A simple conversion of amines into monosubstituted ureas in organic and aqueous solvents

Article abstract of DOI:10.1016/S0040-4039(00)02289-9

A versatile and highly efficient synthesis of monosubstituted ureas is described. The reaction of an amine with 4-nitrophenyl-N-benzylcarbamate, followed by hydrogenolysis, provides the corresponding urea in high yield and purity. This carbamate can also be employed for the derivatization of water-soluble polyamines (e.g. aminoglycoside antibiotics), while other reagents (e.g. benzylisocyanate) fail to give the desired products in any significant yield.

Full text of DOI:10.1016/S0040-4039(00)02289-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1445–1447
A simple conversion of amines into monosubstituted ureas in
organic and aqueous solvents
Qi Liu, Nathan W. Luedtke and Yitzhak Tor*
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093-0358, USA
Received 22 November 2000; accepted 12 December 2000
Abstract—A versatile and highly efficient synthesis of monosubstituted ureas is described. The reaction of an amine with
4-nitrophenyl-N-benzylcarbamate, followed by hydrogenolysis, provides the corresponding urea in high yield and purity. This
carbamate can also be employed for the derivatization of water-soluble polyamines (e.g. aminoglycoside antibiotics), while other
reagents (e.g. benzylisocyanate) fail to give the desired products in any significant yield. © 2001 Elsevier Science Ltd. All rights
reserved.
Substituted ureas are found in natural products,1 phar-
maceutical and agricultural preparations,2 as well as in
numerous artificial receptors and self-assembled
supramolecules.3 During our investigation of small
organic molecules as RNA binders,4 we have become
interested in monosubstituted urea functionalities as
uncharged, isostructural analogs of guanidinium
groups. A general approach for the synthesis of such
derivatives that can tolerate amines of various structure
and complexity, as well as reaction media (i.e. organic
or water-containing), has become a necessity.
reasonably stable in aqueous environments. Here we
report on a highly versatile and efficient two-step syn-
thesis of monosubstituted ureas using 4-nitrophenyl-N-
benzylcarbamate 1 (Scheme 1). The reaction of amines
with 1, followed by hydrogenolysis, provides the corre-
sponding ureas in high yield and purity (Scheme 1).
Importantly, excellent transformations are obtained
when 1 reacts with more sophisticated amines (such as
aminoglycoside antibiotics) in aqueous solvents
(Scheme 2).
4-Nitrophenyl-N-benzylcarbamate 1 was obtained in
high yield by condensing benzylamine with 4-nitro-
phenyl-chloroformate.10 The colorless, crystalline mate-
rial 1 effectively reacts with various amines to give the
corresponding N-benzyl ureas in excellent yields (Table
1).11 Thus, reaction of cyclohexanemethylamine with 1
in dichloromethane in the presence of triethylamine for
30 min, followed by a basic aqueous workup gives the
disubstituted urea 2 in 92% yield and in pure form
(Scheme 1).12 No additional chromatography or recrys-
tallizations are needed. Medium pressure (30–50 psi)
hydrogenolysis in acetic acid, in the presence of Pd
black, yields the desired monosubstituted urea 3 in
Most synthetic approaches to ureas utilize phosgene or
its tamed analogs.5,6 Commercially available reagents,
such as benzylisocyanate,7 also effectively convert
amines into easily deprotected disubstituted ureas.8 We
have suspected, however, that such reagents might not
withstand aqueous conditions or react efficiently with
complex starting materials. Indeed, reactions of amino-
glycoside antibiotics with benzylisocyanate in dioxane/
water mixtures failed to yield the desired products in
any significant yield.9 We have therefore sought to
develop a simple reagent that is electrophilic enough to
effectively react with amines of various structures, yet
O2N
O
O
O
Et3N
H2/Pd
NH2
N
H
N
H
N
H
NH2
O
N
H
+
1
2
3
Scheme 1. The reaction of cyclohexanemethylamine with 1 provides urea 3 in 92% overall yield after hydrogenolysis.
* Corresponding author. Tel.: (858) 534-6401; fax: (858) 534-5383; e-mail: ytor@ucsd.edu
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02289-9

1446
Q. Liu et al. / Tetrahedron Letters 42 (2001) 1445–1447
OH
OH
O
OH
OH
O
O
HO
H2N
HO
HO
OH
NH2
HO
OH
N
1. 1, dioxane/H2O, Et3N
H2N NH
O
O
H
N
NH2
HO
HO
OH
OH
H
O
2. H2, Pd, CH3CO2H
O
O
O
O
NH2
NH2
H2N
NH
H2N
O
O
4
5
Scheme 2. Derivatization of kanamycin A, an aminoglycoside antibiotic, to the fully urea-modified analog.
reaction mixture by extraction is ineffective. Column
chromatography, however, gives the desired protected
urea in 92% yield. Hydrogenolysis quantitatively
affords the desired product (entry 6, Table 1).
quantitative yield after filtration and evaporation of the
solvent (Scheme 1). NMR spectroscopy indicates >95%
purity and the melting point of the ‘crude’ product
(165–168°C) is very close to the literature value (170–
172°C). A single recrystallization from 2-propanol fur-
nishes the analytically-pure cyclohexanemethylurea 3
(entry 1, Table 1).13
Carbamate 1 can also be employed for the derivatiza-
tion of more sophisticated amines. Reaction of the
aminoglycoside antibiotic kanamycin A 4 with 1 in
dioxane/water proceeds to completion within 3 h at
room temperature to give the desired tetra-N-benzy-
lurea derivative in 93% yield (Step 1, Scheme 2).14 The
reaction appears to be driven by the precipitation of the
fully derivatized product and no purification is neces-
sary. Hydrogenolysis of the benzyl protected tetraurea
for 30 h at 55 psi H2 gives the desired fully urea-
modified kanamycin A 5 in 98% yield (Step 2, Scheme
2).15 It is worth noting that similar reactions with
benzylisocyanate results in extremely low yields of the
benzyl-protected ureas,9,16 and reactions with aqueous
potassium cyanate fail to yield the desired product.17
Numerous other amines can be similarly converted into
their corresponding urea derivatives utilizing this simple
two-step procedure. Cyclohexylamine reacts with 1 to
give the desired urea in 93% yield for the two steps
(entry 2, Table 1). Secondary amines also react effec-
tively. Piperidine, for example, gives the substituted
urea in 96% overall yield (entry 3). Sterically hindered
amines, such as t-butylamine, react well and yield the
desired urea in higher than 90% yield (entry 4, Table 1).
Less nucleophilic amines such as aniline require longer
reaction time (ca. 6 h), but react well with 1 to give the
desired product after hydrogenolysis (entry 5, Table 1).
In all these cases, no purification steps are required to
furnish reasonably pure products (>90% by NMR).
In summary, a simple and highly effective procedure for
the conversion of amines into their corresponding ureas
has been described. An easily accessible carbamate 1
reacts rapidly with various amines in apolar as well as
highly polar media to provide the desired N-benzyl
protected urea. Hydrogenolysis quantitatively converts
the disubstituted ureas into the corresponding mono-
substituted ureas.
To investigate the reaction of 1 with water-soluble
amines, 3-amino-1-propanol was allowed to react with
1 in a 3:1 dioxane/water mixture in the presence of
Et3N at room temperature for 45 min. In this particular
case, removal of the 4-nitrophenol from the crude
Table 1. Two-step conversion of amines into ureas
Entry
R
Conditions (step 1)a
Yield Ab
Mp A (°C)c
Yield B
Mp B (°C)d
Mp B (°C)e
1
2
3
4
5
6
C6H11CH2
C6H11
c-C5H10
t-Bu
Ph
CH2Cl2, 20 min
CH2Cl2, 30 min
CH2Cl2, 50 min
CH2Cl2, 30 min
CH2Cl2, 6 h
92%
93%
96%
91%
83%
92%g
166–168
100%
100%
100%
100%
100%
100%
165–168 (170–172)
177–180 (188)
96–98 (97–98)
165–169 (173–175)
134–136 (147)
58–60 (60–61)
169–172
186–188
97–99
173–175
143–145
58–60
173–175 (165–6)
99–101 (98–102)
109–111 (110–12)
175–176 (169–172)
95–97 (94)
f
HO(CH2)3
H2O–dioxane, 45 min
a All reactions have been carried out at room temperature.
b Yields of isolated ‘crude’ products are given.
c Melting points of the isolated ‘crude’ products are given and compared to the literature reported values (in parenthesis).
d Melting points of the isolated ‘crude’ monosubstituted ureas are given and compared to the literature reported values (in parenthesis).
e Melting points after single recrystallization.
f Piperidine.
g Product was purified by chromatography.

Q. Liu et al. / Tetrahedron Letters 42 (2001) 1445–1447
1447
Acknowledgements
86%). 1H NMR indicates >95% purity. If desired, 1 can be
further purified by flash chromatography (20% hexane/
dichloromethane). 1H NMR (400 MHz, CDCl3): l 8.22 (d,
J=9.2 Hz, 2H), 7.37–7.29 (m, 7H), 5.46 (t, J=6 Hz, 1H),
4.45 (d, J=6 Hz, 2H); IR (KBr pellet) 3317, 1708, 1525,
This work was supported by grants from the National
Institutes of Health (AI 47673) and the Universitywide
AIDS Research Program (D00-SD-017).
1348, 1253, 1211, 1036, 1011 cm−1
.
11. General procedure for the synthesis of N-benzyl ureas: In
a typical reaction, 4-nitrophenyl-N-benzylcarbamate 1 (1
mmol) is added to a solution of an amine (1 mmol) and
triethylamine (1 mmol) in dichloromethane (8 ml). The
mixture is stirred at room temperature until 1 is consumed
(as evidenced by TLC). The reaction mixture is then
diluted with dichloromethane (100 ml) and washed with
dilute aq. NaOH, water and brine. After drying (Na2SO4)
and filtering, the solvent is removed under reduced pres-
sure. 1H NMR indicates >95% purity. If desired, the crude
product can be purified by recrystallization or flash chro-
matography. General procedure for hydrogenolysis to a
monosubstituted urea: In a typical reaction, the N-benzy-
lurea (0.5 mmol) is dissolved in acetic acid (6 ml). An equal
weight of Pd black is added and the reaction vessel is
connected to a Parr medium pressure hydrogenation
apparatus (30–50 psi). After completion of the reaction,
the catalyst is filtered and washed with methanol. The
solvent is removed under reduced pressure. 1H NMR
indicates >90% purity. If desired, the crude product can be
purified by recrystallization or flash chromatography.
References
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D.; Ayafor, J. F.; Sterner, O. J. Nat. Prod. 1999, 62,
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J. 1998, 4, 2091–2098; (c) Michael, K.; Wang, H.; Tor, Y.
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6. For a recent example of metal-catalyzed carbonylation of
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Main, A. D.; Johnson, K. S.; Grasso, C. A.; McElwee-
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1
12. Spectral data for 2: H NMR (400 MHz, DMSO-d6): l
7.31–7.20 (m, 5H), 6.21 (t, J=5.6 Hz, 1H), 5.92 (t, J=5.6
Hz, 1H), 4.18 (d, J=5.6 Hz, 2H), 2.84 (t, J=6 Hz, 2H),
1.63 (m, 4H), 1.20 (m, 1H), 1.14 (m, 4H), 0.84 (m, 2H). IR
(KBr pellet) 3329, 1627, 1591, 1581 cm−1
.
13. Spectral data for 3: 1H NMR (400 MHz, DMSO-d6): l 5.92
(t, J=6 Hz, 1H), 5.32 (s, 2H), 2.77 (t, J=6 Hz, 2H), 1.62
(m, 4H), 1.27 (m, 1H), 1.13 (m, 4H), 0.82 (m, 2H). IR (KBr
pellet): 3392, 3213, 1654, 1609, 1551 cm−1
.
14. A solution of kanamycin A (100 mg, 0.21 mmol) and
triethylamine (84 mg, 0.83 mmol) in 1,4-dioxane/water
(3:1, 2.5 ml) is treated with 1 (225 mg, 0.83 mmol). The
reaction mixture is stirred at rt until 1 is consumed (ca. 3
h). The reaction mixture is then evaporated to dryness and
the residue is washed with 1 mM NaOH and water and
dried under reduced pressure to give a white powder (98
7. Knapp, S.; Hale, J.; Bastos, M.; Molina, A.; Cheng, K. J.
Org. Chem. 1992, 57, 6239–6256. For a recent application
of the 4-methoxybenzyl isocyanate, see: Jefferson, E. A.;
Swayze, E. E. Tetrahedron Lett. 1999, 40, 7757–7760.
8. Trimethylsilylisocyanate is another potential but moisture-
sensitive reagent, see: Parker, K. A.; Gibbos, E. G.
Tetrahedron Lett. 1975, 981–984. Potassium cyanate can
directly convert simple amines into monosubstituted ureas
in water, see: Kurzer, F. Org. Syn. 1963, coll. vol. IV,
49–51.
1
mg, 93%). H NMR indicates >95% purity. The product
can be further purified by flash chromatography (5%
methanol/dichloromethane). Hydrogenolysis is performed
as described above with one weight-equivalent of Pd black
per benzyl group. A higher H2 pressure (55 psi) and longer
reaction time (30 h) are employed.
15. Spectral data for kanamycin A derivative 5: MALDI MS
calcd for C22H40N8NaO15 [M−Na]+ 679.2505. Found:
1
679.2495. H NMR (400 MHz, DMSO-d6): 6.20 (d, J=6
9. Hydrolysis of the isocyanate to benzylamine, followed by
condensation of the latter with excess isocyanate gives
N,N%-dibenzylurea as the major product.
Hz, 1H), 6.12 (d, J=6.4 Hz, 1H), 6.03 (t, J=5.6 Hz, 1H),
5.84–5.82 (m, 3H), 5.72–5.65 (m, 5H), 5.58–5.55 (m, 3H),
5.41 (d, J=5.2 Hz, 1H), 5.12–5.07 (m, 3H), 5.23 (d, J=4.4
Hz, 1H), 4.95 (d, J=3.6 Hz, 1H), 4.47 (t, J=6 Hz, 1H),
3.82 (m, 1H), 3.67–3.17 (m, 15H), 2.99 (m, 1H), 2.07 (m,
1H), 1.31 (q, 1H).
10. Benzylamine (1.59 g, 14.9 mmol) is dissolved in a mixture
of dry dichloromethane (80 ml) and pyridine (1.17 g, 14.9
mmol). 4-Nitrophenylchloroformate (2.98 g, 14.9 mmol) is
added and the solution is refluxed for 6 h. The reaction
mixture is then diluted with dichloromethane (200 ml) and
washed with 1 M sodium bicarbonate solution, water and
brine. The solvent is dried (Na2SO4) and removed under
reduced pressure to yield the colorless product (3.35 g,
16. The desired fully derivatized kanamycin A is obtained in
less than 18% yield based on NMR analysis of the crude
mixture when 4 equivalents of benzylisocyanate are used.
17. Multiple products are formed, none of which correspond
to 5.