Phenyl 4,5-dichloro-6-oxopyridazine-1(6H)-carboxylate as carbonyl source: Facile and selective synthesis of carbamates and ureas under mild conditions

Article abstract of DOI:10.1055/s-0029-1217997

The selective syntheses of carbamates, symmetric -ureas, and unsymmetrical ureas have been accomplished by the -reaction of amines with phenyl 4,5-dichloro-6-oxopyridazine-1(6H)-carboxylate as a carbonyl source under mild conditions. It is noteworthy that this process is mild, economic, and convenient.

Full text of DOI:10.1055/s-0029-1217997

LETTER
2809
Phenyl 4,5-Dichloro-6-Oxopyridazine-1(6H)-Carboxylate as Carbonyl
Source: Facile and Selective Synthesis of Carbamates and Ureas under Mild
Conditions
S
ynthesis of Carba
y
mates and U
u
reas under
M
n
ild
C
onditio
g
ns -Geun Lee, Min-Jung Kim, Song-Eun Park, Jeum-Jong Kim, Bo Ram Kim, Sang-Gyeong Lee,
Yong-Jin Yoon*
Department of Chemistry, Research Institute of Natural Sciences, Graduate School for Molecular Materials and Nanochemistry,
Gyeongsang National University, Jinju Gyeognam 660-701, Korea
Fax +82(55)7610244; E-mail: yjyoon@gnu.ac.kr
Received 16 July 2009
for the synthesis of unsymmetrical urea by the one-pot
Abstracts: The selective syntheses of carbamates, symmetric
carbonylation of amines. This paper reports on a more
ureas, and unsymmetrical ureas have been accomplished by the
easily handled, stable, economic, and selective carbonyla-
tion of amines using 3.
reaction of amines with phenyl 4,5-dichloro-6-oxopyridazine-
1(6H)-carboxylate as a carbonyl source under mild conditions. It is
noteworthy that this process is mild, economic, and convenient.
Reaction of 4,5-dichloropyridazin-3(2H)-one (1) with
phenyl chloroformate (2) in the presence of triethylamine
in tetrahydrofuran at low temperature gave the corre-
sponding carboxylate 3 in 90% yield. The structure of 3
was established by IR, NMR, and elemental analysis.
Key words: carbamate, symmetric urea, unsymmetric urea,
carbonyl source, pyridazinone
Pyridazin-3(2H)-ones are inexpensive, very stable, and
easily prepared heterocycles whose utility as synthetic
auxiliaries was recently demonstrated by Yoon et al.1 The
ease with which pyridazin-3(2H)-ones can be removed
and/or recycled spurred our interest in their use for other
transformations. Since pyridazin-3(2H)-ones readily form
stable anions2 and can act as good leaving groups,1 we ex-
plored the application of 2-substitued-pyridazin-3(2H)-
ones as electrophilic transfer reagents. Thus, we have in-
vestigated the carbonylation potency of phenyl 4,5-
dichloro-6-oxopyridazine-1(6H)-carboxylate to amines.
Cl
Cl
Cl
Cl
Et3N, THF
O
N
O
+
O
N
ice bath, 10 min
N
O
N
O
Cl
O
H
1
2
3
Scheme 1 Preparation of phenyl 4,5-dichloro-6-oxopyridazine-
1(6H)-carboxylate
Common carbonyl sources are carbon monoxide and
phosgene,3 however, they can be difficult to handle due to
their toxicity, corrosiveness, and gaseous form. There-
fore, there have recently been many reports on the carbo-
nyl compounds with substitutes for these carbonyl
sources, such as formamide, formic acid, formic anhy-
dride, formate, aldehyde, metal carbonyl, carbamoyl-
silane, carbamoylstanne4 isocyanate,5 carbonate,6
diimidazoles,7 and dichloromethanimines.5 Due to the in-
creasing importance of carbamate and urea derivatives
during the last years there have been considerable interest
toward novel carbonyl sources and the development of
more selective protocols for the preparation of carbamates
and unsymmetrical ureas. Although phenyl chloroformate
(2) is a good carbonyl source to prepare symmetic ureas,
it is not useful for the preparation of unsymmetrical ureas
due to the too high reactivity. Actually, aniline was react-
ed with phenyl chloroformate (2) to give mainly symmet-
ric urea instead of the corresponding carbamate.
Therefore, we developed compound 3 as carbonyl source
To evaluate the carbonyl transfer potentiality, n-butyl-
amine was treated with 3 in THF at room temperature to
give the corresponding carbamate in 91% yield. Some ali-
phatic and aromatic amines were reacted with 3 at room
temperature under neutral conditions to afford the corre-
sponding carbamates 5 in excellent yields (Scheme 2,
Table 1). 4,5-Dichloropyridazin-3(2H)-one was also re-
covered quantitatively.
O
3, THF
2R1RN
O
5
– 4,5-dichloropyridazin-3(2H)-one
carbamates
O
i) 3, THF ii) R3R4NH
2R1RN
NR3R4
R1R2NH
– 4,5-dichloropyridazin-3(2H)-one
6
4
unsymmetric ureas
amines
O
3, DMAP, THF
R1
R2
R1
R2
N
N
– 4,5-dichloropyridazin-3(2H)-one
7
R1, R2 = H, alkyl or aryl
R3, R4 = H, alkyl or aryl
symmetric ureas
SYNLETT 2009, No. 17, pp 2809–2814
Advanced online publication: 30.09.2009
x
x
.x
x
.2
0
0
9
DOI: 10.1055/s-0029-1217997; Art ID: U06909ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 2 Synthesis of carbamate, unsymmetrical ureas and sym-
metric ureas using 3.

2810
H.-G. Lee et al.
LETTER
Table 1 Synthesis of Carbamates Using 3a
O
R1
R2
4
3
R1
R2
NH
N
O
THF
– 4,5-dichloropyridazin-3(2H)-one
5
Entry
Amine 4
Time
Carbamate 5
Yield (%)b
O
NH2
1
10 min
10 min
10 min
91
91
95
n-Bu
N
H
O
4a
5a
5b
5c
NH2
O
2
3
N
H
O
4b
4c
O
NH2
N
H
O
O
H
N
4
5
12 h
91
93
N
N
O
4d
4e
5d
O
NH
10 min
O
O
5e
5f
NH2
6
7
8
10 min
10 min
40 min
98
92
90
N
H
O
O
4f
NH2
N
H
O
4g
5g
Cl
O
Cl
NH2
N
O
H
4h
5h
MeO
O
MeO
NH2
9
10 min
72 h
90
94
N
O
H
4i
5i
O
O
MeO
O
NH2
10
MeO
N
O
H
4j
5j
a Reaction temperature = r.t.
b Isolated yield. 4,5-Dichloropyridazin-3(2H)-one was isolated quantitatively.
Synlett 2009, No. 17, 2809–2814 © Thieme Stuttgart · New York

LETTER
Synthesis of Carbamates and Ureas under Mild Conditions
2811
In addition, we attempted to synthesize unsymmetrical From N-aryl carbamates, both unsymmetrical N,N¢-diaryl
ureas in one pot using compound 3. After forming the N- ureas and N-aryl-N-alkyl ureas were prepared, whereas N-
aryl carbamates from the reaction of aromatic amines with aryl-N-alkyl ureas could not prepared from N-alkyl car-
3, the mixture of the carbamates and aliphatic amines was bamates.
refluxed until the carbamate was disappeared to give N-
aryl-N-alkyl ureas 6a–j in good to excellent yields (entries
1–10, Table 2).
Table 2 Synthesis of Unsymmetrical Ureas Using 3a
O
i) 3, ii) R3R4NH
R1
R2
R1
R2
R3
R4
NH
N
N
THF
– 4,5-dichloropyridazin-3(2H)-one
4
6
Entry
Amines 4
Time (h)
Unsymmetric urea 6
Yield (%)b
R1
NH
R2
R3
R4
NH
O
NH2
NH2
1
2
15
22
92
91
N
H
N
H
4c
4a
4f
6a
6b
O
O
NH2
NH2
n-Bu
N
H
N
H
4f
NH2
NH
3
4
5
10
33
48
89
82
81
N
H
N
N
4f
4e
6c
O
O
H
N
NH2
i-Pr2
N
H
4d
4f
6d
NH2
O
NH
N
H
N
O
O
4k
4f
6e
NH2
NH
6
11
87
N
H
N
4g
4e
4a
6f
O
O
O
NH2
7
8
9
NH2
22
18
35
89
87
80
n-Bu
N
H
N
H
4g
6g
6h
6i
NH2
NH2
N
H
N
H
4g
4c
H
N
NH2
i-Pr2
N
H
N
4g
4d
Synlett 2009, No. 17, 2809–2814 © Thieme Stuttgart · New York

2812
H.-G. Lee et al.
LETTER
Table 2 Synthesis of Unsymmetrical Ureas Using 3a (continued)
O
i) 3, ii) R3R4NH
R1
R2
R1
R2
R3
R4
NH
N
N
THF
– 4,5-dichloropyridazin-3(2H)-one
4
6
Entry
10
Amines 4
Time (h)
48
Unsymmetric urea 6
Yield (%)b
O
82
NH2
O
NH
N
H
N
O
4g
4k
6j
Cl
O
11c
12c
31
26
90
83
NH2
Cl
NH2
N
N
H
H
4h
4f
6k
Cl
O
NH2
Cl
NH2
N
N
H
H
4h
4g
6l
a Reaction conditions: i) Stirring at r.t. until the first amine was disappeared. ii) The second amine was added, and then the mixture was refluxed
until the carbamate was disappeared.
b Isolated yield. 4,5-Dichloropyridazin-3(2H)-one was isolated quantitatively.
c Reaction conditions: i) Stirring at r.t. until the first amine was disappeared. ii) The second amine and DMAP (2 equiv) were added, and then
the mixture was refluxed until the carbamate was disappeared.
On the other hand, aromatic and primary aliphatic amines one-carbonyl source. It is noteworthy that our methods are
were carbonylated with 3 in the presence of 4-(N,N-dime- mild, economic, and convenient. Compound 3 is stable in
thylamino)pyridine (DMAP) to afford the corresponding air and in organic solvents at high temperature, and is pre-
symmetric ureas 7a–f such as N,N-diaryl and N,N-dialkyl pared easily from cheap and commercially available 4,5-
ureas in good to excellent yields (Table 3). The aliphatic dichloropyridazin-3(2H)-one. The reusable pyridazinone
secondary amines did not form the corresponding sym- was recovered quantitatively. We also believe that com-
metric ureas under our conditions. The structures of all pound 3, and these methods should be practically applica-
synthetic compounds were established by IR, NMR, and ble to solid-phase synthesis of small-molecule libraries in
elemental analysis.
combinatorial chemistry.
In conclusion, we have reported the new efficient, simple,
and selective methods for preparing a variety of carba-
mates, symmetric ureas, and symmetric ureas using 3 as
Table 3 Synthesis of Symmetric Ureas 7 Using 3a
O
R1
R2
3, DMAP, THF
R1
R2
R1
R2
2
NH
N
N
– 4,5-dichloropyridazin-3(2H)-one
4
7
Entry
Amine 4
Time (h)
48
Symmetric urea 6
Yield (%)b
81
O
NH2
1
N
N
H
H
4f
7a
7b
O
NH2
2
72
92
N
N
H
H
4g
Synlett 2009, No. 17, 2809–2814 © Thieme Stuttgart · New York

LETTER
Synthesis of Carbamates and Ureas under Mild Conditions
2813
Table 3 Synthesis of Symmetric Ureas 7 Using 3a (continued)
O
R1
R2
3, DMAP, THF
R1
R2
R1
R2
2
NH
N
N
– 4,5-dichloropyridazin-3(2H)-one
4
7
Entry
3
Amine 4
Time (h)
80
Symmetric urea 6
Yield (%)b
90
Cl
Cl
O
Cl
NH2
N
H
N
H
4h
7c
MeO
OMe
O
MeO
NH2
4
5
6
120
120
120
84
72
82
N
H
N
H
4i
7d
O
NH2
N
N
H
H
4c
7e
7f
NH2
O
N
H
N
H
4b
a Reaction conditions: i) Stirring at r.t. until compound 3 was disappeared. ii) After adding DMAP (2 equiv), the mixture was then refluxed until
the carbamate was disappeared.
b Isolated yield. 4,5-Dichloropyridazin-3(2H)-one was isolated quantitatively.
Synthesis of Phenyl 4,5-Dichloro-6-oxopyridazine-1(6H)-car-
boxylate (3)
tography (2.5 × 7–11 cm, elution solvent: EtOAc–n-hexane = 1:2,
v/v).
To a solution of 1 (3 mmol) and Et3N (3.6 mmol) in dry CH2Cl2 (30
mL) was added dropwise the appropriate phenyl chloroformate (2),
and the mixture was stirred for 10 min at 5 °C (Scheme 1). After
evaporating the solvent, the product was extracted with Et2O–H2O
(7:2, v/v). The organic layer was dried over anhyd MgSO4, and then
evaporated under reduced pressure. The resulting residue was re-
crystallized from THF–n-hexane (1:3, v/v) to give the product 3 as
white powder (0.78 g, 90%).
General Procedure for the Synthesis of Symmetric Ureas 7
A mixture of THF (30 mL), compound 3 (0.7 mmol), and amine 4
(1.4 mmol) was stirred at r.t. until compound 3 disappeared (TLC
monitoring). After adding DMAP (1.4 mmol), the mixture was then
refluxed until carbamate 5 disappeared (TLC monitoring). After
evaporating the solvent, the product was isolated by silica gel col-
umn chromatography (2.5 × 7–11 cm, EtOAc–n-hexane = 1:2, v/v).
Mp 140 °C. Rf = 0.77 (CH2Cl2). IR (KBr): 3074, 3043, 1793, 1681,
1602, 1483, 1272, 1188, 1070, 948, 877, 750, 617 cm–1. H NMR
1
Supporting Information for this article is available online at
(300 MHz, DMSO-d6): d = 7.33–7.41 (m, 3 H), 7.53 (t, 2 H, J = 7.2
Hz), 8.38 (s, 1 H). 13C NMR (75 MHz, DMSO-d6): d = 121.52,
127.51, 130.52, 135.42, 136.96, 138.34, 149.53, 150.58, 154.73.
Anal. Calcd for C11H6Cl2N2O3: C, 46.34; H, 2.12; N, 9.83. Found:
C, 46.36; H, 2.15; N, 9.87.
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
This work was supported by the Korea Research Foundation Grant
funded by the Korean Government (KRF-2008-313-C00474)
General Procedure for the Synthesis of Carbamates 5
To a solution of compound 3 (0.7 mmol) in THF (20 mL) was added
amine 4 (0.7 mmol). The mixture was stirred at r.t. until compound
3 disappeared (TLC monitoring). After evaporating the solvent un-
der reduced pressure, the product 5 was isolated by silica gel col-
umn chromatography (2.5 × 7–11 cm) using EtOAc–n-hexane (1:2,
v/v) as the elution solvent.
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Synlett 2009, No. 17, 2809–2814 © Thieme Stuttgart · New York

2814
H.-G. Lee et al.
LETTER
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