Sequential metal-catalyzed N-heteroarylation and C-C cross-coupling reactions: An expedient route to tris(hetero)aryl systems

Article abstract of DOI:10.1002/ejoc.200800018

This paper describes copper-catalyzed N-C heteroarylation of benzimidazole, 1-methylbenzimidazolone, imidazole and pyrrole. The products of these reactions then undergo palladium-catalyzed C-C cross-couplings with aryl or heteroarylboronic acids under Suzuki-Miyaura conditions to provide a rapid entry, from readily-available reagents, into tris(hetero)-aryl scaffolds comprising two or three N-heterocyclic rings. The sequential N-C and C-C couplings can be performed in a one-pot process (two examples are given: >50% overall yields). Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800018

FULL PAPER
DOI: 10.1002/ejoc.200800018
Sequential Metal-Catalyzed N-Heteroarylation and C–C Cross-Coupling
Reactions: An Expedient Route to Tris(hetero)aryl Systems
Jamie S. Siddle,[a] Andrei S. Batsanov,[a] and Martin R. Bryce*[a]
Keywords: N-Heterocycles / Benzimidazole / Benzimidazolone / Imidazole / N-Arylation / Cross-coupling
This paper describes copper-catalyzed N–C heteroarylation
of benzimidazole, 1-methylbenzimidazolone, imidazole and
pyrrole. The products of these reactions then undergo palla-
dium-catalyzed C–C cross-couplings with aryl or heteroaryl-
boronic acids under Suzuki–Miyaura conditions to provide a
rapid entry, from readily-available reagents, into tris(hetero)-
aryl scaffolds comprising two or three N-heterocyclic rings.
The sequential N–C and C–C couplings can be performed in
a one-pot process (two examples are given: Ͼ50% overall
yields).
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
process.[15] The CuOAc-mediated N-arylation of indoles
and carbazole with aryl iodides under base-free and li-
gandless conditions has been reported.[16] New develop-
ments in palladium-[17] and iron-catalysed[18] N-arylations
have also been reported recently.
While many important results have been achieved for N-
arylations, it is notable that much less progress has been
made for N-heteroarylations, i.e. analogous reactions with
heteroaryl halides.[15] The development of this methodology
is, therefore, of considerable interest. Herein we present a
series of heterocyclic N-heteroarylation reactions and ex-
ploit further reaction at an active halide site in the products
via Suzuki–Miyaura cross-coupling reactions leading to the
expedient construction of tris(hetero)aryl scaffolds compris-
ing two or three N-heterocyclic rings.[19]
Introduction
Arylated heterocycles are key structural motifs in a wide
range of pharmaceuticals, agrochemicals, and organic func-
tional materials, hence great effort has been devoted to their
synthesis by a range of metal-catalyzed protocols.[1] Con-
temporary procedures can be readily performed with low
catalyst loadings and good functional-group tolerance.
These include C–heteroaryl bond formation by palladium-
catalyzed Suzuki–Miyaura cross-coupling reactions of aryl-
boronic acids/esters with heteroaryl halides,[2] or by direct
functionalization of heterocyclic C–H bonds with aryl ha-
lides[1d] catalyzed by palladium[3] or copper species.[4] For
heterocyclic N-arylation, which is relevant to the present
work, the classical copper-promoted Ullmann reaction has
been improved by the addition of a variety of ligands, such
as diamines,[5] pipecolinic acid,[6] sterically hindered phos-
phanes,[7] a mixture of 1,10-phenanthroline and dibenz-
ylideneacetone,[8]
4,7-dimethoxy-1,10-phenanthroline,[9]
Results and Discussion
(S)-pyrrolidinylmethylimidazole,[10] N-hydroxyimides[11] or
ninhydrin.[12] A CuCl-catalyzed N-arylation of imidazole
with arylboronic acids has been developed in the absence
of an additional chelating ligand.[13] Combined N(1)- and
C(3)-arylations of 3-iodoindazole using boronic acids and
Cu(OAc)2 have been reported.[14] However, these methods
require additional steps to synthesize the arylboronic acid.
You et al. have very recently shown that imidazoles can be
N-arylated with aryl and heteroaryl halides in the presence
of base and a catalytic amount of CuI: an excess of imid-
azole improved the product yield and it was noted that the
imidazole substrate may also function as a ligand in this
We chose benzimidazole 1 and 1-methylbenzimidazolone
2 as starting reagents for the optimization of our strategy
for two reasons: (i) their derivatives are widespread in struc-
tures of biological and medicinal importance;[20] (ii) their
arylation reactions have been relatively neglected compared
to other NH heterocycles; imidazole is most commonly
used in this context.[3d,8,10,12,15,21] To confirm the versatility
of the procedures, analogous reactions are also reported for
imidazole (3) and pyrrole (4). The general concept of se-
quential N–C and C–C couplings leading to tris(hetero)aryl
systems is depicted for benzimidazole in Scheme 1. The
higher reactivity of iodides compared to bromides was ex-
ploited for selectivity in the reactions of the dihaloarenes in
step 1. Scheme 2 depicts the N–C couplings and the specific
examples are shown in Table 1.
[a] Department of Chemistry, Durham University,
Durham DH1 3LE, UK
Fax: +44-191-384-4737
E-mail: m.r.bryce@durham.ac.uk
In test reactions benzimidazole (1) reacted smoothly with
2-iodopyrimidine (5a) and 2-iodopyrazine (6) under modi-
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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Expedient Route to Tris(hetero)aryl Systems
Scheme 1. Construction of tris(hetero)aryl scaffolds by sequential N–C and C–C couplings.
Table 1. Catalytic N-arylation/heteroarylation (N–C bond forma-
tion)[a]
.
Scheme 2. Synthesis of 10–18. For conditions see Table 1.
fied Ullmann conditions (Cs2CO3, CuI, 1,10-phenan-
throline, DMF, 110 °C)[22] to afford the N-heteroarylated
products 10 and 11 in 50% and 70% isolated yields, respec-
tively (Table 1, Entries 1 and 2). The comparable reaction
of 1 with 2-bromopyrimidine (5b) using the conditions de-
veloped by Cristau, Taillefer, et al.[5d] (Cs2CO3, Cu2O,
Schiff base ligand Chxn-py-al, acetonitrile, reflux) gave 10
in 78% yield. These workers found that the reaction of
imidazole with 4-bromo-1-iodobenzene (1 equiv.) took
place with complete regioselectivity at the iodine site. We
have found that for reactions of the dihalo reagents 7 and
8 with the NH heterocycles 1–4 the optimum conditions to
achieve selective displacement of the iodo substituent[23]
are: 1–4 (1.2 equiv.), 7 or 8 (1.0 equiv.) Cs2CO3 (2.0 equiv.)
CuI (10 mol-%) and 1,10-phenanthroline (10 mol-%) in
DMF at 80 °C (Table 1, Entries 3–6, 8 and 9). Higher reac-
tion temperatures (e.g. 110 °C as used in Entries 1 and 2)
resulted in considerably lower product yields for reactions
of 7 and 8. The reaction of the less activated 4-bromo-1-
iodobenzene (9) with benzimidazolone 2 (Entry 7) required
a higher temperature (100 °C) for efficient formation of 16.
Table 1, Entries 3–9, show that moderate to high isolated
yields were obtained for all the products 12–18, which pos-
sess a bromo substituent suitable for a subsequent C–C
(hetero)arylation reaction. The reactions of 5-bromo-2-
iodopyridine (7) were especially efficient (Entries 3 and 5).
To accomplish step 2 of our strategy (Scheme 1) the com-
pounds 12–18 were treated with the methoxyphenylboronic
acid derivatives 19 and 20, and the pyridylboronic acid de-
rivative 21[24–26] in Pd-catalyzed Suzuki–Miyaura reac-
tions[2] to obtain the tris(hetero)aryl scaffolds 22–31 com-
prising two or three N-heterocyclic rings (Scheme 3). The
alkoxy substituents on the aryl/heteroaryl boronic acids
were chosen to ensure good solubility of the products. The
results are collated in Table 2. Standard conditions using
Pd(PPh3)2Cl2 (ca. 5 mol-%) as catalyst, Na2CO3 (1 ) as
base, in dioxane at 80 °C gave the products 22–26 in high
[a] Reaction conditions, a: 5a, Cs2CO3, CuI, 1,10-phenanthroline,
DMF, 110 °C; b: 5b, Cs2CO3, Cu2O, Schiff base ligand Chxn-py-
al, acetonitrile, reflux; c: Cs2CO3, CuI, 1,10-phenanthroline, DMF,
80 °C; d: Cs2CO3, CuI, 1,10-phenanthroline, DMF, 80Ǟ100 °C.
[b] The quoted yields are for isolated product after purification by
chromatography and/or recrystallization.
Scheme 3. Synthesis of 22–31. For conditions see Table 2.
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J. S. Siddle, A. S. Batsanov, M. R. Bryce
FULL PAPER
Table 2. Suzuki–Miyaura cross-couplings (C–C bond formation).[a] yields (Entries 1–5). To our surprise, applying these condi-
tions to attempted reactions of 14 and 15 with boronic acid
derivative 21 failed to yield any product – unreacted start-
ing materials were recovered in near quantitative yield (En-
tries 6 and 7, conditions a). When the catalyst was changed
to Pd(PPh3)4 (with Na2CO3 as base) or [Pd2(dba)3] (with
K3PO4 as base)[27] product 27 was obtained in 67 and 54%
yields, respectively (Entry 6, conditions b, c). Similarly, con-
ditions b gave 28 in 43% yield. A general trend was that
the Suzuki–Miyaura reactions were less efficient in the
benzimidazolone series, especially Entries 6–8, compared to
benzimidazole, imidazole and pyrrole analogs (Entries 1–4,
9, 10).
Analogous one-pot, two-stage procedures gave com-
pounds 25 and 28 starting from benzimidazole (1) and 1-
methylbenzimidazolone (2) in 67% and 52% overall yields,
respectively.
The molecular structure of 22 obtained by X-ray crystal-
lographic analysis is shown in Figure 1.
Figure 1. X-ray molecular structure of compound 22 (50% thermal
ellipsoids). Dihedral angles [°]: benzimidazole/pyridine 30.7, pyr-
idine/benzene 27.2, benzene/methoxy 10.2.
Conclusions
In summary, we have disclosed a series of reactions which
constitute expedient and powerful methodology for the syn-
thesis of new multi-heteroaryl scaffolds by a combination
of N–C heteroarylation and C–C cross-couplings. Func-
tionalized benzimidazole, benzimidazolone, imidazole and
pyrrole derivatives have thereby been obtained. This proto-
col complements existing strategies which are of great im-
portance in diverse areas of heterocyclic chemistry, espe-
cially the development of new molecular templates for drug
discovery and materials chemistry applications. The practi-
cal benefits include readily-available and inexpensive start-
ing materials, substrate versatility, experimentally straight-
forward procedures and good product yields. The sequen-
tial N–C and C–C couplings can be performed in a one-pot
process in Ͼ50% overall yields.
Experimental Section
General: Details of equipment and techniques used are the same as
those we have reported previously.[28] All synthetic reagents were
[a] Reaction conditions, a: Pd(PPh3)2Cl2, 1,4-dioxane, Na2CO3
used as supplied. Solvents were dried and distilled using standard
(1 ), 80 °C; b: Pd(PPh3)4, 1,4-dioxane, Na2CO3 (1 ), 80–90 °C;
procedures. All reactions were performed under dry argon.
[b]
c: [Pd2(dba)3], 1,4-dioxane, K3PO4 (1.27 ), 100 °C. The quoted
yields are for the isolated product after purification by chromatog-
raphy and/or recrystallization.
General Procedure for the N-Arylation/Heteroarylation Reactions of
N-Heterocycles with Aryl/Heteroaryl Iodides: The halide (4.1 mmol)
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Eur. J. Org. Chem. 2008, 2746–2750

Expedient Route to Tris(hetero)aryl Systems
and 1,10-phenanthroline (0.40 mmol) was added sequentially to a
mixture of the N-heterocycle (4.8 mmol), CuI (0.20 mmol) and
Cs2CO3 (8.0 mmol) in dry degassed DMF (4 mL). The mixture was
stirred and heated under argon at 80 °C until TLC monitoring
showed that the reaction was complete (typically ca. 24 h). The
reaction mixture was cooled to room temperature, diluted with
ethyl acetate (10 mL) and washed through a pad of silica gel with
ethyl acetate (ca. 40 mL) to remove inorganic materials. The eluent
was concentrated in vacuo and the product was purified either by
recrystallization or by chromatography on a silica gel column.
sample prepared by the two-step procedure, as described in the
Supporting Information.
Supporting Information (see also the footnote on the first page of
this article): Experimental methods (p. S2–S9), copies of NMR
spectra (p. S10–S28.
CCDC-665603 contains supplementary crystallographic data
for compound 22. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk./data_request/cif.
1-(5-Bromopyridin-2-yl)-1H-benzimidazole (12): Chromatography
(eluent EtOAc/Et2O, 9:1 v/v) yielded 12 as a white solid in 90%
yield, m.p. 159.6–160.5 °C. H NMR (400 MHz, CDCl3): δ = 8.61
Acknowledgments
1
(d, J = 2.0 Hz, 1 H), 8.51 (s, 1 H), 8.00–7.94 (m, 2 H), 7.86–7.84
(m, 1 H), 7.44 (dd, J = 8.4, 0.4 Hz, 1 H), 7.39–7.32 (m, 2 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 150.7, 148.8, 145.0, 141.7, 141.3,
We thank the Engineering and Physical Sciences Research Council
(EPSRC) for financial support via a DTA award (to J. S. S.).
132.2, 124.7, 123.8, 121.1, 117.9, 115.4, 112.9 ppm. IR (ν
=): ν
˜
˜
max
= 3080, 3051, 1578, 1499, 1476, 1203, 741 cm–1. MS (EI): m/z =
273 (100) [M+, 79Br], 275 (97) [81Br]. C12H8BrN3 (274.1): calcd. C
52.58, H 2.94, N 15.33; found C 52.53, H 2.83, N 15.19.
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Chromatography (eluent EtOAc/dichloromethane, 10:1 v/v) yielded
24 as a white solid in 96% yield, m.p. 106.9–107.7 °C. 1H NMR
(400 MHz, CDCl3): δ = 8.80 (d, J = 2.0 Hz, 1 H), 8.62 (s, 1 H),
8.21 (dd, J = 4.8, 1.6 Hz, 1 H), 8.15 (dd, J = 8.8, 2.8 Hz, 1 H), 8.11
(dd, J = 7.2, 1.2 Hz, 1 H), 7.88 (dd, J = 7.2, 1.6 Hz, 1 H), 7.69 (dd,
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˜
1494, 1457, 1230, 1037, 731 cm–1.
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stirring was continued at 80 °C for 17 h. The reaction was cooled
to room temperature, the solvent removed in vacuo and EtOAc
(100 mL) was added to the residue which was washed with brine
(3ϫ50 mL). The organic layer was separated, dried with MgSO4
and concentrated in vacuo. The product was purified by column
chromatography on silica (eluent DCM/EtOAc, 1:1 v/v) to yield 25
as a white solid (0.425 g, 67%) spectroscopically identical to the
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2749

J. S. Siddle, A. S. Batsanov, M. R. Bryce
FULL PAPER
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Received: January 7, 2008
Published Online: April 11, 2008
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