Novel Direct Synthesis of Asymmetrical Urea Compounds from Trichloroethyl Carbamates Using Catalytic DBU

Full text of DOI:10.1002/bkcs.11314

Note
DOI: 10.1002/bkcs.11314
BULLETIN OF THE
H. S. Jang and H.-K. Kim
KOREAN CHEMICAL SOCIETY
Novel Direct Synthesis of Asymmetrical Urea Compounds from
Trichloroethyl Carbamates Using Catalytic DBU
Ho Seong Jang† and Hee-Kwon Kim‡,
*
†Materials Architecturing Research Center, Korea Institute of Science and Technology, Seoul 02792,
Republic of Korea
‡Department of Nuclear Medicine, Molecular Imaging and Therapeutic Medicine Research Center,
Biomedical Research Institute, Chonbuk National University Medical School and Hospital, Jeonju,
Jeonbuk, 561-712, Republic of Korea. *E-mail: hkkim717@jbnu.ac.kr
Received August 1, 2017, Accepted October 10, 2017
Keywords: Asymmetrical Ureas, 1,8-Diazabicyclo[5.4.0]undec-7-ene, Organocatalyst, 2,2,2-
Trichloroethyl Carbamates
Urea is one of the most common structures present in bio-
logically active compounds,1,2 and a variety of pharmaceu-
ticals including enzyme inhibitors, anticancer agents, and
antimycobacterial agents contain the urea structure.3–6 In
addition, urea units are commonly used to synthesize a
number of useful organic compounds including molecular
gels and chemical sensors due to their rigidity and
polarity.7–12 Several synthetic protocols have been devel-
oped for the production of urea-containing structures.13,14
Among existing protocols, reactions of amines with isocya-
nate generated from phosgene or with carbamoyl chloride
remain prevelent.15 However, the instability of carbamoyl
chloride intermediates and the toxicity of phosgene remain
significant drawbacks of these methods.
Amines are commonly used during chemical synthesis in
the form of carbamate-protecting groups. Two separate
steps are generally employed to synthesize urea from
carbamate-protected amines, namely, deprotection of the
amine group and generation of a new urea via treatment
with other amines. In this way, direct preparation of urea
structures from carbamate-protected amines is an attractive
method that can reduce costs, time, and waste. Among the
many different types of amine protecting groups, 2,2,2-
trichloroethyl carbamate (Troc-carbamate) is prevalent.16,17
Generally, primary or secondary amines are easily protected
via reaction with 2,2,2-chloroethyl chloroformate to gener-
ate Troc-carbamates (Troc-protected amines). However,
transformation of Troc-caramate to asymmetrical ureas has
not been studied in great detail due to the weakly active
nature of Troc-protected amines.18
protocol of urea compounds from Troc-protected amines
using an organic catalyst has not yet been reported. Herein,
we are pleased to present our organic catalytic reagent-
mediated method for preparing asymmetrical urea mole-
cules from Troc-protected molecules.
Troc-protected aniline was used to optimize the amounts
of organic catalysts needed for preparing asymmetrical urea
from Troc-protected amines. First, reactions with Troc-
protected amine 1a were screened with a series of commer-
cially available organic catalysts containing one or two
nitrogen atoms, namely, pyridine, N,N-Diisopropylethyla-
mine (DIPEA), 1,4-diazabicyclo[2.2.2]octane (DABCO),
1,5-diazabicyclo [4.3.0]non-5-ene (DBN), 1,8-diazabicyclo
[5.4.0]undec-7-ene (DBU), and 4-dimethylaminopyridine
(DMAP) (Figure 1).
Reactions were carried out using 1 equiv of Troc-
protected aniline, 1.4 equiv of benzylamine, and 0.5 equiv
of organic catalysts. After performing the reaction for 4 h,
the effect of each reagent on the synthetic yield of the
desired urea was investigated. Likewise, the structures and
purity of the resulting urea compounds were determined by
1H and 13C NMR spectroscopy and HRMS. Our initial
screening results indicated that the catalytic activities of the
organic catalysts varied significantly according their struc-
tures, as shown in Table 1. The catalytic activities of pyri-
dine, DIPEA, DABCO, and DMAP were considered
moderate and low, respectively, while both DBN and DBU
had high activity over a reaction time of 4 h. Based on the
above results, we further investigated the use of DBN and
DBU at lower catalytic amounts (0.2 equiv and 0.05 equiv).
Reactions performed using 0.2 equiv of DBN or DBU as the
catalyst resulted in synthetic yields of the target urea of 65%
and 83%, respectively, while use of 0.05 equiv of DBN or
DBU had corresponding synthetic yields of less than 28%
and 41% after a reaction time of 10 h, respectively (Table 1,
entries 5, 6, 8, and 9). Together, these results suggested that
the loading amount of DBN and DBU influenced the yield
of the corresponding urea compounds. Based on the
The development of practical reagents for the direct con-
version of Troc-protected amines to urea remains a chal-
lenge. In particular, organocatalysts are considered an
attractive method for synthesizing asymmetrical urea
compounds.19,20 We are currently interested in identifying
catalytic amounts of organic base reagents to treat Troc-
protected amines to directly synthesize target asymmetrical
urea compounds in high yield. Indeed, a direct synthetic
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KOREAN CHEMICAL SOCIETY
dioxane and THF resulted in a low yield of urea, while
reactions performed in toluene and MeCN were more effec-
tive for synthesizing the desired product (74% and 83%,
respectively, Table 1 entries 9 and 17). Based on these data,
reaction conditions consisting of 20 mol % DBU, MeCN,
and 80ꢀC were chosen for subsequent studies.
N
N
N
N
N
N
N
N
N
DBN
DABCO
DBU
DIPEA
DMAP
Figure 1. Structure of organic reagents used for screening.
We next examined the scope of our novel catalytic proto-
col for preparing various ureas under the optimized experi-
mental conditions (Table 2). First, aromatic compounds
were used to assess the synthesis of asymmetrical ureas.
Specifically, Troc-protected aniline was reacted with a vari-
ety of amines such as aromatic groups and aliphatic groups,
affording the corresponding asymmetrical ureas (3a–3f) in
high yield for 4 h. Reactions of Troc-protected aromatic
amines bearing electron-donating and electron-withdrawing
groups with different amines also produced the desired
asymmetrical urea compounds in high yield.
We also investigated the scope of the synthetic protocol
employing catalytic DBU by studying Troc-protected ben-
zyl compounds. We found that the reaction method was
useful for the direct synthesis of several corresponding
ureas from Troc-protected benzyl compounds. Specifically,
introduction of 20 mol % of DBU to reactions successfully
generated benzylurea (3g–3i) in high yield, confirming that
DBU is a useful catalytic agent for generating urea com-
pounds from Troc-protected amines. We also extended the
synthetic method to Troc-protected compounds prepared
from secondary amines. Treatment of Troc-protected
methylaniline compound 2a with several amines in the
presence of DBU indicated that the method was efficient
for direct synthesis of the desired asymmetrical trisubsti-
tuted urea in high yield for 4 h. For instance, the trisubsti-
tuted ureas 3k and 3l were readily prepared in good yield
from the same DBU-mediated method (83% for compound
3k and 85% for compound 3l).
To the best of our knowledge, this is the first study to
report on the directed preparation of trisubstituted ureas
from Troc-protected compounds using catalytic amounts of
DBU. Encouraged by our results thus far, the catalytic
reagent system using DBU was next applied to additional
reactions of Troc-protected hydroisoquinoline compound 1f
and Troc-protected dibenzyl amine 1g, a more sterically
hindered amine, to further expand the scope of preparation
of Troc-protected compounds from secondary amines.
Importantly, Troc-protected hydroisoquinolines were suc-
cessfully converted into the corresponding trisubstituted
ureas in high yield (73–85%) with the optimized catalytic
protocol using DBU and various amines (Table 2, entries
15–17). In addition, the reactions of Troc-protected diben-
zyl amines 1g resulted in the target trisubstituted ureas 3q
and 3r in yields of 81% and 72%, respectively (Table 2,
entries 18 and 19).
conversion yield, a catalytic amount of DBU of 0.2 equiv
(20 mol%) was selected for further optimization of the urea
preparation protocol, although it should be noted that reac-
tions containing 0.5 equiv of DBU resulted in a sufficient
yield of the desired product.
We next examined the effect of temperature on conver-
sion yield at room temperature and 80ꢀC. We found that
reaction temperature affected the yield of the corresponding
ureas. Although there was no reactivity at room temperature
and no desired product was obtained from a reaction at
room temperature, reaction yield increased with increasing
reaction temperature: reactions carried out at 80ꢀC resulted
in a higher yield (83%) than reactions at 30ꢀC (2%), 40ꢀC
(4%), and 60ꢀC (32%) (Table 1, entries 9, 11–14).
Reaction conditions were next optimized by investigating
different types of solvents. Reactions performed in 1,4-
Table 1. Screening of reaction conditions for preparing urea
structures.a
NH2
O
O
Organic Cat.
+
N
N
N
O
CCl3
H
H
solvent, 4h
H
1a
3a
2a
Catalyst
Entry (equiv)
Temperature
(ꢀC)
Yieldb
(%)
NRc
7
11
NRc
28
65
71
41
83
85
NRc
2
Solvent
Pyridine (0.5) MeCN
DIPEA (0.5) MeCN
DABCO (0.5) MeCN
1
2
3
80
80
80
80
80
80
80
80
80
80
r.t.
30
40
60
80
80
80
4
DMAP (0.5)
DBN (0.05)
DBN (0.2)
DBN (0.5)
DBU (0.05)
DBU (0.2)
DBU (0.5)
DBU (0.2)
DBU (0.2)
DBU (0.2)
DBU (0.2)
DBU (0.2)
DBU (0.2)
DBU (0.2)
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
5d
6
7
8d
9
10
11
12
13
14
15
16
17
a
4
32
8
58
74
1,4-Dioxane
THF
Toluene
Reaction conditions: Troc-carbamate (1.0 mmol), amine (1.4 mmol),
DBU (0.2 mmol), MeCN, 4 h.
Isolated yields after purification of flash column chromatography.
No reaction.
Finally, we applied our catalytic method to generate bis-
urea structures to establish the wide utility of the DBU
organic catalyst. As shown in Scheme 1, treatment of
1 equiv of Troc-protected m-xylylenediamine 1h with 2.8
b
c
d
Reaction conducted for 10 h.
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Table 2 (continued)
Table 2. Scope of urea formation from amines.a
Yieldc
O
Entry Troc-carbamate
Urea
(%)
O
R3
20 mol % DBU
R1
R1
NH
R3
N
R2
CCl3
+
N
R4
O
1
N
13
83
O
O
R4
2
MeCN
R2
80 oC, 4h
N
O
CCl3
N
N
H
3
CH3
CH3
1e
3m
Yieldc
(%)
14
15
16
75
84
85
O
O
Entry Troc-carbamate
Urea
N
O
CCl3
N
N
H
CH3
CH3
1
83
O
O
3n
1e
N
H
O
O
O
CCl3
CCl3
CCl3
N
N
H
H
O
O
1a
3a
N
N
O
O
CCl3
N
N
H
Cl
2
84
O
O
1f
3o
N
H
N
N
H
H
O
O
3b
1a
CCl3
N
N
3
4
85
87
H
O
O
N
H
N
N
H
3c
3j
H
1f
1a
17
18
O
O
73
81
O
O
N
N
O
O
CCl3
N
N
H
N
H
O
O
CCl3
N
N
H
H
1f
3p
3d
1b
O
O
5
6
86
81
O
O
N
N
CCl3
N
CCl3
N
N
H
H
H
H
1b
3e
1g
3q
Cl
Cl
19
72
O
O
O
O
N
O
CCl3
N
H
N
H
N
O
O
CCl3
N
N
H
H
3f
1c
1g
3r
O
O
7
8
84
77
20
70b
O
O
N
O
CCl3
N
H
N
H
H
N
CCl3
N
N
1d
3g
O
O
O
3s
1g
N
H
O
CCl3
N
H
N
a
Reaction conditions: Troc-carbamate (1.0 mmol), amine (1.4 mmol),
DBU (0.2 mmol), MeCN, 80ꢀC for 4 h.
Reaction conditions: Troc-carbamate (1.0 mmol), amine (1.4 mmol),
DBU (0.2 mmol), MeCN, 80ꢀC for 10 h.
O
1d
3h
b
c
O
CH3
9
85
77
83
O
N
H
O
O
CCl3
CCl3
Isolated yields after purification of flash column chromatography.
N
N
H
H
1d
3i
O
O
10
11
equiv of 1,2,3,4-tetrahydroquinoline 2b in the presence of
DBU successfully afforded the desired bis-urea compound
3t (67% yield).
N
H
N
H
N
3j
1d
In conclusion, we report here a novel method for the direct
synthesis of asymmetrical urea compounds from Troc-
protected amines. Reactions were carried out in the presence
of catalytic amounts of DBU in MeCN for the synthesis of a
variety of target urea structures. Furthermore, the use of DBU
was successfully extended to the preparation of bis-urea com-
pounds. Our results indicate that direct synthesis of asymmet-
rical substituted urea compounds from Troc-protected amines
using a DBU catalyst is a practical method.
O
O
N
O
CCl3
N
N
H
CH3
CH3
1e
3k
12
85
O
O
N
O
CCl3
N
N
H
CH3
CH3
3l
1e
(continued overleaf )
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O
O
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Cl3C
O
N
N
O
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General Procedure for the Preparation of Urea Com-
pounds (3a–3s). To a solution of Troc-protected aniline 1a
(0.26 g, 1.03 mmol) in MeCN (10 mL) benzylamine (0.15 g,
1.40 mmol) and DBU (0.03 g, 0.20 mmol) were added at
room temperature and allowed to stir for 4 h at 80ꢀC. The
reaction mixture was cooled down to room temperature and
extracted with CH2Cl2 (2 × 30 mL). The organic layer was
dried over sodium sulfate and concentrated under reduced
pressure. The resulting residue was then purified by flash col-
umn chromatography on silica gel with hexane–EtOAc as elu-
ent to afford the desired product 3a (0.193 g, 83%).
General Procedure for the Preparation of Bis-Urea
Compound (3t). To
m-xylylenediamine 1h (0.47 g, 1.03 mmol) in MeCN
(10 mL) 1,2,3,4-tetrahydroquinoline 2b (0.38 g,
a
solution of Troc-protected
2.85 mmol) and DBU (0.06 g, 0.40 mmol) were added at
room temperature and allowed to stir for 6 h at 80ꢀC. The
reaction mixture was cooled down to room temperature and
extracted with CH2Cl2 (2 × 30 mL). The organic layer was
dried over sodium sulfate and concentrated under reduced
pressure. The resulting residue was then purified by flash
column chromatography on silica gel with hexane–EtOAc
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Acknowledgments. This research was supported by Basic
Science Research Program through the National Research
Foundation of Korea (NRF) funded by the Ministry of Edu-
cation (2014R1A1A2057943), and by the National
Research Foundation of Korea (NRF) grant funded by the
Korea Government (MSIP) (NRF-2016R1A2B2013629)
Supporting Information. Additional supporting informa-
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Bull. Korean Chem. Soc. 2017
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