2,4,6-Trihydroxybenzoic Acid-Catalyzed Oxidative Ugi Reactions with Molecular Oxygen via Homo- And Cross-Coupling of Amines

Article abstract of DOI:10.1021/acs.joc.9b01422

Metal-free, oxidative four-component Ugi reactions (U-4CRs) were conducted to synthesize dipeptides from two different amines, isocyanides, and carboxylic acids using 2,4,6-trihydroxybenzoic acid catalyst in O₂ atmosphere. The organocatalytic U-4CRs proceed via oxidative cross-coupling of benzylamines with other aliphatic or aromatic amines to form imines, followed by condensation with isocyanides and carboxylic acids. The U-4CRs via cross-coupling of amines are rare, and the simple, metal-free procedures are advantageous for further applications in drug and heterocycle syntheses.

Full text of DOI:10.1021/acs.joc.9b01422

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Article
2,4,6-Trihydroxybenzoic Acid-Catalyzed Oxidative Ugi Reactions
with Molecular Oxygen via Homo- and Cross-Coupling of Amines
Chun-Ping Dong, Akinori Uematsu, Shun Kumazawa, Yuki Yamamoto,
Shintaro Kodama, Akihiro Nomoto, Michio Ueshima, and Akiya Ogawa
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01422 • Publication Date (Web): 21 Aug 2019
Downloaded from pubs.acs.org on August 21, 2019
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2,4,6-Trihydroxybenzoic Acid-Catalyzed Oxidative Ugi Reactions with
Molecular Oxygen via Homo- and Cross-Coupling of Amines
Chun-ping Dong, Akinori Uematsu, Shun Kumazawa, Yuki Yamamoto, Shintaro Kodama,
Akihiro Nomoto, Michio Ueshima, and Akiya Ogawa*
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Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture
University, 1-1 Gakuen-cho, Nakaku, Sakai, Osaka 599-8531, Japan
E-mail: ogawa@chem.osakafu-u.ac.jp
OH
R1
COOH
O
O
R2
H
cat.
NH2
HO
O2 (0.1 MPa)
OH
HO
C
R3
R4
N
R1
N
H2N R2
R3
N
R2
R4
R1
+
N
O
Ugi Reaction
(R2 = Aryl, Aliphatic)
Oxidative Cross-Coupling of Amines
One-Pot Synthesis of Di-Peptides
Organocatalytic Oxidative Ugi Reaction



ABSTRACT
Metal-free, oxidative four-component Ugi reactions (U-4CRs) were conducted to
synthesize di-peptides from two different amines, isocyanides, and carboxylic acids using
2,4,6-trihydroxybenzoic acid catalyst in O2 atmosphere. The organocatalytic U-4CRs proceed
via oxidative cross-coupling of benzylamines with other aliphatic or aromatic amines to form
imines, followed by condensation with isocyanides and carboxylic acids. The U-4CRs via
cross-coupling of amines are rare, and the simple, metal-free procedures are advantageous for
further applications in drug and heterocycle syntheses.
INTRODUCTION
Ugi four-component reactions (U-4CRs) are convergent chemical processes involving
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the condensation of an amine, an aldehyde, a carboxylic acid, and an isocyanide with high
levels of atom efficiency.1 The U-4CRs are among the most widely applied multicomponent
reactions and are considered to be efficient strategies for the synthesis of different scaffolds,
which are usually used in combinatorial,2 pharmaceutical,3 and polymer chemistry.4
Moreover, normal-sized5 or medium-sized6 heterocyclic rings can also be constructed via the
U-4CRs.
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The U-4CRs are believed to proceed through imine intermediates, which generally
formed in situ from the aldehydes and primary amines.7 Based on this, the U-4CRs have
undergone many modifications which involved the combination of two substrates together in
one molecule or the precondensation of the imines.8 Among them, oxidative Ugi reactions,
wherein the imines are formed in situ by oxidation of amines, have recently gained
considerable attention.9-12 The first example was reported by Zhu et al. in 2007, in which 2-
iodoxybenzoic acid was used as an organic oxidant to generate imines from heterocyclic
secondary amines (Scheme 1, eq 1).9 Since then, several oxidative Ugi reactions have been
investigated using different oxidants.10 In particular, molecular oxygen (O2) aroused great
interest as a green, abundant, and easily available oxidant for the oxidative Ugi reactions.
Transition metal catalysts are useful in combination with O2 to accomplish oxidative Ugi
reactions (Scheme 1, eq 2).11 In general, metal-catalyzed reactions attain high selectivity;
however, the resulting products may contain metal contaminations and often cause significant
problems in the further application. In contrast, organocatalytic oxidative Ugi reactions with
O2 are advantageous12 but have remained largely undeveloped; a metal-free method using
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meso-tetraphenylporphyrin (H2TPP) as a photosensitizer was reported as the limited protocol
for performing oxidative Ugi reactions upon photoirradiation in O2 atmosphere (Scheme 1,
eq 3).13 Therefore, the development of organocatalytic oxidative Ugi reactions using O2 as
the terminal oxidant is still strongly desired. Besides, all the reported oxidative Ugi reactions
are based on homo-coupling of amines or oxidation of heterocyclic secondary amines; the
cross-coupling of two different primary amines are seldom involved in the oxidative Ugi
reactions.10a
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Recently, while studying the green oxidation reactions of amines to imines in O2
atmosphere,14 we successfully developed a metal-free oxidative homo-coupling of
benzylamines to imines using salicylic acid derivatives as organocatalysts.15 Moreover, this
metal-free amine oxidation could be applied for synthesizing N-containing heterocycles and
blue dyes.16 In the present study, we have focused our attention on a new and efficient metal-
free multicomponent Ugi reaction involving the oxidation of amines to imines using O2 in the
presence of an organocatalyst, 2,4,6-trihydroxybenzoic acid. It is noteworthy that not only
the homo-coupling of benzylamines but also their cross-coupling with other aliphatic or
aromatic amines could proceed in the presence of this organocatalyst. This oxidative U-4CR
with two different amines, a carboxylic acid, and an isocyanide is a rare example of such a
reaction (Scheme 1, eq 4).
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Scheme 1. Oxidative Ugi Reactions
6
7
8
9
Reported Oxidative Ugi Reactions:
H
N
O
N
Ref. 9
R'
O
IBX (2.0 equiv)
RCOOH, R' NC
NH
R
(1)
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Fe(NO3)3 (10 mol%)
TEMPO (10 mol%)
RCOOH, R' NC
Ref. 11b
Ref. 13
Ph
O
NH2
(2)
R
N
N
R'
N
H
air balloon
O
Ph
Ph
O
R
R'
R
NH
or
N
H
H2TPP (0.1 mol%)
RCOOH, R' NC
O
Ph
(3)
O2 (0.1 MPa)
4 Å MS, hv
NH
N
O
R'
O
N
H
This Work:
OH
COOH
NH2
R1
R1
cat.
HO
OH
O
(4)
+
H
N
R3COOH,R4 NC
O2 (0.1 MPa)
R3
N
R2
R4
R2 NH2
O
(R2 = Aryl, Aliphatic)
RESULTS AND DISCUSSION
The homo-coupling reaction of benzylamine (1a) was conducted according to our
previous work,15 and 2-chloroacetic acid (2a), isocyanocyclohexane (3a), and toluene (2.0
mL) were added to the reaction mixture and stirred at 90 °C in O2 atmosphere (using O2
balloon). This afforded 11% of di-peptide 4a (Table 1, entry 1). Encouraged by this result,
we continued to optimize the reaction conditions of the second step of this oxidative Ugi
reaction. When the Ugi reaction was performed at room temperature, the yield of 4a was
improved to 52% (Table 1, entry 2). Prolonging the reaction time hindered the formation of
4a in O2 atmosphere (Table 1, entry 3). The same reaction in air generated 60% of 4a in 24 h
(Table 1, entry 4). Thus, the reaction conditions of the Ugi reaction were further optimized in
air. Shortening the reaction time led to a decreased yield of the product (Table 1, entry 5).
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Using CH3OH, instead of toluene, as the solvent in the Ugi reaction favored the formation of
4a (Table 1, entry 6). We further examined the first step of this oxidative Ugi reaction using
CH3OH as a solvent; however, the homo-coupling of benzylamine was totally suppressed,
and therefore 4a was not obtained (Table 1, entry 7). The homo-coupling of benzylamine
under neat condition, in combination with the Ugi reaction in CH3OH, afforded 4a in slightly
decreased yield (Table 1, entry 8). Increasing the amount of benzylamine to 3.0 mmol
improved the yield of 4a (93% yield) (Table 1, entry 6 vs entry 9). Based on these
observations, we optimized the reaction conditions for the one-pot oxidative Ugi reaction.
Briefly, 3.0 mmol of 1a was oxidized in toluene at 90 °C in O2 atmosphere for 2 h, using
2,4,6-trihydroxybenzoic acid as the organocatalyst. The O2 balloon was removed after this,
and the reaction mixture was cooled to room temperature and used directly without
evaporating toluene for carrying out the Ugi reaction with 2a (1.0 mmol), 3a (1.0 mmol), and
CH3OH (2.0 mL) for 24 h (for details, see the Experimental Section).
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Table 1. Optimization of Oxidative Ugi Reaction via Homo-Coupling of Benzylamines
1st step
2nd step
O
OH
2a
(1.0 mmol)
Cl
OH
NC
O
COOH
(5.0 mol%)
OH
Cl
3a
(1.0 mmol)
N
N
cat.
H
HO
NH2
N
solvent, 90 C, 2 h
O2 (0.1 MPa)
solvent, temp., time
air
Ugi reaction
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O
4a
1a
(2.0 mmol)
1st step
2nd step
temp. (C)
entry
yield of 4aa (%)
solvent (mL)
toluene (1.0)
toluene (1.0)
toluene (1.0)
toluene (1.0)
toluene (1.0)
toluene (1.0)
CH3OH (1.0)
neat
solvent (mL)
toluene (2.0)
toluene (2.0)
toluene (2.0)
toluene (2.0)
toluene (2.0)
CH3OH (2.0)
CH3OH (2.0)
CH3OH (2.0)
CH3OH (2.0)
time (h)
22
1b
2b
3b
4
90
rt
rt
rt
rt
rt
rt
rt
rt
11
22
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36
40
60
24
5
18
50
6
36
65
7
92
no reaction
62
8
36
9c
toluene (1.0)
24
93 (76)
aDetermined by 1H NMR using bibenzyl as the internal standard (isolated yield); the yields are based on
2a. bUgi reactions were conducted in O2 atmosphere. cBenzylamine 1a (3.0 mmol) was used.
The reaction scope of this oxidative Ugi reaction (Scheme 2) was examined under the
optimized reaction conditions (Table 1, entry 9). A variety of benzylamine derivatives such
as para-tert-butyl, ortho-methoxy, meta-methoxy, para-methoxy, para-methyl, and ortho-
bromo benzylamines could be oxidized, and then the in situ formed imine derivatives were
successfully used in the Ugi reaction with 2-chloroacetic acid and isocyanocyclohexane to
afford the corresponding di-peptides 4b‒4f, and 4h in good to excellent yields, but the
reaction of 4-nitrobenzylamine failed to form the desired product 4g. In addition, 2-
pyridinemethylamine was examined as a substrate. Unfortunately, however, the reaction
hardly proceeded. Isocyanide derivatives and carboxylic acid derivatives were also examined
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under the standard reaction conditions. The oxidative Ugi reactions of benzyl isocyanide (3j),
tert-butyl isocyanide (3k), or 1-isocyanopentane (3l) proceeded well to form the products
4j‒4l. When aromatic carboxylic acids such as benzoic acid (2m) and 4-bromobenzoic acid
(2n), or an aliphatic carboxylic acid (2o) was employed, the di-peptides 4m‒4o were obtained
in high yields.
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Scheme 2. Oxidative Ugi Reactions via Homo-Coupling of Benzylaminesa
R1
OH
O
O
COOH
2
(1.0 mmol)
(1.0 mmol)
R3
OH
(5.0 mol%)
OH
R3
N
R4 NC
cat.
H
3
HO
NH2
R1
N
R4
O2 (0.1 MPa), 90 C, 2 h
toluene (1.0 mL)
air, rt, 24 h
CH3OH (2.0 mL)
R1
O
1
4
(3.0 mmol)
O
O
O
O
O
O
Cl
N
Cl
Cl
N
H
H
N
Cl
H
N
H
N
N
N
N
O
O
O
O
O
O
4a
4b
4c
4d 94% (91%)
93% (76%)
O
95% (94%)
63% (62%)
NO2
O
O
O
O
Br
Cl
Cl
Cl
Cl
N
H
N
H
N
H
N
H
N
N
N
N
O
O
O
O
O
O2N
Br
4e
4f
4g
4h
60% (49%)
78% (58%)
O
trace
60% (33%)
N
O
O
O
Cl
Cl
Cl
Cl
N
H
N
H
N
H
N
H
N
N
N
N
N
O
O
O
O
4k
4l
(89%)
4i
4j
(74%)
trace
82% (71%)
O
O
O
H
N
N
N
N
H
H
N
O
N
Br
O
O
4m
4n
4o
94% (91%)
81% (76%)
95% (91%)
aDetermined by 1H NMR using bibenzyl as the internal standard (Isolated yields); the yields are based on
2.
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The oxidative Ugi reaction via cross-coupling of amines is still unexplored. The cross-
coupling imine products are usually synthesized from the condensation of amines with
aldehydes, alcohols, or other amines.17 Although metal-catalyzed18 and metal-free19 methods
have been studied for the cross-coupling of amines, metal-free methods based on
organocatalysts20 are rarely reported. Thus, the cross-coupling of amines was investigated
next. The reaction conditions for cross-coupling were optimized using benzylamine (1a, 1.0
mmol) and hexylamine (5a, 2.0 mmol) as the model substrates in the presence of 2,4,6-
trihydroxybenzoic acid as an organocatalyst (Table 2). 2,4,6-Trihydroxybenzoic acid (5
mol%) catalyzed the cross-coupling reaction of 1a with 5a to generate 47% of cross-coupling
product 6a and 21% of homo-coupling product 7a (Table 2, entry 1). Increasing the load of
the catalyst to 15 mol% led to the formation of 6a in 79% yield, along with a trace amount of
7a (Table 2, entry 2). Conducting the reaction under neat conditions, lowering the
concentration of the reaction, and varying the reaction time resulted in reduced yields of 6a
(Table 2, entries 3‒6). In the reaction system, no formation of oxidative products derived
from aliphatic amines was observed.
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Table 2. Optimization of Cross-Coupling of Benzylamine with Hexylamine
8
9
OH
COOH
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cat.
HO
OH
NH2
N
+
NH2
O2 (0.1 MPa), 90 C, time
toluene
6a
1a
5a
(1.0 mmol)
(2.0 mmol)
N
+
7a
yield (%)a
cat.
toluene time
entry
(mol %) (mL)
(h)
6a
7a
21
1
2
3
4
5
6
5
1.0
1.0
neat
1.5
1.5
1.5
6
6
47
15
15
15
15
15
79 (71) trace
6
21
61
64
52
trace
6
6
24
trace
2
27
aDetermined by 1H NMR using 1,3,5-trioxane as the
internal standard (isolated yield); the yields are based
on 1a.
With the optimized reaction conditions in hand (Table 2, entry 2), we examined the
coupling of benzylamine derivatives with a series of amines (Scheme 3). The coupling of
benzylamine with aliphatic and aromatic amines could successfully afford the cross-coupling
products 6a‒6f. When benzylamines with a methoxy substituent at ortho, meta, and para
positions were used as the substrates, the corresponding imines 6g‒6i were formed in good
yields. The presence of electron-withdrawing and electron-donating groups at para positions
of benzylamines afforded 6j and 6k in satisfactory yields. The reaction of 1-
naphthylmethylamine 1l also proceeded smoothly under the standard reaction conditions.
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Scheme 3. Cross-Coupling of Benzylamines with Other Aminesa
8
OH
9
COOH
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13
14
15
16
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19
20
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60
(15.0 mol%)
R2
OH
cat.
HO
NH2
N
R1
H2N R2
+
R1
O2 (0.1 MPa), 90 C, 6 h
toluene (1.0 mL)
1
5
6
(1.0 mmol)
(2.0 mmol)
N
N
N
6a
6b
6c
(80%)
79% (71%)
95% (83%)
N
N
N
b
6d
6e
6f
51%
(79%)
11%
O
O
N
N
6g
6h
6j
48%
(66%)
N
N
F
F
O
F
6i
80%
N
(61%)
N
6k
6l
48%
61%
aDetermined by 1H NMR using bibenzyl as the
internal standard (Isolated yields); the yields are
based on 1; 6e, 6f, 6g, 6i, 6k, and 6l were difficult to
b
purify because of hydrolysis. CH3CN was used as
solvent.
Since the cross-coupling of amines was successful, we further examined the oxidative
Ugi reactions based on the cross-coupled imines using 2,4,6-trihydroxybenzoic acid as the
organocatalyst. To carry out the Ugi reaction smoothly, 2.0 mmol of carboxylic acids and 0.8
mmol of isocyanides were added after the cross-coupling of two different amines (Scheme
4). Aliphatic amines such as hexylamine, cyclohexanamine, and 3-phenylpropylamine could
be successfully converted to the corresponding di-peptides 8a, 8b, and 8g, but the reaction of
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2-ethylhexylamine failed to form the product 8c probably due to a steric hindrance of the
amine. When the aromatic amine, aniline, was examined for the oxidative Ugi reaction, the
product 8d was formed in good yield. However, 1-phenylethylamine and
triphenylmethanamine could not be converted to di-peptides 8e and 8f. The failure of these
examples may be because of steric hindrance. Then, the cross-coupling of aniline with several
benzylamines were performed for the oxidative Ugi reactions. Benzylamines with a methoxy
group at the ortho, meta, and para positions were examined, and the corresponding di-
peptides 8h‒8j were formed in satisfactory yields. When benzylamines bearing other
substituents at the para positions, such as 4-tert-butyl and 4-chloro, were employed as
substrates, the desired products 8k and 8l were also obtained successfully. In particular, the
reaction of 4-tert-butylbenzylamine led to di-peptide 8k in 86% yield. Additionally, a series
of isocyanide derivatives and carboxylic acid derivatives were examined. When the oxidative
Ugi reactions of isocyanide derivatives such as benzyl isocyanide, tert-butyl isocyanide, and
1-isocyanopentane were performed, the corresponding products 8m‒8o were generated in
moderate to good yields. Both aromatic and aliphatic carboxylic acids had tolerance under
the reaction conditions of oxidative Ugi reaction, and afforded di-peptides 8p‒8s successfully.
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Scheme 4. Oxidative Ugi Reactions via Cross-Coupling of Aminesa
8
9
OH
O
O
COOH
2
(2.0 mmol)
(0.8 mmol)
R2
O
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R3
N
R3
R4 NC
OH
(15.0 mol%)
OH
H
3
HO
N
NH2
R4
R1
H2N R2
+
R1
O2 (0.1 MPa), 90 C, 6 h
toluene (1.0 mL)
air, rt, 24 h
1
5
8
(1.5 mmol)
(3.0 mmol)
O
O
O
O
O
Cl
Cl
N
Cl
Cl
N
H
N
Cl
Cl
Cl
N
H
H
H
N
N
N
N
N
H
N
O
O
O
O
O
b
8a
8b
8c
8d
8e
62% (39%)
53% (37%)
O
trace
N
77% (61%)
O
N.D.
O
Ph
Ph
Ph
O
O
Cl
Cl
N
H
Cl
Cl
H
N
H
N
N
N
H
N
H
N
N
N
O
O
O
O
O
O
O
O
b
b
b
8j
8f
8g
8h
8i
(56%)
N.D.
58% (64%)
O
61% (57%)
O
66% (58%)
O
O
O
N
Cl
Cl
Cl
Cl
H
N
H
N
H
N
H
N
N
H
N
N
N
N
O
O
O
O
O
Cl
b
8k
8l
8m
8n
8o
(86%)
(37%)
Br
59% (48%)
82% (78%)
63% (46%)
O
N
H
N
O
N
O
N
H
H
O
N
N
N
H
N
O
O
O
O
8p
8q
8r
8s
69% (38%)
42% (41%)
24%
46% (33%)
aDetermined by 1H NMR using bibenzyl as the internal standard (Isolated yields); the yields are based
on 3. b1.0 mL of CH3OH was used as the solvent.
Imines are believed as the intermediates for Ugi reactions.7 To further confirm this, imine
9 was used as the substrate to condense with 2-chloroacetic acid (2a) and
isocyanocyclohexane (3a) in the absence of the catalyst and O2 atmosphere. As a result, the
product 4a was generated in 88% yield (Scheme 5, eq 5). This result suggests that imines are
the real intermediates for Ugi reactions and 2,4,6-trihydroxybenzoic acid only plays the
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catalytic role for the formation of imine intermediates during this oxidative Ugi reactions.
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Scheme 5. Control Experiment
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9
O
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Cl
N
O
H
N
+
+
N
(5)
NC
Cl
MeOH (2 mL)
N2, rt, 24 h
OH
(1.0 mmol)
O
9
2a
3a
4a
(88%)
(1.5 mmol)
(1.0 mmol)
CONCLUSIONS
In summary, we have developed a facile oxidative Ugi reaction in O2 atmosphere that is
promoted by 2,4,6-trihydroxybenzoic acid. 2,4,6-Trihydroxybenzoic acid behaves as an
organocatalyst for the oxidation of amines to imines, whereas other reported oxidative U-
4CRs often require metal catalysts and the resulting metal contaminations of final products
may cause problems in the applications to pharmaceutical discovery process. The present
oxidative Ugi reactions were performed efficiently via both homo-coupling and cross-
coupling of amines, followed by condensation with carboxylic acids and isocyanides. These
reactions demonstrated here are rare examples of the organocatalytic oxidative Ugi reactions.
EXPERIMENTAL SECTION
General Remarks Unless otherwise stated, all starting materials and catalysts were
purchased from commercial sources and used without further purification. All solvents were
1
distilled and degassed with nitrogen before use. H NMR spectra were recorded on JEOL
JNM-ECS400 (400 MHz) FT NMR system or JEOL JNM-ECX400 (400 MHz) FT NMR
13
system in CDCl3 with Me4Si as an internal standard. C NMR spectra were recorded on
JEOL JNM-ECX400 (100 MHz) FT NMR or JEOL JNM-ECS400 (100 MHz) FT NMR in
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9
CDCl3. IR spectra were reported in wave numbers (cm-1). CI and EI mass spectra were
obtained by employing double focusing mass spectrometers. ESI mass spectra were obtained
with a LCMS-IT-TOF mass spectrometer.
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General Procedure for the Synthesis of Di-Peptides (4). Benzylamines 1 (3.0 mmol),
2,4,6-trihydroxybenzoic acid (25.5 mg, 0.15 mmol), and toluene (1.0 mL) were added to a
two-necked flask equipped with O2 balloon at room temperature, and stirred at 90 °C under
O2 atmosphere for 2 h. Then O2 balloon was removed, the reaction mixture was cooled to
room temperature. To the mixture were added methanol (2.0 mL), carboxylic acids 2 (1.0
mmol), and isocyanides 3 (1.0 mmol), and the resulting solution was stirred at room
temperature in air for 24 h. After the reaction was finished, the resulting mixture was
transferred into round-bottom flask using methanol (5 mL) and concentrated under reduced
pressure. Finally, the residue was purified by gel permeation chromatography (eluent:
chloroform) to give product 4.
N-Benzyl-2-chloro-N-(2-(cyclohexylamino)-2-oxo-1-phenylethyl)acetamide (4a). white
o
1
solid, 303.2 mg, 76%, mp 139-141 C; H NMR (400 MHz, CDCl3): δ 7.28-7.36 (m, 5H),
7.15-7.23 (m, 3H), 7.03 (d, J = 6.9 Hz, 2H), 5.93 (s, 1H), 5.76 (d, J = 7.8 Hz, 1H), 4.79 (d, J
= 17.9 Hz, 1H), 4.59 (d, J = 17.9 Hz, 1H), 4.04 (d, J = 12.8 Hz, 1H), 3.92 (d, J = 12.8 Hz,
1H), 3.78 (s, 1H), 1.88 (s, 2H), 1.55-1.67 (m, 3H), 1.28-1.37 (m, 2H), 1.06-1.12 (m, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 168.4, 168.0, 136.8, 134.6, 129.7, 129.0, 128.9, 128.7,
127.5, 126.1, 63.4, 50.1, 48.8, 42.3, 32.8, 25.5, 24.9, 24.8; IR (KBr, ν/cm–1): 3271, 2927,
2854, 1647, 1552, 1451, 1219, 731, 698; HRMS (EI) m/z calcd for C23H28ClN2O2 [M+H]+:
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399.1839, found: 399.1844.
N-(4-(tert-Butyl)benzyl)-N-(1-(4-(tert-butyl)phenyl)-2-(cyclohexylamino)-2-oxoethy-l)-2-
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9
o
1
chloroacetamide (4b). yellow solid, 480.5 mg, 94%, mp 104-105 C; H NMR (400 MHz,
CDCl3): δ 7.27-7.33 (m, 4H), 7.20 (d, J = 8.2 Hz, 2H), 6.90 (d, J = 7.3 Hz, 2H), 5.91 (s, 1H),
5.72 (d, J = 8.2 Hz, 1H), 4.74 (d, J = 17.9 Hz, 1H), 4.54 (d, J = 17.4 Hz, 1H), 4.07 (d, J =
12.8 Hz, 1H), 3.95 (d, J = 12.8 Hz, 1H), 3.79-3.81 (m, 1H), 1.86-1.93 (m, 2H), 1.56-1.67 (m,
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4H), 1.20-1.33 (m, 20H), 1.10-1.11 (m, 3H); C{1H} NMR (100 MHz, CDCl3): δ 168.2,
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151.9, 150.3, 133.8, 131.6, 129.5, 125.9, 125.8, 125.5, 63.0, 49.8, 48.8, 42.4, 34.6, 34.5, 32.8,
31.4, 31.3, 25.5, 24.9, 24.8; IR (KBr, ν/cm–1): 3312, 2933, 2858, 1645, 1515, 1455, 1363,
1274, 819, 559; HRMS (ESI) m/z calcd for C31H43ClN2O2Na [M+Na]+: 533.2905, found:
533.2910.
2-Chloro-N-(2-(cyclohexylamino)-1-(2-methoxyphenyl)-2-oxoethyl)-N-(2-methoxy-
o
1
benzyl)acetamide (4c). white solid, 284.3 mg, 62%, mp 197-199 C; H NMR (400 MHz,
CDCl3): δ 7.40 (d, J = 7.7 Hz, 1H), 7.10-7.21 (m, 3H), 6.85 (t, J = 7.5 Hz, 1H), 6.77 (t, J =
7.5 Hz, 1H), 6.68 (t, J = 7.9 Hz, 2H), 6.03 (s, 1H), 5.56 (d, J = 8.2 Hz, 1H), 4.55-4.67 (m,
2H), 4.19 (d, J = 12.7 Hz, 1H), 4.07 (d, J = 12.7 Hz, 1H), 3.73-3.79 (m, 7H), 1.87 (s, 2H),
1.55-1.66 (m, 3H), 1.27-1.38 (m, 2H), 0.97-1.14 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3):
δ 168.4, 168.0, 157.7, 156.5, 130.4, 130.1, 128.4, 127.2, 124.7, 122.6, 120.6, 120.3, 110.1,
109.7, 58.5, 55.2, 48.5, 46.2, 42.2, 32.9, 32.8, 25.6, 24.9, 24.8; IR (KBr, ν/cm–1): 3279, 2934,
2853, 1645, 1561, 1495, 1467, 1242, 1110, 1032, 949, 751, 540; HRMS (ESI) m/z calcd for
C25H31ClN2O4Na [M+Na]+: 481.1865, found: 481.1865.
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2-Chloro-N-(2-(cyclohexylamino)-1-(3-methoxyphenyl)-2-oxoethyl)-N-(3-methoxy-
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7
8
9
o
1
benzyl)acetamide (4d). white solid, 417.8 mg, 91%, mp 144-145 C; H NMR (400 MHz,
CDCl3): δ 7.22 (t, J = 8.0 Hz, 1H), 7.14 (t, J = 8.0 Hz, 1H), 6.92-6.97 (m, 2H), 6.83 (dd, J =
8.2, 1.8 Hz, 1H), 6.67-6.73 (m, 2H), 6.58 (s, 1H), 5.90 (s, 1H), 5.78 (d, J = 7.3 Hz, 1H), 4.75
(d, J = 17.9 Hz, 1H), 4.58 (d, J = 17.4 Hz, 1H), 4.05 (d, J = 12.8 Hz, 1H), 3.92 (d, J = 13.3
Hz, 1H), 3.75-3.80 (m, 1H), 3.72 (s, 3H), 3.70 (s, 3H), 1.86-1.92 (m, 2H), 1.56-1.67 (m, 3H),
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1.28-1.37 (m, 2H), 1.06-1.12 (m, 3H); C{1H} NMR (100 MHz, CDCl3): δ 168.4, 167.9,
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159.9, 138.6, 136.2, 130.0, 129.8, 121.9, 118.4, 115.0, 114.8, 113.2, 111.5, 63.4, 55.3, 55.3,
50.1, 48.7, 42.3, 32.8, 25.5, 24.9, 24.8; IR (KBr, ν/cm–1): 3276, 2933, 2836, 2360, 1645, 1602,
1490, 1456, 1260, 1042, 872, 692; HRMS (ESI) m/z calcd for C25H31ClN2O4Na [M+Na]+:
481.1865, found: 481.1865.
2-Chloro-N-(2-(cyclohexylamino)-1-(4-methoxyphenyl)-2-oxoethyl)-N-(4-methoxy-
benzyl)acetamide (4e). yellow solid, 225.1 mg, 49%, mp 103-104 oC; 1H NMR (400 MHz,
CDCl3): δ 7.30 (d, J = 8.7 Hz, 2H), 6.99 (d, J = 8.2 Hz, 2H), 6.83 (d, J = 8.7 Hz, 2H), 6.76
(d, J = 8.7 Hz, 2H), 5.78 (s, 1H), 5.63 (d, J = 7.8 Hz, 1H), 4.68 (d, J = 17.4 Hz, 1H), 4.50 (d,
J = 16.9 Hz, 1H), 4.04 (d, J = 12.8 Hz, 1H), 3.92 (d, J = 12.8 Hz, 1H), 3.80-3.83 (m, 1H),
3.78 (s, 3H), 3.75 (s, 3H), 1.88 (s, 2H), 1.56-1.67 (m, 3H), 1.28-1.37 (m, 2H), 1.08-1.12 (m,
3H); C{1H} NMR (100 MHz, CDCl3): δ 168.3, 159.9, 159.0, 131.1, 128.8, 127.5, 126.7,
13
114.4, 114.2, 63.2, 55.4, 55.3, 49.6, 48.7, 42.4, 32.9, 25.5, 24.9, 24.8; IR (KBr, ν/cm–1): 3265,
2924, 2833, 2356, 1645, 1615, 1514, 1419, 1250, 1179, 1036, 796; HRMS (EI) m/z calcd for
C25H32ClN2O4 [M+H]+: 459.2051, found: 459.2049.
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2-Chloro-N-(2-(cyclohexylamino)-1-(4-methylphenyl)-2-oxoethyl)-N-(4-methyl-
benzyl)acetamide (4f). light brown solid, 245.6 mg, 58%, mp 69-70 oC; 1H NMR (400 MHz,
CDCl3): δ 7.26 (d, J = 4.1 Hz, 2H), 7.12 (d, J = 7.8 Hz, 2H), 7.03 (d, J = 7.8 Hz, 2H), 6.95
(d, J = 7.3 Hz, 2H), 5.80 (s, 1H), 5.57 (s, 1H), 4.71 (d, J = 17.4 Hz, 1H), 4.51 (d, J = 17.4 Hz,
1H), 4.03 (d, J = 12.8 Hz, 1H), 3.90 (d, J = 13.3 Hz, 1H), 3.80 (s, 1H), 2.32 (s, 3H), 2.28 (s,
3H), 1.90 (d, J = 11.4 Hz, 2H), 1.55-1.67 (m, 4H), 1.26-1.37 (m, 2H), 1.05-1.15 (m, 2H);
13C{1H} NMR (100 MHz, CDCl3): δ 168.36, 168.25, 138.79, 137.18, 133.90, 131.72, 129.72,
129.44, 126.19, 63.42, 49.94, 48.71, 42.42, 32.81, 25.54, 24.90, 24.82, 21.23, 21.09; IR (KBr,
ν/cm–1):; 3315, 2927, 2854, 1649, 1544, 1514, 1449, 1412, 1348, 1308, 1251, 1181, 799;
HRMS (ESI) m/z calcd for C25H31ClN2O2Na [M+Na]+: 449.1972, found: 449.1974.
2-Chloro-N-(2-(cyclohexylamino)-1-(2-bromophenyl)-2-oxoethyl)-N-(2-bromo-
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benzyl)acetamide (4h). white solid, 185. 8 mg, 33%, mp 201-202 C; H NMR (400 MHz,
CDCl3): δ 7.55 (d, J = 7.3 Hz, 1H), 7.44 (d, J = 6.9 Hz, 2H), 7.38 (d, J = 7.8 Hz, 1H), 7.22
(q, J = 7.3 Hz, 2H), 7.00-7.09 (m, 2H), 6.16 (s, 1H), 5.58 (d, J = 7.3 Hz, 1H), 4.71 (s, 2H),
4.06 (dd, J = 33.7, 13.1 Hz, 2H), 3.75-3.85 (m, 1H), 1.90 (s, 2H), 1.56-1.70 (m, 3H), 1.26-
1.39 (m, 2H), 1.00-1.16 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 168.11, 167.32, 135.02,
133.54, 133.26, 132.67, 130.82, 130.61, 128.93, 128.14, 127.62, 126.44, 121.92, 63.08, 50.46,
48.99, 41.86, 32.76, 32.73, 25.51, 24.90; IR (KBr, ν/cm–1): 3258, 3179, 3081, 2928, 2852,
1639, 1556, 1417, 1367, 1341, 1250, 1226, 1195, 1174, 1122, 1102, 1081, 1026, 989, 949,
927, 891, 877, 858, 841, 791, 774, 745, 723, 662, 630, 572, 540; HRMS (ESI) m/z calcd for
C23H25Br2ClN2O2Na [M+Na]+: 576.9869, found: 576.9864.
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N-Benzyl-2-(N-benzyl-2-chloroacetamido)-2-phenylacetamide (4j). white solid, 288.9 mg,
71%, mp 113-114 oC; 1H NMR (400 MHz, CDCl3): δ 7.33 (s, 2H), 7.22-7.27 (m, 5H), 7.15-
7.20 (m, 6H), 6.97 (d, J = 7.7 Hz, 2H), 6.67-6.70 (m, 1H), 6.09 (s, 1H), 4.76 (d, J = 17.2 Hz,
1H), 4.61 (d, J = 17.7 Hz, 1H), 4.33-4.45 (m, 2H), 3.98 (d, J = 13.1 Hz, 1H), 3.86 (d, J = 13.1
Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 169.1, 168.4, 138.0, 136.7, 134.3, 129.7, 128.9,
128.9, 128.7, 128.6, 127.6, 127.4, 126.1, 63.1, 49.9, 43.6, 42.3; IR (KBr, ν/cm–1): 3247, 3072,
2356, 1645, 1557, 1455, 1404, 1222, 1075, 794, 696; HRMS (EI) m/z calcd for C24H24ClN2O2
[M+H]+: 407.1526, found: 407.1520.
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N-Benzyl-N-(2-(tert-butylamino)-2-oxo-1-phenylethyl)-2-chloroacetamide (4k) [CAS:
1370472-34-6].21 yellow solid, 276.2 mg, 74%, mp 146-147 oC; 1H NMR (400 MHz, CDCl3):
δ 7.35 (s, 2H), 7.27-7.28 (m, 3H), 7.13-7.20 (m, 3H), 6.97 (d, J = 6.3 Hz, 2H), 5.97 (s, 1H),
5.73 (s, 1H), 4.78 (d, J = 17.7 Hz, 1H), 4.61 (d, J = 17.7 Hz, 1H), 4.04 (d, J = 12.7 Hz, 1H),
13
3.91 (d, J = 13.1 Hz, 1H), 1.33 (s, 9H); C{1H} NMR (100 MHz, CDCl3): δ 168.4, 168.3,
136.9, 134.7, 129.7, 128.9, 128.8, 128.6, 127.3, 126.0, 63.4, 51.8, 49.8, 42.4, 28.6.
N-Benzyl-2-chloro-N-(2-oxo-2-(pentylamino)-1-phenylethyl)acetamide (4l). white solid,
344.5 mg, 89%, mp 73-74 oC; 1H NMR (400 MHz, CDCl3): δ 7.17-7.36 (m, 8H), 7.01 (d, J
= 6.8 Hz, 2H), 6.19 (s, 1H), 6.02 (s, 1H), 4.79 (d, J = 18.1 Hz, 1H), 4.63 (d, J = 17.7 Hz, 1H),
4.04 (d, J = 12.7 Hz, 1H), 3.92 (d, J = 12.7 Hz, 1H), 3.18-3.26 (m, 2H), 1.45 (s, 2H), 1.22-
13
1.33 (m, 4H), 0.86 (t, J = 6.8 Hz, 3H); C{1H} NMR (100 MHz, CDCl3): δ 168.9, 168.4,
136.8, 134.6, 129.6, 128.9, 128.8, 128.7, 127.4, 126.1, 63.2, 50.0, 42.3, 39.8, 29.0, 22.3, 14.0;
IR (KBr, ν/cm–1): 3270, 3091, 2932, 2857, 1645, 1557, 1496, 1455, 1404, 1189, 940, 798,
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733, 694, 532; HRMS (ESI) m/z calcd for C22H27ClN2O2Na [M+Na]+: 409.1653, found:
409.1668.
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35-8].10a light yellow solid, 324.0 mg, 76%, mp 71-73 C; H NMR (400 MHz, CDCl3): δ
7.47 (d, J = 6.9 Hz, 2H), 7.29-7.35 (m, 8H), 7.14-7.20 (m, 3H), 7.08 (d, J = 6.4 Hz, 2H), 5.71
(s, 1H), 5.49 (s, 1H), 4.46-4.70 (m, 2H), 3.77-3.85 (m, 1H), 1.80-1.90 (m, 2H), 1.54-1.66 (m,
3H), 1.27-1.38 (m, 2H), 1.04-1.13 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 173.3, 168.3,
136.3, 135.2, 129.9, 129.7, 128.9, 128.7, 128.6, 128.4, 127.1, 126.8, 64.8, 52.9, 48.7, 32.8,
25.6, 24.9, 24.8.
N-Benzyl-4-bromo-N-(2-(cyclohexylamino)-2-oxo-1-phenylethyl)benzamide (4n). light
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yellow solid, 460.2 mg, 91%, mp 83-85 C; H NMR (400 MHz, CDCl3): δ 7.26-7.42 (m,
10H), 7.11-7.18 (m, 3H), 7.02 (d, J = 6.0 Hz, 2H), 5.70 (s, 1H), 5.54 (s, 1H), 4.69 (d, J = 16.5
Hz, 1H), 4.45 (s, 1H), 3.76-3.84 (m, 1H), 1.81-1.88 (m, 2H), 1.54-1.64 (m, 3H), 1.27-1.37
(m, 2H), 1.03-1.12 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 172.2, 168.1, 137.3, 137.1,
135.1, 134.9, 131.6, 129.7, 128.9, 128.8, 128.4, 127.1, 126.9, 124.1, 64.3, 52.2, 48.7, 32.7,
25.5, 24.8, 24.7; IR (KBr, ν/cm–1): 3287, 2930, 2851, 2356, 1622, 1590, 1496, 1455, 1409,
1069, 1013, 832, 696, 554; HRMS (EI) m/z calcd for C28H30BrN2O2 [M+H]+: 505.1491,
found: 505.1488.
N-Benzyl-N-(2-(cyclohexylamino)-2-oxo-1-phenylethyl)octanamide (4o). yellow solid,
408.3 mg, 91%, mp 107-108 oC; 1H NMR (400 MHz, CDCl3): δ 7.34 (s, 2H), 7.12-7.22 (m,
6H), 6.99 (d, J = 7.3 Hz, 2H), 6.02 (s, 1H), 5.94 (d, J = 7.8 Hz, 1H), 4.75 (d, J = 17.9 Hz,
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0.85 (t, J = 6.6 Hz, 3H); C{1H} NMR (100 MHz, CDCl3): δ 175.2, 168.9, 137.9, 135.5,
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129.7, 128.6, 128.4, 128.3, 126.8, 126.1, 62.7, 50.1, 48.5, 34.1, 32.8, 31.7, 29.3, 29.0, 25.5,
25.3, 24.9, 24.8, 22.6, 14.1; IR (KBr, ν/cm–1): 3282, 2924, 2853, 1647, 1558, 1496, 1451,
1419, 1196, 948, 725, 698, 569; HRMS (ESI) m/z calcd for C29H40N2O2Na [M+Na]+:
471.2982, found: 471.3004.
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General Procedure for the Synthesis of Imines (6). Benzylamines 1 (1.0 mmol),
aromatic amines or aliphatic amines 5 (2.0 mmol), 2,4,6-trihydroxybenzoic acid (25.5 mg,
0.15 mmol), and toluene (1.0 mL) were added to a two-necked flask equipped with O2 balloon
at room temperature, and the mixture was stirred at 90 °C under O2 atmosphere for 6 h. After
the reaction was finished, the resulting mixture was transferred into round-bottom flask using
ethyl acetate (5 mL) and concentrated under reduced pressure. The residue was purified by
gel permeation chromatography (eluent: chloroform) to give product 6.
N-Hexyl-1-phenylmethanimine (6a) [CAS: 19340-96-6].22 colorless oil, 134.6 mg, 71%; 1H
NMR (400 MHz, CDCl3): δ 8.26 (s, 1H), 7.69-7.74 (m, 2H), 7.37-7.41 (m, 3H), 3.60 (td, J =
13
7.0, 1.4 Hz, 2H), 1.66-1.73 (m, 2H), 1.28-1.39 (m, 6H), 0.89 (t, J = 6.8 Hz, 3H); C{1H}
NMR (100 MHz, CDCl3): δ 160.8, 136.4, 130.8, 130.5, 128.6, 128.3, 128.1, 127.1, 61.9, 31.8,
31.0, 27.1, 22.7, 14.2.
N-(2-Ethylhexyl)-1-phenylmethanimine (6b) [CAS: 69375-86-6].20b colorless oil, 180.6 mg,
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83%; H NMR (400 MHz, CDCl3): δ 8.24 (s, 1H), 7.71-7.74 (m, 2H), 7.38-7.39 (m, 3H),
3.51-3.53 (m, 2H), 1.68-1.71 (m, 1H), 1.32-1.41 (m, 8H), 0.89 (t, J = 7.3 Hz, 6H); 13C{1H}
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NMR (100 MHz, CDCl3): δ 160.8, 136.6, 130.4, 128.6, 128.1, 65.2, 40.6, 31.5, 29.1, 24.7,
23.2, 14.2, 11.1.
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N-Cyclohexyl-1-phenylmethanimine (6c) [CAS: 2211-66-7].22 colorless oil, 149.8 mg, 80%;
1H NMR (400 MHz, CDCl3): δ 8.30 (s, 1H), 7.71-7.73 (m, 2H), 7.37-7.38 (m, 3H), 3.14-3.21
(m, 1H), 1.54-1.84 (m, 7H), 1.21-1.41 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 158.6,
136.7, 130.4, 128.6, 128.1, 70.1, 34.6, 34.4, 25.7, 24.9.
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1-Phenyl-N-(1-phenylethyl)methanimine (6d) [CAS: 3129-98-4].20b colorless oil, 165.4 mg,
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79%; H NMR (400 MHz, CDCl3): δ 8.35 (s, 1H), 7.76-7.78 (m, 2H), 7.30-7.43 (m, 7H),
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7.19-7.24 (m, 1H), 4.52 (q, J = 6.6 Hz, 1H), 1.58 (d, J = 6.3 Hz, 3H); C{1H} NMR (100
MHz, CDCl3): δ 159.5, 145.3, 136.5, 130.7, 128.6, 128.5, 128.4, 126.9, 126.7, 69.8, 25.0.
N-Hexyl-1-(3-methoxyphenyl)methanimine (6h) [CAS: 2122325-36-2].22 colorless oil,
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144.9 mg, 66%; H NMR (400 MHz, CDCl3): δ 8.24 (s, 1H), 7.29-7.33 (m, 2H), 7.23-7.26
(m, 1H), 6.95-6.98 (m, 1H), 3.85 (s, 3H), 3.60 (td, J = 7.1, 1.2 Hz, 2H), 1.66-1.73 (m, 2H),
1.30-1.38 (m, 6H), 0.89 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 160.8, 160.0,
138.0, 129.7, 121.5, 117.3, 111.5, 61.9, 55.5, 31.8, 31.0, 27.2, 22.8, 14.2.
N-Hexyl-1-(4-(trifluoromethyl)phenyl)methanimine (6j) [CAS: 1153620-92-8].23 colorless
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oil, 157.1 mg, 61%; H NMR (400 MHz, CDCl3): δ 8.31 (s, 1H), 7.83 (d, J = 7.8 Hz, 2H),
7.66 (d, J = 8.2 Hz, 2H), 3.64 (t, J = 6.9 Hz, 2H), 1.67-1.74 (m, 2H), 1.30-1.38 (m, 6H), 0.89
(t, J = 6.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 159.3, 139.6, 132.2 (q, J = 32 Hz),
125.7 (q, J = 3.8 Hz), 123.9 (q, J = 247 Hz), 62.0, 31.8, 30.9, 27.2, 22.7, 14.2.
General Procedure for the Synthesis of Di-Peptides (8). Benzylamines 1 (1.5 mmol),
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aliphatic or aromatic amines 5 (3.0 mmol), 2,4,6-trihydroxybenzoic acid (38.3 mg,
0.225 mmol), and toluene (1.0 mL) were added to a two-necked flask equipped with O2
balloon at room temperature, and the mixture was stirred at 90 °C under O2 atmosphere for 6
h. Then O2 balloon was removed, the reaction mixture was cooled to room temperature. To
the resulted mixture were added carboxylic acids 2 (0.8 mmol) and isocyanides 3 (1.0 mmol),
and the solution was stirred at room temperature in air for 24 h. After the reaction was finished,
the resulting mixture was transferred into round-bottom flask using methanol (5 mL) and
concentrated under reduced pressure. Finally, the residue was purified by gel permeation
chromatography (eluent: chloroform) to give product 8.
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2-Chloro-N-(2-(cyclohexylamino)-2-oxo-1-phenylethyl)-N-hexylacetamide (8a). light
yellow solid, 122.7 mg, 39%, mp 109-110 oC; 1H NMR (400 MHz, CDCl3): δ 7.37 (s, 5H),
5.89 (d, J = 7.3 Hz, 1H), 5.78 (s, 1H), 4.11-4.19 (m, 2H), 3.78-3.80 (m, 1H), 3.32 (t, J = 7.4
Hz, 2H), 1.02-1.99 (m, 18H), 0.80 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ
168.2, 167.4, 135.0, 129.5, 128.9, 128.7, 63.2, 48.7, 47.5, 41.6, 32.8, 31.1, 29.9, 26.5, 25.5,
24.8, 24.8, 22.4, 14.0; IR (KBr, ν/cm–1): 3260, 3088, 2926, 2853, 2348, 1647, 1558, 1419,
1252, 700, 529; HRMS (EI) m/z calcd for C22H34ClN2O2 [M+H]+: 393.2309, found: 393.2315.
2-Chloro-N-cyclohexyl-N-(2-(cyclohexylamino)-2-oxo-1-phenylethyl)acetamide
(8b).
white solid, 115.0 mg, 37%, mp 155-157 oC; 1H NMR (400 MHz, CDCl3): δ 7.27-7.36 (m,
5H), 6.26 (d, J = 6.3 Hz, 1H), 4.87 (s, 1H), 4.07-4.21 (m, 2H), 3.67-3.80 (m, 2H), 1.52-2.02
(m, 11H), 1.26-1.43 (m, 5H), 1.07-1.17 (m, 4H); 13C{1H} NMR (100 MHz, CDCl3): δ 169.3,
167.2, 136.2, 128.8, 128.0, 127.5, 63.6, 59.9, 48.5, 42.2, 32.7, 32.6, 31.8, 31.7, 25.9, 25.6,
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25.2, 24.7, 24.6; IR (KBr, ν/cm–1): 3297, 2929, 2855, 1616, 1539, 1451, 1221, 1151, 1032,
895, 697; HRMS (ESI) m/z calcd for C22H31ClN2O2 [M+Na]+: 413.1966, found: 413.1980.
2-Chloro-N-(2-(cyclohexylamino)-2-oxo-1-phenylethyl)-N-phenylacetamide (8d). white
solid, 187.8 mg, 61%, mp 227-228 oC; 1H NMR (400 MHz, CDCl3): δ 7.11-7.27 (m, 10H),
6.00 (s, 1H), 5.54 (d, J = 7.7 Hz, 1H), 3.79-3.88 (m, 3H), 1.95 (d, J = 9.1 Hz, 1H), 1.84 (d, J
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= 11.3 Hz, 1H), 1.56-1.68 (m, 3H), 1.26-1.40 (m, 2H), 0.97-1.18 (m, 3H); C{1H} NMR
(100 MHz, CDCl3): δ 168.2, 166.9, 138.8, 134.1, 130.5, 129.3, 128.9, 128.8, 128.6, 128.5,
65.9, 49.0, 42.7, 33.0, 32.9, 25.6, 24.9, 24.9; IR (KBr, ν/cm–1): 3265, 2928, 2853, 2357, 1675,
1646, 1557, 1490, 1456, 1244, 699, 668, 554; HRMS (EI) m/z calcd for C22H26ClN2O2
[M+H]+: 385.1683, found: 385.1683.
2-Chloro-N-(2-(cyclohexylamino)-2-oxo-1-phenylethyl)-N-(3-phenylpropyl)acetamide
(8g). brown solid, 219.2 mg, 64%, mp 104-105 oC; 1H NMR (400 MHz, CDCl3): δ 7.35 (s,
3H), 7.17-7.29 (m, 5H), 6.98 (d, J = 7.3 Hz, 2H), 5.77 (s, 1H), 5.76 (s, 1H), 4.00 (s, 1H), 3.96
(d, J = 2.7 Hz, 1H), 3.74-3.81 (m, 2H), 3.31-3.34 (m, 2H), 2.33-2.41 (m, 2H), 1.89 (t, J = 7.3
Hz, 2H), 1.56-1.66 (m, 3H), 1.26-1.37 (m, 3H), 1.05-1.15 (m, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 168.22, 167.50, 140.50, 134.86, 129.56, 129.06, 128.84, 128.59, 128.35, 126.28,
63.09, 48.74, 46.48, 41.47, 32.81, 31.47, 25.53, 24.85, 24.79; IR (KBr, ν/cm–1): 2924, 2852,
2360, 2339, 1649, 1570, 1497, 1452, 1421, 1259, 1224, 1163, 803, 743, 700, 668; HRMS
(ESI) m/z calcd for C25H31ClN2O2Na [M+Na]+: 449.1972, found: 449.1971.
2-Chloro-N-(2-(cyclohexylamino)-1-(2-methoxyphenyl)-2-oxoethyl)-N-phenylacetamide
(8h). yellow solid, 189.7 mg, 57%, mp 178-179 oC; 1H NMR (400 MHz, CDCl3): δ 7.15-7.27
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(m, 5H), 6.86-6.99 (m, 2H), 6.75 (d, J = 8.2 Hz, 1H), 6.67 (t, J = 7.6 Hz, 1H), 6.33 (s, 1H),
5.46 (d, J = 7.3 Hz, 1H), 3.80-3.87 (m, 3H), 3.78 (s, 3H), 1.97 (d, J = 12.4 Hz, 1H), 1.87 (d,
J = 12.4 Hz, 1H), 1.56-1.71 (m, 3H), 1.28-1.40 (m, 2H), 0.97-1.19 (m, 3H); 13C{1H} NMR
(100 MHz, CDCl3): δ 168.8, 166.7, 157.5, 138.9, 131.2, 130.2, 128.9, 128.7, 122.2, 120.5,
110.2, 59.7, 55.3, 48.9, 42.8, 33.0, 32.9, 25.6, 25.0, 24.9; IR (KBr, ν/cm–1): 3284, 3070, 2921,
2851, 1651, 1594, 1496, 1368, 1250, 1109, 1054, 1027, 755, 703, 549; HRMS (ESI) m/z calcd
for C23H27ClN2O3Na [M+Na]+: 437.1602, found: 437.1625.
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2-Chloro-N-(2-(cyclohexylamino)-1-(3-methoxyphenyl)-2-oxoethyl)-N-phenylacetamide
(8i). yellow solid, 192.7 mg, 58%, mp 187-188 oC; 1H NMR (400 MHz, CDCl3): δ 7.18-7.30
(m, 4H), 7.10 (t, J = 8.0 Hz, 1H), 6.68-6.85 (m, 3H), 6.63 (t, J = 2.1 Hz, 1H), 5.97 (s, 1H),
5.60 (d, J = 8.2 Hz, 1H), 3.76-3.88 (m, 3H), 3.62 (s, 3H), 1.95 (d, J = 12.4 Hz, 1H), 1.84 (d,
J = 12.4 Hz, 1H), 1.55-1.70 (m, 3H), 1.27-1.39 (m, 2H), 0.98-1.18 (m, 3H); 13C{1H} NMR
(100 MHz, CDCl3): δ 168.1, 166.9, 159.6, 138.8, 135.4, 130.5, 129.6, 129.2, 128.9, 122.8,
115.4, 115.0, 65.7, 55.3, 49.0, 42.7, 32.9, 32.9, 25.6, 24.9, 24.8; IR (KBr, ν/cm–1): 3267, 3071,
2930, 2855, 1647, 1557, 1494, 1453, 1363, 1239, 1152, 1049, 751, 700, 541; HRMS (ESI)
m/z calcd for C23H27ClN2O3Na [M+Na]+: 437.1602, found: 437.1625.
2-Chloro-N-(2-(cyclohexylamino)-1-(4-methoxyphenyl)-2-oxoethyl)-N-phenylacetamide
(8j). white solid, 186.1 mg, 56%, mp 223-224 oC; 1H NMR (400 MHz, CDCl3): δ 7.20-7.31
(m, 5H), 7.02 (dt, J = 9.3, 2.5 Hz, 2H), 6.70 (dt, J = 9.3, 2.5 Hz, 2H), 5.97 (s, 1H), 5.50 (d, J
= 7.8 Hz, 1H), 3.78-3.87 (m, 3H), 3.74 (s, 3H), 1.95 (d, J = 9.2 Hz, 1H), 1.84 (d, J = 12.8 Hz,
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1H), 1.55-1.70 (m, 3H), 1.27-1.40 (m, 2H), 0.97-1.17 (m, 3H); C{1H} NMR (100 MHz,
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CDCl3): δ 168.4, 166.8, 159.8, 138.8, 131.8, 130.6, 129.3, 128.9, 126.0, 113.9, 65.2, 55.3,
49.0, 42.7, 33.0, 32.9, 25.6, 25.0, 24.9; IR (KBr, ν/cm–1): 3269, 2999, 2933, 2853, 1652, 1557,
1515, 1494, 1387, 1250, 1178, 1035, 838, 754, 730, 700, 523; HRMS (ESI) m/z calcd for
C23H27ClN2O3Na [M+Na]+: 437.1602, found: 437.1621.
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2-(4-(tert-Butyl)phenyl)-2-(2-chloro-N-phenylacetamido)-N-cyclohexylacetamide
(8k).
yellow solid, 303.2 mg, 86%, mp 235-237 oC; 1H NMR (400 MHz, CDCl3): δ 6.91-7.35 (m,
9H), 5.96 (s, 1H), 5.56 (d, J = 6.8 Hz, 1H), 3.88-3.79 (m, 3H), 1.95 (d, J = 11.8 Hz, 1H), 1.86
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(d, J = 11.8 Hz, 1H), 1.56-1.76 (m, 3H), 1.20-1.39 (m, 11H), 0.98-1.16 (m, 3H); C{1H}
NMR (100 MHz, CDCl3): δ 168.3, 166.8, 151.9, 138.9, 130.9, 130.5, 130.1, 129.1, 128.8,
125.5, 65.7, 49.0, 42.7, 34.6, 32.9, 31.3, 25.6, 25.0, 24.9; IR (KBr, ν/cm–1): 3283, 3085, 2930,
2854, 1650, 1556, 1494, 1363, 1244, 1102, 840, 701, 574; HRMS (ESI) m/z calcd for
C26H33ClN2O2Na [M+Na]+: 463.2123, found: 463.2133.
2-Chloro-N-(1-(4-chlorophenyl)-2-(cyclohexylamino)-2-oxoethyl)-N-phenylacetamide (8l).
white solid, 124.5 mg, 37%, mp 264-266 oC; 1H NMR (400 MHz, CDCl3): δ 7.20-7.38 (m,
5H), 7.16 (d, J = 8.2 Hz, 2H), 7.07 (d, J = 8.6 Hz, 2H), 5.96 (s, 1H), 5.59 (d, J = 7.7 Hz, 1H),
3.77-3.87 (m, 3H), 1.96 (d, J = 10.4 Hz, 1H), 1.84 (d, J = 12.2 Hz, 1H), 1.57-1.71 (m, 3H),
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1.26-1.40 (m, 2H), 0.99-1.19 (m, 3H); C{1H} NMR (100 MHz, CDCl3): δ 167.8, 167.1,
138.4, 134.9, 132.5, 131.9, 130.5, 129.5, 129.2, 128.8, 64.9, 49.1, 42.6, 33.0, 32.9, 25.6, 24.9,
24.9; IR (KBr, ν/cm–1): 3268, 2933, 2852, 1649, 1558, 1493, 1383, 1243, 1093, 1017, 721,
701, 541; HRMS (ESI) m/z calcd for C22H24Cl2N2O2Na [M+Na]+: 441.1107, found: 441.1121.
N-Benzyl-2-(2-chloro-N-phenylacetamido)-2-phenylacetamide (8m). white solid, 151.1 mg,
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48%, mp 196-197 oC; 1H NMR (400 MHz, CDCl3): δ 7.11-7.30 (m, 15H), 6.07 (s, 2H), 4.43-
4.54 (m, 2H), 3.79-3.88 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 169.2, 167.0, 138.7,
138.0, 133.7, 130.6, 129.3, 129.0, 128.9, 128.8, 128.7, 127.7, 127.5, 66.0, 44.0, 42.7; IR (KBr,
ν/cm–1): 3296, 3068, 1652, 1557, 1493, 1454, 1394, 1245, 1077, 699, 544; HRMS (EI) m/z
calcd for C23H22ClN2O2 [M+H]+: 393.1370, found: 393.1370.
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N-(tert-Butyl)-2-(2-chloro-N-phenylacetamido)-2-phenylacetamide (8n). white solid, 224.1
mg, 78%, mp 170-171 oC; 1H NMR (400 MHz, CDCl3): δ 7.11-7.29 (m, 10H), 5.93 (s, 1H),
13
5.58 (s, 1H), 3.79-3.88 (m, 2H), 1.34 (s, 9H); C{1H} NMR (100 MHz, CDCl3): δ 168.3,
166.8, 138.7, 134.2, 130.5, 130.4, 129.2, 128.8, 128.7, 128.5, 66.2, 51.8, 42.7, 28.7; IR (KBr,
ν/cm–1): 3295, 3064, 2971, 1674, 1647, 1595, 1544, 1496, 1453, 1431, 1394, 1359, 1222,
1149, 764, 702, 628, 540; HRMS (CI) m/z calcd for C20H24ClN2O2 [M+H]+: 359.1521, found:
359.1523.
2-Chloro-N-(2-oxo-2-(pentylamino)-1-phenylethyl)-N-phenylacetamide (8o). white solid,
137.2 mg, 46%, mp 137-138 oC; 1H NMR (400 MHz, CDCl3): δ 7.11-7.27 (m, 10H), 6.02 (s,
1H), 5.80 (s, 1H), 3.80-3.89 (m, 2H), 3.24-3.30 (m, 2H), 1.43-1.50 (m, 2H), 1.20-1.30 (m,
4H), 0.85 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 169.1, 166.9, 138.7, 134.0,
130.5, 129.3, 128.9, 128.8, 128.6, 65.9, 42.7, 40.0, 29.2, 29.1, 22.4, 14.1; IR (KBr, ν/cm–1):
3272, 2933, 1678, 1652, 1557, 1492, 1455, 1373, 1242, 700, 551; HRMS (ESI) m/z calcd for
C21H25ClN2O2Na [M+Na]+: 395.1497, found: 395.1511.
N-(2-(Cyclohexylamino)-2-oxo-1-phenylethyl)-N-phenylbenzamide (8p) [CAS: 1266385-
49-2].24 white solid, 135.4 mg, 41%, mp 160-161 oC; 1H NMR (400 MHz, CDCl3): δ 7.22-
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7.32 (m, 7H), 7.09-7.19 (m, 3H), 7.00 (s, 5H), 6.17 (s, 1H), 5.88 (d, J = 7.7 Hz, 1H), 3.83-
3.93 (m, 1H), 1.89-1.98 (m, 2H), 1.55-1.70 (m, 3H), 1.29-1.41 (m, 2H), 1.03-1.21 (m, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 171.4, 168.7, 141.5, 136.2, 135.0, 130.3, 130.2, 129.5,
128.6, 128.6, 128.5, 127.7, 127.2, 66.9, 48.8, 32.9, 25.6, 24.9, 24.8; IR (KBr, ν/cm–1): 3285,
2923, 2853, 1645, 1557, 1490, 1447, 1348, 1232, 754, 698, 540, HRMS (EI) m/z calcd for
C27H29N2O2 [M+H]+: 413.2229, found: 413.2223.
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N-(2-(Cyclohexylamino)-2-oxo-1-phenylethyl)-N-phenylcyclohexanecarboxamide
(8r).
yellow solid, 110.7 mg, 33%, mp 140-141 oC; 1H NMR (400 MHz, CDCl3): δ 7.10-7.28 (m,
10H), 6.01 (s, 1H), 5.86 (d, J = 7.7 Hz, 1H), 3.78-3.87 (m, 1H), 2.04-2.12 (m, 1H), 1.84-1.95
(m, 2H), 1.48-1.77 (m, 10H), 1.28-1.40 (m, 2H), 0.85-1.17 (m, 6H); 13C{1H} NMR (100 MHz,
CDCl3): δ 177.0, 169.0, 140.3, 135.0, 130.3, 130.3, 128.8, 128.3, 128.2, 128.0, 65.1, 48.6,
42.2, 32.9, 29.6, 29.2, 25.7, 25.6, 25.5, 25.4, 24.9, 24.8; IR (KBr, ν/cm–1): 3327, 2931, 2854,
1634, 1594, 1544, 1492, 1450, 1398, 1339, 1267, 1220, 754, 697, 556; HRMS (EI) m/z calcd
for C27H34N2O2Na [M+Na]+: 441.2513, found: 441.2533.
N-(2-Cyclohexylamino)-2-oxo-1-phenylethyl)-N-phenyloctanamide (8s). white solid, 132.4
mg, 38%, mp 175-176 oC; 1H NMR (400 MHz, CDCl3): δ 7.11-7.27 (m, 10H), 6.02 (s, 1H),
5.74 (d, J = 7.2 Hz, 1H), 3.79-3.86 (m, 1H), 1.84-2.10 (m, 4H), 1.56-1.69 (m, 5H), 0.99-1.40
(m, 13H), 0.83 (t, J = 6.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 174.0, 169.0, 140.5,
135.0, 130.6, 130.4, 128.9, 128.4, 128.0, 65.3, 48.8, 35.0, 33.0, 31.7, 29.3, 29.1, 25.6, 25.5,
24.9, 24.9, 22.7, 14.2; IR (KBr, ν/cm–1): 3267, 2923, 2852, 1645, 1557, 1493, 1451, 1394,
1241, 699, 565; HRMS (EI) m/z calcd for C28H39N2O2 [M+H]+: 435.3012, found: 435.3014.
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SUPPORTING INFORMATION
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Reaction optimization, and 1H NMR and 13C NMR spectra. This material is available free of
charge via the internet at http://pubs.acs.org.
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AUTHORS INFORMATION
1st Author, Chun-ping Dong, email: shan1_0523@126.com
2ed Author, Akinori Uematsu, email: sxb02009@edu.osakafu-u.ac.jp
3rd Author, Shun Kumazawa, email: swb02057@edu.osakafu-u.ac.jp
4th Author, Yuki Yamamoto, email: syb02137@edu.osakafu-u.ac.jp
5th Author, Shintaro Kodama, email: skodama@chem.osakafu-u.ac.jp
6th Author, Akihiro Nomoto, email: nomoto@chem.osakafu-u.ac.jp
7th Author, Michio Ueshima, email: ueshima@chem.osakafu-u.ac.jp
Corresponding Author, Akiya Ogawa, email: ogawa@chem.osakafu-u.ac.jp
Notes
The authors declare no competing financial interest.
ACKNOWLEDGEMENTS
Dong C. thanks to The Ministry of Education, Culture, Sports, Science and Technology
(MEXT) Scholarship Program. The authors acknowledge Dr. Motohiro Shizuma and Dr.
Takumi Mizuno (Osaka Research Institute of Industrial Science and Technology) for their
help with mass spectrometry. The authors also thank Mr. Miyuto Ota and Mr. Fumiya Sato
(Osaka Prefecture University) for their experimental support. This work is also supported by
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Grant-in-Aid for Scientific Research on Scientific Research (B, 16H04138) and Exploratory
Research (16K14049), from The Japan Society for the Promotion of Science (JSPS), and also
supported Nanotechnology Platform Program on Nara Institute of Science and Technology
(NAIST).
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REFERENCES
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