An efficient procedure for the synthesis of morpholin-2-one-3-carboxamide derivatives in good diastereoselectivity by the Ugi reaction

Article abstract of DOI:10.1055/s-0029-1219533

A series of 5-substituted morpholin-2-one-3-carboxamide derivatives were efficiently synthesized by a Ugi three-component reaction involving chiral 5,6-dihydro[1,4]oxazin-2-one substrates, isocyanides and carboxylic acids. The newly formed chiral center in the product was obtained in good diastereoselectivity. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1219533

LETTER
897
An Efficient Procedure for the Synthesis of Morpholin-2-one-3-carboxamide
Derivatives in Good Diastereoselectivity by the Ugi Reaction
S
ynthesis of Morp
e
holin-2-one
g
-3-carboxam
u
ide Derivativ
a
es ng Zhu, Ruijiao Chen, Haibo Liang, Sheng Li, Li Pan, Xiaochuan Chen*
Key Laboratory of Green Chemistry & Technology of Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064,
P. R. of China
Fax +86(28)85413712; E-mail: chenxc@scu.edu.cn
Received 17 November 2009
R4
O
Abstract: A series of 5-substituted morpholin-2-one-3-carbox-
amide derivatives were efficiently synthesized by a Ugi three-
component reaction involving chiral 5,6-dihydro[1,4]oxazin-2-one
substrates, isocyanides and carboxylic acids. The newly formed
chiral center in the product was obtained in good diastereoselectiv-
ity.
O
R2
O
N
R1
R3
N
R1
3
5
N
+
R3NC
+
R4CO2H
H R2
O
O
O
2
3
1
4
Key words: Ugi reaction, isonitrile, multicomponent reaction,
diastereoselectivity, morpholin-2-one
Scheme 1 The Ugi three-component reaction of 1
isocyanide (2a) and acetic acid (3a), which was used as a
model reaction (Table1).
The Ugi reaction is a very efficient tool that has been used
to quickly prepare various pharmacological compounds,
such as peptides and heterocyclces, and is widely applied
in combinatorial and medical chemistry.1 Morpholinone
derivatives have attracted much attention due to their po-
tential biological and synthetic applications.2 In 2001, the
synthesis of morpholin-2-one-5-carboxamide (I) through
the Ugi condensation was described by Kim and co-work-
ers (Figure1).3 In a subsequent study, the morpholin-2-
one compounds were found to exhibit potent and selective
T-type Ca2+ channel blocking activities.4 However, to our
best knowledge, construction of the morpholin-2-one-3-
carboxamide skeleton (II) has not yet been reported.
R2
N
R1
R3NC
R4CO2H
O
O
2a: R3 = t-Bu
3a: R4 = Me
3b: R4 = H
3c: R4 = Ph
1a: R1 = CH2OTBDPS, R2 = H
1b: R1 = Ph, R2 = H
2b: R3 = n-Bu
2c: R3 = Bn
1c: R1 = Bn, R2 = H
2d: R3 = MeO2CCH2
2e: R3 = Ph
1d: R1 = Ph, R2 = Me
Figure 2 Substrates 1 and 2 and 3
Screening of solvents revealed that when the reaction was
performed in 2,2,2-trifluoroethanol (TFE) it proceeded
much faster than in other solvents, to afford 4a in 70%
yield (Table1, entry 7). Elevating the reaction temperature
did not deliver an improvement in the yields (Table1, en-
try 9). A similar yield was also obtained using CH2Cl2 as
solvent but, in this case, prolonged reaction time was nec-
essary for full consumption of 1a (Table1, entry 5). In the
presence of excess 3a, the required reaction time in
CH2Cl2 was shortened, however, only a slight improve-
ment in yield was observed (Table1, entry 6). Decreasing
the amount of 2a and 3a led to a reduction in both yield
and reaction rate (Table1, entry 7). Reactions performed
in other solvents or at lower temperature often gave di-
minished yield or failed to proceed. Therefore the U-3CR
was preferably carried out in either TFE or CH2Cl2 at
room temperature.
R1
N
O
R1
N
O
R2
R2
N
N
3
5
H
H
I
II
2
2
O
O
O
O
Figure 1
Herein, we wish to present a new Ugi three-component
reaction (U-3CR) based on 5,6-dihydro[1,4]oxazin-2-one
substrates 1 with isocyanides 2 and carboxylic acids 3 that
can be used to effectively synthesize morpholin-2-one-3-
carboxamide derivatives 4 (Scheme1). Such compounds
contain the 2-amidomalonyl subunit, which is present in
numerous bioactive and pharmacological compounds.5
Chiral 5,6-dihydro[1,4]oxazin-2-ones 1a–c (Figure2), as
preformed cyclic imines for the Ugi reaction, were conve-
niently prepared from the corresponding natural (S)-ami-
no alcohols by literature procedures.6 Optimal conditions
were then sought for the Ugi reaction of 1a with tert-butyl
Subsequently, under the optimized conditions, various cy-
clic imines, isocyanides and carboxylic acids were reacted
to provide morpholin-2-one-3-carboxamide derivatives 4
in moderate to good yield (Table2).7 When formic acid
(3b) was used as the acid component, the reactions were
accelerated dramatically even when less acid was used
(1.5 equiv), due to its stronger acidity (Table2, entry 3 vs
entry 2); the reactions completed at a similar rate and gave
SYNLETT 2010, No. 6, pp 0897–0900
Advanced online publication: 18.02.2010
DOI: 10.1055/s-0029-1219533; Art ID: W18109ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
1
0

898
D. Zhu et al.
LETTER
Table 1 Optimization of the U-3CR with 1a, 2a and 3aa
number of cases that have delivered good selectivity were
achieved by induction with chiral amines, including 1-
phenylethylamines,10 α-aminoferrocenylamines,11 amino-
sugars12 and some amino acids.13 In most of the examples
above, the chiral auxiliaries need to be subsequently
cleaved from the Ugi products. It is therefore desirable to
develop further asymmetric Ugi reactions that meet vari-
ous requirements of modern synthetic processes. In prin-
ciple, although two diastereomeric products could be
formed in our reactions, we could not identify two separa-
ble Ugi products by silica gel chromatography. Nonethe-
less, examination of the 1H NMR spectra of these
compounds revealed that most proton signals appeared ei-
ther in pairs or as broadened peaks, however, it was diffi-
cult to conclude whether these pairs of signals were due to
rotameric or disastereomeric protons. We also noted that
the choice of the solvent used in the reaction had no effect
on the ratio of the paired signals. For an example, the
products 4b obtained separately in different solvents
(CH2Cl2, TFE and toluene) showed the same ratio of
Entry
Solvent
MeOH
toluene
THF
Time (h)
Temp (°C)
Yield of 4a (%)
1
2
3
4
5
6
7
8
9
3 d
40
40
50
50
5
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
–30
60
39b
58
trace
48b
67
CH2Cl2
CH2Cl2
CH2Cl2
TFE
73c
70
4
TFE
6
51
TFE
4
68
a General conditions: 1a (1 equiv), 2a (2 equiv), 3a (2.2 equiv), r.t.
b 1a (1 equiv), 2a (1.5 equiv), 3a (1.6 equiv) were used.
c 1a (1 equiv), 2a (2 equiv), 3a (20 equiv) were used.
1
paired signals (about 3.4:1) in their H NMR spectra.
yields comparable to those obtained when the reaction
was carried out in TFE (Table2, entry 5 vs entry 6). The
substituents in imines 1 (R1) had no clear influence on the
yield of the reaction (Table2, entries 3, 6 and 11). Aliphat-
ic and aromatic isocyanides were well tolerated in the
reaction. Finally, imine 1d,8 containing a methyl group at
R2, was tested under the same reaction conditions. Unfor-
tunately, in these cases, the reactions were sluggish and
the desired product was only obtained in low yield, to-
gether with substantial amounts of N-formamide formed
from hydrolysis of the isocyanide. This could be ex-
plained by the steric hindrance of the methyl group.
Hence, we decided to carry out further experiments in or-
der to determine the diastereoselectivity of the reaction.
The 1H NMR spectrum of 4f consisted of two sets of peaks
that appeared in a ratio of 1.8 to 1. Lactone 4f was then re-
duced with LiBH4 to yield two separable diastereomers 5a
and 5b in 70% and 15% yield respectively (Scheme2).
The paired signals in the 1H NMR spectra of both products
showed that each product contained two rotamers (5a in a
ratio of 7:1, 5b in a ratio of 2:1). This suggested that the
paired signals in the NMR spectrum did not arise from
two diastereomers but from two rotamers. Otherwise, four
set of peaks should have been observed. We also believe
that the minor isomer 5b was generated from the epimer-
ization of the C-3 chiral center during reduction because
of the highly acidic nature of the H-3 proton due to the
presence of two carbonyl functional groups in 4f.
As optically active 5,6-dihydro[1,4]oxazin-2-one deriva-
tives have been successfully used to explore asymmetric
Mannich reactions with phenol,6c,9 we were interested in
the possibility of introducing asymmetric induction into
the U-3CR. Until now, controlling the stereochemistry in
the Ugi reaction has been a challenging issue; the limited
Table 2 Synthesis of 5-Substituted Morpholin-2-one-3-carboxamide Derivatives 4a–pa
Entry
R1
R2
H
H
H
H
H
H
H
H
H
H
R3
R4
Me
Me
H
Solvent
TFE
Time (h)
Product
4a
Yield (%)
1
2
CH2OTBDPS
t-Bu
4
70
67
74
66
71
73
78
58
80
71
CH2OTBDPS
t-Bu
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
TFE
50
8
4a
3
CH2OTBDPS
t-Bu
4b
4
CH2OTBDPS
n-Bu
H
12
2.5
2.5
4
4c
5
Ph
Ph
Ph
Ph
Ph
Bn
t-Bu
H
4d
6
t-Bu
H
4d
7
CH2CO2Me
Bn
Me
H
TFE
4e
8
CH2Cl2
CH2Cl2
CH2Cl2
4
4f
9
CH2CO2Me
t-Bu
H
4
4g
10
H
7
4h
Synlett 2010, No. 6, 897–900 © Thieme Stuttgart · New York

LETTER
Synthesis of Morpholin-2-one-3-carboxamide Derivatives
899
Table 2 Synthesis of 5-Substituted Morpholin-2-one-3-carboxamide Derivatives 4a–pa (continued)
Entry
11
R1
R2
H
R3
R4
Me
Ph
Me
Me
Ph
H
Solvent
TFE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
Time (h)
Product
4i
Yield (%)
Bn
Bn
Bn
Bn
Bn
Bn
Ph
Ph
t-Bu
4
62
66
55
64
67
75
31b
37
12
H
t-Bu
5
4j
13
H
Bn
4
4k
14
H
CH2CO2Me
CH2CO2Me
Ph
4.5
5
4l
15
H
4m
4n
16
H
5
17
Me
Me
t-Bu
H
30
40
4o
18
n-Bu
H
4p
a Reaction conditions: the reactions were carried out at r.t., and 1, 2 and 3 were used in a ratio of 1:1.5:1.5 (3b as acid component) or 1:2:2.2
(3a or 3c as acid component).
b Carried out at r.t. with 1/2/3 = 1:1.5:2.2.
O
O
CHO
N
correlation not between H-3 and H-5 but between H-3 and
H-a (δ = 3.70 and 3.52 ppm) of each isomer reveals that
both isomers of 4a have 3,5-trans-configuration, namely
(S)-configuration at C-3 (Figure3). It also confirmed that
the two rotamers of the trans-adduct are responsible for
the paired signals in the NMR spectra. Similarly, in the 1H
NMR spectra of the other Ugi products, almost only one
set of paired peaks was observed. Therefore, cyclic imines
1 have the potential to be used to develop new asymmetric
Ugi reactions. In the reaction, the favorable attack on the
imine from the side opposite to the C-5 substituent gave
the thermodynamically more stable trans-isomer as the
predominant isomer.
O
CHO
N
Bn
Ph
Bn
Ph
LiBH4, THF
*
*
N
N
H
H
O
HO
OH
5a the major isomer
5b the minor isomer
4f
Scheme 2 Reduction of compound 4f
Starting from optically pure (S)-2-amino-2-phenylethanol
(6), the four-component condensation with ethyl glyoxy-
late (7), 2c and 3b was performed in CH2Cl2 to give a Ugi
product mixture containing 8 in 70% yield after column
chromatography. The product was then treated with
LiBH4 to afford 5a and 5b in a 1:3.5 ratio (Scheme3). In-
terestingly, a reversal of stereoselectivity was observed
with our U-3CR compared to the normal U-4CR.
NOE correlation
Ha
Hb
OTBDPS
O
Ac
N
H
H
S
NH2
t-Bu
3
5
N
H
OH
O
CH2Cl2
r.t.
O
O
+
HCO2H
BnNC
+
+
H
CO2Et
Figure 3 Configuration of the Ugi product 4a determined by NOESY
NMR analysis
3b
2c
6
7
O
CHO
O
CHO
N
In conclusion, a new Ugi reaction of chiral 5,6-dihy-
dro[1,4]oxazin-2-one substrates 1, isocyanides 2 and car-
boxylic acids 3 was developed. Using this approach,
morpholin-2-one-3-carboxamide derivatives 4 were effi-
ciently synthesized for the first time, and good diastereo-
selectivity of the new stereocenter at C-3 in the products
was observed. The work will enrich asymmetric Ugi reac-
tions and, currently, an extension of the reaction based on
the cyclic imines is underway.
Bn
N
Ph
Bn
Ph
N
H
LiBH4
THF
N
H
HO
OH
EtO
O
OH
5a the minor isomer
5b the major isomer
8
Scheme 3 Ugi four-component reaction for the synthesis of 8 and
subsequent reduction
To further verify the stereoselectivity, the 1H NMR spec-
trum of 4a, in which the paired H-3 (δ = 4.95 and 4.76
ppm) and H-5 (δ = 3.93 and 4.58 ppm) signals from two
isomers were easily distinguishable and not overlapped
with other proton signals,14 was used to determine the
configuration of the products. The observation of NOE
Supporting Information for this article is available online at
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Synlett 2010, No. 6, 897–900 © Thieme Stuttgart · New York

900
D. Zhu et al.
LETTER
vacuo. The residue was purified by flash chromatography on
silica gel column to give product 4
(8) Harwood, L. M.; Vines, K. J.; Drew, M. G. B. Synlett 1996,
1051.
Acknowledgment
We thank Sichuan University Analytical and Testing Center for
NMR determination. This work was supported by grants from the
National Natural Science Foundation of China (No. 20802045), the
National Basic Research Program of China (973 Program, No.
2012CB833200), the Setup Foundation of Sichuan University and
the Youth Foundation of Sichuan University.
(9) (a) Tohma, S.; Endo, A.; Kan, T.; Fukuyama, T. Synlett
2001, 1179. (b) Tohma, S.; Rikimaru, K.; Endo, A.;
Shimamoto, K.; Kan, T.; Fukuyama, T. Synthesis 2004, 909.
(10) (a) Ugi, I.; Dffermann, K. Angew. Chem. Int. Ed. 1963, 2,
624. (b) Ugi, I.; Kaufhold, G. L. Ann. Chem. 1967, 709, 11.
(c) Madson, U.; Frydenvang, K.; Ebert, B.; Johemsen, T. N.;
Brehm, L.; Krogsgaard-Larsen, P. J. Med. Chem. 1996, 39,
183. (d) Eberle, G.; Ugi, I. Angew. Chem. Int. Ed. 1976, 15,
492.
(11) (a) Merquarding, D.; Hoffman, P.; Heitzer, H.; Ugi, I. J. Am.
Chem. Soc. 1970, 92, 1969. (b) Demharter, A.; Ugi, I.
J. Prakt. Chem. 1993, 335, 244. (c) Siglmuller, F.;
Herrmam, R.; Ugi, I. Tetrahedron 1986, 42, 5931.
(12) (a) Kunz, H.; Pfrengle, W. J. Am. Chem. Soc. 1988, 110,
651. (b) Kunz, H.; Pfrangle, W. Tetrahedron 1988, 44,
5487. (c) Lehnhoff, S.; Goebel, M.; Karl, R. M.; Klosel, R.;
Ugi, I. Angew. Chem. Int. Ed. 1995, 34, 1104. (d) Drabik,
J. M.; Achatz, J.; Ugi, I. Proc. Est. Acad. Sci. Chem. 2002,
51, 156.
References and Notes
(1) For reviews, see: (a) Dömling, A.; Ugi, I. Angew. Chem. Int.
Ed. 2000, 39, 3168. (b) Dömling, A. Chem. Rev. 2006, 106,
17. (c) Boger, D. L.; Desharnais, J.; Capps, K. Angew.
Chem. Int. Ed. 2003, 42, 4138.
(2) (a) He, Q.; Zhu, X.; Shi, M.; Zhao, M.; Zhao, J.; Zhang, S.;
Miao, J. Bioorg. Med. Chem. 2007, 15, 3889. (b) Raparti,
V.; Chitre, T.; Bothara, K.; Kumar, V.; Dangre, S.;
Khachane, C.; Gore, S.; Deshmane, B. Eur. J. Med. Chem.
2009, 44, 3954. (c) Arcelli, A.; Balducci, D.; Neto, S. d. F.
E.; Porzi, G.; Sandri, M. Tetrahedron: Asymmetry 2007, 18,
562.
(3) Kim, Y. B.; Choi, E. H.; Keum, G.; Kang, S. B.; Lee, D. H.;
Koh, H. Y.; Kim, Y. Org. Lett. 2001, 3, 4149.
(13) (a) Demharter, A.; Hörl, W.; Herdtweck, E.; Ugi, I. Angew.
Chem., Int. Ed. Engl. 1996, 35, 173. (b) Dyker, G.;
Breitenstein, K.; Henkel, G. Tetrahedron: Asymmetry 2002,
13, 1929. (c) Park, S. J.; Keum, G.; Kang, S. B.; Koh, H. Y.;
Kim, Y.; Lee, D. H. Tetrahedron Lett. 1998, 39, 7109.
(d) Ugi, I.; Demharter, A.; Hörl, W.; Schmid, T. Tetrahedron
1996, 52, 11657. (e) Zimmer, R.; Ziemer, A.; Gruner, M.;
Brudgam, I.; Hartl, H.; Reissig, H. U. Synthesis 2001, 1649.
(14) 4a: [α]D28 +4 (c 0.5, CHCl3). IR (neat): 3337, 2963, 2932,
1752, 1666, 1539, 1463, 1391, 1289, 1108 cm–1. 1H NMR
(400 MHz, CDCl3): δ (two rotamers) = 7.66–7.61 (m, 4 H),
7.46–7.40 (m, 6 H), 5.98 (s, 1 H), 4.95 (s, 0.8 H), 4.82 (dd,
J = 2.7, 11.5 Hz, 1 H), 4.76 (s, 0.2 H), 4.71 (dd, J = 1.3,
11.4 Hz, 0.8 H), 4.58 (m, 0.2 H), 4.47 (dd, J = 2.8, 12.0 Hz,
0.2 H), 3.93 (m, 0.8 H), 3.86 (dd, J = 4.0, 9.6 Hz, 0.2 H),
3.70 (t, J = 10.6 Hz, 0.8 H), 3.59 (dd, J = 5.3, 10.7 Hz,
0.8 H), 3.52 (t, J = 9.6 Hz, 0.2 H), 1.89 (s, 0.6 H), 1.82 (s,
2.4 H), 1.36 (s, 1.8 H), 1.33 (s, 7.2 H), 1.06 (s, 7.2 H),
1.05 (s, 1.8 H) ppm. 13C NMR (100 MHz, CDCl3): δ (two
rotamers) = 169.9, 169.8, 165.7, 163.3, 162.2, 162.1, 135.4,
135.3, 132.5, 131.9, 130.2, 130.1, 127.9, 127.7, 127.6, 66.7,
65.8, 62.7, 61.0, 60.7, 60.2, 52.9, 52.6, 52.2, 50.0, 29.6, 28.3,
26.6, 21.1, 20.4, 19.0 ppm. HRMS: m/z [M + Na]+ calcd for
C28H38N2O5Si: 533.2448; found: 533.2437.
(4) Ku, I. W.; Cho, S.; Doddareddy, M. R.; Jang, M. S.; Keum,
J. G.; Lee, J. H.; Chung, B. Y.; Kim, Y.; Rhim, H.; Kang,
S. B. Bioorg. Med. Chem. Lett. 2006, 16, 5244.
(5) (a) Antunes, J. E.; Freitas, M. P.; da Cunha, E. F. F.;
Ramalho, T. C.; Rittner, R. Bioorg. Med. Chem. 2008, 16,
7599. (b) Gao, F.; Sexton, P. M.; Christopoulos, A.; Miller,
L. J. Bioorg. Med. Chem. Lett. 2008, 18, 4401. (c) Repine,
J. T.; Himmelsbach, R. J.; Hodges, J. C.; Kaltenbronn, J. S.;
Sircar, I.; Skeean, R. W.; Brennan, S. T.; Hurley, T. R.;
Lunney, E.; Humblet, C. C.; Weishaar, R. E.; Rapundalo, S.;
Ryan, M. J.; Taylor, D. G. Jr.; Olson, S. C.; Michniewicz,
B. M.; Kornberg, B. E.; Belmont, D. T.; Taylor, M. D.
J. Med. Chem. 1991, 34, 1935. (d) Gyöergydeák, Z.;
Hadady, Z.; Felföeldi, N.; Krakomperger, A.; Nagy, V.;
Tóth, M.; Brunyánszki, A.; Docsa, T.; Gergely, P.; Somsák,
L. Bioorg. Med. Chem. 2004, 12, 4861.
(6) (a) Shafer, C. M.; Morse, D. I.; Molinski, T. F. Tetrahedron
1996, 52, 14475. (b) Shafer, C. M.; Molinski, T. F. J. Org.
Chem. 1996, 61, 2044. (c) Chen, X.; Chen, J.; Zhu, J.
Synthesis 2006, 4081.
(7) General procedure for the synthesis of 4: To a solution of 1
were added, successively, acid 3 and isocyanide 2 under
inert atmosphere. The resulting mixture was stirred at room
temperature until completion (TLC), and concentrated in
Synlett 2010, No. 6, 897–900 © Thieme Stuttgart · New York