The investigation of the alkylation reactions of hydroxy and en-oximes with some halohydrins and epoxides

Article abstract of DOI:10.1081/SCC-120030754

Suitable glycol ethers (3a-d, 4a-d) and halohydrin compounds (11a-c) were synthesized in good yield by the alkylation reactions of the oximes, having hydroxy and double bond in its structure, with mono- and dihalogenhydrines in the medium of basic and solid-liquid phase transfer catalyst. A series of aminoalcohols were synthesized from these compounds obtained (16a, 17b, 18b).

Full text of DOI:10.1081/SCC-120030754

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The Investigation of the Alkylation Reactions of
Hydroxy and En‐Oximes with Some Halohydrins and
Epoxides
a
Sultan Kurbanlı , Nejdet Şen a , Ersin Güler a & Ahmet Koçak a
a Department of Chemistry, Faculty of Arts and Sciences , Selçuk University , Kampus,
Konya, 42031, Turkey
Published online: 16 Aug 2006.
To cite this article: Sultan Kurbanlı , Nejdet Şen , Ersin Güler & Ahmet Koçak (2004) The Investigation of the Alkylation
Reactions of Hydroxy and En‐Oximes with Some Halohydrins and Epoxides, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 34:9, 1663-1675, DOI: 10.1081/SCC-120030754
To link to this article: http://dx.doi.org/10.1081/SCC-120030754
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 9, pp. 1663–1675, 2004
The Investigation of the Alkylation
Reactions of Hydroxy and En-Oximes
with Some Halohydrins and Epoxides
*
Sultan Kurbanlı, Nejdet S¸en, Ersin Gu¨ler, and
Ahmet Koc¸ak
Department of Chemistry, Faculty of Arts and Sciences, Selc¸uk
University, Konya, Turkey
ABSTRACT
Suitable glycol ethers (3a–d, 4a–d) and halohydrine compounds (11a–c)
were synthesized in good yield by the alkylation reactions of the oximes,
having hydroxy and double bond in its structure, with mono- and dihalo-
genhydrines in the medium of basic and solid–liquid phase transfer cata-
lyst. A series of aminoalcohols were synthesized from these compounds
obtained (16a, 17b, 18b).
Key Words: Halohydrins; Epoxides; Ethers; Oximes.
*
Correspondence: Nejdet S¸en, Department of Chemistry, Faculty of Arts and Sciences,
Selc¸uk University, Kampus 42031, Konya, Turkey; E-mail: nsen@selcuk.edu.tr.
1663
DOI: 10.1081/SCC-120030754
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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1664
Kurbanlı et al.
INTRODUCTION
It has been recognized that many of the oxime derivatives possess biologi-
cal,[1] physiological,[2] antihistaminic,[3] and antimicrobic[4] properties. O- and
N-alkyl oximes have been obtained by the alkylation of oximes with alkyl
halides,[5,6] monohalohydrins,[7,8] and some epoxides.[9,10] It has also been
reported that only O-alkyl derivatives could be obtained by the alkylation of
oximes with alkyl halides.[11]
In this study, as a continuation of our previous studies, different new gly-
col ethers bonded to oxygen and nitrogen of the oximes which have double
bond and hydroxyl group in its structure, glycide ethers (epoxy compounds)
coupled to 3a–d and 4a–d were synthesized. Depending upon the reaction
conditions and the structure of the output substances (aliphatic or aromatic),
structure and steroisomers of the products obtained were researched. The
properties were given in Tables 1 and 2.
The oximes, used in 1a–d reactions, were used both in the form of isomer
mixtures and also in the form of anti- or syn-isomers.[12,13]
As shown in Eq. (1), the ratio of oximes formed by the syn- and anti-
isomers to the 3a–d and 4a–d products obtained appropriately by the alkyl-
ation with the 1a–d, ethylenechloro(bromo)hydrines is 92 : 7. However, this
ratio is 70 : 30 when the syn-oximes were used. By the usage of anti-
isomers, this ratio decreases further (52 : 48). The other properties were
given in Table 3.
On the other hand, depends on the reaction conditions, catalyst and sol-
vents also have important role. While O-alkyl products gain more superiority
in the medium of acetonitrile and DMSO (Method A), while the yield and
structure of reaction products are not influenced so much in the catalyst of
NaOH, Na2CO3 and in the medium of protic solvents, the yield of (Na2CO3 þ
TDA-1, (Method B), NaOH þ TEBA in benzene (Method C), 3a and 3b
compounds became very high (64–70%) in the liquid–solid transfer catalyst
(Eq. 1).

ORDER
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Alkylation Reactions of Hydroxy and En-Oximes
1665

ORDER
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1666
Kurbanlı et al.
Table 2. Spectroscopic data of the newly synthesized compounds.
IR (nmax/cm21
N–O
)
Compound C55N
OH
Other
—
1H NMR (dH/ppm)
3a
1,670
975
1,080
3,450
1.1 (3H, t, CH3), 2.45 (br, s,
2OH), 2.20 (2H, m, CH2),
3.70–3.80 (4H, m, OCH2
CH2O), 4.1 (1H, m, CH),
6.65 (1H, d, HC55N, anti),
7.40 (1H, d, HC55N, syn)
1.15 (3H, t, CH3), 2.64 (br, s,
2OH), 5.80 (1H, m,55CH),
6.42 (1H, m, CH55N),
3.65 (2H, m, OCH2), 3.72
(2H, m, CH2O), 6.8 (1H,
qv, HC55, trans, J ¼
3b
1,680
995
1,050
3,500
—
16 Hz), 6.65 (1H, m,
HC55N, anti), 7.45 (1H, t,
HC55N, syn), 7.10, 7.25
(5H, m, Ar)
3c
3d
4a
1,675
1,690
1,660
990
1,040
3,400
—
—
—
2.50 (br, s, 2OH), 3.95 (2H,
m, OCH2), 3.78 (2H, m,
OCH2), 1.50–1.85 (4H,
CH2CH2), 4.2 (1H, CHO),
6.72 (1H, t, HC55N, anti),
7.40 (1H, t, HC55N, syn),
7.10, 7.5 (5H, m, Ar)
940
1075
3,450
2.48 (br, s, 2OH), 3.70 (2H,
m, CH2O), 3.75 (2H, m,
OCH2),5.80(1H,m,55CH),
6.50 (1H, m, OCH2), 6.80
(1H, qv, HC55, trans,
J ¼ 16 Hz), 7.10, 7.40
(5H, m, Ar)
1,265
1,080
3,400
1.18 (3H, t, CH3), 2.38 (br, s,
OH), 2.20 (2H, m, CH2),
4.15 (2H, t, N–CH2),
3.65–3.80 (4H, m, 2CH2),
4.36 (1H, m, CHO), 6.70
(1 H, q, HC55N, anti)
(continued)

ORDER
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Alkylation Reactions of Hydroxy and En-Oximes
1667
Table 2. Continued.
IR (nmax/cm21
N–O
)
Compound C55N
OH
Other
1H NMR (dH/ppm)
4b
4c
4d
9a
9b
1,680
1,675
1,665
1,690
1,685
1,275
1,270
1,280
960
1,080 1,180a 1.2 (3H, t, CH3), 2.50 (br, s,
3,400
OH), 3.75 (2H, m, CH2O),
5.80 (1H, m, 55CH), 6.45
(1H, m, CH55N), 6.78
(1H, qv, HC55, trans,
J ¼ 16, 5 Hz), 6.65 (1H,
m, HC55N, anti)
1,035
3,450
—
2.20 (2H, m, CH2), 2.43 (br,
s, 2OH), 3.90 (2H, m,
CH2), 3.65–3.70 (4H, m,
2CH2O), 4.2 (1H, m,
CHO), 6.85 (1H, m,
HC55N, anti), 7.2–7.4
(5H, m, Ar)
1,050 1,185a 2.52 (br, s, 2OH), 3.70 (2H, m,
3,450
CH2O), 3.78 (2H, m, N–
CH2), 5.82 (1H, m,55CH),
6.48 (1H, m, CH55N), 6.84
(1H, qv, HC55, trans,
J ¼ 16Hz), 7.20, 7.40 (5H,
m, C6H5)
1,050
3,450
765b 1.10 (3H, t, CH3), 1.30–1.45
(2H, m, 2OH), 2.20 (2H, m,
OCH2), 2.45 (2H, t, CH2),
3.82 (2H, m, CH2Cl), 4.2
(1H, m, CHO), 6.65 (1H, t,
HC55N, anti), 7.25 (1H, m,
HC55N, syn)
965
1050
3400
740b 1.22 (3H, t, CH3), 2.20 (br, s,
OH), 2.45 (2H, m, OCH2),
3.78 (1H, m, CHO), 3.85
(2H, m, CH2Cl), 6.72 (1H,
m, HC55N, anti), 7.15
(1H, m, HC55N, syn), 6.84
(1H, q, HC55, trans,
J ¼ 15.8 Hz)
(continued)

ORDER
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1668
Kurbanlı et al.
Table 2. Continued.
IR (nmax/cm21
)
Compound C55N
N–O
OH
Other
1H NMR (dH/ppm)
10a
1,675
940
1,040
3450
730b 1.15 (3H, t, CH3), 4.2 (br, t,
OH), 4.47 (1H, q, CHO),
2.3 (2H, m, CH2–C55),
2.45 (2H, m, OCH2), 3.72
(2H, m, CH2O), 4.3 (1H,
q, CH–Br), 7.6 (1H, q,
CH55N, anti, J ¼ 16.4 Hz)
745b 2.1 (3H, d, CH3), 2.42 (2H, m,
OCH2), 4.2 (1H, q, CH–
Br), 3.68 (2H, m, CH2O),
4.35 (br, t, OH), 6.72 (1H,
q, CH55, trans, J ¼ 15,
10b
1,680
935
1,050
3,500
6 Hz), 6.78 (1H, s, CH55N,
trans), 6.82 (1H, q,55CH),
11a
11b
1,690
1,680
930
940
1,040 1,260c 1.1 (3H, d, CH3), 2.25 (br, s,
3,400
OH), 2.3–1.2 (2H, m,
CH2–C55), 2.45 (2H, m,
OCH2), 3.2 (2H, t, CH255),
4, 2 (1H, m, CHO), 6.73
(1H, s, CH55N, trans)
1,050 1,265c 1.6 (3H, t, CH3), 2.25 (2H,
3450
m, OCH2), 3.56 (1H, m,
CHO), 4.15 (2H, t,
CH255), 6.73 (1H, s,
CH55N, trans), 6.82 (1H,
m, 55CH), 7.8 (1H, m,
CH55, trans, J ¼ 16.8 Hz)
1.21 (3H, d, CH3), 2.18 (br, s,
OH), 2.34 (2H, m, CH2–
C55), 6.84 (1H, s, CH55N,
trans, J ¼ 16.8 Hz), 2.44
(2H, m, OCH2), 4.15 (1H,
q, CHO–), 2.40 (1H, s,
OH), 2.3 (2H, m, CH2–N),
1.4–1.8 (4H, m,
16a
1,685
945
1,050
3,450
—
–N(CH2)2), 1.45
(3H, t, CH3)
(continued)

ORDER
REPRINTS
Alkylation Reactions of Hydroxy and En-Oximes
1669
Table 2. Continued.
IR (nmax/cm21
N–O
)
Compound C55N
17b 1,670
OH
Other
—
1H NMR (dH/ppm)
960
1,080
3,400
1.2 (3H, t, CH3), 2.32 (2H,
m, OCH2), 4.1 (1H, q,
CHO), 2.30 (br, s, OH),
3.3–3.8 (4H, t, 2CH2, ring
morpholin), 6.68 (1H, d,
HC55N, anti), 7.32 (br,
HC55N, syn), 6.73 (1H,
brs, CH55N, trans)
18b
1,675
945
1,080
3,450
—
1.12 (3H, t, CH3), 2.42 (2H,
m, OCH2), 4.15 (1H, q,
OH), 1.35–1.65 (6H, m,
3CH2 ring), 4.1 (1H, m,
CHO), 4.42 (br, t, OH), 2.2
(2H, m, CH2N), 6.84 (1H,
m, CH55), 7.6 (1H, t,
55CH, trans), 7.4 (1H, s,
CH55N, trans)
20a
1,670
980
—
—
1.1(3H, d, CH3), 1.3–1.8
(6H, m, 2OCH3), 4.3 (1H,
q, CHO), 2.4 (1H, s, OH),
3.2 (2H, t, CH2C55), 3.90
(1H, m, CHO), 4.10 (2H,
d, OCH2), 6.82 (1H, s,
CH55N, trans)
aC–N.
bC-halide.
cEpoxy.
Compounds 3a–d were characterized by physical methods. Besides this,
compounds 3a and 3b from reaction of 1a–b with ethylene oxide in acetone in
the presence of base are shown in were also characterized by authentic synth-
eses (Eq. 2).

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1670
Kurbanlı et al.
Table 3. The yield of the O- and N-alkyl derivatives from anti- and
syn-oximes.
Product (%)
Anti
O-Alkyl
N-Alkyl
Syn-
O-Alkyl
N-Alkyl
1a
1b
1d
3a (56)
3b (49)
3d (42)
4a (18)
4b (24)
4d (12)
1a
—
1d
3a (64)
4a (4)
3d (58)
4d (17)
In this study, both isomer mixtures and also anti-, syn-isomers were used
as initially. The yield of the products obtained is given (Tables 1 and 3).
Oximes 1a–d reacted easily with 1,3-dichloro-2-propanol (6), 1-bromo-
3-chloro-2-propanol (7), and 2,3-dichloro(bromo)propanol (8) to give the
corresponding O-alkyl derivatives of oximes 9a, b and 10a, b exclusively in
58–72% yield. Compound 9a, b and 10a, b were converted to corresponding
glycidic ethers 11a, b in 82–85% yield by heating in the presence of base
(Eq. 3).
These glycidic ethers were also obtained by the reactions of 1a, b with
epichlorohydrin (Eq. 4). The reaction of sodium salts of oximes with
epichlorohydrines was carried out at heterogeneous phase and obtained with
a high yield. 11b was obtained with a high yield in the reaction of only 3b
compound with epichlorohydrine in the medium of anhydrous THF (Method
A). The reaction of epichlorohydrine with oximes was carried out by either the
transposition of chloride atom or the opening of epoxide ring.[14]
The appropriate aminoalcohols 16a, 17b, 18b and monohalogen salts 19a,
19b has been synthesized by the reactions of 11a with diethylamine (13), and
11b with morpholine (14) and piperydine (15). The reactions are shown as

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Alkylation Reactions of Hydroxy and En-Oximes
1671
follows in Eqs. (5) and (6). It is written in the literature that this kind of com-
pound have the b-adrenergic blocking and adrenaric effect.[15]
The corresponding dioxolane derivatives were obtained from epoxide
compounds by reacting with aldehydes and ketones (20a, b) (Eq. 7).
The compound 16a was also synthesized by treatment of 1a with 21.
EXPERIMENTAL SECTION
Infrared spectra were recorded on a Pye Unicam SP1025 spectrometer.
1H NMR spectra were obtained on a Varian T100-A spectrometer at

ORDER
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1672
Kurbanlı et al.
100 MHz. All spectra used tetramethylsilane as the internal standard and
were run in CDC13. Elemental analyses were obtained using a Carlo Erba
1106 automatic elemental analyses instrument. Melting points were
recorded on a electrothermal digital melting point apparatus, and are uncor-
rected. Thinlayer chromatography was carried out on Merck 5735 Kieselgel
60 F254 fluorescent plates.
Synthesis of Oximes: General Procedure[12–14]
Hydroxylamine hydrochloride (0.5 mol) and Na2CO3 (0.5 mol) in 100 mL
of benzene were stirred at 608C for 45 min. The aldehyde (0.5 mol) was then
added dropwise and stirring was continued at 808C for 4–5 hr, after that
organic phase was separated from the salt by filtration and neutralized with
2 N acetic acid. The separated organic phase was dried over MgSO4 and sol-
vent evaporated in vacuo. The residue was fractionally distilled under reduced
pressure to give 1a–d.
Alkylation of Oximes with 2-Chloro- and 2-Bromoethanol (3a–d,
4a–d). Method A: 0.032 mol 1a, b or 1c, d was added to the solution of
sodium methoxide (prepared from 0.032 mol sodium in 30 mL methanol)
and the mixture was refluxed for 1 hr. After removing the solvent under
reduced pressure, the residue was dissolved in acetonitrile (DMFA,
DMSO). Later, 5 mL (0.063 mol) ethylenechloro(bromo)hydrine were added
and were stirred for 4–5 hr at 40–458C. The precipitated NaCl (NaBr) was
removed by filtration. Solvent was removed under reduced pressure and the
residue was diluted with water and extracted with ether (3 ꢀ 15 mL).
The organic phase was dried over Na2SO4 and the solvent was evaporated.
The crude oil was chromatographed on Al2O3 by using MeOH as cleaner.
Method B: 0.032 mol of corresponding oxime were added to a methanol
solution of sodium methoxide (prepared by the addition of 0.032 mol sodium
in 30 mL dry methanol). The mixture was refluxed for 1 hr and the solvent was
removed under reduced pressure and residue was dissolved in 45 mL aceto-
nitrile solution containing 0.1 mL TDA-1 and later 5 mL (5.9 g, 0.063 mol)
epichlorohydrine were added and after stirring for 10–12 hr. The precipitated
NaCl was filtered. The filtered solution was allowed to stand for 8–10 hr and
later extracted with chloroform (2 ꢀ 30 mL). The organic phase was dried
over Na2SO4, solvent was evaporated, the compounds 3a–d and 4a–d were
crystallized with ethylacetate.
Method C: 15 g (0.21 mol) oxime were added over a period of 30 minutes
at 65–708C to the mixture of 12 g (0.3 mol) NaOH, 12 mL H2O, 20 mL ben-
zene or toluene, 1.2 g (0.0013 mol) TEBA and 0.21 mol (26.6 g) ethylenchloro
(bromo)hydrin or epichlorohydrin. Later, the reaction mixture was stirred for

ORDER
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Alkylation Reactions of Hydroxy and En-Oximes
1673
1 hr at 75–808C and the precipitated NaCl (NaBr) was removed by cooling.
The reaction mixture was dried over Na2SO4 by washing with water. The sol-
vent was evaporated under reduced pressure and product was removed by vac-
uum distillation and purified by transmitting from column chromatography
(Al2O3, CH2Cl2 : ethylacetate ¼ 3 : 1).
Synthesis of 3a and 3b. A mixture of 3-hydroxybutanal (1a) (0.1 mol) or
2-butanol (1b) and NaOH (5 N, 12 mL) in acetone (45 mL) was stirred at
40–458C for 5 hr. The temperature was increased 60–658C and ethylene
oxide gas was passed through the solution. The solution was neutralized
with 2 N acetic acid, extracted with diethyl ether. The solvent was dried
over Na2SO4, evaporated in vacuo and finally the residue was fractionally
distilled to give 3a and 3b in approximately 64% and 68% yields, respectively.
Alkylation of Oximes with Dihalohydrins: General Procedure
A mixture of aldoxime (0.25 mol) and NaOH (5 N, 28.5 mL) in acetone
(65 mL) was stirred at 40–458C for an hour. After the mixture was heated to
60–658C, compound 6 (or 7 or 8) was added and stirred for 3 hr. The sol-
ution was neutralized with 2 N acetic acid, extracted with ether (3 ꢀ 50 mL);
this was followed by extraction with chloroform (3 ꢀ 50 mL) and the
extracts were dried over MgSO4. Compound 9a, b and 10a, b were
obtained from etheral phase after evaporation of the solvent and subsequent
fractional distillation. No product was obtained from the chloroform
extracts.
Synthesis of 11a,b: General Procedure
Compounds 9a, b (0.25 mol) or 10a, b (0.25 mol) and NaOH pellets
(0.30 mol) in Et2O (65 mL) were refluxed for 5 hr. The organic phase was sep-
arated from the precipitated salt, washed with distilled water until the solution
become neutral and dried over Na2SO4. After evaporation of the solvent in
vacuo, the residue was fractionally distilled under reduced pressure to afford
compounds 11a, b.
Synthesis of 11a, b. Compounds 1a or 1b (0.25 mol) and NaOH (5 N,
28.5 mL) in acetone (75 mL) were stirred at 458C for 40 min and 12
(0.25 mol) was added. The reaction mixture was heated up to 60–658C and
stirred for 3 hr, after which the solution was neutralized with 2 N acetic
acid, extracted with diethyl ether and dried over Na2SO4. After evaporation
of the solvent in vacuo, the residue was fractionally distilled under reduced
pressure to afford 11a or 11b in a 85% and 82% yield, respectively.

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1674
Kurbanlı et al.
Synthesis of 16a, 17b, 18b, 19a, and 19b: General Procedure
Compounds 11a/11b (0.18 mol), the amine (13 or 14 or 15) (0.25 mol)
and 5–6 drops of distilled water were heated at 75–808C with stirring for
6–7 hr. After evaporation of excess amine, 16a, 17b, 18b were fractionally
distilled under reduced pressure, after that, 19a and 19b were obtained as
HCl salts of 16a and 17b.
Synthesis of 16a. A mixture of 1a (0.05 mol) and NaOH (5 N, 20 mL) in
acetone (25 mL) were stirred at 408C for 40 min. By increasing the tempera-
ture up to 658C, 21 (0.05 mol) was added and stirring was continued for
5 hr. The solution was neutralized with 2 N acetic acid, extracted with Et2O
and the organic phase was dried over Na2SO4. Evaporation of the solvent
which was followed by fractional distillation, gave 16a in a 74% yield.
Synthesis of 20a, b. To a solution of 11a or 11b (0.25 mol) in acetone at
.
08C was added 4–5 drops of BF3 Et2O. The reaction mixture was allowed to
warm to room temperature and stirred for 7–8 hr. After evaporation of excess
acetone, the residue was fractionally distilled to afford compounds 20a or 20b.
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Received in the UK July 29, 2003

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