24, 130.02, 122.31, 120.00, 117.62, 115.00, 70.51,
70.32, 65.00.
2-Hydroxy-3-phenoxypropyl-4-bromo Benzoate (12)
Column chromatography purification on silica gel with n-hexane–
EtOAc (7:3) gave white crystals (2.50 g, 73%); mp 90–92 ºC; Rf
0.80 (50% n-hexane–EtOAc).
IR (KBr): 3600–3150 (br), 3100, 2980, 1734(s), 1240 cm–1.
1H NMR (250 MHz, CDCl3): = 7.83–7.80 (d, J = 8.4 Hz, 2 H, p-
BrPh), 7.51–7.47 (d, J = 8.4 Hz, 2 H, p-BrPh) 7.24–7.18 (m, 2 H,
Ph), 6.93–6.82 (m, 3 H, Ph), 4.48–4.43(dd, J = 5.1, 2.3 Hz, 2 H, p-
BrPhCO2CH2), 4.32–4.24 (quint, J = 5.1 Hz, 1 H, HCOH), 4.05–
4.00 (dd, J = 5.1, 2.0 Hz, 2 H, CH2OPh), 2.50–2.10 (br, 1 H, OH).
2-Hydroxy-3-phenoxypropyl-4-methyl Benzoate (17)
Column chromatography purification on silica gel with n-hexane–
EtOAc (7:3) gave white crystals (2.60g, 91%); mp 68–70 ºC; Rf
0.93 (50% n-hexane–EtOAc).
13C NMR (62.5 MHz, CDCl3): = 167.36, 159.34, 134.22, 133.89,
130.34, 128.61, 128.02, 123.91, 120.00, 70.36, 70.02, 62.89.
IR (KBr): 3600–3150 (br), 3100, 2985, 1730(s), 1250 cm-1.
1H NMR (250 MHz, CDCl3): = 8.20–8.00 (d, J = 8.0 Hz, 2 H, p-
MePh), 7.53–7.31(d, J = 8.0 Hz, 2 H, p-MePh), 7.31–7.25 (m, 2 H,
Ph), 7.00–6.90 (m, 3 H, Ph) 4.63–4.51 (dd, J = 5.1, 2.2 Hz, 2 H, p-
CH3PhCO2CH2), 4.47–4.38 (quint, J = 5.1 Hz, 1 H, HCOH), 4.29–
4.00 (dd, J = 5.1, 2.0 Hz, 2 H, CH2OPh), 2.85 (s, 1 H, OH), 2.50 (s,
3 H, CH3).
2-Hydroxy-3-phenoxypropyl-4-chloro Benzoate (13)
Column chromatography purification on silica gel with n-hexane–
EtOAc (7:3) gave a colorless oil (2.50 g, 84%); Rf 0.73 (50% n-hex-
ane–EtOAc).
IR (liquid film): 3600–3150 (br), 3100, 2985, 1730(s), 1240 cm–1.
13C NMR (62.5 MHz, CDCl3): = 167.31, 160.23, 145.00, 130.92,
130.68, 130.09, 127.36, 122.46, 115.00, 70.36, 66.24, 66.01, 22.31.
1H NMR (250 MHz, CDCl3): = 7.93–7.91(d, J = 7.8 Hz, 2 H, p-
ClPh,), 7.52–7.42 (d, J = 7.8 Hz, 2 H, p-ClPh), 7.42–7.16 (m, 2 H,
Ph), 7.16–6.83 (m, 3 H, Ph), 4.81–4.52 (dd, J = 4.9, 1.9 Hz, 2 H, p-
Synthesis 2003, No. 16, 2552–2558 © Thieme Stuttgart · New York

2558
A. Khalafi-Nezhad et al.
PAPER
2-Hydroxy-3-phenoxypropyl-4-methoxy Benzoate (18)
Column chromatography purification on silica gel with n-hexane–
EtOAc (5:2) gave white crystals (2.94 g, 98%); mp 82–84 ºC;
Rf 0.56 (50% n-hexane–EtOAc).
Stamm, H. J. Org. Chem. 1987, 52, 4812. (d) Smith, A. B.
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(e) Olah, G. A.; Fung, A. P.; Meidar, D. Synthesis 1981,
280. (f) Posner, G. H.; Rogers, D. Z. J. Am. Chem. Soc.
1977, 99, 8208. (g) Posner, G. H.; Rogers, D. Z. J. Am.
Chem. Soc. 1977, 99, 8214. (h) Posner, G. H.; Rogers, D. Z.;
Kinzig, C. M.; Gurria, G. M. Tetrahedron Lett. 1975, 3597.
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487. (j) Ellestad, G. A.; Whaley, H. A.; Patterson, E. L. J.
Am. Chem. Soc. 1966, 88, 4110.
IR (KBr): 3600–3150 (br), 3100, 2980, 1735(s), 1250 cm–1.
1H NMR (250 MHz, CDCl3): = 8.21–7.90 (d, J = 8.8 Hz, 2 H, p-
MeOPh) 7.49–7.41 (d, J = 8.8 Hz, 2 H, p-MeOPh), 7.00–6.72 (m, 5
H, Ph), 4.73–4.51 (dd, J = 1.9, 5.1 Hz, 2 H, p-MeOPhCO2CH2),
4.50–4.41 (quint, J = 5.1 Hz, 1 H, HCOH), 4.39–4.21 (dd, J = 2.0,
5.1 Hz, 2 H, CH2OPh), 3.90 (s, 3 H, OMe), 3.00 (s, 1 H, OH).
13C NMR (62.5 MHz, CDCl3): = 167.42, 165.00, 160.00, 133.64,
130.00, 123.62, 122.19, 115.00, 114.91, 70.26, 70.00, 65.00, 55.31.
(6) (a) Parker, R. E.; Isaacs, N. S. Chem. Rev. 1959, 59, 737.
(b) Paknikar, S. K.; Kirtane, J. G. Tetrahedron 1983, 39,
2323. (c) Bonini, C.; Righi, G. Synthesis 1994, 225.
(d) Smith, J. G. Synthesis 1984, 629. (e) Kotsuki, H.;
Teraguchi, M.; Shimamoto, N.; Ochi, M. Tetrahedron Lett.
1996, 37, 3727.
(7) (a) Iranpoor, N.; Tarrian, T.; Movahedi, Z. Synthesis 1996,
1473. (b) Iranpoor, N.; Shakarrize, M.; Shiriny, F. Synth.
Commun. 1998, 28, 347. (c) Carron, M.; Sharpless, K. B. J.
Org. Chem. 1985, 50, 1560.
(8) Jacobsen, E. N.; Kakiuchi, F.; Kensler, R. J.; Larrow, J.;
Tokunaga, M. Tetrahedron Lett. 1997, 38, 773.
(9) Gurgiolo, A. E. Chem. Abstr. 1978, 38, 111225P.
(10) Apparo, S.; Schmidt, R. R. Synthesis 1987, 896.
(11) Iranpoor, N.; Firouzabadi, H.; Safavi, A.; Shekarriz, M.
Synth. Commun. 2002, 32, 2287.
2-Hydroxy-3-phenoxypropyl Nicotinate (19)
Column chromatography purification on silica gel with n-hexane–
EtOAc (5:3) gave pale yellow crystals (2.40 g, 90%); mp 82–84 ºC;
Rf 0.19 (50% n-hexane–EtOAc).
IR (KBr): 3600–3150 (br), 3100, 2985, 1735(s), 1250 cm–1.
1H NMR (250 MHz, CDCl3): = 9.32–6.80 (m, 9 H, pyridine, OPh),
4.76–4.51 (dd, J = 5.3, 2.5 Hz, 2 H, C5H4NCO2CH2), 4.43–4.35
(quint, J = 5.3 Hz, 1 H, HCOH), 4.23–4.18 (dd, J = 5.3, 2.1 Hz, 2 H
CH2OPh), 3.81(s, 1 H, OH).
13C NMR (62.5 MHz, CDCl3): = 167.36, 159.22, 154.36, 151.68,
138.09,130.00, 127.09, 124.54,122.16, 115.00, 70.64, 70.23,67.36.
(12) (a) Cohen, T.; Dughi, M.; Nataro, V. A.; Pinkus, G. J. Org.
Chem. 1962, 27, 814. (b) Hirano, M.; Morimoto, T. J.
Chem. Soc., Perkin Trans. 2 1984, 1033.
(13) Khalafi-Nezhad, A.; Soltani Rad, M. N.; Hakimelahi, G. H.
Design and Synthesis of Some Novel Acyclovir Analogs,
Cyclohexan Acyclic Nucleosides; The Preceding of 10th
Iranian Seminar of Organic Chemistry (ISOC10): Guilan
University Iran, 2002, 10-20 September.
Acknowledgment
We appreciate the funding from Shiraz University research council
for the financial support for this work. We thank Prof. N. Iranpoor
and Prof. H. Sharghi for their helpful comments and discussions.
We are also thankful to Mr. H. Sajedian Fard for running the NMR
spectra.
(14) Albanese, D.; Landini, D.; Penso, M. Synthesis 1994, 34.
(15) Santry, L. J.; Azer, S.; McClelland, R. A. J. Am. Chem. Soc.
1988, 110, 2909.
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Synthesis 2003, No. 16, 2552–2558 © Thieme Stuttgart · New York