An improved synthesis and resolution of cis- and trans-2,3-diphenyl morpholines

Article abstract of DOI:10.1016/j.tetasy.2011.11.004

An improved procedure for the synthesis of cis- and trans-2,3-diphenyl morpholines with good overall yield is described. The stereoisomers were efficiently resolved through the corresponding diastereomeric salts using tartaric acid and (R)-mandelic acid.

Full text of DOI:10.1016/j.tetasy.2011.11.004

Tetrahedron: Asymmetry 22 (2011) 1861–1864
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An improved synthesis and resolution of cis- and trans-2,3-diphenyl
morpholines
⇑
Ravindra S. Jagtap, Navalkishore N. Joshi
Division of Organic Chemistry, National Chemical Laboratory, Pune 411 008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 September 2011
Accepted 3 November 2011
An improved procedure for the synthesis of cis- and trans-2,3-diphenyl morpholines with good overall
yield is described. The stereoisomers were efficiently resolved through the corresponding diastereomeric
salts using tartaric acid and (R)-mandelic acid.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
Ph
Ph
O
Ph
Ph
O
Substituted morpholine derivatives are the core of various nat-
ural products and biologically active compounds.1 This class of
compound has found important applications in pharmaceuticals1,2
and in agricultural use.3 Chiral morpholine derivatives have found
numerous applications in asymmetric synthesis as chiral auxilia-
ries4 as well as chiral ligands.5 Various methods are known in
the literature for the synthesis of morpholine derivatives.1,6 In
most of the methods reported, the morpholine ring is constructed
via the reaction of chiral 1,2-amino alcohols with various electro-
philes such as chloroacetyl chloride,7 epoxides,8 activated alkenes9
and others.10 Over the course of our work on asymmetric cataly-
sis,11 we wanted to use morpholine ligands 1 and 2 (Fig. 1).
Although the preparation of the two stereoisomers of these mole-
cules is known, we found the procedure to be unsatisfactory in
terms of yield. Also, the reported rotations were incorrect. Herein
we report an optimized preparation of ( )-1 and ( )-2 which were
then efficiently resolved.
N
H
N
H
1
2
Figure 1.
syntheses of the title compounds 1 and 2 in 14% and 23% overall
yields starting from homochiral aminoalcohols 4 and 7, respec-
tively.14a In asymmetric synthesis, it is always desirable to intro-
duce the chirality in the last possible step. We therefore decided
to redesign the reported procedure for 1 and 2. In order to improve
the yield, erythro amino alcohol 4 was reacted with chlorocetyl chlo-
ride at ꢀ10 °C in the presence of NaHCO3 using methanol as the sol-
vent. Racemic erythro-2-(chloroacetylamino)-1,2-diphenylethanol
5 was obtained as the sole product in a 98% yield (Scheme 1). With-
2. Results and discussion
OH
Ph
Ph
OH
Ph
Ph
Ph
Ph
OH
O
a
b
2.1. Preparation of ( )-1 and ( )-2
Cl
N
H
5
N
OH
NH2
Both the cis- and trans-2,3-diphenyl morpholines can be ac-
cessed from a common intermediate, erythro-2-amino-1,2-diphen-
ylethanol 4. The amino alcohol 412 was prepared by hydrogenation
3
4
of a-benzoin oxime 3 (Scheme 1). Our initial efforts to construct the
Ph
O
morpholine ring using a one step protocol13 by condensation of 4
with 1,2-dibromoethane or ethylene-di-p-toluenesulfonate were
unsuccessful. We therefore decided to investigate the reported
syntheses of these molecules. Stefanovsky et al. reported the
c
d
( )-1
Ph
N
H
O
6
⇑
Corresponding author. Tel.: +91 20 25902055; fax: +91 20 25902629.
E-mail address: nn.joshi@ncl.res.in (N.N. Joshi).
Scheme 1. Reagents and conditions: (a) H2-Pd/C, MeOH; (b) ClCH2COCl, NaHCO3,
MeOH; (c) KOH, EtOH; (d) LiAlH4, THF.
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.11.004

1862
R. S. Jagtap, N. N. Joshi / Tetrahedron: Asymmetry 22 (2011) 1861–1864
out further purification, 5 was cyclized to cis-5,6-diphenylmorpho-
lin-3-one 6 in a 97% yield using potassium hydroxide in ethanol at
reflux. The 1H NMR of the unpurified 6 was clean and showed no
isomerization at the stereocenters under reflux conditions. The
cyclization of 5 to 6 can also be carried out by using sodium hydride
or potassium tert-butoxide in N,N-dimethyl formamide or tert-buta-
nol, respectively, with similar yields. Compound 6 was reduced with
LiAlH4 in THF under reflux for 16 h to obtain racemic cis-2,3-diphe-
nyl morpholine 1 in overall 59% yield from 4 without applying col-
umn chromatographic purification. Further purification was better
achieved through oxalate salt rather than the reported hydrochlo-
ride method. After the usual work-up, the crude compound was
then treated with oxalic acid (0.5 equiv) to give the oxalate salt,
which was subsequently recrystallized from ethanol and basified
with aqueous NaOH to give ( )-1 in a 62% yield. These modified
reaction conditions were successfully scaled up to 100 mmol. An
overall yield of 59% yield was achieved starting from 4.
literature.12a Following the above described reaction conditions, 7
was converted to ( )-2 in 56% overall yield.
2.2. Resolution
The most practical method for the resolution of racemic amines
is the preparation of diastereomeric salt with an optically active
acid, and then separation via crystallization.15 To the best of our
knowledge, the resolution of 1 and 2 is not known in the literature.
Initial examination of various resolving agents, such as (ꢀ)-glu-
tamic acid, (1R)-(ꢀ)-camphorsulphonic acid, (ꢀ)-menthoxyacetic
acid and (ꢀ)-mandelic acid proved unsuccessful. (ꢀ)-Pyroglutamic
acid or (+)-O-acetyl mandelic acid provided resolution, but
required multiple crystallizations. Finally, the resolution of ( )-1
was accomplished through the sequential use of L- and D-tartaric
acid. It was observed that the stoichiometry of the resolving agent
affected the yield as well as the enantiomeric excess. When ( )-1
After the successful optimization of the reaction conditions, we
used this protocol for the preparation of racemic trans-2,3-diph-
and
L
-(+)-tartaric acid were used in a 1:0.5 ratio, (ꢀ)-1 and (+)-1
were isolated in 39% and 42% yields with 94% and 72% ee,
respectively. A ratio of 1:1 did not provide any resolution at all.
The best results were obtained when a ratio of 1:0.25 was used
enylmorpholine
2
(Scheme 2). The racemic threo-2-amino-1,
was obtained from according to the
2-diphenylethanol
7
4
Ph
Ph
OH
Ph
Ph
OH
Ph
Ph
O
ref.12a
a
O
c
b
4
( )-2
Cl
N
H
N
H
O
NH2
7
8
9
Scheme 2. Reagents and conditions: (a) ClCH2COCl, NaHCO3, MeOH/THF; (b) KOH, EtOH; (c) LiAlH4, THF.
1. recrystallization
(2R,3S)-(-)-1
solid salt
2. aq. NaOH, DCM
36%, 99% ee
1. L-(+)-tartaric acid
(0.25 equiv.)
EtOH
Ph
Ph
O
N
H
2. Et2O
1. D-(-)-tartaric acid
2. recrystallization
(2S,3R)-(+)-1
( )-1
filtrate
3. aq. NaOH, DCM
43%, >99% ee
Scheme 3. Resolution of cis-2,3-diphenyl morpholine 1.
Ph
Ph
O
MeOH
diastereomeric salt
+
(R)-(-)-mandelic acid
N
H
aq. NaHCO3, DCM
(2S,3S)-(-)-2
( )-2
precipitate
39%, 92% ee
preferential
precipitation
diastereomeric salt
isopropanol
1. recrystallization
(2R,3R)-(+)-2
filtrate
2. aq. NaHCO3, DCM
44%, >99% ee
Scheme 4. Resolution of trans-2,3-diphenyl morpholine 2.

R. S. Jagtap, N. N. Joshi / Tetrahedron: Asymmetry 22 (2011) 1861–1864
1863
(Scheme 3). In an optimized protocol, ( )-1 and
L
-(+)-tartaric acid
2-diphenylethanol 4 as white crystals. Yield: 8.53 g (80%); mp
163–165 °C (lit.12a 163 °C).
(0.25 equiv) were mixed in ethanol and stirred overnight. The solid
tartrate salt was separated from the unreacted morpholine through
extraction with ether. Subsequent recrystallization of the salt from
ethanol and basification gave (ꢀ)-1. The (+)-enantiomer was ob-
4.3. ( )-Erythro-2-(chloroacetylamino)-1,2-diphenylethanol 5
tained from the mother liquor by similar treatment with
D
-(ꢀ)-tar-
A two liter round-bottomed flask equipped with a magnetic
stirrer bar and an addition funnel was charged with 4 (10.67 g,
50 mmol), NaHCO3 (12.6 g, 150 mmol) and methanol (700 mL).
The assembly was cooled to ꢀ10 °C. Freshly distilled chloroacetyl
chloride (4.4 mL, 55 mmol) was added dropwise through the addi-
tion funnel over 1 h and the mixture was gradually allowed to
warm to room temperature and stirred for a further 2 h. The proce-
dure was repeated by the addition of additional chloroacetyl chlo-
ride (5.6 mL, 70 mmol) in three portions. The reaction mixture was
stirred at room temperature for 24 h. Methanol was then removed
on a rotary evaporator. The residue was suspended in water
(300 mL) and stirred for 15 min. The reaction mixture was then
filtered and dried to give 5 as a white solid, which was used for
the next step without any purification. Yield: 14.18 g (98%); mp
193–194 °C (lit.14a 187–188 °C).
taric acid. Both of the enantiomers were obtained in good yields
and high enantiomeric purity after a single crystallization of the
corresponding tartrate salts. The enantiomeric purity of both enan-
tiomers was found to be P99% by chiral HPLC. The solvent played a
crucial role in the resolution process as revealed by the fact that
racemic 1 was obtained when the salt was prepared in methanol.
In order to resolve the corresponding racemic trans-2,3-diphenyl
morpholine 2, we first tried L-(+)-tartaric acid. However, we could
only isolate one enantiomer in very low yield with 95% ee. Success
was achieved when using (ꢀ)-mandelic acid as the resolving agent
(Scheme 4). The diastereomeric salt was prepared by mixing the
acid and racemic 2 in methanol. However we were unable to sepa-
rate the diastereomeric salts by recrystallization. The preferential
precipitation11c method resulted in clean separation.
The resulting solid was dissolved in boiling isopropanol and
then stirred at room temperature for 2 h followed by filtration.
The purified salt, after basification, gave (ꢀ)-2. The mother liquor
from the aforementioned resolution process was evaporated to
dryness and the solid was crystallized from ethyl acetate. Subse-
quent basification of the salt provided (+)-2. The enantiomeric pur-
ity was determined by chiral HPLC. We observed higher specific
rotation for the cis- as well as trans-isomers as compared to the
known values reported in the literature14a (see Section 4).
4.4. ( )-cis-5,6-Diphenylmorpholin-3-one 6
A two liter round-bottomed flask equipped with a magnetic
stirrer bar and a reflux condenser was charged with crude 5
(28.97 g, 100 mmol), KOH (8.41 g, 150 mmol) and ethanol
(700 mL). The reaction mixture was stirred at reflux for 1.5 h, after
which the mixture was allowed to cool to room temperature. Eth-
anol was then removed on a rotary evaporator. To the residue
0.5 M aqueous HCl (200 mL) was added and the mixture was ex-
tracted with dichloromethane (1 ꢁ 300 mL, 2 ꢁ 150 mL). The com-
bined extracts were washed with brine, dried over Na2SO4 and
concentrated under reduced pressure to give 6 as a white solid,
which was used for the next step without any purification. Yield:
24.54 g (97%); mp 181–182 °C (lit.14a 177–179 °C).
3. Conclusion
In conclusion, we have prepared all four stereoisomers of 2,3-
diphenyl morpholine in excellent overall yields. The resolution of
cis-2,3-diphenyl morpholine was accomplished with high enantio-
meric purity through the sequential use of L- and D-tartaric acid.
Resolution of the trans-isomer was achieved using (ꢀ)-mandelic
acid. The evaluation of these ligands in the enantioselective addi-
tion of organozinc reagents to aldehydes is currently in progress.
4.5. ( )-cis-2,3-Diphenylmorpholine 1
An oven-dried one liter round-bottomed flask with a side arm
equipped with a stirrer bar, addition funnel and a reflux condenser,
was charged with LiAlH4 (8.47 g, 223 mmol). The flask was cooled
to 0 °C in an ice bath and 50 mL of freshly distilled anhydrous THF
was added under an argon atmosphere. To the resulting suspen-
sion, a solution of 6 (20.42 g, 80.61 mmol) in THF (600 mL) was
added dropwise over a period of 2.5 h. After the addition, the ice
bath was removed and the mixture was heated at reflux for 16 h.
The reaction mixture was cooled to 0 °C, diluted with diethyl ether
(200 mL) and quenched cautiously by the dropwise addition of 1 M
NaOH (50 mL). The white solid was removed by filtration. The fil-
trate was dried over Na2SO4 and concentrated under reduced pres-
sure to obtain a crude sticky mass (14.06 g), which was then
dissolved in ethanol (400 mL) and treated with oxalic acidꢂ2H2O
(3.7 g, 0.5 equiv) and filtered. The resulting oxalate salt after
recrystallization from ethanol followed by basification with aque-
ous NaOH gave ( )-1. Yield 12 g (62%); White solid; mp 82–84 °C
(lit.14b 82–84 °C).
4. Experimental
4.1. General
All solvents and reagents were purified and dried according to
the literature procedures.16 The reactions were monitored by TLC
using silica gel 60 F254 pre-coated plates. The products were puri-
fied by column chromatography on silica gel (100–200 or 230–400
mesh). All melting points were recorded on a Büchi B-540 electro
thermal melting point apparatus and are uncorrected. Optical rota-
tions were measured on Bellimheam+Standley ADP220 digital
polarimeter. IR spectra were recorded on a Shimadzu FTIR-8400
spectrophotometer. 1H spectra were recorded at 200 MHz with
TMS as the internal standard. 13C NMR spectra were recorded at
50 MHz with CDCl3 (d = 77) as the reference. Micro analysis was
performed using a Carlo-Erba CHNS-0 EA 1108 elemental analyzer.
All compounds provided satisfactory spectroscopic data. The enan-
tiomeric excess was determined using a chiral column on HPLC.
4.6. Resolution of ( )-1
4.2. ( )-Erythro-2-amino-1,2-diphenylethanol 4
To a solution of L-(+)-tartaric acid (1.5 g, 10 mmol) in ethanol
(30 mL) was added a solution of ( )-1 (9.57 g, 40 mmol) in ethanol
(160 mL) and the resulting mixture was stirred overnight at room
temperature. Ethanol was then removed on a rotary evaporator at
40 °C. To the residue, diethyl ether (150 mL) was added and the
mixture was stirred for 1 h. Filtration of the reaction mixture
provided the tartrate salt (6.52 g), which was recrystallized from
A solution of racemic a-benzoin oxime 3 (11.36 g, 50 mmol) in
methanol (130 mL) was hydrogenated at room temperature and at
50 psi pressure using 10% Pd/C (0.5 g) for 6 h. The usual
work-up12b provided a crude solid (10.13 g, 95%). Recrystallization
of the solid from methanol gave racemic erythro-2-amino-1,

1864
R. S. Jagtap, N. N. Joshi / Tetrahedron: Asymmetry 22 (2011) 1861–1864
ethanol (90 mL) to obtain white crystals 4.53 g (36%); mp 181–
yield. The isomer (ꢀ)-2 of the morpholine was obtained from the
precipitated salt while (+)-2 was obtained from the salt left in
the filtrate. (2S,3S)-(ꢀ)-2; yield: 39%; white solid; mp 74–76 °C;
184 °C; ½a 2D5
¼ ꢀ19:0 (c 0.42, MeOH). The second isomer of the
ꢃ
morpholine was isolated from the mother liquor. To improve the
yield, the mother liquor from the ethanol solution was basified
with aqueous NaOH and gave free morpholine, which was mixed
with the mother liquor from the ether solution. The combined free
½
a 2D5
ꢃ
¼ ꢀ100 (c 2, CHCl3); 92% ee Kromasil-5-Amycoat column; i-
PrOH/PE/TFA (20:80:0.1); 0.5 mL/min; 220 nm; minor isomer:
tR = 9.06 min; major isomer tR = 10.32 min. (2R,3R)-(+)-2; Yield
morpholine (6.18 g, 25.82 mmol) was then treated with
D
-(ꢀ)-tar-
44%; white solid; mp 74–76 °C; ½a D25
ꢃ
¼ þ102 (c 2, CHCl3) [lit.14a
taric acid (1.91 g, 12.72 mmol) in ethanol as described above. The
resulting tartrate salt, after recrystallization from ethanol, pro-
+92.7 (c 2.2, CHCl3)]; >99% ee Kromasil-5-Amycoat column; i-
PrOH/PE/TFA (20:80:0.1); 0.5 mL/min; 220 nm; major isomer:
tR = 8.68 min; minor isomer tR = 10.77 min.
vided white crystals 5.4 g (43%); mp 182–185 °C; ½a D25
¼ þ19:7
ꢃ
(c 0.44, MeOH). Basification of the salt was carried out using aque-
ous NaOH to provide the corresponding enantiomerically pure
morpholines in quantitative yield. Isomer (ꢀ)-1 of the morpholine
was obtained from the (ꢀ)-tartrate salt, while isomer (+)-1 was
obtained from the (+)-tartrate salt. (2R,3S)-(ꢀ)-1; Yield 36%: white
Acknowledgements
Financial support for this work was provided by the Depart-
ment of Science and Technology, New Delhi. One of us (R.S.J.)
thanks the CSIR, New Delhi, for a research scholarship. We are
thankful to Mrs. S. Kunte for chiral HPLC analysis.
solid; mp 73–75 °C. ½a D25
ꢃ
¼ ꢀ77:2 (c 2.59, CHCl3) [lit.14a ꢀ28.3 (c
2.6, CHCl3)]; 99% ee Kromasil-5-Amycoat column; i-PrOH/PE/TFA
(20:80:0.1); 0.5 mL/min; 220 nm; major isomer: tR = 7.76 min;
minor isomer tR = 9.34 min. (2S,3R)-(+)-1; Yield: 43%; white solid;
References
mp 73–75 °C; ½a 2D5
¼ þ76:4 (c 2.59, CHCl3); >99% ee Kromasil-5-
ꢃ
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4.9. ( )-trans-2,3-Diphenylmorpholine 2
The same procedure described above for compound 1 was fol-
lowed for 9 (3.6 g, 14.2 mmol), LiAlH4 (1.34 g, 35.3 mmol) and
THF (160 mL). Yield 2.17 g (64%); white solid; mp 85–87 °C; IR
(CHCl3): 3328, 3018, 2862, 1492, 1450 cmꢀ1 1H NMR (200 MHz,
;
CDCl3): d 1.83 (bs s, 1H, NH), 3.0–3.13 (m, 1H), 3.27 (td, J = 11.5,
3.41 Hz, 1H), 3.77 (d, J = 8.84 Hz, 1H), 3.93 (td, J = 11.24, 2.65 Hz,
1H), 4.05–4.16 (m, 1H), 4.36 (d, J = 8.84 Hz, 1H) 6.95–7.20 (m,
10H) ppm; 13C NMR (50 MHz, CDCl3): d 46.5, 67.4, 67.9, 85.2,
127.3, 127.4, 127.5, 127.6, 127.8, 128.0, 139.0, 140.1 ppm; Anal.
Calcd for C16H17NO: C, 80.30; H, 7.16; N, 5.85. Found: C, 80.29;
H, 7.46; N, 5.90.
4.10. Resolution of ( )-2
To a solution of ( )-2 (7.42 g, 31.03 mmol) in MeOH (120 mL)
was added (R)-(ꢀ)-mandelic acid (4.73 g, 31.03 mmol) and the
reaction mixture was stirred at room temperature for 1 h. Metha-
nol was then evaporated on a rotary evaporator. The resulting salt
was dissolved in boiling isopropanol (160 mL). The mixture was
then allowed to cool to room temperature, stirred for 2 h, and fil-
tered. The residue was washed with hot ethyl acetate to obtain
one of the diastereomeric salts as a white precipitate (4.74 g,
39%); mp 175–177 °C; ½a D25
¼ ꢀ116 (c 1, MeOH). The second iso-
ꢃ
mer of the salt was obtained from the mother liquor by evapora-
tion followed by recrystallization from ethyl acetate (5.36 g,
14. (a) Stefanovsky, J. N.; Spassov, S. L.; Kurtev, B. J.; Balla, M.; Otvos, L. Chem. Ber.
1969, 102, 717; see also (b) Lutz, R. E.; Baker, J. W. J. Org. Chem. 1956, 21, 49.
15. Jacques, Jean; Collet, Andre
´; Wilen, Samuel H. Enantiomers, Racemates and
Resolution; Wiley: New York, 1981.
16. Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory Chemicals, Third Ed.;
Pergamon: Oxford, NewYork, NY, 1988.
44%); mp 150–151 °C; ½a D25
¼ þ32 (c 1, MeOH). Basification of
ꢃ
the salt was carried out using aqueous NaHCO3 to provide the cor-
responding enantiomerically pure morpholines in quantitative