A general method for the synthesis of unsymmetrically substituted ureas via palladium-catalyzed amidation

Article abstract of DOI:10.1021/ol802931m

A general and practical method for the preparation of unsymmetrically substituted ureas has been developed utilizing palladium-catalyzed amidation. Both aryl bromides and chlorides, as well as heteroaryl chlorides, have been coupled to aryl, benzyl, and a

Full text of DOI:10.1021/ol802931m

ORGANIC
LETTERS
2009
Vol. 11, No. 4
947-950
A General Method for the Synthesis of
Unsymmetrically Substituted Ureas via
Palladium-Catalyzed Amidation
Brian J. Kotecki,* Dilinie P. Fernando, Anthony R. Haight, and Kirill A. Lukin
Abbott Laboratories, GPRD Process Research and DeVelopment, Dept. R450, Bldg.
R8, 1401 Sheridan Road, North Chicago, Illinois 60064
brian.kotecki@abbott.com
Received December 19, 2008
ABSTRACT
A general and practical method for the preparation of unsymmetrically substituted ureas has been developed utilizing palladium-catalyzed
amidation. Both aryl bromides and chlorides, as well as heteroaryl chlorides, have been coupled to aryl, benzyl, and aliphatic ureas by using
a novel nonproprietary bipyrazole ligand (bippyphos).
N-Aryl- and N-heteroaryl-substituted ureas, common phar-
macophores in biologically active targets,1,2 are typically
prepared by the coupling of amines with isocyanates, active
esters, or activated carbamates. The most utilized of these
alternatives, isocyanates,3 are in turn prepared by the reaction
of amines with phosgene. Although widely used, this
methodology has numerous deficiencies: most notably, in
low reaction yields resulting from instability of the isocy-
anates, disproportionation leading to symmetrical ureas, and
hazards associated with phosgene handling. It is not surpris-
ing therefore that numerous modifications have been re-
ported, including the development of phosgene surrogates.4
The use of cleaner and inherently safer alternatives such as
carbonates, carbonyl diimidazole, or reactions of activated
carbamates directly with an amine have been reported.5
Nevertheless, none of these procedures provide a general and
practical synthetic method for the preparation of N-aryl or
N-heteroaryl ureas.
Although a significant number of cross-coupling method-
ologies have been developed for N-arylation,6 few have been
applied to the N-arylation of ureas.7-11 It has been reported
that electron poor aryl bromides are suitable coupling partners
for N-arylation of ureas.7 However, unactivated aryl bromides
are less reactive.8 Aryl and heteroaryl chlorides are generally
more attractive from a cost and availability perspective
* Corresponding author.
(1) Gallou, I. Org. Prep. Proced. Int. 2007, 4, 355
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(2) For example: (a) Looker, A. R.; Littler, B. J.; Blythe, T. A.; Snoonian,
J. R.; Ansell, G. K.; Jones, A. D.; Nyce, P.; Chen, M.; Neubert, B. J. Org.
Process Res. DeV. 2008, 12 (4), 666–673. (b) Dai, Y.; Hartandi, K.; Ji, Z.;
Ahmed, A. A.; Albert, D. H.; Bauch, J. L.; Bouska, J. J.; Bousquet, P. F.;
Cunha, G. A.; Glaser, K. B.; Harris, C. M.; Hickman, D.; Guo, J.; Li, J.;
Marcotte, P. A.; Marsh, K. C.; Moskey, M. D.; Martin, R. L.; Olson, A. M.;
Osterling, D. J.; Pease, L. J.; Soni, N. B.; Stewart, K. D.; Stoll, V. S.;
Tapang, P.; Reuter, D. R.; Davidsen, S. K.; Michaelides, M. R. J. Med.
(4) Cotarca, L.; Delogu, P.; Nardelli, A.; Sunjic, V. Synthesis 1996, (5),
553–576.
(5) Bigi, F.; Maggi, R.; Sartori, G. Green Chem. 2000, 2 (4), 140–148.
(6) (a) Hartwig, J. F.; Shekhar, S.; Shen, Q.; Barrios-Landeros, F. In
Chemistry of Anilines; Rapporport, Z., Ed.; Wiley-Interscience: New York,
2007; Vol. 1, p 455. (b) Jiang, L.; Buchwald, S. L. In Metal-Catalyzed
Cross-Coupling Reactions, 2nd ed.; De Meijere, A., Diederich, F., Eds.;
Wiley-VCH: Weinheim, Germany, 2004.
Chem. 2007, 50 (7), 1584–1597
.
(7) Artamkina, G. A.; Sergeev, A. G.; Beletskaya, I. P. Tetrahedron
(3) (a) Sartori, G.; Maggi, R. In Science of Synthesis; Ley, S. V., Knight,
J. G., Eds.; Thieme: Stuttgart, Germany, 2005; Vol. 18, pp 665-758. (b)
Hegarty, A. F.; Drennan, L. J. In ComprehensiVe Organic Functional Group
Transformations; Katritzky, A. R., Meth-Cohn, O.; Rees, C. W., Eds.;
Pergamon: Oxford, UK, 1995; Vol. 6, pp 499-526.
Lett. 2001, 42, 4381
(8) Sergeev, A. G.; Artamkina, G. A.; Beletskaya, I. P. Tetrahedron
Lett. 2003, 44, 4719
(9) Abad, A.; Agullo´, C.; Cun˜at, A. C.; Vilanova, C. Synthesis 2005, 6,
915
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10.1021/ol802931m CCC: $40.75
Published on Web 01/29/2009
2009 American Chemical Society

Figure 1. General scheme.
compared to their iodo or bromo analogues. However, we
have only found literature precedent for urea coupling to
2-chloropyridine9 and intramolecular coupling with aryl-
chlorides.10,11 Prompted by the need to prepare nonsymmetric
ureas as part of our drug development efforts, we undertook
a more comprehensive investigation targeted at identifying
a practical and general method for the coupling of substituted
ureas with aryl bromides and the more commercially
attractive aryl chlorides (Figure 1).12
Table 1. Ligands for the Coupling of Aryl Halides and Ureaa
Figure 2. Ligands for urea arylation.
failed to couple with urea under previously reported condi-
tions.8 Additionally the 4-chlorotoluene and 4-chloroanisole
were selected to screen the more attractive chloride couplings.
Earlier reports indicated the reactions of ureas with aryl
bromides were catalyzed by palladium complexes of Xant-
phos.7,8 In our hands the catalyst generated from bidentate
ligand Xantphos 1 + Pd2(dba)3 (entry 1) gave moderate
conversion of 4-bromotoluene and 4-bromoanisole to their
respective coupled products. In the case of 4-bromotoluene,
biarylmonodentate ligands gave higher conversions (entries
3-6); however, these biaryl ligands are proprietary and their
use in further drug development efforts may be encumbered.
A search for nonproprietary ligands (entries 7-10) led to
the screening of several monodentate phosphine ligands. We
found that the recently reported ligand bippyphos 1013
+
Pd2(dba)3 resulted in high activity for the coupling (entry
10). In the case of 4-bromoanisole, binapthyl 5 + Pd2(dba)3
(entry 5) as well as bippyphos 10 + Pd2(dba)3 (entry 10)
gave high conversions. With both 4-bromotoluene and
4-bromoanisole, the bipyphos 10 + Pd2(dba)3 was signifi-
cantly better and resulted in complete conversion in only
2 h.
a Reaction conditions: 2 mol % of preformed catalyst (entries 2 and 7
available from Johnson Matthey as Pd complex) or 4 mol % of ligand + 1
mol % of Pd2(dba)3, 1.2 equiv of aryl halide, 1.0 equiv of urea, 1.5 equiv
of K3PO4, 85 °C and 20 h. b Conversion determined by HPLC versus isolated
characterized products. Ratio of ((desired)/(SM + desired)). c >99%
conversion at 2 h.
Buoyed by the ease of reaction observed for the unactivated
aryl bromides, we anticipated that even aryl chlorides may also
be suitable coupling partners for ureas under our experimental
conditions. Indeed, both 4-chlorotoluene and 4-chloroanisole
with bippyphos 10 + Pd2(dba)3 (entry 10) gave as high
conversions as observed for the reactions of aryl bromides. We
then focused our subsequent optimization and development
efforts around the bippyphos ligand 10 with aryl chlorides.
The metal precursor as well as the order of addition of ligand
and reagents were important for the success of the coupling
As an initial probe into the viability of such a urea coupling
approach, a series of ligands were screened (Table 1 and
Figure 2). Phenylurea was used as one of the coupling
partners, as the conversion could be easily monitored by
HPLC. Bromo toluenes and anisoles were selected as the
benchmark screening compounds as these substrates had
(10) McLaughlin, M.; Palucki, M.; Davies, I. W. Org. Lett. 2006, 8,
3311.
(11) Willis, M. C.; Snell, R. H.; Fletcher, A. J.; Woodward, R. L. Org.
Lett. 2006, 8, 5089.
(13) (a) Withbroe, G. J.; Singer, R. A.; Sieser, J. E. Org. Proc. Res.
DeV 2008, 12, 480. (b) Singer, R. A.; Dore, M.; Sieser, J. E.; Berliner,
M. A. Tetrahedron Lett. 2006, 47, 3727. (c) Available from Aldrich
(TrippyPhos 67,663-2, BippyPhos 68,155-5).
(12) N-Aryl urea prep. : Lukin, K. A.; Hsu, M. C.; Fernando, D. P.;
Kotecki, B. J.; Leanna, M. R. U.S. Pat. Appl. US2007244178.
948
Org. Lett., Vol. 11, No. 4, 2009

Table 2. Ligand/Metal Ratio and Catalyst Load Effectsa
Table 4. Coupling of Aryl Halides with Ureasa
cat. load
(mol %)
ligand/metal
ratio
conversionb
at 2 h
conversionb
at 20 h
entry
1
2
3
4
5
6
7
0.50
0.50
0.25
0.25
0.25
0.25
0.25
2.5to1
0.8to1
2.5to1
2.0to1
1.2to1
1.0to1
0.8to1
76
77
57
57
55
50
46
96
95
71
69
66
61
55
a Reaction condition: 1.2 equiv of aryl halide, 1.0 equiv of urea, 1.5
equiv of K3PO4, DME, 80 °C. b Conversion determined by HPLC versus
isolated characterized products. Ratio of ((desired)/(SM + desired)).
reactions. The combination of bippyphos ligand 10 with
Pd2(dba)3 showed higher reactivity (Table 1, entry 10) than
bippyphos ligand 10 with Pd(OAc)2 (Table 1, entry 11).14 The
combination of metal, ligand, base, urea, and aryl halide
followed then by addition of the solvent and heating afforded
variable reaction rates. However, the combination of metal,
ligand, base, and the urea followed by addition of solvent and
a complexation period,15 followed then by addition of aryl halide
and heating resulted in consistent reaction rates.
Table 3. Base Effectsa
conversionb
at 2 h
conversionb
at 20 h
entry
base
NaOtBu
1
2
3
4
5
6
7
8
9
57
64
67
92
6
8
6
12
>99
73
90
85
>99
20
17
23
14
>99
K3PO4
a Reaction condition: 4 mol % of bippyphos ligand 10, 1 mol % of
Pd2(dba)3, 1.1 equiv of aryl halide, 1.0 equiv of urea, and 1.5 equiv of
K3PO4, 85 °C. b Conversion determined by HPLC versus isolated character-
ized products. Ratio of ((desired)/(urea SM + desired)). c Ratio of ((desired/
(aryl halide SM)). d Solution assay yield utilizing HPLC assay vs isolated
product purified by crystallization. e Compared to commercially available
materials. f Isolated yields after crystallization from methanol/water; the
products contain up to 3 mol % of bippyphos ligand 10. Products can be
further purified by crystallization/trituration to obtain analytical standards
as indicated in the Supporting Information. g Product isolated by
chromatography.
Cs2CO3
d
K2CO3
Na2CO3
K2HPO4
NaHCO3
KOAc
d
K3PO4, milledc
a Reaction condition: 2 mol % of bippyphos ligand 10, 0.5 mol % of
Pd2(dba)3, 1.2 equiv of aryl halide, 1.0 equiv of urea, 1.5 equiv of base,
DME, and 85 °C. b Conversion determined by HPLC versus isolated
characterized products. Ratio of ((desired)/(SM + desired)). c Milled to mesh
size 16. d Powdered (available from Aldrich 59,068-1 and 45,161-4)
most substrates (entry 1 and 2). The use of lower catalyst
loadings resulted in incomplete reactions (entries 3-7).
Ligand to metal ratios ranging between 2.5 to 1 had no
significant impact on the apparent reaction rate as indicated
by similar conversions at 20 h (entries 3-6). This may
suggest bidentate coordination of the bippyphos 10 with
metal.16 Although in our subsequent studies we use a 2 to 1
The effect of catalyst loading and the ligand/metal ratio
was probed (Table 2). Catalyst loads of 0.5 mol % were
typically required to achieve quantitative conversion with
(14) 2 mol % of Pd(OAc)2 complexed with 4 mol % of bippyphos 10.
The 20 h time point indicated 97%, 91%, >99%, and 50%, respectively.
Org. Lett., Vol. 11, No. 4, 2009
949

ratio of ligand to metal, comparable conversions can also
be obtained by using a 1 to 1 ratio of ligand to metal.
possible in the presence of functional groups such as nitrile
(entry 7) and electron-withdrawing nitro (entry 8).
A notable limitation of these reaction conditions is that
sterically hindered aryl halides resulted in lower conversions.
Moderately sterically hindered aryl chloride (entry 9) af-
forded the product in high yield, sterically hindered 1-chloro-
2,6-dimethylbenzene (entry 10) results in 29% HPLC
conversion and was not isolated. In this case the slow reaction
time resulted in disproportionation of product, yielding N,N′-
diarylurea and N,N′-diphenylurea. The formation of these
byproduct was also noticed earlier7 in the case of reactions
catalyzed by Xantphos or in the abscense of any catalyst.
The reaction could also be extended to achieve the
coupling of aryl chlorides with alkyl ureas such as benzyl,
cyclohexyl, and n-butyl ureas (entries 11-13). Coupling
reactions with pyridyl halides also proceeded efficiently
(Table 4, entries 13-15). Not only the couplings of 2-chlo-
ropyridines (entry 14) were possible, but also the couplings
of more challenging 3-chloropyridines9 was achieved with
80% yield (entry 15). Unfortunately the reaction of 4-chlo-
ropyridine (entry 16) with phenyl urea led to poor conversion
and lower isolated yields (entry 16).
We have developed a practical, general, and highly
efficient method for the preparation of aryl ureas. The use
of a combination of bippyphos ligand 10 with Pd2(dba)3
offers a relatively inexpensive, nonproprietary ligand system
with high reactivity, that enables the coupling of ureas with
not only aryl bromides but also aryl and heteroaryl chlorides.
We intend to further explore the scope of reaction and the
mechanistic detail to elicit a better understanding of the
reaction pathway.
The effect of different bases on the reaction conversion
was investigated (Table 3). The use of the stronger base
NaOtBu (entry 1) resulted in degradation and/or dispropor-
tionation of the ureas especially when higher temperatures
(>90 °C) were used. The use of K3PO4, Cs2CO3, and K2CO3
(entries 2-4) gave conversions >85%. Weaker bases such
as Na2CO3, K2HPO4, NaHCO3, and KOAc (entries 5-8) led
to less than 25% conversion. The heterogeneous bases
performed better when particle size was reduced by milling
or grinding. The highest conversion rate was with milled17
K3PO4 (entry 9) and it was used in subsequent process
optimization efforts.
No optimization of solvent was conducted. The use of
DME was used as a substitute for dioxane, which was used
in the activated aryl bromide couplings previously cited.7,8
After the refinement of several of the reaction parameters,
we looked to establish the scope of the new method (Table
4). High yields were observed for the reactions of bromoben-
zene (entry 1) as well as the previously problematic8
substrates 4-bromotoluene and 4-bromoanisole (entries 2 and
3). Gratifyingly, the unprecidented coupling of urea with
chlorobenzene afforded the coupled product in 90% yield
(entry 4). High yields were also obtained in the reactions of
aryl chlorides with an electron donating group such as
4-chlorotoluene and 4-chloroanisole (entries 5 and 6).
Furthermore, the coupling of urea with aryl chlorides was
(15) During the complexation period, a noticable color change from
purple to amber was observed. Comparable performance was achieved by
stirring the catalyst mixture for as little as 15 min to as long as 1 h at
ambient temperature. Complexation at 50 °C for between 5 and 60 min
also proved effective.
Supporting Information Available: Experimental pro-
cedures and full characterization for all isolated compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(16) Barder, T. E.; Biscoe, M. R.; Buchwald, S. L. Organometallics
2007, 26, 2183. The metal coordination to bippyphos will be a focus of
future investigations.
(17) Milled to mesh size 16.
OL802931M
950
Org. Lett., Vol. 11, No. 4, 2009