Copper- and palladium-catalyzed intramolecular aryl guanidinylation: An efficient method for the synthesis of 2-aminobenzimidazoles

Article abstract of DOI:10.1021/ol027061h

(Matrix presented) The formation of 2-aminobenzimidazoles via intramolecular C-N bond formation between an aryl halide and a guanidine moiety can be achieved using either copper or palladium catalysis. Inexpensive copper salts such as Cul are generally su

Full text of DOI:10.1021/ol027061h

ORGANIC
LETTERS
2003
Vol. 5, No. 2
133-136
Copper- and Palladium-Catalyzed
Intramolecular Aryl Guanidinylation:
An Efficient Method for the Synthesis of
2-Aminobenzimidazoles†
Ghotas Evindar and Robert A. Batey*
DaVenport Research Laboratories, Department of Chemistry, UniVersity of Toronto,
80 St. George Street, Toronto, Ontario, M5S 3H6, Canada
rbatey@chem.utoronto.ca
Received October 9, 2002
ABSTRACT
The formation of 2-aminobenzimidazoles via intramolecular C−N bond formation between an aryl halide and a guanidine moiety can be achieved
using either copper or palladium catalysis. Inexpensive copper salts such as CuI are generally superior to the use of palladium catalysts.
3
Regioselective cyclizations, where R ) H, can be achieved in high yield under CuI/1,10-phenanthroline-catalyzed conditions, whereas palladium
catalysis results in the formation of regioisomeric products.
There have been a number of groundbreaking advances in
cross-coupling methodology over the past few years. One
significant area of improvement is that of metal-catalyzed
C-N bond and other carbon-heteroatom bond formations.
In particular, the palladium-catalyzed amination of aryl
halides, pioneered by the laboratories of Hartwig and
Buchwald, has been enthusiastically adopted in the pharma-
ceutical industry.1 While some limitations still exist, it is clear
that metal-catalyzed cross-coupling reactions will increas-
ingly occupy a key position among the armamentarium of
carbon-heteroatom bond-forming reactions.2
cross-coupling between a guanidine residue and an aryl
halide for the formation of 2-aminobenzimidazoles, which
are known to display a range of biological activities.4,5 The
vast majority of methods for the synthesis of 2-amino-
benzimidazoles originate from o-phenylenediamine precur-
sors. For example, a recent example from Senanayake and
co-workers utilized palladium-catalyzed aryl amination of
2-chlorobenzimidazoles, which are o-phenylenediamine de-
rived.6 Kerr and co-workers have synthesized aminobenz-
imidazoles through a high-pressure SNAr reaction between
2-chlorobenzimidazoles and alkylamines.7 More recently,
Our interest in guanidine chemistry3 and cyclization
reactions led us to consider the feasibility of intramolecular
(3) (a) Batey, R. A.; Powell, D. A. Chem. Commun. 2001, 2362-2363.
(b) Powell, D. A.; Batey, R. A. Org. Lett. 2002, 4, 2913-2916.
(4) Ellingboe, J. W.; Spinelli, W.; Winkley, M. W.; Nguyen, T. T.;
Parsons, R. W.; Moubarak, I. F.; Kitzen, J. M.; Von Engen, D.; Bagli, J. F.
J. Med. Chem. 1992, 35, 705-716.
† This paper is dedicated to our friend and colleague, Professor J. Bryan
Jones, on the occasion of his 65th birthday.
(1) Reviews: (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) Yang, B. H.; Buchwald, S. L. J.
Organomet. Chem. 1999, 576, 125-146.
(2) (a) Shakespeare, W. C. Tetrahedron Lett. 1999, 40, 2035-2038. (b)
Yin, J.; Buchwald, S. L. Org. Lett. 2000, 2, 1101-1104. (c) Artamkina, G.
A.; Sergeev, A. G.; Beletskaya, I. P. Tetrahedron Lett. 2001, 42, 4381-
4384. (d) Cacchi, S.; Fabrizi, G.; Goggiamani, A.; Zappia, G. Org. Lett.
2001, 3, 2539-2541.
(5) (a) Janssens, F.; Torremans, J.; Janssen, M.; Stokbroekx, R. A.;
Luyckx, M.; Janssen, P. A. J. J. Med. Chem. 1985, 28, 1934-1943. (b)
Janssens, F.; Torremans, J.; Janssen, M.; Stokbroekx, R. A.; Luyckx, M.;
Janssen, P. A. J. J. Med. Chem. 1985, 28, 1925-1933. (c) Janssens, F.;
Torremans, J.; Janssen, M.; Stokbroekx, R. A.; Luyckx, M.; Janssen, P. A.
J. J. Med. Chem. 1985, 28, 1943-1947.
(6) Hong, Y.; Tanoury, G. J.; Wilkinson, S. H.; Bakale, R. P.; Wald, S.
A.; Senanayake, C. H. Tetrahedron Lett. 1997, 38, 5607-5610.
(7) Barrett, I. C.; Kerr, M. A. Tetrahedron Lett. 1999, 40, 2439-2442.
10.1021/ol027061h CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/19/2002

Sun and co-workers have used a rapid microwave-assisted
liquid-phase combinatorial approach from o-phenylene-
diamine and isothiocynanates.8
less than 10 min. Treatment of 5 with HgCl2 under basic
conditions in the presence of a primary/secondary amine
generated tri/tetrasubstituted guanidine 1 following filtration
through Celite and aqueous workup with aqueous ammonium
chloride. Dehydrothiolation of thiourea 5 could also be
achieved via Mukaiyama’s reagent, silver salts, or EDCI.
Despite these approaches, a general method for the
generation of 2-aminobenzimidazoles under mild conditions
is desirable, particularly when the corresponding o-phen-
ylenediamines are not readily available. We envisaged that
the cyclization reaction of tri/tetrasubstituted guanidines 1
via an intramolecular aryl guanidinylation, analogous to
Buchwald and Hartwig aryl amination chemistry, would
generate mono/disubstituted 2-aminobenzimidazoles 2 (Scheme
1).1,9 Intramolecular palladium-catalyzed cross-couplings
Bromophenyl guanidine 6 was chosen as a representative
substrate, and optimization studies of palladium source,
ligand, solvent, and temperature were undertaken (Table 1).
Table 1. Palladium-Catalyzed Aryl Guanidinylation: Catalyst,
Ligand, and Temperature Effects on the Cyclization of
Guanidine 6 to Benzimidazole 7
Scheme 1
temp conversiona
entry catalyst
1
mol %
L
mol % (°C)
(%)
80
0
47
55
71
30
85
27
>98
0
8
7
21
5
17
8
resulting in C-N bond formation and cyclization are known
for the generation of a variety of heterocycles such as indoles,
pyrido[2,3-b]indoles, phenazines, indazoles, and several
alkaloid backbones.10
The requisite cyclization precursors are readily synthesized
from commercially available o-haloaryl isothiocyanates or
o-haloanilines (Scheme 2). Reaction of o-haloaniline 3 with
2
3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd(OAc)2
Pd2(dba)3
Pd2(dba)3
Pd(PPh3)4
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
10
10
10
10
10
10
10
10
10
10
10
10
5
PPh3
PPh3
(o-tol)3P
(o-tol)3P
8
20
40
20
20
20
40
80
80
80
80
80
80
80
rt
rt
rt
50
50
80
80
4
5
6
7
8
9
8
PPh3
(o-tol)3P
8
20
20
20
20
10
11
12
13
14
15
(o-tol)3P
Scheme 2a
2
1
a Conversions determined by H NMR.
Intramolecular cyclization of 6 using Pd2(dba)3 (10 mol %),
PPh3 (20 mol %), and Cs2CO3 (2 equiv) at 80 °C was
investigated with various solvents, including toluene, CH3-
CN, DMA, DMF, and DME. Good conversion of 6 to
a Key: (a) R1NCS, DMF, 12-48 h; (b) R1NH2, MeCN, 10 min;
(c) HgCl2, Et3N, R2R3NH, 3-24 h.
1
2-aminobenzimidazole 7 (as analyzed by H NMR) was
observed with DMF, DMA, and DME solvents, with DME
being superior (Table 1, entries 2 and 3). Use of tri-o-
tolylphosphine or Buchwald’s ligand (di-tert-butylphosphi-
nobiphenyl) 8 led to higher conversions at 80 °C (Table 1,
entries 4 and 6). The use of Pd(OAc)2 or a greater amount
of 8 both resulted in poorer conversions (Table 1, entries 5
and 7). However, Pd(PPh3)4 (10 mol %) showed complete
conversion at 80 °C. Reactions at lower temperatures resulted
in poorer conversions for a variety of Pd/ligand combinations
(Table 1, entries 9-13), as did lowering the amount of Pd-
(PPh3)4 catalyst (Table 1, entries 14 and 15). Brain and co-
an isothiocyanate in DMF gave thiourea 5 in 12-48 h.
Alternatively, thiourea 5 can be synthesized in quantitative
yield from o-halophenyl isothiocyanate 4 in acetonitrile in
(8) Bendale, P. M.; Sun, C.-M. J. Comb. Chem. 2002, 4, 359-361.
(9) (a) Louie, J.; Hartwig, J. F. Tetrahedron Lett. 1995, 36, 3609-
3612. (b) Guram, A. S.; Rennels, R. A.; Buchwald, S. L. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 1348-1350. (c) Driver, M. S.; Hartwig, J. F. J.
Am. Chem. Soc. 1996, 118, 7217-7218. (d) Zhao, S.; Miller, A. K.; Berger,
J.; Flippin, L. A. Tetrahedron Lett. 1996, 37, 4463-4466. (e) Wolfe, J. P.;
Buchwald, S. L. J. Org. Chem. 1996, 61, 1133-1135. (f) Wolfe, J. P.;
Rennels, R. A.; Buchwald, S. L. Tetrahedron 1996, 52, 7525-7546. (g)
Song, J. J.; Yee, N. K. Org. Lett. 2000, 2, 519-521.
(10) (a) Peat, A. J.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 1028-
1030. (b) Aoki, K.; Peat, A. J.; Buchwald, S. L. J. Am. Chem. Soc. 1998,
120, 3068-3073. (c) Abouabdellah, A.; Dodd, R. H. Tetrahedron Lett. 1998,
39, 2119-2122. (d) Emoto, T.; Kubosaki, N.; Yamagiwa, Y.; Kamikawa,
T. Tetrahedron Lett. 2000, 41, 355-358. (e) Brown, J. K. Tetrahedron
Lett. 2000, 41, 1623-1626. (f) Song, J. J.; Yee, N. K. Org. Lett. 2000, 2,
519-521. (g) Song, J. J.; Yee, N. K. Tetrahedron Lett. 2001, 42, 2937-
2940. (h) Lee, S.; Hartwig, J. F. J. Org. Chem. 2001, 66, 3402-3415. (i)
Gaertzen, O.; Buchwald, S. L. J. Org. Chem. 2002, 67, 465-475.
134
Org. Lett., Vol. 5, No. 2, 2003

workers have also synthesized a single example of a
2-aminobenzimidazole through an analogous approach using
Pd(PPh3)4 catalyst.11
Table 3. Intramolecular Aryl Guanidinylation of Aryl
Bromides with Pd(PPh3)4 (Method A) and CuI (Method B)
While the palladium-catalyzed reaction was encouraging,
the relatively high catalyst loadings are not ideal. Copper(I)
has recently been used in C-C and C-N bond formation.12,13
Application of copper chemistry to the intramolecular aryl
guanidinylation reaction of 6 was therefore investigated.
Using CuI without any ligand at 80 °C gave partial
conversion to the desired product (Table 2, entry 1).
Table 2. Copper-Catalyzed Aryl Guanidinylation: Catalyst,
Ligand, and Temperature Effects on the Cyclization of
Guanidine 6 to Benzimidazole 7
temp conversiona
entry
catalyst
CuI
CuI
CuSO4‚5H2O
CuBr2
Cu(OAc)2‚H2O
CuI
CuI
CuI
CuI
mol %
L
mol % (°C)
(%)
1
2
3
4
5
6
7
8
9
5
5
5
5
5
5
5
1
80
40
>98
95
>98
95
3
65
66
95
9
9
9
9
9
9
9
9
10
10
10
10
10
10
2
80
80
80
80
rt
50
80
80
2.5
5
1
a Conversions determined by H NMR.
Investigation of various copper salts as a catalyst (5 mol %)
and 1,10-phenanthroline 9 (10 mol %) as a ligand resulted
in excellent conversions, with CuI and CuBr2 achieving
complete conversion (Table 2, entries 2-5). Reaction of 6
at lower temperatures or the use of lower catalyst loadings
resulted in poorer conversions (Table 2, entries 6-8).
However, reaction with the corresponding iodide resulted
in 50% and complete conversions at room temperature and
50 °C, respectively, illustrating the greater reactivity of the
iodide substrates. To our knowledge, this is the first catalytic
intramolecular aryl guanidinylation using copper salts.
The intramolecular aryl guanidinylation was applied to
various aryl bromide substrates (Table 3) using the two sets
of optimized conditions, method A for palladium catalysis
(Table 1, entry 8) and method B for copper catalysis (Table
2, entry 2).14 In general, both sets of conditions resulted in
product formation, with the copper-catalyzed conditions
a All yields are reported after column chromatography. b Conversions
1
determined by H NMR. c Reaction was refluxed for 16 h. d Product was
obtained as a 1:1 mixture of isomers. e Product was obtained as a 1:1 mixture
of mono-Br and debrominated products.
(11) Brain, C. T.; Brunton, S. A. Tetrahedron Lett. 2002, 43, 1893-
1895.
(12) (a) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am.
Chem. Soc. 2001, 123, 7727-7729. (b) Wolter, M.; Klapars, A.; Buchwald,
S. L. Org. Lett. 2001, 3, 3803-3805. (c) Hennessy, E. J.; Buchwald, S. L.
Org. Lett. 2002, 4, 269-272. (d) Kwong, F. Y.; Klapars, A.; Buchwald, S.
L. Org. Lett. 2002, 4, 581-584. (e) Klapars, A.; Huang, X.; Buchwald, S.
L. J. Am. Chem. Soc. 2002, 124, 7421-7428.
(13) For an earlier review of copper-assisted nucleophilic substitutions
of aryl halides, see: Lindley, J. Tetrahedron 1984, 40, 1433-1456.
(14) General Synthetic Procedure. To a mixture of guanidine (0.20
mmol), CuI (0.01 mmol, 0.05 equiv), 1,10-phenanthroline (0.02 mmol, 0.10
equiv), and Cs2CO3 (0.40 mmol, 2.0 equiv) was added reagent-grade
dimethoxyethane (4 mL). The reaction mixture was heated at 80 ° C for 16
h under nitrogen. The reaction was diluted with EtOAc (25 mL) and washed
with H2O (2 × 25 mL) and saturated NaCl (1 × 25 mL). The organic layer
sometimes achieving higher conversions, and with product
purification being more readily accomplished. In cases where
the regioselectivity of cyclization is an issue, the copper-
catalyzed method gives better results (Table 3, entries 7 and
8). Preferential cyclization of guanidine occurs from an NH-
was dried over MgSO4, and then the solvent was removed in vacuo. The
crude product was purified using silica gel column chromatography. For
the Pd(PPh3)4 (23.1 mg, 0.1 equiv) catalyzed reactions, dried dimethoxy-
ethane (from 4 Å molecular sieves) was used as a solvent.
Org. Lett., Vol. 5, No. 2, 2003
135

palladium-catalyzed reaction is unselective (Table 3, entry
8). Also, reaction of a susbstrate incorporating two o-bromo
substituents gave a mixture of bromo and debrominated
aminobenzimidazoles with palladium catalysis, while the
copper-catalyzed variant gave clean reaction without compet-
ing debromination (Table 3, entry 10). These results may
suggest that precoordination of the guanidine is necessary
before oxidative addition of copper into the Ar-Br bond
occurs, a process that is perhaps less important for palladium.
Table 4. Intramolecular Aryl Guanidinylation of Aryl Iodides
with Pd(PPh3)4 (Method A) and CuI (Method B)
Further investigation of the intramolecular aryl guanidi-
nylation with aryl iodides using the optimized conditions was
also pursued (Table 4). Results for the application of these
conditions to various substrates were analogous to those
obtained using aryl bromides, with copper catalysis again
being superior (Table 4).
In summary, we have demonstrated an intramolecular aryl
guanidinylation to form biologically relevant 2-aminobenz-
imidazoles using both palladium and copper catalysts. The
use of inexpensive copper salts such as CuI is shown to be
superior to their palladium counterparts, both in terms of
yields and selectivities. To our knowledge, this is the first
report of the use of copper salts in aryl guanidinylation. We
anticipate that such catalytic cross-coupling with copper will
allow the synthesis of interesting heterocycles in a manner
suitable for combinatorial library generation. Further studies
toward this end will be reported in due course.
Acknowledgment. This work was supported by Cromp-
ton Co., the Natural Sciences and Engineering Research
Council of Canada (NSERC), the Ontario Research and
Development Challenge Fund, and the Environmental Sci-
ence and Technology Alliance of Canada. G.E. thanks the
University of Toronto for fellowship support. R.A.B grate-
fully acknowledges the receipt of a Premier’s Research
Excellence Award. We thank Dr. A. B. Young for mass
spectrometric analysis.
a All yields are reported after column chromatography. b Conversions
determined by H NMR.
1
aryl rather than an NH-alkyl group (Table 3, entry 7).
Significantly, whereas copper-catalyzed reaction of a sub-
strate bearing an NH-benzyl group and an NH-R methyl-
benzyl group results in completely regioselective cyclization
through the less sterically encumbered NH-benzyl group, the
OL027061H
136
Org. Lett., Vol. 5, No. 2, 2003