Aqueous-mediated ring opening of epoxides with oximes: A rapid entry into β-hydroxy oxime O-ethers as potential β-adrenergic blocking agents

Article abstract of DOI:10.1055/s-2008-1067122

Novel β-hydroxy oxime O-ethers, as potential β-adrener-gic blocking agents, were synthesized from the aqueous-mediated (H₂O - DMSO, 7:3) O-alkylation of oximes with epoxides in the presence of potassium hydroxide at room temperature. The O-alkylation was regioselective and (E)-oxime ethers were the main products. The results of quantum mechanical studies used to rationalize the experimental outcomes are discussed. Thieme Stuttgart.

Full text of DOI:10.1055/s-2008-1067122

PAPER
2055
Aqueous-Mediated Ring Opening of Epoxides with Oximes: A Rapid Entry
into b-Hydroxy Oxime O-Ethers as Potential b-Adrenergic Blocking Agents
A
a
queous-Mediated
R
in
o
g
O
pening
o
h
f
Epoxides
w
a
ith
O
xim
e
m
To
G
ive
b
-Hydrox
m
y
O
xime
O
-Ether
s
ad Navid Soltani Rad,*a Somayeh Behrouz,a Manije Dianatb
b
Received 8 February 2008; revised 7 April 2008
of an oxime and epoxide as a precursor for other synthetic
purposes.19
Abstract: Novel b-hydroxy oxime O-ethers, as potential b-adrener-
gic blocking agents, were synthesized from the aqueous-mediated
(H2O–DMSO, 7:3) O-alkylation of oximes with epoxides in the
presence of potassium hydroxide at room temperature. The O-alky-
lation was regioselective and (E)-oxime ethers were the main prod-
ucts. The results of quantum mechanical studies used to rationalize
the experimental outcomes are discussed.
b-Adrenoreceptor antagonists are used clinically for the
treatment of various cardiovascular diseases.20 It is well-
known that b-adrenergic blockers are very homogeneous
in their chemical structures, which stem either from 2-
amino-1-arylethanols 1 or 1-amino-3-(aryloxy)propan-2-
ols 2 (Figure 1).21 It has previously been shown that the
insertion of a carbon–nitrogen double bond into the side
chain of b-blockers does not abolish the b-adrenoreceptor
activity and, in some cases, leads to potent b2-selective
antagonists.22 In this context, structure–activity relation-
ship studies led to the design and synthesis of ketoxime O-
[3-(alkylamino)-2-hydroxypropyl] ethers 3 as potent b2-
selective antagonists (Figure 1).18
Key words: oximes, epoxides, O-alkylations, ring opening, aque-
ous media
Oximes and oxime ether derivatives are important sub-
strates in organic and medicinal chemistry.1 Oximes and
oxime ethers are widely used for the introduction of vari-
ous functional groups into organic compounds,1a,d,e as
well as for amino acid synthesis.2 Moreover, they are a
key structural motif in many drug scaffolds and bioactive
compounds. Many famous drugs with various chemother-
apeutic activities, such as antiviral (e.g., enviroxime)3 and
anti-inflammatory agents (e.g., pifoxime),1b cephalospor-
in antibiotics (e.g., cefixime),4 nerve agent antidotes (e.g.,
pralidoxime),1b,c antifungal agents (e.g., oxiconazole),5
macrolide antibiotics (e.g., roxithromycin),6 antidepres-
sants (e.g., fluvoxamine),1b and thromboxane synthase in-
hibitors (e.g., ridogrel),7 contain an oxime or oxime ether
moiety in their structure.
OH
OH
NR2R3
O
NR2R3
2
R1
NR2R3
1
R1
OH
O
R1
N
R4
3
Figure 1
One of the most common routes to oxime ethers is the re-
action of oximes with carbon electrophiles, including
alkyl or aryl halides,8,9 aryl nitrates,10a arenediazonium
salts,10b alcohols under Mitsunobu conditions,11 activated
olefins,12 trialkyl orthoformates,13 allylic carbonates,14a
acetates,14a,b phosphate esters,14c and Michael acceptors.15
Oxime ethers have also been prepared from the condensa-
tion of O-alkylhydroxylamines with carbonyl com-
pounds.16 The ring opening of epoxides with oximes is an
interesting and attractive strategy for obtaining b-hydroxy
oxime O-ethers;1a however, there are few reports for the
regioselective ring opening of epoxides using oximes.17 In
most cases, the examples are limited to the reaction of
oximes with epibromohydrins to obtain oxime O-oxira-
nylmethyl ether derivatives, via nucleophilic displace-
ment of the bromide,18 and/or the intermolecular reaction
The use of water as a medium for promoting organic reac-
tions has only relatively recently attracted considerable at-
tention, despite the fact that water is the solvent in a vast
majority of biochemical processes.23 Furthermore, water
is a suitable solvent for organic reactions because of its
nontoxicity, cheapness, conformity with green protocols,
and special characteristics, such as its high polarity and di-
electric constant.23
Encouraged by the b-adrenergic blocking activities of
compounds 3 and also as an extension of our interest in
epoxide chemistry,24 we have synthesized compounds 4
by the water–dimethyl sulfoxide (H2O–DMSO) mediated
regioselective O-alkylation of oximes with epoxides in
the presence of potassium hydroxide (KOH) at room tem-
perature (Scheme 1).
The first step to deriving this particular synthetic approach
involved the optimization of the reaction conditions. Ini-
tially, we investigated the effect of using various solvents
SYNTHESIS 2008, No. 13, pp 2055–2064
Advanced online publication: 11.06.2008
DOI: 10.1055/s-2008-1067122; Art ID: Z05108SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
8

2056
M. N. S. Rad et al.
PAPER
among the examined bases in this experiment, a slight ex-
cess of KOH (1.3 equiv, entry 2) was the most efficient
base for the activation of benzophenone oxime. Sodium
hydroxide (entry 1) was not as effective as KOH, even
when its molar ratio was increased up to two equivalents.
The other bases were not efficient at all, even with pro-
longed reaction times.
OH
OH
R2
O
R3
N
N
O
H2O–DMSO, KOH
r.t., 4–10 h
R3
+
R1
R1
R2
4a–y
R1,R2 = alkyl, aryl
R3 = alkyl, alkoxy, aryloxy
Scheme 1
Table 2 Effect of Various Bases on the Ring Opening of 2-(Phen-
oxymethyl)oxirane with Benzophenone Oxime
on the model reaction of benzophenone oxime with 2-
(phenoxymethyl)oxirane to afford benzophenone oxime
O-(2-hydroxy-3-phenoxypropyl) ether. The results are
depicted in Table 1.
Entry
Base
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
NaOH
KOH
6
4
70
91
NRb
35
22
20
10
34
Table 1 Effect of Various Solvents on the Ring Opening of
2-(Phenoxymethyl)oxirane with Benzophenone Oxime
K2CO3
Et3N
24
12
18
18
18
12
Entry
1
Solvent
DMF
Time (h)
Yielda,b (%)
DBU
6
6
76
64
77
NR
70
45
40
66
NR
91
75
60
2
DMFc
DBN
DMAP
DABCO
3
DMSO
5
4
THF
24
6
a Isolated yield.
b No reaction.
5
MeCN
6
H2O
24
10
10
24
4
7
HMPA
To evaluate the generality and versatility of this method
and with the aim of attaining some novel analogues of
compound 3, the optimized conditions were applied to
various structurally diverse terminal and cyclic epoxides
and symmetric and dissymmetric oximes (E- and Z-iso-
mers). The results of these reactions are given in Table 3.
Most of the oximes used in this research were commer-
cially available or could be easily prepared using the pro-
cedure reported in the literature.25 The dissymmetric
oximes, in most cases, were used as mixtures of their E-
and Z-isomers. The ring opening of epoxides with oximes
under basic conditions usually takes place in an SN2 fash-
ion. Consequently, the reaction of cyclohexene oxide with
acetophenone oxime, benzophenone oxime, and 1-(4-
chlorophenyl)ethanone oxime afforded the corresponding
b-hydroxy oxime O-cyclohexyl ethers 4g, 4h, and 4q (en-
tries 7, 8, and 17, respectively) as the trans-isomers (de-
termined by NMR analysis). The ring opening of the
terminal epoxides with oximes was mostly achieved re-
gioselectively by preferential attack at the less-hindered
carbon atom of the epoxide. However, an exception to this
was the reaction of styrene oxide with oximes that afford-
ed two regioisomers in a ratio of approximately 1:3. Thus,
compounds 4d, 4n, and 4u (entries 4, 14, and 21, respec-
tively) were obtained as the main products from the attack
at the less-hindered side; whereas, their regioisomers 4e,
4o, and 4v (entries 5, 15, and 22, respectively) were pro-
duced from attacking the side that was more hindered. The
regioisomers were separated by short column chromatog-
raphy techniques and their structures were characterized
by 1H and 13C NMR spectroscopic analysis.
8
NMP
9
toluene
H2O–DMSOd
H2O–MeCNe
H2O–acetonee
10
11
12
5
10
a Isolated yield.
b NR = no reaction.
c Anhyd DMF.
d In a 7:3 ratio.
e In a 1:1 ratio.
As the data indicate, the solution of H2O–DMSO (7:3)
(Table 1, entry 10) was the most-efficient solvent; hence,
it was the solvent of choice. The use of DMSO or H2O
alone (entries 3 and 6, respectively) was not as efficient as
using the H2O–DMSO (7:3) solution. Furthermore, al-
though the use of N,N-dimethylformamide, acetonitrile
(MeCN), N-methyl-2-pyrrolidinone, H2O–MeCN, and
H2O–acetone (entries 1 and 2, 5, 8, 11, and 12, respective-
ly) also afforded good yields of the corresponding oxime
ether, longer reaction times were required. Finally, when
H2O–MeCN or MeCN were used, MeCN hydrolysis was
a major problem in strong basic conditions.
The choice of base is of great importance for the activa-
tion of the oximes to react with the epoxides. We studied
the potency of several organic and inorganic bases within
the reaction model (Table 2). The results indicated that,
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Aqueous-Mediated Ring Opening of Epoxides with Oximes To Give b-Hydroxy Oxime O-Ethers
2057
Table 3 b-Hydroxy Oxime O-Ethers Synthesized by the Ring
Opening of Epoxides with Oximes
Table 3 b-Hydroxy Oxime O-Ethers Synthesized by the Ring
Opening of Epoxides with Oximes (continued)
Entry Producta
Product Time Yieldb
number (h) (%)
Entry Producta
Product Time Yieldb
number (h) (%)
OH
OH
O
O
O
O
N
N
1
4a
4b
4c
4d
10 85
10
4j
6
5
4
6
6
d
80
89
91
87
75
OH
OH
OH
OH
O
O
O
O
O
O
O
O
O
N
N
N
N
N
N
N
2
3
4
7
82
80
73
11
12
13
14
4k
4l
OH
OH
OH
5
6
4m
4n
O
O
O
c
N
N
N
5
4e
23
87
OH
OH
O
O
N
6
7
4f
4
15
4o
19
88
OH
OH
OH
OH
OH
O
O
O
O
N
4g
10 89
16
17
18
4p
4q
4r
6
Cl
Cl
Cl
HO
O
O
N
N
N
N
8
9
4h
4i
6
5
90
83
10 87
OH
O
O
4
90
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2058
M. N. S. Rad et al.
PAPER
Table 3 b-Hydroxy Oxime O-Ethers Synthesized by the Ring
Dissymmetric ketoximes usually exist as a mixture of the
E- (or anti) and Z- (or syn) isomers, and tautomeric inter-
conversions of the (E)- and (Z)-oximes occur readily (via
1,3-H shift) (Scheme 2).29 The propensity of these inter-
conversions is toward the formation of the more-stable E-
isomer, as was found in the case of acetophenone oxime
and its derivatives: quantum mechanical calculation
methods, including ab initio 6-31G or semiempirical Aus-
tin Model 1 (AM1) and Parameterized Model 3 (PM3),30
indicated that (E)-acetophenone oxime is slightly more
stable than its Z-isomer. However, the results of the O-
alkylation of acetophenone oxime with 2-(phenoxymeth-
yl)oxirane to give product 4a (Table 3, entry 1) indicated
that the E-isomer was produced exclusively (85%). To ra-
tionalize this observation, the quantum mechanical calcu-
lation methods described above were used and the results
indicated that there is a considerable energy difference be-
tween (E)- and (Z)-oxime ethers 4a in comparison with
(E)- and (Z)-acetophenone oxime. The bulkiness of the O-
alkyl group is largely responsible for encouraging the
product to form as the more-stable (E)-oxime ether. This
diastereoselectivity could also be rationalized as a func-
tion of steric hindrance caused by the phenyl group in the
Z-isomers rather than the methyl group in the E-isomers.
The same situation was also observed for compounds 4d
and 4e. Notwithstanding, it could be expected to obtain
four oxime ether isomers from the reaction of (E)- and
(Z)-acetophenone oxime with styrene oxide; however,
only the formation of 4d and 4e was detected. Further-
more, aside from the stereoelectronic factor controlling
the regioselective ring opening of styrene oxide, the lim-
ited synthesis of 4e in comparison with 4d could also be
attributed to the steric repulsion between the phenyl group
in the 2-phenylethanol moiety of 4e and the methyl group.
Opening of Epoxides with Oximes (continued)
Entry Producta
Product Time Yieldb
number (h) (%)
OH
O
O
N
19
4s
6
4
86
Br
OH
OH
O
O
20
4t
91
70
N
O
21
4u
4
N
e
22
23
4v
26
87
O
N
OH
OH
O
O
N
4w
6
4
OH
O
O
N
24
25
4x
4y
78
80
OH
O
O
O
N
O
O
N
H
4
N
H
N
[1,3]-H
[1,3]-H
a All products were characterized by 1H and 13C NMR and IR spec-
troscopy, MS, and CHN analysis.
Z-isomer
(less stable)
nitroso
E-isomer
(more stable)
b Isolated yield.
c Product formed in the same reaction that gave 4d.
d Product formed in the same reaction that gave 4n.
e Product formed in the same reaction that gave 4u.
Scheme 2 Interconversions of the E- and Z-isomers of acetophen-
one oxime via nitroso–oxime tautomerization (1,3-H shift)
The tautomeric interconversions of (E)- and (Z)-oximes
are known to be accelerated in acidic or basic media.28,31
On this basis, when (E)-acetophenone oxime (>98% puri-
ty, indicated by HPLC)32 was O-alkylated with 2-(phen-
oxymethyl)oxirane, a trace amount of the synthesized
(Z)-oxime ether was observed. The geometry of com-
pound 4a, for both the E- and Z-isomeric forms, was opti-
mized using ab initio 6-31G calculations (Figures 2 and 3,
respectively). In the structure shown in Figure 2, the car-
bon–carbon bond frameworks are nearly coplanar, and
this condition allows for ideal conjugation between the
phenyl moiety in the oxime and the carbon–nitrogen dou-
ble bond. However, because of the steric repulsion be-
Oximes are known to be ambident nucleophiles.26 The
alkylation of an oxime can be achieved at the oxygen to
afford an O-alkyl ether or at the nitrogen to generate ni-
trones.27 Like other ambident systems, the site of alkyla-
tion in the oxime anion is affected by a number of factors,
such as the base and solvent types, the nature of the alky-
lating agents and the cation, the geometry of the substrate,
any functional groups present on the oxime, and the de-
gree of dissociation of the oxime salts.27,28 However, us-
ing our presented method, mainly O-alkyl ethers were
obtained and nitrones were not detected, even in trace
amounts.
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Aqueous-Mediated Ring Opening of Epoxides with Oximes To Give b-Hydroxy Oxime O-Ethers
2059
croanalyses were performed on a Perkin–Elmer 240-B microana-
lyzer.
b-Hydroxy Oxime O-Ethers 4; General Procedure
To a 100-mL round-bottomed flask containing a mixture of the ke-
toxime (0.010 mol) and KOH (0.73 g, 0.013 mol) in H2O–DMSO
(7:3, 20 mL) was added the epoxide (0.015 mol). The mixture was
then stirred at r.t. until TLC monitoring indicated no further im-
provement in the reaction (for reaction times, see Table 3). Then,
the mixture was dissolved in CHCl3 (100 mL) and washed with H2O
(3 × 100 mL). The organic layer was dried (Na2SO4) and the solvent
evaporated. The crude product was purified by column chromatog-
raphy as indicated below.
Figure 2 Optimized geometry for the E-isomer of acetophenone
oxime O-(2-hydroxy-3-phenoxypropyl) ether (4a)
Acetophenone Oxime O-(2-Hydroxy-3-phenoxypropyl) Ether
(4a)
Column chromatography (silica gel, EtOAc–n-hexane, 1:9) afford-
ed the product as a bright-yellow oil. Yield: 2.42 g (85%); Rf = 0.64
(EtOAc–n-hexane, 1:2).
IR (liquid film): 3298.5 (br s), 3058.4, 2931.2, 2856.7, 1651.3,
1446.9, 1115.1, 1049.5 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.15 (s, 3 H, CH3), 3.23 (s, 1 H,
OH, exchangeable with D2O), 3.96 (dd, J = 4.0, 10.1 Hz, 2 H,
CH2ON), 4.30–4.35 (complex, 3 H, CHCH2OPh), 6.82–6.85 (m, 3
Figure 3 Optimized geometry for the Z-isomer of acetophenone
oxime O-(2-hydroxy-3-phenoxypropyl) ether (4a)
tween the phenyl moiety in the oxime and the O-alkyl
group, the phenyl group deviates from coplanarity in the
structure in Figure 3.
Harom), 7.15–7.27 (m, 5 Harom), 7.50–7.53 (m, 2 Harom).
13C NMR (75 MHz, CDCl3): d = 11.76, 67.60, 68.96, 73.52, 113.51,
120.17, 125.01, 127.43, 128.44, 129.84, 134.98, 154.93, 157.54.
The synthesized compounds 4a–y have similar features to
compounds 1–3. On comparison of the structure of 1 with
4d, 4n, and 4u, and also that of 2 with products such as 4a,
4p, 4s, and 4w, the oxime ether products delineate com-
pounds 1 and 2 with the amino group being replaced with
an oxime moiety. Most of the synthesized compounds
take the form of 3 in which the amino group is replaced
with various aryloxy, alkoxy, and alkyl groups. The b-
blocking activities of the title compounds are under bio-
logical investigation and will be reported in due course.
HRMS: m/z (M+) calcd for C17H19NO3: 285.1365; found: 285.1362.
Anal. Calcd for C17H19NO3: C, 71.56; H, 6.71; N 4.91. Found: C,
71.53; H, 6.70; N, 4.96.
Acetophenone Oxime O-(3-Butoxy-2-hydroxypropyl) Ether
(4b)
Column chromatography (silica gel, EtOAc–n-hexane, 1:4) afford-
ed the product as a yellow oil. Yield: 2.20 g (82%); Rf = 0.66
(EtOAc–n-hexane, 1:2).
IR (liquid film): 3369.8 (br s), 3052.8, 2984.5, 2865.5, 1667.3,
1428.9, 1309.5, 1028.6 cm–1.
In conclusion, a convenient and highly efficient synthetic
methodology has been described for the preparation of
novel b-hydroxy oxime O-ethers via the O-alkylation of
oxime anions with epoxides in H2O–DMSO (7:3) at room
temperature. The regio- and diastereoselectivity of the re-
action, its conformity with green protocols, simplicity,
mild reaction conditions, and high yields of products indi-
cate the characteristics of this method. Finally, to rational-
ize the experimental outcomes, quantum mechanical
studies have been used to support the considerable prefer-
ence for (E)-oxime ether formation.
1H NMR (300 MHz, CDCl3): d = 0.79 (t, J = 7.2 Hz, 3 H, CH2CH3),
1.23–1.32 (m, 2 H, CH2), 1.42–1.51 (m, 2 H, CH2), 2.15 (s, 3 H,
CH3CN), 3.09 (s, 1 H, OH, exchangeable with D2O), 3.36–3.44
(complex, 4 H, CH2OCH2), 4.04–4.08 (m, 1 H, CHOH), 4.17 (dd,
J = 3.6, 5.3 Hz, 2 H, CH2ON), 7.23–7.26 (m, 3 Harom), 7.50–7.54 (m,
2 Harom).
13C NMR (75 MHz, CDCl3): d = 12.69, 13.90, 19.26, 31.68, 70.07,
71.35, 71.75, 75.11, 126.02, 128.39, 129.22, 136.23, 155.40.
HRMS: m/z (M+) calcd for C15H23NO3: 265.1678; found: 265.1680.
Anal. Calcd for C15H23NO3: C, 67.90; H, 8.74; N, 5.28. Found: C,
67.96; H, 8.78; N, 5.27.
All chemicals were obtained from Merck, Fluka, and Acros chemi-
cal companies. Some of the oximes used in this research were pre-
pared using the described method.25 Solvents were purified and
dried according to the reported methods33 and stored over 3-Å mo-
lecular sieves. The progress of the reaction was followed by TLC
using silica gel SILG/UV 254 plates. Silica gel 60 (0.063–0.200
mm, 70–230 mesh ASTM) was used for column chromatography.
Melting points (mp) were recorded on a Büchi 510 apparatus in
open capillary tubes and are uncorrected. Infrared spectra were run
Acetophenone Oxime O-(2-Hydroxyhexyl) Ether (4c)
Column chromatography (silica gel, EtOAc–n-hexane, 1:9) afford-
ed the product as a bright-yellow oil. Yield: 2.12 g (80%); Rf = 0.45
(EtOAc–n-hexane, 1:2).
IR (liquid film): 3286.5 (br s), 3055.2, 2931.6, 2869.9, 1658.7,
1442.7, 1303.8 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.95 (t, J = 7.3 Hz, 3 H, CH2CH3),
1.38–1.58 (m, 6 H, 3 CH2), 2.29 (s, 3 H, CH3CN), 3.31 (s, 1 H, OH,
exchangeable with D2O), 4.16–4.28 (complex, 3 H, CHCH2ON),
7.37–7.41 (m, 3 Harom), 7.66–7.70 (m, 2 Harom).
1
on a Shimadzu FTIR-8300 spectrophotometer. The H (300 MHz)
and 13C NMR (75 MHz) spectra were run on a Brüker DPX-300 FT-
NMR spectrometer using TMS as an internal standard. High resolu-
tion mass spectra (HRMS) were performed on a VG 70S Magnetic
Sector Mass Spectrometer using FAB ionization technique. Mi-
13C NMR (75 MHz, CDCl3): d = 12.37, 13.82, 22.83, 27.71, 33.03,
71.25, 78.02, 126.13, 128.69, 133.18, 136.77, 155.62.
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2060
M. N. S. Rad et al.
PAPER
HRMS: m/z (M+) calcd for C14H21NO2: 235.1572; found: 235.1569.
IR (liquid film): 3359.1 (br s), 3057.0, 2942.6, 2869.4, 1661.4,
1452.8, 1161.3 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.80–0.87 (m, 4 H, 2 CH2), 1.18
(s, 3 H, CH3), 1.25–1.34 (m, 4 H, 2 CH2), 1.61 (s, 1 H, OH, ex-
changeable with D2O), 4.11–4.18 (complex, 2 H, CHOH, CHON),
7.42–7.48 (m, 3 Harom), 7.60–7.65 (m, 2 Harom).
Anal. Calcd for C14H21NO2: C, 71.46; H, 8.99; N, 5.95. Found: C,
71.48; H, 8.97; N, 5.98.
Acetophenone Oxime O-(2-Hydroxy-2-phenylethyl) Ether (4d)
Column chromatography (silica gel, EtOAc–n-hexane, 1:4) afford-
ed the product as a yellow oil. Yield: 1.86 g (73%); Rf = 0.72
(EtOAc–n-hexane, 1:2).
13C NMR (75 MHz, CDCl3): d = 14.04, 22.97, 23.71, 28.90, 38.70,
59.50, 68.12, 128.43, 128.78, 130.86, 132.42, 167.74.
IR (liquid film): 3328.9 (br s), 3057.1, 2967.5, 2839.2, 1658.6,
1476.3, 1310.2 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.21 (s, 3 H, CH3), 2.92 (s, 1 H,
OH, exchangeable with D2O), 3.89 (dd, J = 7.9, 12.0 Hz, 2 H,
CH2ON), 5.29 (dd, J = 3.3, 7.8 Hz, 1 H, CHOH), 7.15–7.28 (m, 8
HRMS: m/z (M+) calcd for C14H19NO2: 233.1416; found: 233.1420.
Anal. Calcd for C14H19NO2: C, 72.07; H, 8.21; N, 6.00. Found: C,
72.11; H, 8.27; N, 5.98.
Benzophenone Oxime O-(2-Hydroxycyclohexyl) Ether (4h)
Column chromatography (silica gel, EtOAc–n-hexane, 3:7) afford-
ed the product as a white solid. Yield: 2.66 g (90%); mp 62.5 °C;
Rf = 0.70 (EtOAc–n-hexane, 1:2).
Harom), 7.45–7.50 (m, 2 Harom).
13C NMR (75 MHz, CDCl3): d = 13.07, 67.74, 85.81, 126.16,
126.78, 128.02, 128.47, 128.73, 129.38, 136.23, 138.55, 156.06.
HRMS: m/z (M+) calcd for C16H17NO2: 255.1259; found: 255.1258.
IR (KBr): 3379.5 (br s), 3050.1, 2931.6, 2862.2, 1650.9, 1442.7,
1164.9 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.15–1.25 (m, 4 H, 2 CH2), 1.56–
1.59 (m, 2 H, CH2), 1.96–1.99 (m, 2 H, CH2), 3.54 (s, 1 H, OH, ex-
changeable with D2O), 3.57–3.61 (m, 1 H, CHOH), 3.94–3.95 (m,
1 H, CHON), 7.14–7.39 (m, 10 Harom).
13C NMR (75 MHz, CDCl3): d = 23.78, 24.16, 29.63, 32.56, 73.62,
86.48, 128.21, 128.32, 128.73, 129.08, 129.35, 129.47, 133.13,
136.43, 157.23.
Anal. Calcd for C16H17NO2: C, 75.27; H, 6.71; N, 5.49. Found: C,
75.29; H, 6.68; N, 5.53.
Acetophenone Oxime O-(2-Hydroxy-1-phenylethyl) Ether (4e)
Column chromatography (silica gel, EtOAc–n-hexane, 1:4) afford-
ed the product as a yellow oil. Yield: 0.59 g (23%); Rf = 0.70
(EtOAc–n-hexane, 1:2).
IR (liquid film): 3326.4 (br s), 3056.3, 2968.4, 2839.2, 1658.3,
1476.7, 1310.2 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.24 (s, 3 H, CH3), 2.37 (s, 1 H,
OH, exchangeable with D2O), 3.93 (complex, 2 H, CH2OH), 4.83
(dd, J = 3.6, 7.1 Hz, 1 H, OCHPh), 7.18–7.22 (m, 5 Harom), 7.32–
7.38 (m, 3 Harom), 7.42–7.53 (m, 2 Harom).
13C NMR (75 MHz, CDCl3): d = 13.98, 65.43, 83.18, 126.24,
126.39, 128.12, 128.52, 128.69, 129.45, 136.12, 138.59, 156.11.
HRMS: m/z (M+) calcd for C16H17NO2: 255.1259; found: 255.1261.
HRMS: m/z (M+) calcd for C19H21NO2: 295.1572; found: 295.1570.
Anal. Calcd for C19H21NO2: C, 77.26; H, 7.17; N, 4.74. Found: C,
77.29; H, 7.14; N, 4.79.
Benzophenone Oxime O-(3-Allyloxy-2-hydroxypropyl) Ether
(4i)
Column chromatography (silica gel, EtOAc–n-hexane, 1:4) afford-
ed the product as a bright-yellow oil. Yield: 2.58 g (83%); Rf = 0.71
(EtOAc–n-hexane, 1:2).
Anal. Calcd for C16H17NO2: C, 75.27; H, 6.71; N, 5.49. Found: C,
75.28; H, 6.72; N, 5.46.
IR (liquid film): 3386.8 (br s), 3062.7, 2925.5, 2869.9, 1650.9,
1442.7, 1326.9, 1056.1 cm–1.
Acetophenone Oxime O-(3-Allyloxy-2-hydroxypropyl) Ether
(4f)
Column chromatography (silica gel, EtOAc–n-hexane, 1:4) afford-
ed the product as a bright-yellow oil. Yield: 2.17 g (87%); Rf = 0.54
(EtOAc–n-hexane, 1:2).
1H NMR (300 MHz, CDCl3): d = 3.41 (dd, J = 5.9, 9.8 Hz, 2 H,
OCH2CHOH), 3.64 (s, 1 H, OH, exchangeable with D2O), 3.92–
3.95 (m, 2 H, CH2ON), 4.17 (br s, 1 H, CHOH), 4.26–4.28 (m, 2 H,
CH2CH=C), 5.10–5.26 (complex, 2 H, =CH2), 5.77–5.87 (m, 1 H,
=CHvinyl), 7.21–7.51 (m, 10 Harom).
IR (liquid film): 3364.1 (br s), 3071.2, 2969.7, 2844.2, 1661.2,
1472.3, 1332.4, 1054.7 cm–1.
13C NMR (75 MHz, CDCl3): d = 69.53, 71.43, 72.20, 75.49, 117.05,
127.99, 128.17, 128.33, 128.94, 129.31, 129.52, 133.21, 134.78,
136.27, 157.29.
1H NMR (300 MHz, CDCl3): d = 2.01 (s, 3 H, CH3), 3.35 (dd, J =
5.9, 7.4 Hz, 2 H, OCH2CHOH), 3.60 (s, 1 H, OH, exchangeable
with D2O), 3.79 (dd, J = 1.2, 4.3 Hz, 2 H, CH2ON), 4.00–4.02 (m,
1 H, CHOH), 4.09–4.11 (m, 2 H, CH2CH=C), 4.93 (dd, J1, J2 = 1.4,
10.4 Hz, 1 H, =CHAHB), 5.03 (dd, J1, J3 = 1.4, 17.2 Hz, 1 H,
=CHAHB), 5.65–5.69 (m, 1 H, =CHvinyl), 7.10–7.12 (m, 3 Harom),
7.39–7.43 (m, 2 Harom).
HRMS: m/z (M+) calcd for C19H21NO3: 311.1521; found: 311.1523.
Anal. Calcd for C19H21NO3: C, 73.29; H, 6.80; N, 4.50. Found: C,
73.34; H, 6.82; N, 4.46.
Benzophenone Oxime O-(2-Hydroxypropyl) Ether (4j)
Column chromatography (silica gel, EtOAc–n-hexane, 3:7) afford-
ed the product as a colorless oil. Yield: 2.04 g (80%); Rf = 0.62
(EtOAc–n-hexane, 1:2).
13C NMR (75 MHz, CDCl3): d = 12.59, 69.72, 71.43, 72.23, 75.10,
117.02, 126.00, 128.35, 128.83, 134.66, 136.21, 155.12.
HRMS: m/z (M+) calcd for C14H19NO3: 249.1365; found: 249.1360.
IR (liquid film): 3385.6 (br s), 3055.4, 2970.2, 2877.6, 1650.9,
1488.9, 1326.9 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.21 (d, J = 6.1 Hz, 3 H, CH3), 3.27
(s, 1 H, OH, exchangeable with D2O), 4.06–4.14 (m, 1 H, CHOH),
4.16 (dd, J = 2.8, 8.7 Hz, 2 H, CH2ON), 7.30–7.57 (m, 10 Harom).
13C NMR (75 MHz, CDCl3): d = 19.14, 66.96, 79.48, 128.01,
128.15, 128.26, 129.27, 129.45, 129.54, 133.19, 136.23, 157.58.
Anal. Calcd for C14H19NO3: C, 67.45; H, 7.68; N, 5.62. Found: C,
67.51; H, 7.65; N, 5.63.
Acetophenone Oxime O-(2-Hydroxycyclohexyl) Ether (4g)
Column chromatography (silica gel, EtOAc–n-hexane, 3:7) afford-
ed the product as a yellow oil. Yield: 2.08 g (89%); Rf = 0.77
(EtOAc–n-hexane, 1:2).
HRMS: m/z (M+) calcd for C16H17NO2: 255.1259; found: 255.1260.
Synthesis 2008, No. 13, 2055–2064 © Thieme Stuttgart · New York

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Aqueous-Mediated Ring Opening of Epoxides with Oximes To Give b-Hydroxy Oxime O-Ethers
2061
Anal. Calcd for C16H17NO2: C, 75.27; H, 6.71; N, 5.49. Found: C,
75.30; H, 6.76; N, 5.52.
IR (KBr): 3289.4 (br s), 3062.1, 2935.7, 2894.3, 1667.1, 1485.2,
1232.6 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.46 (s, 1 H, OH, exchangeable
with D2O), 3.64 (dd, J = 6.0, 19.4 Hz, 2 H, CH2ON), 5.28 (dd, J =
3.7, 7.5 Hz, 1 H, CHOH), 7.14–7.33 (m, 15 Harom).
13C NMR (75 MHz, CDCl3): d = 67.03, 86.31, 114.77, 121.45,
125.55, 126.78, 128.20, 128.30, 128.42, 129.26, 129.59, 133.24,
136.18, 138.50, 158.14.
Benzophenone Oxime O-(3-Butoxy-2-hydroxypropyl) Ether
(4k)
Column chromatography (silica gel, EtOAc–n-hexane, 1:4) afford-
ed the product as a colorless oil. Yield: 2.91 g (89%); Rf = 0.63
(EtOAc–n-hexane, 1:2).
IR (liquid film): 3381.6 (br s), 3055.0, 2962.2, 2869.9, 1658.7,
1442.7, 1110.9, 1056.9 cm–1.
HRMS: m/z (M+) calcd for C21H19NO2: 317.1416; found: 317.1415.
1H NMR (300 MHz, CDCl3): d = 0.75 (t, J = 7.2 Hz, 3 H, CH3),
1.18–1.27 (m, 2 H, CH2), 1.36–1.44 (m, 2 H, CH2), 3.25 (t, J = 3.2
Hz, 2 H, OCH2CH2), 3.31 (s, 1 H, OH, exchangeable with D2O),
3.32 (dd, J = 3.3, 4.7 Hz, 2 H, OCH2CHOH), 4.00–4.04 (m, 1 H,
CHOH), 4.13–4.15 (m, 2 H, CH2ON), 7.04–7.22 (m, 8 Harom), 7.34–
7.38 (m, 2 Harom).
13C NMR (75 MHz, CDCl3): d = 14.02, 19.32, 31.70, 69.60, 71.24,
71.98, 75.58, 127.96, 128.10, 128.27, 129.29, 129.45, 129.68,
133.22, 136.29, 157.26.
Anal. Calcd for C21H19NO2: C, 79.47; H, 6.03; N, 4.41. Found: C,
79.52; H, 6.04; N, 4.37.
Benzophenone Oxime O-(2-Hydroxy-1-phenylethyl) Ether (4o)
Column chromatography (silica gel, EtOAc–n-hexane, 1:4) afford-
ed the product as a bright-yellow oil. Yield: 0.60 g (19%); Rf = 0.66
(EtOAc–n-hexane, 1:2).
IR (liquid film): 3291.5 (br), 3064.5, 2938.8, 2900.4, 1665.4,
1492.6, 1232.6 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.41(s, 1 H, OH, exchangeable
with D2O), 3.96 (complex, 2 H, CH2OH), 5.28 (dd, J = 3.5, 7.4 Hz,
1 H, OCHPh), 7.16–7.38 (m, 15 Harom).
13C NMR (75 MHz, CDCl3): d = 66.12, 87.75, 114.56, 121.44,
125.59, 126.83, 128.29, 128.33, 128.39, 129.24, 129.62, 133.24,
136.25, 138.54, 158.19.
HRMS: m/z (M+) calcd for C20H25NO3: 327.1834; found: 327.1831.
Anal. Calcd for C20H25NO3: C, 73.37; H, 7.70; N, 4.28. Found: C,
73.39; H, 7.75; N, 4.25.
Benzophenone Oxime O-(2-Hydroxy-3-phenoxypropyl) Ether
(4l)
Column chromatography (silica gel, EtOAc–n-hexane, 1:9) afford-
ed the product as a bright-yellow oil. Yield: 3.16 g (91%); Rf = 0.61
(EtOAc–n-hexane, 1:2).
HRMS: m/z (M+) calcd for C21H19NO2: 317.1416; found: 317.1414.
Anal. Calcd for C21H19NO2: C, 79.47; H, 6.03; N, 4.41. Found: C,
79.50; H, 6.05; N, 4.41.
IR (liquid film): 3379.1 (br s), 3062.7, 2921.2, 2877.6, 1668.7,
1496.7, 1242.1, 1049.2 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.73 (s, 1 H, OH, exchangeable
with D2O), 3.97 (br s, 2 H, CH2ON), 4.39 (br s, 3 H, CHCH2OPh),
6.86–6.99 (m, 3 Harom), 7.20–7.32 (m, 10 Harom), 7.51 (d, J = 7.5 Hz,
2 Harom).
1-(4-Chlorophenyl)ethanone Oxime O-(2-Hydroxy-3-phenoxy-
propyl) Ether (4p)
Column chromatography (silica gel, EtOAc–n-hexane, 3:7) afford-
ed the product as a white foam. Yield: 2.81 g (88%); Rf = 0.65
(EtOAc–n-hexane, 1:2).
13C NMR (75 MHz, CDCl3): d = 69.27, 69.50, 75.34, 114.96,
121.28, 128.47, 128.64, 128.99, 129.26, 129.52, 129.89, 130.37,
133.36, 136.36, 158.02, 158.97.
IR (liquid film): 3286.5 (br s), 3052.4, 2994.4, 2878.4, 1664.2,
1458.7, 1325.3, 1054.2 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.51 (s, 3 H, CH3), 4.43–4.45
(complex, 3 H, OH, CH2ON), 4.83 (br s, 3 H, CHCH2OPh), 7.28–
7.31 (m, 3 Harom), 7.58–7.65 (m, 4 Harom), 7.82–7.85 (m, 2 Harom).
13C NMR (75 MHz, CDCl3): d = 12.91, 69.57, 69.86, 75.52, 115.18,
121.61, 127.88, 129.07, 129.63, 135.03, 135.60, 154.87, 159.21.
HRMS: m/z (M+) calcd for C22H21NO3: 347.1521; found: 347.1524.
Anal. Calcd for C22H21NO3: C, 76.06; H, 6.09; N, 4.03. Found: C,
76.01; H, 6.08; N, 4.05.
HRMS: m/z (M+) calcd for C17H18ClNO3: 319.0975; found:
319.0970.
Benzophenone Oxime O-(2-Hydroxyoctyl) Ether (4m)
Column chromatography (silica gel, EtOAc–n-hexane, 1:9) afford-
ed the product as a colorless oil. Yield: 2.83 g (87%); Rf = 0.83
(EtOAc–n-hexane, 1:2).
Anal. Calcd for C17H18ClNO3: C, 63.85; H, 5.67; Cl, 11.09; N, 4.38.
Found: C, 63.91; H, 5.66; Cl, 11.12; N, 4.34.
IR (liquid film): 3386.8 (br s), 3055.6, 2923.9, 2862.2, 1658.7,
1442.7, 1319.2, 1058.1 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.75 (t, J = 6.8 Hz, 3 H, CH3),
1.18–1.36 (m, 10 H, 5 CH2), 2.75 (s, 1 H, OH, exchangeable with
D2O), 3.85–3.97 (m, 1 H, CHOH), 4.06 (dd, J = 2.3, 11.1 Hz, 2 H,
CH2ON), 7.18–7.37 (m, 10 Harom).
1-(4-Chlorophenyl)ethanone Oxime O-(2-Hydroxycyclohexyl)
Ether (4q)
Column chromatography (silica gel, EtOAc–n-hexane, 3:7) afford-
ed the product as a bright-yellow oil. Yield: 2.32 g (87%); Rf = 0.56
(EtOAc–n-hexane, 1:2).
13C NMR (75 MHz, CDCl3): d = 14.16, 22.66, 25.43, 29.39, 31.82,
33.21, 71.17, 78.38, 127.93, 128.21, 128.33, 129.02, 129.14,
129.59, 133.07, 136.09, 157.72.
IR (liquid film): 3387.2 (br s), 3052.2, 2965.5, 2878.4, 1652.9,
1445.1, 1168.2 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.17–1.33 (m, 4 H, 2 CH2), 1.61–
1.67 (m, 2 H, CH2), 1.96–2.00 (m, 2 H, CH2), 2.14 (s, 3 H, CH3),
3.59–3.68 (complex, 2 H, CHOH), 3.92–3.93 (m, 1 H, CHON),
7.21–7.31 (m, 2 Harom), 7.51–7.53 (m, 2 Harom).
13C NMR (75 MHz, CDCl3): d = 12.56, 23.73, 24.18, 29.66, 32.56,
74.29, 86.07, 125.99, 127.24, 128.61, 135.22, 154.13.
HRMS: m/z (M+) calcd for C14H18ClNO2: 267.1026; found:
267.1023.
HRMS: m/z (M+) calcd for C21H27NO2: 325.2042; found: 325.2039.
Anal. Calcd for C21H27NO2: C, 77.50; H, 8.36; N, 4.30. Found: C,
77.53; H, 8.41; N, 4.33.
Benzophenone Oxime O-(2-Hydroxy-2-phenylethyl) Ether (4n)
Column chromatography (silica gel, EtOAc–n-hexane, 1:4) afford-
ed the product as a bright-yellow solid. Yield: 2.38 g (75%); mp
125.7 °C; Rf = 0.68 (EtOAc–n-hexane, 1:2).
Synthesis 2008, No. 13, 2055–2064 © Thieme Stuttgart · New York

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M. N. S. Rad et al.
PAPER
Anal. Calcd for C14H18ClNO2: C, 62.80; H, 6.78; Cl, 13.24; N, 5.23.
Found: C, 62.76; H, 6.75; Cl, 13.29; N, 5.27.
IR (liquid film): 3368.4 (br s), 3058.5, 2977.5, 2856.3, 1574.2,
1328.4 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.80 (s, 6 H, 2 CH3), 3.65 (s, 1 H,
OH, exchangeable with D2O), 3.92 (dd, J = 8.2, 12.0 Hz, 2 H,
CH2ON), 4.92 (dd, J = 2.1, 8.2 Hz, 1 H, CHOH), 7.18–7.33 (m, 5
1-(4-Chlorophenyl)ethanone Oxime O-(3-Butoxy-2-hydroxy-
propyl) Ether (4r)
Column chromatography (silica gel, EtOAc–n-hexane, 1:4) afford-
ed the product as a bright-yellow oil. Yield: 2.70 g (90%); Rf = 0.63
(EtOAc–n-hexane, 1:2).
Harom).
13C NMR (75 MHz, CDCl3): d = 15.64, 21.93, 74.11, 78.19, 126.26,
127.66, 128.45, 140.43, 156.29.
HRMS: m/z (M+) calcd for C11H15NO2: 193.1103; found: 193.1105.
IR (liquid film): 3364.8 (br s), 3057.3, 2957.6, 2871.4, 1642.4,
1453.1, 1161.7, 1041.9 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.74 (t, J = 7.3 Hz, 3 H, CH2CH3),
1.18–1.27 (m, 2 H, CH2), 1.37–1.45 (m, 2 H, CH2), 2.05 (s, 3 H,
CH3CN), 3.30 (t, J = 6.6 Hz, 2 H, OCH2CH2), 3.34 (s, 1 H, OH, ex-
changeable with D2O), 3.38 (dd, J = 6.0, 9.1 Hz, 2 H, OCH2CHOH),
4.00–4.04 (m, 1 H, CHOH), 4.12–4.14 (m, 2 H, CH2ON), 7.14–7.19
(m, 2 Harom), 7.38–7.42 (m, 2 Harom).
13C NMR (75 MHz, CDCl3): d = 12.28, 13.83, 19.18, 31.57, 69.58,
71.25, 71.87, 75.26, 127.17, 128.41, 134.60, 134.98, 153.75.
HRMS: m/z (M+) calcd for C15H22ClNO3: 299.1288; found:
299.1291.
Anal. Calcd for C11H15NO2: C, 68.37; H, 7.82; N, 7.25. Found: C,
68.39; H, 7.86; N, 7.23.
Propan-2-one Oxime O-(2-Hydroxy-1-phenylethyl) Ether (4v)
Column chromatography (silica gel, EtOAc–n-hexane, 1:9) afford-
ed the product as a bright-yellow oil. Yield: 0.50 g (26%); Rf = 0.43
(EtOAc–n-hexane, 1:2).
IR (liquid film): 3371.4 (br s), 3059.4, 2978.4, 2857.4, 1577.2,
1330.2 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.82 (s, 6 H, 2 CH3), 3.54 (s, 1 H,
OH, exchangeable with D2O), 3.92 (complex, 2 H, CH2OH), 4.97
(dd, J = 3.6, 7.7 Hz, 1 H, OCHPh), 7.21–7.30 (m, 5 Harom).
13C NMR (75 MHz, CDCl3): d = 15.66, 22.00, 73.81, 78.22, 126.23,
127.72, 128.41, 140.48, 156.32.
Anal. Calcd for C15H22ClNO3: C, 60.09; H, 7.40; Cl, 11.83; N, 4.67.
Found: C, 60.12; H, 7.46; Cl, 11.78; N, 4.69.
1-(4-Bromophenyl)ethanone Oxime O-(2-Hydroxy-3-phenoxy-
propyl) Ether (4s)
HRMS: m/z (M+) calcd for C11H15NO2: 193.1103; found: 193.1104.
Column chromatography (silica gel, EtOAc–n-hexane, 1:4) afford-
ed the product as a white solid. Yield: 3.13 g (86%); mp 55.9 °C;
Rf = 0.58 (EtOAc–n-hexane, 1:2).
Anal. Calcd for C11H15NO2: C, 68.37; H, 7.82; N, 7.25. Found: C,
68.40; H, 7.81; N, 7.27.
IR (KBr): 3378.5 (br s), 3058.3, 2944.2, 2886.3, 1657.6, 1495.6,
1245.7, 1047.9 cm–1.
4-Phenylbutan-2-one Oxime O-(2-Hydroxy-3-phenoxypropyl)
Ether (4w)
1H NMR (300 MHz, CDCl3): d = 2.12 (s, 3 H, CH3), 3.65 (s, 1 H,
OH, exchangeable with D2O), 4.00 (br s, 2 H, CH2ON), 4.35 (br s,
3 H, CHCH2OPh), 6.84–6.92 (m, 3 Harom), 7.17–7.23 (m, 2 Harom),
7.34–7.37 (m, 4 Harom).
13C NMR (75 MHz, CDCl3): d = 12.64, 68.95, 69.60, 74.95, 114.69,
121.61, 123.72, 127.69, 129.63, 131.99, 134.99, 154.76, 158.66.
Column chromatography (silica gel, EtOAc–n-hexane, 1:4) afford-
ed the product as a bright-yellow oil. Yield: 2.73 g (87%); Rf = 0.58
(EtOAc–n-hexane, 1:2).
IR (liquid film): 3397.4 (br s), 3061.2, 2952.1, 2874.8, 1667.3,
1495.6, 1245.2, 1047.9 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.96 (s, 3 H, CH3), 2.02 (s, 1 H,
OH, exchangeable with D2O), 2.53 (t, J = 7.1 Hz, 2 H, CH2CN),
2.88 (t, J = 7.1 Hz, 2 H, CH2Ph), 4.11–4.13 (m, 2 H, CH2ON), 4.22–
4.24 (m, 1 H, CHOH), 4.34–4.37 (m, 2 H, CH2OPh), 7.05–7.11 (m,
3 Harom), 7.27–7.42 (m, 7 Harom).
13C NMR (75 MHz, CDCl3): d = 14.59, 32.65, 37.75, 69.13, 69.83,
74.18, 114.83, 121.14, 126.36, 128.29, 128.53, 129.71, 141.09,
158.12, 158.94.
HRMS: m/z (M+) calcd for C17H18BrNO3: 363.0470; found:
363.0472.
Anal. Calcd for C17H18BrNO3: C, 56.06; H, 4.98; N, 3.85. Found: C,
56.02; H, 5.01; N, 3.89.
Propan-2-one Oxime O-(2-Hydroxy-3-phenoxypropyl) Ether
(4t)
Column chromatography (silica gel, EtOAc–n-hexane, 1:4) afford-
ed the product as a bright-yellow oil. Yield: 2.03 g (91%); Rf = 0.65
(EtOAc–n-hexane, 1:2).
HRMS: m/z (M+) calcd for C19H23NO3: 313.1678; found: 313.1675.
Anal. Calcd for C19H23NO3: C, 72.82; H, 7.40; N, 4.47. Found: C,
72.88; H, 7.36; N, 4.45.
IR (liquid film): 3300.5 (br s), 3054.5, 2933.5, 2855.1, 1650.3,
1443.4, 1115.5, 1052.5 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.95 (s, 6 H, 2 CH3), 3.30 (s, 1 H,
OH, exchangeable with D2O), 3.87 (dd, J = 3.8, 10.1 Hz, 2 H,
CH2ON), 4.32–4.37 (complex, 3 H, CHCH2OPh), 7.23–7.35 (m, 5
Fluoren-9-one Oxime O-(3-Butoxy-2-hydroxypropyl) Ether
(4x)
Column chromatography (silica gel, EtOAc–n-hexane, 3:7) afford-
ed the product as a yellow oil. Yield: 2.54 g (78%); Rf = 0.55
(EtOAc–n-hexane, 1:2).
Harom).
13C NMR (75 MHz, CDCl3): d = 15.67, 21.88, 67.23, 68.36, 74.07,
114.02, 120.17, 128.44, 154.45, 157.55.
IR (liquid film): 3374.6 (br s), 3053.5, 2975.7, 2884.2, 1651.4,
1449.6, 1113.4, 1058.2 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.63 (t, J = 5.2 Hz, 3 H, CH3),
1.05–1.11 (m, 2 H, CH2), 1.27–1.29 (m, 2 H, CH2), 3.14–3.16 (m, 2
H, CH2), 3.32–3.34 (m, 2 H, OCH2CHOH), 3.64 (s, 1 H, OH, ex-
changeable with D2O), 4.08 (br s, 1 H, CHOH), 4.28–4.31 (m, 2 H,
CH2ON), 6.91–7.15 (m, 6 Harom), 7.47–7.49 (m, 1 Harom), 8.03–8.05
(m, 1 Harom).
HRMS: m/z (M+) calcd for C12H17NO3: 223.1208; found: 223.1211.
Anal. Calcd for C12H17NO3: C, 64.55; H, 7.67; N, 6.27. Found: C,
64.50; H, 7.70; N, 6.30.
Propan-2-one Oxime O-(2-Hydroxy-2-phenylethyl) Ether (4u)
Column chromatography (silica gel, EtOAc–n-hexane, 1:9) afford-
ed the product as a yellow oil. Yield: 1.35 g (70%); Rf = 0.45
(EtOAc–n-hexane, 1:2).
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Aqueous-Mediated Ring Opening of Epoxides with Oximes To Give b-Hydroxy Oxime O-Ethers
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13C NMR (75 MHz, CDCl3): d = 14.13, 19.19, 31.60, 69.44, 71.21,
71.89, 76.81, 116.83, 119.66, 121.48, 127.66, 128.01, 129.22,
129.76, 130.29, 130.84, 135.21, 140.07, 141.17, 152.44.
(6) (a) Mordi, M. N.; Petta, M. D.; Boote, V.; Morris, G. A.;
Barber, J. J. Med. Chem. 2000, 43, 467. (b) Gharbi-
Benarous, J.; Delaforge, M.; Jankowski, C. K.; Girault, J. P.
J. Med. Chem. 1991, 34, 1117.
HRMS: m/z (M+) calcd for C20H23NO3: 325.1682; found: 325.1682.
(7) (a) De Clerk, F.; Beetens, J.; Van de Water, A.; Vercammen,
E.; Janssen, P. A. J. Thromb. Haemostasis 1989, 61, 43.
(b) Bossche, H. V.; Willemsens, G.; Bellens, D.; Janssen, P.
A. J. Biochem. Pharmacol. 1992, 43, 739.
Anal. Calcd for C20H23NO3: C, 73.82; H, 7.12; N, 4.30. Found: C,
73.79; H, 7.14; N, 4.36.
Fluoren-9-one Oxime O-(3-Allyloxy-2-hydroxypropyl) Ether
(4y)
Column chromatography (silica gel, EtOAc–n-hexane, 3:7) afford-
ed the product as a yellow oil. Yield: 2.47 g (80%); Rf = 0.45
(EtOAc–n-hexane, 1:2).
(8) (a) Abele, E.; Abele, R.; Rubina, K.; Popelis, J.; Sleiksa, I.;
Lukevics, E. Synth. Commun. 1998, 28, 2621. (b) Yamada,
T.; Goto, K.; Mitsuda, Y.; Tsuji, J. Tetrahedron Lett. 1987,
28, 4557. (c) Karakurt, A.; Dalkara, S.; Özalp, M.; Özbey,
S.; Kendi, E.; Stables, J. P. Eur. J. Med. Chem. 2001, 36,
421. (d) Merkaš, S.; Litvić, M.; Cepanec, I.; Vinković, V.
Molecules 2005, 10, 1429. (e) Abele, E.; Lukevics, E. Org.
Prep. Proced. Int. 2000, 32, 237. (f) Banerjee, T.; Dureja, P.
Molecules 2005, 10, 990. (g) Li, C. B.; Cui, Y.; Zhang, W.
Q.; Li, J. L.; Zhang, S. M.; Choi, M. C. K.; Chan, A. S. C.
Chin. Chem. Lett. 2002, 113, 95.
IR (liquid film): 3374.3 (br s), 3051.7, 2954.1, 2875.9, 1654.7,
1447.2, 1321.3, 1059.2 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.52–3.53 (m, 2 H, OCH2CHOH),
3.86 (s, 1 H, OH, exchangeable with D2O), 3.91–3.93 (m, 2 H,
CH2ON), 4.26–4.28 (m, 1 H, CHOH), 4.44–4.46 (m, 2 H,
CH2CH=C), 5.10–5.22 (complex, 2 H, =CH2), 5.75–5.91 (m, 1 H,
=CHvinyl), 7.13–7.35 (m, 6 Harom), 7.63–7.66 (m, 1 Harom), 8.17–8.20
(m, 1 Harom).
13C NMR (75 MHz, CDCl3): d = 69.50, 71.36, 72.23, 76.73, 117.08,
119.76, 121.56, 127.76, 128.10, 129.29, 129.87, 130.31, 130.95,
134.60, 135.21, 140.12, 141.22, 152.57, 160.84.
(9) (a) Nanoppa, P. D.; Pandurangan, K.; Maitra, U.; Wailes, S.
Org. Lett. 2007, 9, 2767. (b) Mooradian, A.; Dupont, P. E.
J. Heterocycl. Chem. 1967, 4, 441.
(10) (a) Jacob, B. B. Synthesis 1975, 782. (b) Nesynov, E. P.
Zh. Org. Khim. 1976, 12, 1955.
(11) Bittner, S.; Grinberg, S. J. Chem. Soc., Perkin Trans. 1 1976,
1708.
(12) Stefani, A. P.; Lacher, J. R.; Park, J. D. J. Org. Chem. 1960,
25, 676.
(13) Kolene, I.; Kočevar, M.; Polanc, S. Acta Chim. Slov. 1999,
46, 281.
HRMS: m/z (M+) calcd for C19H19NO3: 309.1365; found: 309.1369.
Anal. Calcd for C19H19NO3: C, 73.77; H, 6.19; N, 4.53. Found: C,
73.79; H, 6.23; N, 4.59.
(14) (a) Miyabe, H.; Yoshida, K.; Reddy, V. K.; Matsumura, A.;
Takemoto, Y. J. Org. Chem. 2005, 70, 5630. (b) Miyabe,
H.; Matsumura, A.; Yoshida, K.; Yamauchi, M.; Takemoto,
Y. Synlett 2004, 2123. (c) Miyabe, H.; Matsumura, A.;
Moriyama, K.; Takemoto, Y. Org. Lett. 2004, 6, 4631.
(15) (a) Bhuniya, D.; Mohan, S.; Narayanan, S. Synthesis 2003,
1018. (b) Bertelsen, S.; Dinér, P.; Johansen, R. L.;
Jørgensen, K. A. J. Am. Chem. Soc. 2007, 129, 1536.
(c) Vanderwal, C. D.; Jacobsen, E. N. J. Am. Chem. Soc.
2004, 126, 14724. (d) Fouchet, B.; Joucla, M.; Messager, J.
C.; Toupet, L. J. Chem. Soc., Chem. Commun. 1982, 858.
(e) Bhuniya, D.; Gujjary, S.; Sengupta, S. Synth. Commun.
2006, 36, 151.
(16) (a) Goda, H.; Sato, M.; Ihara, H.; Hirayama, C. Synthesis
1992, 849. (b) Watson, K. G.; Brown, R. N.; Cameron, R.;
Chalmers, D. K.; Hamilton, S.; Jin, B.; Krippner, G. Y.;
Luttick, A.; McConnell, D. B.; Reece, P. A.; Ryan, J.;
Stanislawski, P. C.; Tucker, S. P.; Wu, W.-Y.; Barnard, D.
L.; Sidwell, R. W. J. Med. Chem. 2003, 46, 3181.
(c) Jahnson, S. M.; Petrassi, H. M.; Palaninathan, S. K.;
Mohamedmohaideen, N. N.; Purkey, H. E.; Nichols, C.;
Chiang, K. P.; Walkup, T.; Sacchettini, J. C.; Sharpless, K.
B.; Kelly, J. W. J. Med. Chem. 2005, 48, 1576. (d) Goda,
H.; Ihara, H.; Hirayama, C.; Sato, M. Tetrahedron Lett.
1994, 35, 1565.
Acknowledgment
We wish to thank the Shiraz University of Technology Research
Council for partial support of this work. We are also grateful to Pro-
fessor G. H. Hakimelahi for helpful discussions.
References
(1) (a) March, J. Advanced Organic Chemistry, 4th ed.; John
Wiley & Sons (Asia) Pte. Ltd.: Singapore, 2005.
(b) Kleeman, A.; Engel, J.; Kutscher, B.; Reichert, D.
Pharmaceutical Substances, 3rd ed.; Thieme: Stuttgart,
1999. (c) Kassa, J. Clin. Toxicol. 2002, 40, 803.
(d) Freeman, J. P. Chem. Rev. 1973, 73, 283.
(e) Gowenlock, B. G.; Richter-Addo, G. B. Chem. Rev.
2004, 104, 3315.
(2) (a) Miyabe, H.; Ushiro, C.; Naito, T. Chem. Commun. 1997,
1789. (b) Miyabe, H.; Fujii, K.; Naito, T. Org. Biomol.
Chem. 2003, 1, 381. (c) Miyabe, H.; Ueda, M.; Yoshiko, N.;
Yamakawa, K.; Naito, T. Tetrahedron 2000, 56, 2413.
(d) Marco, J. A.; Carda, M.; Murga, J.; Conzález, F.;
Falomir, E. Tetrahedron Lett. 1997, 38, 1841.
(3) (a) Phillpotts, R. J.; Delong, D. C.; Wallace, J.; Jones, R. W.;
Reed, S. E.; Tyrrell, D. A. J. Lancet 1981, 1, 1342.
(b) Hayden, F. G.; Gawaltney, J. M. Jr. Antimicrob. Agents
Chemother. 1982, 21, 892. (c) Dewolfe Miller, F.; Monto,
A. S.; Delong, D. C.; Exelby, A.; Bryan, E. R.; Srivastava, S.
Antimicrob. Agents Chemother. 1985, 27, 102.
(17) (a) Kliegel, W. Justus Liebigs Ann. Chem. 1970, 733, 192.
(b) Buchalska, E.; Plenkiewicz, J. J. Mol. Catal. B: Enzym.
2001, 11, 255. (c) Bakunova, S. M.; Grigor’ev, I. A.;
Volodarsky, L. B. Russ. Chem. Bull. 1999, 48, 1389.
(d) Şen, N.; Kar, Y.; Kurbanov, S. Russ. J. Org. Chem.
(Engl. Transl.) 2007, 43, 449.
(4) Sakene, K.; Kawabata, K.; Inamoto, Y.; Yamanaka, H.;
Takaya, T. Yakugaku Zasshi 1993, 113, 605.
(5) (a) Mixich, G.; Thiele, K. Arzneim.-Forsch. 1979, 29, 1510.
(b) Artico, M.; Rango, R.; Porretta, G. C.; Massa, S.; Musin,
C.; Spiga, M. G.; Carrias, S.; La Colla, P. Med. Chem. Res.
1996, 137. (c) Wihbi, Y.; Caujolle, R.; Tournaire, C.;
Payard, M.; Linas, M. D.; Seguela, J. P. Eur. J. Med. Chem.
1995, 30, 955.
(18) (a) Bouzoubaa, M.; Leclerc, G.; Decker, N.; Schwartz, J.;
Andermann, G. J. Med. Chem. 1984, 27, 1291.
(b) Macchia, B.; Balsamo, A.; Lapucci, A.; Martinelli, A.;
Macchia, F.; Brewhi, M. C.; Fantoni, B.; Martinotti, E.
J. Med. Chem. 1985, 28, 153. (c) Blanc, M.; Tamir, A.;
Aubriot, S.; Michel, M. C.; Bouzoubaa, M.; Leclerc, G.;
Synthesis 2008, No. 13, 2055–2064 © Thieme Stuttgart · New York

2064
M. N. S. Rad et al.
PAPER
Demenge, P. J. Med. Chem. 1998, 41, 1613.
(24) (a) Khalafi-Nezhad, A.; Soltani Rad, M. N.; Khoshnood, A.
Synthesis 2003, 2552. (b) Khalafi-Nezhad, A.; Soltani Rad,
M. N.; Khoshnood, A. Synthesis 2004, 583.
(25) Buck, J. S.; Ide, W. S. Org. Synth., Coll. Vol. II 1943, 623.
(26) Smith, P. A. S.; Robertson, J. E. J. Am. Chem. Soc. 1962, 84,
1197.
(27) Buehler, E. J. Org. Chem. 1967, 32, 261.
(28) Smith, S. G.; Milligan, D. V. J. Am. Chem. Soc. 1968, 90,
2393; and references cited therein.
(19) (a) Albrecht, U.; Gerwien, K.; Langer, P. Tetrahedron Lett.
2005, 46, 1017. (b) Donald, J. R.; Edwards, M. G.; Taylor,
R. J. K. Tetrahedron Lett. 2007, 48, 5201. (c) Wan, X.;
Doridot, G.; Joullié, M. M. Org. Lett. 2007, 9, 977.
(d) Koca, M.; Ahmedzade, M.; Çukurovali, A.; Kazaz, C.
Molecules 2005, 10, 747.
(20) Wilson, C. O.; Gisvold, O.; Block, J. H. Wilson and
Gisvold’s Textbook of Organic Medicinal and
Pharmaceutical Chemistry, 11th ed; Block, J. H.; Beale, J.
M. Jr., Eds.; Lippincott Williams & Wilkins: Philadelphia,
2004.
(29) Raczyńska, E. D.; Krygowski, T. M.; Zachara, J. E.;
Ośmiałowski, B.; Gawinecki, R. J. Phys. Org. Chem. 2005,
18, 892.
(30) The ab initio (6-31G) quantum mechanical calculations were
run using Gaussian 98 Version 9.2 software. The
semiempirical AM1 and PM3 calculations were run on
MOPAC in CS Chem 3D Ultra 8 (CambridgeSoft, 2004) and
Hyperchem (Hypercube Inc., Version 7).
(31) Paul, J. H. US Patent 4158015, 1979; Chem. Abstr. 1979, 91,
P107810v.
(32) The separation of (E)- and (Z)-acetophenone oximes was
achieved following a procedure in ref. 31.
(21) (a) Nogrady, T.; Weaver, D. F. Medicinal Chemistry: A
Molecular and Biochemical Approach, 3rd ed.; Oxford
University Press: New York, 2005. (b) Thomas, G.
Medicinal Chemistry: An Introduction; John Wiley & Sons
Ltd.: New York, 2000. (c) Yuzhakov, S. D.; Glushkov, R.
G.; Mashkovskii, M. D. Pharm. Chem. J. 1991, 25, 283.
(22) (a) Leclerc, G.; Mann, A.; Wermuth, C. G. J. Med. Chem.
1977, 20, 1657. (b) Mann, A.; Leclerc, G.; Wermuth, C. G.;
Miesch, F.; Imbs, J. L.; Schwartz, J. A. Br. J. Pharmacol.
1977, 60, 357.
(33) Vogel, A. I. In Practical Organic Chemistry; Longmans,
Green and Co.: London, 1954, Chap. II, 161–176.
(23) Grieco, P. A. Organic Synthesis in Water; Blackie
Academic & Professional: London, 1998.
Synthesis 2008, No. 13, 2055–2064 © Thieme Stuttgart · New York