Improvement and simplification of synthesis of 3-aryloxy-1,2-epoxypropanes using solvent-free conditions and microwave irradiations. Relation with medium effects and reaction mechanism

Article abstract of DOI:10.1016/j.tet.2006.08.067

Some 3-aryloxy-1,2-epoxypropanes, interesting as potential synthons in β-adrenergic receptor antagonists preparation, were obtained in excellent yields (65-96% within 2-17 min) by microwave activation (monomode system) using solid-liquid solvent-free phase transfer catalysis (PTC). The best results for the O-alkylation of some phenols with epichlorohydrin were obtained using TBAB and NaOH/K₂CO₃ (1:4 mol/mol) as phase transfer catalyst and more acceptable basic system, respectively. These new procedure is compared with classical methods. Significant specific microwave effect (non-purely thermal) was evidenced in all cases. They were discussed in terms of reaction medium and mechanism, taking into account the variations in polarity of the systems.

Full text of DOI:10.1016/j.tet.2006.08.067

Tetrahedron 62 (2006) 10968–10979
Improvement and simplification of synthesis of 3-aryloxy-1,2-
epoxypropanes using solvent-free conditions and microwave
irradiations. Relation with medium effects and reaction
mechanism
*
Beata K. Pchelka, Andre Loupy and Alain Petit
Laboratoire des Reactions Selectives sur Supports (CNRS UMR 8615), Institut de Chimie Moleculaire et des Materiaux d’Orsay
(I.C.M.M.O.), Ba^t. 410, Universite de Paris-Sud, 91405 Orsay-Cedex, France
Received 25 April 2006; revised 9 August 2006; accepted 18 August 2006
Available online 20 September 2006
Abstract—Some 3-aryloxy-1,2-epoxypropanes, interesting as potential synthons in b-adrenergic receptor antagonists preparation, were ob-
tained in excellent yields (65–96% within 2–17 min) by microwave activation (monomode system) using solid–liquid solvent-free phase
transfer catalysis (PTC). The best results for the O-alkylation of some phenols with epichlorohydrin were obtained using TBAB and
NaOH/K2CO3 (1:4 mol/mol) as phase transfer catalyst and more acceptable basic system, respectively. These new procedure is compared
with classical methods. Significant specific microwave effect (non-purely thermal) was evidenced in all cases. They were discussed in terms
of reaction medium and mechanism, taking into account the variations in polarity of the systems.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
polarization, ionic polarization can be involved. It results
in the separation of positive and negative charges induced
by the electromagnetic field. Therefore, this phenomenon
can also be considered in the acceleration of organic synthe-
sis under microwave irradiation after the generation of more
reactive species by ionic dissociation.
During last 10 years our interest in an efficient and econom-
ical technology for the preparation of some organic synthons
has promoted the research in the field of microwave irradia-
tion.1–3 The use of such non-conventional reaction condi-
tions reveals several features like: a short reaction time
compared to conventional heating, ease of work-up after a re-
action, and reduction in the usual thermal degradation and
better selectivity.4–5 In recent years some important reviews,
concerning study of microwave assisted organic reactions,
have been published.6–7
In this work, we want to check this second hypothesis as
a possible cause, like dipolar polarization effects, of micro-
wave enhancement. For this purpose we assume that the ac-
celeration observed previously10 in the case of O-alkylation
reactions of some phenols with epichlorohydrin, could also
have consequences for the reaction selectivity. In previous
paper we reported preliminary results for O-alkylation of
some selected phenols 1c,f,g,j with epichlorohydrin by
microwave irradiation under solid–liquid solvent-free phase
transfer catalysis.10 The aim of this work was to reproduce
some of these reactions in classical conditions (aqueous
solution of NaOH) and in solvent-free conditions under
microwave irradiation (MW) or classical heating (D). These
conditions were extended to another case of phenols such as:
1a–b,d–e,h–i (Scheme 1). It is important to note that the
alkylation of phenols to give aromatic ethers is well known
(Williamson reaction). However, in classical conditions the
reaction time is very long. The phase transfer catalysis tech-
nique11,12 under classical heating13 or microwave irradia-
tion14 has been successfully applied to the Williamson
ether synthesis. Concerning 3-aryloxy-1,2-epoxypropanes
Generally, interpretation of microwave enhancements in
organic synthesis is now well-demonstrated and fully ac-
knowledged.8 Their interpretation lies in a consideration of
the concept of dielectric polarization9 and, more precisely,
dipolar polarization, which is at the origin of microwave
heating due to the alignment of polar molecules along an
electromagnetic field. As microwaves consist in an alter-
nating electric field of high frequency (n¼2450 MHz,
l¼12.2 cm), inversion in the dipole orientation at each alter-
nance results in the stirring and friction of molecules, induc-
ing energy dissipation into internal homogenous heating.
Among other physical phenomena concerned in dielectric
* Corresponding author. Tel.: +33 147 077 110/+33 609 325 049/+48 22
751 65 38; e-mail: beatpchel@hotmail.fr
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.08.067

B. K. Pchelka et al. / Tetrahedron 62 (2006) 10968–10979
10969
OH
O
O
base
O
Cl
Cl
O
+
+
Ar OH
1a-
Ar
Ar
j
3a-j
4a-j
2
Scheme 1. Ar¼a: C6H5–, b: 2-CH3–C6H4–, c: 3-CH3–C6H4–, d: 4-CH3–C6H4–, e: 4-Cl–C6H4–, f: 3-CH3–4-Cl–C6H3–, g: 1-naphthyl-, h: 2-CH3O–C6H4–,
i: 2,6-Cl–C6H3–, j: 2-CN–C6H4.
3, the simplest and more popular method for their prepara-
tion consist in one-step O-alkylation of the suitably
substituted phenol 1 with epichlorohydrin 2 in the presence
of base (Stephenson procedure).15 Generally, in all proce-
dures described, the epichlorohydrin is used in a significant
excess and the reaction is carried out in an aqueous solution
of a base (NaOH, KOH, K2CO3, etc.) or in an organic solvent
containing pyridine or piperidine.16,17 Concerning chemical
industry and high scale, only last methods were used.16i,j De-
pending on the substituent position or nature in the phenol 1,
it takes 6–20 h at reflux or 24–26 h at room temperature to
complete the reaction. It is important to note that, these clas-
sical methods can suffer from some inconvenience due
to moderate isolated yields (50–70%), moderate purity of
products and poor reaction selectivity (1-chloro-3-aryloxy-
propan-2-ols 4 were formed in an important amount as non-
suitable by-product15,16a). Some from these inconvenience
may be limited by addition of the phase transfer catalyst
(e.g. benzyltriethylammonium chloride) to the aqueous
solution of base (K2CO3, etc.).16a,h,k,n,17a,i,r However, as
described by Bevinakatti and Banerji,16h the acceptable
reaction rates, selectivities and isolated yields of product 3
were obtained, in PTC procedures, only by using very high
concentrations of the base.
experiments, the efficiency of known classical procedure de-
scribed by Biniecki,17g for O-alkylation of various phenols
with epichlorohydrin, was investigated. For this purpose,
various phenols 1a–i were treated, at reflux, with 1.26 equiv
of epichlorohydrin in an aqueous sodium hydroxide
(Scheme 1).
The reactions were performed in high scale (0.19 mol of
phenol and 0.24 mol of epichlorohydrin) and monitored by
GC. The 3-aryloxy-1,2-epoxypropanes 3 were separated
by silica gel column chromatography from the correspond-
ing 1-chloro-3-aryloxypropan-2-ols 4, which were formed
as by-products. The main results are given in Table 1.
The results presented in Table 1 clearly show that the condi-
tions described by Biniecki were sligthly acceptable, con-
cerning selectivity and isolated yield of suitable product 3.
It is important to note that, for all phenols tested 1a–i, the
arylglycidyl ethers 3 were formed as major product with
moderate yields (yield of 3¼58–76%). On the other hand,
the quantities of non-suitable by-product 4, determined in
the reaction mixture by GC analysis, were important (10–
32%, yield of 4¼5–23%). Generally, we observe a notable
effect of the phenyl-ring substituent in terms of reaction
time (94–99% conversion within 5–12 h). Concerning selec-
tivity, the values of ratio 3:4 depend only slightly on the
nature and position of the phenyl-ring substituent. In fact,
the values of ratio 3:4 were only slightly different when the
electronic effects of the substituent changed (e.g.: 76:24 for
4-CH3–C6H4–, 70:30 for 2-CH3O–C6H4–, 68:32 for 4-Cl–
C6H4–). Concerning 1-naphthol 1g, the value of ratio 3:4
was notably higher (ratio 3:4¼90:10) than in all other
cases. Finally, we note that when the reaction conversion
We have sought to develop a general method of the O-alkyl-
ation of phenols 1a–j with epichlorohydrin 2. Such a proce-
dure should retain the convenience of PTC methods but
should be free from some limitations related to PTC systems
and much faster. Therefore, we decided to explore the use of
microwave heating under solvent-free phase transfer cataly-
sis (PTC) conditions.
2. Results and discussion
Table 1. Reaction of epichlorohydrin 2 with several phenols 1a–i by using
aqueous solution of NaOH at refluxa
The conditions for O-alkylation of various phenols 1a–j with
epichlorohydrin 2 were optimized according to the conven-
tional scheme described in the literature (Scheme 1). In the
first time, one selected classical procedure was tested, in
term of conversion, selectivity and isolated yield. In second
time, the same reactions were performed in non-classical
conditions by using solid–liquid PTC catalysis under micro-
wave irradiation or classical heating. Concerning all method
tested, the effects of nature and position of the substituent on
the phenyl ring were evaluated on conversion, selectivity and
isolated yield of suitable product 3.
Phenol Ar
1
Time Conv. Ratio Yield of Yield of
(h)
(%)b,c 3:4d 3 (%)e 4 (%)e
a
b
c
C6H5–
5
10
7
14
11
19
6
98 80:20 69
99 85:15 75
97 68:32 58
99 75:25 66
98 70:30 63
99 78:22 77
98 76:24 70
97 68:32 61
96 82:18 65
94 90:10 69
98 70:30 68
>99 81:19 76
14
7
2-CH3–C6H4–
3-CH3–C6H4–
18
13
19
16
16
22
11
5
d
e
f
4-CH3–C6H4–
4-Cl–C6H4–
4-Cl–3-CH3–C6H3– 12
7
g
h
i
1-Naphthyl
2-CH3O–C6H4–
2,6-Di-Cl–C6H3–
6
7
8
23
10
2.1. Classical conditions
a
Generally, it is always difficult to anticipate the best choice
of classical method for the preparation, in high scale, of 3-
aryloxy-1,2-epoxypropanes 3. On the other hand, for these
compounds, the correlations between nature or position of
substituent on the aromatic ring and conversion, selectivity
or reaction yield were newer evaluated. In a first series of
Conditions: 1a–i (0.19 mol), epichlorohydrin 2 (0.24 mol) in 100 mL of
aqueous solution of NaOH (0.24 mol) under reflux.
Determined by GC and 1H NMR.
b
c
d
e
Complement to 100% conversion is an unreacted substrate phenol.
Determined by GC and 1H NMR.
Yields calculated after purification and separation by chromatography on
silica gel 60.

10970
B. K. Pchelka et al. / Tetrahedron 62 (2006) 10968–10979
was 97–98%, the further prolongation of the reaction time
produce only slight increase in the yield of product 3 and
as a consequence the yield of non-suitable by-product 4
decreased. For example, in the case of phenol 1a, the isolated
yield of 3a increase from 69 to 75% when the reaction time
was prolonged from 5 to 10 h, but in this case the yield of
corresponding chloroalcohol 4 was decreased from 14 to
7%. This last observations can justify our thesis that in the
reaction mixture exists permanent competition of two dif-
ferent mechanisms (Scheme 2) mechanism 1¼the direct
nucleophilic substitution (SN2) of phenate ion (ArOꢀ) on
epichlorohydrin 2 with destruction of C–Cl bond and mech-
anism 2¼the ring opening of epichlorohydrin 2 with ArOꢀ
followed by intramolecular cyclization (SNi) of correspond-
ing alcoholate 5 formed in situ.
homogeneous distribution of the field. It can be used with
a low emitted power and therefore produces a high energetic
yield. The use of such an apparatus was shown to lead to con-
siderable improvements in organic synthesis at very low
emitted powers and with a good temperature homogeneity.
In order to check for the possible intervention of specific
(not purely thermal) effects of microwaves (such as those
that might be due to a different temperature increase profile,
better temperature homogeneity, or modifications of the
activation parameters DHs and DSs), reactions were per-
formed with the two activation methods, microwave irradia-
tion (MW) and classical heating (D), keeping the reaction
time, final temperature and pressure the same. In control
experiments performed by using microwave irradiation and
classical heating, it was shown that the reaction did not pro-
ceed in the absence of phase transfer catalyst (TBAB) and
base within the reaction time indicated in the Tables 2 and
3, concerning all bases and phenols tested. The temperature
of sample was measured in each experiment immediately
upon termination of the microwave exposure. Reference
reactions were then carried out at this temperature with con-
ventional heating. In all cases of reactions performed by
using microwave irradiation, the 1H NMR, IR and GC anal-
yses revealed that the reaction product was pure 3-aryloxy-
1,2-epoxypropane 3 and not mixture of 3 and 4. The main
results are given in Tables 2 and 3.
2.2. Non-classical conditions
In second series of experiments, the O-alkylations were per-
formed by mixing selected phenol 1, the solid base, the solid
phase transfer catalyst [tetrabutylammonium bromide
(TBAB)], and the liquid alkylating agent epichlorohydrin
2, without any organic solvent in the relative amounts indi-
cated in the Tables 2 and 3. All reactions were performed
under atmospheric pressure by using microwave irradiation
(MW, power¼60 W) or classical heating in a thermostated
oil bath (D). The microwave irradiations were carried out
using a monomode Synthewave 402 Prolabo reactor18 fitted
with an infrared detector to measure the temperature
throughout the reaction. The interest of a monomode reactor
lies in its focalization of the electromagnetic waves using
an accurately proportioned waveguide, which allows a
2.2.1. Effect of the base. The effect of the base nature on the
selectivity, conversion and reaction yield of some O-alkyl-
ation reactions is well documented in the literature. There-
fore, in a first series of experiments, the influence of the
base nature on the selectivity, conversion and reaction yield
SN2
O
O
Base
ArO-M+
+
+
M+Cl-
ArOH
1
Cl
ArO
2
3
Ring opening
H+
or H2O
SNi
Intramolecular
cyclization
O
M+Cl-
+
ArO
ArO
Cl
ArO
Cl
+
O-
, M
3
OH
5
4
Scheme 2.
Table 2. Reaction of epichlorohydrin 2 with phenol 1f by using different solid bases under focused microwave irradiation (MW) or classical heating (D)a
Entry
Base
Relative amounts
1f/2/TBAB/(base)
Activation
modeb
Temp
(ꢁC)c
Time
(min)
Conv.
(%)d,e
Ratio
Yield of
Yield of
3f:4fd
3f (%)f
4f (%)f
1
2
3
4
5
NaOH
1/1.5/0.1/(1)
1/1.5/0.1/(4)
1/1.5/0.1/(1:4)
1/1.5/0.1/(1:4)
1/1.5/0.1/(1:4)
MW
D
MW
D
MW
D
MW
D
105
105
108
108
110
110
112
112
114
114
5
5
5
5
5
5
7
7
15
15
65
20
20
9
99
56
28
8
100:0
65:35
100:0
75:25
100:0
85:15
100:0
95:5
51
9
16
5
81
36
21
5
64
10
—
6
—
2
—
8
—
—
—
5
K2CO3
NaOH/K2CO3
NaOH/Al2O3basic
NaOH/Ca(OH)2
MW
D
70
23
97:3
69:31
a
Conditions: 1f (20 mmol), epichlorohydrin 2 (30 mmol), TBAB (2 mmol), solid base as presented in the table, under atmospheric pressure, without solvent
under microwave irradiation (power¼60 W) or classical heating in a thermostated oil bath.
Incident emitted power all along the reaction.
b
c
d
e
f
Temperature at the end of the microwave irradiation (MW) or classical heating (D).
Determined by GC and 1H NMR.
Complement to 100% conversion is an unreacted substrate phenol.
Yields calculated after purification and separation by chromatography on silica gel 60.

B. K. Pchelka et al. / Tetrahedron 62 (2006) 10968–10979
10971
Table 3. Reaction of epichlorohydrin 2 with several phenols 1a–i by using of solid–liquid solvent-free phase transfer catalysis under microwave irradiation
(MW) or classical heating (D)a
Entry
Phenol 1
Ar
Activation
modeb
Tempc
(ꢁC)
Time
(min)
Conv.
(%)b,c
Ratio 3:4d
Yield
Yield
of 3 (%)e
of 4 (%)e
1
2
a
b
c
d
e
f
C6H5–
MW
D
MW
D
MW
D
MW
D
MW
D
MW
D
MW
D
MW
D
113
113
110
110
112
112
110
110
113
113
110
110
116
116
111
111
110
110
106
106
6
6
7
7
5
5
7
7
11
11
5
5
2
2
5
5
99
48
96
38
99
50
98
41
95
40
99
56
99
55
98
36
96
57
98
33
100:0
76:24
95:5
83:17
100:0
66:34
95:5
88:12
99:1
69:31
100:0
85:15
99:1
90
31
89
26
95
29
87
30
68
20
81
36
96
38
87
19
65
28
67
20
—
10
2
2-CH3–C6H4–
3-CH3–C6H4–
4-CH3–C6H4–
4-Cl–C6H4–
6
3
—
15
4
5
—
9
4
5
6
4-Cl–3-CH3–C6H3–
1-Naphthyl-
—
8
7
g
h
i
—
12
—
10
—
10
—
5
76:24
99:1
8
2-CH3O–C6H4–
2,6-Di-Cl–C6H3–
2-CN–C6H4–
66:34
100:0
73:27
100:0
80:20
9
MW
D
MW
D
12
12
17
17
10
j
a
Conditions: 1a–i (0.19 mol), epichlorohydrin 2 (0.24 mol) in 100 mL of aqueous solution of NaOH (0.24 mol) under reflux and atmospheric pressure.
Determined by GC and 1H NMR.
Complement to 100% conversion is an unreacted substrate phenol.
b
c
d
e
Determined by GC and 1H NMR.
Yields calculated after purification and separation by chromatography on silica gel 60.
of TBAB catalyzed O-alkylation of phenol 1f, taken as model
formed in an important amount (35, 25, 15, 5 and 31% for
NaOH, K2CO3, NaOH/K2CO3, NaOH/Al2O3basic and
NaOH/Ca(OH)2, respectively).
substrate, with epichlorohydrin was investigated. The reac-
tions were carried out by employing dry powdered bases
or basic systems such as: NaOH, K2CO3, NaOH/K2CO3
(1:4 mol/mol), NaOH/Al2O3basic (1:4 mol/mol), NaOH/
Ca(OH)2 (1:4 mol/mol). Concerning all reactions performed
under microwave irradiation, it is important to note, that the
power¼60 W was sufficient to maintain the temperature at
a limited imposed value 105–114 ꢁC. The main results and
the reaction conditions are presented in Table 2.
Finally, we showed that the best conditions for O-alkylation
of phenol 1f with epichlorohydrin 2 were obtained by using
the mixture NaOH/K2CO3 (1:4 mol/mol) as basic system,
concerning microwave irradiation and classical heating.
However, using of microwave irradiation result in both sig-
nificantly higher conversion and isolated yield of product 3f
(conv. of 1a¼99% and yield of 3f¼81%) when compared to
classical heating (conv. of 1a¼56% and yield of 3f¼36%),
concerning the same conditions like: time (5 min), tempera-
ture (110 ꢁC) and pressure. On the other hand, changing the
base from pure NaOH (1 mol) or pure K2CO3 (4 mol) to the
mixture of both bases cited NaOH/K2CO3 (1:4 mol/mol)
produce high increase in the reaction rate (conversion in-
creased from 65 and 20 to 99%, respectively) and isolated
yield of 3f (yield of 3f increased from 51% and 16%–81%,
respectively). Finally, changing the base from K2CO3 to
Al2O3basic or to Ca(OH)2 in the mixture with NaOH induces
important decrease in the reaction rate and consequently in
the isolated yield of product 3f. In fact, we observe 70% of
conversion within 15 min when the mixture of NaOH/
Ca(OH)2 was used under microwave irradiation at 114 ꢁC.
On the other hand, the use of NaOH in the mixture with basic
Al2O3 at 112 ꢁC under microwave irradiation results in only
28% of conversion within 7 min. Evidently, in both cases
cited the results obtained under microwave irradiation
were significantly better when compared to classical heating
(8 and 23% conversion within 7 and 15 min, respectively).
It can be clearly seen from Table 2, that it is possible to run
the O-alkylation of phenol 1f with epichlorohydrin 2 by
microwave activation or classical heating using solid–liquid
solvent-free phase transfer catalysis (PTC). Generally, for all
bases the tested results of these reaction were significantly
better in the case of microwave irradiation when compared
to classical heating, concerning conversion, selectivity and
the yield of isolated product 3f. It also indicates the presence
of a specific microwave effect (non-purely thermal) on the
O-alkylation of phenol 1f with epichlorohydrin 2, conform-
ing thus some conclusions already described in the literature
for other types of reactions. In fact, for all the bases tested
conversions of phenol 1f as well as the isolated yields of suit-
able product 3f were significantly higher under microwave
irradiation when compared to classical heating, concerning
the same conditions like: time, temperature and pressure.
It is important to note that, all reactions performed by using
microwave irradiation were totally selective and the suitable
arylglycidyl ether 3f was obtained as an unique product of
the reaction (ratio 3f:4f¼100:0). As expected, the reaction
performed by using NaOH/Ca(OH)2 as basic system is not
totally selective. In this case the traces of by-product 4f
were observed in the reaction mixture by GC analysis (ratio
3f:4f¼97:3). On the other hand, in the case of the reactions
performed by using classical heating, the by-product 4f was
2.2.2. Effects of nature and position of the substituent
on the phenyl ring. Finally, in order to investigate the influ-
ence of the nature and position of the substituent on the
phenyl ring various phenols 1a–j were used as substrates

10972
B. K. Pchelka et al. / Tetrahedron 62 (2006) 10968–10979
Phenol 1a
in O-alkylation with epichlorohydrin 2. All reactions were
carried out in the best conditions previously selected for phe-
nol 1f. In fact, tetrabutylammonium bromide (TBAB) and
the mixture NaOH/K2CO3 (1:4 mol/mol) were used as phase
transfer catalyst and basic system, respectively, concerning
microwave irradiation (MW) and classical heating (D).
The results are collected in Table 3.
120
100
80
microwave irradiation (MW)
classical heating (Δ)
The comparative analysis of the results presented in Table 3
clearly showed that, all reactions performed under micro-
wave irradiation were totally (ratio 3:4¼100:0 and 99:1 for
1a, 1c, 1f, 1i–j and for 1e, 1g–h) or highly selective (ratio
3:4¼95:5 for 1b and 1d). On the other hand, we observe
that the nature of the substituent on the phenyl ring produces
an important effect on the conversion and isolated yield of
product 3. In fact, the excellent yields of product 3 were
obtained (yield of 3¼87–95% within 96–99% conversion),
when the substituent of phenol was an electron-releasing
group (2-CH3–, 3-CH3–, 4-CH3–, 2-CH3O–). However, the
yields of suitable product 3 were significantly lower when
the substituent of the phenol was an electron withdrawing
group such as: 4-Cl–, 2,6-di-Cl– or 2-CN– (yield of
3¼65–68% within 95–99% conversion). It is important to
note that for all phenols 1a–j tested the results of O-alkyl-
ation reaction with epichlorohydrin 2 were significantly bet-
ter under microwave irradiation when compared to classical
heating, concerning the same conditions like: time, temper-
ature and pressure. Finally, the results summarized in Table 3
and Figures 1 and 2 indicates the presence of a specific
microwave effect (non-purely thermal). Figure 1 shows the
course of the conversion of selected phenols, 1a and 1e,
under microwave irradiation (MW) and classical heating
(D), with time. The reactions of 1a and 1e under MW irradi-
ation lead to a nearly 100% conversion within 6 and 11 min,
respectively, with a final temperature of 113 ꢁC. Heating in
an oil bath gave only 48 and 40% conversion, respectively,
under similar conditions of temperature, reaction time and
pressure. The temperature–time profiles for the reactions
of 1a and 1e under MW irradiation and in an oil bath are
shown in Figure 2. It is important to note that, under classical
60
40
20
0
3
6
9
12
15
t (min.)
Phenol 1e
120
100
80
microwave irradiation (MW)
classical heating (Δ)
60
40
20
0
3
6
9
12
15
t (min.)
Figure 2. Thermal behaviour of the reaction mixture for phenols 1a and 1e
under microwave irradiation (MW) and in an oil bath (D).
heating (D) the conversion of 1a can be enhanced up to 63%
by increasing the reaction time to 13 min (Fig. 1).
3. Effects according to reaction mechanism
Generally, microwave effects19 result from material-wave
interactions and, due to the dipolar polarization pheno-
menon, the greater the polarity of a molecule (such as the
solvent) the more pronounced the microwave effect when
the rise in temperature is considered. In terms of reactivity
and kinetics, the specific effect has therefore to be consid-
ered according to the reaction mechanism and particularly
with regard to how the polarity of the system is altered
during the progress of the reaction. Specific microwave
effects can be expected for the polar mechanism, when the
polarity is increased during the reaction from the ground
state (GS) towards the transition state (TS). The outcome
is essentially dependent on the medium and the reaction
mechanism. If stabilization of the transition state (TS) is
more effective than that of the ground state (GS), this results
in an enhancement of reactivity by a decrease in the acti-
vation energy (DGs) (Fig. 3). It is important to note that
this decrease in the activation energy provoke direct increase
in the rate constant (k) according to the Eyring equation:19a
phenol 1a - classical heating (Δ)
phenol 1a - microwave irradiation (MW)
phenol 1e - classical heating (Δ)
phenol 1e - microwave irradiation (MW)
100
80
60
40
20
0
0
3
6
9
12
15
t (min.)
Figure 1. Conversion versus time for the reaction of epichlorohydrin 2 with
phenol 1a and 1e by using of solid–liquid solvent-free phase transfer catal-
ysis under microwave irradiation (MW) or classical heating in an oil bath
(D).
k ¼ A expð ꢀ DGs=RTÞ:

B. K. Pchelka et al. / Tetrahedron 62 (2006) 10968–10979
10973
probably more important for second stage due to more
marked localization of negative charge on the oxygen
atom in the alcoholate 5, which is the intermediate of this
reaction.
≠
≠
ΔGΔ
>
ΔGMO
TS
≠
ΔGΔ
(a)
Mechanism 1:
H
H
-
-
≠
GS
ΔGMO
O
+
ArO--------C------Cl,
n-Bu4N
ArO-, n-Bu4N+
+
Cl
Ground state (GS)
O
Figure 3. Relative stabilization of a more polar TS when compared to the
GS (polar mechanism).
Transition state (TS)
It is important to note that the reaction between any
substituted phenol 1 and epichlorohydrin 2 may be consid-
ered as an anionic bimolecular reaction involving neutral
electrophile, which is epichlorohydrin 2. Generally, this
case of reaction involve the reactivity of anionic species
Nuꢀ associated as ion pairs having several possible struc-
tures with counterions M+. The main results presented in
Table 3 clearly show that the reaction between the phenate
ion (ArOꢀ) and epichlorohydrin 2 reveals two competitive
mechanisms (Schemes 3 and 4):
(b)
Mechanism 2:
-
Stage 1
O
O
ArO-, n-Bu4N+
Cl
+
, n-Bu4N+
Cl
-
Ground state (GS)
ArO
Transition state (TS)
-
Cl
Stage 2
n-Bu4N+
+
Cl
ArO
n-Bu4N+
-
, n-Bu4N
ArO
O-
ArO-
O
n-Bu4N+Cl-
+
OAr
Cl
O
O
5
Transition state (TS)
3
2
Scheme 3.
Scheme 5.
Mechanism 1. One-step nucleophilic substitution (mecha-
nism SN2) with cleavage of C–Cl bond (Scheme 3).
4. Conclusion
Mechanism 2. Ring opening of epichlorohydrin 2 with ArOꢀ
(mechanism SNi) followed by intramolecular cyclization
(SNi) of corresponding alcoholate 5, containing one atom
of chlorine in b-position, formed in situ (Scheme 4).
In this paper we present a general procedure to realize selec-
tive O-alkylation of diversely substituted phenols 1a–j. High
reaction selectivities and high isolated yields of correspond-
ing 3-aryloxy-1,2-epoxypropanes 3a–j were obtained using
solvent-free phase transfer catalysis (PTC) coupled with mi-
crowave irradiation (MW). We have shown that the best con-
ditions for O-alkylation were obtained using the mixture
NaOH/K2CO3 (1:4 mol/mol) as basic system and tetrabutyl-
ammonium bromide (TBAB) as phase transfer catalyst. It is
important to note that the results obtained under microwave
irradiation were much better than those derived from classi-
cal methods described in the literature, concerning selectiv-
ity, conversion and yield of suitable product. Generally, our
procedure is very mild, inexpensive and very easy to operate
and can replace advantageously the classical ones.
In both cases of mechanism (Schemes 3 and 4), the ground-
states (GS) were identical and composed, on the first hand,
of an ion pair between anionic species as ArOꢀ, formed in
situ, and counterions n-Bu4N+ coming from the phase trans-
fer catalyst, and on the other hand, from epichlorohydrin 2.
The transition states (TS) were composed, in both cases of
mechanism, of loose ion pairs in so far as they involve
a charge delocalized anion possessing one atom of chlorine,
thereby conferring an enhancement in polarity with respect
to the ground state (in which the ion pairs are tighter) due
to an increase in anionic dissociation as the more bulky prod-
uct anion formed. As a consequence, specific microwave
effects, directly connected to polarity enhancement were ob-
served (Scheme 5a and b). It is important to note that in the
case of O-alkylation reaction performed in two stages (under
mechanism 2) the conversion and selectivity should be in-
creased under microwave irradiation thanks to acceleration
of both stages and we suppose that this acceleration is
5. Experimental
5.1. General methods
All the commercially available chemicals were obtained
from Aldrich and Fluka. Solvents of analytical-grade quality
were purchased from Lab Scan Ltd. and Aldrich.
SN2
SNi
ArO-, n-Bu4N+
+
n-Bu4N+Cl-
OAr
3
Cl
ArO
n-Bu4N+
Cl
+
O
O
O-
2
5
Scheme 4.

10974
B. K. Pchelka et al. / Tetrahedron 62 (2006) 10968–10979
5.2. Analytical methods
performed under microwave reactor or in an oil bath were
agitated by using mechanical stirring. After cooling to
room temperature, 100 mL of water was added to the reac-
tion mixture to remove mineral salts and the obtained solu-
tion was extracted with diethyl ether (3ꢂ50 mL). The
collected ethereal extract was washed with water and dried
over anhydrous MgSO4. Finally, the organic solution was
evaporated to dryness under reduced pressure. The products,
suitable 3-aryloxy-1,2-epoxypropane 3 and/or by-product
1-chloro-3-aryloxypropan-2-ol 4, were purified by flash
chromatography on silica gel with n-hexane/ethyl acetate
(10:1 and 15:1 v/v, for phenol 1a–d,1g–h and 1e–f,1i–j,
respectively) as the eluent. The purity of products was
checked by GC analysis and their structure was confirmed
by 1H, 13C NMR and MS spectra, IR data as well as
micro-analyses. 1H and 13C NMR spectra of 3-aryloxy-
1,2-epoxypropanes 3a–j were identical with those presented
Microanalyses were performed by the Laboratoire Central
de Microanalyse du CNRS, Gif sur Yvette, France. 1H
(200 or 250 MHz) and 13C (50.23 or 62.9 MHz) NMR spec-
tra were recorded on Bruker AC-200 or 250 spectrometer in
CDCl3 with TMS as an internal standard. Chemical shifts (d)
are given in parts per million. Gas chromatographic analyses
were run on a 6000 Vega Series instrument equipped with
a FID detector and Spectra-Physics SP 4290 integrator and
an OV1 column (12 m). The detector and the injector tem-
peratures were set at 300 ꢁC and 290 ꢁC, respectively. Col-
umn tempeꢀra1ture was programmed in the range 70–280ꢀꢁ1C
(10 ꢁC min ) for 3a and 4a, and 100–280 ꢁC (10 ꢁC min
)
for 3b–j, and 4b–j. The retention times (tR/min) were as fol-
lows for 3-aryloxy-1,2-epoxypropanes: 3a: 5.18; 3b: 4.29;
3c: 4.32; 3d: 4.51; 3e: 5.47; 3f: 5.63; 3g: 9.21; 3h: 5.32;
3i: 6.37; 3j: 6.01 and were as follows for corresponding
1-chloro-3-aryloxypropan-2-ols: 4a: 7.15; 4b: 5.93; 4c:
5.66; 4d: 6.51; 4e: 7.35; 4f: 7.18; 4g: 11.36; 4h: 6.94; 4i:
8.23; 4j: 8.33. Column chromatography was performed on
Merck silica gel 60 (230–400 mesh). TLC was carried out us-
ing glass sheets pre-coated with silica gel 60 F254 prepared by
Merck. The reaction under microwave irradiations was per-
formed in a monomode microwave reactor (Synthewave 402
from Prolabo), fitted with a stirring system and an IR temper-
ature detector, which indicates the surface temperature.
1
in the literature. H, 13C NMR and MS spectra, IR data as
well as micro-analyses of 3a–j are as follows.
5.4.1. 3a: 1,2-Epoxy-3-phenoxypropane.
O
1
9
6
O
8
7
2
4
5
3
1H NMR (250 MHz, CDCl3, ppm): d 2.74–2.81 (1H, dd,
Jgem¼4.89 Hz, J1–2¼2.70 Hz, H1), 2.80–2.91 (1H, m,
H10), 3.35–3.46 (1H, m, H2), 3.80–4.10 (1H, dd,
Jgem¼11.0 Hz, J3–2¼5.40 Hz, H3), 4.18–4.32 (1H, dd,
5.3. Typical O-alkylation procedure of phenols 1a–i with
epichlorohydrin under classical conditions (aqueous
solution of NaOH)
Jgem¼10.99 Hz, J3 –2¼2.99 Hz, H30), 6.70–7.09 (3H, m,
0
To a stirred solution of 9.6 g of sodium hydroxide (0.24 mol)
in 100 mL of water, 0.19 mol of the phenol 1 (0.19 mol) was
added. The solution was stirred for 15 min at room temper-
ature and the alkylating agent, epichlorohydrin (0.24 mol,
22.2 g) was added. The final solution was stirred under reflux
and monitored by thin layer chromatography (TLC). After
the appropriate time (Table 1), the stirring was stopped
and the reaction solution was extracted with diethyl ether
(3ꢂ50 mL). The collected solutions were dried over anhy-
drous MgSO4 and evaporated to dryness under reduced
pressure. The crude mixture of two products, 3-aryloxy-
1,2-epoxy-propane 3 and by-product 1-chloro-3-aryloxypro-
pan-2-ol 4, was separated by flash chromatography on silica
gel with n-hexane/ethyl acetate (10:1 and 15:1 v/v, for phe-
nol 1a–d,1g–h and 1e–f,1i, respectively) as the eluent.
H5, H7, H9), 7.13–7.42 (2H, m, H6, H8); 13C NMR
(62.9 MHz, CDCl3, ppm): d 44.36 (CH2, Cl), 68.50 (CH2,
C3), 114.52 (Carom, C5, C9), 120.99 (Carom, C7), 130.41
(Carom, C6, C8), 156.73 (Carom, C4). IR (neat, cmꢀ1):
O
1245 cmꢀ1
71.98; H, 6.71. Found: C, 71.91; H, 6.61. MS (electr.
:
C; Anal. Calcd for C9H10O2 (150.17): C,
C
ꢃ
impact, 70 eV, m/z): (M)+ ¼150 (53), (MꢀCH2O)+¼120
(13.6), (MꢀC2H3O)+¼107 (13), (MꢀC3H4O)+¼94 (64),
(MꢀC3H5O2)+¼77 (41.8), (MꢀC4H5O2)+¼65 (31), (Mꢀ
C6H7O2)+¼39 (100). Colourless oil, bp¼244–246 ꢁC,
bpLit.¼245 ꢁC.20a
5.4.2. 3b: 1,2-Epoxy-3-(2-methylphenoxy)propane.
O
1
9
6
O
8
7
2
4
5.4. Typical O-alkylation procedure for phenols 1a–j
with epichlorohydrin using solvent-free phase transfer
catalysis conditions (PTC) under microwave irradiation
and classical heating
3
10
5
1H NMR (200 MHz, CDCl3, ppm): d 2.26 (3H, s, H10),
2.72–2.84 (1H, dd, Jgem¼4.96 Hz, J1–2¼2.61 Hz, H1),
2.85–2.95 (1H, m, H10), 3.30–3.41 (1H, m, H2), 3.88–4.05
(1H, dd, Jgem¼11.07 Hz, J3–2¼5.44 Hz, H3), 4.15–4.30
(2H, m, H7, H9), 7.05–7.20 (2H, m, H6, H8); 13C NMR
(50.23 MHz, CDCl3, ppm): d 16.13 (CH3, Cl0), 44.56
Into a Pyrex tube (2 cm diameter) were introduced 20 mmol
of phenol 1, 0.8 g (20 mmol) of powdered sodium hydrox-
ide, 11.6 g (80 mmol) of anhydrous potassium carbonate
and 0.6 g (2 mmol) of tetrabutylammonium bromide
(TBAB). After stirring at room temperature during 2 min,
2.76 g (30 mmol) of epichlorohydrin was added. The reac-
tion mixture was either introduced into the monomode
microwave reactor (Synthewave 402 from Prolabo, power¼
60 W) or in a thermostated oil bath for the times indicated
in Tables 2 and 3. It is important to note that all reactions
(1H, dd, Jgem¼11.09 Hz, J3 –2¼3.04 Hz, H30), 6.70–6.92
0
(CH2, Cl), 50.25 (CH, C2), 68.55 (CH2, C3), 111.13 (Carom
C9), 120.82 (Carom, C7), 126.69 (Carom, C8), 126.93 (Carom
,
,
C5), 130.71 (Carom, C6), 156.53 (Carom, C4). IR (neat,
cmꢀ1): 1240 cmꢀ1
O
:
C; Anal. Calcd for C10H12O2
C

B. K. Pchelka et al. / Tetrahedron 62 (2006) 10968–10979
10975
O
(164.20): C, 73.15; H, 7.36. Found: C, 73.02; H, 7.28. Col-
ourless oil, bp¼109–110 ꢁC/0.2 mmHg.
C; Anal. Calcd for C9H9O2Cl (184.62): C, 58.55; H,
4.91. Found: C, 58.41; H, 4.78; MS (electr. impact, 70 eV,
C
ꢃ
m/z): (M+2)+¼186 (26), (M)+ ¼184 (73), (MꢀCH2O)+¼154
(11.5), (MꢀC2H3O)+¼141 (21.7), ([M+2]ꢀC3H4O)+¼130
(26.5), (MꢀC3H4O)+¼128 (100), (MꢀC3H5O2)+¼111
(26), (MꢀC4H5O2)+¼99 (17.8). Yellowish oil, bp¼110–
114 ꢁC/0.1 mmHg.
5.4.3. 3c: 1,2-Epoxy-3-(3-methylphenoxy)propane.
O
1
9
O
8
7
2
4
5
3
6
5.4.6. 3f: 1,2-Epoxy-3-(4-chloro-3-methylphenoxy)propane.
10
O
1
9
O
8
1H NMR (250 MHz, CDCl3, ppm): d 2.34 (3H, s, H10),
2.71–2.81 (1H, dd, Jgem¼4.95 Hz, J1–2¼2.62 Hz, H1),
2.84–2.93 (1H, m, H10), 3.31–3.43 (1H, m, H2), 3.83–4.01
(1H, dd, Jgem¼11.10 Hz, J3–2¼5.36 Hz, H3), 4.13–4.28
(3H, m, H5, H7, H9), 7.18 (1H, m, H8); 13C NMR
(62.9 MHz, CDCl3, ppm): d 21.63 (CH3, Cl0), 44.61 (CH2,
Cl), 50.09 (CH, C2), 68.83 (CH2, C3), 112.00 (Carom, C9),
2
4
5
3
7
Cl
6
10
(1H, dd, Jgem¼11.13 Hz, J3 –2¼3.10 Hz, H30), 6.76–7.92
0
1H NMR (250 MHz, CDCl3, ppm): d 2.39 (3H, s, H10),
2.68–2.80 (1H, dd, Jgem¼4.89 Hz, J1–2¼2.74 Hz, H1),
2.90–2.98 (1H, m, H10), 3.33–3.47 (1H, m, H2), 3.78–4.03
(1H, dd, Jgem¼11.06 Hz, J3–2¼5.69 Hz, H3), 4.12–4.29
114.99 (Carom, C5), 122.12 (Carom, C7), 129.43 (Carom
C8), 139.82 (Carom, C6), 157.99 (Carom, C4). IR (neat,
,
(1H, dd, Jgem¼11.01 Hz, J3 –2¼2.99 Hz, H30), 6.69–6.94
0
(2H, m, H5, H9), 7.21–7.28 (1H, m, H8); 13C NMR
(62.9 MHz, CDCl3, ppm): d 20.54 (CH3, Cl0), 44.59 (CH2,
Cl), 53.17 (CH, C2), 68.76 (CH2, C3), 113.23 (Carom, C9),
O
cmꢀ1): 1244 cmꢀ1
:
C; Anal. Calcd for C10H12O2
C
(164.20): C, 73.15; H, 7.36. Found: C, 73.09; H, 7.24.
Colourless oil, bp¼112–113 ꢁC/0.1 mmHg, bpLit.¼112–
115 ꢁC/0.1 mmHg.10
116.96 (Carom, C5), 127.00 (Carom, C7), 129.64 (Carom,
C8), 137.46 (Carom, C6), 156.24 (Carom, C4). IR (neat,
O
cmꢀ1): 1237 cmꢀ1
:
C; Anal. Calcd for C10H11O2Cl
C
5.4.4. 3d: 1,2-Epoxy-3-(4-methylphenoxy)propane.
(198.65): C, 60.46; H, 5.58. Found: C, 60.35; H, 5.49.
Colourless oil, bp¼120–121 ꢁC/0.1 mmHg, bpLit.¼119–
123 ꢁC/0.1 mmHg.20b
O
9
O
8
2
4
5
1
3
5.4.7. 3g: 1,2-Epoxy-3-(1-naphthoxy)propane.
10
7
6
10
11
12
9
8
1H NMR (250 MHz, CDCl3, ppm): d 2.28 (3H, s, H10),
2.70–2.81 (1H, dd, Jgem¼4.92 Hz, J1–2¼2.60 Hz, H1),
2.86–2.95 (1H, m, H10), 3.28–3.40 (1H, m, H2), 3.85–4.02
(1H, dd, Jgem¼11.02 Hz, J3–2¼5.59 Hz, H3), 4.12–4.22
(2H, m, H5, H9), 7.03–7.15 (2H, m, H6, H8); 13C NMR
(62.9 MHz, CDCl3, ppm): d 20.42 (CH3, Cl0), 44.70 (CH2,
Cl), 50.17 (CH, C2), 68.77 (CH2, C3), 114.41 (Carom, C5,
O
1
O
2
4
5
13
7
3
6
(1H, dd, Jgem¼11.04 Hz, J3 –2¼3.23 Hz, H30), 6.77–6.89
0
1H NMR (200 MHz, CDCl3, ppm): d 2.80–2.90 (1H, dd,
Jgem¼4.93 Hz, J1–2¼2.65 Hz, H1), 2.92–3.01 (1H, m, H10),
3.42–3.55 (1H, m, H2), 4.03–4.18 (1H, dd, Jgem¼11.07 Hz,
J3–2¼5.61 Hz, H3), 4.32–4.45 (1H, dd, Jgem¼11.08 Hz,
C9), 129.88 (Carom, C6, C8), 130.40 (Carom, C7), 156.31
:
J3 –2¼3.02 Hz, H30), 6.75–6.87 (1H, m, H5), 7.34–7.61
0
O
(Carom, C4). IR (neat, cmꢀ1): 1245 cmꢀ1
for C10H12O2 (164.20): C, 73.15; H, 7.36. Found: C,
C; Anal. Calcd
C
(4H, m, H6, H7, H10, H11), 7.80–7.90 (1H, m, H9), 8.31–
8.45 (1H, m, H8). 13C NMR (62.9 MHz, CDCl3, ppm):
d 44.83 (CH2, Cl), 50.20 (CH, C2), 69.89 (CH2, C3),
73.07; H, 7.26. Colourless oil, bp¼121–126 ꢁC/0.2 mmHg.
104.05 (Carom, C5), 119.80 (Carom, C7), 120.85 (Carom,
C11), 125.10 (Carom, C10), 125.48 (Carom, C6, C12), 126.45
5.4.5. 3e: 1,2-Epoxy-3-(4-chlorophenoxy)propane.
(Carom, C9), 127.32 (Carom, C8), 135.00 (Carom, C13), 154.67
(Carom, C4). IR (neat, cmꢀ1): 1248 cmꢀ1
Calcd for C13H12O2 (200.24): C, 77.98; H, 6.04. Found: C,
77.86; H, 5.92. Colourless oil, bp¼148–149 ꢁC/0.5 mmHg,
bpLit.¼145–149 ꢁC/0.5 mmHg.20c
O
:
C; Anal.
O
1
9
6
C
O
8
2
4
5
3
7
Cl
1H NMR (250 MHz, CDCl3, ppm): d 2.70–2.82 (1H, dd,
Jgem¼4.87 Hz, J1–2¼2.71 Hz, H1), 2.87–2.98 (1H, m, H10),
3.29–3.45 (1H, m, H2), 3.80–4.01 (1H, dd, Jgem¼11.02 Hz,
J3–2¼5.77 Hz, H3), 4.15–4.30 (1H, dd, Jgem¼11.00 Hz,
(2H, m, H6, H8); 13C NMR (62.9 MHz, CDCl3, ppm):
d 44.53 (CH2, Cl), 49.98 (CH, C2), 68.98 (CH2, C3),
5.4.8. 3h: 1,2-Epoxy-3-(2-methoxyphenoxy)propane.
O
1
9
O
O
8
7
2
4
3
J3 –2¼2.97 Hz, H30), 6.80–6.95 (2H, m, H5, H9), 7.18–7.32
0
5
6
10
115.84 (Carom, C5, C9), 126.02 (Carom, C7), 129.31 (Carom
C6, C8), 157.00 (Carom, C4). IR (neat, cmꢀ1): 1240 cmꢀ1
,
:
1H NMR (250 MHz, CDCl3, ppm): d 2.67–2.82 (1H, m, H1),
2.83–2.98 (1H, m, H10), 3.31–3.49 (1H, m, H2), 3.87 (3H, s,

10976
B. K. Pchelka et al. / Tetrahedron 62 (2006) 10968–10979
H10), 3.98–4.11 (1H, dd, Jgem¼11.40 Hz, J3–2¼5.61 Hz,
H30), 6.78–7.05 (4H, m, H6, H7, H8, H9). 13C NMR
(62.9 MHz, CDCl3, ppm): d 44.92 (CH2, Cl), 50.15 (CH,
5.4.10.1. 4a: 1-Chloro-3-phenoxypropan-2-ol.
0
H3), 4.17–4.32 (1H, dd, Jgem¼11.42 Hz, J3 –2¼3.58 Hz,
OH
9
O
Cl
8
7
2
4
5
1
3
C2), 55.80 (CH3, C10), 70.13 (CH2, C3), 111.83 (Carom
C6), 114.12 (Carom, C9), 120.76 (Carom, C7), 121.86 (Carom
,
,
6
C8), 147.88 (Carom, C5), 149.54 (Carom, C4). IR (neat,
:
1H NMR (250 MHz, CDCl3, ppm): d 2.49 (1H, s, OH), 3.75
(2H, d, J1–2¼3.98 Hz, H1), 4.11–4.27 (3H, m, H2, H3),
6.67–6.98 (3H, m, H5, H7, H9), 7.08–7.35 (2H, m, H6,
H8). IR (neat, cmꢀ1): 3400 cmꢀ1: OH; Anal. Calcd for
C9H11O2Cl (186.64): C, 57.92; H, 5.94. Found: C, 57.85;
H, 5.84. MS (electr. impact, 70 eV, m/z): (M+2)+¼188
O
cmꢀ1): 1245 cmꢀ1
(180.20): C, 66.65; H, 6.71. Found: C, 66.53; H, 6.58.
C; Anal. Calcd for C10H12O3
C
ꢃ
MS (electr. impact, 70 eV, m/z): (M)+ ¼180 (99.7),
(MꢀCH2O)+¼150 (11.8), (MꢀC2H3O)+¼137 (20.00),
(MꢀC3H4O)+¼124 (48), (MꢀC3H5O)+¼123 (15.7),
(MꢀC3H6O)+¼122 (21.8), (MꢀC3H7O)+¼121 (25),
(MꢀC4H7O)+¼109 (100), (MꢀC4H8O2)+¼92 (13),
(MꢀC4H7O3)+¼77 (83.10), (MꢀC5H7O3)+¼65 (34.70),
(MꢀC5H8O3)+¼64 (25.90), (MꢀC5H9O3)+¼63 (35.40),
(MꢀC6H8O3)+¼52 (87), (MꢀC6H9O3)+¼51 (55.90). Yel-
lowish oil, bp¼110–114 ꢁC/0.03 Torr, bpLit.¼115–116 ꢁC/
0.03 Torr.20d
ꢃ
(5.40), (M)+ ¼186 (18), (MꢀCH3OCl)+¼119 (7.30),
(MꢀC2H3OCl)+¼108
(5.90),
(MꢀC2H4OCl)+¼107
(25.70), (MꢀC3H4OCl)+¼95 (24.50), (MꢀC3H5OCl)+¼94
(74), (MꢀC3H6O2Cl)+¼77 (100), (MꢀC4H5O2Cl)+¼66
(30), (MꢀC4H6O2Cl)+¼65 (26). Colourless oil.
5.4.10.2. 4b: 1-Chloro-3-(2-methylphenoxy)propan-2-ol.
5.4.9. 3i: 1,2-Epoxy-3-(2,6-bischlorophenoxy)propane.
OH
9
O
Cl
8
7
2
4
1
3
Cl
O
10
9
5
O
8
6
2
4
1
3
1H NMR (250 MHz, CDCl3, ppm): d 2.14 (3H, s, H10), 2.45
(1H, s, OH), 3.84 (2H, d, J1–2¼4.07 Hz, H1), 4.11–4.36 (3H,
m, H2, H3), 6.77–6.90 (2H, m, H7, H9), 7.09–7.24 (2H, m,
H6, H8). IR (neat, cmꢀ1): 3390 cmꢀ1: OH; Anal. Calcd for
C10H13O2Cl (200.66): C, 59.86; H, 6.53. Found: C, 59.79; H,
6.46. Colourless oil.
7
Cl
5
6
1H NMR (250 MHz, CDCl3, ppm): d 2.68–2.75 (1H, dd,
Jgem¼4.90 Hz, J1–2¼2.57 Hz, H1), 2.86–2.95 (1H, m, H10),
3.40–3.51 (1H, m, H2), 3.98–4.12 (1H, dd, Jgem¼10.91 Hz,
J3–2¼5.97 Hz, H3), 4.17–4.28 (1H, dd, Jgem¼10.95 Hz,
J3 –2¼3.69 Hz, H30), 6.92–7.08 (1H, m, H7), 7.22–7.35
5.4.10.3. 4c: 1-Chloro-3-(3-methylphenoxy)propan-2-ol.
0
(2H, m, H6, H8); 13C NMR (62.9 MHz, CDCl3, ppm):
d 44.59 (CH2, Cl), 50.03 (CH, C2), 74.31 (CH2, C3),
OH
9
O
Cl
8
7
2
4
5
125.33 (Carom, C7), 128.90 (Carom, C6, C8), 129.34 (Carom
C5, C9), 151.01 (Carom, C4). IR (neat, cmꢀ1): 1247 cmꢀ1
,
:
1
3
6
O
C; Anal. Calcd for C9H8O2Cl2 (219.07): C, 49.34;
H, 3.68. Found: C, 49.26; H, 3.56. Yellowish oil.
C
10
1H NMR (250 MHz, CDCl3, ppm): d 2.24 (3H, s, H10), 2.51
(1H, s, OH), 3.73 (2H, d, J1–2¼4.11 Hz, H1), 4.09–4.30 (3H,
m, H2, H3), 6.63–6.78 (3H, m, H5, H7, H9), 7.10 (1H, m,
H8). IR (neat, cmꢀ1): 3400 cmꢀ1: OH; Anal. Calcd for
C10H13O2Cl (200.66): C, 59.86; H, 6.53. Found: C, 59.76;
H, 6.50. Colourless oil.
5.4.10. 3j: 1,2-Epoxy-3-(2-cyanophenoxy)propane.
O
1
9
6
O
8
7
2
4
3
5 CN
5.4.10.4. 4d: 1-Chloro-3-(4-methylphenoxy)propan-2-ol.
1H NMR (250 MHz, CDCl3, ppm): d 2.74–2.80 (1H, dd,
Jgem¼4.78 Hz, J1–2¼2.76 Hz, H1), 2.85–2.96 (1H, m, H10),
3.28–3.46 (1H, m, H2), 3.10–4.18 (1H, dd, Jgem¼11.12 Hz,
J3–2¼5.76 Hz, H3), 4.17–4.48 (1H, dd, Jgem¼11.13 Hz,
13C NMR (62.9 MHz, CDCl3, ppm): d 43.28 (CH2, Cl),
48.70 (CH, C2), 69.90 (CH2, C3), 97.91 (Carom, C5),
114.62 (Carom, C9), 118.51 (CN, C10), 121.61 (Carom, C7),
OH
9
O
Cl
8
2
4
5
1
3
10
7
6
J3 –2¼3.06 Hz, H30), 6.98–7.39 (4H, m, H6, H7, H8, H9);
0
1H NMR (250 MHz, CDCl3, ppm): d 2.19 (3H, s, H10), 2.43
(1H, s, OH), 3.78 (2H, d, J1–2¼3.99 Hz, H1), 4.12–4.32 (3H,
m, H2, H3), 6.70–6.90 (2H, m, H5, H9), 7.09–7.24 (2H, m,
H6, H8). IR (neat, cmꢀ1): 3400 cmꢀ1: OH; Anal. Calcd for
C10H13O2Cl (200.66): C, 59.86; H, 6.53. Found: C, 59.80; H,
6.45. Colourless oil.
133.08 (Carom, C6), 133.77 (Carom, C8), 162.80 (Carom, C4).
IR (neat, cmꢀ1): 1245 cmꢀ1
O
:
C; Anal. Calcd for
C
C10H9NO2 (175.18): C, 68.56; H, 5.18; N, 8.00. Found: C,
68.43; H, 5.03; N, 7.92. Colourless oil, bp¼128–129 ꢁC/
0.1 mmHg, bpLit.¼124–127 ꢁC/0.1 mmHg.10
1H NMR (and MS for 4a) spectra, IR data as well as micro-
analyses of 1-chloro-3-aryloxypropan-2-ols 4a–j are as
follows.
5.4.10.5. 4e: 1-Chloro-3-(4-chlorophenoxy)propan-2-ol.
OH
9
O
Cl
8
2
4
5
1
3
Cl
7
6

B. K. Pchelka et al. / Tetrahedron 62 (2006) 10968–10979
10977
1H NMR (250 MHz, CDCl3, ppm): d 2.50 (1H, s, OH), 3.76
(2H, d, J1–2¼4.06 Hz, H1), 4.05–4.41 (3H, m, H2, H3),
6.78–6.89 (2H, m, H5, H9), 7.15–7.29 (2H, m, H6, H8).
IR (neat, cmꢀ1): 3400 cmꢀ1: OH; Anal. Calcd for
C9H10O2Cl2 (221.08): C, 48.90; H, 4.56. Found: C, 48.78;
H, 4.50. Yellowish oil.
(neat, cmꢀ1): 3400 cmꢀ1: OH; Anal. Calcd for C9H9O2Cl3
(255.53): C, 42.30; H, 3.55. Found: C, 42.21; H, 3.45. Col-
ourless oil.
5.4.10.10. 4j: 1-Chloro-3-(2-cyanophenoxy)propan-
2-ol.
OH
9
5.4.10.6. 4f: 1-Chloro-3-(4-chloro-3-methylphenoxy)-
propan-2-ol.
O
Cl
8
7
2
4
1
3
5 CN
6
OH
9
O
Cl
8
2
1H NMR (250 MHz, CDCl3, ppm): d 2.38 (1H, s, OH), 3.81
(2H, d, J1–2¼4.19 Hz, H1), 4.09–4.36 (3H, m, H2, H3),
6.80–7.31 (4H, m, H6, H7, H8, H9). IR (neat, cmꢀ1):
3400 cmꢀ1: OH; Anal. Calcd for C10H10O2ClN (211.65):
C, 56.75; H, 4.76. Found: C, 56.67; H, 4.66. Colourless oil.
4
5
1
3
Cl
7
6
10
1H NMR (250 MHz, CDCl3, ppm): d 2.29 (3H, s, H10), 2.70
(1H, s, OH), 3.68 (2H, d, J1–2¼3.87 Hz, H1), 4.03–4.32 (3H,
m, H2, H3), 6.53–6.79 (2H, m, H5, H9), 7.16–7.26 (1H, m,
H8). IR (neat, cmꢀ1): 3400 cmꢀ1: OH; Anal. Calcd for
C10H12O2Cl2 (235.11): C, 51.09; H, 5.14. Found: C, 50.95;
H, 5.09. Yellowish oil.
Acknowledgements
We thank the Universite Paris XI (Orsay), which provided
support towards the cost for part of this work.
5.4.10.7. 4g: 1-Chloro-3-(1-naphthoxy)propan-2-ol.
10
11
References and notes
9
8
OH
2
12
O
Cl
4
5
13
1
3
1. (a) Gedye, R.; Smith, F.; Westaway, K.; Ali, H.; Baldisera, L.;
Laberge, L.; Roussel, J. Tetrahedron Lett. 1986, 27, 279; (b)
Loupy, A. Microwave in Organic Synthesis; Wiley-VCH:
Weinheim, 2006.
2. Giguere, R. J.; Bray, T. L.; Duncan, S. M.; Majetich, G.
Tetrahedron Lett. 1986, 27, 4945.
3. (a) Thuillier, F. M.; Jullien, H.; Grenier-Loustalot, M. F.
Makromol. Chem., Macromol. Symp. 1987, 9, 57; (b) Hwang,
D. R.; Moerlein, S. M.; Welch, M. J. J. Chem. Soc., Chem.
Commun. 1987, 1799; (c) Vanderhoff, J. W. U.S. Patent
3,432,413; Chem. Abstr. 1969, 70, 22; (d) Gourdenne, A.;
Maassaran, A. H.; Monchaux, P.; Aussudre, S.; Thourel, L.
Polym. Prepr. 1979, 20, 471; (e) Gourdenne, A.; Le Van, Q.
Polym. Prepr. 1981, 22, 125; (f) Jullien, H.; Valot, H.
Polymer 1983, 24, 810; (g) Loupy, A.; Song, S. J.; Cho, S. J.;
Park, D. K.; Kwon, T. W. Synth. Commun. 2005, 35, 79; (h)
7
6
1H NMR (250 MHz, CDCl3, ppm): d 2.63 (1H, d,
J¼5.48 Hz, OH), 3.84 (2H, d, J1–2¼4.05 Hz, H1), 4.23–
4.48 (3H, m, H2, H3), 6.68 (1H, m, H5), 7.26–7.71 (4H,
m, H6, H7, H10, H11), 7.70–7.89 (1H, m, H9), 8.13–8.22
(1H, m, H8). IR (neat, cmꢀ1): 3400 cmꢀ1: OH; Anal. Calcd
for C13H13O2Cl (236.70): C, 65.97; H, 5.54. Found: C,
65.89; H, 5.44. Colourless oil.
5.4.10.8. 4h: 1-Chloro-3-(2-methoxyphenoxy)propan-
2-ol.
OH
9
O
Cl
8
7
2
4
1
3
5
´
ꢀ
O
Micro-ondes et Hautes Frequences; Congres International:
Nice, France, 8–10 Octobre, 1991; Vol. 1 cours, pp 9–571; (i)
Wan, J. K. S. U.S. Patent 1,159,010, 1983; (j) Wan, J. K. S.;
Wolf, K.; Heyding, R. D. Catalysis on the Energy Scene;
Elsevier: Amsterdam, 1984; pp 561–568; (k) Wan, J. K. S.;
Kriz, J. F. U.S. Patent 4,545,879, 1985; (l) Wan, J. K. S. U.S.
Patent 4,574,083, 1986; (m) Mingos, D. M. P.; Baghurst,
D. R. Chem. Soc. Rev. 1991, 20, 1; (n) Yat Tse, M.; Depew,
M. C.; Wan, J. K. S. Res. Chem. Intermed. 1990, 13, 221; (o)
Hesek, J. A.; Wilson, R. C. Anal. Chem. 1974, 46, 1160; (p)
Kingston, H. M.; Jassie, L. B. Anal. Chem. 1986, 58, 2534;
(r) Fischer, L. B. Anal. Chem. 1986, 58, 261; (s) Grillo, A. C.
Spectroscopy 1988, 4, 16; (t) Katsuta, A. Japan Kokai JP
5,102,7893, 1976; Chem. Abstr. 87, 70374; (u) Mukai, A.;
Tanaka, M.; Ikeda, A., Japan Kokai JP 5,103,7890; Chem.
Abstr. 85, 35167; (w) Goerz, D. J.; Leonard, B. H., Jr. U.S.
Patent 3,523,076; (x) Labrador, J.; Laviec, J.; Lorthioir-
Pommier, J. Prod. Probl. Pharm. 1971, 622.
6
10
1H NMR (250 MHz, CDCl3, ppm): d 2.50 (1H, s, OH), 3.72
(2H, d, J1–2¼3.98 Hz, H1), 3.89 (3H, s, H10), 4.14–4.35
(3H, m, H2, H3), 6.71–7.10 (4H, m, H6, H7, H8, H9). IR
(neat, cmꢀ1): 3400 cmꢀ1
:
OH; Anal. Calcd for
C10H13O3Cl (216.66): C, 55.44; H, 6.05. Found: C, 55.36;
H, 5.91. Colourless oil.
5.4.10.9. 4i: 1-Chloro-3-(2,6-bischlorophenoxy)propan-
2-ol.
Cl
OH
2
9
O
Cl
8
7
4
1
3
5 Cl
6
1H NMR (250 MHz, CDCl3, ppm): d 2.46 (1H, s, OH), 3.62
(2H, d, J1–2¼4.15 Hz, H1), 4.20–4.33 (3H, m, H2, H3),
6.89–7.06 (1H, m, H7), 7.19–7.31 (2H, m, H6, H8). IR
4. Loupy, A.; Haudrechy, A. Effets de Milieu en Syntheꢀse
Organique; Masson: Paris, 1996.

10978
B. K. Pchelka et al. / Tetrahedron 62 (2006) 10968–10979
5. (a) Lewis, D. A.; Summers, J. D.; Ward, T. C.; McGrath, J. E.
J. Polym. Sci., Part A 1992, 30, 1647; (b) Berlan, J.; Giboreau,
P.; Lefeuvre, S.; Marchand, C. Tetrahedron Lett. 1991, 32,
2363.
Boron, A. Synth. Commun. 1998, 28, 3029; (c) Bratulesu, G.;
Le Bigot, Y.; Delmas, M.; Pogany, L. Rev. Roum. Chim.
1998, 43, 321; (d) Bogdal, D.; Pielichowski, J.; Boron, A.
Synth. Commun. 1998, 28, 3029; (e) Bogdal, D.; Warzala, M.
Tetrahedron 2000, 56, 8769; (f) Mariani, E.; Genta, M. T.;
Bargagna, A.; Neuhoff, C.; Loupy, A.; Petit, A. In
Application of the Microwave Technology to Synthesis and
Materials Processing; Mucchi Editore: Modena, 2000; p 157;
(g) Villa, C.; Genta, M. T.; Bargagna, A.; Mariani, E.; Loupy,
A. Green Chem. 2001, 3, 196; (h) Reddy, Y. T.; Rao, M. K.;
Rajitha, B. Indian J. Heterocycl. Chem. 2000, 10, 73; (i)
Oussaid, A.; Pentek, E.; Loupy, A. New J. Chem. 1997, 21,
1339; (j) Wang, J.-X.; Zhang, M.; Hu, Y. Synth. Commun.
1998, 28, 2407; (k) Wang, J.-X.; Zhang, M.; Xing, Z.; Hu, Y.
Synth. Commun. 1996, 26, 301; (l) Li, J.; Pang, J.; Gao, G.;
Xi, Z. Synth. Commun. 2000, 30, 1337; (m) Jiang, Y.-L.; Hu,
Y.-Q.; Pang, J.; Yuan, Y.-Ch. J. Am. Oil Chem. Soc. 1996, 73,
847; (n) Khadilkar, B. M.; Bendale, P. M. Synth. Commun.
1997, 27, 2051; (o) Vass, A.; Toth, J.; Pallai-Varsanyi, E.
Effect of Inorganic Solid Support for Microwave Assisted
Organic Reactions. International Conference on Microwave
Chemistry, Prague, Tcheque Republic, 6–11 Septembre,
1998; pp 42–43; (p) Varma, R. S. Green Chem. 1999, 1, 43.
15. (a) Bradley, W.; Forest, J.; Stephenson, O. J. Chem. Soc. 1951,
1589; (b) Stephenson, O. J. Chem. Soc. 1954, 1571.
16. (a) Fischer, E. Chem.-Ztg. 1973, 97, 635; Chem. Abstr. 80,
95413; (b) Gupta, V. S.; Ghosh, P. K.; Guha Sarkar, D. K.;
Dutta, B. K. Technology 1973, 9, 392; (c) Obase, H.;
Tatsuno, H.; Goto, K.; Shigenobu, K.; Kasuya, Y.; Yamada,
Y.; Fujii, K.; Yada, S. Chem. Pharm. Bull. 1978, 26, 1443;
(d) Erhard, P. W.; Woo, C. M.; Gorczynski, R. J.; Anderson,
W. G. J. Med. Chem. 1982, 25, 1402; (e) Newman, M. S.;
Fones, W.; Renoll, M. J. Am. Chem. Soc. 1947, 69, 718; (f)
Schmolka, S. J.; Zimmer, H. Synthesis 1984, 29; (g) Schulz,
H. Pharmazie 1968, 23, 240; (h) Bevinakatti, H. S.; Banerji,
A. A. J. Org. Chem. 1991, 56, 5372; (i) Sittig, M.
Pharmaceutical Manufacturing Encyclopedia; Noyes
Publications: Park Ridge, NJ, 1988; Chapter 2, p 1314; (j)
Crowther, A. F.; Smith, L. H. (ICI Chem. Ind. Ltd.). U.S.
Patent 3,337,628, 1967; (k) Smith, D. R. (Dow Chemical
Co., USA). Jp. Patent 5,100,6125, 1976; Chem. Abstr. 85,
178382; (l) Wiesner, I.; Kroupa, J. Czech Patent 146,646,
1972; Chem. Abstr. 78, 147557; (m) DiMenna, W. S.;
Piantadosi, C. J. Med. Chem. 1978, 21, 1073; (n) Lafon, V.
(Orsymonde, S.A., Fr.). Ger. Offen. 2,166,869, 1976; Chem.
Abstr. 85, 62850; (o) Thai, D. T.; Nguyen, B. L.; Tran, V. D.
Tap Chi Hoa Hoc 1996, 34, 1; Chem. Abstr. 126, 225832; (p)
Stepanyan, M. M.; Vardanyan, V. D.; Torosyan, G. O., et al.
Armyan. Khim. Zh. 1991, 44, 178; Chem. Abstr. 115, 232005;
(q) Murata, Y.; Tanaka, R. Jpn. Kokai Tokkyo Koho 6,315,
9376, 1988; Chem. Abstr. 110, 76266; (r) Monnier, Ch. E.;
Stockinger, F. Eur. Pat. Appl. 226,543, 1987; Chem. Abstr.
108, 6958; (s) Ito, I.; Toyoshima, Y.; Takagishi, H.;
Takahashi, T. Ger. Offen 3,315,365, 1983; Chem. Abstr. 100,
104396.
6. Loupy, A.; Petit, A.; Hamelin, J.; Texier-Boullet, F.; Jacquault,
ꢁ
P.; Mathe, D. Synthesis 1998, 1213.
7. (a) Perreux, L.; Loupy, A. Tetrahedron 2001, 57, 9199; (b)
Loupy, A.; Perreux, L.; Liagre, M.; Burle, K.; Moneuse, M.
Pure Appl. Chem. 2001, 73, 161.
´
8. Jullien, H.; Delmotte, M. Micro-ondes et Hautes Frequences;
Congres International: Nice, France, 8–10 Octobre, 1991;
ꢀ
Vol. 1 cours, pp 654–746.
9. (a) Mingos, D. M. P.; Baghurst, D. R. Microwave Enhanced
Chemistry; Kingston, H. M., Haswell, S. J., Eds.; American
Chemical Society: Washington, DC, 1997; pp 4–7; (b)
Zenatti, P.; Forgeat, M.; Marchand, C.; Rabette, P.
´
Technologie et strategie, Biulletin de l’OTS 1992, 55, 4.
10. Pchelka, B.; Plenkiewicz, J. Org. Prep. Proc. Int. 1998, 30,
87.
11. (a) Loupy, A.; Bram, G.; Sansoulet, J. New J. Chem. 1992, 16,
233; (b) Toda, F. Synlett 1993, 303; (c) Toda, F. Acc. Chem. Res.
1995, 28, 480; (d) Bram, G.; Loupy, A.; Villemin, D. Solid
Supports and Catalysis in Organic Synthesis; Smith, K.,
Ed.; 1992; Chapter 12, p 302; (e) Latouche, R.; Texier-
Boullet, F.; Hamelin, J. Tetrahedron Lett. 1991, 32, 1179; (f)
Pilard, J. F.; Klein, B.; Texier-Boullet, F.; Hamelin, J. Synlett
1992, 219; (g) Rechsteiner, B.; Texier-Boullet, F.; Hamelin,
J. Tetrahedron Lett. 1993, 34, 5071; (h) Bram, G.; Loupy, A.;
Majdoub, M. Synth. Commun. 1990, 20, 125; (i) Handbook
of Phase Transfer Catalysis; Sasson, Y., Neumann, R., Eds.;
Blackie Academic and Professional (Chapman & Hall):
Londres, 1997; (j) Bram, G.; Loupy, A.; Sansoulet, J. Isr. J.
Chem. 1985, 26, 291; (k) Starks, C. M. J. Am. Chem. Soc.
1971, 93, 195; (l) Weber, W. P.; Gokel, W. Phase Transfer
Catalysis in Organic Synthesis, Reactivity and Selectivity
Concept in Organic chemistry; Springer: Berlin, 1977.
12. (a) Heimann, V.; Vogtle, F. Chem. Ber. 1979, 112, 3054; (b)
Dietrich, H. J.; Steiger, E. L. Mol. Cryst. Liq. Cryst. 1972,
16, 263; (c) Neubert, M. E.; Laskos, S. J., Jr.; Maurer, L. J.;
Carlino, L. T.; Ferrato, J. P. Mol. Cryst. Liq. Cryst. 1978, 44,
197; (d) Smith, R. G.; Vanterpool, A.; Kulak, H. J. Can. J.
Chem. 1969, 47, 2015; (e) Mac Killop, A.; Fiaud, J. C.; Hug,
R. P. Tetrahedron 1974, 30, 1379; (f) Ando, T.; Yamawaki,
J.; Kawate, T.; Sumi, S.; Hanafusa, T. Bull. Chem. Soc. Jpn.
1982, 55, 2504; (g) Mac Kenzie, W. M.; Sherrington, D. C.
J. Chem. Soc., Chem. Commun. 1978, 541; (h) Liu, Z.-Z.;
Chen, H.-Ch.; Cao, S.-L.; Li, R.-T. Synth. Commun. 1994,
24, 833; (i) Zhang, L.; Xu, B. Z.; Chen, S. X.; Tang, H. T.
Huaxue Shiji 1990, 12, 40; Chem. Abstr. 113, 114596.
13. (a) Merker, R. L.; Scott, M. J. J. Org. Chem. 1961, 26, 5180; (b)
Barry, J.; Bram, G.; Decodts, G.; Loupy, A.; Pigeon, P.;
Sansoulet, J. Tetrahedron 1984, 40, 2945; (c) Loupy, A.;
Sansoulet, J.; Vaziri-Zand, F. Bull. Soc. Chim. Fr. 1987, 6,
1027; (d) Bram, G.; Loupy, A.; Sansoulet, J.; Vaziri-Zand, F.
Tetrahedron Lett. 1984, 25, 5035; (e) Bram, G.; Loupy, A.;
Sansoulet, J.; Vaziri-Zand, F. Nouv. J. Chim. 1986, 10, 765;
(f) Bram, G.; Loupy, A.; Sansoulet, J.; Strzelecka, H. Synth.
Commun. 1984, 14, 889; (g) Kornblum, N.; Seltzer, R.;
Haberfield, P. J. Am. Chem. Soc. 1963, 85, 1148; (h) Loupy,
A. Spectra Anal. 1993, 175, 33; (i) Deshayes, S.; Liagre, M.;
Loupy, A.; Luche, J.-L.; Petit, A. Tetrahedron 1999, 55, 10851.
14. (a) Campbell, L. J.; Borges, L. F.; Heldrich, F. J. BioMed.
Chem. Lett. 1994, 4, 2627; (b) Bogdal, D.; Pielichowski, J.;
17. (a) Beasley, Y. M.; Petrow, V.; Stephenson, O. J. Pharm.
Pharmacol. 1958, 10, 47; (b) Cvengrosova, Z.; Rattay, V.;
Repasova, I.; Spankova, Z.; Fancovic, K. Czech Patent
200,382, 1983; Chem. Abstr. 100, 68148; (c) Kiersznicki, T.;
Najzarek, Z.; Szeja, W. Pol. Patent 86,612, 1976; Chem.
Abstr. 90, 87234 ; (d) Fancovic, K.; Rattay, V.; Mrazova, M.
et al. Czech Patent 163,132, 1976; Chem. Abstr. 85, 192184;
(e) Simon, J.; Gorodinskaja, V. Khim. Farm. Zh. 1968, 7, 13;

B. K. Pchelka et al. / Tetrahedron 62 (2006) 10968–10979
10979
(f) Nakayama, K.; Murakami, N.; Yoshizaki, S.; Tominaga, M.;
Movi, H.; Yabkuchi, Y.; Shintani, S. J. Med. Chem. 1974, 17,
52; (g) Biniecki, S. Preparatyka srodkow leczniczych;
PZWL: Warszawa, 1980; p 129; (h) Simon, I. B., U.S.S.R.
Patent 318,561, 1971; Chem. Abstr. 76, 34016; (i) Li, R.;
Yang, J.; Chen, H.; Cao, S. Huaxue Shiji 1995, 17, 7; Chem.
Abstr. 123, 111765; (j) Smith, D. R. (Dow Chemical Co.,
USA). Brit. Patent 1,155,543, 1969; Chem. Abstr. 71, 81126;
(k) Sanko Chemical Co., Ltd. Japan, Jp. Patent 5,703,1679,
1982; Chem. Abstr. 96, 217680; (l) Wiesner, I. Czech Patent
136,171, 1970; Chem. Abstr. 75, 21707; (m) Wiesner, I.
Czech Patent 176,772, 1979; Chem. Abstr. 90, 187909; (n)
Wiesner, I. Czech Patent 176,770, 1979; Chem. Abstr. 90,
187911; (o) Wiesner, I. Czech Patent 176,771, 1979; Chem.
Abstr. 90, 187910; (p) Wiesner, I. Czech Patent 176,773,
1979; Chem. Abstr. 90, 205153; (q) Kuliev, A. M.;
Movsumzade, M. M.; Mamedov, F. N. Azerb. Khim. Zh.
1966, 6, 20; Chem. Abstr. 67, 53826; (r) Egorenkov, A. A.;
Rumyantseva, Y. G. U.S.S.R. Patent 1,618,746, 1991; Chem.
Abstr. 115, 8557.
18. Jacquault, P. Brevet Prolabo 92420477.9, 21.12.1992.
19. (a) See Ref. 5a; (b) Stuerga, D.; Gonon, K.; Lallemant, M.
Tetrahedron 1993, 49, 6229; (c) Berlan, J.; Giboreau, P.;
Lefeuvre, S.; Marchand, C. Tetrahedron Lett. 1991, 32, 2363;
(d) Raner, K. D.; Strauss, C. R.; Vyskoc, F.; Mokbel, L.
J. Org. Chem. 1993, 58, 950; (e) Stuerga, D.; Gaillard, P.
Tetrahedron 1996, 52, 5505.
ˆ
20. (a) Acros Organics Catalogue of Products, 2006; (b) Schulz, H.
Pharmazie 1968, 23, 240; (c) Pitha, J.; Milecki, J.;
Czajkowska, T.; Kusiak, J. W. J. Med. Chem. 1983, 26, 7; (d)
Gokel, G. W.; Dishong, D. M.; Diamond, C. J. J. Chem. Soc.,
Chem. Commun. 1980, 1053–1054.