4,7-Dimethoxy-1,10-phenanthroline: An excellent ligand for the Cu-catalyzed N-arylation of imidazoles

Article abstract of DOI:10.1021/ol0608505

4,7-Dimethoxy-1,10-phenanthroline (L) was found to be an efficient ligand for the copper-catalyzed N-arylation of imidazole with aryl iodides and bromides under mild conditions. A variety of hindered and functionalized imidazoles and aryl halides were transformed in good to excellent yields.

Full text of DOI:10.1021/ol0608505

ORGANIC
LETTERS
2
006
Vol. 8, No. 13
779-2782
4
,7-Dimethoxy-1,10-phenanthroline: An
2
Excellent Ligand for the Cu-Catalyzed
N-Arylation of Imidazoles
Ryan A. Altman and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
sbuchwal@mit.edu
Received April 7, 2006
ABSTRACT
4,7-Dimethoxy-1,10-phenanthroline (L) was found to be an efficient ligand for the copper-catalyzed N-arylation of imidazole with aryl iodides
and bromides under mild conditions. A variety of hindered and functionalized imidazoles and aryl halides were transformed in good to excellent
yields.
N-Aryl imidazoles are structural motifs found in many
biologically active compounds. Traditionally, this moiety
Stoichiometric reagents that can be employed for the Cu-
mediated N-arylation of imidazoles include (a) aryllead
1
5
6
7
has been prepared by nucleophilic aromatic substitution of
an activated aryl halide and by copper-mediated coupling
of the heterocycle with an aryl iodide. In the former case,
the scope of the reaction is limited to those targets that can
be assembled from aryl halides bearing strongly electron-
withdrawing substituents. In the latter case, the utility of the
classical Ullmann reaction has been limited by the harsh
conditions often required (exposure of substrates to high
temperatures, typically 150-200 °C, for extended periods
triacetates, (b) arylboronic acids, (c) triarylbismuths, (d)
8
9
hypervalent aryl siloxanes, (e) diaryl iodonium salts, and
1
0
(f) arylstannanes. A major drawback of the methods that
employ these reagents is the use of toxic and/or unstable
reagents that can be difficult to access. Furthermore, in some
cases, only one of multiple aryl groups is transferred to the
heterocycle. The use of aryl halides as the electrophilic
coupling partner resolves many of these issues.
We have previously reported that 10 mol % of copper (I)
triflate facilitates the coupling of imidazole with aryl iodides
2
of time using stoichiometric copper). Because of these
shortcomings, newer and milder transition-metal-catalyzed
under moderate conditions (100% 1,10-phenanthroline/10%
approaches have been pursued.3
,4
11
dba/Cs
2
CO
3
/xylenes/110-125 °C/24-48 h). However, the
Despite the recent development of Pd-catalyzed C-N
scope of the process was primarily limited to the coupling
of unhindered imidazoles with unhindered aryl iodides. Aryl
bromides did react, though sluggishly. Other drawbacks of
this method include long reaction times and the use of both
bond-forming reactions, these new methods have yet to
3
become general for the N-arylation of imidazoles. In
contrast, recent modifications to the Ullmann coupling have
allowed this reaction to maintain its longstanding grasp on
the synthesis of N-arylated imidazoles.4
air-sensitive (CuOTf)
1,10-phenanthroline.
2
‚PhH and stoichiometric quantities of
1
0.1021/ol0608505 CCC: $33.50
© 2006 American Chemical Society
Published on Web 06/02/2006

Recently, we have developed effective systems for the Cu-
catalyzed coupling of aryl iodides and bromides with cyclic
hindered substrate (either a 2- or 4-substituted imidazole or
a 2-substituted aryl halide) have been disclosed. Herein, we
describe our recent work, which significantly expands the
substrate scope for the coupling of imidazoles with aryl
halides.
12a,b
12c,d,f
12d,e
12f,g
secondary alkylamines,
amides,
indoles,
pyrroles,
12g
pyrazoles, indazoles, and triazoles. Despite these protocols
that could be carried out under mild conditions for the
N-arylation of a number of nitrogen heterocycles through
the use of N,N′-dimethylethylenediamine-based ligands, little
progress in our own work had been made for the coupling
Our initial investigations of the coupling of 2-iodotoluene
with imidazole demonstrated that 4,7-dimethoxy-1,10-
phenanthroline (L) in combination with (CuOTf)
2
‚PhH and
1
2g
of imidazoles.
Cs CO in CH CN provided an improved catalyst system
2
3
3
for this transformation. As tetraethylammonium carbonate
(TEAC) had been recently shown to increase reaction rates
in the Cu-catalyzed N-arylation of imidazoles and benzimid-
Subsequent reports by other groups have disclosed the use
13a
13b,c
of salicylaldoxime derivatives, amino acid derivatives,
DMEDA,1 4,7-dichloro-1,10-phenanthroline, and 8-hy-
3d
13e
1
3f
1
3f
13g
azoles, we attempted to employ this base in our system.
However, yields of N-o-tolyl imidazole were low due to
N-alkylation of the imidazole. This problem could be
alleviated while maintaining increased reaction rates by using
droxyquinoline, aminoarenethiol, and oxime-phosphine
oxides
1
3h
as ligands in the Cu-catalyzed N-arylation of
imidazoles with aryl halides. However, very few examples
of the coupling of imidazoles with aryl bromides or of a
1
4
poly(ethylene glycol) (PEG) as a solid-liquid phase-
1
5
transfer catalyst with Cs
PEG as an additive, we were able to use a wider variety of
inexpensive and stable copper precursors (e.g., Cu O, CuI)
and polar aprotic solvents (e.g., CH CN, EtCN, n-PrCN,
2 3
CO as base. Furthermore, with
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2
3
DMF, DMSO, NMP) to effect the desired transformation.
Using the catalyst system based on L, we first explored
the scope of the reaction with m- and p-substituted aryl
halides (Table 1). We found that we were able to arylate
imidazole with iodobenzene in excellent yields in 3 h with
5
% Cu at 110 °C in NMP and in 48 h with 0.05% Cu in
n-PrCN (entry 1). To the best of our knowledge, no Cu-
based system for C-N bond formation has previously been
reported to achieve 2000 turnovers. The reactions of aryl
bromides possessing ester and nitrile groups were inefficient
under the standard conditions because of the partial hydroly-
sis of the ester to benzoic acid and of the nitrile to amide.
However, by using lower reaction temperatures (80-90 °C)
with aryl iodide substrates, excellent yields of the ester- and
nitrile-bearing N-arylated products could be obtained (entries
2
004, 47, 720. (i) Roppe, J.; Smith, N. D.; Huang, D.; Tehrani, L.; Wang,
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C.; Marchais-Oberwinkler, S.; Hartmann, R. W. J. Med. Chem. 2005, 48,
632.
(
6
(
(
2) Lindley, J. Tetrahedron 1984, 40, 1433.
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2
and 4). We were able to exploit the intrinsic reactivity
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nd ed.; de Meijere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004;
2
2,4
tions (I > Br . Cl > F), to couple aryl iodides selectively
pp 699-760.
in the presence of substrates containing aryl bromides,
chlorides, and fluorides (entries 7, 10, and 15). Electron-
rich, -neutral, and -deficient aryl iodides all provide products
(
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2
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6
(
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(
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(
9) Kang, S. K.; Lee, S. H.; Lee, D. Synlett 2000, 1022.
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(
1
(
5
A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 7421. (d)
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2
(15) Crown-6 has been used to accelerate the coupling of diarylamines
with aryl iodides using Cu (stoichiometric)/K2CO3/o-dichlorobenzene/
reflux: Gauthier, S.; Fr e´ chet, J. M. J. Synthesis 1987, 383.
5
578.
2780
Org. Lett., Vol. 8, No. 13, 2006

Table 1. Cu-Catalyzed Coupling of Unhindered Aryl Halides
with Imidazolea
Table 2. Cu-Catalyzed Coupling of Hindered Imidazole-Aryl
Halide Combinationsa
a
General reaction conditions: 1.2 mmol of imidazole, 1.0 mmol of ArX,
1
.4 mmol of Cs2CO3, 200 mg of PEG, 0.25-1.0 mL of butyronitrile under
b
c
d
Ar or N2 atmosphere at 110 °C. 3 h. NMP used as solvent. MeCN used
e
f
g
as solvent. 80 °C. 90 °C. 100 mg flame-activated 3 Å molecular sieves.
h
6
:1 Ratio of iodo-/bromo-substituted arenes.
in good to excellent yields. Imidazole can be selectively
arylated in the presence of a free -OH or -NH group
entries 5, 6, and 12). This is particularly interesting as 1,-
a
General reaction conditions: 1.2 mmol of imidazole, 1.0 mmol of ArX,
2
1
.4 mmol of Cs2CO3, 200 mg of PEG, 0.25-1.0 mL of butyronitrile under
(
Ar or N2 atmosphere at 110 °C. No PEG. c 120 °C. d NMP used as solvent.
b
10-phenanthroline derivatives have also been reported as
ligands in the Cu-catalyzed syntheses of aryl ethers and
arylamines from aryl halides.16
imidazoles could be coupled with aryl iodides and bromides
in good to excellent yields (entries 10, 15-17). This system
Because the Cu-catalyzed coupling imidazoles with aryl
halides employing hindered substrates are rare, we decided
to examine the expansion of the scope of this coupling further
by utilizing our Cu/L-based system in reactions of hindered
imidazoles and with hindered aryl halides (Table 2). We were
pleased to discover that 2-methyl- and 2-phenyl-substituted
17
could also be successfully applied to imidazole N-arylation
with o-substituted aryl halides. In this way, good yields of
N-aryl imidazoles were obtained using 2-alkyl and 2-phenyl
18
iodobenzene (entries 11-13, 18). The coupling of 1-io-
(
17) The coupling of 2-methylimidazole with 4-iodoanisole proceeds to
(
16) (a) Gujadhur, R. K.; Bates, C. G.; Venkataraman, D. Org. Lett. 2001,
, 4315. (b) Wolter, M.; Nordmann, G.; Job, G. E.; Buchwald, S. L. Org.
Lett. 2002, 4, 973. (c) Nordmann, G.; Buchwald, S. L. J. Am. Chem. Soc.
003, 125, 4978.
65% conversion in 48 h (10% (CuOTf)2‚PhH/10% dba/100% 1,10-
phenanthroline/xylenes/125 °C/48 h).11 The coupling of 2-methylimidazole
with 5-bromo-m-xylene (10% CuI, 10% 8-hydroxyquinoline/TEAC/10:1
DMF/H2O/ 130 °C/ 16 h) yields 64% of N-aryl imidazole.1
3
3f
2
Org. Lett., Vol. 8, No. 13, 2006
2781

donaphthalene could also be accomplished using this im-
proved catalyst system (entry 14).
Acknowledgment. We would like to thank the National
Institutes of Health (GM58160) for financial support of
this project. We are grateful to Merck, Amgen, and Boe-
hringer-Ingelheim for additional support. We also thank
Dr. Alex Shafir for providing L. We are indebted to
Dr. Catharine Larsen for aid in the preparation of this
manuscript. The Varian NMR instruments used for this
publication were supported by the NSF (CHE 9808061 and
DBI 9729592).
In conclusion, we have described a new electron-rich 1,-
10-phenanthroline ligand for the Cu-catalyzed N-arylation
of imidazoles with aryl iodides and bromides. This system
not only is capable of coupling hindered substrate combina-
tions but also operates under conditions mild enough to
tolerate a wide array of functional groups. A detailed
comparison of ligands commonly used for Cu-catalyzed
imidazole arylation will subsequently be reported as part of
a full paper.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new and known
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(
18) The coupling of 1-bromo-2,4-dimethoxy-benzene with imidazole
13c
gives 62% yield (10% CuI/40% L-proline/K2CO3/DMSO/110 °C/40 h).
The coupling of imidazole with 2-bromotoluene (10% CuI, 10% 8-hydroxy
quinoline/TEAC/10:1 DMF/H2O/ 130 °C/16 h) yields 46% of N-o-tolyl
13f
imidazole. The coupling of 2-iodotoluene with imidazole gives 92% yield
1
3a
(5% Cu2O/20% Salox/Cs2CO3/CH3CN/82 °C/36 h).
OL0608505
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Org. Lett., Vol. 8, No. 13, 2006