Synthesis and characterization of new 4-alkyl-2-arylmorpholin-2-ol hydrochlorides

Article abstract of DOI:10.1081/SCC-200048931

The synthesis of 4-alkyl-2-arylmorpholin-2-ol hydrochlorides by diastereoselective reaction of 2-bromoacetophenones with β-aminoalcohols has been accomplished. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1081/SCC-200048931

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Synthesis and
Characterization of New
4‐Alkyl‐2‐Arylmorpholin‐2‐ol
Hydrochlorides
Teresa Mancilla a , Luis S. Zamudio‐Rivera a , Hiram
I. Beltrán a , Lourdes Carrillo a & Norberto Farfán a
a Departamento de Química , Centro de
Investigación y de Estudios Avanzados del Instituto
Politécnico Nacional , Apartado Postal 14‐740,
México D.F., CP 07360, México
Published online: 28 Jul 2007.
To cite this article: Teresa Mancilla , Luis S. Zamudio‐Rivera , Hiram I. Beltrán ,
Lourdes Carrillo & Norberto Farfán (2005) Synthesis and Characterization of
New 4‐Alkyl‐2‐Arylmorpholin‐2‐ol Hydrochlorides, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 35:3,
357-369, DOI: 10.1081/SCC-200048931
To link to this article: http://dx.doi.org/10.1081/SCC-200048931
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Synthetic Communicationsw, 35: 357–369, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200048931
Synthesis and Characterization of New
4-Alkyl-2-Arylmorpholin-2-ol
Hydrochlorides
´
Teresa Mancilla, Luis S. Zamudio-Rivera, Hiram I. Beltran,
´
Lourdes Carrillo, and Norberto Farfan
´ ´
Departamento de Quımica, Centro de Investigacion y de Estudios
´ ´
Avanzados del Instituto Politecnico Nacional, Mexico
Abstract: The synthesis of 4-alkyl-2-arylmorpholin-2-ol hydrochlorides by diastereo-
selective reaction of 2-bromoacetophenones with b-aminoalcohols has been
accomplished.
Keywords: Arylmorpholine, hydrochlorides, morpholinol, hemiacetal, hydroxyalkyl-
amino ketones, NMR, X-ray structure, theoretical calculations
4-Alkyl-2-arylmorpholin-2-ol hydrochlorides are biologically important
compounds that exhibit hypocholesterolemic, hypolipidemic, antioxidant,
and analgesic activity[1–7] Various 4-alkyl-2-arylmorpholin-2-ol hydrochlo-
rides have been prepared in yields between 34 and 87%[1,6,8] by stirring a
mixture of a b-aminoalcohol for 16 to 24 h with a variety of 2-bromoaceto-
phenones at room temperature.
Our current interest in 4-alkyl-2-arylmorpholin-2-ol hydrochlorides
prompted us to develop better reaction conditions to synthesize these
compounds in good yield. Thus, we describe herein the synthesis and charac-
terization of nine new 4-alkyl-2-arylmorpholin-2-ol hydrochlorides (1a–1c,
Received in the USA October 29, 2004
Address correspondence to Teresa Mancilla, Departamento de Quımica, Centro de
´ ´
Investigacion y de Estudios Avanzados del Instituto Politecnico Nacional, Apartado
´
´ ´
Postal 14-740, Mexico D.F. CP 07360, Mexico. E-mail: tmancill@mail.cinvestav.mx

358
T. Mancilla et al.
Scheme 1.
2a–2c, 3a–3c) (Scheme 1). The structure of compound 2b was further
established by a single-crystal X-ray diffraction study.
RESULTS AND DISCUSSION
4-Alkyl-2-arylmorpholin-2-ol hydrochlorides 1a–1c, 2a–2c, and 3a–3c were
prepared in yields between 84–93% by reaction of 2-bromoacetophenones
a–c with N-benzylamino ethanol (1), (1S,2S)-( þ )-pseudoephedrine (2),
and (1R,2R)-( 2 )-pseudoephedrine (3). 1H NMR spectra evidenced
formation of a single diastereoisomer with the OH group axial due to the
anomeric effect. In all cases the proton spectra showed a broad signal for
the NþH2Cl proton in the range between 10.38 to 10.85 ppm and AB
systems for diastereotopic protons at position 3 (3.00–3.65 ppm) and the
1
benzylic protons (4.33–4.47 ppm). Tables 1 and 2 summarize the H NMR
spectra data for compounds 1a, 1c and 2a–2c, 3a–3c, respectively. The 13C
NMR chemical shift for C-2 (93.50 to 94.80 ppm) remains fairly constant.
Since the signals for C3, and C6, and C15 in 1a, 1b, and 1c; C3–C5 in
2a–2c and 3a–3c and the signals for the aromatic protons, have similar
chemical shifts, unambiguous assignment was established using HETCOR
spectra. Moreover the signals for C7, C10, and C11 in 1c; C7, C10, C11,
1
and C17 in 2c and 3c were assigned using H-(2JCH)13C COLOC spectra.
Tables 3 and 4 summarize the 13C NMR data for the compounds studied.
The IR spectra show the nOH band (3406 and 3422 cm21), nNH (2362 to

New 4-Alkyl-2-Arylmorpholin-2-ol Hydrochlorides
359
d

360
T. Mancilla et al.
d

New 4-Alkyl-2-Arylmorpholin-2-ol Hydrochlorides
361
d

362
T. Mancilla et al.
d

New 4-Alkyl-2-Arylmorpholin-2-ol Hydrochlorides
363
2702 cm21), nCHarom. (3004 to 3062 cm21), and nCO in the range between 1062
to 1094 cm21
.
The 70 eV EI mass spectra did not show the ion molecular in any of the
cases. The ion fragments at m/z ¼ 91 and m/z ¼ 58 correspond to the base
peak for compounds 1a–1c and 2a–2c, 3a–3c, respectively.
The structure of 2b was established by a single-crystal X-ray diffraction
analysis (Fig. 1). In general, all bond distances are within the expected values,
and the torsion angles indicate that the methyl and phenyl groups are in
equatorial positions and the hydroxyl group in axial ones due to anomeric
effect. The configuration of new stereogenic center (C-1) is R while that of
nitrogen is S. The crystal structure shows O-H and Cl-H intermolecular, as
well as O-H and N-H intramolecular contacts, which are significantly
shorter than the sum of their van der Waals radii.[9] Selected geometrical
parameters are given in Table 5.
It is important to notice that the 1H and 13C NMR spectra of the reaction
mixture in CDCl3, before acidification, showed the presence of a mixture
of 4-alkyl-2-arylmorpholin-2-ols and 2-[(2 hydroxyethyl)alkylamino]-1-aryl-
ethanones in a 95 : 5 ratio approximately. However, the mixture of compounds
could not be separated using different solvents and chromatographic pro-
cedures, probably due to the existence of a tautomeric equilibrium between
hemiacetal and hydroxyalkylamino ketones forms[8] (Scheme 2).
In general the chemical shifts of the morpholinols are very similar to
their corresponding hydrochlorides. The N-benzyl derivatives show four
bond couplings between H3a and H5a. Unambiguous identification of the dia-
stereotopic H5 and H6 protons was established from their coupling constant
values and (1H-1H) NOESY techniques, which allowed to assign H5B and
Figure 1. Molecular structure of 2b showing the crystallograpic numbering.

364
T. Mancilla et al.
˚
Table 5. Select bond distances (A), torsion angles (deg), intermolecular and intra-
˚
molecular contacts (A) for 2b
Bond distances
C1-O1
1.411 (7)
1.405 (7)
1.418 (6)
C2-N1
C3-N1
1.488 (7)
1.512 (8)
C1-O2
C4-O1
Torison angles
C12-C3-N1-C11
C12-C3-C4-C13
H2b-C2-N1-C11
Intermolecular contacts
O1-H11b
70.39
268.33
269.41
H2c-C2-N1-C11
O2-C1-C2-H2b
O2-C1-C2-H2c
48.29
53.39
2171.39
2.562
Cl1-H2a
2.339
Intramolecular contacts
O1-H2a
O1-H2a
2.464
1.958
2.471
2.493
2.442
2.777
N1-H11a
N1-H1b
N1-H11c
N1-H12a
N1-H12c
2.024
2.034
2.036
2.640
2.650
O2-H4a
O2-H2b
O2-H6a
Cl2-H9a
H6A to the axial position while H5A and H6A are equatorial. The com-
pounds derived from pseudoephedrines exhibit a doublet for H6 in the
range between 4.69–4.70 ppm with an average coupling constant of 9.5 Hz,
which indicates that the methyl (R3) and phenyl groups (R6) are equatorial.
This was confirmed using (1H-1H) NOESY spectra which showed a
correlation between H8 and H6.
The 13C NMR data for morpholinols shows C-2 is in the range between
94.71 to 94.91 ppm, characteristic of a hemiacetal carbon. Since the signals
of C-3, C-6, and C-7 for compounds derived from 2-benzylaminoethanol,
and C-3 and C-5 for compounds derived from pseudoephedrines have
Scheme 2.

New 4-Alkyl-2-Arylmorpholin-2-ol Hydrochlorides
365
Figure 2. Conformation calculated for the intermediate a-(N-benzyl-ethanolamino)-
acetophone.
similar chemical shifts, unambiguous identification was established using
HETCOR spectra and aromatic carbons with similar chemical shifts using
13C-1H COLOC spectra.
In order to investigate if the formation of 4-benzyl-2-phenylmorpholin-2-
ol is thermodynamically favored, a theoretical calculation (AMI) was
performed providing a DHreac ¼ 0.596 Kcal/mol at 298 K for the formation
of the intermediate a-(N-benzyl ethanolamino)-acetophenone. This value is
indicative of a thermodynamic process for the transformation to 4-benzyl-2-
phenylmorpholin-2-ol, which should proceed through a prefered confor-
mation, which was also calculated. Figure 2 depicts this particular con-
formation where there is an intramolecular interaction between the OH
group and the carbonyl group, which increases the nucleophilicity of this O
group an favors formation to the morpholinol.
EXPERIMENTAL
General
NMR spectra were recorded on JEOL GXS-270, JEOL ECLIPSE-400,
and Bruker Avance 300-DPX spectrometers. 1H and 13C chemical shifts
are relative to internal SiMe4 (TMS), (d1H ¼ 0, d13C ¼ 0). CDCl3 and
DMSO-d6 were used as solvents. Mass spectra were obtained with a

366
T. Mancilla et al.
Hewlett-Packard 5994-A instrument, and Infrared spectra were recorded as
KBr pellets on a Perkin-Elmer 16F PC FT-IR spectrometer. Melting points
were taken in open capillary tubes on a Gallemkamp MFB-595 apparatus
and are uncorrected. The single-crystal X-ray study was performed on an
ENRAF NONIUS CAD4 diffractometer. Compound 2b, C18H21Cl2NO2
(MW ¼ 353.82), crystallized in the space group P212121, orthorhombic,
from acetone/ethanol as colorless rectangular prisms, size: 0.16 ꢀ 0.12 ꢀ
3
˚
0.10 mm with a ¼ 6.8560(10), b ¼ 12.097(2), c ¼ 21.849(4) A, V ¼ 1812.5
3
(5) A . Lattice constants were determined from least-squares refinement
˚
on diffractometer angles for 24 automatically centered reflections; r
1.172 Mg/m3, Z ¼ 4, m ¼ 0.217 mm21, F (000) ¼ 680. Data collection:
monitoring of check reflexion showed no signs of decay. A total of 2552
reflections were measured (2 . u . 268), 2373 were independent, and of
these 928 were considered observed [Fo . 4.0s(Fo)]. Absorption correction
was not necessary.
Solution and refinement: direct methods, all nonhydrogen atoms were
refined anisotropically, all hydrogens were located by difference Fourier
maps and refined with an overall isotropic thermal parameter R ¼ 0.0455,
Rw ¼ 0.1194, w ¼ 1/s2, GOOF ¼ 0.966, parameter to data ratio 11.4 : 1,
largest residual electron density peak/hole in the final difference map:
0.514/ 2 0.266 eA23. Atomic scattering factors were taken from the
˚
International Tables for X-ray Crystallography.[10] Data reduction was
performed by Jana 98.[11] All calculations were carried out on a VAX 4000
computer using the SHELX 93 (Sheldrick G. M.) program package.[12]
The procedure outlined below is general for the preparation of 1a–1c,
2a–2c, 3a–3c.
4-Benzyl-2-phenylmorpholin-2-ol hydrochloride (1a). To a solution
of 1.32 g (6.61 mmol) of 2-bromoacephenone (a) and 1.00 g (6.61 mmol)
of 2-benzylaminoethanol (1) in 50 mL of acetonitrile was added 0.99 g
(9.92 mmol) of potassium bicarbonate at room temperature. The resulting
suspension was refluxed and stirred during 7 h, cooled to room temperature
and filtered. To the filtrate was added 4 mL of a 2.2 M solution of HCl and
evaporated in vacuo to get a yellow solid, which was recrystallized from
acetone/ethanol to yield 1.74 g (86%) of compound 1a as a white solid, mp
136–1398 (decomp). MS: m/z (%) ¼ 270 (2), 161 (12), 134 (13), 105 (9),
91 (100). IR: nOH 3406, nNH 2702, 2612, 2358, nCHarom. 3062, 3006, 3036,
nCHaliph. 2948, 2888, nC55C 1636, 1496, 1456, nC22O 1084 cm21 (KBr). Anal.
Calcd. for C17H20ClNO2 (305.63): C, 66.75; H, 6.59; N, 4.58. Found: C,
66.60; H, 7.00; N, 4.59.
4-Benzyl-2-(40-chlorophenyl)-morpholin-2-ol hydrochloride (1b). The
reaction of 1.54 g (6.61 mmol) of 2-bromo-40-chloroacetophenone (b),
1.00 g (6.61 mmol) of 2-benzylaminoethanol (1) and 0.99 g (9.92 mmol)
of potassium bicarbonate gave a yellow solid, which was recrystallized
from acetone/methanol to yield 2.06 g (92%) of compound 1b as a white

New 4-Alkyl-2-Arylmorpholin-2-ol Hydrochlorides
367
solid, mp 145–1468 (decomp). MS: m/z (%) ¼ 164 (26), 139 (5), 91 (100).
IR: nOH 3416, nNH 2700, 2608, 2362, nCHarom. 3068, 3034, nCHaliph. 2948,
2884, nC55C 1636, 1598, 1490, 1458, nC22O 1094 cm21 (KBr). Anal. Calcd.
for C17H19Cl2NO2 (340.07): C, 59.99; H, 5.63; N, 4.11. Found: C, 59.83;
H, 5.78; N, 4.05.
4-Benzyl-2-(40-biphenyl)morpholin-2-ol hydrochloride (1c). The reaction
of 1.82g (6.61 mmol) of 2-bromo-40-phenylacetophenone (c), 100 g
6.61mmol) of 2-benzylaminoethanol (1) and 0.99 g (9.92 mmol) of
potassium bicarbonate gave a yellow solid, which was recrystallized from
acetone/ethanol to yield 2.21/g (88%) of compound 1c as a white solid,
mp 166–1698 (decomp.). MS: m/z (%) ¼ 327 (13), 236 (29), 164 (73), 152
(23), 91 (100), 65 (8). IR: nOH3424, nNH 2770, 2636, 2364, nCHarom. 3030,
3006, nCHaliph. 2948, 2832, nC55C 1636, 1560, 1486, 1456, nC22O 1084 cm21
(KBr). Anal. Calcd. for C23H24ClNO2 (381.67): C; 72.31; H, 6.33; N, 3.66.
Found: C, 71.90; H, 6.31; N, 3.72.
(2R,4S,5S,6S)-2,6-Diphenyl-4,5-dimethylmorpholin-2-ol hydrochloride
(2a). The reaction of 1.32 g (6.61 mmol) of 2-bromoacephenone (a), 1.09 g
(6.61 mmol) of (1S,2S)-( þ )-pseudoephedrine (2) and 0.99 g (9.92 mmol)
of potassium bicarbonate gave a yellow solid, which was recrystallized from
acetone/ethanol and to yield 1.87 g (89%) of compound 2a as a white solid,
mp 158–1608 (decomp.). MS: m/z (%) ¼ 265 (5), 176 (67), 132 (12), 118
(36), 117 (31), 105 (27), 91 (21), 77 (36), 58 (100), 44 (25). IR: nOH 3422,
n
NH 2658, 2362, nCHarom. 3060, 3034, nCHaliph. 2992, 2950, 2832, nC55C 1636,
1558, 1496, 1454, nC55O 1082 cm21 (KBr). Anal. Calcd. for C18H22ClNO2
(319.65): C, 67.57; H, 6.93; N, 4.38. Found: C, 67.62; H, 7.07; N, 4.40.
(2R,4S,5S,6S)-2-(40-Chlorophenyl)-4,5-dimethylmorpholin-2-ol hydro-
chloride (2b). The reaction 1.54 g (6.61 mmol) of 2-bromo-40-chloroacetophe-
none (b), 1.09 g (6.61 mmol) of (1S,2S)-( þ )-pseudoephedrine (2) and 0.99 g
(9.91 mmol) of potassium bicarbonate gave a yellow solid, which was recrys-
tallized from acetone/ethanol and yield 2.18 g (93%) of compound 2b as
a white solid, mp 182–1848 (decomp.). MS: m/z (%) ¼ 318 (1), 300 (1),
210 (31), 178 (7), 154 (7), 148 (6), 139 (12), 131 (11), 118 (17), 91 (10), 77
(14), 58 (‘00), 44 (20), 42 (16). IR: nOH 3416, nNH 2656, 2364, nCHarom.
3062, 3032, 3004, nCHaliph. 2990, 2960, 2904, 2864, nC55C 1636, 1598, 1492,
1456, nC22O 1092 cm21 (KBr). Anal. Calcd. for C18H21Cl2NO2 (354.09): C,
61.00; H, 5.97; N, 3.95. Found: C, 60.70; H, 5.89; N, 4.05.
(2R,4S,5S,6S)-2-Phenyl(40-biphenyl)-4,5-dimethylmorpholin-2-olhydrochlo-
ride (2c). The reaction 1.54 g (6.61 mmol) of 2-bromo-40-phenylacetophenone
(c), 1.09 g (6.61 mmol) of (1S,2S)-( þ )-pseudoephedrine (2) and 0.99 g
(9.92 mmol) of potassium bicarbonate gave a yellow solid, which was recrys-
tallized from acetone/ethanol and to yield 2.18 g (84%) of compound 2c as a
white solid, mp 169–1718 (decomp.). MS: m/z (%) ¼ 360 (1), 342 (6), 181
(19), 178 (6), 176 (5), 120 (1), 58 (100). IR: nOH 3412, nNH 2636, 2362,
nCHarom. 3056, 3032, nCHaliph. 2994, 2946, 2832, nC55C 1636, 1614, 1486,

368
T. Mancilla et al.
1456, nC22O 1062 cm21 (KBr). Anal. Calcd. for C24H26ClNO2 (395.68): C,
72.79; H, 6.62; N, 3.53. Found: C, 73.21; H, 6.75; N, 3.61.
(2S,4R,5R,6R)-2,6-Diphenyl-4,5-dimethylmorpholin-2-ol hydrochloride
(3a). The reaction 1.32 g (6.61 mmol) of 2-bromoacetophenone (a), 1.09 g
(6.61 mmol) of (1R,2R)-( 2 )-pseudoephedrine (3) and 0.99 g (9.92 mmol)
of potassium bicarbonate gave a yellow solid, which was recrystallized
from acetone/ethanol and to yield 1.93 g (91%) of compound 3a as a white
solid, mp 158–1608 (decomp.). MS: m/z (%) ¼ 266 (10), 191 (11), 176
(22), 132 (20), 118 (33), 117 (47), 105 (26), 91 (21), 77 (35), 58 (100), 44
(24). IR: nOH 3420, nNH 2656, 2362, nCHarom. 3060, 3034, nCHaliph. 2992,
2950, 2832, nC55C 1636, 1558, 1494, 1456, nC55O 1080 cm21 (KBr). Anal.
Calcd. for C19H22ClNO2 (319.65): C, 67.57; H, 6.93; N, 4.38. Found: C,
67.63; H, 7.13; N, 4.38.
(2S,4R,5R,6R)-2-(40-Chlorophenyl)-4,5-dimethylmorpholin-2-ol hydro-
chloride (3b). The reaction 1.54 g (6.61 mmol) of 2-bromo-40-chloroacetophe-
none (b), 1.09 g (6.61 mmol) of (1R,2R)-( 2 )-pseudoephedrine (3) and 0.99 g
(9.92 mmol) of potassium bicarbonate gave a yellow solid, which was recrys-
tallized from acetone/ethanol and to yield 2.04 g (87%) of compound 3b as
a white solid, mp 182–1848 (decomp.). MS: m/z (%) ¼ 318 (1), 300 (1),
210 (40), 178 (8), 154 (7), 148 (10), 139 (14), 131 (12), 118 (18), 91 (12),
77 (18), 58 (100), 44 (23), 42 (20). IR: nOH 3418, nNH 2656, 2366, nCHarom.
3062, 3032, 3004, nCHaliph. 2990, 2960, 2864, nC55C 1636, 1598, 1492, 1456,
nC22O 1092 cm21 (KBr). Anal. Cald. for C18H21Cl2NO2 (354.09): C, 61.00;
H, 5.97; N, 3.95. Found: C, 61.35; H, 6.11; N, 3.98.
(2S,4R,5R,6R)-2-(40-Chlorophenyl)-4,5-dimethylmorpholin-2-ol hydro-
chloride (3c). The reaction 1.54 g (6.61 mmol) of 2-bromo-40-phenylacetophe-
none (c), 1.09 g (6.61 mmol) of (1R,2R)-( 2 )-pseudoephedrine (3) and 0.99 g
(9.92 mmol) of potassium bicarbonate gave a yellow solid, which was recrys-
tallized from acetone/ethanol and to yield 2.29 g (88%) of compound 3c as
a white solid, mp 169–1718 (decomp.). MS: m/z (%) ¼ 360 (1), 342 (5),
181 (20), 178 (10), 176 (4), 120 (3), 58 (100) IR: nOH 3412; n
2368,
NH
2364, nCHarom. 3056, 3032, nCHaliph. 2994, 2946, 2832, nC55C 1636, 1614,
1486, 1456, nC22O 1064 cm21 (KBr). Anal. Calcd. for C24H26ClNO2
(395.68): C, 72.79; H, 6.68; N, 3.53. Found: C, 72.90; H, 6.66; N, 3.63.
Supplementary material: Crystallographic data for 2b has been deposited
at the Cambridge Crystallographic Data Center, UK, CCDC as supplementary
material No. 236159. e-mail: deposit@ccdc.cam.ac.uk
ACKNOWLEDGMENTS
`
The authors wish to thank to “Consejo Nacional de Ciencia y Tecnologıa”
´
(Conacyt, Mexico) for financial support and scholarship to Luis

New 4-Alkyl-2-Arylmorpholin-2-ol Hydrochlorides
369
S. Zamudio-Rivera. We thank Dr. Rosa Luisa Santillan for reading the
manuscript and for her helpful comments.
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