Asymmetric synthesis, crystal structure, and antidepressant activity of 2-aryl-3-alkyl-5-methyl-2-morpholinol hydrochlorides

Article abstract of DOI:10.1139/V06-184

2-Aryl-3-alkyl-5-methyl-2-morpholinols were synthesized from the reactions of chiral 2-aminopropan-1-ol with 2-bromo-1-phenylpropan-1-one, 2-bromo-1-(3-chlorophenyl)propan-1-one, 1-(4-(benzyloxy)phenyl)-2-bromopropan1- one, 2-bromo-1-(6-methoxy- naphthalen-2-yl)propan-1-one, and 1-(4-(benzyloxy)phenyl)pentan-1-one in N-methyl-2-pyrrolidone (NMP), respectively. The 2-aryl-3-alkyl-5-methyl-2-morpholinols were reacted with hydrogen chloride to give the hydrochloride salts with yields of 56%-77%. The structures of the products were proven by means of their ¹H NMR, IR, and MS spectroscopic data. The stereochemical properties of representative products were established unambiguously by the X-ray single crystal analysis. The antidepressant activities of the title compounds were assayed by the mouse forced swimming test (FST). The FST results confirm the antidepressant properties of our products.

Full text of DOI:10.1139/V06-184

29
Asymmetric synthesis, crystal structure, and
antidepressant activity of 2-aryl-3-alkyl-5-methyl-
2-morpholinol hydrochlorides
Gao Cao, Ai-Xi Hu, and Xin-Rong Xiao
Abstract: 2-Aryl-3-alkyl-5-methyl-2-morpholinols were synthesized from the reactions of chiral 2-aminopropan-1-ol
with 2-bromo-1-phenylpropan-1-one, 2-bromo-1-(3-chlorophenyl)propan-1-one, 1-(4-(benzyloxy)phenyl)-2-bromopropan-
1-one, 2-bromo-1-(6-methoxy- naphthalen-2-yl)propan-1-one, and 1-(4-(benzyloxy)phenyl)pentan-1-one in N-methyl-2-
pyrrolidone (NMP), respectively. The 2-aryl-3-alkyl-5-methyl-2-morpholinols were reacted with hydrogen chloride to
1
give the hydrochloride salts with yields of 56%–77%. The structures of the products were proven by means of their H
NMR, IR, and MS spectroscopic data. The stereochemical properties of representative products were established unam-
biguously by the X-ray single crystal analysis. The antidepressant activities of the title compounds were assayed by the
mouse forced swimming test (FST). The FST results confirm the antidepressant properties of our products.
Key words: morpholinol hydrochloride, hemiacetal, chiral synthesis, X-ray diffraction, absolute configuration, antide-
pressant activity.
Résumé : Opérant dans la N-méthylpyrrolid-2-one (NMP), on a réalisé la synthèse de 2-aryl-3-alkyl-5-méthylmorpholin-
2-ols par les réactions du 2-aminopropan-1-ol avec respectivement de la 2-bromo-1-phénylpropan-2-one, de la 2-bromo-
1-(3-chlorophényl)propan-1-one, de la 1-[4-(benzyloxy)phényl]-2-bromopropan-2-one, de la 2-bromo-1-(6-méthoxynaphtalén-
2-yl)propan-1-one et de la 1-[4-(benzyloxy)phényl]pentan-1-one. Les réactions des 2-aryl-3-alkyl-5-méthylmorpholin-2-
ols avec de l’acide chlorhydrique conduit à la formation des chlorhydrates avec des rendements allant de 56 % à 77 %.
1
On a confirmé l’identité des structures des produits à l’aide de données de résonance magnétique nucléaire du H, de
spectroscopie IR et de spectrométrie de masse. Les propriétés stéréochimiques de produits représentatifs ont été établies
sans ambiguïté à l’aide de la diffraction de rayons X par des cristaux uniques. On a évalué les propriétés antidépressi-
ves des composés mentionnés dans le titre en les administrant à des souris impliquées dans un test où elles sont for-
cées de nager. Les résultats de ces études permettent de confirmer les propriétés antidépressives de ces produits.
Mots-clés : chlorhydrates de morpholinols, hémiacétal, synthèse chirale, diffraction des rayons X, configuration absolue,
activité antidépressive.
[Traduit par la Rédaction] Cao et al. 36
Introduction
antifungal properties, and they are especially widely de-
scribed for their antidepressant activities. 2-Aryl-2-
morpholinol derivatives also have been used to treat human
diseases such as tardive dyskinesia, minimal brain dysfunc-
tion, obesity, migraine, sexual dysfunction, chronic fatigue,
restless legs syndrome, Parkinson’s disease (1–9).
2-Aryl-2-morpholinol derivatives have been utilized ex-
tensively by chemists because of their pharmaceutical im-
portance in drug design and extensive application in organic
synthesis. The biological utility of 2-aryl-2-morpholinol de-
rivatives is wide-ranging, including analeptic, antioxidant,
hypocholesterolemic, anorectic, adrenergic blocking, and
Research on phenylmorpholinols has led to the discovery
of (3,5-difluorophenyl)morpholinol, a novel antidepressant
agent and selective inhibitor of norepinephrine uptake,
which is active in animal behavioral models that respond to
effective clinical antidepressant drugs (10). The racemate
compound 2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol
has been synthesized and the (+) and (–) enantiomers of the
racemate have been subsequently separated via chromatogra-
phy (11, 12) or dynamic kinetic resolutions (13–15). This
product is useful in prophylaxis or therapy, especially as a
stimulant and antidepressant for the central nervous system.
Musso (16) designed and synthesized a chiral hapten for
radioimmunoassay of the antidepressant (2S,3S,5R)-2-(3,5-
difluorophenyl)-3,5-dimethyl-2-morpholinol hydrochloride.
However, the problem of the synthesis of 2-aryl-2-
morpholinol derivatives is that the preparation requires a
Received 4 October 2006. Accepted 1 December 2006.
Published on the NRC Research Press Web site at
http://canjchem.nrc.ca on 26 January 2007.
G. Cao. The School of Chemical and Energy Engineering,
South China University of Technology, Guangzhou, P. R.
China.
A.-X. Hu.1 The School of Chemical and Energy Engineering,
South China University of Technology, Guangzhou, P. R.
China; College of Chemistry and Chemical Engineering,
Hunan University, P. R. China.
X.-R. Xiao. College of Chemistry and Chemical Engineering,
Hunan University, Changsha, P. R. China.
1Corresponding author (e-mail: axhu0731@yahoo.com.cn).
Can. J. Chem. 85: 29–36 (2007)
doi:10.1139/V06-184
© 2007 NRC Canada

30
Can. J. Chem. Vol. 85, 2007
Scheme 1. Synthesis of 2-aryl-3-alkyl-5-methyl-2-morpholinol hydrochlorides.
long reaction time and that the solvent is volatile and poi-
sonous (17–20).
tion. 2-Aryl-3-alkyl-5-methyl-2-morpholinol hydrochlorides
synthesized from contrary configuration 2-aminopropan-1-
ols should be a pair of enantiomers.
By structural modification of the drug, it is possible to ob-
tain new compounds with comparable activity and lower
toxicity. On the other hand, enantiomers of the same drug
can have different pharmacodynamic and pharmacokinetic
properties. Today, most new drugs and those under develop-
ment consist of a single optically active isomer. The current
trend in drug markets is a rapid increase in the sales of chiral
drugs. Chiral drugs represent close to 40% of all drug sales
worldwide in 2001 (21). Therefore, the synthesis of chiral 2-
aryl-3-alkyl-5-methyl-2-morpholinol hydrochlorides was un-
dertaken.
In this study, we report the synthesis of novel chiral 2-
aryl-3-alkyl-5-methyl-2-morpholinols 2a–2e and their hydro-
chloride salts 1a–1e by the reactions of chiral 2-
aminopropan-1-ol with α-bromo-aromatic ketones 3a–3e in
N-methyl-2-pyrrolidone (NMP) and their antidepressant ac-
tivities. The synthesis of the title compounds was shown in
Scheme 1.
When 2-amino-2-methyl-1-propanol reacted with chiral α-
ketotriflate, the enantiopure hydroxylbupropion products
conformationally locked at (2S,3S) or (2R,3R). The (2R,3S)
or (2S,3R) isomer was not observed (22). In our products,
the 1H NMR spectra show only one double singlet at δ:
0.90–1.10 for the 3-CH3 group of the morpholine ring,
which shows that the synthesized compounds are single en-
antiomers. If the products are diastereomeric [(2R,3R,5S)-1a
to (2R,3R,5S)-1e and (2R,3S,5S)-1a to (2R,3S,5S)-1e] or
[(2S,3S,5R)-1a to (2S,3S,5R)-1e and (2S,3R,5R)-1a to
(2S,3R,5R)-1e], the methyl group at the axial position should
be in the downfield position because the deshielding effect is
stronger than at the equatorial position. So, the 3-CH3 group
of the morpholine ring should have two double singlets in
1
the H NMR spectrum.
Single crystal investigation of the representative
products
Results and discussion2
The structure and stereochemical properties of (2S,3S,5R)-
3,5-dimethyl-2-(3-chlorophenyl)-2-morpholinol hydrochlo-
ride and (2R,3R,5S)-3,5-dimethyl-2-(6-methoxy-2-naphthyl)-
2-morpholinol hydrochloride were investigated by X-ray dif-
fraction. Colorless crystals suitable for X-ray diffraction
analysis were grown by slow evaporation of the mixture of
ethanol and ether (1:1 v/v). X-ray data were collected on a
Bruker AXS SMART 1000 CCD diffractometer equipped
with graphite monochromated Mo Kα radiation (λ =
0.710 73 Å). The data set was recorded at RT in ω–φ scan
mode. Preliminary orientation matrices were obtained from
the first frames using SMART (23). The data were empiri-
cally corrected for absorption and other effects using
Synthesis of optically active 2-aryl-3-alkyl-5-methyl-2-
morpholinol hydrochlorides
The optical rotations of 2-aryl-3-alkyl-5-methyl-2-
morpholinol hydrochlorides by the reactions of (S)-2-
aminopropan-1-ol and (R)-2-aminopropan-1-ol with α-
bromo-aromatic ketones are levorotatory and dextrotatory,
respectively. The detailed data are tabulated in Table 1.
2-Aryl-3-alkyl-5-methyl-2-morpholinol
hydrochlorides
synthesized from opposite configuration 2-aminopropan-1-ol
have the analogous melting points and the analogous numer-
ical value, but the optical rotation is in the opposite direc-
2 Supplementary data for this article are available on the journal Web site (http://canjchem.nrc.ca) or may be purchased from the Depository
of Unpublished Data, Document Delivery, CISTI, National Research Council Canada, Ottawa, ON K1A 0R6, Canada. DUD 5120. For more
information on obtaining material refer to http://cisti-icist.nrc-cnrc.gc.ca/irm/unpub_e.shtml. CCDC 292641 and 292642 contain the crystal-
lographic data for this manuscript. These data can be obtained, free of charge, via http://www.ccdc.cam.ac.uk/conts/retrieving.html
(Or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax +44 1223 336033; or
deposit@ccdc.cam.ac.uk).
© 2007 NRC Canada

Cao et al.
31
Table 1. 2-Aryl-3-alkyl-5-methyl-2-morpholinol hydrochlorides.
(+)-1a to (+)-1e
(–)-1a to (–)-1e
Ar
R
mp (°C)
[α]20 (°)a
yield (%)b
mp (°C)
[α]20 (°)a
yield (%)b
D
D
a
b
c
C6H5
Me
Me
Me
Me
n-Pr
178–180
203 to 204
161–163
182–184
169–171
+30.8
+40.6
+10.8
+13.7
+5.6
59.6
59.6
77.0
69.4
60.4
176–178
200 to 201
159–162
181–183
169–171
–32.8
–44.6
–11.5
–13.6
–5.2
56.0
56.2
63.4
64.9
60.8
3-Cl-C6H4
4-PhCH2O-C6H4
6-MeO-C10H6
4-PhCH2O-C6H4
d
e
aSolvent was EtOH, concn. = 1.0.
bYields are based on the starting 3a–3e.
Table 2. Crystallographic data and structure refinement for (+)-1b and (–)-1d.
Compound
(+)-1b
(–)-1d
CCDC No.
292641
292642
Empirical formula
C12H17NO2Cl2
C17H22NO3Cl
Formula mass
278.17
323.81
Colour, habit
Colourless, block
0.26 × 0.22 × 0.20
Orthorhombic
P21212
Colourless, block
0.50 × 0.38 × 0.18
Orthorhombic
P212121
Crystal dimensions (mm3)
Crystal system
Space group
Z
4
4
a (Å)
b (Å)
c (Å)
Collection ranges
8.718(2)
20.264(6)
7.882(2)
–10 ≤ h ≤ 9,
7.1093(4)
7.6947(5)
29.8868(19)
–8 ≤ h ≤ 9,
–23 ≤ k ≤ 25,
–9 ≤ k ≤ 7,
–9 ≤ l ≤ 9
294(2)
1392.5(6)
1.327
–24 ≤ l ≤ 38
292(2)
1634.93(17)
1.316
T (K)
V (Å3)
Calculated density (g/cm3)
Mo Kα radiation (Å)
0.710 73
0.710 73
Absorption correction
F(000)
Multiscan
584
Multiscan
688
θ Range for data collection (°)
Measured reflections
Independent reflections
2.77–25.09
7875
2836 (Rint = 0.0293)
2.65–26.71
8797
3562 (Rint = 0.0185)
Data, restraints, parameters
Goodness-of-fit on F2
2836, 0, 168
1.029
3562, 0, 203
1.055
Final R indices [I > 2σ(I)]
R indices (all data)
Absolute structure parameter
Largest diff. peak and hole (e Å–3)
R1 = 0.0350, wR2 = 0.0724
R1 = 0.0541, wR2 = 0.0808
–0.02(6)
R1 = 0.0544, wR2 = 0.0964
R1 = 0.0408, wR2 = 0.1092
0.07(8)
0.185 and –0.253
0.350 and –0.170
SADABS (24). The structure was solved by direct methods
and refined by the full-matrix least-squares methods on F2
with the program SHELXTL-97 (25). H atoms were posi-
tioned at geometrically possible positions and refined using
the riding model with Ueq set equal to the Ueq of the parent
atom multiplied by 1.2 (or 1.5 for the methyl groups). O–H
and N–H of (+)-1b were freely refined. Further details of
data collection and structure refinement are given in Table 2.
C(2) and sharpened at C(5), and the dihedral angles between
the C(3)–C(2)–O(1) and C(1)–C(5)–N(1) planes and the
N(1)–C(3)–O(1)–C(1) plane are 45.9(2)° and 52.4(2)°, re-
spectively. The 3-methyl group and the 5-methyl group
make dihedral angles of 39.8(3)° and 38.4(3)° with respect
to the C(2)–C(3)–N(1) and C(1)–C(5)–N(1) planes; the 2-
hydroxy group and the 2-(6-methoxy-2-naphthyl) group make
dihedral angles of 38.9(2)° and 31.0(3)° with respect to the
C(3)–C(2)–O(1) plane, respectively. The 3- and 5-methyl
groups and the 2-hydroxy group are on the same side of the
morpholine ring, but the 2-(6-methoxy-2-naphthyl) group is
Absolute configuration of the representative compounds
According to the molecular structure of (–)-1d with atom
labeling (Fig. 1), the naphthalene ring C(7)–C(16) is essen-
tially planar with a mean deviation of 0.0242(3) Å. The
morpholine ring is a distorted chair somewhat flattened at
on the reverse side. The chiral carbon atoms of
(–)-1d,
C(2) and C(3) are (R)-configuration, and C(5) is (S)-configu-
ration. The absolute configuration of (–)-1d is (2R,3R,5S).
© 2007 NRC Canada

32
Can. J. Chem. Vol. 85, 2007
Fig. 1. The ORTEP (26) plot of the X-ray crystal structure of compound (–)-1d with 30% probability displacement ellipsoids.
Cl(1)
C(9)
C(10)
C(11)
C(12)
C(8)
C(17)
O(3)
C(5)
C(3)
N(1)
C(4)
C(6)
C(7)
C(13)
C(15)
C(16)
C(1)
O(1)
C(2)
O(2)
C(14)
Fig. 2. The crystal packing of (–)-1d. For the sake of clarity, H atoms bonded to C atoms have been omitted. Hydrogen bonds have
been shown as dashed lines.
b
c
a
The data obtained from the NMR spectral analysis and X-
ray investigation are in good agreement, giving evidence of
similar conformational behavior in the crystal and in solu-
tion. In addition, the structure exhibits intermolecular hydro-
gen bonds of type N–H–Cl and O–H–Cl. The hydrogen
bonds are N(1)–H(1C)–Cl(1)i (2.27 Å, 162.1°) with symme-
try codes x–1/2, 1/2–y, –z and N(1)–H(1D)–Cl(1)ii (2.23 Å,
173.6°) and O(2)–H(2)–Cl(1)ii (2.51 Å, 176.7°) with sym-
metry codes x–1, y–1, z. (Fig. 2).
The molecular structure of (–)-1d in crystal is stabilized
by the intermolecular hydrogen bonds and the inter-
molecular electrostatic interactions between the positively
charged atom N+ and Cl–; the chlorine atom is set apart from
the hydroxyl oxygen atom (on the reverse side of the
morpholine ring), and the hydroxyl oxygen atom of (–)-1d
does not itself form a hydrogen bond with the chlorine atom.
The structure of (+)-1b with atom numbering is shown in
Fig. 3 (27).
Compared with (–)-1d, the chlorine atom of (+)-1b is
closer to the hydroxyl oxygen atom and this is probably
caused by the 2-Ar substitutes. Atom O(1) in the hydroxyl
group acts as a hydrogen-bond donor via H(1) to atom Cl(2)
forming the hydrogen bond O(1)–H(1)–Cl(2) (2.29 Å, 166°).
Atom N(1) of the morpholine ring acts as a hydrogen-bond
donor via H(1C) and H(1D) to two of the other chlorine at-
oms of the molecule forming the hydrogen bonds N(1)–
H(1C)–Cl(2)i (2.27 Å, 173.1°) and N(1)–H(1D)–Cl(2)ii
(2.34 Å, 151°) (Fig. 4).
Our synthesis of 1a–1e produced a chair model of a six-
membered ring, and the configuration is stable when the aryl
and alkyl groups are at an equatorial position. Thus, the two
formed chiral carbon atoms C(2) and C(3) in our products
maintain “Z” shape and not “E” shape. The configuration of
the products is determined by the chirality of 2-aminopro-
pan-1-ol. The products were (2R,3R,5S)-1a to (2R,3R,5S)-
1e, namely (–)-1a to (–)-1e when (S)-2-aminopropan-1-ol
was used. The products were (2S,3S,5R)-1a to (2S,3S,5R)-
1e, namely (+)-1a to (+)-1e) when (R)-2-aminopropan-1-ol
was used. (Fig. 5).
When R was an H atom, we did not obtain 2-aryl-5-
methyl-2-morpholinol hydrochloride products by the same
procedure. α-Bromo-1-aromatic ethanones, such as 2-bromo-
1-(4-methoxyphenyl)ethanone, 1-(4-(benzylo-xy) phenyl)-2-
bromoethanone, or 2-bromo-1-(6-methoxynaphthalen-2-
yl)ethanone, reacted with chiral 2-aminopropan-1-ol during
the HCl acidification process initially obtaining a solid,
which absorbed water from the environment to form a stag-
nant oil. The 1H NMR spectra did not indicate cyclic
(morpholine) structure, and the IR spectra showed a car-
bonyl group absorption band of the hydrochloride salt. The
hemiketals with R = H are likely to exhibit ring-opening in
aq. HCl.
© 2007 NRC Canada

Cao et al.
33
Fig. 3. The ORTEP plot of the X-ray crystal structure of compound (+)-1b.
Cl(1)
C(9)
C(8)
O(2)
C(5)
C(1)
C(7)
C(10)
C(2)
C(6)
C(3)
C(4)
N(1)
C(11)
C(12)
O(1)
Cl(2)
Fig. 4. Autostereogram of the crystal structure of (+)-1b with hydrogen bonds.
c
b
a
nent and affects about 15% of the population at some point
during their lives. The present study was undertaken to
investigate the effect of 2-aryl-3-alkyl-5-methyl-2-
morpholinols hydrochloride on depression in the mouse
Antidepressant activities of 2-Aryl-3-alkyl-5-methyl-2-
morpholinols hydrochloride
Clinical depression is one of the most complex human
diseases. It has an unequivocally strong hereditary compo-
© 2007 NRC Canada

34
Can. J. Chem. Vol. 85, 2007
Fig. 5. Absolute configuration of the title compound.
Table 3. Effects of target compounds on the time in mice forced
swimming test.
Treatment
No. of mice
IP dose (mg/kg)
Immobilitya
CMC (1%)
Amitriptyline
(–)-1d
(+)-1d
(–)-1e
10
8
8
8
8
—
20
40
40
40
40
138.0 21.7
18.5 4.4b
40.3 10.3b
8.4 6.8b
62.1 13.7
24.8 7.3
(+)-1e
8
forced swimming test (FST), an animal model of depression
that is widely used to predict the antidepressant action of
drugs in humans (28).
aResults are expressed as mean S.E.M.
bP < 0.05 vs. CMC (1%).
Male KM mice (the KM mouse strain is one of the
outbred strains of mice introduced from Swiss mice to
Kunming City, Yunnan Province, China) weighing 20–30 g
were used in this study. The animals were housed in plastic
cages under standard light (light on from 0700 to 2100
hours) and temperature (22 1 °C) conditions for at least
three days before experimentation with free access to stan-
dard laboratory food and tap water. Compounds 1d and 1e
were chosen as title compounds and were suspended in a
CMC solution (1%) with a concentration of 4 mg/mL in a
dose volume of 0.1 mL per 10 g body weight in mice. Be-
havioral observations took place between 0800 and 1500 and
each animal was used only once. A standard antidepressant
drug amitriptyline was employed to standardize the animal
models of depression and to compare the antidepressant effi-
cacy of the title compounds.
Thirty minutes after intraperitoneal (IP) injection of the
drugs, the mice were individually placed in a vertical glass
cylinder (height of 25 cm, diameter of 12 cm) containing
water (depth of 15 cm at 22 °C) and forced to swim. After
an initial 2 min period of vigorous activity, each animal as-
sumed a typical immobile posture. A mouse was considered
to be immobile when it remained floating in the water with-
out struggling, making only minimum movements of its
limbs necessary to keep its head above water. The total dura-
tion of immobility was recorded during the next 4 min of a
total 6 min test. The changes in immobility duration were
studied after administering drugs in separate groups of ani-
mals. (Table 3).
According to the results in Table 3, the title compounds
showed potent antidepressant activity, where the title com-
pounds (+)-1d and (+)-1e show better activity than (–)-1d
and (–)-1e, which shows that the configuration of (2S,3S,5R)
compounds have greater antidepressant activity than the
(2R,3R,5S) configuration.
Following the test, animals were allowed to dry and re-
turned to their home cage. Adverse drug reactions were not
observed in the 24 h period after the FST test. These results
confirm the antidepressant properties of our products, sug-
gesting the possible use of this drug in depressive patients
that may be resistant to classical antidepressant therapy.
excellent overall yields. The title compounds exhibited po-
tent antidepressant activity in the FST test.
Materials and methods
Instrumentation
All melting points were measured on an X-4
electrothermal digital melting point apparatus and were un-
corrected. 1H NMR spectra were recorded on a Varian
Inova-400 instrument with TMS as internal standard operat-
ing at 399.970 MHz. IR spectra were recorded on Avatar
360FT infrared spectrometer, using KBr discs. ESI-MS mea-
surements were recorded on a Finngan LCQ LC-MS spec-
trometer. Optical rotations were measured on a WZZ-3
polarimeter. TLC analysis was carried out on glass plates,
kept in iodine, using silica gel. X-ray data were collected on
a Bruker AXS Smart 1000 CCD diffractometer.
General experimental procedure for the preparation of
␣-bromo-aromatic ketones
α-Aromatic ketone (0.1 mol) was dissolved in anhydrous
ethanol (200 mL) and the mixture was stirred and heated to
reflux. Cupric bromide (0.2 mol) was added to the reaction
mixture in batches and the course of the reaction was fol-
lowed by TLC analysis. After the reaction finished, the mix-
ture was filtered and concentrated in vacuo. The resulting
residue was taken up in dichloromethane, washed with 10%
hydrochloric acid, washed with water until neutral, dried
over anhydrous sodium sulfate, and concentrated in vacuo to
give racemic α-bromo-aromatic ketones 3a–3e (29).
Preparation of 2-aryl-3-alkyl-5-methyl-2-morpholinols
hydrochloride
The general experimental procedure was as follows. α-
Bromo-aromatic ketones 3a–3e (0.01 mol) were added to a
solution of (S)-2-aminopropan-1-ol (0.04 mol) in NMP
(10 mL), and stirred for 1 h at RT. When no trace of starting
material remained (by TLC analysis), an excess of water
(30 mL) was added to the mixture, then extracted with di-
ethyl ether (30 mL). The aqueous layer was extracted further
with diethyl ether (15 mL) three times. The organic extracts
were combined, washed (10 mL water), and dried by anhy-
drous sodium sulfate. After filtering, the filtrate was stirred
in an ice bath, the pH adjusted to acidity by passing anhyd.
HCl through it slowly, yielding a white crystalline substance,
which was filtered and washed with acetone, and dried to
give (–)-1a to (–)-1e. Compounds (+)-1a to (+)-1e) were
synthesized using (R)-2-aminopropan-1-ol by the same pro-
Conclusions
In summary, we report herein a rapid and efficient synthe-
sis of some novel 2-aryl-3-alkyl-5- methyl-2-morpholinol
hydrochlorides by the reaction of chiral 2-aminopropan-1-ol
with α-bromo-aromatic ketones in NMP. Advantages of this
approach include short reaction time, ease of operation, and
© 2007 NRC Canada

Cao et al.
35
cedure. Selected characterization data of the products fol-
lows.
(2S,3S,5R)-3,5-Dimethyl-2-phenyl-2-morpholinol
hydrochloride (+)-1a
1H NMR (CD3SOCD3, 400MHz) δ: 0.96 (d, J = 6.4 Hz,
3H, CH3), 1.23 (d, J = 6.4 Hz, 3H, CH3), 3.54–3.60 (br m,
H, morpholine ring3, 5-H), 3.83–3.97 (m, 2H, morpholine
ring 6-H), 7.41–7.56 (m, 5H, C6H5), 8.02 (s, 1H, OH), 8.75,
10.17 (2 × bs, 2H, NH, HCl). IR (KBr, cm–1) ν: 3244, 3037,
2936, 2787, 2738, 2681, 2532, 1560, 1541, 1452, 1388,
1350, 1261, 1092, 1057, 1001, 764, 702. ESI-MS m/z: 209
(M+ + 2 – HCl), 208 (M+ + 1 – HCl), 190 (M+ + 1 – HCl –
H2O).
(2R,3R,5S)-3,5-Dimethyl-2-phenyl-2-morpholinol
hydrochloride (–)-1a
1H NMR (CD3SOCD3, 400 MHz) δ: 0.94 (d, J = 6.4 Hz,
3H, CH3), 1.22 (d, J = 6.4 Hz, 3H, CH3), 3.28–3.50 (br m,
2H, morpholine ring 3,5-H), 3.79–3.93 (m, 2H, morpholine
ring 6-H), 7.36–7.54 (m, 6H, C6H5, OH), 8.75, 10.34 (2 ×
bs, 2H, NH, HCl). IR (KBr, cm–1) ν: 3244, 3037, 2937,
2787, 2738, 2681, 2532, 2438, 1560, 1452, 1388, 1350,
1261, 1178, 1138, 1090, 1057, 1001, 764, 702. ESI-MS m/z:
209 (M+ + 2 – HCl), 208 (M+ + 1 – HCl), 190 (M+ + 1 –
HCl – H2O).
(2S,3S,5R)-3,5-Dimethyl-2-(3-chlorophenyl)-2-
morpholinol hydrochloride (+)-1b
1H NMR (CD3SOCD3 + D2O, 400MHz) δ: 0.97 (d, J =
6.4 Hz, 3H, CH3), 1.23 (d, J = 6.4 Hz, 3H, CH3), 3.40–3.60
(br m, 2H, morpholine ring 3, 5-H), 3.85–3.95 (m, 2H,
morpholine ring 6-H), 7.47–7.58 (m, 4H, C6H4), 7.890 (s,
1H, OH), 8.78, 10.39 (2 × bs, 2H, NH, HCl). IR (KBr, cm–1)
ν: 3209, 2942, 2790, 2458, 1572, 1551, 1454, 1254, 1201,
1145, 1090, 1002. ESI-MS m/z: 244 (M+ + 2 – HCl), 243
(M+ + 1 – HCl), 242 (M+ – HCl), 226 (M+ + 2 – HCl –
H2O), 224 (M+ – HCl – H2O).
(2R,3R,5S)-3,5-Dimethyl-2-(3-chlorophenyl)-2-
morpholinol hydrochloride (–)-1b
1H NMR (CD3SOCD3, 400 MHz) δ: 0.98 (d, J = 6.4 Hz,
3H, CH3), 1.24 (d, J = 6.4 Hz, 3H, CH3), 3.36–3.56 (br m,
2H, morpholine ring 3,5-H), 3.81–3.94 (m, 2H, morpholine
ring 6-H), 7.45–7.59 (m, 4H, C6H4), 7.89 (s, 1H, OH), 8.78,
10.39 (2 × bs, 2H, NH, HCl). IR (KBr, cm–1) ν: 3211, 2976,
2947, 2898, 2790, 2681, 2551, 2515, 2459, 1572, 1450,
1373, 1250, 1184, 1142, 1093, 1059, 997, 906, 800, 708.
ESI-MS m/z: 244 (M+ + 2 – HCl), 243 (M+ + 1 – HCl), 242
(M+ – HCl), 226 (M+ + 2 – HCl – H2O), 224 (M+ – HCl –
H2O).
(2S,3S,5R)-3,5-Dimethyl-2-(4-benzyloxyphenyl)-2-
morpholinol hydrochloride (+)-1c
1H NMR (CD3SOCD3, 400MHz) δ: 0.96 (d, J = 6.4 Hz,
3H, CH3), 1.22 (d, J = 6.4 Hz, 3H, CH3), 3.29–3.51 (br m,
2H, morpholine ring 3, 5-H), 3.79–3.93 (m, 2H, morpholine
ring 6-H), 5.12 (s, H, OCH2), 7.03–7.47 (m, 10H, C6H4,
C6H5, OH), 8.70, 10.01 (2 × bs, 2H, NH, HCl). IR
(KBr, cm–1) ν: 3286, 2941, 2792, 2679, 2455, 1604, 1575,
1508, 1456, 1387, 1240, 1173, 1057, 1005, 831, 741, 698.
ESI-MS m/z: 315 (M+ + 2 – HCl), 314 (M+ + 1 – HCl), 296
(M+ + 1 – HCl – H2O).
(2R,3R,5S)-3,5-Dimethyl-2-(4-benzyloxyphenyl)-2-
morpholinol hydrochloride (–)-1c
1H NMR (CD3SOCD3, 400 MHz) δ: 0.95 (d, J = 6.4 Hz,
3H, CH3), 1.20 (d, J = 6.4 Hz, 3H, CH3), 3.26–3.49 (br m,
2H, morpholine ring 3,5-H), 3.78–3.91 (m, 2H, morpholine
ring 6-H), 5.10 (s, 2H, OCH2), 7.01–7.45 (m, 10H, C6H4,
C6H5, OH), 8.71, 10.20 (2 × bs, 2H, NH, HCl). IR
(KBr, cm–1) ν: 3286, 2941, 2792, 2679, 2553, 2455, 1604,
1510, 1456, 1387, 1240, 1173, 1057, 1005, 831, 41, 698.
ESI-MS m/z: 315 (M+ + 2 – HCl), 314 (M+ + 1 – HCl), 296
(M+ + 1 – HCl – H2O).
(2S,3S,5R)-3,5-Dimethyl-2-(6-methoxy-2-naphthyl)-2-
morpholinol hydrochloride (+)-1d
1H NMR (CD3SOCD3, 400MHz) δ: 1.00 (d, J = 6.4 Hz,
3H, CH3), 1.26 (d, J = 6.4 Hz, 3H, CH3), 3.59–3.65 (br m,
2H, morpholine ring 3, 5-H), 3.88 (s, 3H, OCH3), 3.88–4.03
(m, 2H, morpholine ring 6-H), 7.19–8.03 (m, 6H, C10H6),
8.03 (s,1H, OH), 8.81, 10.29 (2 × bs, 2H, NH, HCl). IR
(KBr, cm–1) ν: 3401, 2951, 2893, 2800, 2740, 2682, 2596,
2490, 1610, 1485, 1387, 1269, 1198, 1063, 1001, 854. ESI-
MS m/z: 289 (M+ + 2 – HCl), 288 (M+ + 1 – HCl), 270
(M+ + 1 – HCl – H2O).
(2R,3R,5S)-3,5-Dimethyl-2-(6-methoxy-2-naphthyl)-2-
morpholinol hydrochloride (–)-1d
1H NMR (CD3SOCD3, 400 MHz) δ: 0.97 (d, J = 6.4 Hz,
3H, CH3), 1.23 (d, J = 6.4 Hz, 3H, CH3), 3.57 (br m, 2H,
morpholine ring 3,5-H), 3.87 (s, 3H, OCH3), 3.92–3.97 (m,
2H, morpholine ring 6-H), 7.16–8.05 (m, 7H, C10H6, OH),
8.81, 10.17 (2 × bs, 2H, NH, HCl). IR (KBr, cm–1) ν: 3404,
2951, 2893, 2800, 2740, 2682, 2596, 2490, 1610, 1485,
1387, 1269, 1198, 1063, 1001, 854. ESI-MS m/z: 289 (M+
+2 – HCl), 288 (M+ + 1 – HCl), 270 (M+ + 1 – HCl – H2O).
(2S,3S,5R)-3-Propyl-5-methyl-2-(4-benzyloxyphenyl)-2-
morpholinol hydrochloride (+)-1e
1H NMR (CD3SOCD3, 400MHz) δ: 0.81 (t, J = 6.8Hz,
3H, 5-CH3), 1.16–1.33 (m, 5H, CH2CH3), 1.84–1.89 (m, 2H,
CH2), 3.23–3.96 (br m, 4H, morpholine ring 3,5-H, 6-H),
5.25 (s, 2H, OCH2), 7.02–7.48 (m, 9H, C6H4, C6H5), 8.06 (s,
1H, OH). IR (KBr, cm–1) ν: 3164, 2956, 2798, 1613, 1587,
1513, 1467, 1402, 1312, 1249, 1098, 1011. ESI-MS m/z:
342 (M+ + 1 – HCl).
(2R,3R,5S)-3-Propyl-5-methyl-2-(4-benzyloxyphenyl)-2-
morpholinol hydrochloride (–)-1e
1H NMR (CD3SOCD3, 400 MHz) δ: 0.57–1.38 (m, 10H,
CH3, CH2CH2CH3), 3.21–3.53 (br m, 2H, morpholine
ring3,5-H), 3.75–3.91 (m, 2H, morpholine ring 6-H), 5.11 (s,
2H, OCH2), 7.01–7.45 (m, 10H, C6H4, C6H5, OH), 8.78,
9.67 (2 × bs, 2H, NH, HCl). IR (KBr, cm–1) ν: 3198,
2968, 1630, 1565, 1508, 1455, 1330, 1254, 1080, 1010. ESI-
MS m/z: 342 (M+ + 1 – HCl).
Acknowledgement
This research was performed with the support of the Spe-
© 2007 NRC Canada

36
Can. J. Chem. Vol. 85, 2007
13. J.J. Partridge. PCT Int. Appl. WO 2005-042503, 12 May 2005.
14. M.A. Harris and A. Negus. PCT Int. Appl. WO 2005-040141,
6 May 2005.
15. J.J. Partridge. PCT Int. Appl. WO 2005-044809, 19 May 2005.
16. D.L. Musso and J.L. Kelley. Tetrahedron: Asymmetry, 6, 841
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cialized Research Fund for the Doctoral Program of Higher
Education (SRFDP) (No. 20040532002). We also gratefully
acknowledge the financial support of the Hunan Provincial
Science and Technology Project of China (No. 04SK3053–3).
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