Catalytic ugi-type condensation of α-isocyanoacetamide and chiral cyclic imine: Access to asymmetric construction of several heterocycles

Article abstract of DOI:10.1021/jo4000702

Several novel heterocycles have been constructed asymmetrically on the basis of a catalytic Ugi-type condensation of α-isocyanoacetamide and chiral cyclic imine. The combination of phenylphosphilic acid and trifluoroethanol is exploited to promote an Ugi-type reaction with α-isocyanoacetamide for the first time. By means of this reaction, chiral 3-oxazolyl morpholin-2-one/piperazin-2-one derivatives are synthesized with high yields and excellent stereoselectivities. As electron-rich azadienes, these condensation products are further transformed to fused tricyclic frameworks by treatment with appropriate dienophiles such as maleic anhydride and unsaturated acyl chlorides via domino processes. Moreover, a one-pot, three-component synthesis of the chiral tricyclic frameworks from isocyanoacetamide, imine, and maleic anhydride is also feasible.

Full text of DOI:10.1021/jo4000702

Article
pubs.acs.org/joc
Catalytic Ugi-Type Condensation of α‑Isocyanoacetamide and Chiral
Cyclic Imine: Access to Asymmetric Construction of Several
Heterocycles
Liang Xia,† Sheng Li,† Ruijiao Chen, Kai Liu, and Xiaochuan Chen*
Key Laboratory of Green Chemistry & Technology of the Ministry of Education, College of Chemistry, Sichuan University, Chengdu
610064, People’s Republic of China
S
* Supporting Information
ABSTRACT: Several novel heterocycles have been constructed asym-
metrically on the basis of a catalytic Ugi-type condensation of α-
isocyanoacetamide and chiral cyclic imine. The combination of
phenylphosphilic acid and trifluoroethanol is exploited to promote an
Ugi-type reaction with α-isocyanoacetamide for the first time. By means
of this reaction, chiral 3-oxazolyl morpholin-2-one/piperazin-2-one
derivatives are synthesized with high yields and excellent stereo-
selectivities. As electron-rich azadienes, these condensation products
are further transformed to fused tricyclic frameworks by treatment with
appropriate dienophiles such as maleic anhydride and unsaturated acyl
chlorides via domino processes. Moreover, a one-pot, three-component
synthesis of the chiral tricyclic frameworks from isocyanoacetamide,
imine, and maleic anhydride is also feasible.
Scheme 1. Representative Ugi-Type Reaction of an α-
Isocyanoacetamide, an Amine, and an Aldehyde
INTRODUCTION
■
Polyfunctionalized heterocyclic compounds, particularly nitro-
gen-containing heterocycles, have assumed important roles in
the structural identification of biological macromolecules and in
the discovery of drugs via their special interaction with
biological macromolecules or therapeutic targets.1 With the
rapid progress on biologically active macromolecule studies by
means of genomics and proteomics,2 the design and synthesis
of novel heterocycle libraries is becoming more and more
urgent to meet the growing demands of biological and medical
research.3 The classical four-component Ugi reaction and its
variants have shown great potential in the generation of
molecular complexity and diversity and have served as an
efficient and versatile synthetic toolbox to quickly build a range
of pharmacological compounds, including heterocycles.4
Among them, Ugi-type reactions of α-isocyanoacetamide 1,
amine 2, and carbonyl compound 3 open a highly efficient
access to the synthesis of substituted oxazole derivatives 4.5 The
proposed mechanism is shown in Scheme 1. The imine or
iminium 5, formed via condensation of amine 2 with carbonyl
compound 3, would react with isonitrile 1 to produce the
nitrilium intermediate 6, where the oxygen originally in the
isocyanoacetamide component attacked the nitrilium moiety
instead of carboxylic acid in the classical Ugi reaction, leading to
cyclization. When secondary amines were employed as inputs,
the yield of the reaction is usually better than for primary
amines due to the higher activity of iminium.5a,d,e The oxazole
unit is found in many bioactive natural products and
pharmaceutically relevant molecules,5a,6 and structure 4 has
been applied to the design of important peptidomimetic
platforms.7 Moreover, by means of various chemical trans-
formations involving oxazole frameworks,8 the Ugi products
containing oxazole are probably converted to more kinds of
complex heterocyclic scaffolds.
Although one chiral center is generated in the condensation
process, very little attention has been paid to the stereo-
selectivity of this Ugi-type condensation in previous studies.
Until now, only one enantioselective version has been achieved
in a chiral acid-catalyzed reaction of aldehydes, anilines, and α-
isocyanoacetamides with 56−90% ee.9 Examples employing
chiral substrates in the condensation are very limited and have
shown low or no diastereoselectivity.5d,e,10 Few studies have
Received: January 14, 2013
© XXXX American Chemical Society
A
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been carried out on the stereochemistry of the reactions
employing chiral substrates. Therefore, although Ugi reactions
as well as their combination with the appropriate postfunction-
alizations have been applied widely to synthesize various
heterocycles,11 the synthesis of chiral heterocycles with high
stereoselectivity has seldom been achieved by this strategy. The
development of asymmetric Ugi reactions will provide some
short cuts to chiral molecule libraries with potential
applicability in medicine and agriculture. After all, optically
pure compounds are of uttermost importance during the
development of most drugs because of the possible different
activities of various stereoisomers.12 Recently we reported an
asymmetric Ugi reaction of isocyanide, carboxylic acid, and
chiral cyclic imine 7 in 2,2,2-trifluoroethanol (TFE).13 As a
continuation of our study on developing asymmetric Ugi
reactions using imine 7, herein we report the asymmetric
syntheses of new 3-oxazolyl morpholin-2-one/piperazin-2-one
species 8 by a catalytic Ugi-type reaction of 1 and 7 with
excellent stereoselectivity.14 Moreover, the post-transformation
of 8 to novel fused tricyclic systems 9 by treatment with the
appropriate dienophiles has been achieved (Scheme 2).
Phenylphosphilic acid (10) is used to catalyze an Ugi-type
reaction of isocyanoacetamide for the first time.
instability and the side reactions caused by the competing
nucleophilic methylene carbon lead to more complexity and
uncertainty.15b,16 Thus, in our initial experiments, unsubstituted
and substituted isocyanoacetamides 1a,b were chosen to react
with 7a for the screening of suitable conditions for both type of
isocyanoacetamides. However, none of the existing conditions
could achieve the condensation of the special substrate 7 and 1
to produce 8 with acceptable results. In the absence of additive,
the reaction of 1 and 7 did not take place at all in various
solvents (MeOH, toluene, CH2Cl2, THF, TFE) and temper-
atures. Under the previous conditions for similar Ugi-type
reactions (NH4Cl (11), Et3N·HCl (12) or LiBr (13) as
promoter, MeOH or toluene as solvent, from room to reflux
temperature), our reaction ran sluggishly and gave poor yields
or failed to give results.14 Simply prolonging the reaction time
resulted in serious decomposition of imines 7 and increased the
tautomerization of 1, particularly 1a, to 2H-oxazole 14. This
means that the Ugi-type reactions based on 7 proceed with
much more difficulty than all the precedents. 7, imines derived
from the condensation of primary amines and ketones, are
probably less reactive than their iminium counterparts from
secondary amines or imines from aldehydes. Therefore, a new
efficient reaction system is required to promote the slow
reactions of 1 and 7.
In 2008 an Ugi reaction of aldehydes, amines, and isonitriles
in toluene promoted by phenylphosphilic acid (10) was
described.17 However, the potential of 10 in the development
of new catalytic Ugi reactions has not been further investigated
and extended. To our delight, the reactions of 1 and 7 could be
activated effectively by 10 after solvent screening. In the
presence of 0.25 equiv of 10, 3-oxazolylmorpholin-2-one 8a was
obtained in 52% yield at −40 °C in TFE (Table 1, entry 2). In
other solvents including toluene,17 the catalytic effect of 10
decreased dramatically (entries 3, 4, 13, and 14). As far as we
know, TFE has never before been utilized as a solvent in the
Ugi-type reactions of α-isocyanoacetamides. On the other hand,
employment of those additives commonly used, such as
Et3N·HCl (11), NH4Cl (12), LiBr (13), TsOH (15), ZnCl2
(16), and Sc(OTf)3 (17), to promote the reaction in TFE also
gave inferior results (entries 6−10, 15, and 16). It is thus clear
that phenylphosphilic acid and TFE are both necessary to
facilitate this reaction. By further optimization of various
parameters (temperature, concentration, amount of 10, etc.),
the desired products 8a,b were obtained in high yields
whenever unsubstituted isocyanoacetamide 1a or substituted
isocyanoacetamide 1b was employed (entries 11 and 17). It is
noteworthy that the tautomerization of 1 to 14 could not be
inhibited entirely; therefore, the addition of 1 at the midway
point is essential for thorough conversion of 7 and high yields
of 8.
With the optimal conditions in hand, the generality of this
new catalytic Ugi-type reaction was next examined (Table 2).
Gratifyingly, under the mild conditions the reactions of various
1 species and 5,6-dihydro-1,4-oxazin-2-one substrates 7a−e
proceeded quickly to give the desired products 8 in good to
excellent yields, no matterwhether R on the oxazole is a
hydrogen, alkyl, or aryl group. When the amino function (X) in
1 is morpholinyl, the reactions usually were complete in around
1 h with high yields. For some isocyanoacetamide inputs with
other amino groups, the reaction process seemed somewhat
slow, and more catalyst was needed to accelerate it (entries 15−
19). Furthermore, 5,6-dihydropyrazin-2(1H)-ones 7f,g (Y =
NR) as imine inputs also react well with 1 to yield the 3-
Scheme 2. Syntheses of 8 and 9 Starting from 1 and 7
RESULTS AND DISCUSSION
■
Similar to the classical Ugi reation, the favorable solvent for the
Ugi-type condensation of α-isocyanoacetamide 1 with 2 and 3
is MeOH, in which the reactions usually proceed quite
smoothly at heating or room temperature. Some additives,
such as NH4Cl, LiBr, Et3N·HCl, Sc(OTf)3, and sulfoic acid,
could promote the Ugi-type condensation in toluene, benzene,
or MeOH,5b−d,10,15 and satisfactory results are obtained.
However, it is noteworthy that aldehydes, due to the minor
steric hindrance around their carbonyl group, are employed
rather than ketones in most cases. Furthermore, the
unsubstituted α-isocyanoacetamides have rarely been inves-
tigated, despite their prospective utility, because their inherent
B
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a
Table 1. Optimization of the Ugi-Type Reaction with 7a and 1a,b
entry
R
solvent
t (h)
catalyst
x (mol %)
T (°C)
yield of 8 (%)
d
1
2
3
4
5
6
7
8
9
10
H
TFE
2
3
10
10
10
10
10
11
12
13
15
16
10
10
10
10
17
12
10
25
25
room temp
−40
−30
40 (16 )
d
H
TFE
52 (27 )
d
H
MeOH
CH2Cl2
TFE
6
25
trace (41 )
d
H
11
1.5
120
1
25
room temp
room temp
room temp
room temp
room temp
−40
room temp
room temp
−40
10 (68 )
d
H
10
51 (26 )
d
H
TFE
150
100
100
25
trace (47 )
d
H
TFE
8 (trace )
H
TFE
1
12
d
H
TFE
2.5
2.5
1.5
3
10 (18 )
d
H
TFE
100
10
6 (39 )
bc
,
11
12
13
14
15
16
17
H
TFE
86
bc
,
d
Bn
Bn
Bn
Bn
Bn
Bn
TFE
25
62 (24 )
bc
,
d
Toluene
MeOH
TFE
10
5
100
10
70
trace (69 )
bc
,
d
70
38 (trace )
bc
,
d
4
10
70
38 (trace )
bc
,
d
TFE
18
100
10
room temp
room temp
12 (57 )
bc
,
TFE
1.25
93
a
b
c
General conditions: 7a/1 = 1:/1, c = 0.2 M. c = 0.4 M. Additional 1 was supplemented at the midway point (0.8 equiv for 1a, 0.4 equiv for 1b).
Recovered 7a.
d
oxazolylpiperazin-2-one scaffolds (entries 9−11). In this Ugi-
type reaction all cyclic imines 7 showed excellent stereo-
induction for the new chiral quaternary carbon, and quite a few
products were obtained as single stereoisomers. In a few cases
another diastereoisomer was detected in a trace amount
(entries 1, 2, 4, 12, 13, and 15); nevertheless, dr values were
all at least 10:1, as determined by NMR spectra or
chromatography.
The diastereoselectivity in this reaction is better than that in
our previous three-component Ugi reaction.13 The NOESY 1H
NMR spectra of 8d,h,j were analyzed to determine the
stereochemistry of the products (Figure 1). The lack of an
NOE correlation between Me-3 and H-5 signals but a
correlation between Me-3 and aromatic or benzylic hydrogen
illustrates the trans relationship of the C-3 oxazolyl and C-5
alkyl (R1) group, namely an S configuration at C-3. It is
reasonable that isocyanoacetamide 1 as nucleophile preferen-
tially approaches imine 7 from the side opposite to the R1
group to generate predominantlt the trans product.13,18 The
Ugi-type condensation allows access to chiral heterocycles 8
with five points of diversity derived from the isocyanoacetamide
and imine inputs. Structurally, 8 also may be regarded as varied
derivatives of chiral α,α-disubstitued oxazole-containing amino
acids, which are of importance for the design and synthesis of
various conformationally restricted and biologically active
pseudopeptides, including galmic.19
Taking advantage of reactivity of 5-aminooxazoles as
electron-rich azadienes with dienophiles,20 several ingenious
strategies for the combination of the Ugi-type reaction and
Diels−Alder (D-A) cycloaddition have been devised to
construct interesting and complex heterocycle scaffolds.5d,15d,21
However, an asymmetric tandem methodology to gain rapid
access to chiral heterocycles has not been reported. Thus, the
reactions of chiral oxazole 8 and several dienophiles were
examined. After the conditions and dienophiles were screened,
the desired cycloaddition could take place when maleic
anhydride (18) was used. Stirring a mixture of 8d and 18 (2
equiv) in toluene at 110 °C provided the novel tricyclic
framework 9, which incorporates a pyrrolopyridine unit with a
morpholine or piperazine ring in modest yield (40%). It is
envisaged that 9 is produced via sequential decarboxylation and
dehydration of cycloaddition intermediate 19. Addition of acid
(AcOH) or base (DBU) to promote conversion of 19 to 9 led
to deteriorative results. To our delight, 4 Å molecular sieves
showed a beneficial effect on improving the yield of 9 by
removal of water produced in the dehydration process (Scheme
3). Under similar conditions, several chain dienophiles,
including maleic acid, diethyl maleate, fumaric acid, and diethyl
fumarate, did not react with oxazole 8, and no cycloaddition
products were detected. Presumably cyclic dienophiles with
inherent ring strain, such as maleic anhydride, have adequate
activity and could react with the relatively inert oxazoles 8,
which are hindered by bulky substituents.
C
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a
Table 2. Synthesis of 3-Oxazolyl Morpholin-2-one/Piperazin-2-one Derivatives 8a−s
entry
R
R1
R2
Y
X
t (h)
10 (x mol %)
product
yield (%)
dr
b
1
H
Bn
Bn
Ph
Bn
Bn
Ph
i-Pr
Ph
Bn
Ph
Bn
i-Pr
Bn
Bn
Bn
Bn
i-Pr
Bn
Bn
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
O
O
O
O
O
O
O
O
morpholinyl
morpholinyl
morpholinyl
morpholinyl
morpholinyl
morpholinyl
morpholinyl
morpholinyl
morpholinyl
morpholinyl
morpholinyl
morpholinyl
morpholinyl
piperidinyl
1
10
10
10
10
10
10
10
10
10
10
10
10
10
10
25
25
25
25
50
8a
8b
8c
8d
8e
8f
86
93
85
93
92
91
87
84
64
75
81
88
78
72
90
73
54
85
78
14:1
b
2
Bn
H
1
19:1
3
1
single
b
4
i-Pr
Me
Bn
Bn
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
Bn
Ph
1.25
1
12:1
5
single
single
single
single
single
single
single
6
1.25
1.25
1.25
1
7
8g
8h
8i
8
9
NMe
NMe
Nn-Bu
O
10
11
12
13
14
15
16
17
18
19
1.25
1
8j
8k
8l
b
1.25
1.25
1
14:1
b
Et
O
8m
8n
8o
8p
8q
8r
8s
10:1
Et
O
single
c
Me
Me
Me
Me
Me
O
piperidinyl
4
13:1
Bn
Bn
Ph
O
piperidinyl
4
single
single
single
single
O
piperidinyl
1.25
1.5
2
O
pyrrolidiny
diethylamino
Bn
O
a
General conditions: reactions were performed in TFE° (c = 0.4 M of 7) at room temperature, 1 + 0.8 equiv of 1a or 1 + 0.4 equiv of 1b−i.
b
c
1
Determined by H NMR spectra. Determined by column chromatography.
results. In comparison with other oxazoles 8, 8a (R = H) from
unsubstituted isocyanoacetamide 1a gave a relatively low yield
(entry 1). In a few cases, the conversion of 8 proceeded a bit
slowly, and a small amount of oxzaoles was recovered even
when the heating time was prolonged (entries 3, 6, 7, and 11).
All products 9 were obtained as single isomers, and other
isomers were not detected. Analysis of the X-ray diffraction data
of 9e established the three-dimensional structure of the tricyclic
systems (see the Supporting Information): planar pyrrolopyr-
idine fused with the morpholine adopting a twist-boat
conformation, where the methyl and isopropyl in a pseudoaxial
orientation are on the same side of the morpholine ring as the
lone pair electrons of nitrogen.22 Absolute configurations at the
three chiral centers are S (C-3), R (N-4), and S (C-5). The
pyrrolopyridine, with a structure analogous to that of
isoindolinones, nicotinamide, etc., is a potential pharmacophore
and synthetic intermediate.23 Heterocycles 9, which incorporate
pyrrolopyridine with the medically relevant morpholinone24 or
ketopiperazine25 unit, possibly possess interesting bioactivity.
To further enrich the structural diversity of 9, D-A
cycloadditions of 8 with substituted maleic anhydrides were
tried to prepare heterocycle 9 with a substituent at C-4 on the
pyridine ring. Unfortunately, even the simplest substituted
anhydride, 20 (R′ = Me), did not react with 8d under the same
conditions, and no product was observed (Scheme 4). The
reactions of 8 with unsaturated acyl chlorides 21 were then
investigated. Unsubstituted acryloyl chloride 21a (R′ = H)
instead of 18 was employed to react with 8 first. After
preliminary attempts, heating a mixture of 8d (or 8b) and 21a
in toluene in the presence of DIPEA also furnished the same
product, 9c (or 9b), as from 18 (Table 4, entries 1 and 2).
However, in contrast with the reaction of 18, the reactions of
acyl chlorides with 8 became sluggish and complicated. The
yields of 9 decreased to a great extent due to the formation of
Figure 1. Configuration determination of Ugi products by NOESY
analysis.
Scheme 3. Synthesis of Fused Tricyclic System 9 by the
Reaction of 8 with Maleic Anhydride via a Multiple Domino
Process
Next, the cycloadditions of various 8 species with 18 were
performed under the optimized conditions (Table 3). Most
reactions were complete within 12 h and gave satisfactory
D
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a
Table 3. Synthesis of Fused Tricyclic Frameworks 9a−n from 8 and 18
entry
R
R1
R2
Y
X
t (h)
product
yield (%)
1
H
Bn
Bn
Bn
Bn
i-Pr
Ph
i-Pr
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Me
Me
Me
Me
Me
Me
Et
O
O
O
O
O
O
O
O
morpholinyl
morpholinyl
morpholinyl
morpholinyl
morpholinyl
morpholinyl
morpholinyl
morpholinyl
morpholinyl
morpholinyl
piperidinyl
2.5
8
9a
9b
9c
9d
9e
9f
47
93
2
Bn
b
3
i-Pr
Me
Bn
12
6
76 (8 )
78
4
5
6
77
b
6
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
Ph
12
18
12
12
11
13
5
84 (11 )
b
7
9g
9h
9i
65 (22 )
8
Et
83
70
90
9
Me
Me
Me
Me
Me
Me
NMe
N-n-Bu
O
10
11
12
13
14
9j
b
9k
9l
51 (24 )
Bn
O
piperidinyl
65
63
72
Ph
O
pyrrolidiny
diethylamino
5
9m
9n
Bn
O
5
a
General conditions: unless otherwise noted, all reactions were carried out with 8 (1 equiv), maleic anhydride (2 equiv), and molecular sieves (4 Å,
b
powder, 50 mg) in toluene° (c = 0.04 M) at 110 °C. Recovered 8.
The formation of 9 from 8 and 18 is proposed to occur via
the bridged tetracyclic intermediate 19, which is produced by a
domino process involving D-A addition and acylation in two
possible sequences (path a or b, Scheme 5). Any intermediate
Scheme 4. Attempt To React 8d with Substituted Maleic
Anhydride 20
Scheme 5. Bridged Tetracyclic Intermediate 19 Produced by
a D-A Addition/Acylation Process in Two Possible
Sequences
Table 4. Synthesis of Fused Tricyclic System 9 by the
a
Reaction of 8 with Unsaturated Acyl Chlorides 21
entry
R
R′
t (h)
product
yield (%)
1
2
3
4
5
Bn
H
H
2.5
8
9b
9c
9o
9p
9q
27
32
i-Pr
i-Pr
i-Pr
i-Pr
b
Me
36
20
20
31 (38 )
Ph
60
33
CO2Et
a
General conditions: unless otherwise noted, all reactions were carried
out with 8b/8d (1 equiv), DIPEA (5 equiv), unsaturated acyl chlorides
21 (2.5 equiv), and molecular sieves (4 Å, powder, 50 mg) in toluene°
b
(c = 0.04 M) at 110 °C. Recovered 8.
some indeterminable species. Under similar conditions, several
substituted acryloyl chlorides 21b−d could also react with 8 to
produce new heterocycles 9o−q with z fully substituted
pyridine ring. The R′ group in 21 appears to have some effect
on the yield of 9, and cinnamoyl chloride (21c) gave better
results than other acyl chlorides in the domino transformation
(entry 4). The employment of the unsaturated acyl chlorides
21 instead of 18 allows us to introduce more variable points on
9. However, for our oxazoles 8, 18 has a great advantage over
the unsaturated acyl chloride 21a in the syntheses of
heterocycles without a substituent at C-4, such as 9a−n (R′
= H).
such as 19, 22, or 23 in the course of the reaction could not be
separated. Therefore, the exact reaction sequence is not clear.
In previous reports on the reactions of 5-aminooxazoles and
exotic dienophiles, such as unsaturated acyl chlorides or
pentafluorophenyl esters, the sequence of acylation prior to
the intramolecular D-A reaction is accepted (path a).5d,e,21b,26
However, we found that the acylation of 8 is quite difficult, and
the acylated product was not observed by heating a toluene
solution of 8d and succinic anhydride (24) or acetyl chloride.
However, under similar conditions the intermolecular D-A
reaction of 8d and N-phenylmaleimide (26) occurred readily to
E
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give the resulting oxa-bridged heterocycle 27 with excellent
yield (92%) and stereoselectivity (single diastereoisomer). It
seems as if 8 reacts with 18 in a reverse sequence (D-A
reaction/acylation, path b).
phenylphosphilic acid leading to 3-oxazolyl morpholin-2-one or
piperazin-2-one derivatives 8, in which excellent stereo-
selectivity of the new chiral center was achieved. The
combination of phenylphosphilic acid and TFE efficiently
promoted the condensation of 7 with 1 and showed potential
to exploit more Ugi reactions. Whereas, under the previous
conditions for Ugi reactions of α-isocyanoacetamides, imines 7,
as relatively inert substrates, react with 1 very sluggishly. The
subsequent reaction of aminooxazoles 8 with maleic anhydride
led to the novel fused heterocycles 9 in good yield via a
multiple domino sequence involving cycloaddition. acylation,
decarboxylation, and dehydration. The absolute stereochemis-
try of 9 was determined. The reactions of the unsaturated acyl
chlorides 21 with 8 were also carried out to produce 9 with
more substituents. Furthermore, a one-pot, three-component
synthesis of 9 from 1, 7, and 18 was performed via combination
of an Ugi-type condensation and cycloaddition. This method-
ology opens a shortcut to various interesting chiral hereocycles
with potential activity such as 8 and 9, which are not easily
synthesized by other approaches.
One-pot protocols combining two or more reaction steps
show higher efficiency because of simpler operation, lower
costs, and shorter time.27 Therefore, a one-pot, three-
component synthesis of 9 from 1, 7, and 18 was then
investigated by combining Ugi-type condensation and cyclo-
addition. In primary tests, TFE and toluene, as ideal solvents in
the respective steps, do not fit for the other step. Therefore,
when the one-pot operation was performed throughout in a
single solvent including toluene and TFE, the desirable 9 was
produced in low yield (<20%) or was not produced at all. We
noticed that the D-A addition could work well even at a low
concentrations. Thus, a one-pot synthesis of 9 from 1 and 7
was devised. A solution of 1 and 7 in TFE at high concentration
(0.4 M for 7) was stirred at room temperature. Once 7 was
consumed completely, 1 equiv of Et3N with respect to 10 was
added to neutralize the acid. The resulting mixture was diluted
with a large amount of toluene, and then 18 and molecular
sieves were added. Refluxing the reaction mixture gave 9 in
satisfactory yield. A small quantity of TFE in the mixture did
not have an obviously negative effect on the reaction. Just the
amount of 18 needs to be properly increased (3 equiv), because
2H-oxazoles 14 isomerized from 1 itself would partially
consume 18 by possibly a similar cycloaddition. Moreover,
the addition of Et3N after completion of the Ugi reaction could
reduce the harm of 10 to a subsequent cycloaddition step and
favor the final yield of 9. Particularly for those cases in which
more 10 (0.25 equiv) was used, addition of Et3N was essential
and promoted the yield drastically. Under the optimized
conditions, the one-pot yields are nearly equal to or slightly
higher than the two-step method (Table 5), indicating higher
efficiency in the synthesis of complex heterocycles 9 with five
points of diversity.
EXPERIMENTAL SECTION
■
General Considerations. IR spectra were recorded on a
commercial spectrophotometer. Optical rotations were reported as
follows: [α]DT° (c in units of g/100 mL, in solvent). 1H and 13C NMR
were recorded on were recorded on commercial instruments (400 or
600 MHz) with TMS as the internal standard and were calibrated
using residual undeuterated solvent as an internal reference (CDCl3:
1H NMR, 7.26 ppm; 13C NMR, 77.16 ppm). The following
abbreviations were used to explain the multiplicities: s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet, br = broad. Coupling
constants (J) are reported in hertz (Hz). HRMS spectra were recorded
using a commercial apparatus, and methanol or dichloromethane was
used to dissolve the sample. Solvents for reaction were distilled prior
to use: toluene from CaH2, methanol from magnesium turnings.
Trifluoroethanol (TFE), phenylphosphilic acid, and other reagents
were obtained from commercial suppliers unless otherwise stated.
Molecular sieves (4 Å) was powdered <50 μm, was activated at 120 °C
for 5 h, and was stored under nitrogen.
General Procedure for the Synthesis of 8 by the Ugi-Type
Condensation of α-Isocyanoacetamides 1 and Cyclic Imines 7.
To a solution of imine 7 (0.20 mmol) in TFE (0.5 mL) were added
successively α-isocyanoacetamides 1 (0.20 mmol) and phenyl-
phosphilic acid (10; 0.020 mmol generally, 0.050 mmol for 1f−h,
0.10 mmol for 1i) at room temperature. After the mixture was stirred
at room temperature for 20 min, additional 1 (0.16 mmol for 1a, 0.080
mmol for 1b−i) was added. The resulting mixture was stirred for 1−4
h, quenched with 0.1% aqueous NaHCO3, and extracted with CH2Cl2.
The combined organic layers were dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The residue was purified by
flash column chromatography on silica gel (petroleum ether/EtOAc)
to afford the desired product 8.
CONCLUSION
■
Herein we have reported a new asymmetric Ugi-type reaction
of α-isocyanoacetamides 1 and chiral imines 7 catalyzed by
Table 5. Comparison of Yield of 9 from 1 and 7 by One-Pot
Synthesis with the Two-Step Procedure
(3S,5S)-5-Benzyl-3-methyl-3-(5-morpholinooxazol-2-yl)-
morpholin-2-one (8a). After the mixture was stirred for 1 h, the
product was isolated by flash column chromatography using petroleum
ether/ethyl acetate (5/1 to 3/2) as eluent: yield 63 mg, 86%; yellow
gel; [α]D20 = −51° (c 0.9, CH2Cl2); IR (neat) 3311, 2968, 2856, 1744,
yield (%)
entry
product
one-pot synthesis
two-step procedure
1
1609, 1452, 1240, 1117, 898, 752, 702 cm−1; H NMR (400 MHz,
a
a
1
2
3
4
5
6
9c
9d
9e
9k
9l
68 (9 )
70 (8 )
CDCl3) δ (ppm) 7.12−7.36 (m, 5H), 5.97 (s, 1H), 4.31 (dd, J = 3.2,
10.5 Hz, 1H), 4.18 (t, J = 10.3 Hz, 1H), 3.72−3.85 (m, 4H), 3.48−
3.58 (m, 1H), 2.93−3.02 (m, 4H), 2.75 (dd, J = 5.4, 13.6 Hz, 1H),
2.62 (dd, J = 8.4, 13.5 Hz, 1H), 2.51 (br s, 1H), 1.73 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ (ppm) 167.7, 157.5, 155.5, 136.3, 129.0,
128.8, 127.0, 102.8, 74.3, 66.0, 60.6, 49.5, 48.1, 37.8, 26.1; HRMS
(ESI-TOF): m/z calcd for C19H23N3O4Na [M + Na]+ 380.1586, found
380.1589.
71
70
71
67
a
a
47 (26 )
42 (24 )
55
56
47
53
9m
a
Recovered 8.
F
dx.doi.org/10.1021/jo4000702 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(3S,5S)-5-Benzyl-3-(4-benzyl-5-morpholinooxazol-2-yl)-3-methyl-
morpholin-2-one (8b). After the mixture was stirred for 1 h, the
product was isolated by flash column chromatography using petroleum
ether/ethyl acetate (5:1 to 3:1) as eluent: yield 84 mg, 93%; Colorless
petroleum ether/ethyl acetate (3/1 to 2/3) as eluent: yield 70 mg,
87%; yellow gel; [α]D20 = −23° (c 4.1, CH2Cl2); IR (neat) 3314, 2960,
2854, 1744, 1233, 1116, 755, 700 cm−1; 1H NMR (400 MHz, CDCl3)
δ (ppm) 7.16−7.31 (m, 5H), 4.34 (dd, J = 3.4, 10.4 Hz, 1H), 4.18 (t, J
= 10.4 Hz, 1H), 3.81 (s, 2H), 3.65−3.74 (m, 4H), 2.94−3.01 (m, 4H),
2.86−2.94 (m, 1H), 2.34 (br s, 1H), 1.76 (s, 3H), 1.57−1.67 (m, 1H),
0.94 (d, J = 6.7 Hz, 3H), 0.90 (d, J = 6.8 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ (ppm) 168.1, 158.1, 152.3, 139.4, 128.5, 128.4, 126.2,
124.9, 73.4, 66.8, 60.8, 54.2, 50.9, 31.8, 29.8, 26.4, 18.7, 18.6; HRMS
(ESI-TOF) m/z calcd for C22H29N3O4Na [M + Na]+ 422.2056, found
422.2062.
20
gel; [α]D = = −12°° (c 1.5, CH2Cl2); IR (neat) 3314, 2960, 2915,
1
2854, 1744, 1453, 1233, 1116, 755, 700 cm−1; H NMR (400 MHz,
CDCl3) δ (ppm) 7.05−7.34 (m, 10H), 4.30 (dd, J = 3.4, 10.5 Hz, 1H),
4.18 (t, J = 10.4 Hz, 1H), 3.80 (d, J = 15.4 Hz, 1H), 3.75 (d, J = 15.7
Hz, 1H), 3.64−3.70 (m, 4H), 3.52−3.61 (m, 1H), 2.81−2.89 (m, 4H),
2.73 (dd, J = 5.2, 13.7 Hz, 1H), 2.55 (dd, J = 8.7, 13.7 Hz, 1H), 2.27
(br s, 1H), 1.73 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm)
167.8, 157.5, 152.3, 139.5, 136.3, 128.9, 128.8, 128.5, 128.4, 127.0,
126.3, 124.8, 74.4, 66.8, 60.9, 50.8, 49.5, 37.6, 31.8, 26.1; HRMS (ESI-
TOF) m/z calcd for C26H30N3O4 [M + H]+ 448.2236, found
448.2229.
(3S,5S)-3-(4-Isopropyl-5-morpholinooxazol-2-yl)-3-methyl-5-phe-
nylmorpholin-2-one (8h). After the mixture was stirred for 1.25 h, the
product was isolated by flash column chromatography using petroleum
ether/acetone (12/1 to 8/1) as eluent: yield 65 mg, 84%; yellow gel;
20
[α]D = −45° (c 0.1, CH2Cl2); IR (neat) 3353, 2935, 2854, 1741,
(3S,5S)-3-Methyl-3-(5-morpholinooxazol-2-yl)-5-phenylmorpho-
lin-2-one (8c). After the mixture was stirred for 1 h, the product was
1
1631, 1448, 1198, 754, 701 cm−1; H NMR (400 MHz, CDCl3) δ
isolated by flash column chromatography using petroleum ether/ethyl
(ppm) 7.31−7.45 (m, 5H), 4.54 (dd, J = 6.0, 8.4 Hz, 1H), 4.38 (s,
1H), 4.35−4.39 (m, 2H), 3.74−3.82 (m, 4H), 2.98−3.06 (m, 4H),
2.82−2.93 (m, 1H), 1.85 (s, 3H), 1.22 (d, J = 5.4 Hz, 3H), 1.20 (d, J =
5.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 167.7, 157.7,
150.5, 137.7, 132.5, 128.9, 128.7, 127.4, 75.2, 66.9, 61.1, 53.7, 51.4,
26.5, 25.5, 21.9; HRMS (ESI-TOF) m/z calcd for C21H28N3O4 [M +
H]+ 386.2080, found 386.2072.
20
acetate (5/1 to 3/2) as eluent: yield 58 mg, 85%; yellow gel; [α]D
=
−36° (c 0.14, CH2Cl2); IR (neat) 3422, 2923, 1743, 1609, 1454, 1222,
1
1153, 1115, 893 cm−1; H NMR (400 MHz, CDCl3) δ (ppm) 7.34−
7.43 (m, 5H), 6.03 (s, 1H), 4.46−4.52 (m, 1H), 4.31−4.38 (m, 2H),
3.79−3.83 (m, 4H), 3.07−3.12 (m, 4H), 1.86 (s, 3H); 13C NMR (100
MHz, CDCl3) δ (ppm) 167.6, 157.8, 155.8, 137.6, 129.0, 128.9, 127.4,
103.0, 74.5, 66.0, 61.0, 53.7, 48.3, 26.7; HRMS (ESI-TOF) m/z calcd
for C18H22N3O4 [M + H]+ 344.1610, found 344.1614.
(3S,5S)-5-Benzyl-3-(4-isopropyl-5-morpholinooxazol-2-yl)-1,3-di-
methylpiperazin-2-one (8i). After the mixture was stirred for 1 h, the
product was isolated by flash column chromatography using petroleum
ether/ethyl acetate (2/3 to 1/3) as eluent: yield 55 mg, 64%; colorless
gel; [α]D20 = −1° (c 0.7, CH2Cl2); IR (neat) 3299, 2964, 2856, 1656,
1499, 1452, 1200, 1115, 754, 702 cm−1; 1H NMR (400 MHz, CDCl3)
δ (ppm) 7.12−7.32 (m, 5H), 3.55−3.64 (m, 1H), 3.28 (t, J = 11.1 Hz,
1H), 3.15 (dd, J = 3.7, 11.3 Hz, 1H), 3.00 (s, 3H), 2.86−2.91 (m, 4H),
2.77−2.86 (m, 2H), 2.63 (dd, J = 8.8, 13.7 Hz, 1H), 2.20 (br s, 1H),
1.66 (s, 3H), 1.14−1.22 (m, 6H); 13C NMR (100 MHz, CDCl3) δ
(ppm) 167.6, 159.4, 149.8, 137.1, 132.2, 128.9, 128.7, 126.8, 66.9, 60.7,
55.5, 51.4, 49.3, 39.6, 35.2, 26.0, 25.5, 22.0, 21.9; HRMS (ESI-TOF)
m/z calcd for C23H32N4O3Na [M + Na]+ 435.2372, found 435.2368.
(3S,5S)-3-(4-Isopropyl-5-morpholinooxazol-2-yl)-1,3-dimethyl-5-
phenylpiperazin-2-one (8j). After the mixture was stirred for 1.25 h,
the product was isolated by flash column chromatography using
petroleum ether/ethyl acetate (2/3 to 1/3) as eluent: yield 61 mg,
(3S,5S)-5-Benzyl-3-(4-isopropyl-5-morpholinooxazol-2-yl)-3-
methylmorpholin-2-one (8d). After the mixture was stirred for 1.25 h,
the product was isolated by flash column chromatography using
petroleum ether/ethyl acetate (4/1 to 2/1) as eluent: yield 75 mg,
20
93%; yellow gel; [α]D = −22° (c 2, CH2Cl2); IR (neat) 3314, 2964,
1
2855, 1747, 1656, 1452, 1200, 1115, 918, 701 cm−1; H NMR (400
MHz, CDCl3) δ (ppm) 7.15−7.36 (m, 5H), 4.30−4.36 (m, 1H), 4.23
(t, J = 10.7 Hz, 1H), 3.71−3.77 (m, 4H), 3.62−3.71 (m, 1H), 2.88−
2.94 (m, 4H), 2.75−2.87 (m, 2H), 2.51−2.61 (m, 1H), 2.34 (br s,
1H), 1.78 (s, 3H), 1.17 (t, J = 7.4 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 168.0, 157.6, 150.4, 136.3, 132.3, 128.9, 128.8, 127.0,
74.4, 66.9, 60.8, 51.3, 49.3, 37.6, 26.3, 25.3, 21.9, 21.8; HRMS (ESI-
TOF) m/z calcd for C22H29N3O4Na [M + Na]+ 422.2056, found
422.2057.
(3S,5S)-5-Benzyl-3-methyl-3-(4-methyl-5-morpholinooxazol-2-
yl)morpholin-2-one (8e). After the mixture was stirred for 1 h, the
product was isolated by flash column chromatography using petroleum
ether/ethyl acetate (2/1 to 1/2) as eluent: yield 68 mg, 92%; colorless
20
75%; colorless gel; [α]D = +26° (c 1.11, CH2Cl2); IR (neat) 3291,
2962, 2856, 1727, 1660, 1545, 1497, 1452, 1400, 1267, 1200, 1115,
920, 841, 758, 701 cm−1; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.30−
7.44 (m, 5H), 4.47 (dd, J = 3.8, 11.1 Hz, 1H), 3.76−3.78 (m, 4H),
3.52 (t, J = 11.3 Hz, 1H), 3.27 (dd, J = 3.8, 11.6 Hz, 1H), 3.03 (s, 3H),
3.00−3.02 (m, 4H), 2.82−2.92 (m, 1H), 2.40 (s, 1H), 1.77 (s, 3H),
1.21 (d, J = 4.4 Hz, 3H), 1.20 (d, J = 4.3 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ (ppm) 167.6, 159.7, 150.0, 140.2, 132.5, 128.9, 128.4,
127.3, 67.1, 61.2, 57.0, 53.7, 51.6, 35.3, 26.4, 25.7, 22.1, 22.1; HRMS
(ESI-TOF) m/z calcd for C22H31N4O3 [M + H]+ 399.2396, found
399.2399.
(3S,5S)-5-Benzyl-1-butyl-3-(4-isopropyl-5-morpholinooxazol-2-
yl)-3-methylpiperazin-2-one (8k). After the mixture was stirred for 1
h, the product was isolated by flash column chromatography using
petroleum ether/ethyl acetate (2/1 to 1/1) as eluent: yield 75 mg,
81%; yellow gel; [α]D20 = +2° (c 3.3, CH2Cl2); IR (neat) 3300, 2962,
2859, 1656, 1452, 1115, 735, 701 cm−1; 1H NMR (400 MHz, CDCl3)
δ (ppm) 7.12−7.30 (m, 5H), 3.73−3.75 (m, 4H), 7.44−7.55 (m, 2H),
3.32−3.39 (m, 1H), 3.26 (dd, J = 11.1, 21.9 Hz, 1H), 3.16 (dd, J = 3.8,
11.2 Hz, 1H), 2.87−2.89 (m, 4H), 2.78−2.85 (m, 2H), 2.61 (dd, J =
9.0, 13.8 Hz, 1H), 2.16 (br s, 1H), 1.66 (s, 3H), 1.54−1.60 (m, 2H),
1.35−1.40 (m, 2H), 1.17 (d, J = 2.1 Hz, 3H), 1.15 (d, J = 2.1 Hz, 3H),
0.94 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 167.3,
156.0, 150.0, 137.1, 132.2, 128.8, 128.7, 126.8, 67.0, 60.7, 53.2, 51.5,
49.4, 47.1, 39.6, 29.0, 25.7, 25.4, 22.0, 21.9, 20.0, 13.9; HRMS (ESI-
TOF) m/z calcd for C26H39N4O3 [M + H]+ 455.3022, found
455.3024.
20
gel; [α]D −31° (c 0.7, CH2Cl2); IR (neat) 3312, 2922, 2854, 1744,
1
1213, 1116, 753, 701 cm−1; H NMR (400 MHz, CDCl3) δ (ppm)
7.22−7.33 (m, 5H), 4.33 (dd, J = 3.5, 10.5 Hz, 1H), 4.19 (t, J = 10.4
Hz, 1H), 3.72−3.78 (m, 4H), 3.46−3.55 (m, 1H), 2.88−2.93 (m, 4H),
2.76 (dd, J = 5.1, 13.7 Hz, 1H), 2.59 (dd, J = 8.7, 13.7 Hz, 1H), 2.06
(s, 3H), 1.73 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 167.8,
157.1, 151.7, 136.3, 128.9, 128.8, 127.0, 121.3, 74.3, 66.8, 60.8, 50.7,
49.6, 37.7, 25.9, 11.2; HRMS (ESI-TOF) m/z calcd for
C20H25N3O4Na [M + Na]+ 394.1743, found 394.1749.
(3S,5S)-3-(4-Benzyl-5-morpholinooxazol-2-yl)-3-methyl-5-phe-
nylmorpholin-2-one (8f). After the mixture was stirred for 1.25 h, the
product was isolated by flash column chromatography using petroleum
ether/ethyl acetate (2/1 to 1/2) as eluent: yield 79 mg, 91%; colorless
gel; [α]D20 = −31° (c 1.2, CH2Cl2); IR (neat) 3292, 3060, 3030, 2963,
2915, 2856, 1744, 1633, 1546, 1495, 1454, 1400, 1330, 1266, 1121,
1153, 1116, 1028, 921, 734, 701 cm−1; 1H NMR (400 MHz, CDCl3) δ
(ppm) 7.33−7.38 (m, 5H), 7.20−7.31 (m, 5H), 4.46 (t, J = 7.2 Hz,
1H), 4.35−4.37 (m, 2H), 3.82 (s, 2H), 3.70−3.73 (m, 4H), 2.98−3.10
(m, 4H), 2.59 (br s, 1H), 1.85 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ (ppm) 167.6, 157.8, 152.4, 139.4, 137.5, 128.9, 128.8, 128.5, 128.4,
127.4, 126.2, 124.8, 75.2, 66.8, 61.1, 53.7, 50.8, 31.8, 26.5; HRMS
(ESI-TOF): m/z calculated for C25H28N3O4 [M + H]+ 434.2080,
found 434.2075.
(3S,5S)-3-(4-Benzyl-5-morpholinooxazol-2-yl)-5-isopropyl-3-
methylmorpholin-2-one (8g). After the mixture was stirred for 1.25 h,
the product was isolated by flash column chromatography using
(3S,5S)-3-Ethyl-5-isopropyl-3-(4-isopropyl-5-morpholinooxazol-
2-yl)morpholin-2-one (8l). After the mixture was stirred for 1.25 h,
G
dx.doi.org/10.1021/jo4000702 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
the product was isolated by flash column chromatography using
(ESI-TOF) m/z calcd for C26H30N3O3 [M + H]+ 432.2287, found
432.2279.
petroleum ether/acetone (20/1 to 10/1) as eluent: yield 66 mg, 88%;
20
colorless gel; [α]D = −9° (c 0.5, CH2Cl2); IR (neat) 3334, 2964,
(3S,5S)-5-Benzyl-3-(4-benzyl-5-(piperidin-1-yl)oxazol-2-yl)-3-
methylmorpholin-2-one (8p). After the mixture was stirred for 4 h,
the product was isolated by flash column chromatography using
petroleum ether/ethyl acetate (6/1 to 3/2) as eluent: yield 66 mg,
1
1747, 1656, 1459, 1201, 1117 cm−1; H NMR (400 MHz, CDCl3) δ
(ppm) 4.30 (dd, J = 3.0, 10.2 Hz, 1H), 4.17 (t, J = 10.4 Hz, 1H),
3.73−3.81 (m, 4H), 2.98−3.05 (m, 5H), 2.80−2.92 (m, 1H), 2.40 (br
s, 1H), 2.16−2.30 (m, 1H), 1.97 (dq, J = 7.6, 21.4 Hz, 1H), 1.69 (dq, J
= 7.0, 20.6 Hz, 1H), 1.19 (d, J = 1.2 Hz, 3H), 1.18 (d, J = 1.2 Hz, 3H),
1.03 (d, J = 6.7 Hz, 3H), 0.93−1.00 (m, 6H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 167.8, 157.6, 150.7, 132.1, 73.3, 66.9, 64.9, 54.3, 51.4,
33.2, 29.7, 25.3, 22.0, 21.9, 18.7, 18.6, 8.2; HRMS (ESI-TOF) m/z
calcd for C19H31N3O4Na [M + Na]+ 388.2212, found 388.2219.
(3S,5S)-5-Benzyl-3-ethyl-3-(4-isopropyl-5-morpholinooxazol-2-
yl)morpholin-2-one (8m). After the mixture was stirred for 1.25 h, the
product was isolated by flash column chromatography using petroleum
ether/ethyl ether (2/1 to 1/1) as eluent: yield 85 mg, 98%; colorless
gel; [α]D20 = −21° (c 1.6, CH2Cl2); IR (neat) 3316, 2965, 2854, 1745,
1654, 1456, 1199, 1116, 977, 702 cm−1; 1H NMR (400 MHz, CDCl3)
δ (ppm) 7.13−7.54 (m, 5H), 4.28 (dd, J = 3.2, 10.3 Hz, 1H), 4.16 (t, J
= 10.3 Hz, 1H), 3.67−3.83 (m, 5H), 2.89−2.95 (m, 4H), 2.76−2.87
(m, 2H), 2.61 (dd, J = 8.9, 13.8 Hz, 1H), 2.30 (br s, 1H), 2.24 (dq, J =
7.4, 21.3 Hz, 1H), 1.92 (dq, J = 7.4, 21.3 Hz, 1H), 1.17 (d, J = 6.9 Hz,
3H), 1.13 (d, J = 6.9 Hz, 3H), 0.93 (t, J = 7.3 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ (ppm) 167.6, 157.3, 150.6, 136.5, 132.1, 129.0, 128.8,
126.9, 74.3, 66.9, 64.9, 51.3, 49.4, 37.7, 32.8, 25.3, 21.9, 21.8, 8.2;
HRMS (ESI-TOF) m/z calcd for C23H32N3O4 [M + H]+ 414.2393,
found 414.2387.
(3S,5S)-5-Benzyl-3-(4-benzyl-5-(piperidin-1-yl)oxazol-2-yl)-3-eth-
ylmorpholin-2-one (8n). After the mixture was stirred for 1 h, the
product was isolated by flash column chromatography using petroleum
ether/ethyl ether (2/1 to 1/1) as eluent: yield 66 mg, 72%; colorless
gel; [α]D20 = −9° (c 0.95, CH2Cl2); IR (neat) 3317, 2936, 2855, 1745,
1637, 1495, 1451, 1156, 730, 700 cm−1; 1H NMR (400 MHz, CDCl3)
δ (ppm) 7.25−7.32 (m, 3H), 7.17−7.24 (m, 5H), 7.09−7.15 (m, 2H),
4.22 (dd, J = 3.3, 10.3 Hz, 1H), 4.13 (t, J = 10.3 Hz, 1H), 3.78 (d, J =
15.6 Hz, 1H), 3.73 (d, J = 15.5 Hz, 1H), 3.59−3.66 (m, 1H), 2.84−
2.86 (m, 4H), 2.73 (dd, J = 5.7, 13.7 Hz, 1H), 2.62 (dd, J = 8.2, 13.7
Hz, 1H), 2.18−2.27 (m, 2H), 1.90−1.99 (m, 1H), 1.64 (s, 1H), 1.56−
1.60 (m, 4H), 1.50−1.52 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ (ppm) 167.6, 156.7, 154.0, 139.9, 136.4, 129.0,
128.7, 128.5, 128.3, 126.9, 126.0, 123.5, 74.2, 64.9, 51.9, 49.5, 37.9,
32.7, 31.8, 25.8, 23.8, 8.2; HRMS (ESI-TOF) m/z calcd for
C28H34N3O3 [M + H]+ 460.2600, found 460.2604.
20
73%; colorless gel; [α]D = −7° (c 0.6, CH2Cl2); IR (neat) 3313,
1
2937, 2852, 1746, 1451, 1232, 1156, 1119, 728, 699 cm−1; H NMR
(400 MHz, CDCl3) δ (ppm) 7.05−7.35 (m, 10H), 4.28 (dd, J = 3.5,
10.4 Hz, 1H), 4.17 (t, J = 10.4 Hz, 1H), 3.79 (d, J = 15.6 Hz, 1H), 3.73
(d, J = 15.6 Hz, 1H), 3.52−3.61 (m, 1H), 2.80−2.88 (m, 4H), 2.73
(dd, J = 5.4, 13.7 Hz, 1H), 2.56 (dd, J = 8.6, 13.7 Hz, 1H), 2.29 (br s,
1H), 1.72 (s, 3H), 1.46−1.61 (m, 6H); 13C NMR (100 MHz, CDCl3)
δ (ppm) 168.0, 156.9, 153.8, 139.8, 136.3, 128.9, 128.8, 128.5, 128.3,
126.9, 126.1, 123.6, 74.3, 60.8, 51.9, 49.4, 37.7, 31.8, 26.1, 25.8, 23.8;
HRMS (ESI-TOF) m/z calcd for C27H31N3O3Na [M + Na]+
468.2263, found 468.2268.
(3S,5S)-3-(4-Benzyl-5-(piperidin-1-yl)oxazol-2-yl)-5-isopropyl-3-
methylmorpholin-2-one (8q). After the mixture was stirred for 1.25 h,
the product was isolated by flash column chromatography using
petroleum ether/ethyl acetate (6/1 to 3/2) as eluent: yield 43 mg,
20
54%; colorless gel; [α]D = −10° (c 1.24, CH2Cl2); IR (neat) 3329,
1
2937, 1735, 1639, 1450, 1375, 1283, 1171, 1072, 730, 700 cm−1; H
NMR (400 MHz, CDCl3) δ (ppm) 7.14−7.30 (m, 5H), 4.32 (dd, J =
3.7, 10.5 Hz, 1H), 4.17 (t, J = 10.4 Hz, 1H), 3.81 (d, J = 15.6 Hz, 1H),
3.75 (d, J = 15.6 Hz, 1H), 2.92−2.94 (m, 4H), 2.84−2.90 (m, 1H),
2.33 (s, 1H), 1.75 (s, 3H), 1.56−1.64 (m, 5H), 1.47−1.55 (m, 2H),
0.93 (d, J = 6.7 Hz, 3H), 0.88 (d, J = 6.8 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ (ppm) 168.2, 157.5, 153.8, 139.8, 128.5, 128.3, 126.0,
123.7, 73.3, 60.8, 54.1, 52.0, 31.8, 29.8, 26.4, 25.9, 23.8, 18.6, 18.6;
HRMS (ESI-TOF) m/z calcd for C23H32N3O3 [M + H]+ 398.2444,
found 398.2449.
(3S,5S)-5-Benzyl-3-methyl-3-(4-phenyl-5-(pyrrolidin-1-yl)oxazol-
2-yl)morpholin-2-one (8r). After the mixture was stirred for 1.5 h, the
product was isolated by flash column chromatography using petroleum
ether/ethyl acetate (3/1 to 3/2) as eluent: yield 72 mg, 85%; yellow
gel; [α]D20 = −3° (c 0.7, CH2Cl2); IR (neat) 3312, 2973, 2873, 1743,
1621, 1449, 1234, 1156, 751, 701 cm−1; 1H NMR (400 MHz, CDCl3)
δ (ppm) 7.58−7.63 (m, 2H), 7.18−7.40 (m, 8H), 4.34 (dd, J = 3.5,
10.5 Hz, 1H), 4.22 (t, J = 10.4 Hz, 1H), 3.75−3.82 (m, 1H), 3.13−
3.26 (m, 4H), 2.80 (dd, J = 4.9, 13.7 Hz, 1H), 2.61 (dd, J = 8.9, 13.7
Hz, 1H), 1.88−1.97 (m, 4H), 1.75 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 167.9, 154.7, 151.0, 136.4, 132.5, 129.1, 128.8, 128.1,
127.0, 126.5, 126.1, 119.2, 74.4, 60.8, 50.2, 49.5, 37.8, 26.8, 25.4;
HRMS (ESI-TOF) m/z calcd for C25H28N3O3 [M + H]+ 418.2131,
found 418.2137.
(3S,5S)-5-Benzyl-3-methyl-3-(4-phenyl-5-(piperidin-1-yl)oxazol-2-
yl)morpholin-2-one (8o) (Major Isomer). After the mixture was
stirred for 4 h, the product was isolated by flash column
chromatography using petroleum ether/ethyl acetate (4/1 to 3/1) as
eluent: yield 73 mg, 84%; colorless gel; [α]D20 = −12° (c 0.6, CH2Cl2);
IR (neat) 3315, 2938, 2851, 1744, 1629, 1448, 1235, 1197, 702 cm−1;
1H NMR (400 MHz, CDCl3) δ (ppm) 7.80−7.86 (m, 2H), 7.20−7.42
(3S,5S)-5-Benzyl-3-(4-benzyl-5-(diethylamino)oxazol-2-yl)-3-
methylmorpholin-2-one (8s). After the mixture was stirred for 2 h,
the product was isolated by flash column chromatography using
dichloromethane/ethyl ether (100/1 to 40/1) as eluent: yield 68 mg,
78%; white gel; [α]D20 = −13° (c 0.4, CH2Cl2); IR (neat) 3297, 2975,
(m, 8H), 4.35 (dd, J = 3.5, 10.4 Hz, 1H), 4.22 (t, J = 10.4 Hz, 1H),
3.67−3.78 (m, 1H), 2.92−3.00 (m, 4H), 2.81 (dd, J = 4.6, 13.7 Hz,
1H), 2.58 (dd, J = 9.2, 13.7 Hz, 1H), 2.51 (br s, 1H), 1.75 (s, 3H),
1.54−1.72 (m, 6H); 13C NMR (100 MHz, CDCl3) δ (ppm) 167.8,
156.8, 153.1, 136.4, 132.0, 129.1, 128.9, 128.3, 127.0, 126.7, 125.8,
122.6, 74.5, 60.9, 51.2, 49.6, 37.7, 26.6, 25.8, 23.8; HRMS (ESI-TOF)
m/z calcd for C26H30N3O3 [M + H]+ 432.2287, found 432.2290.
(3R,5S)-5-Benzyl-3-methyl-3-(4-phenyl-5-(piperidin-1-yl)oxazol-
2-yl)morpholin-2-one (8o′) (Minor Isomer). After the mixture was
stirred for 4 h, the product was isolated by flash column
chromatography using dichloromethane as eluent: yield 5.6 mg,
1
2932, 2850, 1734, 1449, 1230, 729, 701 cm−1; H NMR (400 MHz,
CDCl3) δ (ppm) 7.04−7.32 (m, 10H), 4.30 (dd, J = 3.1, 10.4 Hz, 1H),
4.18 (t, J = 10.4 Hz, 1H), 3.68−3.80 (m, 2H), 3.53−3.63 (m, 1H),
2.88 (q, J = 7.2 Hz, 4H), 2.74 (dd, J = 5.2, 13.7 Hz, 1H), 2.55 (dd, J =
8.7, 13.5 Hz, 1H), 2.24 (br s, 1H), 1.73 (s, 3H), 0.90 (t, J = 7.2 Hz,
6H); 13C NMR (100 MHz, CDCl3) δ (ppm) 168.1, 158.5, 151.3,
139.7, 136.3, 129.0, 128.9, 128.8, 128.7, 128.3, 127.1, 126.1, 74.4, 60.9,
49.5, 48.0, 38.0, 31.6, 26.1, 13.4; HRMS (ESI-TOF) m/z calcd for
C26H32N3O3 [M + H]+ 434.2444, found 434.2449.
General Procedure for the Synthesis of 9 by the Reaction of
8 with Maleic Anhydride (18). To a solution of the compound 8
(0.10 mmol) in toluene (2.5 mL) were added successively maleic
anhydride (18; 0.20 mmol) and molecular sieves (4 Å, powder, 50
mg) at room temperature. The resulting mixture was heated to 110 °C
until 8 was no longer detected by TLC analysis. The mixture was
filtered, and the filtrate was concentrated under reduced pressure. The
residue was purified by flash column chromatography on silica gel
(petroleum ether/EtOAc) to give the desired product 9.
20
6.5%; colorless gel; [α]D = −73° (c 0.4, CH2Cl2); IR (neat) 3305,
1
2938, 2852, 1743, 1631, 1448, 1221, 755, 702 cm−1; H NMR (400
MHz, CDCl3) δ (ppm) 7.77−8.00 (m, 2H), 7.19−7.42 (m, 8H),
4.28−4.34 (m, 2H), 3.51−3.67 (m, 1H), 3.00−3.13 (m, 4H), 2.88 (dd,
J = 6.9, 13.6 Hz, 1H), 2.88 (dd, J = 6.7, 13.6 Hz, 1H), 2.42 (br s, 1H),
1.82 (s, 3H), 1.55−1.75 (m, 6H); 13C NMR (100 MHz, CDCl3) δ
(ppm) 169.1, 156.6, 153.2, 136.7, 132.0, 129.1, 128.9, 128.3, 127.0,
126.7, 125.9, 122.6, 73.4, 59.7, 51.2, 50.5, 38.5, 25.9, 25.0, 23.9; HRMS
H
dx.doi.org/10.1021/jo4000702 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(7S,10aS)-7-Benzyl-10a-methyl-3-morpholino-7,8-dihydro-5H-
pyrido[2′,3′:3,4]pyrrolo[2,1-c][1,4]oxazine-5,10(10aH)-dione (9a).
After the mixture was heated for 2.5 h, the product was isolated by
flash column chromatography using petroleum ether/ethyl acetate (5/
3 to 1/3) as eluent: yield 21 mg, 47%; white gel; [α]D20 = +130° (c 0.3,
CH2Cl2); IR (neat) 2923, 2856, 1760, 1699, 1499, 1373, 1114, 1037,
909, 751 cm−1; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.55 (d, J = 2.8
Hz, 1H), 7.50 (d, J = 2.8 Hz, 1H), 7.22−7.36 (m, 5H), 4.61−4.71 (m,
1H), 4.43−4.55 (m, 2H), 3.86−3.92 (m, 4H), 3.18−3.35 (m, 6H),
1.57 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 168.3, 167.4,
153.6, 148.0, 143.0, 135.6, 129.7, 128.8, 127.4, 123.9, 115.9, 67.8, 66.5,
63.9, 50.8, 48.4, 37.5, 23.7; HRMS (ESI-TOF) m/z calcd for
C22H23N3O4Na [M + Na]+ 416.1586, found 416.1580.
(7S,10aS)-2,7-Dibenzyl-10a-methyl-3-morpholino-7,8-dihydro-
5H-pyrido[2′,3′:3,4]pyrrolo[2,1-c][1,4]oxazine-5,10(10aH)-dione
(9b). After the mixture was heated for 8 h, the product was isolated by
flash column chromatography using petroleum ether/ethyl acetate (3/
1 to 1/1) as eluent: yield 40 mg, 80%; colorless gel; [α]D20 = +76° (c
0.4, CH2Cl2); IR (neat) 2962, 2924, 2855, 1765, 1702, 1446, 1355,
1112, 902, 754, 703 cm−1; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.80
(s, 1H), 7.13−7.37 (m, 10H), 4.60−4.69 (m, 1H), 4.33−4.57 (m, 4H),
3.76−3.91 (m, 4H), 3.30 (dd, J = 3.6, 13.8 Hz, 1H), 3.22 (dd, J = 7.9,
13.7 Hz, 1H), 2.83−2.90 (m, 2H), 2.73−2.80 (m, 2H), 1.59 (s, 3H);
13C NMR (100 MHz, CDCl3) δ (ppm) 168.2, 166.9, 163.2, 157.9,
(7S,10aS)-2-Isopropyl-10a-methyl-3-morpholino-7-phenyl-7,8-di-
hydro-5H-pyrido[2′,3′:3,4]pyrrolo[2,1-c][1,4]oxazine-5,10(10aH)-
dione (9f). After the mixture was heated for 12 h, the product was
isolated by flash column chromatography using petroleum ether/ethyl
acetate (8/1 to 3/2) as eluent: yield 36 mg, 84% (recovered 8h: 4.2
20
mg, 11%); colorless gel; [α]D = +68° (c 0.4, CH2Cl2); IR (neat)
2963, 2927, 2856, 1767, 1707, 1438, 1344, 1114, 908, 756, 701 cm−1;
1H NMR (400 MHz, CDCl3) δ (ppm) 7.70 (s, 1H), 7.32−7.46 (m,
5H), 5.48 (dd, J = 6.6, 10.7 Hz, 1H), 4.74 (dd, J = 6.6, 12.5 Hz, 1H),
4.61−4.69 (m, 1H), 3.84−3.93 (m, 4H), 3.62−3.72 (m, 1H), 2.86−
2.98 (m, 4H), 2.00 (s, 3H), 1.38 (d, J = 7.6 Hz, 3H), 1.32 (d, J = 7.6
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 169.8, 168.4, 166.7,
157.8, 147.5, 136.2, 129.2, 128.5, 126.3, 122.1, 121.3, 69.0, 67.1, 64.6,
53.8, 53.3, 30.1, 24.4, 22.5; HRMS (ESI-TOF) m/z calcd for
C24H27N3O4Na [M + Na]+ 444.1899, found 444.1898.
(7S,10aS)-10a-Ethyl-2,7-diisopropyl-3-morpholino-7,8-dihydro-
5H-pyrido[2′,3′:3,4]pyrrolo[2,1-c][1,4]oxazine-5,10(10aH)-dione
(9g). After the mixture was heated for 18 h, the product was isolated
by flash column chromatography using petroleum ether/ethyl acetate
(4/1 to 3/2) as eluent: yield 30 mg, 65% (recovered 8l: 8.1 mg, 22%);
white gel; [α]D20 = +17° (c 0.3, CH2Cl2); IR (neat) 2964, 2857, 1762,
1
1702, 1437, 1358, 1116, 755 cm−1; H NMR (400 MHz, CDCl3) δ
(ppm) 7.67 (s, 1H), 4.63 (dd, J = 7.0, 12.2 Hz, 1H), 4.44 (dd, J = 10.2,
12.0 Hz, 1H), 4.17−4.27 (m, 1H), 3.83−3.94 (m, 4H), 3.60−3.70 (m,
1H), 2.84−3.00 (m, 4H), 2.78 (dq, J = 7.4, 21.6 Hz, 1H), 2.14 (dq, J =
7.1, 21.2 Hz, 1H), 1.98−2.08 (m, 1H), 1.37 (d, J = 6.7 Hz, 3H), 1.28
(d, J = 6.7 Hz, 3H), 1.16 (d, J = 6.8 Hz, 3H), 1.04 (d, J = 6.7 Hz, 3H),
0.65 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 169.6,
169.5, 167.7, 155.9, 147.1, 122.5, 121.7, 69.0, 67.7, 67.2, 54.4, 53.3,
32.3, 30.0, 27.6, 22.7, 22.4, 20.4, 18.5, 6.7; HRMS (ESI-TOF) m/z
calcd for C22H32N3O4 [M + H]+ 402.2393, found 402.2397.
148.7, 138.9, 135.6, 129.8, 128.9, 128.8, 128.3, 127.4, 126.3, 123.5,
122.5, 67.7, 67.1, 64.2, 52.9, 50.8, 40.5, 37.5, 23.4; HRMS (ESI-TOF)
m/z calcd for C29H30N3O4 [M + H]+ 484.2236, found 484.2230.
(7S,10aS)-7-Benzyl-2-isopropyl-10a-methyl-3-morpholino-7,8-di-
hydro-5H-pyrido[2′,3′:3,4]pyrrolo[2,1-c][1,4]oxazine-5,10(10aH)-
dione (9c). After the mixture was heated for 12 h, the product was
isolated by flash column chromatography using petroleum ether/ethyl
ether (1/1 to 1/4) as eluent: yield 35 mg, 76% (recovered 8d: 3.3 mg,
8%); white gel; [α]D20 = +82° (c 0.3, CH2Cl2); IR (neat) 2960, 2926,
(7S,10aS)-7-Benzyl-10a-ethyl-2-isopropyl-3-morpholino-7,8-dihy-
dro-5H-pyrido[2′,3′:3,4]pyrrolo[2,1-c][1,4]oxazine-5,10(10aH)-dione
(9h). After the mixture was heated for 12 h, the product was isolated
by flash column chromatography using petroleum ether/ethyl acetate
(8/1 to 5/2) as eluent: yield 39 mg, 83%; colorless gel; [α]D20 = +24°
(c 0.6, CH2Cl2); IR (neat) 2964, 2963, 2854, 1764, 1700, 1438, 1357,
1
2856, 1768, 1703, 1440, 1352, 1114, 908, 751, 705 cm−1; H NMR
(400 MHz, CDCl3) δ (ppm) 7.71 (s, 1H), 7.22−7.36 (m, 5H), 4.60−
4.69 (m, 1H), 4.41−4.55 (m, 2H), 3.85−3.93 (m, 4H), 3.61−3.70 (m,
1H), 3.30 (dd, J = 3.6, 13.8 Hz, 1H), 3.21 (dd, J = 8.2, 13.8 Hz, 1H),
2.86−2.99 (m, 4H), 1.58 (s, 3H), 1.34 (d, J = 6.7 Hz, 3H),1.29 (d, J =
6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 169.5, 168.6,
166.8, 157.7, 147.3, 135.7, 129.8, 128.8, 127.3, 121.9, 121.4, 67.7, 67.2,
64.3, 53.3, 50.8, 37.6, 30.1, 23.5, 22.5, 22.4; HRMS (ESI-TOF) m/z
calcd for C25H30N3O4 [M + H]+ 436.2236, found 436.2229.
(7S,10aS)-7-Benzyl-2,10a-dimethyl-3-morpholino-7,8-dihydro-
5H-pyrido[2′,3′:3,4]pyrrolo[2,1-c][1,4]oxazine-5,10(10aH)-dione
(9d). After the mixture was heated for 6 h, the product was isolated by
flash column chromatography using petroleum ether/ethyl acetate (3/
1 to 2/3) as eluent: yield 33 mg, 78%; colorless gel; [α]D20 = +105° (c
0.6, CH2Cl2); IR (neat) 2923, 2853, 1760, 1700, 1452, 1369, 1111
cm−1; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.66 (s, 1H), 7.21−7.36
(m, 5H), 4.61−4.70 (m, 1H), 4.43−4.56 (m, 2H), 3.86−3.91 (m, 4H),
3.30 (dd, J = 3.6, 13.8 Hz, 1H), 3.22 (dd, J = 8.1, 13.8 Hz, 1H), 2.88−
3.04 (m, 4H), 2.71 (s, 3H), 1.56 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 168.4, 167.1, 160.6, 156.9, 148.5, 135.6, 129.8, 128.8,
127.3, 122.0, 120.7, 67.7, 67.0, 64.1, 52.0, 50.7, 37.5, 23.5, 22.2; HRMS
(ESI-TOF) m/z calcd for C23H25N3O4Na [M + Na]+ 430.1743, found
430.1749.
1
1111, 1081, 927, 702 cm−1; H NMR (400 MHz, CDCl3) δ (ppm)
7.69 (s, 1H), 7.28−7.38 (m, 5H), 4.60−4.70(m, 1H), 4.42−4.50 (m,
1H), 4.36 (dd, J = 6.3, 12.2 Hz, 1H), 3.83−3.96 (m, 4H), 3.61−3.70
(m, 1H), 3.57 (dd, J = 4.0, 13.6 Hz, 1H), 2.84−3.01 (m, 5H), 2.67
(dq, J = 7.4, 21.6 Hz, 1H), 2.09 (dq, J = 7.2, 21.3 Hz, 1H), 1.36 (d, J =
6.7 Hz, 3H), 1.28 (d, J = 6.6 Hz, 3H), 0.59 (t, J = 7.3 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ (ppm) 169.6, 169.2, 166.9, 156.2, 147.1,
135.9, 129.1, 128.9, 127.3, 122.6, 121.5, 68.4, 68.2, 67.1, 53.3, 51.0,
38.5, 30.1, 28.8, 22.7, 22.4, 6.6; HRMS (ESI-TOF) m/z calcd for
C26H32N3O4 [M + H]+ 450.2393, found 450.2397.
(7S,10aS)-7-Benzyl-2-isopropyl-9,10a-dimethyl-3-morpholino-
8,9-dihydropyrido[2′,3′:3,4]pyrrolo[1,2-a]pyrazine-5,10(7H,10aH)-
dione (9i). After the mixture was heated for 12 h, the product was
isolated by flash column chromatography using petroleum ether/ethyl
acetate (2/1 to 2/3) as eluent: yield 33 mg, 70%; white crystal; mp
20
205−206 °C; [α]D = +76° (c 0.6, CH2Cl2); IR (KBr): 2965, 2853,
1
1701, 1663, 1430, 1362, 1114, 960, 904, 705 cm−1; H NMR (400
MHz, CDCl3) δ (ppm) 7.69 (s, 1H), 7.22−7.39 (m, 5H), 4.67−4.77
(m, 1H), 3.83−3.93 (m, 4H), 3.56−3.70 (m, 2H), 3.32−3.44 (m, 2H),
3.07 (dd, J = 9.5, 13.5 Hz, 1H), 2.95 (s, 3H), 2.83−2.99 (m, 4H), 1.70
(s, 3H), 1.37 (d, J = 6.7 Hz, 3H), 1.30 (d, J = 6.7 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ (ppm) 169.0, 168.3, 167.9, 158.8, 146.9, 136.7,
129.5, 128.8, 127.0, 121.8, 121.7, 67.2, 66.0, 53.3, 50.6, 50.5, 39.2, 35.0,
30.0, 23.5, 22.6, 22.5; HRMS (ESI-TOF) m/z calcd for
C26H32N4O3Na [M + Na]+ 471.2372, found 471.2368.
(7S,10aS)-2-Benzyl-7-isopropyl-10a-methyl-3-morpholino-7,8-di-
hydro-5H-pyrido[2′,3′:3,4]pyrrolo[2,1-c][1,4]oxazine-5,10(10aH)-
dione (9e). After the mixture was heated for 6 h, the product was
isolated by flash column chromatography using petroleum ether/ethyl
acetate (3/1 to 3/2) as eluent: yield 34 mg, 77%; white crystal; mp
20
198−200 °C; [α]D = +50° (c 1.2, CH2Cl2); IR (neat) 2962, 2893,
1
2851, 1755, 1707, 1444, 1346, 1346, 1226, 1109, 894, 702 cm−1; H
(7S,10aS)-7-Benzyl-9-butyl-2-isopropyl-10a-methyl-3-morpholi-
no-8,9-dihydropyrido[2′,3′:3,4]pyrrolo[1,2-a]pyrazine-5,10-
(7H,10aH)-dione (9j). After the mixture was heated for 11 h, the
product was isolated by flash column chromatography using petroleum
ether/ethyl acetate (3/1 to 3/2) as eluent: yield 46 mg, 90%; colorless
NMR (400 MHz, CDCl3) δ (ppm) 7.78 (s, 1H), 7.13−7.39 (m, 5H),
4.62 (dd, J = 6.8, 12.3 Hz, 1H), 4.35−4.57 (m, 3H), 4.21−4.30 (m,
1H), 3.76−3.88 (m, 4H), 2.81−2.90 (m, 2H), 2.71−2.80 (m, 2H),
2.20−2.32 (m, 1H), 2.00 (s, 3H), 1.12 (d, J = 6.8 Hz, 3H), 1.07 (d, J =
6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 168.3, 167.0,
163.2, 157.5, 148.8, 139.1, 128.9, 128.3, 126.3, 123.6, 122.5, 67.3, 67.1,
64.7, 54.6, 52.9, 40.5, 31.0, 23.7, 19.6, 18.3; HRMS (ESI-TOF) m/z
calcd for C25H30N3O4 [M + H]+ 436.2236, found 436.2240.
20
gel; [α]D = +8° (c 0.4, CH2Cl2); IR (neat) 2959, 2958, 2857, 1673,
1430, 1356, 1112, 1111, 902, 702 cm−1; 1H NMR (400 MHz, CDCl3)
δ (ppm) 7.69 (s, 1H), 7.24−7.38 (m, 5H), 4.58−4.68 (m, 1H), 3.83−
3.94 (m, 4H), 3.58−3.72 (m, 2H), 3.40−3.50 (m, 1H), 3.32−3.40 (m,
I
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Article
2H), 3.14−3.23 (m, 1H), 3.07 (dd, J = 9.2, 13.6 Hz, 1H), 2.84−2.98
(m, 4H), 1.64 (s, 3H), 1.40−1.55 (m, 2H), 1.37 (d, J = 6.7 Hz, 3H),
1.29 (d, J = 6.6 Hz, 3H), 1.20−1.27 (m, 2H), 0.88 (t, J = 7.3 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ (ppm) 168.9, 168.3, 167.5, 158.9,
IR (neat) 3318, 2967, 2854, 1716, 1497, 1454, 1369, 1116, 699 cm−1;
1H NMR (400 MHz, CDCl3) δ (ppm) 7.08−7.43 (m, 10H), 4.55 (d, J
= 8.1 Hz, 1H), 4.33 (dd, J = 3.0, 10.2 Hz, 1H), 4.20 (t, J = 10.5 Hz,
1H), 3.73−3.80 (m, 4H), 3.71 (d, J = 8.2 Hz, 1H), 3.52−3.62 (m,
1H), 2.97−3.08 (m, 2H), 2.66 (dd, J = 2.9, 13.2 Hz, 1H), 2.53−2.62
(m, 2H), 2.29−2.42 (m, 2H), 1.95 (s, 3H), 1.63 (br s, 1H), 0.85 (d, J
= 7.0 Hz, 3H), 0.76 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ (ppm) 186.3, 170.9, 170.8, 170.5, 137.5, 131.2, 129.0, 128.9, 128.7,
128.5, 127.0, 125.9, 108.0, 104.0, 74.8, 66.8, 60.8, 51.1, 50.0, 48.6, 44.9,
38.1, 29.5, 26.5, 20.4, 20.0; HRMS (ESI-TOF) m/z calcd for
C32H37N4O6 [M + H]+ 573.2713, found 573.2709.
General Procedure for the Synthesis of 9 by the Reaction of
8 with Unsaturated Acyl Chlorides 21. To a solution of the
compound 8 (0.12 mmol) in toluene (3 mL) were added successively
DIPEA (0.60 mmol), 21 (0.30 mmol), and molecular sieves (4 Å,
powder, 60 mg) under an argon atmosphere at room temperature. The
resulting mixture was heated to reflux for 20−36 h. The mixture was
filtered, and the filtrate was concentrated under reduced pressure. The
residue was purified by flash column chromatography on silica gel
(petroleum ether/EtOAc) to give the desired product 9.
146.9, 136.7, 129.6, 128.7, 127.0, 121.7, 67.2, 66.1, 53.3, 51.1, 48.4,
47.2, 39.3, 30.0, 29.6, 23.1, 22.6, 22.5, 20.1, 13.8; HRMS (ESI-TOF)
m/z calcd for C29H38N4O3Na [M + Na]+ 513.2842, found 513.2838.
(7S,10aS)-7-Benzyl-10a-methyl-2-phenyl-3-(piperidin-1-yl)-7,8-
dihydro-5H-pyrido[2′,3′:3,4]pyrrolo[2,1-c][1,4]oxazine-5,10(10aH)-
dione (9k). After the mixture was heated for 13 h, the product was
isolated by flash column chromatography using petroleum ether/ethyl
acetate (4/1 to 3/2) as eluent: yield 24 mg, 51% (recovered 8o: 11
20
mg, 24%); pale green gel; [α]D = +97° (c 0.3, CH2Cl2); IR (neat)
1
2925, 2852, 1761, 1696, 1423, 1349, 1105, 777, 695 cm−1; H NMR
(400 MHz, CDCl3) δ (ppm) 8.06−8.13 (m, 2H), 7.67 (s, 1H), 7.22−
7.47 (m, 8H), 4.61−4.72 (m, 1H), 4.41−4.56 (m, 2H), 3.32 (dd, J =
3.5, 13.8 Hz, 1H), 3.22 (dd, J = 8.3, 13.8 Hz, 1H), 2.74−2.91 (m, 4H),
1.60 (s, 3H), 1.44−1.59 (m, 6H); 13C NMR (100 MHz, CDCl3) δ
(ppm) 168.7, 167.1, 157.1, 155.7, 149.5, 139.7, 135.7, 132.0, 129.8,
128.9, 128.8, 128.1, 127.3, 122.3, 120.4, 67.7, 64.3, 52.5, 50.8, 37.6,
25.7, 23.7, 23.6; HRMS (ESI-TOF) m/z calcd for C29H29N3O3Na [M
+ Na]+ 490.2107, found 490.2110.
(7S,10aS)-7-Benzyl-2-isopropyl-4,10a-dimethyl-3-morpholino-
7,8-dihydro-5H-pyrido[2′,3′:3,4]pyrrolo[2,1-c][1,4]oxazine-5,10-
(10aH)-dione (9o). After the mixture was heated for 36 h, the product
was isolated by flash column chromatography using petroleum ether/
ethyl acetate (3/1 to 1/1) as eluent: yield 14 mg, 31% (recovered 8d:
(7S,10aS)-2,7-Dibenzyl-10a-methyl-3-(piperidin-1-yl)-7,8-dihy-
dro-5H-pyrido[2′,3′:3,4]pyrrolo[2,1-c][1,4]oxazine-5,10(10aH)-dione
(9l). After the mixture was heated for 5 h, the product was isolated by
flash column chromatography using petroleum ether/acetone (7/1 to
20
15 mg, 38%); yellow gel; [α]D = +73° (c 0.21, CH2Cl2); IR (neat)
20
4/1) as eluent: yield 32 mg, 65%; yellow gel; [α]D = −25° (c 0.4,
2960, 2925, 2853, 1767, 1697, 1578, 1448, 1346, 1261, 1112, 1036,
921, 737, 704 cm−1; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.22−7.36
(m, 5H), 4.56−4.60 (m, 1H), 4.40−4.54 (m, 2H), 3.84 (m, 4H), 3.33
(dd, J = 3.4, 13.8 Hz, 1H), 3.00−3.23 (m, 5H), 2.73 (s, 3H), 1.60 (s,
3H), 1.31 (d, J = 6.7, 3H), 1.28 (d, J = 6.7, 3H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 172.1, 169.6, 167.0, 159.9, 146.4, 143.6, 136.0, 129.8,
128.9, 127.4, 120.0, 68.1, 68.0, 67.8, 63.5, 50.9, 50.5, 50.4, 38.0, 31.5,
23.8, 22.8, 22.4, 13.4; HRMS (ESI-TOF) m/z calcd for C26H32N3O4
[M + H]+ 450.2393, found 450.2396.
CH2Cl2); IR (neat) 2934, 2859, 1730, 1449, 1217, 1166, 755, 701
cm−1; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.73 (s, 1H), 7.12−7.43
(m, 10H), 4.59−4.68 (m, 1H), 4.30−4.55 (m, 4H), 3.29 (dd, J = 3.6,
13.8 Hz, 1H), 3.22 (dd, J = 8.0, 13.7 Hz, 1H), 2.80−2.88 (m, 2H),
2.68−2.77 (m, 2H), 1.66−1.78 (m, 4H), 1.54−1.62 (m, 5H); 13C
NMR (100 MHz, CDCl3) δ (ppm) 168.6, 167.1, 163.3, 156.9, 150.3,
139.3, 135.6, 129.8, 129.0, 128.8, 128.2, 127.3, 126.1, 122.9, 122.2,
67.7, 64.2, 54.1, 50.8, 40.2, 37.5, 26.3, 23.9, 23.5; HRMS (ESI-TOF)
m/z calcd for C30H32N3O3 [M + H]+ 482.2444, found 482.2449.
(7S,10aS)-7-Benzyl-10a-methyl-2-phenyl-3-(pyrrolidin-1-yl)-7,8-
dihydro-5H-pyrido[2′,3′:3,4]pyrrolo[2,1-c][1,4]oxazine-5,10(10aH)-
dione (9m). After the mixture was heated for 5 h, the product was
isolated by flash column chromatography using petroleum ether/ethyl
(7S,10aS)-7-Benzyl-2-isopropyl-10a-methyl-3-morpholino-4-phe-
nyl-7,8-dihydro-5H-pyrido[2′,3′:3,4]pyrrolo[2,1-c][1,4]oxazine-5,10-
(10aH)-dione (9p). After the mixture was heated for 20 h, the product
was isolated by flash column chromatography using petroleum ether/
ethyl acetate (3/1 to 1/1) as eluent: yield 37 mg, 60%; yellow gel;
20
20
ether (3/4 to 1/4) as eluent: yield 29 mg, 63%; pale green gel; [α]D
[α]D = +88° (c 0.65, CH2Cl2); IR (neat) 2960, 2853, 1766, 1704,
1
1560, 1437, 1348, 1263, 1208, 1110, 912, 703 cm−1; H NMR (400
= +62° (c 0.3, CH2Cl2); IR (neat) 2927, 1764, 1699, 1456, 1435, 1353,
1
1253, 753, 701 cm−1; H NMR (400 MHz, CDCl3) δ (ppm) 7.71−
MHz, CDCl3) δ (ppm) 7.48−7.53 (m, 3H), 7.27−7.33 (m, 4H),
7.16−7.26 (m, 3H), 4.45−4.50 (m, 2H), 4.34−4.40 (m, 1H), 3.63−
3.71 (m, 1H), 3.43−3.63 (m, 4H), 3.31 (dd, J = 2.6, 13.9 Hz, 1H),
3.00 (dd, J = 8, 13.6 Hz, 1H), 2.51−2.94 (m, 4H), 1.70 (s, 3H), 1.38
(d, J = 6.7 Hz, 3H), 1.35 (d, J = 6.7 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 172.4, 167.9, 167.1, 159.0, 146.5, 143.4, 135.8, 134.0,
129.6, 129.4, 128.8, 128.7, 128.5, 127.9, 127.2, 119.2, 67.8, 67.4, 36.3,
52.2, 51.9, 50.8, 38.0, 31.2, 23.6, 22.7, 22.4; HRMS (ESI-TOF) m/z
calcd for C31H34N3O4 [M + H]+ 512.2549, found 512.2545.
7.75 (m, 2H), 7.46 (s, 1H), 7.23−7.44 (m, 8H), 4.62−4.71 (m, 1H),
4.41−4.55 (m, 2H), 3.32 (dd, J = 3.5, 13.8 Hz, 1H), 3.21 (dd, J = 8.2,
13.7 Hz, 1H), 2.96−3.04 (m, 2H), 2.88−2.96 (m, 2H), 1.72−1.92 (m,
4H), 1.61 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 169.1,
167.5, 152.0, 151.8, 145.6, 141.3, 135.8, 129.8, 129.0, 128.8, 128.1,
128.0, 127.3, 122.0, 114.7, 67.8, 64.2, 51.4, 50.9, 37.7, 25.6, 23.3;
HRMS (ESI-TOF) m/z calcd for C28H28N3O3 [M + H]+ 454.2131,
found 454.2137.
(7S,10aS)-2,7-Dibenzyl-3-(diethylamino)-10a-methyl-7,8-dihy-
dro-5H-pyrido[2′,3′:3,4]pyrrolo[2,1-c][1,4]oxazine-5,10(10aH)-dione
(9n). After the mixture was heated for 5 h, the product was isolated by
flash column chromatography using dichloromethane/ethyl ether (80/
1 to 40/1) as eluent: yield 35 mg, 72%; yellow gel; [α]D20 = +114° (c
0.5, CH2Cl2); IR (neat) 2972, 2929, 1766, 1703, 1447, 1352, 1205,
(7S,10aS)-Ethyl 7-Benzyl-2-isopropyl-10a-methyl-3-morpholino-
5,10-dioxo-7,8,10,10a-tetrahydro-5H-pyrido[2′,3′:3,4]pyrrolo[2,1-c]-
[1,4]oxazine-4-carboxylate (9q). After the mixture was heated for 20
h, the product was isolated by flash column chromatography using
petroleum ether/ethyl acetate (3/1 to 1/1) as eluent: yield 21 mg,
20
33%; yellow gel; [α]D = +61° (c 0.25, CH2Cl2); IR (neat) 2926,
1
746, 702 cm−1; H NMR (400 MHz, CDCl3) δ (ppm) 7.74 (s, 1H),
2855, 1763, 1636, 1600, 1567, 1469, 1395, 1321, 1114, 1078, 1024,
903, 753, 707 cm−1; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.31−7.34
(m, 2H), 7.22−7.28 (m, 3H), 4.35−4.65 (m, 5H), 3.75−3.82 (m, 4H),
3.55−3.66 (m, 1H), 3.31−3.35 (dd, J = 4.0, 12.0 Hz, 1H), 3.12−3.15
(m, 1H), 3.08−3.09 (m, 4H), 1.61 (s, 3H), 1.46−1.49 (t, J = 7.2 Hz,
3H), 1.35 (d, J = 6.8 Hz, 3H), 1.29 (d, J = 6.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ (ppm) 173.4, 166.5, 166.3, 165.6, 159.2, 140.9,
136.7, 135.5, 129.7, 128.8, 127.3, 117.9, 67.7, 67.7, 64.2, 62.6, 51.4,
51.3, 50.8, 37.6, 31.3, 23.3, 22.4, 22.3, 14.2; HRMS (ESI-TOF) m/z
calcd for C28H33N3O6Na [M + Na]+ 530.2267, found 530.2270.
General Procedure for the One-Pot Synthesis of 9 from α-
Isocyanoacetamides 1, Cyclic Imines 7, and Maleic Anhydride
(18). To a solution of the imine 7 (0.20 mmol) in TFE (0.5 mL) were
added successively α-isocyanoacetamides 1 (0.20 mmol) and phenyl-
7.11−7.37 (m, 10H), 4.60−4.69 (m, 1H), 4.29−4.56 (m, 4H), 3.31
(dd, J = 3.5, 13.8 Hz, 1H), 3.21 (dd, J = 8.2, 13.8 Hz, 1H), 2.91−3.04
(m, 4H), 1.61 (s, 3H), 0.91 (t, J = 7.04 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 168.6, 167.1, 164.6, 157.1, 147.4, 139.3, 135.7, 129.8,
129.1, 128.8, 128.1, 127.3, 126.0, 125.0, 121.9, 67.8, 64.2, 50.8, 47.5,
40.4, 37.7, 23.6, 12.0; HRMS (ESI-TOF) m/z calcd for
C29H31N3O3Na [M + Na]+ 492.2263, found 492.2257.
(4S)-4-((3S,5S)-5-Benzyl-3-methyl-2-oxomorpholin-3-yl)-6-iso-
propyl-7-morpholino-2-phenyl-3a,4,7,7a-tetrahydro-1H-4,7-
epoxypyrrolo[3,4-c]pyridine-1,3(2H)-dione (27). After the mixture
was heated for 11 h, the product was isolated by flash column
chromatography using petroleum ether/ethyl acetate (4/1 to 3/2) as
eluent: yield 52 mg, 90%; colorless gel; [α]D20 = −48° (c 0.3, CH2Cl2);
J
dx.doi.org/10.1021/jo4000702 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
phosphinic acid (10; 0.020 mmol for 1b,d, 0.050 mmol for 1f,h) at
room temperature. After the mixture was stirred at room temperature
for 20 min, additional 1 (0.080 mmol) was added. The resulting
mixture was stirred until 7 was converted thoroughly (monitored by
TLC), and then 1 equiv of Et3N with respect to 10 was added. After
this mixture was stirred for 5 min, toluene (5 mL), maleic anhydride
18 (0.60 mmol), and 4 Å molecular sieves (powder, 100 mg) were
added. The mixture was refluxed until 8 was no longer detected by
TLC analysis and filtered. The filtrate was concentrated under vacuum,
and the residue was purified by flash column chromatography on silica
gel (petroleum ether/EtOAc) to give the desired product 9.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Text giving a description of the general experimental
procedures, figures giving NMR spectra of the compounds,
and a table, figure, and CIF file giving crystallographic data for
9e. This material is available free of charge via the Internet at
http://pubs.acs.org.
(9) Yue, T.; Wang, M. X.; Wang, D. X.; Masson, G.; Zhu, J. Angew.
Chem., Int. Ed. 2009, 48, 6717−6721.
(10) Bughin, C.; Masson, G.; Zhu, J. J. Org. Chem. 2007, 72, 1826−
1829.
AUTHOR INFORMATION
Corresponding Author
*X.C.: fax, (+)(+86) 28-8541-2095; e-mail, chenxc@scu.edu.cn.
■
(11) (a) Huang, Y.; Khoury, K.; Chanas, T.; Domling, A. Org. Lett.
̈
2012, 14, 5916−5919. (b) Domling, A.; Huang, Y. Synthesis 2010,
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2859−2883. (c) Liu, H.; Domling, A. J. Org. Chem. 2009, 74, 6895−
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Author Contributions
†These individuals contributed equally to this work.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Sichuan University Analytical and Testing Center as
well as the group of Prof. Xiaoming Feng for NMR
determinations. This work was supported by grants from the
National Natural Science Foundation of China (20802045,
21172153, and J1103315/J0104) and the National Basic
Research Program of China (973 Program, No.
2012CB833200).
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