An asymmetric Ugi three-component reaction induced by chiral cyclic imines: Synthesis of morpholin- or piperazine-keto-carboxamide derivatives

Article abstract of DOI:10.1021/jo2021967

A series of chiral 5,6-dihydro-1,4-oxazin-2-one substrates, as preformed cyclic aldimines and ketoimines, were employed to develop a new asymmetric Ugi three-component reaction for the first time. The Ugi reaction of the imines, isocyanides, and carboxylic acids opens an efficient access to novel morpholin-2-one-3-carboxamide compounds. The chiral imines showed promising stereoinduction for the new chiral center of the Ugi products, and predominant trans-isomers were obtained in the most cases. Addition of some Lewis acids or proton acids could improve the diastereoselectivity further but usually led to a drop in total yield. The Ugi-3CR could be extended to the stereoselective synthesis of ketopiperazine-2-carboxamide derivatives.

Full text of DOI:10.1021/jo2021967

Article
pubs.acs.org/joc
An Asymmetric Ugi Three-Component Reaction Induced by Chiral
Cyclic Imines: Synthesis of Morpholin− or Piperazine−Keto-
carboxamide Derivatives
Deguang Zhu,†,§ Liang Xia,†,§ Li Pan,† Sheng Li,† Ruijiao Chen,† Yongren Mou,†
and Xiaochuan Chen*,†,‡
†Key Laboratory of Green Chemistry & Technology of Ministry of Education, College of Chemistry, Sichuan University, Chengdu
610064, PR China
‡State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, PR China
S
* Supporting Information
ABSTRACT: A series of chiral 5,6-dihydro-1,4-oxazin-2-one substrates,
as preformed cyclic aldimines and ketoimines, were employed to develop
a new asymmetric Ugi three-component reaction for the first time. The
Ugi reaction of the imines, isocyanides, and carboxylic acids opens an
efficient access to novel morpholin-2-one-3-carboxamide compounds.
The chiral imines showed promising stereoinduction for the new chiral
center of the Ugi products, and predominant trans-isomers were obtained
in the most cases. Addition of some Lewis acids or proton acids could improve the diastereoselectivity further but usually led to a
drop in total yield. The Ugi-3CR could be extended to the stereoselective synthesis of ketopiperazine-2-carboxamide derivatives.
amino acids,9 ferrocenylamines,10 aminosugars,11 1-phenyl-
INTRODUCTION
Multicomponent reactions (MCRs) refer to the reactions in
■
ethylamines,12 and acyclic and cyclic aldimines13 were used as
substrates. It is necessary to develop more asymmetric Ugi
which at least three materials assemble to form a product in one
reactions to meet various requirements.
pot. MCRs showed high synthetic efficiency in forming
complex structures and introducing molecular diversity by a
Chiral 5,6-dihydro-1,4-oxazin-2-one derivatives have demon-
simple operation.1 The Ugi reaction is one of the most studied
strated good diastereocontrol in Mannich-type reactions with
some nucleophiles.14 However, the potentiality of the cyclic
multicomponent reactions owing to its inherent potential in
imines for exploiting new asymmetric Ugi reactions, by which
molecule creation and drug discovery and is widely applied in
combinatorial and medical chemistry.2 A classical Ugi four-
some interesting morpholinone derivatives could be synthe-
sized quickly, has still not been studied. Morpholinone
component reaction (U-4CR) combines an amine, carbonyl
compounds have attracted much attention because of their
compound, isocyanide, and carboxylic acid to α-acylamino
amides by a domino process involving formation of imine, α-
addition of isocyanide, and Mumm-type rearrangement. A
preformed imine could be employed instead of amine and
biological and synthetic applications.15 In 2001, Kim and co-
workers described the synthesis of morpholin-2-one-5-carbox-
amide (Figure 1, I),16 which showed potent and selective T-
carbonyl components in Ugi three-component (U-3CR).
Although in these reactions a new chiral center is created,
most of them were reported as racemic cases or in low
stereoselectivity.
With increasing application of the Ugi reaction in
pharmaceutical and agricultural chemistry, development of
Figure 1. Structures of morpholin-2-one-5-carboxamide (I) and
asymmetric Ugi reactions3 is in strong demand because of the
morpholin-2-one-3-carboxamide (II).
possible different activities of various stereoisomers.4 Until
type Ca2+ channel blocking activities in the subsequent study.17
now, only one enantioselective version is achieved in a special
Ugi-type reaction of aldehydes, anilines, and α-isocyanoaceta-
However, construction of the morpholin-2-one-3-carboxamide
mides.5 For common U-4R or U-3CR wherein a carboxylic acid
skeleton (Figure 1, II) is rarely reported. To the best of our
component participates, diastereoselective approaches using
knowledge, only the Wollf group has previously described a
chiral materials are possible solutions to stereocontrol. Chiral
compound with structure II produced in 6% yield by a
amines have been found to be more promising than chiral
isocyanides,6 carboxylic acids,7 or carbonyl compounds8 as
stereochemical inductors in the reaction, but only limited
examples with good selectivity were achieved when several
Received: October 25, 2011
Published: January 6, 2012
© 2012 American Chemical Society
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a
photoreaction of aminophenazone and ephedrine under UV
irradiation.18
Table 1. Optimization of the U-3CR with 1a, 2a, and 3a
entry
solvent
time (h)
temp (°C)
yield of 4a (%)
Herein we describe an asymmetric Ugi three-component
reaction (U-3CR) of 5,6-dihydro-1,4-oxazin-2-one substrates 1
with isocyanides 2 and carboxylic acids 3 to effectively
synthesize morpholin-2-one-3-carboxamide derivatives 4 and
5 (Scheme 1), in which the 2-amidomalonyl subunit is present
in many bioactive and pharmacological compounds.19
b
1
2
3
4
5
6
7
8
9
MeOH
PhMe
THF
72
40
40
50
50
5
rt
rt
39
58
rt
trace
b
CH2Cl2
CH2Cl2
CH2Cl2
TFE
rt
48
rt
67
c
rt
73
4
rt
70
51
68
Scheme 1. Ugi Three-Component Reaction of 1−3
TFE
6
−30
60
TFE
4
a
General conditions: the reaction was usually carried out in a ratio of
b
1a (1 equiv)/2a (2 equiv)/3a (2.2 equiv). 1a (1 equiv)/2a (1.5
equiv)/3a (1.5 equiv) were used. 1a (1 equiv)/2a (2 equiv)/3a (20
c
equiv) were used.
improvement in the yield (Table 1, entry 9). Hence, the U-3CR
is preferably carried out in TFE or CH2Cl2 at room
temperature.
Subsequently, the generality of the Ugi-3CR was examined,
and results are outlined in Table 2. Under the optimized
conditions, various cyclic imines, isocyanides, and carboxylic
acids reacted to provide morpholin-2-one-3-carboxamide
derivatives 4 in moderate to good yield (Table 2). When
formic acid (3b) was employed as a carboxylic acid component,
the reactions were accelerated dramatically even using less acid
(1.5 equiv) due to stronger acidity of 3b (Table 2, entry 3 vs
entry 2), and the reactions in CH2Cl2 completed at a similar
rate to that in TFE (Table 2, entry 5 vs entry 6). The
substituents in imines 1 (R1) had no clear influence on the yield
of the reaction (Table 2, entries 3, 6, and 10). Aliphatic and
aromatic isocyanides were well tolerated in the reaction. In all
cases, no Ugi product was obtained as two isolatable isomers on
silica gel chromatography, which indicated potential good
stereoselectivity of the reaction. However, amide functional
groups in the products caused the paired signals from two
RESULT AND DISCUSSION
■
Chiral 5,6-dihydro-1,4-oxazin-2-one 1a−c, as preformed cyclic
aldimines in the Ugi reaction, were conveniently prepared from
the corresponding (S)-amino alcohols 7 in two steps by the
literature procedures (Scheme 2).20 In the initial study, imine
Scheme 2. Preparation of imines 1a−c
1
rotamers in the most H and 13C NMR spectra.
One-pot protocols combining two or more reaction steps
show higher efficiency because of simpler operation, lower
costs, and shorter time.21 As a mild versatile reagent, IBX has
been employed in a wide array of chemical transformations,22
including direct oxidation of benzyl amines to the correspond-
ing imines.23 On the basis of the methods, Zhu group
developed an efficient IBX-mediated Ugi-type reaction of
tetrahydroisoquinoline, isocyanides and carboxylic acids, in
which formation of imine and Ugi-3CR were realized
ingeniously in one-pot taking advantage of compatibility of
IBX with the Ugi reaction conditions.24 We found that
secondary amines with an α-carbonyl group such as 8 also
could be oxidized to imine by IBX. Encouraged by the results, a
one-pot IBX oxidation/Ugi-3CR procedure to synthesize 4b
was attempted preliminarily using 8a (R1 = CH2OTBDPS), 2a,
and 3b (Scheme 3). DMSO or THF is efficient reaction media
for the oxidation stage, and complete conversion of 8a to 1a
occurred in a short time. However, only a trace amount of 4b
was produced in the subsequent Ugi-3CR, whereas CH2Cl2 as
an unfavorable solvent in the oxidation stage also gave a low
yield of 4b. The better common choice to both reaction stages
is TFE, in which 4b was obtained in a moderate yield from 8a
without further optimization. It indicated that the secondary
amines with α-carbonyl group were promising to develop a new
IBX-mediate Ugi reaction.
1a, tert-butyl isocyanide (2a), and acetic acid (3a) were
employed to screen the conditions of the Ugi 3-CR. As shown
in Table 1, the yield and velocity of the Ugi reaction remarkably
depended on solvent. The reaction performed in 2,2,2-
trifluoroethanol (TFE) proceeded much faster than in other
solvents and finished in just about 4 h to afford 4a in 70% yield
(Table 1, entry 7). Usually CH2Cl2 was seldom chosen as
solvent in normal U-4CR because of the possibility of Passerini-
type products, but for this U-3CR, a similar good yield was
obtained in CH2Cl2. Certainly, prolonged reaction times are
necessary for full consumption of 1a (Table 1, entry 5). In the
presence of much excessive 3a, the required reaction time in
CH2Cl2 was efficiently shortened, whereas only a slight
improvement in yield was observed (Table 1, entry 6). The
reaction performed in other solvents including MeOH, which is
the most common solvent in Ugi reactions, gave diminished
yield. Lowering the reaction temperature (Table 1, entry 8) or
decreasing the amount of 2a and 3a (Table 1, entry 4) led to a
drop in yield. Higher reaction temperature did not show an
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a
Table 2. Synthesis of 5-Substituted Morpholin-2-one-3-carboxamide Derivatives 4a−l from Aldimines 1a−c
entry
R1
R2
R3
solvent
time (h)
product
yield (%)
1
2
CH2OTBDPS
t-Bu
t-Bu
t-Bu
n-Bu
t-Bu
t-Bu
Me
Me
H
TFE
4
50
8
4a
4a
4b
4c
4d
4d
4e
4f
70
67
74
66
71
73
78
58
80
71
62
55
67
75
CH2OTBDPS
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
TFE
3
CH2OTBDPS
4
CH2OTBDPS
H
12
2.5
2.5
4
5
Ph
Ph
Ph
Ph
Ph
Bn
Bn
Bn
Bn
Bn
H
6
H
7
CH2CO2Me
Me
H
TFE
8
Bn
CH2Cl2
CH2Cl2
CH2Cl2
TFE
4
9
CH2CO2Me
H
4
4g
4h
4i
10
11
12
13
14
t-Bu
H
7
t-Bu
Me
Me
Ph
H
4
Bn
TFE
4
4j
CH2CO2Me
Ph
TFE
4.5
5
4k
4l
TFE
a
General conditions: the reactions were carried out at room temperature, and 1−3 were used in a ratio of 1/1.5/1.5 (formic acid as acid component)
or 1/2/2.2 (other acid as acid component).
Scheme 3. Synthesis of 4b from 8a by a One-Pot Procedure
phenylphosphinic acid (dr up to 7:1), whereas the total yield of
two diastereoisomers generally diminished in a different extent
(Table 3, entries 5−7). Hence, the optimized conditions for the
ketoimines were 1.5 + 0.5 equiv of isocyanides by two-portion
addition, no catalyst, TFE, reaction time, and room temper-
ature.
A variety of imines, isocyanides, and carboxylic acids were
employed to construct the morpholin-2-one-3-carboxamide
derivatives 5 containing a chiral quatenary carbon (Table 4).
The Ugi-3CR formic acid participated usually showed relative
good conversion and yield. When other carboxyl acids were
used, the amount of remaining imine increased to different
extent, though the acid loading was enhanced to 3 equiv to
promote the reactions (Table 4, entries 2, 3, 5, 9, 11, and 13).
However, in these cases, the yields based on recovered imines
were very high. Gratifyingly, the most Ugi products were
obtained in higher stereoselectivity than 5a, and in some cases
only a single diastereoisomer was obtained (Table 4, entries 2,
3, 6, 8, 10, and 13). In the presence of phenylphosphinic acid,
similar positive effects on stereoselectivity and a negative effect
on yield were verified again (Table 4, entry 14 vs entry 15).
Diastereoisomers in these cases are easily separated through
column chromatography, and each diastereoisomer of consid-
erable Ugi products still contains two rotamers according to the
paired signals in their NMR spectra. To further expand the
scope of the approach, 5,6-dihydropyrazin-2(1H)-one 10 (10a
and 10b) instead of 1 were attempted in the Ugi-3CR to form
the substituted piperazine scaffold, which is a pharmacologically
important core found in many marketed drugs and bioactive
compounds.26 Gratifyingly, the reactions of 10a/2a/3b and
10b/2d/3b proceeded smoothly under similar conditions to
give the desired products 11a (74%) and 11b (63%),
respectively, as single isomer (Scheme 4). It opens a promising
route to chiral 2-ketopiperazine-2-carboxamides with high
stereoselectivity. The construction of the 2-ketopiperazine-2-
carboxamide skeleton was achieved by several groups,27 but
asymmetric cases have not been reported. In general, the cyclic
ketoimines could be served as good asymmetric inductors in
the Ugi-3CR too.
Next, we prepared several ketoimines 1d−g according to the
literature25 and moved our attention to the Ugi-3CR of
ketoimines. Under the same reaction conditions as for
aldimines, the Ugi reactions of ketoimine 1d, 2a, and 3b
proceed so sluggishly that the Ugi products 5a (5a1 + 5a2) were
obtained in low yield even after a long span, together with
considerable N-formamide byproduct from 2a and remaining
1d (Table 3, entry 1). It is attributed to the enhanced hindrance
a
Table 3. Optimization of the U-3CR with 1d, 2a, and 3b
yield of
time
(h)
5a1 +
entry
1d:2a:3b
1:1.5:1.5
1:1.5:2.2
catalyst
dr
5a2 (%)
1
2
3
4
5
6
7
48
11
31
10
4
3.4:1
3.8:1
3.9:1
2.4:1
4.7:1
5.4:1
7.3:1
50
51
76
69
63
28
58
b
1:(1.5 + 0.5) :2.2
b
1:(2.0 + 0.5) :10
1:2:2.2
1 equiv of LiBr
1:2:1.1
1 equiv of ZnCl2
5
b
1:(1.5 + 0.5) :2.2 0.25 equiv of
24
phenylphosphinic
acid
a
General conditions: the reactions were carried out at room
b
temperature. The two values in parentheses mean isocyanide 2a
was added in two portions.
of the ketoimines. When formic acid was increased to 2.2 equiv,
velocity and yield were improved dramatically (Table 3, entry
2), but consumption of isocyanide was much faster than imine
due to its conversion to formamide. Supplementing isocyanide
is effective and necessary in the middle of the reaction, and the
better result was brought about by the two-portion addition
fashion (Table 3, entry 3). It is noteworthy that two
diastereoisomers 5a1 and 5a2 (dr = 3.9:1) were obtained in
the case. Excessive acid led to the dropped stereoselectivity
(Table 3, entry 4). An improved dr value was obtained by
addition of some Lewis acids or proton acids, particularly
The stereochemistry of the Ugi-3CR was then investigated
via NOESY 1H NMR analysis. Among the Ugi products 4 from
aldimines, 4a was used to determine the configuration of the
1
morpholin-2-one-3-carboxamide compounds because in its H
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a
Table 4. Synthesis of 5-Substituted Morpholin-2-one-3-carboxamide Derivatives 5a−o from Ketimines
entry
R1
R
R2
R3
time (h)
product
dr
yield (%)
recovered 1 (%)
1
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Bn
Ph
i-Pr
Ph
Ph
Bn
Bn
i-Pr
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
t-Bu
t-Bu
t-Bu
n-Bu
t-Bu
H
31
40
40
36
23
34
21
25
24
29
38
28
36
24
20
24
5a1 + 5a2
5b
3.9:1
76
63
51
81
41
63
86
68
59
72
48
88
78
71
50
87
10
29
41
8
2
Me
Et
H
3
5c
4
5d1 + 5d2
5e1 + 5e2
5f
8.2:1
4.1:1
5
Ph
H
45
18
8
6
CH2CO2CH3
7
Cy
H
5g1 + 5g2
5h
4.6:1
5.5:1
8
CH2CH2OCbz
H
17
36
16
40
7
9
t-Bu
Me
H
5i1 + 5i2
5j
10
11
12
13
14
CH2CH2OAc
t-Bu
Me
H
5k1 + 5k2
5l1 + 5l2
5m
4.3:1
8.2:1
t-Bu
Et
t-Bu
Me
H
18
11
14
9
Me
Me
Me
t-Bu
5n1 + 5n2
5n1 + 5n2
5o1 + 5o2
3.5:1
8.1:1
6.0:1
b
15
t-Bu
H
16
t-Bu
H
a
General conditions: the reactions were carried out at room temperature in TFE, and 1, 2 and 3 were used in a ratio of 1/(1.5 + 0.5)/2.2 (formic
b
acid as acid component) or 1/(1.5 + 0.5)/3 (other acid as acid component). 0.25 equiv phenyl phosphinic acid was added.
Scheme 4. Synthesis of Piperazine-2-carboxamide 11a and
11b via the U-3CR
the NMR spectra. As two models of the Ugi products 5 from
ketoimines for NOESY analysis, 5c is obtained as a single
isomer, and 5l1 is the major one of two diastereoisomers.
Obvious interaction between methyl (5c) or ethyl (5l1) and
protons of the phenyl groups illustrates the trans-relationship
between C-3 carboxamide and C-5 phenyl group in them.
1
Furthermore, in combination with H NMR spectra analysis,
their conformations were established as shown in Figure 2. In
accordance with stereochemistry observed in other reactions of
the similar cyclic imines,14a,28 preferential access of isocyanide
to imine from the side opposite to the C-5 alkyl group gives
thermodynamically more stable trans-isomer as a major
product.
NMR the paired H-3 (4.95 and 4.76 ppm) and H-5 (3.93 and
4.58 ppm) signals from two rotamers are easily distinguishable
and not overlapped with other proton signals. The NOE
correlation not between H-3 and H-5 signals but between H-3
and H-a signals, observed in each rotamer separately, reveal that
both rotamers of 4a have 3,5-trans-configurations, namely the
(S)-configuration at C3 (Figure 2). It is also further confirmed
that the two rotamers are responsible for the paired signals in
Combinations of Ugi reaction with other reactions are
becoming highly efficient tools to create more complex
structures.29 Ugi products 4 from the aldimines are a kind of
potential nucleophiles which would react with appropriate
electrophiles at the C-3 activated by two carbonyl groups in
alkylation, Michael addition, and so on. Compound 4d was
employed to test the possibility of C-alkylation primarily. After
screening conditions, 4d reacted smoothly with iodoethane to
provide 5l2 exclusively in 75% yield (Scheme 5). It is reasonable
that halide approaches the resulting cyclic enolate from the less
hindered face and is attacked to result in cis product with high
stereoselectivity, which a owns complementary configuration
with the predominant trans-isomer in the Ugi-3CR of
ketoimines. Therefore, by a different synthetic method,
stereochemistry of the quantanary center in 5 could be
controlled to produce the trans- or cis-isomer.
Scheme 5. Synthesis of cis-Isomer 5l2 by Stereoselective
Alkylation of 4d
Figure 2. Configuration determination of Ugi products by NOESY
analysis.
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7.0, 12.9 Hz, 1.6 H), 3.19 (dd, J = 3.6, 5.9 Hz, 0.4H), 1.48 (m, 2 H),
1.32 (m, 2 H), 1.06 (s, 8 H), 1.05(s, 1 H), 0.91 (t, J = 7.3 Hz, 3H)
ppm; 13C NMR (100 MHz, CDCl3, major rotamer) δ = 164.4, 163.7,
162.4, 135.5, 132.5, 132.2, 132.1, 130.3, 130.2, 128.1, 128.0, 66.1, 63.1,
58.3, 52.1, 40.1, 31.2, 26.8, 19.8, 19.1, 13.7 ppm; HRMS m/z calcd for
C27H36N2O5Si [M + H]+ 497.2472, found 497.2470.
CONCLUSION
■
In summary, an asymmetric Ugi reaction of chiral cyclic imines
1, isocyanides 2, and carboxylic acids 3 was described first by
which novel morpholin-2-one-3-carboxamide derivatives 4 and
5 were efficiently synthesized from both aldimines and
ketoimines. Furthermore, the Ugi-3CR also showed potential
in the synthesis of substituted ketopiperazine-2-carboxamide
compounds such as 11. Good diastereoselectivity of the new
stereocenter at C-3 in the products was observed in most cases.
In the primary extended studies, 4 could be obtained directly
from the amines 8 by a new IBX-mediated Ugi-type reaction,
and alkylation of 4 showed excellent but opposite stereo-
selectivity to give cis-5. The work will enrich asymmetric Ugi
reactions, and further investigations on the employment of 4 as
nucleophile in post-transformation with high stereoselectivity
are underway.
(3S,5S)-N-tert-Butyl-4-formyl-2-oxo-5-phenylmorpholine-3-car-
boxamide (4d): yield 73% (stirred in CH2Cl2 for 2.5 h); yellow gel;
[α]28D +16 (c = 1.1, CHCl3); IR (neat) 3347, 2971, 1757, 1671, 1537,
1
1457, 1366, 1255, 1203, 1046, 761, 702 cm−1; H NMR (400 MHz,
CDCl3, two rotamers 2:1) δ = 8.18 (s, 0.33 H), 8.07 (s, 0.66 H), 7.55−
7.52 (m, 1.4 H), 7.48−7.38 (m, 2.6 H), 7.23−7.18 (m, 1 H), 6.39 (s,
0.66 H), 6.25 (s, 0.33 H), 5.46 (s, 0.66 H), 5.41 (s, 0.33 H), 5.18 (t, J
= 3.0 Hz, 0.33 H), 5.02 (dd, J = 3.2, 11.6 Hz, 0.33 H), 4.93 (dd, J =
4.3, 11.6 Hz, 0.66 H), 4.76 (t, J = 11.8 Hz, 0.66 H), 4.53 (dd, J = 3.0,
11.6 Hz, 0.33 H), 4.29 (dd, J = 4.3, 11.9 Hz, 0.66 H), 1.41 (s, 6 H),
1.38 (s, 3 H) ppm; 13C NMR (100 MHz, CDCl3, two rotamers) δ =
165.0, 164.9, 163.9, 163.3, 162.8, 162.3, 137.0, 134.7, 129.5, 129.3,
128.8, 127.8, 126.3, 125.8, 70.6, 69.3, 59.2, 58.5, 56.7, 54.4, 52.4, 52.2,
28.3 ppm; HRMS m/z calcd for C16H20N2O4Na [M + Na]+ 327.1321,
found 327.1309.
EXPERIMENTAL SECTION
■
General Procedure for the Ugi Three-Component Reaction
of Aldimines 1a−c. To a 0.25 M solution of the imine 1a−c (1
equiv) in solvent (TFE or CH2Cl2) were added carboxylic acid 3 (1.5
equiv for formic acid or 2.2 equiv for other acid) and isocyanide 2 (1.5
equiv when formic acid as acid component or 2 equiv when other acid
as acid component) at room temperature. The resulting mixture was
stirred until imine was consumed thoroughly and concentrated in
vacuo. The product 4 was isolated by flash column chromatography
using petroleum ether/ethyl acetate (3:1 to 1:1) as eluent.
Methyl 2-((3S,5S)-4-acetyl-2-oxo-5-phenylmorpholine-3-
carboxamido)acetate (4e): yield 78% (stirred in TFE for 4 h);
yellow oil; [α]28 +50 (c = 1.0, CHCl3); IR (neat) 3346, 2954, 2926,
D
2854, 1751, 1671, 1529, 1438, 1382, 1296, 1208, 1037, 758, 705 cm−1;
1H NMR (400 MHz, CDCl3, two rotamers 1.5:1) δ = 7.48−7.37 (m, 3
H), 7.16−7.13 (m, 2 H), 5.94 (s, 0.4 H), 5.77 (s, 0.6 H), 5.16 (s, 0.6
H), 5.05 (dd, J = 2.9, 11.7 Hz, 0.6 H), 4.98 (dd, J = 5.1, 11.6 Hz, 0.4
H), 4.55 (t, J = 12.4 Hz, 0.6 H), 4.44 (dd, J = 1.6, 11.8 Hz, 0.6 H), 4.33
(dd, J = 5.1, 10.0 Hz, 0.4 H), 4.30 (s, 0.4 H), 4.27 (d, J = 6.4 Hz, 0.4
H), 4.13 (dd, J = 5.7, 14.9 Hz, 0.4 H), 4.10 (d, J = 5.6 Hz, 0.6 H), 4.05
(d, J = 5.3 Hz, 0.6 H), 4.01 (t, J = 5.0 Hz, 0.4 H), 3.97 (d, J = 5.1 Hz,
0.4 H), 3.79 (s, 1.2 H), 3.77 (s, 1.8 H), 1.98 (s, 1.8 H), 1.80 (s, 1.2 H)
ppm; 13C NMR (100 MHz, CDCl3, two rotamers) δ = 173.0, 171.3,
169.8, 169.3, 166.8, 165.5, 165.4, 165.0, 161.4, 137.6, 135.9, 129.4,
129.3, 128.9, 128.4, 126.7, 125.3, 70.5, 68.9, 59.8, 58.7, 58.1, 56.1, 52.3,
41.5, 41.2, 39.8, 22.9, 21.5 ppm; HRMS m/z calcd for C16H18N2O6Na
[M + Na]+ 357.1063, found 357.1040.
(3S,5R)-4-Acetyl-N-tert-butyl-5-(((tert-butyldiphenylsilyl)oxy)-
methyl)-2-oxomorpholine-3-carboxamide (4a): yield 70% (stirred in
TFE for 4 h); colorless gel; [α]28 +4 (c = 0.5, CHCl3); IR (neat)
D
3337, 2963, 2932, 1752, 1666, 1539, 1463, 1391, 1289, 1108, 746, 705
1
cm−1; H NMR (400 MHz, CDCl3, two rotamers 4:1) δ = 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, two rotamers) δ =
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
calcd for C28H38N2O5SiNa [M + Na]+ 533.2448, found 533.2437.
(3S,5R)-N-tert-Butyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-4-
formyl-2-oxomorpholine-3-carboxamide (4b): yield 74% (stirred in
CH2Cl2 for 8 h); colorless gel; [α]28D +18 (c = 0.7, CHCl3); IR (neat)
3346, 2933, 2860, 1754, 1678, 1539, 1464, 1429, 1387, 1109, 704
cm−1; 1H NMR (400 MHz, CDCl3, two rotamers 4:1) δ = 8.14 (s, 0.2
H), 8.12 (s, 0.8 H), 7.62−7.58 (m, 4 H), 7.45−7.39, 6 H), 6.27 (s, 0.2
H), 6.10 (s, 0.8 H), 5.34 (s, 0.2 H), 4.90 (s, 0.8 H), 4.81 (dd, J = 2.9,
11.8 Hz, 1 H), 4.57 (dd, J = 5.0, 11.0 Hz, 0.2 H), 4.51 (dd, J = 1.2, 11.7
Hz, 0.8 H), 3.94 (m, 1 H), 3.75 (dd, J = 7.1, 10.8 Hz, 1 H), 3.61 (dd, J
= 7.3, 10.8 Hz, 1 H), 1.34 (s, 7.2 H), 1.27 (s, 1.8 H), 1.07 (s, 1.8 H),
1.06 (s, 7.2 H) ppm; 13C NMR (100 MHz, CDCl3, two rotamers) δ =
165.0, 164.6, 162.8, 162.5, 162.4, 162.2, 135.5, 132.5, 132.2, 130.3,
130.2, 130.0, 128.1, 128.0, 127.8, 67.0, 66.1, 63.1, 62.8, 59.0, 56.7, 52.5,
52.2, 52.0, 51.8, 28.4, 26.8, 19.1 ppm; HRMS m/z calcd for
C27H37N2O5Si [M + H]+ 497.2472, found 497.2481.
(3S,5S)-N-Benzyl-4-formyl-2-oxo-5-phenylmorpholine-3-carbox-
amide (4f): yield 58% (stirred in CH2Cl2 for 4 h); colorless gel; [α]28
D
+16 (c = 0.6, CHCl3); IR (neat) 3338, 3063, 2925, 1757, 1675, 1530,
1
1496, 1455, 1359, 1205, 756, 701 cm−1; H NMR (400 MHz, CDCl3,
two rotamers 1.9:1) δ = 8.16 (s, 0.35 H), 8.04 (s, 0.65 H), 7.46−7.19
(m, 10 H), 6.99 (m, 0.65 H), 6.87 (m, 0.35 H), 5.56 (s, 0.65 H), 5.53
(s, 0.35 H), 5.19 (t, J = 3.1 Hz, 0.35 H), 5.03 (dd, J = 3.2, 11.6 Hz,
0.35 H), 4.92 (dd, J = 4.2, 11.6 Hz, 0.65 H), 4.75 (t, J = 11.8 Hz, 0.65
H), 4.63−4.40 (m, 2.35 H), 4.28 (dd, J = 4.2, 11.9 Hz, 0.65 H) ppm;
13C NMR (150 MHz, CDCl3, two rotamers) δ = 164.9, 164.3, 164.6,
163.5, 163.3, 162.8, 137.0, 136.8, 134.4, 129.5, 129.3, 128.9, 128.7,
128.6, 127.8, 127.6, 127.5, 127.4, 126.3, 70.7, 69.5, 58.7, 57.8, 56.7,
54.5, 44.1, 44.0 ppm; HRMS m/z calcd for C19H18N2O4Na [M + Na]+
361.1159, found 361.1166.
Methyl 2-((3S,5S)-4-formyl-2-oxo-5-phenylmorpholine-3-
carboxamido)acetate (4g): yield 80% (stirred in CH2Cl2 for 4 h);
yellow gel; [α]28 +28 (c = 0.6, CHCl3); IR (neat) 3349, 3064, 2954,
D
1
1752, 1673, 1533, 1439, 1374, 1207, 1069, 1038, 762, 703 cm−1; H
NMR (400 MHz, CDCl3, two rotamers 2:1) δ = 8.19 (s, 0.33 H), 8.10
(s, 0.66 H), 7.61−7.59 (m, 1 H), 7.45−7.40 (m, 4 H), 7.23−7.21 (m,
1 H), 7.15 (s, 0.66 H), 7.10 (s, 0.33 H), 5.66 (s, 0.66 H), 5.65 (s, 0.33
H), 5.19 (t, J = 3.0 Hz, 0.33H), 4.97 (tt, J = 3.4, 11.8 Hz, 1 H), 4.69 (t,
J = 11.9 Hz, 0.66 H), 4.55 (dd, J = 3.0, 11.8 Hz, 0.33 H), 4.31 (dd, J =
4.2, 12.0 Hz, 0.66 H), 4.19 (dd, J = 5.9, 18.0 Hz, 1 H), 4.04 (dd, J =
5.3, 18.0 Hz, 1 H), 3.78 (s, 2 H), 3.77 (s, 1 H) ppm; 13C NMR (100
MHz, CDCl3, two rotamers) δ = 169.3, 169.1, 165.5, 164.5, 164.2,
164.1, 163.4, 163.0, 136.9, 134.4, 129.5, 129.3, 128.9, 128.0, 126.3,
125.8, 70.5, 69.5, 58.2, 57.5, 56.8, 54.5, 52.4, 52.3, 41.6, 41.5 ppm;
HRMS m/z calcd for C15H16N2O6Na [M + Na]+ 343.0906, found
343.0915.
(3S,5R)-N-Butyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-4-formyl-
2-oxomorpholine-3-carboxamide (4c): yield 66% (stirred in CH2Cl2
for 12 h); yellow gel; [α]28 +17 (c = 0.9, CHCl3); IR (neat) 3333,
D
2932, 2860, 1755, 1677, 1539, 1466, 1384, 1109, 741, 705 cm−1; H
1
NMR (400 MHz, CDCl3, two rotamers 4:1) δ = 8.13 (s, 1 H), 7.63−
7.59 (m, 4 H), 7.47−7.38 (m, 6 H), 6.46 (s, 0.2 H), 6.30 (s, 0.8 H),
5.39 (s, 0.2 H), 4.98 (s, 0.8 H), 4.82 (dd, J = 3.0, 11.8 Hz, 0.8 H), 4.59
(dd, J = 5.2, 11.6 Hz, 0.2 H), 4.52 (dd, J = 1.4, 11.8 Hz), 4.46 (dd, J =
4.0, 11.6 Hz, 0.2 H), 3.96 (m, 0.8 H), 3.87 (m, 0.6 H), 3.76 (dd, J =
7.0, 10.8 Hz, 0.8 H), 3.62 (dd, J = 7.3, 10.8 Hz, 0.8 H), 3.26 (dd, J =
(3S,5S)-5-Benzyl-N-tert-butyl-4-formyl-2-oxomorpholine-3-car-
boxamide (4h): yield 71% (stirred in CH2Cl2 for 7 h); yellow gel;
1390
dx.doi.org/10.1021/jo2021967 | J. Org. Chem. 2012, 77, 1386−1395

The Journal of Organic Chemistry
Article
[α]28D −41 (c = 0.5, CHCl3); IR (neat) 3280, 2969, 2927, 1654, 1565,
concentrated in vacuo and the residue was purified by flash
chromatography on silica gel column using petroleum ether/ethyl
acetate (3:1 to 1:1) as the eluent to give product 4b (23.3 mg, 46%) as
a colorless gel.
1
1446, 1384, 1221, 1169, 758, 701 cm−1; H NMR (400 MHz, CDCl3,
two rotamers 2.3:1) δ = 8.11 (s, 0.3 H), 7.91 (s, 0.7 H), 7.36−7.28 (m,
4 H), 7.18−7.16 (m, 1 H), 6.40 (s, 0.3 H), 6.21 (s, 0.7 H), 5.42 (s, 0.3
H), 5.06 (s, 0.7 H), 4.82 (dd, J = 2.6, 11.6 Hz, 1H), 4.37 (dd, J = 5.8,
14.9 Hz, 0.3 H), 4.30 (dd, J = 1.6, 11.6 Hz, 0.7 H), 4.22 (m, 0.7 H),
3.26 (m, 0.3 H), 2.99 (dd, J = 8.3, 14.0 Hz, 1 H), 2.92 (dd, J = 7.9, 13.8
Hz, 1 H), 1.35 (s, 2 H), 1.34 (s, 7 H) ppm; HRMS m/z calcd for
C17H23N2O4 [M + H]+ 319.1658, found 319.1653.
General Procedure for the Ugi Three-Component Reaction
of Ketoimines 1d−g or 10a,b. To a 0.25 M solution of the imine
1d−g or 10a,b (1 equiv) in TFE were added successively carboxylic
acid 3 (2.2 equiv for formic acid or 3 equiv for other acid) and
isonitrile 2 (1.5 equiv) under argon atmosphere. The resulting mixture
was stirred at room temperature for about 12 h (2 was exhausted), and
then additional 2 (0.5 equiv) was added. The resulting mixture was
stirred unceasingly until 2 was exhausted again and concentrated in
vacuo. The residue was purified by flash chromatography on silica gel
column using petroleum ether/ethyl acetate (3:1 to 1:2) as the eluent
to give product 5 or 11.
(3S,5S)-4-Acetyl-5-benzyl-N-tert-butyl-2-oxomorpholine-3-car-
boxamide (4i): yield 62% (stirred in TFE for 4 h); yellow gel; [α]28
D
−31 (c = 0.3, CHCl3); IR (neat) 3334, 2950, 1751, 1695, 1530, 1455,
1
1390, 1219, 1090, 1044, 752, 702 cm−1; H NMR (400 MHz, CDCl3,
two rotamers 2.3:1) δ = 7.37−7.30 (m, 3 H), 7.22−7.19 (m, 2 H),
6.14 (s, 0.7 H), 6.12 (s, 0.3 H), 5.10 (s, 0.7 H), 4.90 (s, 0.3 H), 4.77
(dd, J = 2.2, 11.6 Hz, 0.7 H), 4.59 (d, J = 11.2 Hz, 0.3 H), 4.19 (dd, J =
1.4, 11.6 Hz, 1 H), 4.11 (m, 1 H), 3.16 (dd, J = 3.4, 12.9 Hz, 0.3 H),
2.93 (m, 1.4 H), 2.61 (dd, J = 11.4, 12.9 Hz, 0.3 H), 2.17 (s, 2.1 H),
2.00 (s, 0.9 H), 1.34 (s, 9 H) ppm; 13C NMR (100 MHz, CDCl3, two
rotamers) δ = 169.8, 169.7, 166.5, 165.9, 163.5, 162.3, 136.8, 135.5,
129.5, 129.2, 128.8, 127.6, 127.0, 67.0, 66.9, 62.6, 60.9, 54.2, 52.7, 52.3,
51.4, 37.8, 35.7, 28.4, 21.5, 21.0 ppm; HRMS m/z calcd for
C18H25N2O4 [M + H]+ 333.1814, found 333.1806.
(3S,5S)-4-Acetyl-N,5-dibenzyl-2-oxomorpholine-3-carboxamide
(4j): yield 55% (stirred in TFE for 4 h); yellow oil; [α]28D −33 (c = 0.4,
CHCl3); IR (neat) 3322, 3029, 2927, 1748, 1654, 1534, 1456, 1389,
1287, 1210, 745, 701 cm−1; 1H NMR (400 MHz, CDCl3, two rotamers
3:1) δ = 7.35−7.31 (m, 7 H), 7.22−7.19 (m, 3 H), 6.98 (s, 0.25 H),
6.71 (s, 0.75 H), 5.51 (s, 0.25 H), 5.25 (s, 0.75 H), 4.80 (dd, J = 2.0,
11.6 Hz, 0.75 H), 4.53 (m, 0.75 H), 4.44 (dd, J = 3.0, 5.6 Hz, 1 H),
4.32 (dd, J = 2.8, 11.7 Hz, 0.5 H), 4.21 (dd, J = 1.3, 11.6 Hz, 1 H), 4.14
(m, 1 H), 3.17 (dd, J = 3.6, 12.9 Hz, 0.25 H), 2.93 (m, 1.5 H), 2.61
(dd, J = 11.4, 12.9 Hz, 0.25 H), 2.17 (s, 2.25 H), 2.15 (s, 0.75 H) ppm;
13C NMR (100 MHz, CDCl3, two rotamers) δ = 169.8, 165.5, 164.7,
(3S,5S)-N-tert-Butyl-4-formyl-3-methyl-2-oxo-5-phenylmorpho-
line-3-carboxamide (5a1): yield 61%; colorless gel; [α]26 +67 (c =
D
1.9, CHCl3); IR (neat) 3409, 2967, 2932, 1740, 1699, 1670, 1522,
1
1455, 1359, 1276, 1199, 1058, 742, 697 cm−1; H NMR (400 MHz,
CDCl3, two rotamers 3:1) δ = 8.50 (s, 0.75 H), 8.28 (s, 0.25 H), 7.42−
7.29 (m, 3.8 H), 7.22−7.19 (m, 1.2 H), 6.05 (s, 0.25 H), 5.77 (s, 0.75
H), 5.66 (s, 0.75 H), 5.20 (dd, J = 2.6, 11.5 Hz, 0.25 H), 5.11 (s, 0.25
H), 4.88 (dd, J = 2.2, 11.4 Hz, 0.25 H), 4.61 (dd, J = 0.6, 11.6 Hz, 0.75
H), 4.56 (dd, J = 2.8, 12.0 Hz, 0.75 H), 2.04 (s, 2.25 H), 1.87 (s, 0.75
H), 1.37 (s, 2.25 H), 1.36 (s, 6.75 H) ppm; 13C NMR (100 MHz,
CDCl3, two rotamers) δ = 168.9, 167.3, 166.1, 165.6, 162.8, 162.5,
137.5, 135.6, 129.3, 129.0, 128.7, 128.1, 126.9, 126.1, 69.9, 69.2, 67.2,
66.7, 54.9, 52.8, 52.3, 52.1, 28.3, 24.5, 20.6 ppm; HRMS m/z calcd for
C17H23N2O4 [M + H]+ 319.1658, found 319.1651.
(3R,5S)-N-tert-Butyl-4-formyl-3-methyl-2-oxo-5-phenylmorpho-
line-3-carboxamide (5a2): yield 15%; colorless gel; [α]26 +73 (c =
D
1.6, CHCl3); IR (neat) 3397, 2976, 2937, 1749, 1676, 1526, 1453,
1
1386, 1335, 1219, 1198, 757, 700 cm−1; H NMR (400 MHz, CDCl3,
two rotamers 5.7:1) δ = 8.57 (s, 0.85 H), 7.93 (s, 0.15 H), 7.45−7.44
(m, 2 H), 7.31−7.29 (m, 3 H), 6.65 (s, 0.85 H), 6.06 (s, 0.15 H), 5.97
(s, 0.85 H), 5.93 (s, 0.15 H), 4.96 (dd, J = 2.9, 11.8 Hz, 0.85 H), 4.88
(d, J = 8.9 Hz, 0.258 H), 4.73 (dd, J = 3.8, 11.8 Hz, 0.85 H), 4.35 (d, J
= 10.8 Hz, 0.25 H), 2.05 (s, 0.45 H), 1.96 (s, 2.55 H), 1.34 (s, 1.35 H),
1.05 (s, 7.65 H) ppm; 13C NMR (100 MHz, CDCl3, major rotamer) δ
= 169.9, 165.3, 162.4, 134.4, 128.9, 128.6, 128.2, 70.2, 64.8, 51.6, 48.1,
28.0, 27.0 ppm; HRMS m/z calcd for C17H23N2O4 [M + H]+
319.1658, found 319.1648.
137.2, 137.0, 136.7, 129.5, 129.2, 129.1, 128.9, 128.8, 128.0, 127.6,
127.4, 127.0, 67.0, 66.9, 62.3, 60.3, 54.3, 51.5, 44.5, 44.2, 37.8, 35.7,
21.5, 21.0 ppm; HRMS m/z calcd for C21H23N2O4 [M + H]+
367.1658, found 367.1651.
Methyl 2-((3S,5S)-4-benzoyl-5-benzyl-2-oxomorpholine-3-
carboxamido)acetate (4k): yield 67% (stirred in TFE for 5 h);
yellow oil; [α]28 −26 (c = 0.8, CHCl3); IR (neat) 3359, 3028, 2954,
D
1
1750, 1648, 1529, 1490, 1378, 1284, 1210, 1006, 733, 703 cm−1; H
NMR (400 MHz, CDCl3, two rotamers 1.5:1) δ = 7.52−7.30 (m, 6
H), 7.18−7.06 (m, 4 H), 6.86 (s, 0.6 H), 6.60 (s, 1 H), 5.90 (s, 0.4 H),
5.67 (s, 0.4 H), 4.69 (d, J = 11.5 Hz, 0.6 H), 4.23 (s, 2 H), 4.09 (s, 2
H), 3.78 (s, 1.8 H), 3.75 (s, 1.2 H), 2.78 (t, J = 13.1 Hz, 2 H) ppm;
13C NMR (100 MHz, CDCl3, major rotamers) δ = 171.1, 169.2, 164.7,
134.7, 128.7, 128.6, 126.3, 66.2, 59.0, 54.5, 52.2, 41.6, 36.0 ppm;
HRMS m/z calcd for C22H22N2O6Na [M + Na]+ 433.1376, found
433.1372.
(3S,5S)-4-Acetyl-N-tert-butyl-3-methyl-2-oxo-5-phenylmorpho-
line-3-carboxamide (5b): yield 63%; yellow gel; [α]26 +41 (c = 1.7,
D
CHCl3); IR (neat) 3394, 2977, 2926, 1735, 1674, 1507, 1452, 1387,
1
1197, 1153, 751, 703 cm−1; H NMR (400 MHz, CDCl3) δ = 7.64−
7.27 (m, 5 H), 6.13 (s, 1 H), 5.32 (d, J = 11.4 Hz, 1 H), 5.22 (s, 1 H),
4.77 (d, J = 11.3 Hz, 1 H), 2.17 (s, 3 H), 2.02 (s, 3 H), 1.36 (s, 9 H)
ppm; 13C NMR (100 MHz, CDCl3) δ = 170.5, 167.9, 167.0, 136.0,
129.3, 128.5, 126.5, 69.0, 68.5, 56.6, 52.1, 28.3, 22.9, 21.5 ppm; HRMS
m/z calcd for C18H25N2O4 [M + H]+ 333.1814, found 333.1823.
(3S,5S)-N-tert-Butyl-3-methyl-2-oxo-5-phenyl-4-propionylmor-
(3S,5S)-5-Benzyl-4-formyl-2-oxo-N-phenylmorpholine-3-carbox-
amide (4l): yield 75% (stirred in TFE for 4.5 h); yellow gel; [α]28
D
−30 (c = 0.6, CHCl3); IR (neat) 3327, 2922, 1739, 1651, 1547, 1495,
pholine-3-carboxamide (5c): yield 51%; yellow gel; [α]26 +38 (c =
D
1
1386, 1171, 1076, 750, 696 cm−1; H NMR (400 MHz, CDCl3, two
0.9, CHCl3); IR (neat) 3281, 1978, 2939, 1762, 1659, 1547, 1461,
1387, 1282, 1173, 1067, 756, 702 cm−1; 1H NMR (400 MHz, CDCl3)
δ = 7.43−7.27 (m, 5 H), 6.14 (s, 1 H), 5.32 (dd, J = 2.5, 11.4 Hz, 1 H),
5.25 (s, 1 H), 4.75 (d, J = 11.1 Hz, 1 H), 2.49 (dt, J = 7.6, 16.1 Hz, 1
H), 2.27 (dt, J = 7.3, 16.0 Hz, 1 H), 2.03 (s, 3 H), 1.37 (s, 9 H), 1.12
(t, J = 7.3 Hz, 3 H) ppm; 13C NMR (100 MHz, CDCl3) δ = 173.6,
168.0, 167.1, 136.4, 129.3, 128.4, 126.4, 69.1, 68.6, 55.6, 52.1, 28.3,
27.6, 21.7, 9.2 ppm; HRMS m/z calcd for C19H27N2O4 [M + H]+
347.1971, found 347.1973.
major rotamers 2:1) δ = 8.80 (s, 0.33 H), 8.78 (s, 0.67 H), 8.08 (s,
0.33 H), 7.97 (s, 0.47 H), 7.60−7.49 (m, 2 H), 7.47−7.27 (m, 6 H),
7.20−7.16 (m, 2 H), 5.59 (s, 0.33 H), 5.39 (s, 0.67 H), 4.82 (dd, J =
2.5, 11.8 Hz, 0.67 H), 4.43 (dd, J = 4.5, 11.8 Hz, 0.33 H), 4.39 (dd, J =
4.0, 11.8 Hz, 0.33 H), 4.33 (d, J = 10.6 Hz, 0.67 H), 4.17 (br t, J = 7.8
Hz, 0.67 H), 4.07 (m, 0.33 H), 3.27 (dd, J = 6.8, 14.0 Hz, 0.33 H),
3.00 (m, 1.67 H) ppm; 13C NMR (100 MHz, CDCl3, two major
rotamers) δ = 164.2, 164.1, 162.1, 161.8, 161.7, 136.9, 136.8, 135.5,
135.0, 129.2, 129.1, 129.0, 128.9, 128.8, 127.6, 127.3, 124.9, 124.8,
120.0, 119.9, 69.2, 67.8, 59.1, 57.2, 52.9, 52.6, 39.2. 37.5 ppm; HRMS
m/z calcd for C19H19N2O4 [M + H]+ 339.1345, found 339.1355.
One-Pot Procedure for the Synthesis of 4b from 8a. The
mixture of 8a (37.6 mg, 0.102 mmol) and IBX (31.4 mg, 0.112 mmol)
in TFE (1.0 mL) was stirred for 14 h at room temperature, and then
3b (5.8 μL, 0.153 mmol) and 2a (17.4 μL, 0.153 mmol) were added.
After being stirred for an additional 4 h, the reaction mixture was
(3S,5S)-N-Butyl-4-formyl-3-methyl-2-oxo-5-phenylmorpholine-3-
carboxamide (5d1): yield 72%; yellow oil; [α]26 +59 (c = 0.6,
D
CHCl3); IR (neat) 3358, 2959, 2870, 1750, 1674, 1528, 1459, 1381,
1
1254, 1198, 1065, 749, 699 cm−1; H NMR (400 MHz, CDCl3, two
rotamers 2:1) δ = 8.52 (s, 0.68 H), 8.28 (s, 0.32 H), 7.44−7.20 (m, 5
H), 6.25 (s, 0.32 H), 6.05 (s, 0.68 H), 5.69 (s, 0.68 H), 5.22 (dd, J =
2.7, 11.4 Hz, 0.32 H), 5.13 (s, 0.32 H), 4.89 (dd, J = 2.2 11.5 Hz, 0.32
H), 4.63 (t, J = 13.2 Hz, 1.36 H), 3.30 (m, 2 H), 2.05 (s, 2 H), 1.93 (s,
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1 H), 1.51 (m, 2 H), 1.33 (m, 2 H), 0.93 (t, J = 7.3 Hz, 3 H) ppm; 13
C
(3R,5S)-N-Cyclohexyl-4-formyl-3-methyl-2-oxo-5-phenylmorpho-
line-3-carboxamide (5g2): yield 15%; yellow oil; [α]27D +42 (c = 0.2,
CHCl3); IR (neat) 3387, 2919, 2851, 1749, 1660, 1530, 1452, 1408,
1117, 753, 698 cm−1; 1H NMR (400 MHz, CDCl3, two rotamers
4.9:1) δ = 8.63 (s, 0.83 H), 7.91 (s, 0.17 H), 7.44 −7.42 (m, 2 H),
7.32−7.30 (m, 3 H), 6.60 (d, J = 6.4 Hz, 0.83 H), 6.13 (d, J = 5.8 Hz,
0.17 H), 6.00 (m, 0.83 H), 4.98 (dd, J = 2.3, 11.6 Hz, 0.83 H), 4.95
(m, 0.17 H), 4.88 (br d, J = 7.4 Hz, 0.17 H), 4.73 (dd, J = 3.5, 11.7 Hz,
0.83 H), 4.33 (br d, J = 11 Hz, 0.17 H), 3.78 (m, 0.17 H), 3.37 (m,
0.83 H), 2.09 (s, 0.5 H), 1.98 (s, 2.5 H), 1.72−1.24 (m, 10 H) ppm;
13C NMR (100 MHz, CDCl3, major rotamer) δ = 169.7, 165.6, 162.4,
NMR (100 MHz, CDCl3, two rotamers) δ = 168.6, 167.1, 166.8,
166.7, 137.2, 135.5, 129.4, 129.0, 128.9, 128.2, 126.9, 126.2, 67.0, 69.2,
66.7, 66.3, 55.1, 51.9, 40.7, 40.4, 31.2, 24.9, 20.6, 20.0, 19.9, 13.7 ppm;
HRMS m/z calcd for C17H23N2O4 [M + H]+ 319.1658, found
319.1662.
(3R,5S)-N-Butyl-4-formyl-3-methyl-2-oxo-5-phenylmorpholine-3-
carboxamide (5d2): yield 9%; yellow oil; [α]25D +57 (c = 0.1, CHCl3);
IR (neat) 3342, 2926, 1749, 1677, 1533, 1458, 1377, 1225, 1126, 762,
1
701 cm−1; H NMR (400 MHz, CDCl3, two rotamers 5.7:1) δ = 8.65
(s, 0.85 H), 7.90 (s, 0.15 H), 7.43−7.32 (m, 3 H), 7.29−7.26 (m, 2
H), 6.70 (s, 0.85 H), 6.25 (s, 0.15 H), 6.01 (br s, 1 H), 4.99 (d, J =
11.6 Hz, 1 H), 4.87 (d, J = 8.3 Hz, 0.15 H), 4.73 (dd, J = 3.4, 11.8 Hz,
0.85 H), 4.33 (d, J = 11.9 Hz, 0.15 H), 3.32 (m, 0.3 H), 2.92 (dd, J =
6.1, 12.4 Hz, 1.7 H), 2.10 (s, 0.45 H), 1.99 (s, 2.55 H), 1.55−1.08 (m,
4 H), 0.93 (t, J = 7.3 Hz, 0.45 H), 0.82 (t, J = 6.8 Hz, 2.55 H) ppm;
13C NMR (100 MHz, CDCl3, major rotamer) δ = 169.8, 166.7, 162.4,
134.1, 128.8, 128.6, 128.3, 70.3, 64.5, 48.2, 40.1, 31.0, 27.2, 19.8, 13.6
ppm; HRMS m/z calcd for C17H23N2O4 [M + H]+ 319.1658, found
319.1669.
134.1, 128.8, 128.6, 128.2, 70.2, 64.5, 49.1, 48.2, 32.2, 32.0, 27.1, 25.3,
24.4, 24.3 ppm; HRMS m/z calcd for C19H25N2O4 [M + H]+
345.1814, found 345.1820.
Benzyl (2-((3S,5S)-4-formyl-3-methyl-2-oxo-5-phenylmorpholine-
3-carboxamido)ethyl)carbonate (5h): yield 68%; yellow oil; [α]25
D
+44 (c = 0.7, CHCl3); IR (neat) 3343, 2935, 1743, 1689, 1530, 1455,
1
1393, 1261, 1065, 755, 699 cm−1; H NMR (400 MHz, CDCl3, two
rotamers 1.9:1) δ = 8.47 (s, 0.65 H), 8.20 (s, 0.35 H), 7.40−7.31 (m,
8.5 H), 7.20−7.18 (m, 1.5 H), 6.80 (s, 0.35 H), 6.53 (t, J = 5.3 Hz,
0.65 H), 5.63 (s, 0.65 H), 5.17 (s, 0.7 H), 5.16 (s, 1.3 H), 5.13 (dd, J =
2.7, 8.8 Hz, 0.35 H), 5.07 (s, 0.35 H), 4.84 (dd, J = 2.4, 11.5 Hz, 0.35
H), 4.62 (dd, J = 2.9, 12.1 Hz, 0.65 H), 4.54 (d, J = 12.0 Hz, 0.65 H),
4.32−4.21 (m, 2 H), 3.60−3.57 (m, 2 H), 2.00 (s, 1.95 H), 1.90 (s,
1.05 H) ppm; 13C NMR (100 MHz, CDCl3, two rotamers) δ = 168.1,
167.5, 166.7, 162.7, 162.6, 155.2, 155.1, 137.2, 135.4, 135.0, 134.9,
129.4, 129.0, 128.9, 128.8, 128.7, 128.6, 128.5, 128.4, 128.1, 126.9,
126.2, 70.1, 70.0, 69.9, 69.2, 66.6, 66.3, 66.1, 65.7, 55.1, 51.9, 40.1,
39.9, 24.7, 20.5 ppm; HRMS m/z calcd for C23H25N2O7 [M + H]+
441.1662, found 441.1650.
(3S,5S)-4-Benzoyl-N-tert-butyl-3-methyl-2-oxo-5-phenylmorpho-
line-3-carboxamide (5e1): yield 33%; yellow gel; [α]26D +60 (c = 0.4,
CHCl3); IR (neat) 3412, 2970, 2922, 1745, 1651, 1518, 1455, 1374,
1
1292, 1197, 1110, 757, 701 cm−1; H NMR (400 MHz, CDCl3) δ =
7.41−7.33 (m, 8 H), 7.26−7.24 (m, 2 H), 5.95 (s, 1 H), 5.41 (dd, J =
2.7, 11.2 Hz, 1 H), 5.21 (s, 1 H), 4.69 (dd, J = 1.0, 11.1 Hz, 1 H), 2.05
(s, 3 H), 1.40 (s, 9 H) ppm; 13C NMR (100 MHz, CDCl3) δ = 171.3,
167.9, 166.4, 136.7, 135.5, 130.2, 129.2, 128.6, 128.4, 126.8, 126.4,
69.7, 68.7, 57.1, 52.3, 28.3, 21.5 ppm; HRMS m/z calcd for
C23H26N2O4Na [M + Na]+ 417.1790, found 417.1788.
(3R,5S)-4-Benzoyl-N-tert-butyl-3-methyl-2-oxo-5-phenylmorpho-
(3S,5S)-4-Acetyl-5-benzyl-N-tert-butyl-3-methyl-2-oxomorpho-
line-3-carboxamide (5e2): yield 8%; yellow gel; [α]26 +45 (c = 0.3,
line-3-carboxamide (5i1): yield 50%; colorless gel; [α]27 −54 (c =
D
D
CHCl3); IR (neat) 3313, 2970, 2911, 1685, 1580, 1520, 1375, 1219,
1154, 1085, 1021, 812 cm−1; 1H NMR (400 MHz, CDCl3) δ = 8.09 (s,
1H), 7.38−6.95 (m, 10 H), 5.95 (s, 1 H), 5.01 (dd, J = 4.2, 10.2 Hz, 1
H), 4.50 (dd, J = 10.5, 12.4 Hz, 1 H), 4.21 (dd, J = 4.2, 12.5 Hz, 1 H),
2.17 (s, 3 H), 1.50 (s, 9 H) ppm; 13C NMR (100 MHz, CDCl3) δ =
175.1, 169.8, 167.4, 137.3, 136.5, 131.0, 128.9, 128.3, 128.2, 127.3,
126.8, 70.0, 68.7, 61.7, 51.9, 28.6, 21.7 ppm; HRMS m/z calcd for
C23H26N2O4Na [M + Na]+ 417.1790, found 417.1793.
1.4, CHCl3); IR (neat) 3428, 2970, 2931, 1744, 1653, 1518, 1460,
1409, 1279, 1202, 1002, 753, 703 cm−1; 1H NMR (400 MHz, CDCl3)
δ = 7.38−7.28 (m, 3 H), 7.23−7.21 (m, 2 H), 5.85 (s, 1 H), 4.98 (d, J
= 11.3 Hz, 1 H), 4.19 (d, J = 11.0 Hz, 1 H), 4.08 (t, J = 6.8 Hz, 1 H),
2.94 (m, 2 H), 2.06 (s, 3 H), 2.03 (s, 3 H), 1.36 (s, 9 H) ppm; 13C
NMR (100 MHz, CDCl3) δ = 168.7, 168.4, 166.8, 136.0, 129.2, 129.1,
127.5, 67.9, 67.4, 55.3, 52.1, 37.4, 28.3, 22.3, 21.8 ppm; HRMS m/z
calcd for C19H27N2O4 [M + H]+ 347.1971, found 347.1961.
Methyl 2-((3S,5S)-4-formyl-3-methyl-2-oxo-5-phenylmorpholine-
(3R,5S)-4-Acetyl-5-benzyl-N-tert-butyl-3-methyl-2-oxomorpho-
3-carboxamido)acetate (5f): yield 63%; yellow oil; [α]27 +79 (c =
line-3-carboxamide (5i2): yield 9%; yellow gel; [α]25 −7 (c = 0.6,
D
D
0.7, CHCl3); IR (neat) 3356, 3007, 2953, 1750, 1673, 1527, 1447,
CHCl3); IR (neat) 3343, 2973, 1735, 1677, 1453, 1385, 1274, 1136,
1088, 765 cm−1; 1H NMR (400 MHz, CDCl3) δ = 7.36−7.32 (m, 2H),
7.29−7.25 (m, 3 H), 5.69 (s, 1 H), 4.30 (dd, J = 2.3, 11.8 Hz, 1 H),
4.23 (dd, J = 1.7, 11.8 Hz, 1 H), 4.04 (s, 1 H), 3.16 (m, 2 H), 2.22 (s, 3
H), 1.92 (s, 3 H), 1.42 (s, 9 H) ppm; 13C NMR (100 MHz, CDCl3) δ
= 169.1, 167.7, 166.7, 136.4, 130.9, 129.3, 129.1, 128.8, 127.2, 71.8,
66.4, 66.3, 52.0, 36.5, 28.4, 27.7, 22.3, 19.2 ppm; HRMS m/z calcd for
C19H27N2O4 [M + H]+ 347.1971, found 347.1975.
1
1362, 1208, 1064, 754, 700 cm−1; H NMR (400 MHz, CDCl3, two
rotamers 2.3:1) δ = 8.52 (s, 0.7 H), 8.27 (s, 0.3 H), 7.43−7.29 (m, 3.5
H), 7.21−7.19 (m, 1.5 H), 7.02 (s, 0.3 H), 6.88 (t, J = 5.5 Hz, 0.7 H),
5.63 (s, 0.7 H), 5.15 (s, 0.3 H), 5.13 (dd, J = 2.7, 14.2 Hz, 0.3 H), 4.87
(dd, J = 2.3, 11.4 Hz, 0.3 H), 4.75 (dd, J = 3.0, 12.2 Hz, 0.7 H), 4.60
(d, J = 12.1 Hz, 0.7 H), 4.05 (t, J = 5.5 Hz, 0.6 H), 4.02 (dd, J = 1.0,
5.9 Hz, 1.4 H), 3.76 (s, 0.9 H), 3.75 (s, 2.1 H), 2.10 (s, 2.1 H), 1.99 (s,
0.9 H) ppm; 13C NMR (100 MHz, CDCl3, two rotamers) δ = 169.6,
169.3, 168.0, 167.9, 167.4, 166.6, 162.8, 162.7, 137.3, 135.4, 129.4,
129.0, 128.9, 128.2, 126.8, 126.1, 69.8, 69.2, 55.3, 52.6, 52.5, 52.3, 42.0,
24.3, 20.5 ppm; HRMS m/z calcd for C16H19N2O6 [M + H]+
335.1243, found 335.1231.
2-((3S,5S)-4-Formyl-3-methyl-2-oxo-5-phenylmorpholine-3-
carboxamido)ethyl acetate (5j): yield 72%; yellow oil; [α]25 +54 (c
D
= 0.5, CHCl3); IR (neat) 3362, 2925, 1743, 1676, 1528, 1453, 1364,
1231, 1062, 754, 700 cm−1; 1H NMR (600 MHz, CDCl3, two rotamers
1.5:1) δ = 8.50 (s, 0.6 H), 8.25 (s, 0.4 H), 7.42−7.29 (m, 4 H), 7.22−
7.21 (m, 1 H), 6.80 (t, J = 4.9 Hz, 0.4 H), 6.57 (t, J = 5.3 Hz, 0.6 H),
5.69 (s, 0.6 H), 5.16 (dd, J = 2.7, 11.5 Hz, 0.4 H), 5.13 (s, 0.4 H), 4.88
(dd, J = 2.3, 11.5 Hz, 0.4 H), 4.65 (d, J = 1.6 Hz, 1.2 H), 4.27−4.15
(m, 2 H), 3.58−3.51 (m, 2 H), 2.09 (s, 1.2 H), 2.07 (s, 1.8 H), 2.04 (s,
1.8 H), 1.91 (s, 1.2 H) ppm; 13C NMR (100 MHz, CDCl3, two
rotamers) δ = 171.7, 171.1, 168.2, 167.3, 166.8, 162.7, 162.8, 137.1,
135.4, 129.4, 129.1, 128.9, 128.2, 126.9, 126.2, 69.9, 69.3, 66.7, 66.3,
62.3, 55.2, 51.8, 40.2, 40.1, 24.9, 20.9, 20.8, 20.5 ppm; HRMS m/z
calcd for C17H21N2O6 [M + H]+ 349.1400, found 349.1406.
(3S,5S)-4-Acetyl-N-tert-butyl-5-isopropyl-3-methyl-2-oxomor-
pholine-3-carboxamide (5k1): yield 39%; yellow gel; [α]25D −64 (c =
1.0, CHCl3); IR (neat) 3393, 2969, 2920, 1734, 1667, 1387, 1199,
1152 cm−1; 1H NMR (600 MHz, CDCl3) δ = 5.77 (s, 1 H), 5.07 (d, J
= 10.8 Hz, 1 H), 4.49 (d, J = 10.9 Hz, 1 H), 3.57 (d, J = 10.6 Hz, 1 H),
2.14 (s, 3 H), 1.90 (s, 3 H), 1.87 (m, 1 H), 1.35 (s, 9 H), 1.08 (d, J =
(3S,5S)-N-Cyclohexyl-4-formyl-3-methyl-2-oxo-5-phenylmorpho-
line-3-carboxamide (5g1): yield 71%; yellow oil; [α]27D +60 (c = 0.7,
CHCl3); IR (neat) 3347, 2931, 2856, 1749, 1679, 1523, 1452, 1357,
1
1254, 1197, 1065, 743, 698 cm−1; H NMR (400 MHz, CDCl3, two
rotamers 2.3:1) δ = 8.52 (s, 0.7 H), 8.28 (s, 0.3 H), 7.41−7.30 (m, 3.5
H), 7.22−7.20 (m, 1.5 H), 6.08 (d, J = 7.1 Hz, 0.3 H), 5.83 (d, J = 7.1
Hz, 0.7 H), 5.68 (s, 0.7 H), 5.22 (dd, J = 2.5, 11.4 Hz, 0.3 H), 5.12 (s,
0.3 H), 4.89 (dd, J = 1.8, 11.4 Hz, 0.3 H), 4.64 (d, J = 11.9 Hz, 0.7 H),
4.59 (dd, J = 2.9, 12.3 Hz, 0.7 H), 3.76 (m, 1 H), 2.05 (s, 2.1 H), 1.93
(s, 0.9 H), 1.89 (m, 1 H), 1.71 (m, 2 H), 1.64 (m, 2 H), 1.36 (m, 2 H),
1.19 (m, 3 H) ppm; 13C NMR (100 MHz, CDCl3, two rotamers) δ =
168.6, 167.1, 166.0, 165.8, 162.7, 162.5, 137.3, 135.6, 129.4, 129.0,
128.8, 128.1, 126.9, 126.2, 69.9, 69.2, 66.8, 66.3, 55.1, 52.0, 50.0, 49.6,
32.5, 32.4, 32.3, 25.5, 25.2, 24.8, 24.7, 24.6, 20.5 ppm; HRMS m/z
calcd for C19H25N2O4 [M + H]+ 345.1814, found 345.1823.
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6.5 Hz, 6H) ppm; 13C NMR (100 MHz, CDCl3) δ = 168.9, 168.5,
166.8, 68.2, 67.9, 59.8, 52.0, 28.3, 22.7, 21.1, 19.8, 19.2 ppm; HRMS
m/z calcd for C15H27N2O4 [M + H]+ 299.1971, found 299.1966.
(3R,5S)-4-Acetyl-N-tert-butyl-5-isopropyl-3-methyl-2-oxomor-
0.36 H), 1.43 (s, 1.08 H), 1.38 (s, 7.92H) ppm; 13C NMR (100 MHz,
CDCl3, major rotamer) δ = 170.0, 166.0, 162.3, 136.6, 129.3, 128.9,
127.1, 68.6, 65.0, 52.1, 47.8, 34.0, 28.3, 26.6 ppm; HRMS m/z calcd
for C18H25N2O4 [M + H]+ 333.1814, found 333.1812.
pholine-3-carboxamide (5k2): yield 9%; yellow gel; [α]27 −39 (c =
(3S,5S)-N-tert-Butyl-4-formyl-5-isopropyl-3-methyl-2-oxomor-
pholine-3-carboxamide (5o1): yield 75%; yellow gel; [α]27D −29 (c =
0.4, CHCl3); IR (neat) 3379, 2972, 2929, 1740, 1679, 1521, 1389,
1367, 1266, 1199, 1118 cm−1; 1H NMR (400 MHz, CDCl3, two
rotamers 1.5:1) δ = 8.35 (s, 0.40 H), 8.03 (s, 0.60 H), 5.94 (s, 0.60 H),
5.82 (s, 0.40 H), 5.04 (dd, J = 2.2, 11.2 Hz, 0.60 H), 4.56 (dd, J = 1.1,
11.2 Hz, 0.60 H), 4.52 (d, J = 10.9 Hz, 0.40 H), 4.35−4.30 (m, 0.80
H), 3.35 (d, J = 10.6 Hz, 0.60 H), 1.93 (s, 3 H), 1.87 (m, 1 H), 1.36 (s,
5.40 H), 1.34 (s, 3.60 H), 1.08−0.98 (m, 6 H) ppm; 13C NMR (100
MHz, CDCl3, two rotamers) δ = 169.2, 167.6, 165.8, 165.4, 163.1,
161.7, 68.1, 67.8, 66.8, 66.5, 59.3, 53.3, 52.7, 52.3, 29.0, 28.3, 27.9,
25.8, 20.5, 19.6, 19.5, 19.1 ppm; HRMS m/z calcd for C14H25N2O4 [M
+ H]+ 285.1814, found 285.1821.
D
0.3, CHCl3); IR (neat) 3445, 2921, 2852, 1747, 1657, 1385, 1257,
1127, 1066 cm−1; 1H NMR (400 MHz, CDCl3) δ = 5.62 (s, 1 H), 4.60
(d, J = 10.8 Hz, 1 H), 4.42 (d, J = 11.0 Hz, 1 H), 3.57 (bs, 1 H), 2.15
(s, 4 H), 1.91 (s, 3 H), 1.39 (s, 9 H), 1.16 (d, J = 6.1 Hz, 3 H), 1.08 (d,
J = 6.6 Hz, 3 H) ppm; 13C NMR (100 MHz, CDCl3) δ = 169.4, 169.2,
166.2, 67.3, 66.7, 51.8, 29.1, 28.4, 22.8, 20.7, 19.1 ppm; HRMS m/z
calcd for C15H27N2O4 [M + H]+ 299.1971, found 299.1969.
(3S,5S)-N-tert-Butyl-3-ethyl-4-formyl-2-oxo-5-phenylmorpholine-
3-carboxamide (5l1): yield 78.5%; colorless gel; [α]27 +57 (c = 0.6,
D
CHCl3); IR (neat) 3395, 2974, 2933, 1734, 1655, 1517, 1458, 1363,
1207, 1136, 728, 703 cm−1; 1H NMR (400 MHz, CDCl3, two rotamers
5.7:1) δ = 8.38 (s, 0.85 H), 8.29 (s, 0.15 H), 7.41−7.30 (m, 5 H), 6.04
(s, 0.15 H), 5.79 (s, 0.85 H,), 5.66 (d, J = 2.8 Hz, 0.85 H), 5.09 (s, 0.15
H), 4.85 (dd, J = 2.6, 11.7 Hz, 0.15 H), 4.71 (d, J = 5.4 Hz, 0.15 H),
4.66 (d, J = 12.0 Hz, 0.85 H), 4.54 (dd, J = 3.3, 12.1 Hz, 0.85 H), 2.87
(q, J = 7.4 Hz, 0.15 H), 2.68 (q, J = 7.3 Hz, 0.85 H), 2.33 (q, J = 7.0
Hz, 0.15 H), 2.09 (q, J = 7.3 Hz, 0.85 H), 1.36 (s, 9 H), 0.86 (t, J = 7.2
Hz, 2.55 H), 0.70 (t, J = 7.3 Hz, 0.45 H) ppm; 13C NMR (100 MHz,
CDCl3, major rotamer) δ = 168.5, 165.5, 163.4, 138.1, 128.8, 128.1,
127.1, 71.4, 69.3, 52.7, 51.2, 29.6, 28.4, 9.1 ppm; HRMS m/z calcd for
C18H25N2O4 [M + H]+ 333.1814, found 333.1804.
(3R,5S)-N-tert-Butyl-4-formyl-5-isopropyl-3-methyl-2-oxomor-
pholine-3-carboxamide (5o2): yield 12%; yellow gel; [α]27D −31 (c =
0.2, CHCl3); IR (neat) 3427, 2966, 2922, 1750, 1672, 1446, 1362,
1252, 1181, 1111, 1054 cm−1; 1H NMR (400 MHz, CDCl3, two
rotamers 5.7:1) δ = 8.54 (s, 0.85 H), 8.05 (s, 0.15 H), 7.51 (s, 0.85 H),
5.77 (s, 0.15 H), 4.67 (d, J = 11.6 Hz, 0.15 H), 4.60 (d, J = 11.3 Hz,
0.85 H), 4.43 (br d, J = 10.4 Hz, 1 H), 4.35 (dd, J = 2.7, 11.5 Hz, 0.85
H), 3.30 (br d, J = 9.8 Hz, 0.15 H), 1.96 (s, 3 H), 1.63 (m, 1 H), 1.39
(s, 1.34 H), 1.36 (s, 7.66 H), 1.12 (d, J = 6.6 Hz, 0.45 H),1.06 (d, J =
6.8 Hz, 0.45 H), 1.02 (d, J = 6.6 Hz, 2.55 H), 0.98 (d, J = 6.6 Hz, 2.55
H) ppm; 13C NMR (100 MHz, CDCl3, major rotamer) δ = 170.8,
165.9, 162.6, 70.1, 64.2, 51.8, 51.3, 28.3, 27.4, 19.9, 19.6 ppm; HRMS
m/z calcd for C14H25N2O4 [M + H]+ 285.1814, found 285.1812.
(2S,6S)-6-Phenyl-N-tert-butyl-4-butyl-1-formyl-2-methyl-3-oxopi-
perazine-2-carboxamide (11a): yield 74%; yellow oil; [α]27D +33 (c =
0.6, CHCl3); IR (neat) 3384, 2962, 2928, 2870, 1662, 1524, 1453,
(3R,5S)-N-tert-Butyl-3-ethyl-4-formyl-2-oxo-5-phenylmorpholine-
3-carboxamide (5l2): yield 9.5%; colorless gel; [α]26 +89 (c = 0.7,
D
CHCl3); IR (neat) 3360, 2972, 1728, 1683, 1534, 1459, 1367, 1279,
1216, 1134, 728, 698 cm−1; 1H NMR (400 MHz, CDCl3, major
rotamer) δ = 8.56 (s, 1 H), 7.45−7.40 (m, 2.5 H), 7.30−7.26 (m, 2.5
H), 7.09 (s, 1 H), 6.15 (d, J = 3.2 Hz, 1 H), 5.06 (d, J = 11.6 Hz, 1 H),
4.73 (dd, J = 3.6, 11.6 Hz, 1 H), 2.36 (q, J = 7.4 Hz, 2 H), 1.06 (t, J =
7.4 Hz, 3 H), 0.99 (s, 9 H) ppm; 13C NMR (100 MHz, CDCl3, major
rotamer) δ = 170.1, 164.9, 162.8, 134.2, 128.7, 128.6, 128.5, 70.6, 69.7,
51.4, 46.3, 33.6, 28.0, 8.4 ppm; HRMS m/z calcd for C18H25N2O4 [M
+ H]+ 333.1814, found 333.1808.
1
1365, 1303, 1206, 1088, 1026, 700; H NMR (400 MHz, CDCl3, two
rotamers 7.3:1) δ = 8.49 (s, 0.88 H), 8.22 (s, 0.12 H), 7.13−7.33 (m, 5
H), 5.96 (s, 0.88 H), 5.88 (s, 0.12 H), 5.65 (br s, 0.88 H), 5.11 (br s,
0.12 H), 4.27 (dd, J = 3.4, 12.6 Hz, 0.12 H), 3.81 (dd, J = 3.8, 13.5 Hz,
0.88 H), 3.66 (m, 0.12 H), 3.57 (m, 0.88 H), 3.35 (d, J = 13.4 Hz, 1
H), 3.04 (m, 0.12 H), 2.78 (m, 0.88 H), 2.04 (s, 2.64 H), 1.96 (s, 0.36
H), 1.35 (s, 1.08 H), 1.34 (s, 7.92 H), 1.05−1.23 (m, 4 H), 0.85 (t, J =
7.3 Hz, 0.36 H), 0.80 (t, J = 7.3 Hz, 2.64 H) ppm; 13C NMR (100
MHz, CDCl3, two rotamers) δ = 167.5, 167.2, 163.5, 139.7, 128.7,
127.6, 125.9, 67.1, 53.0, 52.0, 50.3, 48.4, 28.9, 28.4, 24.0, 19.8, 13.6
ppm; HRMS m/z calcd for C21H32N3O3 [M + H]+ 374.2444, found
374.2442.
(3S,5S)-4-Acetyl-N-tert-butyl-3-ethyl-2-oxo-5-phenylmorpholine-
3-carboxamide (5m): yield 78%; colorless gel; [α]24 +24 (c = 0.3,
D
CHCl3); IR (neat) 3288, 2972, 2925, 1761, 1660, 1541, 1457, 1388,
1
1219, 1162, 763, 706 cm−1; H NMR (400 MHz, CDCl3) δ = 7.39−
7.35 (m, 5 H), 6.62 (s, 1 H), 5.17 (bs, 1 H), 5.05 (bs, 1 H), 4.55 (bs, 1
H), 2.90 (bs, 1 H), 2.61 (q, J = 6.6 Hz, 1 H), 2.18 (bs, 3 H), 1.36 (s, 9
H), 0.80 (bs, 3 H) ppm; 13C NMR (100 MHz, CDCl3) δ = 172.8,
167.8, 167.1, 138.0, 129.2, 128.6, 127.0, 74.5, 68.6, 57.6, 52.2, 28.5,
27.5, 24.2, 10.7; HRMS m/z calcd for C19H26N2O4K [M + K]+
385.1530, found 385.1535.
Methyl 2-((2S,6S)-6-benzyl-1-formyl-2,4-dimethyl-3-oxopipera-
zine-2-carboxamido)acetate (11b): yield 63%; yellow oil; [α]10.6
D
(3S,5S)-5-Benzyl-N-tert-butyl-4-formyl-3-methyl-2-oxomorpho-
line-3-carboxamide (5n1): yield 55%; yellow oil; [α]27 −7 (c = 0.6,
−52 (c = 0.9, CH2Cl2); IR (neat) 3358, 3059, 3027, 2949, 1751, 1672,
D
1
1522, 1439, 1402, 1366, 1208, 1095, 1051, 1021, 979, 737, 703; H
CHCl3); IR (neat) 3395, 2931, 1734, 1687, 1517, 1452, 1386, 1307,
1253, 745, 701 cm−1; 1H NMR (400 MHz, CDCl3, two rotamers 2:1)
δ = 8.41 (s, 0.67 H), 7.86 (s, 0.33 H), 7.36−7.25 (m, 4 H), 7.21 - 7.18
(m, 1 H), 6.06 (s, 0.33 H), 5.75 (s, 0.67 H), 4.99 (dd, J = 2.3, 11.0 Hz,
0.33 H), 4.63 (dd, J = 2.8, 11.2 Hz, 0.67 H), 4.31 (d, J = 10.5 Hz, 0.33
H), 4.19 (d, J = 12.0 Hz, 0.67 H), 4.11 (dd, J = 1.9, 12.1 Hz, 0.67 H),
4.04 (t, J = 7.9 Hz, 0.33 H), 2.04 (s, 0.99 H), 1.96 (s, 2.01 H), 1.35 (s,
2.97 H), 1.33 (s, 6.03 H) ppm; 13C NMR (100 MHz, CDCl3, two
rotamers) δ = 169.3, 167.5, 165.9, 165.5, 162.6, 161.5, 136.3, 135.5,
129.5, 129.2, 128.9, 127.6, 127.1, 68.8, 66.6, 66.3, 66.0, 54.4, 52.7, 52.3,
50.4, 38.5, 36.4, 28.3, 25.2, 21.1 ppm; HRMS m/z calcd for
C18H25N2O4 [M + H]+ 333.1814, found 333.1819.
NMR (400 MHz, CDCl3, two rotamers 2.8:1) δ = 8.32 (s, 0.74 H),
7.86 (s, 0.26 H), 7.13−7.33 (m, 5 H), 6.80 (s, 0.74 H), 6.62 (s, 0.26
H), 4.71 (d, J = 10.8 Hz, 0.74 H), 3.84−4.13 (m, 2.52 H), 3.69 (s, 0.78
H), 3.66 (s, 2.22 H), 3.40 (dd, J = 2.7, 13.3 Hz, 0.74 H), 3.00 (s, 2.22
H), 2.99 (s, 0.78 H), 2.80−2.96 (m, 2.26 H), 2.54 (t, J = 11.7 Hz, 0.74
H), 2.00 (s, 0.78 H), 1.95 (s, 2.22 H) ppm; 13C NMR (100 MHz,
CDCl3, two rotamers) δ = 172.4, 169.8, 169.6, 169.2, 168.4, 166.6,
165.7, 163.4, 137.3, 136.4, 129.3, 129.2, 129.1, 129.0, 127.5, 127.1,
66.0, 65.9, 58.4, 55.0, 52.5, 52.5, 50.4, 50.1, 47.3, 42.1, 41.9, 39.5, 37.5,
36.6, 25.8, 20.2 ppm; HRMS m/z calcd for C21H32N3O3 [M + H]+
362.1716, found 362.1720.
Procedure for Synthesis of 5l2 via Alkylation of 4d. To a
solution of 4d (25.6 mg, 0.084 mmol) in DMF (0.84 mL) were added
successively Cs2CO3 (27.4 mg, 0.084 mmol) and C2H5I (67.3 μL, 0.84
mmol) under argon atmosphere. The resulting mixture was stirred at
room temperature for 1.5 h and diluted with brine, and the aqueous
phase was extracted with EtOAc. The combined organic layers were
washed with water, dried with Na2SO4, and concentrated under
vacuum. The residue was further purified by flash column
chromatography on silica gel using petroleum ether/ethyl acetate
(3R,5S)-5-Benzyl-N-tert-butyl-4-formyl-3-methyl-2-oxomorpho-
line-3-carboxamide (5n2): yield 16%; yellow oil; [α]27D −26 (c = 0.1,
CHCl3); IR (neat) 3427, 2976, 2923, 1740, 1703, 1676, 1511, 1460,
1
1374, 1254, 1189, 746, 701 cm−1; H NMR (400 MHz, CDCl3, two
rotamers 7.3:1) δ = 8.46 (s, 0.88 H), 7.97 (s, 0.12H), 7.33−7.31 (m, 3
H), 7.28−7.26 (m, 2 H), 7.12 (s, 0.88 H), 5.84 (s, 0.12 H), 4.78 (ddd,
J = 3.2, 3.3, 11.9 Hz, 0.88 H), 4.38 (br s, 0.24 H), 4.26 (d, J = 3.0 Hz,
1.76 H), 3.96 (m, 0.12 H), 3.19 (m, 0.24 H), 3.08 (dd, J = 3.6, 13.2
Hz, 0.88 H), 2.46 (t, J = 12.6 Hz, 0.88 H), 1.99 (s, 2.64 H), 1.94 (s,
1393
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The Journal of Organic Chemistry
Article
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ASSOCIATED CONTENT
* Supporting Information
Description of the general experimental procedures and NMR
spectra of the compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
*E-mail: chenxc@scu.edu.cn
■
Tetrahedron Lett. 1998, 39, 7109−7112. (e) Demharter, A.; Horl, W.;
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Herdtweck, E.; Ugi, I. Angew. Chem. Int. Ed.. 1996, 35, 173−175.
Author Contributions
(f) Ugi, I.; Demharter, A.; Horl, W.; Schmid, T. Tetrahedron 1996, 52,
̈
§These individuals contributed equally to this work.
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ACKNOWLEDGMENTS
■
We thank Sichuan University Analytical and Testing Center for
NMR determination. We also thank Prof. Xiaoming Feng
group for optical rotation tests. This work was supported by
grants from the National Natural Science Foundation of China
(No. 20802045 and 21172153), the National Basic Research
Program of China (973 Program, No. 2012CB833200), and the
Foundation of the Education Ministry of China for Returnees.
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