One-Pot Synthesis of N-Monosubstituted Ureas from Nitriles via Tiemann Rearrangement

Article abstract of DOI:10.1055/s-0034-1381007

Amidoximes, obtained from the reaction of nitriles with hydroxylamine, underwent Tiemann rearrangement in the presence of benzenesulfonyl chlorides (TsCl or o-NsCl) to form the N-substituted cyanamides. Subsequently, acidic hydrolysis of the cyanamides afforded the corresponding N-monosubstituted ureas. The synthesis of N-monosubstituted ureas from nitriles was accomplished by three steps in one pot, which provides a direct access to versatile N-monosubstituted urea derivatives from a wide variety of nitriles.

Full text of DOI:10.1055/s-0034-1381007

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 1823–1826
letter
1823
C.-H. Wang et al.
Letter
Synlett
One-Pot Synthesis of N-Monosubstituted Ureas from Nitriles via
Tiemann Rearrangement
Chien-Hong Wang
Tsung-Han Hsieh
Chia-Chi Lin
OH
(i)
NH2OH
(ii)
ArSO2Cl
(iii)
aq HCl
N
C
O
C
H
N
R
CN
R
R
CN
R
NH2
N
NH2
EtOH
reflux, 3 h
EtOH
reflux
DIPEA
CH2Cl2
H
Wen-Hsiung Yeh
Chih-An Lin
Tun-Cheng Chien*
Department of Chemistry, National Taiwan Normal University,
No.88, Sec.4, Ting-Zhou Road, Taipei 11677, Taiwan
tcchien@ntnu.edu.tw
Received: 19.04.2015
Accepted after revision: 26.05.2015
Published online: 20.07.2015
proach to N-monosubstituted ureas is the addition reaction
of primary amines with inorganic cyanate salts under aque-
ous acidic condition (Scheme 1,B).15 Similar approaches in-
volve a nucleophilic addition of primary amines to ureas,
carbamates or thiocarbamates, and extra steps for the re-
moval of protecting groups may be required (Scheme 1,C).16
Other methods include addition of ammonia or ammonia
equivalents to organic isocyanates and hydrolysis of N-sub-
stituted cyanamides (Scheme 1,D and E).5,6,17,18 The meth-
ods depicted in Scheme 1 (B–E) are mutually complemen-
tary since they are all originated from the corresponding
primary amines with multistep manipulations.
DOI: 10.1055/s-0034-1381007; Art ID: st-2015-u0285-l
Abstract Amidoximes, obtained from the reaction of nitriles with hy-
droxylamine, underwent Tiemann rearrangement in the presence of
benzenesulfonyl chlorides (TsCl or o-NsCl) to form the N-substituted cy-
anamides. Subsequently, acidic hydrolysis of the cyanamides afforded
the corresponding N-monosubstituted ureas. The synthesis of N-mono-
substituted ureas from nitriles was accomplished by three steps in one
pot, which provides a direct access to versatile N-monosubstituted urea
derivatives from a wide variety of nitriles.
Key words urea, cyanamide, amidoxime, hydrolysis, Tiemann rear-
rangement
(A) SN2 reaction (R = alkyl) or metal-catalyzed amination (R = aryl):
O
O
O
O
Urea is among the most stable nitrogen-containing
functionalities which widely exists in natural substances,1
biological metabolites,2 synthetic reagents or catalysts,3,4
pharmaceutical or agricultural ingredients,5–7 and func-
tional macromolecules.8 Owing to its broad application
prospect, various synthetic approaches for multisubstituted
ureas have been developed and utilized for laboratorial and
industrial preparation.
N-Monosubstituted ureas are of our particular interest
from the synthetic perspective. N-Monosubstituted ureas
have been extensively used as organocatalsts, neighboring
directing groups,9 and, more importantly, N–C–N building
blocks for the synthesis of heterocycles, more complicated
ureas, and other CN2 or CN3 functionalities.10 Nevertheless,
only a limited number of synthetic strategies for N-mono-
substituted ureas have been practically employed in the lit-
erature. The direct alkylation or arylation of urea is a
straightforward approach. But O-alkylation cannot be com-
pletely excluded, and multialkylation or diarylation are of-
ten obtained due to the competing reactions of the mono-
substituted ureas (Scheme 1,A).11–14 The most common ap-
R
X
+
R
R
R
H2N
NH2
H2N
H2N
N
H
(B) amines with inorganic cyanate salt:
R
NH2
+
M [OCN]
N
H
(C) amines with urea, carbamate or thiocarbamate:
O
R
NH2
+
P
N
X
H2N
N
H
H
X = NH2, OR' or SR'; P = H or protecting group
(D) isocyanates with ammonia:
O
R
N
C
O
+
NH3
R
H2N
N
H
(E) hydrolysis of N-substituted cyanamides:
O
hydrolysis
N
C
R
R
N
H2N
N
H
H
Scheme 1 Literature procedures for the preparation of N-monosubsti-
tuted ureas
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1823–1826

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C.-H. Wang et al.
Letter
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In 1891, F. Tiemann reported that N-phenylurea was ob-
tained from the arylsulfonylation of benzamidoxime, which
is known as the Tiemann rearrangement.19,20 The unusual
formation of N-phenylurea dated back to the late 19th cen-
tury has attracted our attention. However, a thorough sur-
vey of literature revealed that the arylsulfonylation of ami-
doximes could lead to diverse reaction outcomes with in-
definite scopes, which substantially limited the synthetic
application of Tiemann rearrangement.19–23 The rearrange-
ment reaction remains lack of practicality for over one cen-
tury until few breakthroughs were recently disclosed.21,22,24
Our previous investigation established that the reaction of
amidoximes with TsCl or o-NsCl under anhydrous condi-
tions afforded exclusively the N-substituted cyanamides in
very good yields.24 The proposed mechanism is sketched in
Scheme 2 (A). The reaction starts with the O-arylsulfonyla-
tion of amidoximes to form the O-arylsulfonyl amidoxime
intermediates. Subsequently, the N–O bond cleavage occurs
with concomitantly R group migration over the C–N bond
to furnish the N-substituted cyanamides. It is noteworthy
that the rearrangement step is mechanistically similar to
several well-known rearrangement reactions, including
Lossen rearrangement, Hofmann rearrangement, and Curti-
us rearrangement (Scheme 2,B–D).
The rearrangement reaction features a broad substrate
scope and provides a viable synthesis of N-substituted cy-
anamide derivatives from corresponding nitriles. We ratio-
nalized that the formation of N-phenylurea from benzami-
doxime originally observed by F. Tiemann was
a
consequence from the hydrolysis of the N-phenylcyana-
mide.19,20,23 Thus, we embarked on the investigation to eval-
uate whether the Tiemann rearrangement followed by a
consecutive acidic hydrolysis would be a general and feasi-
ble approach for the preparation of various types of N-mo-
nosubstituted urea derivatives.
A perusal of literature suggested that the hydrolysis of
N-substituted cyanamides to ureas can be achieved under
the catalysis of either Brønsted or Lewis acids.18 We envi-
sioned that the byproducts from Tiemann rearrangement
are arylsulfonic acid and hydrogen chloride. In order to
keep two consecutive reactions in consistent conditions, a
simple diluted hydrochloric acid condition was chosen to
examine the hydrolysis reaction of N-substituted cyan-
amides,6 which would later allow the development of the
one-pot reaction sequence. Therefore, a series of N-substi-
tuted cyanamide derivatives 3, prepared from the nitriles 1
via Tiemann rearrangement,24 were subjected to the acidic
hydrolysis in aqueous ethanolic HCl solution. The results
showed that N-aryl, N-heteroaryl-, and N-alkyl cyanamides
3 could all be hydrolyzed to the corresponding N-monosub-
stituted ureas 4 in good yields (method a in Scheme 3).25,26
We estimated that the byproducts, arylsulfonic acid and
hydrogen chloride, from Tiemann rearrangement should be
adjuvant to the acidic hydrolysis of cyanamides to ureas.
Since there is no need to isolate the N-substituted cyan-
amides 3, a one-pot process from amidoximes to ureas
would be viable. We demonstrated that the amidoximes 2
were subjected to the Tiemann rearrangement conditions
followed by a successive acidic hydrolysis to give the corre-
sponding N-monosubstituted ureas 4 presumably in the
same yields (method b in Scheme 3). Moreover, the reaction
of nitriles 1 with hydroxylamine could afford the amidox-
imes 2 in fairly good yields, which allowed the one-pot re-
action sequence to be further extended. Thus, the prepara-
tion of the N-monosubstituted ureas 4 can be accomplished
by sequential reactions from nitriles 1 in one-pot, starting
from the conversion of nitriles to amidoximes followed by
the Tiemann rearrangement and immediate acidic hydroly-
sis, to give comparable yields (method c in Scheme 3).
In summary, our investigation has provided a facile and
practical synthesis of N-monosubstituted ureas directly
from nitriles via Tiemann rearrangement. The methodology
features a broad substrate scope to achieve a wide variety of
N-aryl, N-heteroacryl, and N-alkyl ureas. Although the hy-
drolysis of individual N-substituted cyanamides remains to
be further optimized, we anticipated that alternative meth-
ods from the literature can also be adopted.6,18 The feasibili-
(A) Tiemann rearrangement:
OSO2Ar
N
H
OH
R
N
H
N
H
ArSO2Cl
base
N
N
C
NH
R
C
R
R
NH2
N
H
R
OSO2Ar
NH
N
(B) Lossen rearrangement:
OH
H
OSO2Ar
O
HN
N
ArSO2Cl
base
N
N
N
C
C
C
O
O
O
R
R
R
R
O
R
(C) Hofmann rearrangement:
H
Br
O
NH2
N
N
Br2
R
O
R
base
(D) Curtius rearrangement:
N
N
R
O
Scheme 2 Proposed mechanism for: (A) Tiemann rearrangement; (B)
Lossen rearrangement; (C) Hofmann rearrangement; (D) Curtius rear-
rangement
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1823–1826

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C.-H. Wang et al.
Letter
Synlett
References and Notes
OH
N
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(ii)
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b
c
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Pr 62
4m Bn 59
a
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–
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c
45
49
4l
4h Me 73 42 53
4i Cl 86 51 60
Scheme 3 One-pot synthesis of N-monosubstituted ureas 4 from ni-
triles 1 [percentage yield (%)]. Reagents and conditions: (i) NH2OH, EtOH,
reflux; (ii) ArSO2Cl, DIPEA, CH2Cl2; (iii) aq HCl–EtOH, reflux.
ty of the reaction sequence was validated and characterized
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Acknowledgment
This work was supported by Research Grants 103-2113-M-003-007-
and 102-2113-M-003-004- from Ministry of Science and Technology,
Taiwan.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1381007.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
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(26) Analytical Data of Compounds 4e–k
N-(4-Nitrophenyl)urea (4e)
Mp 213–215 °C. 1H NMR (400 MHz, DMSO-d6): δ = 9.29 (s, 1 H,
NH), 8.11 (d, 2 H, J = 9.2 Hz), 7.62 (d, 2 H, J = 9.2 Hz), 6.20 (s, 2 H,
NH2). 13C NMR (100 MHz, DMSO-d6): δ = 155.4, 147.3, 140.5,
125.1 (CH), 117.0 (CH). MS (EI, 20 eV): m/z = 108 (56), 138
(100), 181 (40) [M+]. ESI-MS: m/z = 167 (100), 182 (73) [M + 1].
HRMS (EI): m/z calcd for C7H7N3O3: 181.0487; found: 181.0486.
N-(4-Trifluoromethylphenyl)urea (4f)
Mp 144–145 °C. 1H NMR (400 MHz, DMSO-d6): δ = 8.95 (s, 1 H,
NH), 7.60 (d, 2 H, J = 8.7 Hz), 7.54 (d, 2 H, J = 8.7 Hz), 6.04 (s, 2 H,
NH2). 13C NMR (100 MHz, DMSO-d6): δ = 155.7, 144.3, 125.9 (q, J
= 3.0 Hz, CH), 124.6 (q, J = 270.0 Hz, CF3), 121.1 (q, J = 32.0 Hz),
117.4 (CH). MS (EI, 20 eV): m/z = 161 (100), 204 (41) [M+]. ESI-
MS: m/z = 205 (100) [M + 1]. HRMS (EI): m/z calcd for
C8H7F3N2O: 204.0510; found: 204.0508.
N-(3-Methoxyphenyl)urea (4g)
Mp 128–130 °C. 1H NMR (400 MHz, DMSO-d6): δ = 8.51 (s, 1 H,
NH), 7.08–7.12 (m, 2 H), 6.87 (d, 1 H, J = 7.9 Hz), 6.47 (d, 1 H, J =
8.0 Hz), 5.81 (s, 2 H, NH2), 3.69 (s, 3 H, CH3). 13C NMR (100 MHz,
DMSO-d6): δ = 159.7, 156.0, 141.8, 129.4 (CH), 110.2 (CH), 106.5
(CH), 103.6 (CH), 54.9 (CH). ESI-MS: m/z = 167 [M + 1]. HRMS
(EI): m/z calcd for C8H10N2O2: 166.0742; found: 166.0741.
N-(2-Methylphenyl)urea (4h)
Mp 194–196 °C. 1H NMR (400 MHz, DMSO-d6): δ = 7.77 (d, 1 H, J
= 8.0 Hz), 7.66 (s, 1 H, NH), 7.12–7.06 (m, 2 H), 6.87 (t, 1 H, J =
7.3), 6.00 (s, 2 H, NH2), 2.18 (s, 3 H, CH3). 13C NMR (100 MHz,
DMSO-d6): δ = 156.1, 138.2, 130.0 (CH), 127.0 (CH), 126.0, 123.0
(CH), 120.9 (CH), 17.9 (CH3). MS (EI, 20 eV): m/z = 107 (100),
150 (62) [M+]. HRMS (EI): m/z calcd for C8H10N2O: 150.0793;
found: 150.0792.
N-(2-Chlorophenyl)urea (4i)
Mp 190–192 °C. 1H NMR (400 MHz, DMSO-d6): δ = 8.12 (dd, 1
H, J = 8.4, 1.3 Hz), 8.03 (s, 1 H, NH), 7.38 (dd, 1 H, J = 8.3, 0.9 Hz),
7.24–7.20 (m, 1 H), 6.96–6.92 (m, 1 H), 6.37 (s, 2 H, NH2). 13C
NMR (100 MHz, DMSO-d6): δ = 155.6, 136.7, 129.0, 127.4, 122.5,
121.4, 121.1. MS (EI, 20 eV): m/z = 127 (100), 129 (30), 135 (40),
170 (18) [M+], 172 (8) [M + 2]. HRMS (EI): m/z calcd for C7H7-
ClN2O: 170.0247; found: 170.0246.
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1980, 45, 1315. (c) Dondoni, A.; Barbaro, G.; Battaglia, A. J. Org.
Chem. 1977, 42, 3372. (d) Garapon, J.; Sillion, B.; Bonnier, J. M.
Tetrahedron Lett. 1970, 11, 4905. (e) Boyer, J. H.; Frints, P. J. A.
J. Org. Chem. 1970, 35, 2449.
1,3-Dimethyl-5-ureidouracil (4j)
(24) Lin, C.-C.; Hsieh, T.-H.; Liao, P.-Y.; Liao, Z.-Y.; Chang, C.-W.; Shih,
Y.-C.; Yeh, W.-H.; Chien, T.-C. Org. Lett. 2014, 16, 892.
(25) General Procedure for the One-Pot Synthesis of N-Monosub-
stituted Urea 4 from Nitrile 1 (Scheme 3)
Mp 254–258 °C. 1H NMR (400 MHz, DMSO-d6): δ = 8.09 (s, 1 H,
NH), 7.84 (s, 1 H), 6.26 (s, 2 H, NH2), 3.29 (s, 3 H, CH3), 3.20 (s, 3
H, CH3). 13C NMR (100 MHz, DMSO-d6): δ = 160.2, 156.5, 149.8,
128.5, 115.0, 70.2, 37.1, 28.4. MS (EI, 20 eV): m/z = 70 (42), 155
(100), 198 (10) [M+]. HRMS (EI): m/z calcd for C7H10N4O3:
198.0753; found: 198.0760.
To the solution of nitrile 1 in EtOH (0.1 M) was added 50 wt% aq
hydroxylamine solution (1.2 equiv). The mixture was stirred at
reflux temperature for 1.5 h. After cooling to r.t., the reaction
mixture was concentrated under reduced pressure. The crude
amidoxime product 2 was dissolved in CH2Cl2 (0.1 M), and
ArSO2Cl (TsCl or o-NsCl, 1.05 equiv) and DIPEA (1.05 equiv)
were added at 0 °C. The mixture was stirred under nitrogen
atmosphere at r.t. for 3 h or at reflux temperature for 1 h.24 The
mixture was concentrated under reduced pressure. The crude
cyanamide product 3 was dissolved in the mixture of 1 N aq HCl
2-Chloro-3-ureidopyridine (4k)
Mp 210–212 °C. 1H NMR (400 MHz, DMSO-d6): δ = 8.50 (dd, 1
H, J = 8.2, 1.5 Hz), 8.19 (s, 1 H, NH), 7.96 (dd, 1 H, J = 4.5, 1.5 Hz),
7.32 (dd, 1 H, J = 8.2, 4.6 Hz), 6.52 (s, 2 H, NH2). 13C NMR (100
MHz, DMSO-d6): δ = 155.4, 141.5 (CH), 138.5, 133.9, 128.3 (CH),
123.3 (CH). ESI-MS: m/z = 155 (28), 172 (100) [M + 1]. HRMS
(EI): m/z calcd for C6H6ClN3O: 171.0199; found: 171.0201.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1823–1826