Copper catalyzed arylation of urea

Article abstract of DOI:10.1016/j.tetlet.2003.12.150

An efficient copper catalyzed amidation of aryl iodides with urea is described. This method is milder than the palladium catalyzed arylation and avoids the use of toxic phosphine ligands.

Full text of DOI:10.1016/j.tetlet.2003.12.150

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1989–1990
Copper catalyzed arylation of urea
Mecheril V. Nandakumar*
Organic Chemistry Division, Regional Research Laboratory (CSIR), Thiruvananthapuram 695 019, India
Received 2 October 2003; revised 11 December 2003; accepted 18 December 2003
Abstract—An efficient copper catalyzed amidation of aryl iodides with urea is described. This method is milder than the palladium
catalyzed arylation and avoids the use of toxic phosphine ligands.
Ó 2004 Elsevier Ltd. All rights reserved.
Biphenyl ureas are important subunits present in a
number of naturally occurring compounds and have
found numerous applications such as drugs, pesticides,
and antioxidants.1 The most straightforward route for
the synthesis of biphenyl ureas involves the reaction of
aryl amines with isocyanates or phosgene, which are
highly toxic and require harsh reaction conditions.
Recent developments in the palladium and copper cat-
alyzed amination of aryl halides dramatically simplified
classical amination reactions such as the Ullmann and
Goldberg reactions, which require very high tempera-
tures and toxic reagents.2 Among these the palladium
catalyzed reactions are very sensitive to functional
groups such as –OH, –NH2, exogenous air or moisture
and also very expensive compared to the copper
reagent.3 Recently, Belestkaya has reported the palla-
dium catalyzed amidation of urea with different aryl
halides and Xantphos was found to be a suitable ligand
for these coupling reactions. However, this method
suffers from the following disadvantages: (1) the use of
toxic phosphine ligands, (2) the palladium catalyst is
expensive, and (3) the formation of substantial amounts
of N-phenylation products arising from aryl group ex-
change between the aryl group bound to the palladium
and the phenyl group of the Xantphos.4 In a recent
paper, the same group has reported that the electron
poor ligand 3,5-(CF3)2-Xantphos is more effective than
Xantphos and requires lower catalyst loading and gives
higher yields of products than Xantphos. An attempt by
the same group for the arylation of urea using a copper
catalyst was unsuccessful.5
There have been many reports recently on the arylation
of different compounds such as amines,3 amides,6
hydrazides,7 etc. using copper catalysts in the presence
of suitable ligands. As a part of our program to syn-
thesize different biologically active molecules using
copper catalyzed coupling reactions, we carried out the
following investigations and preliminary results are
given below. We report a simple and mild copper cata-
lyzed amidation of aryl halides with urea. A preliminary
screening of ligands showed that both 1,2-diamino-
cyclohexane and N,N0-dimethylethylenediamine affor-
ded products in the coupling reactions, with the latter
giving low yields. Efforts to use other ligands such as
ethylenediamine, 1,2-ethanediol, etc. were not success-
ful. We chose 1,2-diaminocyclohexane as the preferred
ligand for the coupling reactions.
The reaction of iodobenzene with urea in presence of the
CuI, 1,2-diaminocyclohexane catalyst system afforded
the biphenyl urea 3 in good yield (see Scheme 1).
The product was characterized on the basis of its spec-
tral data and by comparison of its melting point with the
literature.8
Similar reactivity was also observed with other aryl
iodides and the results are summarized in Table 1.9
I
O
O
i
Ph
Ph
+
HN
NH
H2N
NH2
Keywords: Copper; Urea; Amidation; Aryl iodides.
* Tel.: +91-471-2515-275; fax: +91-471-2491-712; e-mail: nanda-
kumarmv@yahoo.com
1
3
2
Scheme 1. (i) CuI, 1,2-diaminocyclohexane, K3PO4, DMF, 80 °C, 24 h.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.12.150

1990
M. V. Nandakumar / Tetrahedron Letters 45 (2004) 1989–1990
Table 1. CuI catalyzed N,N0-bisarylation of ureaa
Acknowledgements
Entry
Iodobenzene
Ligand
Yield
(%)b
M.V.N. thanks the Council of Scientific and Industrial
Research (CSIR), New Delhi, for research funding
(Task force Project CMM 005.3 on specialty chemicals).
43
60
HN CH3
H3C NH
1
I
NH2
NH2
References and notes
1. Vyshnyakova, T. P.; Golubeva, I. A.; Glebova, E. V. Russ.
Chem. Rev. (Engl. Transl.) 1985, 54, 249–261.
2. (a) Wolfe, J. P.; Wagaw, S.; Marcoux, J. F.; Buchwald, S.
L. Acc. Chem. Res. 1998, 31, 805–818; (b) Hartwig, J. F.
Angew. Chem., Int. Ed. 1998, 37, 2046–2067; (c) Sun, L.-Q.;
He, H.; Chen, J.; Wu, Y.-J. Tetrahedron Lett. 2002,
43, 9291–9294; (d) Ogawa, K.; Radke, K. R.; Rothstein,
S. D.; Rasmussen, S. C. J. Org. Chem. 2001, 66, 9067–
9070.
3. Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org. Lett.
2002, 4, 581–584.
4. Artamkina, G. A.; Sergeev, A. G.; Beletskaya, I. P.
Tetrahedron Lett. 2001, 42, 4381–4384.
5. Sergeev, A. G.; Artamkina, G. A.; Beletskaya, I. P.
Tetrahedron Lett. 2003, 44, 4719–4723.
6. Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc.
2002, 124, 7421–7428.
7. Wolter, M.; Klapars, A.; Buchwald, S. L. Org. Lett. 2001,
23, 3803–3805.
8. Davis, T. L.; Blanchard, K. C. J. Am. Chem. Soc. 1929, 51,
1790.
9. General procedure for coupling reactions: CuI (10 mol %)
and K3PO4 (3 mmol) were added to a Schlenk tube with a
Teflon cap. The tube was evacuated and back filled with
argon three times. Urea (1 mmol), iodobenzene (2.2 mmol),
1,2-diaminocyclohexane (10 mol %), and 3 mL dry DMF
were added. The tube was sealed and heated at 80 °C. The
reaction mixture was cooled to room temperature after
heating for the specified time. The reaction mixture was
filtered and the filtrate was concentrated in vacuo. The
crude product was purified by column chromatography
using EtOAc–hexane (1:2) as eluants to afford coupled
products. N,N0-Biphenyl urea: (Table 1, entry 1): Following
the general procedure, urea (60 mg, 1 mmol), iodobenzene
(449 mg, 2.2 mmol), CuI (19 mg, 10 mol %), 1,2-diam-
inocylcohexane (11.4 mg, 10 mol %), K3PO4 (636 mg,
3 mmol), and 3 mL of dry DMF at 80 °C for 24 h gave the
biphenyl urea 3 (127 mg, 60%) as white solid. Mp 238–
240 °C.
12
56
HN CH3
H3C NH
2
I
H3C
NH2
NH2
28
65
HN CH3
H3C NH
n
3
I
Bu
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
4
5
6
Cl
I
57
63
29
I
H3C
F3C
I
a Reaction conditions: 1 equiv urea, 2.2 equiv aryl iodide, 10 mol %
CuI, 10 mol % 1,2-diaminocyclohexane (mixture of cis and trans),
3 mL DMF, 24 h, 80 °C.
b Isolated yield.
In summary, an efficient copper catalyzed amidation of
aryl iodides with urea is described. In all the cases, 1,2-
diaminocyclohexane as the ligand afforded good yields
of coupled products.