Facile direct synthesis of unsymmetrical ureas from N-Alloc-, N-Cbz-, and N-Boc-protected amines using DABAL-Me3

Article abstract of DOI:10.1016/j.tet.2018.06.011

A practical synthetic method for the direct synthesis of unsymmetrically substituted ureas from N-Alloc-, N-Cbz-, and N-Boc-protected amines is described. In this study, efficient direct conversion of the Alloc-, Cbz-, and Boc-carbamate compounds to ureas was achieved in the presence of DABAL-Me₃, an air stable and easily handled reagent. Using this reaction method, both protected aromatic and aliphatic amines were successfully transformed into various trisubstituted and tetrasubstituted ureas with high yields without side product. Our findings offer promising guidelines for direct preparation of useful ureas from N-Alloc-, N-Cbz-, and N-Boc-carbamates.

Full text of DOI:10.1016/j.tet.2018.06.011

Tetrahedron xxx (2018) 1e11
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Tetrahedron
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Facile direct synthesis of unsymmetrical ureas from N-Alloc-, N-Cbz-,
and N-Boc-protected amines using DABAL-Me3
,
, c, *
Soosung Kang a **, Hee-Kwon Kim b
a College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Republic of Korea
b Department of Nuclear Medicine, Molecular Imaging & Therapeutic Medicine Research Center, Chonbuk National University Medical School and Hospital,
Jeonju, 54907, Republic of Korea
c Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Jeonju,
54907, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A practical synthetic method for the direct synthesis of unsymmetrically substituted ureas from N-Alloc-,
N-Cbz-, and N-Boc-protected amines is described. In this study, efficient direct conversion of the Alloc-,
Cbz-, and Boc-carbamate compounds to ureas was achieved in the presence of DABAL-Me3, an air stable
and easily handled reagent. Using this reaction method, both protected aromatic and aliphatic amines
were successfully transformed into various trisubstituted and tetrasubstituted ureas with high yields
without side product. Our findings offer promising guidelines for direct preparation of useful ureas from
N-Alloc-, N-Cbz-, and N-Boc-carbamates.
Received 15 March 2018
Received in revised form
1 June 2018
Accepted 5 June 2018
Available online xxx
Keywords:
Unsymmetrical ureas
DABAL-Me3
© 2018 Elsevier Ltd. All rights reserved.
Protected carbamates
Urea synthesis
1. Introduction
been reported.8 A commonly used traditional method for the
preparation of ureas involves reaction of isocyanate generated from
Urea is a structure frequently found in many natural products
and biologically active compounds including antitumor agents,1
antagonists of natural receptors,2 anti-mycobacterial agents,3
enzyme inhibitors,4 inhibitors of HIV protease.5 and plant growth
regulators.6 The urea has unique properties such as rigidity and
polarity, and it can form hydrogen bonding when gels were formed
from ureas or self-assemblies of urea oligomers were achieved.
Thus, the synthetic method of urea has been utilized to prepare
various useful organic materials. Particularly, preparation of a va-
riety of molecular gels and self-assembling molecular capsules has
been successfully achieved via reactions to produce urea
structures.7
the treatment of phosgene with the corresponding amines, or re-
action of carbamoyl chlorides with the corresponding amines.9
Even though these approaches have been widely employed, the
syntheses of ureas should be carried out more carefully under safe
environment due to toxicity related to phosgene and the instability
of carbamoyl chloride intermediates. Alternatively, 1,10-carbon-
yldiimidazole (CDI) and p-nitrophenyl carbamates have been used
in the preparation of various urea units.10 The synthesis of urea
derivatives using CDI and p-nitrophenyl carbamates is often ach-
ieved in good yield.
Amines are a popular functional group in organic chemistry. In
many multi-step syntheses, amines are used as a protected type by
a carbamate protecting group to prevent the generation of un-
wanted side products during reactions. In particular, allyl-
carbamate (Alloc-carbamate), benzyl-carbamate (Cbz-carbamate),
and Boc-carbamate are widely employed as protecting groups of
amines in process chemistry and medicinal chemistry,11 because
Alloc-, Cbz-, and Boc-protected amines are readily prepared from
primary or secondary amines using several methods, including
treatment with allyl chloroformate or benzyl chloroformate.
Several synthetic protocols for the synthesis of urea units have
* Corresponding author. Department of Nuclear Medicine, Molecular Imaging &
Therapeutic Medicine Research Center, Chonbuk National University Medical
School and Hospital, Jeonju, 54907, Republic of Korea.
** Corresponding author.
E-mail addresses: sskang@ewha.ac.kr (S. Kang), hkkim717@jbnu.ac.kr
(H.-K. Kim).
https://doi.org/10.1016/j.tet.2018.06.011
0040-4020/© 2018 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kang S, Kim H-K, Facile direct synthesis of unsymmetrical ureas from N-Alloc-, N-Cbz-, and N-Boc-protected
amines using DABAL-Me3, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.06.011

2
S. Kang, H.-K. Kim / Tetrahedron xxx (2018) 1e11
However, in order to produce ureas from both protected amines,
two separate reaction procedures are needed: removal of the pro-
tecting group of amines and generation of urea by the attack of
another nucleophile amine. Thus, development of effective direct
preparation of ureas from both protected amines is valuable chal-
lenge to multi-step organic chemistry. However, the direct con-
version of Alloc-carbamate or Cbz-carbamate or Boc-carbamate to
unsymmetrical ureas has not been extensively reported, because
Alloc-, Cbz-, and Boc-protected amines are weakly activated. To the
best of our knowledge, practical and simple direct synthesis of urea
from Alloc-carbamate or Cbz-carbamate or Boc-carbamate using
easily handled reagents has not yet been reported. Herein, we are
pleased to describe a novel direct preparation method of various
unsymmetrical ureas from Alloc-, Cbz-, and Boc-protected amines
that is easily applicable to multi-step organic synthesis.
Fig. 1. Bis(trimethylaluminum)-1,4-diazabicyclo[2.2.2]octane adduct.
Next, several solvents were examined to further optimized re-
action conditions. Reactions in THF and 1,4-dioxane resulted in low
yield synthesis of urea. When CH3CN was used as a reaction solvent,
the synthetic yield of urea was enhanced to 44%, but was still un-
satisfactory. However, when toluene was employed in the reaction,
the yield of target urea increased significantly (95%), indicating that
toluene was the most effective solvent for direct urea formation
from Alloc-protected amines.
The effect of temperature on the reaction was also investigated,
and elevated reaction temperature increased the yield of the
desired urea (95% for reaction at 90 ꢀC, and 95% for reaction at
105 ꢀC; Table 2). We chose a reaction temperature of 90 ꢀC for the
next study of urea synthesis because 90 ꢀC was lower than 105 ꢀC
with the same transformation yield.
In additions, we investigated the use of DABAL-Me3 in a series of
amounts, including 0.5 equiv, 1.2 equiv, 2.0 equiv, and 3.0 equiv in
toluene. The results suggested that the synthetic yield was influ-
enced by the amount of DABAL-Me3. When 0.5 equiv. of DABAL-
Me3 was used, we obtained a 45% yield of the desired urea. Addition
of an enhanced amount of DABAL-Me3 into the reaction resulted in
an increase yield of the conversion to corresponding urea. However,
levels greater than 1.2 equiv. of DABAL-Me3 did not increase syn-
thetic yield any further during urea formation.
Thus, based on our primary optimization results, the reaction
conditions of 1.2 equiv. of DABAL-Me3, toluene, and 90 ꢀC were
chosen for the next studies. The structure and purity of the pre-
pared urea compounds were confirmed by analysis with HRMS and
1H and 13C NMR spectroscopy.
2. Results and discussion
Alloc-protected aniline was selected as the model substrate and
n-butylamine was used as the nucleophilic amine in the initial
study to find optimized conditions for the synthesis of unsym-
metrical ureas from Alloc-protected amines. In the optimization
study, the synthetic yield of the corresponding urea was evaluated
after the reaction proceeded for 2 h.
We first attempted the reaction experiment with a series of
commercial available and widely used reagents such as triethyl-
amine, NaHCO3, K2CO3, DMAP, and DBU, but product was either not
observed or had a low yield (Table 1, entries 1e5). We next used
Lewis acids, including TiCl4, and SnCl4, as a direct conversion re-
action agent from Alloc-protected amines into unsymmetrical
ureas, and obtained a slightly greater yield (Table 1, entries 6 and 7).
It was discovered that bis(trimethylaluminum)-1,4-diazabicyclo
[2.2.2]octane adduct (DABAL-Me3) is an air stable, white solid
that can be easily handled (see Fig. 1). In particular, DABAL-Me3 has
been used for several organic reactions such as the synthesis of
amides and the asymmetric synthesis of chiral alcohols because
reactions using DABAL-Me3 do not require an inert reaction envi-
ronment such as N2 gas.12 In this study, DABAL-Me3 was employed
for the direct urea formation reaction, and the target urea was
synthesized with a significantly higher yield (95%), indicating that
DABAL-Me3 is effective for direct urea synthesis from Alloc-
protected amines (Table 1, entry 8).
With the optimized reaction conditions in hand, we examined
the scope of this procedure for the direct synthesis of ureas
(Table 3). First, reactions of Alloc-protected anilines, an aromatic
compound, were investigated for the direct synthesis of unsym-
metrical ureas. Reactions of Alloc-protected aniline with different
amines in the presence of DABAL-Me3 produced the corresponding
unsymmetrical ureas (3a-3c) at high yield (Table 3, entries 1e3). In
particular, the reactions of Alloc-protected aniline with secondary
Table 1
Screening of reaction conditions for the preparation of urea structurea.
Entry
Reagent
Time
Temp.
90 ꢀC
Yieldb (%)
1
2
3
4
5
6
7
8
9
triethylamine
NaHCO3
K2CO3
DMAP
DBU
TiCl4
SnCl4
DABAL-Me3
None
2 h
2 h
2 h
2 h
2 h
2 h
2 h
2 h
2 h
NR
NR
4
NR
NR
5
8
95
NR
90 ꢀ
90 ꢀ
90 ꢀ
90 ꢀ
90 ꢀ
90 ꢀ
90 ꢀ
90 ꢀ
C
C
C
C
C
C
C
C
a
Reaction conditions: 1a Alloc-protected amine (1.0 mmol), amine (1.2 mmol), reagent (1.2 mmol), toluene (5 mL), 2 h.
Isolated yield after column purification.
b
Please cite this article in press as: Kang S, Kim H-K, Facile direct synthesis of unsymmetrical ureas from N-Alloc-, N-Cbz-, and N-Boc-protected
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S. Kang, H.-K. Kim / Tetrahedron xxx (2018) 1e11
3
Table 2
Screening of reaction conditions for the preparation of urea structuresa.
Entry
DABAL-Me3 (equiv)
Solvent
Temp.
Yieldb (%)
1
2
3
4
5
6
7
8
9
1.2
1.2
1.2
1.2
1.2
1.2
1.2
0.5
2.0
3.0
THF
1,4-dioxane
CH3CN
toluene
toluene
toluene
toluene
toluene
toluene
toluene
reflux
90 ꢀC
reflux
32
24
44
95
12
41
95
45
95
96
90 ꢀ
40 ꢀ
65 ꢀ
C
C
C
105 ꢀ
C
90 ꢀ
90 ꢀ
90 ꢀ
C
C
C
10
a
Reaction conditions: 1a Alloc-protected amine (1.0 mmol), amine (1.2 mmol), DABAL-Me3 (1.2 mmol), solvent (5 mL), 2 h.
Isolated yield after column purification.
b
amines 2c generated the desired trisubstituted urea 3c with 90%
yield (Table 3, entry 3).
high yields (Table 4, entries 1e8). The reaction of Cbz-protected
amines with different aromatic amines containing electron-
donating (methyl, methoxy, and piperonyl) and electron-
withdrawing (chloro, nitro, and cyano) groups to generate un-
symmetrical ureas was also examined, and then it was discovered
that the reaction method using DABAL-Me3 readily yield unsym-
metrical ureas from Cbz-protected amines with high yield (Table 4,
entries 3e7). Next, Cbz-protected 2-(4-chlorophenyl)ethylamine
was utilized as a substrate to assess its reaction with a variety of
amines to yield ureas. The reaction using Cbz-protected 2-(4-
chlorophenyl)ethylamine confirmed that treatment of several
amines including aromatic amines, aliphatic amines, ally amines
(unsaturated amine), cyclic amines, and secondary amines in the
presence of DABAL-Me3 led to successful synthesis of ureas at high
yields (Table 4, entries 9e17).
Next, scaled-up urea formation from N-Alloc-protected amines
was carried out (Scheme 1). A gram-scale reaction was successfully
achieved. The reaction of N-Alloc-protected benzylamine 1b
(10.5 mmol, 1.0 equiv., 2.00 g) with aniline 2h (12.6 mmol, 1.2
equiv.) gave the corresponding product 3b in a 90% yield under the
optimized reaction conditions, indicating that the reaction method
was both scalable and practical.
In addition, Alloc-protected benzyl amine was employed to
extend the scope of this protocol, and the reaction method using
DABAL-Me3 was proven useful for the preparation of unsymmet-
rical benzylureas (Table 3, entries 4e10). In particular, the treat-
ment of Alloc-protected benzyl amine with different aromatic
amines containing electron-donating (methyl, methoxy, and
piperonyl) and electron-withdrawing (chloro, nitro, and cyano)
groups under the same reaction conditions provided unsymmet-
rical ureas at high yield (Table 3, entries 5e10). These findings
clearly demonstrate that DABAL-Me3 was an efficient conversion
reagent to turn Alloc-protected amines into unsymmetrical ureas
during the reaction process.
Next, the scope of our method using DABAL-Me3 was extended
to prepare trisubstituted and tetrasubstituted ureas from Alloc-
protected compounds prepared from secondary amines. The reac-
tion of various amines with Alloc-protected methylaniline 1c and
piperidine 1d in the presence of DABAL-Me3 readily yielded the
desired unsymmetrical trisubstituted ureas with yields ranging
from 82 to 96% in 2 h (Table 3, entries 11e16). In particularly, the
reaction protocol using secondary amines such as Alloc-protected
methylaniline and piperidine provided tetrasubstituted ureas
with good yields (91% for compound 3m and 82% for compound 3p,
respectively).
Furthermore, we evaluated the impact of steric hindrance on the
reaction scope of Alloc-protected amines by performing the reac-
tion of Alloc-protected dibenzyl compounds (1e) with two bulky
phenyl groups (Table 3, entries 17e19). Under the same optimized
conditions, trisubstituted and tetrasubstituted ureas were suc-
cessfully prepared from Alloc-protected dibenzyl compounds with
yields ranging from 86% to 92% (Table 3, entries 17e19). These
findings demonstrate that Alloc-protected amines were readily
converted into the desired ureas in high yields via DABAL-Me3-
mediated reactions.
Cbz-protected amines are widely found in numerous multi-step
organic synthesis strategies. Thus, our novel direct urea formation
method using DABAL-Me3 was applied for the conversion of N-Cbz-
protected amines to unsymmetrical ureas, as shown in Table 4. We
found that the reaction of different Cbz-protected amines from
aniline, benzylamine, and methylaniline with primary and sec-
ondary amines successfully generated the corresponding ureas in
To further examine the substrate scope for the urea synthesis
method using DABAL-Me3, amines bearing Boc and Fmoc group
were evaluated. As shown in Table 5. We found that the reaction of
Boc-protected benzylamine and aniline in the presence of DABAL-
Me3 successfully yielded the corresponding ureas in high yields
(Table 5, entries 1e4). In additions, unsymmetrical ureas were
prepared via the treatment of Fmoc-protected benzylamine and
aniline with DABAL-Me3 (Table 5, entries 5e7).
3. Conclusions
In conclusion, a novel method for the direct synthesis of un-
symmetrical ureas from N-Alloc-, N-Cbz-and N-Boc-protected
amines has been developed. In this study, after investigation of
several reagents, we employed DABAL-Me3, an air stable reagent, to
increase activation of N-Alloc-, N-Cbz- and N-Boc-protected amines
for direct preparation of target unsymmetrical ureas, including
trisubstituted and tetrasubstituted ureas, with high yields. Our re-
sults suggest that this novel direct DABAL-Me3-mediated trans-
formation of N-Alloc-, N-Cbz, and N-Boc-protected amines into
Please cite this article in press as: Kang S, Kim H-K, Facile direct synthesis of unsymmetrical ureas from N-Alloc-, N-Cbz-, and N-Boc-protected
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S. Kang, H.-K. Kim / Tetrahedron xxx (2018) 1e11
Table 3
Scope of urea formation from Alloc-protected aminesa.
unsymmetrical substituted ureas is practical and applicable to the
synthesis of many different ureas.
laboratory as well as stored in standard container. Proton and 13C
NMR spectra were recorded on a 600 MHz & 150 MHz respectively
JNM-ECA600 spectrometer. The chemical shifts are reported in
d
units (ppm) relative to tetramethylsilane (TMS) and the coupling
4. Experimental section
constants (J) quoted in Hz. Reaction progress was monitored by
thin-layer chromatography (TLC) analysis. TLC analysis was per-
formed using an aluminum plate with silica gel 60 F254 and TLC
spots were visualized by UV light (254 nm) exposure. Flash chro-
matography was performed using 230e400 mesh silica gel and
analytical grade solvent. HRMS spectrometry was performed on a
water Q-TOF mass spectrometer to obtain high-resolution mass
4.1. General procedure
All chemicals were purchased from Sigma-Aldrich and used
without further purification. DABAL-Me3 is a free-flowing solid and
has a hydrolytic stability. The reagent can be treated without the
need for an inert atmosphere, and can be weighed out freely in the
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S. Kang, H.-K. Kim / Tetrahedron xxx (2018) 1e11
5
spectra.
that previously reported.13
4.2.2. 1-Benzyl-3-phenylurea (3b)
4.2. General procedure for the preparation of urea compounds from
alloc-protected amine (3a-3s)
Yellow solid; mp 173e174 ꢀC; 1H NMR (600 MHz, DMSO‑d6)
8.49 (s, 1H), 7.37e7.17 (m, 9H), 6.86 (m, 1H), 6.56 (s, 1H), 4.26 (d,
d
J ¼ 6.0 Hz, 2H); 13C NMR (150 MHz, DMSO‑d6)
d 155.8, 140.9, 140.8,
To a solution of butylamine (0.099 g, 1.355 mmol) in toluene
(5 mL) DABAL-Me3 (0.347 g. 1.356 mmol) was added. The mixture
was stirred for 20 min at 40 ꢀC. 1a (0.200 g, 1.129 mmol) were added
and allowed to stir for 2 h at 90 ꢀC. The reaction mixture was
quenched by the addition of 1 M HCl (2 mL) and extracted with
CH2Cl2 (2 ꢁ 20 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 as eluent to afford the desired product 3a
(0.206 g, 95%).
129.2, 128.8, 127.6, 127.2, 121.6, 118.2, 43.3; HRMS (ESI) m/z
(M þ H)þ calcd for C14H15N2O ¼ 227.1179, found 227.1178. Data are
consistent with that previously reported.14
4.2.3. N-Phenylpiperidine-1-carboxamide (3c)
White solid; mp 169e171 ꢀC; 1H NMR (600 MHz, CDCl3)
d
7.34e7.31 (d, J ¼ 7.8 Hz, 2H), 7.26e7.23 (t, J ¼ 7.8 Hz, 2H), 6.99 (t,
J ¼ 1.8, 1H), 6.48 (s, 1H), 3.42 (m, 4H), 1.63e1.57 (m, 6H); 13C NMR
(150 MHz, CDCl3)
d 155.1, 139.4, 128.9, 122.9, 119.9, 45.3, 25.8, 24.5;
HRMS (ESI) m/z (M þ H)þ calcd for C12H17N2O ¼ 205.1335, found
205.1344. Data are consistent with that previously reported.15
4.2.1. 1-Butyl-3-phenylurea (3a)
White solid; mp 128e130 ꢀC; 1H NMR (600 MHz, DMSO‑d6)
d
8.31 (s, 1H), 7.33 (d, J ¼ 8.4 Hz, 2H), 7.16 (t, J ¼ 7.8 Hz, 2H), 6.82 (t,
4.2.4. N-Benzylmorpholine-4-carboxamide (3d)
J ¼ 7.2 Hz, 1H), 6.04 (t, J ¼ 5.4 Hz, 1H), 3.03 (dd, J ¼ 6.6, 12.5 Hz, 2H),
White solid; mp 138ꢂ140 ꢀC; 1H NMR (600 MHz, CDCl3)
1.38e1.35 (m, 2H), 1.28e1.24 (m, 2H), 0.85 (t, J ¼ 7.2 Hz, 3H); 13C
d
7.33e7.25 (m, 5H), 4.79 (s, 1H), 4.41 (s, 2H), 3.67 (t, J ¼ 4.8 Hz, 4H),
NMR (150 MHz, DMSO‑d6)
d
155.7, 141.1, 129.1, 121.3, 118.0, 39.5,
3.34 (t, J ¼ 4.8 Hz, 4H); 13C NMR (150 MHz, CDCl3)
d 157.7, 139.2,
32.4, 20.5, 14.7; HRMS (ESI) m/z (M
C
þ
H)þ calcd for
128.8, 127.9, 127.5, 66.6, 45.1, 44.1; HRMS (ESI) m/z (M þ H)þ calcd
for C12H17N2O2 ¼ 221.1290, found 221.1285. Data are consistent
11H17N2O ¼ 193.1335, found 193.1346. Data are consistent with
Please cite this article in press as: Kang S, Kim H-K, Facile direct synthesis of unsymmetrical ureas from N-Alloc-, N-Cbz-, and N-Boc-protected
amines using DABAL-Me3, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.06.011

6
S. Kang, H.-K. Kim / Tetrahedron xxx (2018) 1e11
Table 4
Scope of urea formation from Cbz-protected aminesa.
with that previously reported.16
4.2.6. 1-Benzyl-3-p-tolylurea (3f)
White solid; mp 183ꢂ185 ꢀC; 1H NMR (600 MHz, CDCl3)
d 8.39
(s, 1H), 7.31e7.11 (m, 7H), 6.89 (m, 2H), 6.51 (s, 1H), 4.24 (d,
4.2.5. 1-(benzo[d][1,3]dioxol-5-ylmethyl)-3-benzylurea (3e)
White solid; mp 162e164 ꢀC.; 1H NMR (400 MHz, CDCl3)
J ¼ 6.0 Hz, 2H), 2.18 (s, 3H); 13C NMR (150 MHz, CDCl3)
d 155.8,
140.9, 138.4, 130.3, 129.6, 128.8, 127.6, 127.2, 118.3, 43.3, 20.8; HRMS
(ESI) m/z (M þ H)þ calcd for C15H17N2O ¼ 241.1335, found 241.1345.
Data are consistent with that previously reported.18
d
7.33e7.22 (m, 5H), 6.85e6.72 (m, 3H), 6.42e6.38 (m, 2H), 5.98 (s,
2H), 4.23e4.22 (d, J ¼ 6 Hz, 2H), 4.14e4.13 (d, J ¼ 5.6 Hz, 2H); 13C
NMR (100 MHz, CDCl3) d 158.5, 147.6, 146.3, 141.3, 136.3, 128.6 (2C),
127.4 (2C),127.0, 120.5, 108.4, 108.1, 101.1, 43.4, 43.2; HRMS (ESI) m/z
(M þ H)þ calcd for C16H17N2O3 ¼ 285.1239, found 285.1235. Data
are consistent with that previously reported.17
4.2.7. 1-Benzyl-3-(4-methoxyphenyl)urea (3g)
White solid; mp 168e170 ꢀC; 1H NMR (400 MHz, DMSO‑d6)
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S. Kang, H.-K. Kim / Tetrahedron xxx (2018) 1e11
7
Scheme 1. The gram-scale reaction of N-Alloc-protected benzylamines with aniline.
d
8.35 (s, 1H), 7.24e7.35 (m, 7H), 6.83 (d, J ¼ 12 Hz, 2H), 6.51 (t,
4.2.10. 1-Benzyl-3-(4-nitrophenyl)urea (3j)
J ¼ 6 Hz, 1H), 4.29 (d, J ¼ 6 Hz, 2H) 3.69 (s, 3H); 13C NMR (100 MHz,
Yellow solid; mp 216e218 ꢀC; 1H NMR (400 MHz, CDCl3)
d
9.39
CDCl3)
d
154.9, 147.6, 140.9, 140.2, 128.8 (2C), 127.6 (2C),127.2, 125.5
(s, 1H), 8.16e8.13 (m, 2H), 7.66e7.63 (m, 2H), 7.36e7.25 (m, 5H),
(2C), 117.3 (2C), 43.2; HRMS (ESI) m/z (M þ H)þ calcd for
6.95 (t, J ¼ 6, 1H); 13C NMR (100 MHz, CDCl3)
d 152.9, 139.9, 139.2,
C
15H17N2O2 ¼ 257.1290, found 221.1288. Data are consistent with
129.3, 129.1, 125.8, 122.4, 120.1, 118.8; HRMS (ESI) m/z (M þ H)þ
calcd for C14H14N3O3 ¼ 272.1035, found 272.1037.
that previously reported.19
4.2.8. 1-Benzyl-3-(4-chlorophenyl)urea (3h)
4.2.11. 3-Benzy-1-methyl-1-phenylurea (3k)
White solid; mp 190ꢂ192 ꢀC; 1H NMR (600 MHz, DMSO‑d6)
White solid; mp 92e94 ꢀC; 1H NMR (600 MHz, CDCl3)
d
8.66 (s, 1H), 7.40e7.38 (m, 2H), 7.29e7.21 (m, 7H), 6.62 (s, 1H),
d 7.41e7.38 (m, 2H), 7.29e7.20 (m, 8H), 4.66 (s, 1H), 4.38 (d,
4.25 (d, J ¼ 6.0 Hz, 2H); 13C NMR (150 MHz, DMSO‑d6)
d
155.6,140.8,
J ¼ 5.4 Hz, 2H), 3.29 (s, 3H); 13C NMR (150 MHz, CDCl3)
d 157.3,
140.0, 129.0, 128.8, 127.6, 125.0, 120.3, 119.7, 43.2; HRMS (ESI) m/z
(M þ H)þ calcd for C14H14ClN2O ¼ 261.0789, found 261.0798. Data
are consistent with that previously reported.20
134.4, 139.6, 130.2, 128.9, 127.5, 127.4, 127.2, 44.8, 37.4; HRMS (ESI)
m/z (M þ H)þ calcd for C15H17N2O ¼ 241.1335, found 241.1346. Data
are consistent with that previously reported.21
4.2.9. 1-Benzyl-3-(4-cyanophenyl)urea (3i)
4.2.12. 3-Butyl-1-methyl-1-phenylurea (3l)
White solid; m.p 177e178 ꢀC; 1H NMR (400 MHz, CDCl3)
d
9.14
White solid; mp 46e48 ꢀC; 1H NMR (600 MHz, CDCl3)
(s, 1H), 7.68e7.58 (m, 4H), 7.34e7.31 (m, 5H), 6.87 (t, J ¼ 5.6 Hz,1H),
d
7.40e7.37 (m, 2H), 7.28e7.20 (m, 3H), 4.28 (brs, 1H), 3.23 (s, 3H),
4.32 (d, J ¼ 5.6 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 155.9, 145.4,
3.13 (m, 2H), 1.36e1.33 (m, 2H), 1.23e1.19 (m, 2H), 0.84 (t, J ¼ 7.2 Hz,
140.4,133.6 (2C),128.8 (2C),127.6 (2C),127.3,119.9,117.9 (2C),102.9,
43.2; HRMS (ESI) m/z (M þ H)þ calcd for C15H14N3O ¼ 252.1137,
found 252.1139.
3H); 13C NMR (150 MHz, CDCl3)
d 157.4, 143.5, 130.1, 127.4, 127.2,
40.6, 37.2, 32.4, 20.1, 13.9; HRMS (ESI) m/z (M þ H)þ calcd for
C
12H19N2O ¼ 207.1492, found 207.1498. Data are consistent with
Please cite this article in press as: Kang S, Kim H-K, Facile direct synthesis of unsymmetrical ureas from N-Alloc-, N-Cbz-, and N-Boc-protected
amines using DABAL-Me3, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.06.011

8
S. Kang, H.-K. Kim / Tetrahedron xxx (2018) 1e11
Table 5
Scope of urea formation from Boc- and Fmoc-protected aminesa.
that previously reported.22
4.2.15. N-Phenylpiperidine-1-carboxamide (3o)
White solid; mp 169e171 ꢀC; 1H NMR (600 MHz, CDCl3)
7.34e7.31 (d, J ¼ 7.8 Hz, 2H), 7.26e7.23 (t, J ¼ 7.8 Hz, 2H), 6.99 (t,
d
J ¼ 1.8, 1H), 6.48 (s, 1H), 3.42 (m, 4H), 1.63e1.57 (m, 6H); 13C NMR
4.2.13. N-Methyl-N-phenylpyrrolidine-1-carboxamide (3m)
Peach solid; mp 64e66 ꢀC; 1H NMR (600 MHz, CDCl3)
(150 MHz, CDCl3)
d 155.1, 139.4, 128.9, 122.9, 119.9, 45.3, 25.8, 24.5;
HRMS (ESI) m/z (M þ H)þ calcd for C12H17N2O ¼ 205.1335, found
d
7.31e7.28 (m, 2H), 7.10e7.08 (m, 3H), 3.21 (s, 3H), 3.03 (m, 4H),
205.1344. Data are consistent with that previously reported.15
1.67e1.64 (m, 4H); 13C NMR (150 MHz, CDCl3)
d 159.9, 146.5, 129.3,
125.1, 124.6, 47.9, 39.8, 25.4; HRMS (ESI) m/z (M þ H)þ calcd for
C
12H17N2O ¼ 205.1335, found 205.1345. Data are consistent with
4.2.16. N-Methyl-N-phenylpiperidine-1-carboxamide (3p)
that previously reported.23
A colorless oil. 1H NMR (600 MHz, CDCl3):
d
7.30e7.27 (m, 2H),
7.07e7.04 (m, 3H), 3.18 (s, 3H), 3.14e3.12 (m, 4H), 1.45e1.43 (m,
2H), 1.33e1.29 (m, 4H); 13C NMR (150 MHz, CDCl3):
d 161.3, 147.3,
129.4, 124.2, 123.6, 46.7, 39.5, 25.4, 24.6; HRMS (ESI) m/z (M þ H)þ
calcd for C13H19N2O ¼ 219.1492, found 219.1494. Data are consis-
tent with that previously reported.25
4.2.14. N-Benzylpiperidine-1-carboxamide (3n)
White solid; mp 101ꢂ104 ꢀC; 1H NMR (600 MHz, CDCl3)
d
7.32e7.22 (m, 5H), 4.81 (s, 1H), 4.40e4.39 (m, 2H), 3.32e3.30 (m,
4H), 1.59e1.50 (m, 6H); 13C NMR (150 MHz, CDCl3)
d 157.7, 139.8,
128.6, 127.8, 127.3, 45.1, 45.0, 25.7, 24.5; HRMS (ESI) m/z (M þ H)þ
calcd for C13H19N2O ¼ 219.1492, found 219.1495. Data are consis-
tent with that previously reported.24
4.2.17. 1,1-Dibenzyl-3-butylurea (3q)
White solid; mp 72e74 ꢀC; 1H NMR (600 MHz, CDCl3)
d
7.34e7.31 (m, 4H), 7.28e7.23 (m, 6H), 4.48 (s, 4H), 4.33 (s,1H), 3.19
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S. Kang, H.-K. Kim / Tetrahedron xxx (2018) 1e11
9
(m, 2H), 1.36e1.32 (m, 2H), 1.17e1.13 (m, 2H), 0.83e0.81 (m, 3H);
J ¼ 6.0 Hz, 2H), 2.18 (s, 3H); 13C NMR (150 MHz, CDCl3)
d
155.8,
13C NMR (150 MHz, CDCl3)
d
158.6, 137.8, 128.8, 127.5, 127.3, 50.4,
140.9, 138.4, 130.3, 129.6, 128.8, 127.6, 127.2, 118.3, 43.3, 20.8; HRMS
(ESI) m/z (M þ H)þ calcd for C15H17N2O ¼ 241.1335, found 241.1345.
Data are consistent with that previously reported.18
40.8, 32.3, 19.9, 13.8; HRMS (ESI) m/z (M þ H)þ calcd for
C
19H25N2O ¼ 297.1961, found 297.1965. Data are consistent with
that previously reported.26
4.3.5. 1-Benzyl-3-(4-methoxyphenyl)urea (6e)
White solid; mp 168e170 ꢀC; 1H NMR (400 MHz, DMSO‑d6)
4.2.18. 1,1-Dibenzyl-3-cyclohexylurea (3r)
White solid; mp 140e142 ꢀC; 1H NMR (600 MHz, CDCl3)
d
8.35 (s, 1H), 7.24e7.35 (m, 7H), 6.83 (d, J ¼ 12 Hz, 2H), 6.51 (t,
J ¼ 6 Hz, 1H), 4.29 (d, J ¼ 6 Hz, 2H) 3.69 (s, 3H); 13C NMR (100 MHz,
d
7.34e7.31 (m, 4H), 7.27e7.21 (m, 6H), 4.47 (s, 4H), 4.2 (m, 1H),
3.68e3.64 (m, 1H), 1.83e1.81 (m, 2H), 1.52 (m, 3H), 1.31e1.27 (m,
CDCl3) d 154.9, 147.6, 140.9, 140.2, 128.8 (2C), 127.6 (2C),127.2, 125.5
2H), 1.07e1.04 (m, 1H), 0.91e0.96 (m, 2H); 13C NMR (150 MHz,
(2C), 117.3 (2C), 43.2; HRMS (ESI) m/z (M þ H)þ calcd for
CDCl3)
d 157.9, 137.9, 128.8, 127.5, 127.3, 50.4, 49.4, 33.7, 25.7, 24.8;
C
15H17N2O2 ¼ 257.1290, found 221.1288. Data are consistent with
HRMS (ESI) m/z (M þ H)þ calcd for C21H27N2O ¼ 323.2118, found
that previously reported.19
323.2127. Data are consistent with that previously reported.12(c)
4.3.6. 1-Benzyl-3-(4-cyanophenyl)urea (6f)
White solid; m. p 177e178 ꢀC; 1H NMR (400 MHz, CDCl3)
d 9.14
4.2.19. N,N-Dibenzylmorpholine-4-carboxamide (3s)
White solid; mp 106e108 ꢀC; 1H NMR (600 MHz, CDCl3):
(s, 1H), 7.68e7.58 (m, 4H), 7.34e7.31 (m, 5H), 6.87 (t, J ¼ 5.6 Hz,1H),
4.32 (d, J ¼ 5.6 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d
155.9, 145.4,
d
7.33e7.25 (m, 6H), 7.16e7.15 (m, 4H), 4.31 (s, 4H), 3.69 (t,
J ¼ 4.8 Hz, 4H), 3.32 (t, J ¼ 4.8 Hz, 4H); 13C NMR (150 MHz, CDCl3)
140.4,133.6 (2C),128.8 (2C),127.6 (2C),127.3,119.9,117.9 (2C),102.9,
43.2; HRMS (ESI) m/z (M þ H)þ calcd for C15H14N3O ¼ 252.1137,
found 252.1139.
d
164.9, 137.3, 128.7, 127.9, 127.5, 66.7, 50.7, 47.8; HRMS (ESI) m/z
(M þ H)þ calcd for C19H23N2O2 ¼ 311.1754, found 311.1764. Data are
consistent with that previously reported.23
4.3.7. 1-Benzyl-3-(4-nitrophenyl)urea (6g)
4.3. General procedure for the preparation of urea compounds from
Cbz-protected amine (6a-6q)
Yellow solid; mp 216e218 ꢀC; 1H NMR (400 MHz, CDCl3)
d 9.39
(s, 1H), 8.16e8.13 (m, 2H), 7.66e7.63 (m, 2H), 7.36e7.25 (m, 5H),
6.95 (t, J ¼ 6, 1H); 13C NMR (100 MHz, CDCl3)
d 152.9, 139.9, 139.2,
To a solution of morpholine (0.115 g, 1.321 mmol) in toluene
(5 mL) DABAL-Me3 (0.406 g. 1.321 mmol) was added. The mixture
was stirred for 20 min at 40 ꢀC. 4a (0.250 g,1.100 mmol) were added
and allowed to stir for 2 h at 90 ꢀC. The reaction mixture was
quenched by the addition of 1 M HCl (4 mL) and extracted with
CH2Cl2 (2 ꢁ 20 mL). The organic layer was dried over magnesium
sulfate and concentrated under reduced pressure. The resulting
residue was then purified by flash column chromatography on silica
gel with hexane-EtOAc as eluent to afford the desired product 6a
(0.213 g, 94%).
129.3, 129.1, 125.8, 122.4, 120.1, 118.8; HRMS (ESI) m/z (M þ H)þ
calcd for C14H14N3O3 ¼ 272.1035, found 272.1037.
4.3.8. 3-Cyclohexyl-1-methyl-1-phenylurea (6h)
White solid; mp 112e114 ꢀC; 1H NMR (600 MHz, CDCl3)
d
7.40e7.37 (m, 2H)), 7.27e7.21 (m, 3H), 4.1 (m, 1H), 3.61e3.55 (m,
1H), 3.23 (s, 3H), 1.84e1.81 (m, 2H), 1.58e1.51 (m, 3H), 1.31e1.26 (m
2H), 1.06e1.02 (m, 1H), 0.96e0.90 (m, 2H); 13C NMR (150 MHz,
CDCl3)
d 156.6, 143.7, 130.0, 127.3, 127.1, 49.4, 37.1, 33.7, 25.6, 24.9;
HRMS (ESI) m/z (M þ H)þ calcd for C14H21N2O ¼ 233.1648, found
233.1652. Data are consistent with that previously reported.29
4.3.1. N-Phenylmorpholine-4-carboxamide (6a)
White solid; mp 150ꢂ152 ꢀC; 1H NMR (600 MHz, CDCl3)
4.3.9. 1-(4-Chlorophenethyl)-3-phenylurea (6i)
d
7.33e7.25 (m, 4H), 7.03 (m,1H), 6.58 (s,1H), 3.67 (t, J ¼ 4.8 Hz, 4H),
White solid; mp 116e119 ꢀC; IR nmax (KBr) 3321, 1628, 1596,
3.43 (t, J ¼ 5.4 Hz, 4H); 13C NMR (150 MHz, CDCl3)
d 155.3, 138.8,
1574 cmꢂ1; 1H NMR (400 MHz, DMSO‑d6)
d
7.40e7.20 (m, 9H), 6.89
128.9, 123.5, 120.3, 66.6, 44.3; HRMS (ESI) m/z (M þ H)þ calcd for
(bs, 1H), 5.12 (bs, 1H), 3.34 (m, 2H), 2.75 (m, 2H); 13C NMR
C
11H15N2O2 ¼ 207.1128, found 207.1137. Data are consistent with
that previously reported.27
(100 MHz, DMSO‑d6)
d 155.6, 141.0, 139.1, 131.1, 129.1, 128.7, 128.5,
127.1, 121.5, 40.8, 35.6; HRMS (ESI) m/z (M þ H)þ calcd for
C15H16ClN2O ¼ 275.0946, found 275,0949.
4.3.2. N-Benzylpyrrolidine-1-carboxamide (6b)
White solid; mp 119ꢂ121 ꢀC; 1H NMR (600 MHz, CDCl3)
4.3.10. 1-(4-Chlorophenethyl)-3-(3-trifluoromethylbenzyl)urea (6j)
White solid; mp 121e123 ꢀC; IR nmax (KBr) 3326,1617,1576,1331,
d
7.29e7.19 (m, 5H), 4.66 (s,1H), 4.39 (s, 2H), 3.29 (m, 4H),1.87e1.83
(m, 4H); 13C NMR (150 MHz, CDCl3)
d 156.8, 140.0, 128.6, 127.8,
1115 cmꢂ1; 1H NMR (400 MHz, DMSO‑d6)
d 7.57e7.53 (m, 4H), 7.32
127.2, 45.6, 44.6, 25.6; HRMS (ESI) m/z (M þ H)þ calcd for
(d, J ¼ 8.4 Hz, 2H), 7.21 (d, J ¼ 8.4 Hz, 2H), 6.52 (bs, 1H), 6.05 (bs, 1H),
C
12H17N2O ¼ 205.1335, found 205.1346. Data are consistent with
4.28 (d, J ¼ 6.0 Hz, 2H), 3.25 (m, 2H), 2.69 (t, J ¼ 7.2 Hz, 2H); 13C NMR
that previously reported.28
(100 MHz, DMSO‑d6)
d 158.4, 143.2, 139.2, 131.5, 131.1, 131.0, 129.5,
129.4 (q, J ¼ 31.2), 128.6, 124.8 (q, J ¼ 270.6 Hz), 123.7 (2C, m), 42.8,
41.2, 35.8; HRMS (ESI) m/z (M
H)þ calcd for
17H17ClF3N2O ¼ 357.0976, found 357.0977.
4.3.3. 1-(benzo[d][1,3]dioxol-5-ylmethyl)-3-benzylurea (6c)
White solid; mp 162e164 ꢀC.; 1H NMR (400 MHz, CDCl3)
þ
C
d
7.33e7.22 (m, 5H), 6.85e6.72 (m, 3H), 6.42e6.38 (m, 2H), 5.98 (s,
2H), 4.23e4.22 (d, J ¼ 6 Hz, 2H), 4.14e4.13 (d, J ¼ 5.6 Hz, 2H); 13C
NMR (100 MHz, CDCl3)
d
158.5, 147.6, 146.3, 141.3, 136.3, 128.6 (2C),
4.3.11. 1-(3-Chlorophenethyl)-3-(4-chlorophenethyl)urea (6k)
White solid; mp 119e121 ꢀC; IR nmax (KBr) 3324, 1617,
127.4 (2C),127.0, 120.5, 108.4, 108.1, 101.1, 43.4, 43.2; HRMS (ESI) m/z
(M þ H)þ calcd for C16H17N2O3 ¼ 285.1239, found 285.1235. Data
are consistent with that previously reported.17
1582 cmꢂ1; 1H NMR (400 MHz, DMSO‑d6)
d
7.33 (d, J ¼ 8.4 Hz, 2H),
7.30e7.15 (m, 6H), 5.88 (bs, 1H), 5.87 (bs, 1H), 3.21 (m, 4H), 2.66 (m,
4H); 13C NMR (100 MHz, DMSO‑d6)
158.3,142.9,139.3,133.3, 131.1,
d
4.3.4. 1-Benzyl-3-p-tolylurea (6d)
131.0, 130.5, 129.0, 128.6, 127.9, 126.4, 41.1, 40.9, 36.1, 35.8; HRMS
(ESI) m/z (M þ H)þ calcd for C17H19Cl2N2O ¼ 337.0869, found
337.0872.
White solid; mp 183ꢂ185 ꢀC; 1H NMR (600 MHz, CDCl3)
d 8.39
(s, 1H), 7.31e7.11 (m, 7H), 6.89 (m, 2H), 6.51 (s, 1H), 4.24 (d,
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10
S. Kang, H.-K. Kim / Tetrahedron xxx (2018) 1e11
4.3.12. 1-Butyl-3-(4-chlorophenethyl)urea (6l)
resulting residue was then purified by flash column chromatog-
raphy on silica gel with hexane-EtOAc as eluent to afford the
desired product 9a (0.230 g, 93%).
White solid; mp 95e98 ꢀC; IR nmax (KBr) 3320, 1618, 1576,
1559 cmꢂ1; 1H NMR (400 MHz, DMSO‑d6)
d
7.34 (d, J ¼ 8.4 Hz, 2H),
7.22 (d, J ¼ 8.4 Hz, 2H), 5.84 (t, J ¼ 5.6 Hz, 1H), 5.77 (t, J ¼ 5.6 Hz, 1H),
3.21 (m, 2H), 2.96 (m, 2H), 2.67 (t, J ¼ 7.2 Hz, 2H), 1.34e1.21 (m, 4H),
4.4.1. 1-Benzyl-3-cyclohexylurea (9a)
1.88 (t, J ¼ 7.3 Hz, 3H); 13C NMR (100 MHz, DMSO‑d6)
d
158.4, 139.3,
White solid; mp 133ꢂ134 ꢀC; 1H NMR (400 MHz, CDCl3)
131.1, 131.0, 128.6, 41.1, 39.3, 35.9, 32.6, 20.0, 14.2; HRMS (ESI) m/z
(M þ H)þ calcd for C13H20ClN2O ¼ 255.1259, found 255.1269.
d
7.25e7.34 (m, 5H), 4.33 (s, 2H), 3.52 (m, 1H), 1.91 (dd, J ¼ 3.2,
14.8 Hz, 2H), 1.66 (m, 3H), 1.31 (m, 3H), 1.09 (m, 3H); 13C NMR
(100 MHz, CDCl3) 157.6, 139.4, 128.6, 127.4, 127.2, 19.1, 44.4, 33.9,
25.6, 24.9; HRMS (ESI) m/z (M
H)þ calcd for
14H21N2O ¼ 233.1648, found 233.1658. Data are consistent with
that previously reported.30
d
4.3.13. 1-(4-Chlorophenethyl)-3-cyclopentylurea (6m)
þ
White solid; mp 105e107 ꢀC; IR nmax (KBr) 3311, 2961, 1622,
C
1585 cmꢂ1; 1H NMR (400 MHz, DMSO‑d6)
7.22 (d, J ¼ 8.0 Hz, 2H), 5.84 (d, J ¼ 7.2 Hz, 1H), 5.64 (m, 1H), 3.82 (m,
1H), 3.20 (q, J ¼ 6.8 Hz, 4H), 2.66 (t, J ¼ 7.0 Hz, 2H), 1.74 (m, 2H),
1.57e1.49 (m, 4H), 1.25 (m, 2H); 13C NMR (100 MHz, DMSO‑d6)
d
7.33 (d, J ¼ 8.0 Hz, 2H),
4.4.2. N-Benzylpiperidine-1-carboxamide (9b)
White solid; mp 101ꢂ103 ꢀC; 1H NMR (400 MHz, CDCl3)
7.26e7.37 (m, 5H), 4.74 (s, 1H), 4.46 (d, J ¼ 5.2 Hz, 2H) 3.36 (t,
d
158.1, 139.3, 131.1, 131.0, 128.6, 51.3, 41.0, 35.9, 33.5, 23.9; HRMS
d
(ESI) m/z (M þ H)þ calcd for C14H20ClN2O ¼ 267.1259, found
J ¼ 5.6 Hz, 4H), 1.61 (m, 6H); 13C NMR (100 MHz, CDCl3)
d157.5,
267.1260.
139.6, 128.6, 127.8, 127.2, 24.1, 45.02, 25.6, 24.4; HRMS (ESI) m/z
(M þ H)þ calcd for C13H19N2O ¼ 219.1492, found 219.1499. Data are
consistent with that previously reported.24
4.3.14. 1-Allyl-3-(4-chlorophenethyl)urea (6n)
White solid; mp 107e109 ꢀC; IR nmax (KBr) 3326, 1623,
1595 cmꢂ1; 1H NMR (400 MHz, DMSO‑d6)
d
7.34 (d, J ¼ 8.4 Hz, 2H),
4.4.3. 3-Phenyl-1,1-dipropylurea (9c)
7.22 (d, J ¼ 8.4 Hz, 2H), 6.00 (t, J ¼ 5.6 Hz, 1H), 5.89 (t, J ¼ 5.6 Hz, 1H),
5.80 (m, 1H), 5.08 (dd, J ¼ 17.2, 1.6 Hz, 1H), 5.08 (dd, J ¼ 10.0, 1.6 Hz,
1H), 3.63 (m, 2H), 3.24 (q, J ¼ 6.8 Hz, 2H), 2.68 (t, J ¼ 7.2, 2H); 13C
White solid; mp 70ꢂ72 ꢀC; 1H NMR (400 MHz, CDCl3)
d 7,41 (m,
2H), 7.29 (m, 2H), 7.03 (m, 1H), 6.34 (s, 1H), 3,28 (t, J ¼ 7.2 Hz, 4H),
1.66 (m, 4H), 0,97 (t, J ¼ 7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3)
NMR (100 MHz, DMSO‑d6)
d
158.2, 139.2, 137.3, 131.1, 131.0, 128.6,
d 154.9, 139.3, 128.8, 122.7, 119.7, 49.5 (2C), 21.9 (2C), 11.4 (2C);
114.7, 42.1, 41.1, 35.9; HRMS (ESI) m/z (M þ H)þ calcd for
HRMS (ESI) m/z (M þ H)þ calcd for C13H21N2O ¼ 221.1648, found
C
12H16ClN2O ¼ 239.0946, found 239.0946.
221.1658. Data are consistent with that previously reported.31
4.3.15. 3-(4-Chlorophenethyl)-1,1-diethylurea (6o)
4.4.4. 1-Phenyl-3-p-tolylurea (9d)
Colorless gel; IR nmax (KBr) 3345, 2974, 1625, 1533, 1492, 1281,
White solid; mp 212ꢂ213 ꢀC; 1H NMR (400 MHz, CDCl3)
d 8.61
1091 cmꢂ1; 1H NMR (400 MHz, DMSO‑d6)
d
7.25 (d, J ¼ 8.0 Hz, 2H),
(s, 1H), 8.55 (s, 1H), 7.44e7.46 (m, 2H), 7.26e736 (m, 4H), 7.07 (d,
7.13 (d, J ¼ 8.0 Hz, 2H), 4.50 (t, J ¼ 5.2 Hz,1H), 3.44 (q, J ¼ 6.8 Hz, 2H),
J ¼ 8.0 Hz, 2H), 6.96 (m, 1H) 2.45 (s, 3H); 13C NMR (100 MHz, CDCl3)
3.21 (q, J ¼ 7.2 Hz, 4H), 2.80 (t, J ¼ 6.8 Hz, 2H), 1.08 (t, J ¼ 7.2 Hz, 6H);
d
153.0, 140.2, 137.7, 137.6, 131.1, 130.9, 129.6, 129.2, 122.1, 118.7,
13C NMR (100 MHz, DMSO‑d6)
d
157.1, 138.1, 132.0, 130.2, 128.5, 41.9,
118.7, 118.6, 118.5, 20.8; HRMS (ESI) m/z (M þ H)þ calcd for
41.1, 35.8, 13.8; HRMS (ESI) m/z (M
13H20ClN2O ¼ 255.1259, found 255.1289.
þ
H)þ calcd for
C
14H15N2O ¼ 227.1179, found 227.1189. Data are consistent with
C
that previously reported.32
4.3.16. N-(4-Chlorophenethyl)piperidine-1-carboxamide (6p)
White solid; mp 115e118 ꢀC; IR nmax (KBr) 3338, 2934, 2855,
4.4.5. 3-Benzyl-1,1-dipropylurea (9f)
White solid; mp 43ꢂ45 ꢀC; 1H NMR (400 MHz, CDCl3)
1622, 1539, 1492, 1271 cmꢂ1
;
1H NMR (400 MHz, DMSO‑d6)
d
7.33
d
7.26e7.37 (m, 5H), 4.65 (s, 1H), 4.67 (d, J ¼ 4.8 Hz, 2H), 3.19 (t,
(d, J ¼ 8.4 Hz, 2H), 7.21 (d, J ¼ 8.4 Hz, 2H), 6.50 (t, J ¼ 5.2 Hz, 1H),
J ¼ 8.0 Hz, 4H), 1.55e1.65 (m, 4H), 0.92 (t, J ¼ 7.2 Hz, 6H), 2.43 (s,
3.24 (m, 6H), 2.71 (t, J ¼ 7.2 Hz, 2H), 1.50 (m, 2H), 1.38 (m, 4H); 13
C
3H); 13C NMR (100 MHz, CDCl3)
d 157.6, 139.9, 128.6, 127.6, 127.1,
NMR (100 MHz, DMSO‑d6)
d
157.7, 139.4, 131.0, 130.9, 128.6, 44.7,
49.2 (2C), 44.9, 21.8 (2C), 11.39 (2C); HRMS (ESI) m/z (M þ H)þ calcd
for C14H23N2O ¼ 235.1805, found 235.1815. Data are consistent with
that previously reported.33
42.1, 35.7, 25.8, 24.7; HRMS (ESI) m/z (M þ H)þ calcd for
C
14H20ClN2O ¼ 267.1259, found 267.1257.
4.3.17. N-(4-Chlorophenethyl)morpholine-4-carboxamide (6q)
White solid; mp 100e102 ꢀC; IR nmax (KBr) 3346, 2858, 1627,
4.4.6. 1-(4-Chlorophenyl)-3-phenylurea (9g)
White solid; mp 248ꢂ250 ꢀC; 1H NMR (400 MHz, CDCl3)
d 8.81
1575, 1263 cmꢂ1; 1H NMR (400 MHz, DMSO‑d6)
d
7.33 (d, J ¼ 8.4 Hz,
(s, 1H), 8.70 (s, 1H), 7.44e7.50 (m, 4H), 7.31e7.33 (m, 4H), 7.26e7.29
2H), 7.21 (d, J ¼ 8.4 Hz, 2H), 6.63 (t, J ¼ 5.6 Hz,1H), 3.52 (m, 4H), 3.22
(m, 1H); 13C NMR (100 MHz, CDCl3)
d 152.9, 139.9, 139.2, 129.3,
(m, 6H), 2.71 (m, 2H); 13C NMR (100 MHz, DMSO‑d6)
d
158.0, 139.3,
129.1, 125.8, 122.4, 120.1, 118.8; HRMS (ESI); HRMS (ESI) m/z
(M þ H)þ calcd for C13H12ClN2O ¼ 247.0633, found 247.0689. Data
are consistent with that previously reported.28
131.1, 131.0, 128.6, 66.4, 44.3, 42.1, 35.6; HRMS (ESI) m/z (M þ H)þ
calcd for C13H18ClN2O2 ¼ 269.1051, found 269.1056.
4.4. General procedure for the preparation of urea compounds from
Conflicts of interest
Boc- and Fmoc-protected amine (9a-9g)
There are no conflicts to declare.
Acknowledgments
To a solution of cyclohexylamine (0.126 g, 1.275 mmol) in
toluene (5 mL) DABAL-Me3 (0.327 g. 1.275 mmol) was added. The
mixture was stirred for 20 min at 40 ꢀC. 6a (0.220 g, 1.063 mmol)
were added and allowed to stir for 2 h at 90 ꢀC. The reaction
mixture was quenched by the addition of 1 M HCl (4 mL) and
extracted with CH2Cl2 (2 ꢁ 20 mL). The organic layer was dried over
magnesium sulfate and concentrated under reduced pressure. The
This research was supported by Basic Science Research Program
through the National Research Foundation of Korea (NRF) funded
by the Ministry of Education (2018R1D1A1B07047572), and by the
Ewha Womans University Research Grant of 2017.
Please cite this article in press as: Kang S, Kim H-K, Facile direct synthesis of unsymmetrical ureas from N-Alloc-, N-Cbz-, and N-Boc-protected
amines using DABAL-Me3, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.06.011

S. Kang, H.-K. Kim / Tetrahedron xxx (2018) 1e11
11
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Appendix A. Supplementary data
Supplementary data related to this article can be found at
https://doi.org/10.1016/j.tet.2018.06.011.
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Please cite this article in press as: Kang S, Kim H-K, Facile direct synthesis of unsymmetrical ureas from N-Alloc-, N-Cbz-, and N-Boc-protected
amines using DABAL-Me3, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.06.011