Efficient access to cyclic ureas via Pd-catalyzed cyclization

Article abstract of DOI:10.1021/ol061233j

An efficient regioselective method for the preparation of structurally diverse imidazopyridinones and benzoimidazolones starting from readily available and economical starting materials is described. High-yielding reductive alkylation of electron-deficient o-haloarylamines followed by treatment with inexpensive N-chlorosulfonyl isocyanate afforded primary ureas in good overall yields. A Pd-catalyzed urea cyclization reaction furnished imidazopyridinones and benzoimidazolones in excellent yields. Overall, the developed chemistry provides rapid access to pharmaceutically important heterocyclic compounds with high efficiency.

Full text of DOI:10.1021/ol061233j

ORGANIC
LETTERS
2006
Vol. 8, No. 15
3311-3314
Efficient Access to Cyclic Ureas via
Pd-Catalyzed Cyclization
Mark McLaughlin,* Michael Palucki, and Ian W. Davies
Department of Process Research, Merck Research Laboratories, P.O. Box 2000,
Rahway, New Jersey 07065
mark_mclaughlin@merck.com
Received May 19, 2006
ABSTRACT
An efficient regioselective method for the preparation of structurally diverse imidazopyridinones and benzoimidazolones starting from readily
available and economical starting materials is described. High-yielding reductive alkylation of electron-deficient o-haloarylamines followed by
treatment with inexpensive N-chlorosulfonyl isocyanate afforded primary ureas in good overall yields. A Pd-catalyzed urea cyclization reaction
furnished imidazopyridinones and benzoimidazolones in excellent yields. Overall, the developed chemistry provides rapid access to
pharmaceutically important heterocyclic compounds with high efficiency.
Benzoimidazolones, imidazopyridinones, and the related
benzimidazoles/imidazopyridines are heterocyclic substruc-
tures embedded in many biologically active molecules with
pharmaceutical relevance.1 As a consequence, the develop-
ment of efficient methods for the preparation of such
compounds constitutes an important area of synthetic re-
search. In particular, the ability to generate these cyclic urea
structures in a regioselective fashion, with control of the
substituent on each nitrogen atom, is desirable. Current
techniques for the synthesis of unsymmetrically substituted
benzoimidazolones often rely upon inefficient manipulations
of 1,2-diamino compounds followed by carbonyl installation
using phosgene or its equivalent.2 The use of protecting
groups is an inevitable feature of such strategies. As part of
our ongoing studies in this area, an alternative approach was
envisaged, centered around a Pd-catalyzed urea cyclization
reaction.
Scheme 1. Regiocontrolled Synthesis of Unsymmetrical
Imidazolones
(1) For selected examples, see: (a) Kuethe, J. T.; Wong, A.; Davies, I.
W. J. Org. Chem. 2004, 69, 7752-7754 and references cited therein. (b)
McClure, K. F.; Abramov, Y. A.; Laird, E. R.; Barberia, J. T.; Cai, W.;
Carty, T. J.; Cortina, S. R.; Danley, D. E.; Dipesa, A. J.; Donahue, K. M.;
Dombroski, M. A.; Elliott, N. C.; Gabel, C. A.; Han, S.; Hynes, T. R.;
LeMotte, P. K.; Mansour, M. N.; Marr, E. S.; Letavic, M. A.; Pandit, J.;
Ripin, D. B.; Sweeney, F. J.; Tan, D.; Tao, Y. J. Med. Chem. 2005, 48,
5728-5737. (c) Terefenko, E. A.; Kern, J.; Fensome, A.; Wrobel, J.; Zhu,
Y.; Cohen, J.; Winneker, R.; Zhang, Z.; Zhang, P. Bioorg. Med. Chem.
Lett. 2005, 15, 3600-3603. (d) Li, Q.; Li, T.; Woods, K. W.; Gu, W.-Z.;
Cohen, J.; Stoll, V. S.; Galicia, T.; Hutchins, C.; Frost, D.; Rosenberg, S.
H.; Sham, H. L. Bioorg. Med. Chem. Lett. 2005, 15, 2918-2922. (e) Zuev,
D.; Michne, J. A.; Huang, H.; Beno, B. R.; Wu, D.; Gao, Q.; Torrente, J.
R.; Xu, C.; Conway, C. M.; Macor, J. E.; Dubowchik, G. M. Org Lett.
2005, 7, 2465-2468.
As outlined retrosynthetically in Scheme 1, it was proposed
that formation of cyclic ureas could be accomplished via an
intramolecular transition-metal-catalyzed amidation reaction.
Although this class of reaction has been intensively studied3
in recent times, examples in which ureas are employed in
intramolecular reactions are rare.4,5 The urea cyclization
10.1021/ol061233j CCC: $33.50
© 2006 American Chemical Society
Published on Web 06/22/2006

substrates would ultimately derive from cheaply available
o-chloroanilines or o-chloroaminopyridines. The preceding
report from these laboratories described an effective reductive
alkylation procedure applicable to either of these electron-
poor arylamines, substrates that are normally viewed as
inferior partners in this reaction.6 The present research sought
to utilize this reductive alkylation chemistry as a means to
prepare various N-substituted o-chloroarylamines and dem-
onstrate their further elaboration into benzoimidazolones and
imidazopyridinones. The results of this work are described
herein.
Table 1. Choice of Base for the Pd-Catalyzed Urea
Cyclizationa
entry
base (mol %)
conversionb (%)
assay yieldb (%)
With a series of N-substituted o-chloroarylamines in hand,
attention was focused on their conversion into primary ureas.
In this regard, trichloroacetyl isocyanate was shown to deliver
the desired ureas in reasonable yield.7 However, the expense
of this reagent and the two-step nature of the process
prompted investigation of an alternative reagent.
1
2
3
4
Cs2CO3 (300)
K3PO4 (300)
K2CO3 (300)
NaHCO3 (300)
99
90
99
67
74
87
87
100
a Reaction conditions: Urea 3a (100 mol %), Pd2(dba)3 (4 mol % Pd),
Xantphos (6 mol %), base (300 mol %), toluene (10 mL/g, 150 ppm H2O),
110 °C, 16 h. b Conversion and assay yield determined by LC versus purified
standards.
Chlorosulfonyl isocyanate (CSI) is an extremely inexpen-
sive reagent that converts amines into the corresponding
primary ureas.8 However, the reported yields for this
transformation are generally moderate, and detailed experi-
mental procedures are uncommon.9 Following some experi-
mentation using 1a (Figure 1), it was determined that the
N-chlorosulfonylurea 2 to accumulate in the presence of 1a
and resulted in the formation of dimeric-type species, via
further reaction at the chlorosulfonyl group. This problem
could be overcome by rapid addition (<1 min) of the CSI,
since the secondary reaction was significantly slower. A more
practical solution was to adopt an inverse addition protocol,
which reproducibly afforded clean conversion to 2.10 Hy-
drolysis of 2 was facile and complete in <10 min upon
addition of water to the reaction mixture. Simple extractive
workup and subsequent concentration of the organic phase
allowed for isolation of pure 3a in excellent yield by
crystallization.
Application of this developed procedure to an array of
arylamines delivered high yields without exception. Due to
the high efficiency of the previous reductive alkylation step,6
it was possible to conduct the urea formation directly on the
crude stream (Table 4). The exceptional crystallinity of the
product ureas enabled facile rejection of impurities during
crystallization.
Figure 1. Urea formation using CSI and urea cleavage with strong
bases.
order of reagent addition was critical for success when using
CSI. Slow addition of CSI to 1a allowed the intermediate
Cyclization of the prepared urea intermediates was initially
investigated in the pyridine series. The activated nature of
the 2-position of 3a suggested that an uncatalyzed cyclization
process might be feasible; however, tests under both acidic
and basic and also thermal conditions met with failure.11
(2) (a) Zecchini, G. P.; Torrini, I.; Paradisi, M. P. J. Heterocycl. Chem.
1985, 22, 1061-1064. (b) Meanwell, N. A.; Sit, S. Y.; Gao, J.; Wong, H.
S.; Gao, Q.; St. Laurent, D. R.; Balasubramanian, N. J. Org. Chem. 1995,
60, 1565-1582 and references cited therein.
(3) For examples of intramolecular Pd-catalyzed amidation, see: (a)
Yang, B. H.; Buchwald, S. L. Org. Lett. 1999, 1, 35-37. (b) Poondra, R.
R.; Turner, N. J. Org. Lett. 2005, 6, 863-866.
(4) In a study directed toward the sysnthesis of benzothiazoles via
cyclization of o-bromophenylthioureas, two benzimidazolones were prepared
by Pd-catalyzed urea cyclization under relatively harsh conditions/high
catalyst loadings; see: Benedi, C.; Bravo, F.; Uriz, P.; Ferna´ndez, E.; Claver,
C.; Castillo´n, S. Tetrahedron Lett. 2003, 44, 6073-6077.
(5) For examples of intermolecular Pd-catalyzed amidation using cyclic
ureas, see: (a) Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 6043-
6048. For examples of Cu-catalyzed amidation using cyclic and acyclic
ureas, see: (b) Trost, B. M.; Stiles, D. T. Org. Lett. 2005, 7, 2117-2120.
(c) Nandakumar, M. V. Tetrahedron Lett. 2005, 45, 1989-1990. For Pd-
and Cu-catalyzed synthesis of 2-aminobenzimidazoles via intramolecular
C-N bond formation between an aryl bromide or iodide and a guanidine,
see: Evindar, G.; Batey, R. A. Org. Lett. 2003, 5, 133-136.
(6) See the accompanying paper from these laboratories: McLaughlin,
M.; Palucki, M.; Davies, I. W. Org. Lett. 2006, 8, 3307-3310.
(7) (a) Espino, C. G.; DuBois, J. Angew. Chem., Int. Ed. 2001, 40, 598-
600. (b) Kocovsky, P. Tetrahedron Lett. 1986, 27, 5521-5524.
(8) For a review on the use of CSI for various transformations, see: Dhar,
D. N.; Murthy, K. S. K. Synthesis 1986, 437-449.
(9) Carril, M.; SanMartin, R.; Churruca, F.; Tellitu, I.; Dominguez, E.
Org. Lett. 2005, 7, 4787-4789 and references cited therein.
(10) Notably, the published procedures advocate a “normal” addition
protocol, in which CSI is added to the substrate. Based on the observations
from the current work, this could account for the moderate yields obtained
in these cases.
(11) Attempted thermal cyclizations in a variety of solvents (DMSO,
MeCN, NMP, water, toluene, i-PrOH, DMAc, pyridine, n-BuOH, and
AcOH) were not successful, generally returning unchanged starting
material.
3312
Org. Lett., Vol. 8, No. 15, 2006

Table 2. Optimization of the Pd-Catalyzed Urea Cyclizationa
Table 3. o-Haloaniline Urea Cyclizationsa
convb assay yieldb
solvent
T
convc assay
entry
X
[Pd] (mol %) L (mol %)
(%)
(%)
entry [Pd] (mol %)
L (mol %) (H2O)b (°C) (%) yieldc (%)
1
2
3
4
5
6
Cl (3b) Pd(OAc)2 (2) dppb (4)
Cl (3b) Pd(OAc)2 (1) X-Phos (3)
Br (3c) Pd(OAc)2 (2) dppb (4)
Br (3c) Pd(OAc)2 (1) X-Phos (3)
0
99
0
0
1
2
3
4
5
6
7
8
9
Pd2(dba)3 (4) Xantphos (6) toluene 110
99
30
20
30
36
90
77
64
99
67
0
99 (89)c
(150)
0
70d
5
Pd/C
toluene 110
(150)
72d
5
I (3d)
I (3d)
Pd(OAc)2 (2) dppb (4)
Pd(OAc)2 (1) X-Phos (3) 100c
Pd(OAc)2 (2) Ph3P (8)
Pd(OAc)2 (0.5)
toluene 110
(150)
DMAc 110
(285)
0
99c
a Reaction conditions: Urea 3b-d (100 mol %) and NaHCO3 (300 mol
%) with the indicated catalyst/ligand in i-PrOH (10 mL/g) at 83 °C.
b Conversion and assay yield determined by LC versus purified standards.
c Yield in parentheses refers to isolated material. d After 72 h.
0
Pd(OAc)2 (2) DABCO (4) DMAc 110
(285)
0
Pd(OAc)2 (2) dppb (4)
Pd(OAc)2 (2) dppb (4)
Pd(OAc)2 (2) dppb (4)
Pd(OAc)2 (2) dppb (4)
toluene 110
(150)
toluene 110
(35)
90
70
60
98
99
99
1, entries 3 and 4), and NaHCO3 was chosen for further study
owing to its extremely mild nature.13
Although good yields were obtained under these condi-
tions, further exploration of the reaction variables ultimately
led to a superior catalytic system (Table 2). An attempt to
employ a heterogeneous catalyst for this reaction was
unsuccessful (Table 2, entry 2). With respect to homogeneous
systems, ligand-free conditions met with failure (Table 2,
entry 4). Monodentate Ph3P and DABCO were also inef-
fectual (Table 2, entries 3 and 5). Having demonstrated that
Xantphos promoted the reaction, attention was focused on
alternative, less expensive bidentate phosphines, and bis-
(diphenylphosphino)butane (dppb) surfaced as a good ligand
for this reaction. Seeking to gain control of the urea
hydrolysis problem, the reaction was conducted in the
presence of varying amounts of water (Table 2, entries 6
and 7). When the water content of the system was reduced
to 35 ppm, the reaction stalled at 77% conversion whereas
an increased water content gave better results. The exact role
played by water in this case is unknown at present. The
temperature could be reduced to 75-85 °C and a reasonable
reaction rate maintained (complete conversion within 16 h).
Significantly, the urea cleavage side-reaction was completely
suppressed at the lower temperature. The reaction functioned
in alternative solvents, and ultimately, i-PrOH was chosen
as the optimum solvent. Catalyst loading was reduced to 1
mol % of Pd(OAc)2 and 2 mol % of dppb, routinely affording
>99% conversion and 99% assay yield.
THF
(30)
75
THF
(725)
75
10 Pd(OAc)2 (2) dppb (4)
11 Pd(OAc)2 (1) dppb (2)
i-PrOH 83 100
(1250)
i-PrOH 83 100
(1250)
a Reaction conditions: Urea 3a (100 mol %) and NaHCO3 (300 mol %)
with the indicated catalyst/ligand/solvent (10 mL/g)/temperature for
16 h. b Water content values are in ppm, determined by Karl-Fisher titra-
tion. c Conversion and assay yield determined by LC versus purified
standards.
Interestingly, when 3a was treated with LiHMDS or i-
PrMgCl smooth cleavage of the urea occurred and returned
the precursor 1a, presumably via elimination of cyanate ion
(Figure 1).
At this stage, the use of transition-metal catalysis was
examined, and palladium was chosen as the starting point.12
An initial encouraging result was obtained using Pd2(dba)3
and Xantphos with Cs2CO3 as the base in toluene at 110 °C.
Under these conditions, the conversion of starting material
was high while the assay yield was only moderate (Table 1,
entry 1). The mass balance was accounted for in urea
cleavage, returning 1a, as observed previously under more
strongly basic conditions. After screening several bases, both
K2CO3 and NaHCO3 emerged as suitable candidates (Table
These conditions proved effective throughout the pyridine
series, and essentially quantitative yields were obtained with
all substrates (Table 4).
As anticipated, for the haloaniline series the Pd(OAc)2/
dppb system was ineffective with the o-chloroanilines. More
(12) Cu-catalyzed conditions were less successful for this reaction,
affording only 67% conversion of starting material. See: Klapars, A.;
Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123,
7727-7729.
(13) Again, the mass balance was found in the urea cleavage side reaction,
apparently suppressed under the less basic conditions.
Org. Lett., Vol. 8, No. 15, 2006
3313

surprising was the lack of reactivity with both the o-bromo
and o-iodo derivatives. This situation was partially remedied
when dppb was replaced with Buchwald’s highly active
X-Phos ligand. Under these conditions, the chloroaniline
derivative reacted smoothly while both the bromo and iodo
compounds were less efficient. In fact, the iodoaniline
required 72 h at 83 °C to reach completion, and the
bromoaniline only reached 72% conversion before stalling.14
The reasons for this unusual trend in reactivity across the
halogen series are unclear at this time (Table 3).
Table 4. Urea Formationa and Pd-Catalyzed Cyclizationb
Table 4 illustrates the substrate scope for this chemistry
and displays the isolated yields for both the CSI-mediated
urea formation and the Pd-catalyzed cyclization. In all
cases, the efficiency of the urea cyclization reaction combined
with the lack of byproducts rendered product isolation a
straighforward task. Dilution with a suitable extraction
solvent and an aqueous wash to remove inorganics leaves a
solution from which the product can be crystallized in high
purity.
In summary, we have demonstrated an efficient conversion
of o-chloro-N-substituted arylamine products into benzoimi-
dazolones and imidazopyridinones via a novel method. The
use of readily available CSI for the formation of primary
ureas was studied, and a high-yielding, reproducible proce-
dure was developed. Critical to the success of this step was
the use of an inverse addition protocol. Further, a Pd-
catalyzed cyclization of these ureas was optimized to proceed
in generally excellent yields. The Pd(OAc)2/dppb catalyst
system is simple, economical, and effective for the 2-chlo-
ropyridine series. For the less reactive o-chloroanilines, the
more active X-Phos ligand produced the desired result.
Overall, the described chemistry represents a method by
which inexpensive starting materials can be rapidly elabo-
rated into more complex heterocyclic structures of pharma-
ceutical importance.
Acknowledgment. We thank Robert A. Reamer and Tom
J. Novak (Department of Process Research, Merck and Co.
Inc.) for assistance with NMR data and mass spectrometry
data acquisition, respectively.
Supporting Information Available: Experimental pro-
cedures, characterization data, and NMR spectra for all
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
a Reaction conditions: reductive alkylation, o-chloroarylamine (100 mol
%), carbonyl (110 mol %), TFA (200 mol %), and STAB (120 mol %) in
i-PrOAc at rt; urea formation, CSI (120 mol %), THF/i-PrOAc, -10 °C, then
H2O. b Reaction conditions: (A) urea (100 mol %), Pd(OAc)2 (1 mol %), dppb
(2 mol %), and NaHCO3 (300 mol %) in i-PrOH (10 mL/g) at 83 °C; (B)
urea (100 mol %), Pd(OAc)2 (1 mol %), X-Phos (3 mol %), and NaHCO3
(300 mol %) in i-PrOH (10 mL/g) at 83 °C. cYields refer to isolated material.
OL061233J
(14) Xantphos/Pd(OAc)2 was also ineffective in attempts to cyclize the
bromoaniline substrate.
3314
Org. Lett., Vol. 8, No. 15, 2006