Racemization-Free Synthesis of Morpholinone Derivatives from α-Amino Acids

Article abstract of DOI:10.1055/s-0035-1560088

A simple strategy is reported for the synthesis of chiral N-protected morpholinone derivatives by a base (potassium carbonate)-mediated cyclization reaction of N-protected α-amino acids with 1,2-dibromoethane. The morpholinone derivatives are obtained in

Full text of DOI:10.1055/s-0035-1560088

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2015, 47, 3776–3782
paper
3776
S. Samanta et al.
Paper
Synthesis
Racemization-Free Synthesis of Morpholinone Derivatives from
α-Amino Acids
R
Sauvik Samanta
Abhijit Mal
O
ee > 99%
N
PG
Sandipan Halder
Manas K. Ghorai*
O
PG = Ts
2 examples
(65–73%)
R
CO2H
PG
R
O
ee > 99%
HN
Department of Chemistry, Indian Institute of Technology,
Kanpur-208016, India
N
PG
Me
mkghorai@iitk.ac.in
PG = Ts, Bn
10 examples
(60–75%)
CO2Me
ee > 99%
O
N
PG
PG = Ts
(64%)
Received: 12.05.2015
Accepted after revision: 11.07.2015
Published online: 25.08.2015
one and aromatic imines has been reported.16 We surmised
that enantiopure morpholin-2-one derivatives might be
readily synthesized from N-protected chiral α-amino acids
by a base-mediated cyclization reaction with a 1,2-diha-
loethane (Scheme 1).
DOI: 10.1055/s-0035-1560088; Art ID: ss-2015-z0313-op
Abstract A simple strategy is reported for the synthesis of chiral N-
protected morpholinone derivatives by a base (potassium carbonate)-
mediated cyclization reaction of N-protected α-amino acids with 1,2-
dibromoethane. The morpholinone derivatives are obtained in good
yields and in enantiomerically pure forms.
O
R
CO2H
base
R
X
+
O
X
polar
aprotic solvent
HN
PG
N
Key words morpholines, asymmetric synthesis, amino acids, cycliza-
PG
X = halogen
tions
1
2
Scheme 1 Racemization-free synthesis of morpholin-2-ones
Morpholines and morpholinones are important classes
of heterocyclic compounds that form structural units of
many natural products and synthetic compounds of biolog-
ical and pharmaceutical relevance.1 In particular, N- and/or
2-substituted morpholines2 and morpholinones3 exhibit a
wide spectrum of biological activities. Chiral morpholine
derivatives have been synthesized from naturally occurring
amino acids,4 amino alcohols,5 epoxides,6 small-ring aza-
heterocycles,7 olefins,8 carbohydrates,9 or vinylsulfonium
salts.2d,10 Asymmetric hydrogen-transfer reactions11 and
metal-catalyzed cyclization reactions12 are also important
routes to chiral morpholines. There are only a few reports
on syntheses of chiral morpholinone derivatives. Syntheses
of optically active morpholinones from amino alcohols, α-
bromo esters, and α-amino acids by various base-catalyzed
cyclization reactions have been reported.13 Another novel
strategy for the synthesis of 4-aminomorpholinone deriva-
tives from (S)-malic acid has also been reported.3a Enantio-
selective syntheses of morpholinone derivatives have also
been accomplished by using chiral auxiliary approaches.14
Morpholinone derivatives have also been synthesized from
α-bromo esters by L-malate-mediated dynamic kinetic res-
olution.15 Very recently, the synthesis of trans-selective
oxomorpholinecarboxylic acid derivatives from dioxanedi-
In continuation of our research activities on the synthe-
sis of six-membered carbacycles17 and heterocycles,7a,b,18
we have developed a simple strategy for the synthesis of
chiral N-protected morpholinone derivatives 2 from N-pro-
tected chiral α-amino acids. Here, we report our results in
detail.
To test the viability of our approach, we first treated N-
tosylphenylalanine (1a) with 1,2-dibromoethane in the
presence of 2.5 equivalents of sodium hydroxide in dimeth-
yl sulfoxide. Addition of the reagents at 0 °C, followed by
stirring at room temperature for 24 hours led to the forma-
tion of the acyclic dialkylated product 3, along with the O-
alkylated ester 4 (Table 1, entry 1). When potassium car-
bonate (2.5 equiv.) was used as the base at room tempera-
ture, the ester 4 was isolated as the sole product after 24
hours (entry 2). To effect cyclization, another 2.5 equiva-
lents of potassium carbonate were added to the reaction
mixture, which was stirred at room temperature for a fur-
ther 24 hours. The N-tosylmorpholinone derivative 2a was
obtained in only 18% yield (entry 3). When the reaction
mixture was heated at 100 °C, the acyclic dialkylated prod-
uct 3 along with the allyl ester 5 were formed instead of the
cyclic product 2a (entry 4).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3776–3782

3777
S. Samanta et al.
Paper
Synthesis
Table 1 Optimization Study
Table 2 Synthesis of Chiral N-Tosylmorpholin-2-one Derivatives
O
O
O
K2CO3 (5.0 equiv)
DMF
R
CO2H
Ts
R
CO2H
Ph
Br
2
Ph
O
Br
+
Ph
O
O
Br
HN
0 °C to r.t., 16 h
N
Br
N
N
HN
Ts
Ts
Ts
2
Ts
1a
2a
1
2
base, solvent
3
+
0 °C to temp
O
O
Entry
1
Substrate
R
Product
Yielda (%)
Br
Br
2
Br
Ph
Ph
O
O
O
NH
NH
Ts
Ts
Ph
O
5
4
1a
Bn
72
N
Ts
Entry Base (equiv)
Solvent
Temp Time Yield (%)a
2a
(°C)
(h)
2a
3
4
5
O
O
1
2
3
NaOH (2.5)
K2CO3 (2.5)
DMSO
DMSO
DMSO
r.t.
r.t.
r.t.
24
–
–
12 28
–
–
–
2
3
4
5
6
1b
1c
1d
1e
1f
s-Bu
i-Bu
i-Pr
75b
68
70
65
62
O
24
–
–
40
15
N
Ts
K2CO3 (2.5,
2.5)
24 +
24b
18
2b
2c
4
5
6
7
8
K2CO3 (2.5)
K2CO3 (5.0)
K2CO3 (5.0)
K2CO3 (5.0)
K2CO3 (5.0)
DMSO
DMSO
DMF
100
24
16
16
16
16
–
15
–
–
32
–
O
r.t.
r.t.
r.t.
r.t.
42
72
20
-
10
-
N
O
–
–
Ts
N
MeCN
–
16
30
–
acetone
–
–
a Yield of the isolated product.
O
b After 24 h reaction with 2.5 equiv of base, the reaction was continued for
another 24 h with excess (2.5 equiv) base.
Ts
2d
With excess base (5.0 equiv) and a longer reaction time
(16 h) at room temperature, the morpholinone derivative
2a was obtained in moderate yield (Table 1, entry 5). The
base-catalyzed cyclization step was also studied in other
polar aprotic solvents (entries 6–8). The best result was ob-
tained in N,N-dimethylformamide, where 2a was obtained
as the only product in 72% yield (entry 6).
The strategy was generalized with various N-tosyl α-
amino acids 1b–e and 1,2-dibromoethane to give the corre-
sponding morpholinones 2b–e in 62–75% yields (Table 2) in
enantiomerically pure forms.19,20 Our strategy worked well
with other unnatural α-amino acids; for example, the tert-
leucine derivative 1f afforded the corresponding morpholi-
none 2f (Table 2, entry 6) in good yield.
O
MeS
O
(CH2)2SMe
N
O
Ts
O
2e
t-Bu
N
Ts
2f
a Yield of the isolated product.
b > 99% ee, as determined by chiral HPLC analysis.
The structures of the morpholinone derivatives 2a and
2b were unambiguously confirmed by X-ray crystallo-
graphic analysis (Figure 1).21
Next, we extended our strategy to the synthesis of the
chiral morpholinecarboxylate derivative 7. When we sub-
jected the methyl ester of N-tosylthreonine (6) to our cy-
clization protocol, we obtained the corresponding N-to-
sylmorpholinecarboxylate derivative
7 in good yield
(Scheme 2) as a single stereoisomer (de, ee > 99%).
Figure 1 X-ray crystal structure of 2a and 2b
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3776–3782

3778
S. Samanta et al.
Paper
Synthesis
ered to 65 °C, the morpholinone product 11a was obtained
in enantiopure form, but with a slightly reduced yield (en-
try 3). Note that N-tosylmorpholinones 2a–f and morpho-
lines 9a–b were obtained in enantiopure form when the re-
actions were performed at room temperature.
Me
Me
K2CO3 (5.0 equiv)
CO2Me
DMF
CO2Me
Ts
Br
HO
+
O
Br
0 °C to r.t., 16 h
HN
N
Ts
6
7 64%
A number of N-benzyl-protected morpholinone deriva-
tives 11a–d in enantiomerically pure forms20,23 were syn-
thesized in good yields starting from various N-benzyl α-
amino acids 10a–d (Table 4).
Scheme 2 Synthesis of chiral morpholinecarboxylate
The cyclization reaction of N-tosyl α-amino alcohols 8a
and 8b with 1,2-dibromoethane under the same reaction
condition gave the nonracemic20,22 morpholine derivatives
9a and 9b, respectively, in good yields as single enantio-
mers (Scheme 3).
Table 4 Synthesis of Chiral N-Benzylmorpholinone Derivatives
O
K2CO3 (3.0 equiv)
R
CO2H
Ph
DMF
R
Br
+
O
Br
0–65 °C, 16 h
K2CO3 (5.0 equiv)
HN
R
R
Ph
N
OH
O
DMF
Br
+
Br
10
11
HN
N
0 °C to r.t., 16 h
Ts
Ts
Entry
1
Substrate
R
Product
Yielda (%)
8a R = Ph
8b R = s-Bu
9a 65%, ee >99%
9b 73%
O
Scheme 3 Synthesis of chiral morpholines
10a
Bn
65b
Ph
O
Next, we extended our protocol to the synthesis of non-
racemic N-benzylmorpholinone derivatives. Surprisingly,
the expected morpholine product could not be obtained
from the reaction of N-benzylphenylalanine (10a) with 1,2-
dibromoethane under the reaction conditions mentioned in
Table 2 (Table 3, entry 1). When the amount of potassium
carbonate was decreased to 3.0 equivalents and the mix-
ture was heated to 100 °C after addition of all the reagents
at 0 °C, the N-benzylmorpholinone 11a was obtained in
high yield, albeit with a reduced enantiomeric excess (entry
2). Interestingly, when the reaction temperature was low-
Ph
N
11a
O
O
O
2
3
4
10b
10c
10d
s-Bu
i-Bu
i-Pr
66
60
62
Ph
N
11b
O
N
Ph
11c
Table 3 Optimization of the Synthesis of 3,4-Dibenzylmorpholin-2-
one (11a)
O
O
O
CO2H
Ph
N
Ph
Ph
Ph
O
11d
HN
Ph
N
a Yield of the isolated product.
K2CO3 (equiv)
DMF
10a
11a
O
b ee > 99%; racemic morpholinone was synthesized starting from racemic
+
α-amino acid.
0 °C to temp, 16 h
Br
Br
2
Br
Ph
Ph
O
Earlier, 11d and another example of an N-benzyl-
protected morpholinone were reported by Kashima and
Harada, who used similar reaction condition (K2CO3, DMF,
80 °C, 12 h).13 However, we found that 65 °C is the optimal
temperature for obtaining enantiopure compounds. At
higher temperatures, the products were obtained with re-
duced enantiomeric excesses, albeit in higher yields.
In conclusion, we have developed a simple and efficient
strategy for the synthesis of chiral N-tosylmorpholinones,
morpholinecarboxylates, and other morpholine derivatives
from N-tosyl α-amino acids under mild reaction conditions.
N-Benzylmorpholinones were also synthesized in enantio-
N
Br
2
12
Entry
K2CO3
(equiv)
Temp
(°C)
Yield (%)a
eeb (%)
of 11a
11a
12
1
2
3
5.0
3.0
3.0
r.t.
–
30
–
100
65
78
65
–
–
72
>99
a Yield of the isolated product.
b Racemic morpholinone 11a was synthesized from the racemic α-amino
acid.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3776–3782

3779
S. Samanta et al.
Paper
Synthesis
pure forms by using our strategy. Our method will be very
useful for the syntheses of various morpholine derivatives
in enantiopure forms.
1H NMR (500 MHz, CDCl3): δ = 0.96 (t, J = 10.4 Hz, 3 H), 1.02 (d, J = 6.8
Hz, 3 H), 1.29−1.35 (m, 1 H), 1.80−1.85 (m, 1 H), 1.97−2.02 (m, 1 H),
2.43 (s, 3 H), 3.34−3.39 (m, 1 H), 3.62−3.67 (m, 1 H), 4.11−4.15 (m, 1
H), 4.22 (d, J = 7.3 Hz, 1 H), 4.31−4.36 (m, 1 H), 7.33 (d, J = 7.9 Hz, 2 H),
7.68 (d, J = 7.9 Hz, 2 H).
13C NMR (125 MHz, CDCl3): δ = 11.5, 15.4, 21.7, 26.3, 39.5, 41.7, 62.4,
64.8, 127.6, 130.3, 134.1, 144.7, 167.0.
HRMS (ESI): m/z [M + H]+ calcd for C15H22NO4S: 312.1270; found:
312.1270.
All commercial reagents were purchased from Sigma-Aldrich, Spec-
trochem Pvt. Ltd. and Avra Laboratories Pvt. Ltd. and used directly.
1,2-Dibromoethane was purified by distillation under reduced pres-
sure. Solvents were dried by using standard procedures and preserved
under 4 Å molecular sieves. Melting points were determined on a
MEL-TEMP® capillary melting point apparatus and are uncorrected. IR
spectra were recorded on a Bruker Vector 22 FTIR spectrophotometer.
1H and 13C NMR spectra were recorded on Jeol JNM-LA 400 FT-NMR or
Jeol JNM-LA 500 FT-NMR spectrometers. Chemical shifts (δ) are refer-
enced to TMS as an internal standard. Mass spectra were recorded on
a Jeol SX 102/DA-6000 spectrometer operated in the ESI mode. Opti-
cal rotations were measured on a Rudolph Autopol IV polarimeter.
Enantiomeric excess (ee) values were determined on a Perkin-Elmer
Flexer HPLC. X-ray crystal diffraction data were collected on a Bruker
AXS smart APEX CCD diffractometer.
The enantiomeric excess was determined by chiral HPLC analysis
[column: Chiralpak Cellulose 2; hexane–i-PrOH (90:10), flow rate =
1.0 mL/min; tR (1) = 25.21 min (major)].
3-Isobutyl-4-tosylmorpholin-2-one (2c)
Prepared from N-tosylleucine (1c, 100 mg, 0.35 mmol) and
Br(CH2)2Br (0.04 mL, 0.46 mmol) as a yellowish gummy liquid; yield:
74 mg (68%); Rf = 0.37 (30% EtOAc–PE); [α]D25 −1.88 (c 0.29, CH2Cl2).
IR (neat): 2960, 2872, 1748, 1598, 1495, 1470, 1403, 1358, 1307,
1280, 1262, 1215, 1165, 1122, 1090, 1028, 967, 868, 816, 707 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 0.94 (d, J = 6.0 Hz, 3 H), 0.98 (d, J = 6.0
Hz, 3 H), 1.65−1.72 (m, 1 H), 1.78−1.83 (m, 2 H), 2.42 (s, 3 H),
3.49−3.54 (m, 1 H), 3.57−3.62 (m, 1 H), 4.12−4.16 (m, 1 H), 4.26−4.31
(m, 1 H), 4.46 (t, J = 7.2 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 2 H), 7.69 (d, J = 8.3
Hz, 2 H).
13C NMR (125 MHz, CDCl3): δ = 21.7, 22.0, 22.5, 24.4, 40.0, 43.0, 55.9,
65.9, 127.4, 130.4, 135.1, 144.8, 167.9.
4-Tosylmorpholin-2-ones 2a–f; General Procedure
Anhyd DMF (10 mL) was added to dried K2CO3 (5.0 equiv), and the
mixture was cooled to 0 °C. Solid N-tosyl amino acid 1 (1.0 equiv) was
added under an inert gas (argon or N2), and the mixture was stirred
for 30 min at 0 °C. 1,2-Dibromoethane (1.3 equiv) was then added at 0
°C, and the mixture was warmed to r.t. and stirred for 16 h. The reac-
tion was quenched with ice-cold water, the organic and aqueous lay-
ers were separated, and the aqueous layer was extracted with EtOAc
(3 × 10.0 mL). The organic extracts were combined, washed with
brine (5 mL), dried (Na2SO4), and concentrated under reduced pres-
sure. The crude mixture was purified by flash column chromatogra-
phy [silica gel (230–400 mesh), 10% EtOAc–PE].
HRMS (ESI): m/z [M + Na]+ calcd for C15H21NNaO4S: 334.1089; found:
334.1088.
3-Isopropyl-4-tosylmorpholin-2-one (2d)
Prepared from N-tosylvaline (1d, 100 mg, 0.37 mmol) and Br(CH2)2Br
(0.04 mL, 0.48 mmol) as yellowish gummy liquid; yield: 77 mg (70%);
Rf = 0.35 (30% EtOAc–PE); [α]D25 +63.85 (c 0.26, CH2Cl2).
3-Benzyl-4-tosylmorpholin-2-one (2a)
IR (neat): 2963, 2925, 2871, 1749, 1596, 1495, 1467, 1409, 1364,
1350, 1308, 1286, 1163, 1116, 1070, 1021, 997, 919, 846, 766, 709
Prepared from N-tosylphenylalanine (1a, 100 mg, 0.31 mmol) and
Br(CH2)2Br (0.03 mL, 0.4 mmol) as a white solid; yield: 78 mg (72%);
cm–1
.
25
mp 104–108 °C; Rf = 0.40 (30% EtOAc–PE); [α]D −12.62 (c 0.21,
1H NMR (500 MHz, CDCl3): δ = 1.07 (d, J = 6.55 Hz, 3 H), 1.15 (d, J = 6.6
Hz, 3 H), 2.16−2.24 (m, 1 H), 2.42 (s, 3 H), 3.35−3.41 (m, 1 H),
3.60−3.65 (m, 1 H), 4.09−4.14 (m, 2 H), 4.30−4.34 (m, 1 H), 7.32 (d, J =
8.1 Hz, 2 H), 7.67 (d, J = 8.3 Hz, 2 H).
13C NMR (125 MHz, CDCl3): δ = 19.1, 20.1, 21.7, 33.0, 41.5, 63.6, 64.9,
127.6, 130.3, 134.3, 144.7, 167.0.
CH2Cl2).
IR (neat): 3058, 3024, 2971, 2948, 2926, 2900, 2851, 2588, 1940,
1741, 1597, 1494, 1455, 1402, 1351, 1289, 1243, 1195, 1163, 1100,
1022, 1001, 932, 906, 853, 821, 756, 704 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 2.44 (s, 3 H), 3.13−3.27 (m, 2 H),
3.35−3.46 (m, 3 H), 3.90−3.94 (m, 1 H), 4.62 (t, J = 4.3 Hz, 1 H),
7.23−7.25 (m, 3 H), 7.27−7.30 (m, 2 H), 7.32 (d, J = 8.0 Hz, 2 H), 7.65 (d,
J = 8.3 Hz, 2 H).
HRMS (ESI): m/z [M + NH4]+ calcd for C14H23N2O4S: 315.1375; found:
315.1379.
13C NMR (125 MHz, CDCl3): δ = 21.6, 40.7, 41.6, 58.8, 65.8, 127.5,
128.6, 130.2, 133.7, 135.3, 144.7, 167.5.
3-[2-(Methylsulfanyl)ethyl]-4-tosylmorpholin-2-one (2e)
Prepared from N-tosylmethionine (1e, 100 mg, 0.33 mmol) and
Br(CH2)2Br (0.04 mL, 0.43 mmol) as a yellowish gummy liquid; yield:
71 mg (65%); Rf = 0.23 (30% EtOAc–PE); [α]D25 +63.5 (c 0.27, CH2Cl2).
HRMS (ESI): m/z [M + Na]+ calcd for C18H19NaNO4S: 368.0933; found:
368.0931.
IR (neat): 2921, 2856, 1747, 1597, 1494, 1441, 1403, 1346, 1306,
3-sec-Butyl-4-tosylmorpholin-2-one (2b)
1282, 1226, 1165, 1113, 1089, 1019, 984, 896, 816, 740, 721, 707 cm–1
.
Prepared from N-tosylisoleucine (1b, 100 mg, 0.35 mmol) and
Br(CH2)2Br (0.04 mL, 0.46 mmol) as a white solid; yield: 82 mg (75%);
mp 114−116 °C; Rf = 0.32 (30% EtOAc–PE); [α]D25 +37.6 (c 0.28, CHCl3)
(>99% ee sample).
1H NMR (500 MHz, CDCl3): δ = 2.09 (s, 3 H), 2.23−2.27 (m, 2 H), 2.44
(s, 3 H), 2.60−2.67 (m, 2 H), 3.50−3.54 (m, 1 H), 3.61−3.66 (m, 1 H),
4.14−4.22 (m, 1 H), 4.31−4.35 (m, 1 H), 4.51 (t, J = 6.4 Hz, 1 H), 7.34 (d,
J = 7.9 Hz, 2 H), 7.70 (d, J = 8.3 Hz, 2 H).
IR (neat): 2962, 2929, 2873, 2852, 1735, 1596, 1453, 1405, 1351,
1302, 1252, 1212, 1165, 1097, 1017, 978, 939, 841, 819, 782, 711 cm–1
13C NMR (125 MHz, CDCl3): δ = 15.3, 21.7, 29.9, 33.4, 41.2, 56.3, 66.3,
.
127.5, 130.4, 134.5, 145.0, 167.3.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3776–3782

3780
S. Samanta et al.
Paper
Synthesis
HRMS (ESI): m/z [M + Na]+ calcd for C14H19NNaO4S2: 352.0653; found:
3-Phenyl-4-tosylmorpholine (9a)
352.0651.
Prepared from alcohol 8a (100 mg, 0.34 mmol) and Br(CH2)2Br (0.04
mL, 0.45 mmol) as a white solid; yield: 71 mg (65%); mp 118–120 °C;
25
3-tert-Butyl-4-tosylmorpholin-2-one (2f)
Rf = 0.33 (15% EtOAc–PE); [α]D +23.6 (c 0.42, CHCl3) for a > 99% ee
sample.
Prepared from N-tosyl-tert-leucine (1f, 100 mg, 0.35 mmol) and
Br(CH2)2Br (0.04 mL, 0.46 mmol) as a yellowish gummy liquid; yield:
68 mg (62%); Rf = 0.36 (30% EtOAc–PE).
IR (neat): 3087, 3051, 3026, 2964, 2924, 2854, 1925, 1597, 1494,
1447, 1401, 1360, 1345, 1328, 1307, 1271, 1237, 1161, 1114, 1092,
1034, 1017, 1002, 986, 946, 922, 909. 839, 817, 762, 735, 706 cm–1
.
IR (neat): 2968, 2926, 2874, 1741, 1598, 1476, 1402, 1358, 1296,
1253, 1226, 1201, 1119, 1088, 1019, 983, 933, 887, 818, 769, 707 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 2.42 (s, 3 H), 3.31−3.36 (m, 1 H),
3.45−3.55 (m, 2 H), 3.71 (dd, J = 3.8, 12.4 Hz, 1 H), 3.79 (dt, J = 2.9, 11.5
Hz, 1 H), 4.13 (dd, J = 2.4, 11.9 Hz, 1 H), 4.76 (br s, 1 H), 7.22 (d, J = 7.2
Hz, 2 H), 7.25−7.30 (m, 3 H), 7.43−7.45 (m, 2 H), 7.56 (d, J = 8.2 Hz, 2
H).
13C NMR (125 MHz, CDCl3): δ = 21.6, 42.2, 56.2, 66.3, 69.4, 127.4,
127.8, 128.4, 128.5, 129.7, 137.0, 137.8, 143.5.
1H NMR (500 MHz, CDCl3): δ = 1.17 (s, 9 H), 2.43 (s, 3 H), 3.64−3.73
(m, 2 H), 3.79−3.84 (m, 1 H), 4.15−4.19 (m, 1 H), 4.38 (s, 1 H), 7.32 (d,
J = 8.6 Hz, 2 H), 7.69 (d, J = 8.3 Hz, 2 H).
13C NMR (125 MHz, CDCl3): δ = 21.7, 28.9, 37.4, 39.7, 64.9, 66.0, 127.2,
130.4, 136.3, 144.7, 166.2.
HRMS (ESI): m/z [M + Na]+ calcd for C15H21NNaO4S: 334.1089; found:
334.1082.
HRMS (ESI): m/z [M + H]+ calcd for C17H20NO3S: 318.1164; found:
318.1163.
The enantiomeric excess was determined by chiral HPLC analysis
[column: Chiralpak Cellulose 2; hexane–i-PrOH (90:10), flow rate =
1.0 mL/min; tR (1) = 26.23 min (major)].
Methyl 2-Methyl-4-tosylmorpholine-3-carboxylate (7)
Anhyd DMF (5 mL) was added to dried K2CO3 (242 mg, 1.75 mmol),
and the mixture was cooled to 0 °C. A soln of methyl N-tosylthreon-
inate (6, 100 mg, 0.35 mmol) in DMF (5 mL) was added, and the mix-
ture was stirred for 30 min at 0 °C. Br(CH2)2Br (0.04 mL, 0.46 mmol)
was added at 0 °C, and the mixture was heated to r.t. and stirred for
16 h. The reaction was quenched with ice-cold water, and the organic
and the aqueous layers were separated. The aqueous layer was ex-
tracted with EtOAc (3 × 10.0 mL), and the organic extracts were com-
bined, washed with brine (5 mL), dried (Na2SO4), and concentrated
under reduced pressure. The crude mixture was purified by flash col-
umn chromatography [silica gel (230–400 mesh), 10% EtOAc–PE] to
give a yellowish gummy liquid; yield: 70 mg (64%); Rf = 0.42 (30%
EtOAc–PE).
3-sec-Butyl-4-tosylmorpholine (9b)
Prepared from alcohol 8b (100 mg, 0.37 mmol) and Br(CH2)2Br (0.04
mL, 0.48 mmol) as a white solid; yield: 80 mg (73%); mp 108–111 °C;
Rf = 0.33 (15% EtOAc–PE).
IR (neat): 3048, 2963, 2926, 2859, 1597, 1495, 1455, 1381, 1344,
1267, 1249, 1159, 1096, 1031, 981, 957, 915, 838, 818, 801, 773, 742,
720, 720, 709 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 0.86−0.92 (m, 6 H), 1.03−1.10 (m, 1 H),
1.61−1.67 (m, 1 H), 2.00−2.06 (m, 1 H), 2.43 (s, 3 H), 3.11−3.21 (m, 2
H), 3.26−3.32 (m, 1 H), 3.39−3.41 (m, 1 H), 3.55−3.60 (m, 2 H),
3.80−3.83 (m, 1 H), 7.30 (d, J = 7.9 Hz, 2 H), 7.71 (d, J = 8.2 Hz, 2 H).
13C NMR (125 MHz, CDCl3): δ = 11.3, 16.0, 21.6, 25.4, 31.7, 41.4, 58.5,
65.5, 66.3, 127.2, 129.9, 138.9, 143.4.
IR (neat): 2954, 2925, 2873, 1747, 1598, 1495, 1450, 1349, 1307,
1284, 1166, 1122, 1089, 1073, 1050, 1026, 933, 922, 904, 864, 845,
818, 805, 745, 708 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.29 (d, J = 6.1 Hz, 3 H), 2.43 (s, 3 H),
2.94−2.99 (m, 1 H), 3.45−3.49 (m, 1 H), 3.62−3.66 (m, 2 H), 3.70 (s, 3
H), 3.87−3.91 (m, 1 H), 4.10−4.15 (m, 1 H), 7.33 (d, J = 8.3 Hz, 2 H),
7.68 (d, J = 8.3 Hz, 2 H).
HRMS (ESI): m/z [M + H]+ calcd for C15H24NO3S: 298.4130; found:
298.4134.
4-Benzylmorpholin-2-ones 11; General Procedure
13C NMR (125 MHz, CDCl3): δ = 16.9, 21.7, 29.8, 43.3, 52.6, 61.8, 71.9,
Anhyd DMF (10 mL) was added to dried K2CO3 (3.0 equiv), and the
mixture was cooled to 0 °C. Solid N-benzyl amino acid 10 (1.0 equiv)
was added under an inert gas (Ar or N2), and the mixture was stirred
for 30 min at 0 °C. Br(CH2)2Br (1.3 equiv) was added at 0 °C, and the
mixture was heated to 65 °C and stirred for 16 h. The reaction was
quenched with ice-cold water, and the organic and aqueous layers
were separated. The aqueous layer was extracted with EtOAc (3 × 10.0
mL), and the organic extracts were combined, washed successively
with ice-cold water (5 mL) and brine (5 mL), dried (Na2SO4), and con-
centrated under reduced pressure. The crude mixture was purified by
flash column chromatography [silica gel (230–400 mesh), 10% EtOAc–
PE].
128.1, 129.7, 133.6, 144.1, 169.8.
HRMS (ESI): m/z [M + H]+ calcd for C14H20NO5S: 314.1062; found:
314.1060.
N-Tosylmorpholines 9; General Procedure
Anhyd DMF (5 mL) was added to dried K2CO3 (5.0 equiv), and the mix-
ture was cooled to 0 °C. A solution of the appropriate N-tosyl amino
alcohol 8 (1.0 equiv) in DMF (5 mL) was added, and the mixture was
stirred for 30 min at 0 °C. Br(CH2)2Br (1.3 equiv) was added at 0 °C,
and the mixture was warmed to r.t. and stirred for 16 h. The reaction
was quenched with ice-cold water, and the organic and the aqueous
layers were separated. The aqueous layer was extracted with EtOAc (3
× 10.0 mL), and the organic extracts were combined, washed with
brine (5 mL), dried (Na2SO4), and concentrated under reduced pres-
sure. The crude mixture was purified by flash column chromatogra-
phy [silica gel (230–400 mesh), 10% EtOAc–PE].
3,4-Dibenzylmorpholin-2-one (11a)
Prepared from N-benzylphenylalanine (10a, 100 mg, 0.39 mmol) and
Br(CH2)2Br (0.04 mL, 0.51 mmol) as a yellowish gummy liquid; yield:
71 mg (65%); Rf = 0.4 (30% EtOAc–PE); [α]D25 +13.6 (c 0.36, CHCl3) for a
99% ee sample.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3776–3782

3781
S. Samanta et al.
Paper
Synthesis
IR (neat): 3062, 3029, 2954, 2816, 1737, 1603, 1495, 1454, 1407,
1365, 1331, 1287, 1221, 1195, 1161, 1129, 1101, 1075, 1060, 1028,
13C NMR (125 MHz, CDCl3): δ = 18.4, 19.9, 32.6, 47.1, 60.7, 67.6, 70.6,
127.6, 128.4, 128.7, 137.9, 170.3.
HRMS (ESI): m/z [M + H]+ calcd for C14H20NO2: 234.1494, found:
944, 813, 750, 701 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 2.43−2.50 (m, 1 H), 2.81 (dt, J = 4.6,
12.92 Hz, 1 H), 3.19 (dd, J = 4.7, 13.9 Hz, 1 H), 3.31 (dd, J = 4.6, 13.9 Hz,
1 H), 3.39, (d, J = 13.2 Hz, 1 H), 3.69 (t, J = 4.7 Hz, 1 H), 3.84 (td, J = 2.7,
10.0 Hz, 1 H), 4.05 (d, J = 13.2 Hz, 1 H), 4.10 (dt, J = 2.9, 11.0 Hz, 1 H),
7.23−7.34 (m, 10 H).
234.1490.
Acknowledgements
13C NMR (100 MHz, CDCl3): δ = 37.6, 46.6, 59.2, 66.2, 67.5, 126.9,
127.7, 128.3, 128.7, 128.8, 128.9, 130.2, 137.1, 137.5, 170.7.
HRMS (ESI): m/z [M + H]+ calcd for C18H20NO2: 282.1494; found:
M.K.G. is grateful to IIT-Kanpur and DST, India, for financial support.
S.S. and A.M. are grateful to CSIR, India, and S.H. thanks UGC, India, for
research fellowships.
282.1498.
The enantiomeric excess was determined by chiral HPLC analysis
[column: Chiralpak cellulose 2 column; hexane–i-PrOH = 90:10), flow
rate = 1.0 mL/min; tR (1) = 15.8 min (major)].
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560088.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
4-Benzyl-3-sec-butylmorpholin-2-one (11b)
Prepared from N-benzylisoleucine (10b, 100 mg, 0.45 mmol) and
Br(CH2)2Br (0.05 mL, 0.59 mmol) as a yellowish gummy liquid; yield:
74 mg (66%); Rf = 0.52 (30% EtOAc–PE); [α]D25 +72 (c 0.2, CH2Cl2).
References
(1) Wijtmans, R.; Vink, M. K. S.; Schoemaker, H. E.; van Delft, F. L.;
Blaauw, R. H.; Rutjes, F. P. J. T. Synthesis 2004, 641; and refer-
ences therein.
IR (neat): 3064, 3029, 2964, 2933, 2876, 1733, 1604, 1496, 1454,
1381, 1329, 1278, 1172, 1144, 1073, 1028, 996, 908, 742 cm–1
.
(2) (a) Grinsteiner, T. J.; Kishi, Y. Tetrahedron Lett. 1994, 35, 8333.
(b) Grinsteiner, T. J.; Kishi, Y. Tetrahedron Lett. 1994, 35, 8337.
(c) Clark, S. M.; Osborn, H. M. I. Tetrahedron: Asymmetry 2004,
15, 3643. (d) Yar, M.; McGarrigle, E. M.; Aggarwal, V. K. Org. Lett.
2009, 11, 257. (e) Hajós, M.; Fleishaker, J. C.; Filipiak-Reisner, J.
K.; Brown, M. T.; Wong, E. H. F. CNS Drug Rev. 2004, 10, 23.
(f) Versiani, M.; Cassano, G.; Perugi, G.; Benedetti, A.; Mastalli,
L.; Nardi, A.; Savino, M. J. Clin. Psychiatry 2002, 63, 31. (g) Wong,
E. H. F.; Sonders, M. S.; Amara, S. G.; Tinholt, P. M.; Piercey, M. F.
P.; Hoffmann, W. P.; Hyslop, D. K.; Franklin, S.; Porsolt, R. D.;
Bonsignori, A.; Carfagna, N.; McArthur, R. A. Biol. Psychiatry
2000, 47, 818. (h) Pendergrass, K.; Hargreaves, R.; Petty, K. J.;
Carides, A. D.; Evans, J. K.; Horgan, K. J. Drugs Today 2004, 40,
853. (i) Hikichi, M.; Yokokura, T.; Furuta, T.; Yaegashi, T. JP
62135472, 1987; Chem. Abstr. 1987, 107, 198358 (j) Gharpure, J.
S.; Prasad, K. V. J. J. Org. Chem. 2011, 76, 10325.
(3) (a) Nilsson, J. W.; Kvarnström, I.; Musil, D.; Nilsson, I.;
Samuelsson, B. J. Med. Chem. 2003, 46, 3985. (b) Gonzalez, A. Z.;
Eksterowicz, J.; Bartberger, M. D.; Beck, H. P.; Canon, J.; Chen, A.;
Chow, D.; Duquette, J.; Fox, B. M.; Fu, J.; Huang, X.; Houze, J. B.;
Jin, L.; Li, Y.; Li, Z.; Ling, Y.; Lo, M.-C.; Long, A. M.; McGee, L. R.;
McIntosh, J.; McMinn, D. L.; Oliner, J. D.; Osgood, T.; Rew, Y.;
Saiki, A. Y.; Shaffer, P.; Wortman, S.; Yakowec, P.; Yan, X.; Ye, Q.;
Yu, D.; Zhao, X.; Zhou, J.; Olson, S. H.; Medina, J. C.; Sun, D.
J. Med. Chem. 2014, 57, 2472.
(4) (a) Dave, R.; Sasaki, N. A. Org. Lett. 2004, 6, 15. (b) Dave, R.;
Sasaki, N. A. Tetrahedron: Asymmetry 2006, 17, 388. (c) Bettoni,
G.; Frachini, C.; Perrone, P.; Tortorella, V. Tetrahedron 1980, 36,
409. (d) Sladojevich, F.; Trabocchi, A.; Guarna, A. J. Org. Chem.
2007, 72, 4254.
(5) (a) Breuning, M.; Winnacker, M.; Steiner, M. Eur. J. Org. Chem.
2007, 2100. (b) Lanman, B. A.; Myers, A. G. Org. Lett. 2004, 6,
1045. (c) Métro, T.-X.; Pardo, D. G.; Cossy, J. J. Org. Chem. 2008,
73, 707. (d) Brenner, E.; Baldwin, R. M.; Tamagnan, G. Org. Lett.
2005, 7, 937. (e) Cupples, C. A.; Morton, H. N. WO 9638465,
1996. (f) Fish, P. V.; Mackenny, M.; Bish, G.; Buxton, T.; Cave, R.;
Drouard, D.; Hoople, D.; Jessiman, A.; Miller, D.; Pasquinet, C.;
Patel, B.; Reeves, K.; Ryckmans, T.; Skerten, M.; Wakenhut, F.
Tetrahedron Lett. 2009, 50, 389.
1H NMR (500 MHz, CDCl3): δ = 0.83−0.91 (m, 6 H), 1.18−1.27 (m, 1 H),
1.56−1.61 (m, 1 H), 1.72−1.76 (m, 1 H), 3.13 (d, J = 6.3 Hz, 1 H), 3.53 (t,
J = 5.8 Hz, 2 H), 3.61 (d, J = 12.6 Hz, 1 H), 3.84 (d, J = 13.2, 1 H),
4.37−4.45 (m, 2 H), 7.23−7.35 (m, 5 H).
13C NMR (125 MHz, CDCl3): δ = 11.5, 15.8, 25.6, 28.8, 38.3, 52.6, 63.9,
65.5, 127.1, 128.4, 140.0, 174.9.
HRMS (ESI): m/z [M + H]+ calcd for C15H22NO2: 248.1651; found:
248.1653.
4-Benzyl-3-isobutylmorpholin-2-one (11c):
Prepared from N-benzylleucine (10c, 100 mg, 0.45 mmol) and
Br(CH2)2Br (0.05 mL, 0.59 mmol) as colorless liquid; yield: 67 mg
(60%); Rf = 0.46 (30% EtOAc–PE).
IR (neat): 3062, 2956, 2871, 1731, 1502, 1454, 1373, 1355, 1272,
1215, 1166, 1139, 1052, 1018, 1010, 936, 872, 756 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 0.85 (d, J = 6.5 Hz, 3 H), 0.91 (d, J = 6.4
Hz, 3 H), 1.48–1.52 (m, 2 H), 1.76−1.80 (m, 1 H), 3.34 (t, J = 7.3 Hz, 1
H), 3.64 (d, J = 12.9 Hz, 1 H), 3.81–3.83 (m, 3 H), 4.21–4.29 (m, 2 H),
7.24–7.32 (m, 5 H).
13C NMR (125 MHz, CDCl3): δ = 22.6, 22.9, 25.0, 42.8, 52.2, 59.3, 61.3,
66.3, 127.2, 128.4, 128.5, 139.7, 176.3.
HRMS (ESI): m/z [M + NH4]+ calcd for C15H25N2O2: 265.1916; found:
265.1911.
4-Benzyl-3-isopropylmorpholin-2-one (11d)
Prepared from N-benzylvaline (10d, 100 mg, 0.48 mmol) and
Br(CH2)2Br (0.05 mL, 0.63 mmol) as a yellowish liquid; yield: 70 mg
(62%); Rf = 0.42 (30% EtOAc–PE); [α]D25 +67.67 (c 0.32, CHCl3).
IR (neat): 2961, 2931, 2874, 1733, 1496, 1454, 1386, 1366, 1283,
1207, 1168, 1143, 1060, 1028, 1012, 941, 871, 742 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.10 (d, J = 6.9 Hz, 3 H), 1.16 (d, J = 6.9
Hz, 3 H), 2.08–2.21 (m, 1 H), 2.50–2.56 (m, 1 H), 2.87 (dt, J = 2.3, 13.2
Hz, 1 H), 3.25 (d, J = 3.5 Hz, 1 H), 3.92 (d, J = 13.8 Hz, 1 H), 4.25–4.38
(m, 3 H), 7.23–7.35 (m, 5 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3776–3782

3782
S. Samanta et al.
Paper
Synthesis
(6) (a) Albanese, D.; Salsa, M.; Landini, D.; Lupi, V.; Penso, M. Eur. J.
Org. Chem. 2007, 2107. (b) Abdel-Jalil, R. J.; Ali Shah, S. T.; Khan,
K. M.; Voelter, W. Lett. Org. Chem. 2005, 2, 306. (c) Henegar, K. E.
J. Org. Chem. 2008, 73, 3662. (d) Lupi, V.; Albanese, D.; Landini,
D.; Scaletti, D.; Penso, M. Tetrahedron 2004, 60, 11709.
(7) (a) Ghorai, M. K.; Shukla, D.; Bhattacharyya, A. J. Org. Chem.
2012, 77, 3740. (b) Ghorai, M. K.; Shukla, D.; Das, K. J. Org. Chem.
2009, 74, 7013. (c) Wang, L.; Liu, Q.-B.; Wang, D.-S.; Li, X.; Han,
X.-W.; Xiao, W.-J.; Zhou, Y.-G. Org. Lett. 2009, 11, 1119. (d) Bera,
M.; Roy, S. J. Org. Chem. 2009, 74, 8814. (e) D’hooghe, M.;
Vanlangendonck, T.; Törnroos, K. W.; De Kimpe, N. J. Org. Chem.
2006, 71, 4678. (f) Taylor, A. M.; Schreiber, S. L. Tetrahedron Lett.
2009, 50, 3230. (g) Kogami, Y.; Okawa, K. Bull. Chem. Soc. Jpn.
1987, 60, 2963. (h) Mollet, K.; Goossens, H.; Piens, N.; Catak, S.;
Waroquier, M.; Törnroos, K. W.; Van Speybroeck, V.; D’hooghe,
M.; De Kimpe, N. Chem. Eur. J. 2013, 19, 3383.
(8) (a) Siddiqui, S. A.; Narkhede, U. C.; Lahoti, R. J.; Srinivasan, K. V.
Synlett 2006, 1771. (b) Nishi, T.; Ishibashi, K.; Nakajima, K.; Iio,
Y.; Fukuzawa, T. Tetrahedron: Asymmetry 1998, 9, 3251.
(c) Takemoto, T.; Iio, Y.; Nishi, T. Tetrahedron Lett. 2000, 41,
1785. (d) D’Arrigo, P.; Lattanzio, M.; Pedrocchi, G.; Servi, S. Tet-
rahedron: Asymmetry 1998, 9, 4021. (e) Wilkinson, M. C. Tetra-
hedron Lett. 2005, 46, 4773.
(15) Baek, J.; Jang, J. I.; Park, Y. S. Bull. Korean Chem. Soc. 2011, 32,
4067.
(16) Burdzhiev, N.; Stanoeva, E.; Shivachev, B.; Nikolova, R. C. R.
Chim. 2014, 17, 420.
(17) (a) Samanta, S.; Bhattacharyya, A.; Das, S.; Ghorai, M. K. Curr.
Org. Chem. 2014, 18, 2842. (b) Talukdar, R.; Tiwari, D. P.; Saha,
A.; Ghorai, M. K. Org. Lett. 2014, 16, 3954. (c) Ghorai, M. K.;
Samanta, S.; Das, S. Asian J. Org. Chem. 2013, 2, 1026.
(18) (a) Ghorai, M. K.; Nanaji, Y.; Yadav, A. K. Org. Lett. 2011, 13,
4256. (b) Ghorai, M. K.; Das, K.; Kumar, A. Tetrahedron Lett.
2007, 48, 4373. (c) Ghorai, M. K.; Ghosh, K. Tetrahedron Lett.
2007, 48, 3191. (d) Ghorai, M. K.; Das, K.; Kumar, A. Tetrahedron
Lett. 2009, 50, 1105. (e) Ghorai, M. K.; Das, K.; Kumar, A.; Ghosh,
K. Tetrahedron Lett. 2005, 46, 4103. (f) Ghorai, M. K.; Das, K.;
Kumar, A.; Das, A. Tetrahedron Lett. 2006, 47, 5393. (g) Ghorai,
M. K.; Sahoo, A. K.; Kumar, S. Org. Lett. 2011, 13, 5972.
(h) Ghorai, M. K.; Halder, S.; Samanta, S. Aust. J. Chem. 2012, 65,
1262. (i) Ghorai, M. K.; Halder, S.; Das, R. K. J. Org. Chem. 2010,
75, 7061.
(19) The ee of morpholinone 2b (>99%), as a representative example
of morpholinones 2a–f, was determined by chiral HPLC analy-
sis.
(20) See the Supporting Information for details.
(9) (a) Grotenberg, G. M.; Christina, A. E.; Buizert, A. E. M.; van der
Marel, G. A.; Overkleeft, H. S.; Overhand, M. J. Org. Chem. 2004,
69, 8331. (b) Du, M.; Hindsgaul, O. Synlett 1997, 395.
(10) Yar, M.; McGarrigle, E. M.; Aggarwal, V. K. Angew. Chem. Int. Ed.
2008, 47, 3784.
(11) Ritzen, B.; Hoekman, S.; Duràn Verdasco, E.; van Delft, F. L.;
Rutjes, F. P. J. T. J. Org. Chem. 2010, 75, 3461.
(12) (a) Pedrosa, R.; Andrés, C.; Mendiguchia, P.; Nieto, J. J. Org.
Chem. 2006, 71, 8854. (b) Yamazaki, A.; Achiwa, K. Tetrahedron:
Asymmetry 1995, 6, 1021.
(21) Crystallographic data for compounds 2a and 2b have been
deposited with the accession numbers CCDC 1033183 and
1033184, respectively, and can be obtained free of charge from the
Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; Fax: +44(1223)336033; E-mail: deposit@ccdc.cam.ac.uk;
Web site: www.ccdc.cam.ac.uk/conts/retrieving.html.
(22) The ee of morpholine 9a (>99%), as a representative example of
morpholines 9a and 9b, was determined by chiral HPLC analy-
sis.
(23) The ee of morpholine 11a (>99%), as a representative example
of morpholines 11a–d, was determined by chiral HPLC analysis.
(13) Kasima, C.; Harada, K. J. Chem. Soc., Perkin Trans. 1 1988, 1521.
(14) (a) Devine, P. N.; Foster, B. S.; Grabowski, E. J. J.; Reider, P. J. Het-
erocycles 2002, 58, 119. (b) Park, Y. S.; Lee, Y. M.; Kang, K. H.;
Min, H. M.; Lim, H. J.; Park, E. H. ARKIVOC 2010, (ii), 1.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3776–3782