Simple and efficient one pot synthetic protocol to construct morpholin-2-ones

Article abstract of DOI:10.3987/COM-10-S(E)14

A new one pot synthetic method to construct 3-substituted morpholine-2-one derivatives is presented. Amino acids refluxed with 1,2-dibromoethane and potassium carbonate in acetonitrile followed by treatment with benzyl bromide in same pot furnished the 3-

Full text of DOI:10.3987/COM-10-S(E)14

HETEROCYCLES, Vol. 82, No. 1, 2010
431
HETEROCYCLES, Vol. 82, No. 2, 2010, pp. 431 - 439. © The Japan Institute of Heterocyclic Chemistry
Received, 16th March, 2010, Accepted, 14th May, 2010, Published online, 17th May, 2010
DOI: 10.3987/COM-10-S(E)14
SIMPLE AND EFFICIENT ONE POT SYNTHETIC PROTOCOL TO
CONSTRUCT MORPHOLIN-2-ONES
Gorakh S. Yellol,a Debendra K. Mohapatra,b Mukund K. Gurjar,c,* and
Chung-Ming Suna,*
aDepartment of Applied Chemistry, National Chiao-Tung University, Hsinchu
b
300-10, Taiwan, Email: cmsun@mail.nctu.edu.tw; Indian Institute of Chemical
Technology, Hyderabad, India, Email: mohapatra@iict.res.in; cEmcure
Pharmaceuticals Ltd., Pune 411057, India, Email: mukund.gurjar@emcure.co.in
Abstract– A new one pot synthetic method to construct 3-substituted
morpholine-2-one derivatives is presented. Amino acids refluxed with
1,2-dibromoethane and potassium carbonate in acetonitrile followed by treatment
with benzyl bromide in same pot furnished the 3-substituted
N-benzyl-morpholine-2-ones in good yields. The simplicity of the reaction
conditions and versatility of resulted scaffold to generate wide variety of
molecules makes this method more attractive for synthetic organic chemists.
INTRODUCTION
Heterocycles are among the most frequently encountered scaffolds in drugs and pharmaceutically relevant
substances. Because of the drug-like character and considerable range of structural diversity, large
collections or libraries of diverse heterocycles are routinely employed in high-throughput screening at
early stages of drug discovery programs. Consequently, relatively small focused libraries of heterocycles
are frequently generated for SAR studies. Among the different synthetic methodologies available for the
production of compound libraries, one-pot multi-step synthesis constitutes a convenient alternative as it
can avoid workup and purification of the intermediates between different reaction steps.1
The asymmetric synthesis of chiral heterocycles has been traditionally challenging as the process involves
stereo-controlled formation of chiral centers. The synthesis of N-heterocycles in enantiomerically pure
This paper is dedicated to Professor Dr. Albert Eschenmoser, ETH Zürich, on his 85th birthday.

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form is of great ongoing interest, particularly for the synthesis of bioactive natural products and medicinal
applications.2 Although many strategies are available for the preparation of such compounds, there is
still a need to develop new and practical methods for the synthesis of these molecules. The chiral amino
acids act as privileged chiral tools to generate the relative chiral centers in stereo-controlled manner.3 The
rigid geometry of 5- or 6-membered ring system embedded with amino acid allows unprecedented
diastereoselectivity during establishment of new chiral center in a molecular structure. In particular,
morpholin-2-one system has been fully tested as an effective template for asymmetric reactions.4
Harwood and Williams have shown that 5-phenyl-morpholinone system is an excellent template for
making enantiomerically cyclic and acyclic amino acids.5
CH3
N
O
O
N
F
O
NH
CH3
N
HN
N
N
CF3
N
N
O
F3C
F
O
N
N
H
O
CF3
O
O
F
UR-9751
Antifungal activity
Aprepitant
Tadalafil
PDE-5 inhibitor
NK1 receptor antagonist
Figure 1. Biologically active morpholinone derivatives
Moreover, morpholinones are known subunits in many natural products and biologically active
pharmaceuticals.6 Varied biological activities have been attributed to morpholinone compounds.
Compounds containing morpholin-2-one derivatives demonstrated for blocking T-type calcium channel,
for prevention and treatment of myocardial disease, pain, heart attack, hypertension and epilepsy.7
Recently morpholin-2-one is identified as one of the major metabolite in an inhibition of human
immunodeficiency virus-type 1 (HIV-1) protease.8 Morpholine ring embedded compounds like UR-9751
have been demonstrated high efficacy in animal models of systemic and vaginal candidosis9 (Figure 1).
Some of the morpholine constituted natural products possess the anti-platelet activity.10 Tadalafil shows
potential phosphordiesterase type 5 (PDE-5) inhibition activities.11 Aprepitant is a potent and orally active
antiemetic drug well-known in the class of non-peptide antagonists to the tachykinin neurokinin NK1
receptor12 (Figure 1).
Additionally, the morpholine-2-ones have also been studied as chiral building blocks for many
pharmaceutically interesting compounds. The morpholine-2-ones would investigated as a privileged
synthons to generate various types of scaffolds (Figure 2). It would used for the stereoselective synthesis
of quaternary proline analogues13 (A), opening of ring by ammonia to get a variety of amides14 (B),

HETEROCYCLES, Vol. 82, No. 1, 2010
433
stereoselective reduction of carbonyl carbon to afford chiral alcoholes15 (C), stereocontrolled substitution
at α-position to produce α-disubstituted amino acid derivatives16 (D) and also its dimerized product17 (E).
R1
O
N
OH
R2
O
A
OH
R1
R2
R1
R2
NH2
OH
O
O
N
N
R1
R2
O
B
C
N
R1, R2 = Alkyl / Aryl
O
O
O
R3
R2
R1
O
R1
N
N
N
R1
O
R2
R2
O
D
E
Figure 2. Uses of morpholin-2-one template to generate different scaffolds
Based on these applications of morpholinone derivatives, we have sought to develop a protocol which
enables us to synthesis a number of 3-substituted morpholin-2-one derivatives starting from commercially
available α–amino acids. Herein, we present a concise approach to both enantiomeric forms of substituted
morpholinones from amino acids which could be useful as chiral building blocks for pharmaceutically
important compounds.
RESULTS AND DISCUSSION
Recently, Kim et al. have reported an efficient synthesis of morpholin-2-one derivatives using
glycol-aldehyde dimer with various α–amino acids and isocyanides using Ugi’s multicomponent
reaction.18 Kashima and his co-worker described the synthesis of morpholine-2-ones by treatment of
amino-acids with 2-bromoethanol and also with its tosyl derivative in two-three steps reaction sequence.19
In further studies, they observed the formation of morpholinone in poor yields and sometimes with loss of
chirality when chiral amino-acids heated with dichloroethanol or dibromoethane in DMF. The present
paper concerns the extension of our earlier work20 and moreover the one pot synthesis of novel
3-substituted morpholine-2-ones in moderate to good yields.
O
O
K2CO3, MeCN
reflux, 8 h
Br
OH
O
Br
NH2
HN
1
2
Scheme 1. Synthesis of morpholinones

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HETEROCYCLES, Vol. 82, No. 1, 2010
In our first attempt, treatment of L-phenyl alanine 1 with 1,2-dibromoethane in refluxing acetonitrile in
present of excess K2CO3 furnished desired product 2a with very low yield (Scheme 1). After few attempts
with varying conditions, it was concluded that the low yield was due to less stability of these compounds
at room temperature. Hence we decided to carry out the experiments with protected amino acids. In first
attaimpt the reaction of N-Boc protected L-phenyl alanine 3 furnished the N-Boc-morpholinone 4 in low
yield due to the stearic crowding to form morpholinone ring. Whereas N-benzyl protected L-phenyl
alanine 5 demonstrated a substantial increase in the yield of N-benzyl-morpholinone 2a (Scheme 2).
O
O
K2CO3, MeCN
Br
OH
O
Br
reflux, 10 h
23%
NHBoc
N
Boc
3
4
O
O
K2CO3, MeCN
Br
OH
NHBn
O
Br
reflux, 10 h
68%
N
Bn
5
2a
Scheme 2. Synthesis of morpholin-2-ones with protected amino acids
In our effort to develop a one pot strategy, we treated the L-phenyl alanine with one equivalent of
1,2-dibromoethane and three equivalents of K2CO3 in acetonitrile. The reaction was monitored by thin
layer chromatography. After complete conversion within 6 h, additional one equivalent of K2CO3 and one
equivalent of benzyl bromide was added in the reaction mixture and the reaction was further refluxed for
4 h (Scheme 3). The workup procedure was very simple involving evaporation of the solvent under
reduced pressure and the residue purified by column chromatography to afford the
(S)-3,4-dibenzylmorpholin-2-one (2a) in 78% yield over two steps.
O
O
K2CO3, MeCN
O
Br
Br
OH
Br
N
80 °C, 10-12 h
NH2
Bn
2a
1
Scheme 3. One pot strategy for synthesis of morpholin-2-ones
After successful development of the one-pot protocol for the synthesis of morpholin-2-ones, we
investigate with other 1,2-dihaloethanes and observed that 1,2-dibromoethane gave superior results. We
also tested various other bases and solvents and concluded that K2CO3 as a base and acetonitrile as a
solvent at 80 °C temperature are the most favorable conditions for this one-pot conversion.

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435
We have verified the versatility of this protocol by examining a number of commercially available
α–amino acids (Table 1). This methodology was applied to variety of aromatic amino acids as well as
aliphatic amino acids. Both the amino acids acts as a prominent substrates giving rise to moderate to good
yields. This strategy is highly versatile and allows the synthesis of many types of novel molecules from
readily available amino acids.
Table 1. Versatility of one pot synthesis of morpholin-2-one derivatives
BrCH2CH2Br, BnBr
NH2
R
NBn
R
HO
O
K2CO3, MeCN
80 °C, 10-12h
O
O
2
aminoacids
Yielda (%)
Entry
Substrate
Time (h)
Product
NBn
NH2
2a
12
O
78
HO2C
HO2C
O
O
NH2
H
NBn
H
2b
2c
2d
10
10
10
O
O
52
66
68
NH2
NBn
HO2C
HO2C
CH3
Me
O
O
NBn
NH2
O
CH3
CH3
CH3
NH2 CH3
CH3
CH3
CH3
NBn
O
O
2e
2f
10
10
69
68
66
60
CH3
HO2C
HO2C
O
O
NH2
NBn
CH3
CH3
SMe
CH3
CH3
NH2
NBn
2g
O
O
10
12
HO2C
HO2C
SMe
O
O
NH2
NBn
2h
2i
OBn
OH
NBn
NBn
NH2
NH2
65
62
12
12
O
O
HO2C
HO2C
O
O
NBn
NBn
2j
aIsolated yield after column purification.

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HETEROCYCLES, Vol. 82, No. 1, 2010
CONCLUSION
In conclusion, we have developed simple, scalable and synthetically useful one pot protocol for the
preparation of 3-substituted-N-benzyl-morpholin-2-one derivatives. This method is expected to have high
potential for the synthesis of other biologically active molecules containing the morpholin-2-one ring
system.
EXPERIMENTAL
Solvents were distilled following standard procedures before use. Dimethylformamide and acetonitrile
were dried over calcium hydride. TLC was performed on the pre-coated silica gel on aluminium plates
1
13
Merck 60 F254. IR spectra were recorded on ATI Mattson RS-1 FT-IR spectrometer. H and C NMR
spectra were recorded on Bruker AC-200 spectrometer with TMS as an internal standard. Mass spectra
were obtained with a TSQ 70, Finningen MAT mass spectrometer. Optical rotations were determined on
JASCO 370 digital polarimeter with sodium light source. Elemental analyses were carried out on a Carlo
Erba CHNS-O analyzer.
General procedure for 3-substituted-N-benzylmorpholin-2-one (2a-2j)
α-Amino acid 1 (1.0 mmol) was stirred with K2CO3 (3.0 mmol) in acetonitrile at 40 °C for 15 min.
1,2-dibromoethane (1.1 mmol) was added in the reaction mixture and heated to 80 °C for 6-8 h. The
reaction was monitored by thin layer chromatography for complete conversion. The reaction mixture then
cooled to the room temperature. Benzyl bromide (1.1 mmol) and K2CO3 (1.0 mmol) was added and
reaction mixture was refluxed for additional 4 h. After completion, reaction mixture was cooled to room
temperature and filtered to remove excess K2CO3. Filtrate was concentrated under reduced pressure and
residual oil was purified by silica gel column chromatography using EtOAc and hexane (1:3) as an eluent
to afford the 3-substituted-N-benzyl-morpholin-2-ones 2a-2j (52-78% overall yield) as colorless liquids.
25
(S)-3,4-Dibenzylmorpholin-2-one (2a). [α]D +4.6 (c 1.18, CHCl3); IR (neat) 3019, 1731, 1215, 757
cm−1; 1H NMR (200 MHz, CDCl3) δ 7.28 (m, 10H), 4.58 (s, 2H), 4.00 (dt, J = 9.7, 2.9 Hz, 1H), 3.76 (dt, J
= 9.7, 2.9 Hz, 1H), 3.32 (d, J = 13.2 Hz, 1H), 3.22 (dd, J = 12.7, 4.8 Hz, 2H), 2.72 (dt, J = 13.2, 2.9 Hz,
13
1H), 2.46 (ddd, J = 12.7, 9.7, 2.9 Hz, 1H); C NMR (50 MHz, CDCl3) δ 169.9, 140.9, 136.6, 129.5,
128.8, 128.2, 127.6, 126.8, 126.2, 65.3, 63.9, 58.2, 45.7, 36.8; MSI m/z: 281 (M+). Anal. Calcd for
C18H19NO2 (281.35): C, 76.84; H, 6.80; N, 4.98. Found: C, 77.04; H, 7.11; N, 4.25.
4-Benzylmorpholin-2-one (2b). IR (neat) 3028, 1729 cm−1; 1H NMR (200 MHz, CDCl3) δ 7.30 (m, 5 H),
4.19 (t, J = 6.3 Hz, 2H), 3.65 (s, 2H), 3.38 (s, 2H), 2.80 (t, J = 6.3 Hz, 2H); 13C NMR (50 MHz, CDCl3) δ
171.2, 136.8, 129.4, 128.8, 127.2, 68.3, 63.5, 58.7, 45.7. Anal. Calcd for C11H13NO2 (191.23): C, 69.09;

HETEROCYCLES, Vol. 82, No. 1, 2010
437
H, 6.85; N, 7.32. Found: C, 70.08; H, 7.12, N, 7.19.
25
(S)-4-Benzyl-3-methylmorpholin-2-one (2c). [α]D +16.5 (c 0.98, CHCl3); IR (neat) 3024, 1735 cm−1;
1H NMR (200 MHz, CDCl3) δ 7.30 (m, 5 H), 4.27 (m, 2H), 3.95 (d, J = 13.2 Hz, 1H), 3.36 (q, J = 6.8 Hz,
1H), 3.30 (d, J = 13.2 Hz, 1H), 2.85 (dt, J = 12.7, 3.6 Hz, 1H), 2.48 (dt, J = 12.7, 3.6 Hz, 1H), 1.54 (d, J =
6.8 Hz, 3H); 13C NMR (50 MHz, CDCl3) δ 170.7, 137.2, 129.4, 128.7, 127.0, 68.0, 60.0, 58.3, 46.3, 16.3.
Anal. Calcd for C12H15NO2 (205.26): C, 70.22; H, 7.37; N, 6.83. Found: C, 70.44; H, 7.43, N, 7.32.
25
(S)-4-Benzyl-3-isopropylmorpholin-2-one (2d). [α]D +24.5 (c 1.12, CHCl3); IR (neat) 3019, 2964,
1729 cm−1; 1H NMR (200 MHz, CDCl3) δ 7.30 (m, 5H), 4.29 (m, 2H), 3.94 (d, J = 13.6 Hz, 1H), 3.45 (d,
J = 13.6 Hz, 1H), 3.24 (d, J = 3.9 Hz, 1H), 2.86 (dt, J = 12.7, 2.9 Hz, 1H), 2.52 (ddd, J = 12.7, 2.9 Hz,
1H), 2.20 (m, 1H), 1.17 (d, J = 6.8 Hz, 3H), 1.10 (d, J = 6.8 Hz, 3H); 13C NMR (50 MHz, CDCl3) δ 169.2,
137.9, 128.5, 128.2, 127.3, 70.3, 67.1, 60.3, 46.8, 32.3, 19.9, 18.3. Anal. Calcd for C14H19NO2 (233.28):
C, 72.08; H, 8.20; N, 6.00. Found: C, 71.56; H, 8.23, N, 5.53.
(S)-4-Benzyl-3-isobutylmorpholin-2-one (2e). [α]D25 +34.2 (c 1.17, CHCl3); IR (neat) 2957, 1737, 1214,
755 cm−1; 1H NMR (200 MHz, CDCl3) δ 7.31 (m, 5 H), 4.35 (m, 2H), 3.95 (d, J = 13.2 Hz, 1H), 3.35 (d,
J = 13.2 Hz, 1H), 3.30 (t, J = 6.8 Hz, 1H), 2.94 (dt, J = 12.7, 4.4 Hz, 1H), 2.50 (dt, J = 12.7, 4.4 Hz, 1H),
13
1.98 (m, 1H), 1.86 (t, J = 6.8 Hz, 2H), 0.95 (d, J = 6.8 Hz, 3H), 0.92 (d, J = 6.8 Hz, 3H); C NMR (50
MHz, CDCl3) δ 170.8, 137.3, 128.4, 127.5, 126.8, 67.0, 62.8, 58.6, 45.9, 39.6, 24.7, 23.0, 22.2; MSI m/z:
247 (M+).
(3S)-4-Benzyl-3-sec-butylmorpholin-2-one (2f). [α]D +28.7 (c 0.91, CHCl3); IR (neat) 3023, 1737, 758
1
cm−1; H NMR (200 MHz, CDCl3) δ 7.26 (m, 5H), 4.32 (m, 2H), 3.92 (d, J = 13.2 Hz, 1H), 3.79 (d, J =
13.2 Hz, 1H), 3.29 (d, J = 6.8 Hz, 1H), 2.54 (dt, J = 12.7, 4.8 Hz, 1H), 2.00 (m, 2H), 1.84 (m, 2H), 1.23
13
(d, J = 6.3 Hz, 3H), 0.98 (t, J = 6.3 Hz, 3H); C NMR (50 MHz, CDCl3) δ 168.8, 139.6, 128.3, 127.8,
126.7, 68.6, 64.8, 60.4, 47.9, 37.6, 24.7, 21.0, 18.2; MSI m/z: 247 (M+).
(S)-4-Benzyl-3-(2-(methylthio)ethyl)morpholin-2-one (2g). [α]D25 +6.4 (c 1.10, CHCl3); IR (neat) 3027,
1
1730, 1151, 698 cm−1; H NMR (200 MHz, CDCl3) δ 7.28 (m, 5H), 4.47 (m, 2H), 3.90 (d, J = 13.2 Hz,
13
1H), 3.72 (d, J = 13.2 Hz, 1H), 3.57 (m, 3H), 2.42 (m, 2H), 1.98 (q, J = 6.8 Hz, 2H), 1.97 (s, 3H); C
NMR (50 MHz, CDCl3) δ 170.2, 137.0, 128.8, 128.7, 128.1, 67.5, 63.3, 58.6, 46.9, 30.0, 29.3, 15.0; MSI
m/z: 265 (M+).
25
(S)-4-Benzyl-3-phenylmorpholin-2-one (2h). [α]D +9.0 (c 1.06, CHCl3); IR (neat): 3025, 1737, 1216,
699 cm−1; 1H NMR (200 MHz, CDCl3) δ 7.29 (m, 10H), 4.64 (s, 1H), 4.47 (m, 2H), 3.76 (s, 2H), 3.51 (t,
13
J = 5.9 Hz, 3H); C NMR (50 MHz, CDCl3) δ 171.3, 139.2, 136.4, 128.7, 128.6, 128.2, 128.0, 127.3,
126.4, 65.7, 63.7, 54.2, 28.4; MSI m/z: 267 (M+).
25
(S)-4-Benzyl-3-(4-(benzyloxy)benzyl)morpholin-2-one (2i). [α]D −14.3 (c 1.05, CHCl3); IR (neat)
3024, 1734 cm−1; 1H NMR (200 MHz, CDCl3) δ 7.29 (m, 12 H), 7.17 (d, J = 7.1 Hz, 2H), 5.14 (s, 2H),

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4.24 (m, 2H), 3.78 (d, J = 12.7 Hz, 1H), 3.63 (m, 1H), 3.55 (d, J = 12.7 Hz, 1H), 3.09 (m, 2H), 2.67 (dt, J
13
= 13.2, 4.4 Hz, 1H), 2.58 (dt, J = 13.2, 4.4 Hz, 1H); C NMR (50 MHz, CDCl3) δ 170.9, 156.2, 137.4,
136.6, 129.5, 129.2, 129.0, 128.2, 128.0, 127.6, 127.4, 126.2, 72.4, 68.5, 66.3, 64.9, 46.7, 36.8; MSI m/z:
281 (M+). Anal. Calcd for C25H25NO3 (387.47): C, 77.49; H, 6.50, N, 3.61. Found: C, 77.01; H, 6.16, N,
3.72.
25
(S)-4-Benzyl-3-((1-benzyl-1H-indol-3-yl)methyl)morpholin-2-one (2j). [α]D −17.34 (c 1.0, CHCl3);
1
IR (neat) 3022, 1728 cm-1; H NMR (200 MHz, CDCl3) δ 8.16 (d, J = 7.8 Hz, 1H), 7.65 (d, J = 7.8 Hz,
1H), 7.24 (m, 12H), 7.01 (s, 1H), 5.06 (s, 2H), 4.69 (m, 1H), 3.84 (m, 1H), 3.82 (d, J = 13.2 Hz, 1H), 3.64
(d, J = 13.2 Hz, 1H), 3.55 (t, J = 6.8 Hz, 1H), 3.22 (dd, J = 13.2, 4.4 Hz, 1H), 2.81 (dd, J = 13.2, 4.4 Hz,
1H), 2.46 (m, 2H); 13C NMR (50 MHz, CDCl3) δ 169.6, 137.0, 136.3, 135.9, 128.0, 127.8, 127.6, 127.5,
127.2, 126.3, 125.7, 120.9, 118.6, 118.4, 108.6, 66.3, 65.2, 58.5, 49.0, 45.9, 26.8; MSI m/z: 410 (M+).
Anal. Calcd for C27H26N2O2 (410.51): C, 79.00; H, 6.38; N, 6.82. Found: C, 78.61; H, 6.16; N, 7.02.
ACKNOWLEDGEMENTS
Gorakh S. Yellol thanks to CSIR, India and NSC, Taiwan for a research fellowship.
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