A concise and efficient synthesis of substituted morpholines

Article abstract of DOI:10.1055/s-0034-1379641

A simple and efficient method has been developed for the synthesis of substituted morpholines by a sequence of coupling, cyclization, and reduction reactions of easily available amino alcohols and α-halo acid chlorides. Various mono-, di-, and trisubstituted morpholines, spiro morpholines, and ring-fused morpholines, as well as morpholine homologues, were synthesized in good to excellent yields by a single methodology under similar reaction conditions. The method was also used in a multigram synthesis of (3S)-3-methylmorpholine.

Full text of DOI:10.1055/s-0034-1379641

Journal of Synthetic 0rganic Chemistry
SUPPORTING INFORMATION
6<17+(6,6
Supporting Information
for DOI: 10.1055/s-0034-1379641
© Georg Thieme Verlag KG Stuttgart · New York 2014
Thieme

SUPPORTING INFORMATION
A Concise and Efficient Synthesis of Substituted Morpholines
Sundeep Dugar1, Amit Sharma2, Bilash Kuila2 and Dinesh Mahajan2*, Sandeep Dwivedi 2and
Vinayak Tripathi2
1Sphaera Pharma Pte. Ltd., Singapore, 038988
2Sphaera Pharma Pvt. Ltd., IMT Manesar, India, 122051
Contents:
I. General Procedure:
II. Experimental Procedure:
III. Characterization data:
IV. References:
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General information
Methods and Materials:
Unless otherwise noted, commercial available materials were used without further purification.
Air sensitive reactions were carried out under nitrogen atmosphere. Anhydrous solvents were
obtained from Sigma Aldrich. NMR spectra were recorded on a Bruker 300 MHz spectrometer.
Chemical shifts (δ) are quoted in Parts per million (ppm) relative to internal solvent reference.
Coupling constants are given in Hz and chemical shifts are reported in δ values in ppm. Data are
reported as followed: chemical shift, multiplicity (s = singlet, s br = broad singlet, d = doublet, t
= triplet, dd = double doublet, dt = double triplet, ddd = double double doublet, m = multiplet),
coupling constants (Hz), and integration.
General Procedure
Scheme 1:- Three step synthesis of substituted morpholines
R2
R2
O
R2
R1
R3
R3
O
O
R2
R1
R1
a
c
b
R1
NH2
Cl
OH
HO
NH
R3
N
H
N
H
O
(S)-1
(R)-1
(S)-3
(R)-3
(S)-5
(R)-5
(S)-4
(R)-4
Reagents and conditions: (a) α-Chloroacid chloride, K2CO3, THF, H2O, -10oC; (b) KOBut, IPA, DCM, RT; (c)
LAH, THF, 0oC to RT.
General Procedure for synthesis of 3: To a solution of 1 (1 equiv.) in THF (50 mL) was added
a solution of K2CO3 (3 equiv.) in water (50 mL) at -10oC. To the resulting solution at -10oC was
added slowly via syringe α-Chloroacid chloride 2 (1.1 equiv.) with vigorous stirring, and the
reaction mixture was stirred at same temperature for 1 h. The mixture was poured in water (50
mL) and extracted with CH2Cl2 (2 X 100 mL), and the organic layer was dried (Na2SO4), filtered
and concentrated to afford 3 as a colorless oil.
General Procedure for synthesis of 4: To a solution of 3 (1 equiv.) in CH2Cl2 (100 mL) was
dropwise added KOBut (4 equiv.) in IPA (100 mL) at 0oC. The resulting solution was stirred at
RT for 1h. 2N HCl was added to adjust the pH 7 of reaction mixture. The solvent was removed
under reduced pressure to obtain white precipitate. The precipitates were taken in ethyl acetate
(100 mL) and washed with H2O, The organic layer was separated, dried (Na2SO4), filtered and
concentrated to obtain 4 as colorless oil.
General Procedure for synthesis of 5: LAH (2 equiv.) in THF (100 mL) was cooled to 0oC in
an ice bath under nitrogen. A solution of 4 (1 equiv.) in THF (20 mL) was added dropwise, and
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the resulting solution was stirred at RT for 16 hrs. The reaction mixture was cooled to 0oC and
carefully quenched with water (2 mL), 2 N NaOH (2 mL) and water (8 mL). The resulting slurry
was stirred at RT for 1 h and filtered through Celite. The filter cake was washed with ethyl
acetate and discarded. The filtrate was dried (Na2SO4), separated and concentrated to afford 5 as
a colorless oil.
Experimental Procedure
(S)-2-chloro-N-(1-hydroxypropan-2-yl)acetamide(3a):- To a solution of 2-(S)-amino-propan-
1-ol (1.0 g, 13.33 mmol) in THF (50 mL) was added a solution of K2CO3 (5.52 g, 39.99 mmol)
in water (50 mL) at -10oC. To the resulting solution at -10oC was added slowly via syringe α-
Chloroacetylchloride 2 (1.16 mL, 14.66 mmol) with vigorous stirring, and the reaction mixture
was stirred at same temperature for 1 h. The mixture was poured in water (50 mL) and extracted
with CH2Cl2 (2 X 100 mL), and the organic layer was dried (Na2SO4), filtered and concentrated
to afford titled compound 3a as a colorless oil (1.71 g, 85%).1H NMR (300 MHz, CDCl3): δ 6.73
(br, 1H), 4.1 (m, 1H), 4.05(s, 2H), 3.70 (m, 1H), 3.57 (m, 1H), 2.57 (br, 1H), 1.22 (d, J= 6.0 Hz,
3H); MS m/z = 152 [M+1].
(S)-5-methylmorpholin-3-one (4a):- To a solution of (S)-2-chloro-N-(1-hydroxypropan-2-
yl)acetamide 3a (1.50 g, 9.93 mmol) in CH2Cl2 (100 mL) was dropwise added KOBut (4.45 g,
39.72 mmol) in IPA (100 mL) at 0oC. The resulting solution was stirred at RT for 1h. 2N HCl
was added to adjust the pH 7 of reaction mixture. The solvent was removed under reduced
pressure to obtain white precipitate. The precipitates were taken in ethyl acetate (100 mL) and
washed with H2O, The organic layer was separated, dried (Na2SO4), filtered and concentrated to
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obtain titled compound 4a as colorless oil (0.92 g, 80%). H NMR (300 MHz, CDCl3): δ 6.75
(br, 1H), 4.21-4.06 (m, 2H), 3.91-3.86 (m, 1H), 3.71 (m, 1H), 3.35 (m, 1H), 1.19 (d, J= 6.0 Hz,
3H); MS m/z = 116 [M+1].
(S)-3-methylmorpholine (5a): LAH (0.892 g, 23.47 mmol) in THF (100 mL) was cooled to
0oC in an ice bath under nitrogen. A solution of (S)-5-methylmorpholin-3-one (0.90 g, 7.82
mmol) in THF (20 mL) was added dropwise and the resulting solution was stirred at RT for 16
hrs. The reaction mixture was cooled to 0oC and carefully quenched with water (2 mL), 2 N
NaOH (4 mL) and water (6 mL). The resulting slurry was stirred at RT for 1 h and filtered
through Celite. The filter cake was washed with ethyl acetate and discarded. The filtrate was
dried (Na2SO4), separated and concentrated to afford titled compound 5a as a colorless oil (0.56
g, 71%). 1H NMR (300 MHz, CDCl3): δ 3.75 (m, 2H), 3.45 (m, 1H), 3.07(m, 1H), 3.01-2.81 (m,
3H), 0.95 (d, J = 6.3 Hz, 3H); MS m/z = 102 [M+1].
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Multi gram (100g) procedure for (S)-3-methylmorpholine (5a)
2-Amino-1-propanol (1a): In three necked 5 Liter RBF, 1.5 liter dry THF was taken and cooled
to 0oC. LAH (59 g, 1.5 mol) was added to it very carefully with temperature maintained at 0oC.
L-Alanine (70 g, 0.78 mol) was added portion wise at same temperature over 45 min. Reaction
mixture was slowly allowed to warm to room temperature and heated to refluxed for 24 hrs.
After completion, reaction mixture was cooled to 0oC and quenched with saturated K2CO3
solution and stirred for 1 hrs. Added 5% MeOH/DCM solution (2 Liter) and stirred for additional
1 hrs. Crude mixture was filtered on celite pad and dried over anhydrous Na2SO4 and finally
concentrated under reduced pressure to get product (55g, 85%) as colorless oil.
(S)-2-chloro-N-(1-hydroxypropan-2-yl)acetamide(a):- To a solution of 2-(S)-amino-propan-1-
ol (55 g, 0.73 mol) in THF (1 Liter) was added a solution of K2CO3 (303.5 g, 2.19 mol) in water
(600 mL) at -10oC. To the resulting solution at -10oC was added slowly via droping funnel α-
Chloroacetylchloride (65 mL, 0.80 mol) with vigorous stirring, and the reaction mixture was
stirred at same temperature for 1 h. The mixture was poured in water (50 mL) and extracted with
CH2Cl2 (3 X 500 mL), and the organic layer was dried (Na2SO4), filtered and concentrated to
afford titled compound 3a as a colorless oil (95 g, 85%).
(S)-5-methylmorpholin-3-one (4a):- To a solution of (S)-2-chloro-N-(1-hydroxypropan-2-
yl)acetamide (95 g, 0.62 mol) in CH2Cl2 (1 Liter) was dropwise added KOBut (307 g, 2.51 mol)
in IPA (1 Liter) at 0oC. The resulting solution was stirred at RT for 1h. 2N HCl was added to
adjust the pH 7 of reaction mixture. The solvent was removed under reduced pressure to obtain
white precipitate. The precipitates were taken in ethyl acetate (3 X 500 mL) and washed with
H2O, The organic layer was separated, dried (Na2SO4), filtered and concentrated to obtain titled
compound 4a as colorless oil (60 g, 83%).
(S)-3-methylmorpholine (5a)1: LAH (59.32 g, 1.51 mol) in THF (1 Liter) was cooled to 0oC in
an ice bath. A solution of (S)-5-methylmorpholin-3-one (60 g, 0.52 mol) in THF (500 mL) was
added dropwise and the resulting solution was stirred at RT for 16 hrs. The reaction mixture was
cooled to 0oC and carefully quenched with water (2 mL), 2 N NaOH (35 mL) and water (70 mL).
The resulting slurry was stirred at RT for 1 h and filtered through Celite. The filter cake was
washed with ethyl acetate and discarded. The filtrate was dried (Na2SO4), separated and
concentrated to afford titled compound 5a as a colorless oil (45 g, 86%).
1H NMR spectrum of 5g
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1H NMR Spectrum of 5K
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COSEY Spectra of 4r
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COSEY Spectra of 4r
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COSEY Spectra of 4r
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COSEY Spectra of 4r
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COSEY Spectra of Compound 4t
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COSEY Spectra of Compound 4t
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COSEY Spectra of Compound 4t
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Chem. 2011, 54, 1871–1895.
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