Per-6-amino-β-cyclodextrin as an efficient supramolecular ligand and host for Cu(I)-catalyzed N-arylation of imidazole with aryl bromides

Article abstract of DOI:10.1021/jo801811w

(Chemical Presented) Per-6-amino-β-cyclodextrin (per-6-ABCD), acting simultaneously as a supramolecular ligand for CuI and host for aryl bromides, catalyzes N-arylation of imidazole with aryl bromides under mild conditions. This simple method proceeds with excellent yield for the coupling of imidazole with various substituted aryl bromides demonstrating good tolerance of other functionalities.

Full text of DOI:10.1021/jo801811w

ally, this moiety has been prepared by nucleophilic aromatic
substitution of an activated aryl halide with heterocycles by
copper-mediated coupling or via Ullmann-type coupling.5
These protocols often require use of stoichiometric amounts
of copper reagents6 which lead to environmental problems
such as waste disposal, harsher conditions (exposure of
substrates to high temperature for extended periods of time),
and low tolerance of other functional groups. In some
instances palladium7 catalysts have been employed, but this
protocol is not general for the N-arylation of imidazoles due
to its toxicity, high cost, and specificity to ligands. This factor
coupled with economic attractiveness of copper has led to a
resurgence of interest in the Ullmann-type coupling reaction.8
Stoichiometric reagents such as aryllead triacetate,9 arylbo-
ronic acids,10 triarylbismuths,11 hypervalent arylsiloxanes,12
diaryl iodonium salts,13 arylstannanes,14 and copper triflate-
benzene15 are used in Cu-mediated N-arylation. However,
many of them have inherent disadvantages as they are toxic,
unstable, and difficult to access. In some cases only one of
the multiple aryl groups is transferred to the heterocycle. This
difficulty can be overcome by employing stable and readily
available aryl halides as the electrophilic coupling partners.
Recently N-arylation has been applied to many heterocycles
and various organic ligands such as amino acids,16 aliphatic
diamines,17 Schiff bases,18 ethylene glycol,19 diethyl salicy-
lamide,20 oxime-phosphine containing ligands,21 aminoarene
Per-6-amino-ꢀ-cyclodextrin as an Efficient
Supramolecular Ligand and Host for
Cu(I)-Catalyzed N-Arylation of Imidazole with
Aryl Bromides
Palaniswamy Suresh and Kasi Pitchumani*
School of Chemistry, Madurai Kamaraj UniVersity,
Madurai-625021, India
pit12399@yahoo.com
ReceiVed June 21, 2008
Per-6-amino-ꢀ-cyclodextrin (per-6-ABCD), acting simulta-
neously as a supramolecular ligand for CuI and host for aryl
bromides, catalyzes N-arylation of imidazole with aryl
bromides under mild conditions. This simple method pro-
ceeds with excellent yield for the coupling of imidazole with
various substituted aryl bromides demonstrating good toler-
ance of other functionalities.
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10.1021/jo801811w CCC: $40.75
Published on Web 10/15/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 9121–9124 9121

thiolate,22 2-aminopyrimidine-4,6-diol,23 hydroxyquinoline,24
(S)-pyrrolidinylmethylimidazoles,25 4,7-dimethoxy-1,10-
phenanthroline,26 2-oxocyclohexane carboxylate,27 fluora-
patite,28 benzotriazole,29 DMEDA,16b pipecolinic acid,30
phosphoramidite,31 N-hydroxyimides,32 copper salts,33 and
D-glucosamine,34 have been employed in Cu-mediated N-
arylation. However, a more practical ligand-promoted Cu-
catalyzed chemistry needs to be developed as many of the
earlier methods are not general for N-arylation. Also only
limited studies are available for the coupling of imidazoles
with aryl bromides and even they are restricted only to less
hindered substrates.26,34,18b
Cyclodextrins are cyclic oligomers which catalyze a wide
range of chemical reactions through the formation of a reversible
host-guest complex.35 Functionalization of CDs improves their
properties and enhances their capability for complexation with
metal ions resulting in manifold increase in their applications
in catalysis.36 Amino-CDs are homogeneous CD derivatives
modified by persubstitution at the primary face with amino
pendant groups and this manifests combined hydrophobic and
electrostatic binding of guest molecules relative to native CDs.
They are employed as biomimetic catalysts in Kemp
TABLE 1. Optimization of Reaction Conditions in
Cu(I)-Catalyzed N-Arylation of Imidazole 3 with Bromobenzene 2aa
conversionb
entry
ligand
none
base
solvent
catalyst
(%)
01
02
03
04
05
06
07
08
09
10
11
12
13
14
15
16
17
18
K2CO3 DMSO
DMSO
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
4
nil
3
per-6-ABCD
R-CD
ꢀ-CD
K2CO3 DMSO
K2CO3 DMSO
2
per-6-ABCD Cs2CO3 DMSO
per-6-ABCD K3PO4 DMSO
per-6-ABCD K2CO3 DMSO
per-6-ABCD K2CO3 DMF
per-6-ABCD K2CO3 ACN
per-6-ABCD K2CO3 MeOH
91
75
99
55
58
52
87
20
65
49
per-6-ABCD K2CO3 DMSO-waterc CuI
per-6-ABCD K2CO3 water
per-6-ABCD K2CO3 DMSO
per-6-ABCD K2CO3 DMSO
per-6-ABCDd K2CO3 DMSO
per-6-ABCDe K2CO3 DMSO
per-6-ABCDf K2CO3 DMSO
per-6-ABCDg K3CO3 DMSO
CuI
CuBr
CuCl
CuI
CuI
CuI
35
51
CuI
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a Reaction conditions: bromobenzene 2a (1.2 mmol), imidazole 3 (1
mmol), CuI (0.2 mmol), ligand (8%), and base (2.1 mmol) in 2 mL of
solvent at 110 °C for 24 h. b Analyzed by GC. c DMSO and water are in
a 1:1 ratio. d 50 °C. e 80 °C. f Time 6 h, g time 12 h.
elimination,37a deprotonation,37b and chiral recognition
processes.37c As amino-functionalized organic moieties17,34 are
widely employed as ligands for N-arylation of imidazoles, it is
proposed to utilize per-6-amino-ꢀ-cyclodextrin (per-6-ABCD)
as a ligand for Cu-catalyzed arylation. The hydrophobic cavity
of cyclodextrin is also expected to act as a binding site for aryl
halide, which will catalyze the reaction. Herein we report our
preliminary investigations on the use of per-6-ABCD as an
efficient ligand in Cu(I)-catalyzed N-arylation of imidazole with
aryl bromides.
Imidazole 3 and bromobenzene 2a are chosen as model
substrates to optimize the reaction conditions such as amount
of ligand, base, solvent, copper source, and reaction temperature.
Without any ligand, treatment of 3 with 2a using K2CO3 as
base and CuI as copper source in DMSO affords very poor
conversion, yielding only 4% of 4a (Table 1, entry 1). In the
absence of base, reaction fails completely (entry 2). When native
R- and ꢀ-cyclodextrins are used as ligands, there is very little
reaction indicating that per-6-ABCD has a major role as an
efficient supramolecular ligand (entries 3 and 4). Bases such as
Cs2CO3, K3PO4, and K2CO3 are found to facilitate this coupling
reaction and among them K2CO3 is the best. Solvents such as
DMF, ACN, MeOH, and DMSO are investigated and it is found
that polar solvents are more favored. With DMF, ACN, and
MeOH, yields are comparatively low. Consequently DMSO is
chosen as the medium of choice for this coupling. Though the
reaction is very slow in water, use of a DMSO-water (1:1 v/v
%) mixture results in affordable (87%) yield indicating that this
(37) (a) McCracken, P. G.; Ferguson, C. G.; Vizitiu, D.; Walkinshaw, C. S.;
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Lincoln, S. F.; Easton, C. J.; May, B. L. J. Chem. Soc., Faraday Trans. 1993,
89, 1035.
9122 J. Org. Chem. Vol. 73, No. 22, 2008

TABLE 2. N-Arylation of Imidazole 3 with Aryl Bromides in the
Presence of CuI and per-6-ABCD
coupling process is fairly insensitive to the presence of water
and no special precautions are required to exclude moisture from
this reaction. Also when per-6-ABCD is used, the coupling is
insensitive to air and hence there is no need to maintain an inert
atmosphere, which is the problem with previous studies.18,32
Readily available copper salts such as CuI, CuBr, and CuCl
afford satisfactory results in this reaction in agreement with the
previous reports23,34 illustrating that copper compounds are
catalytically active and give better conversion.
This arylation is also found to be highly sensitive to reaction
temperature and time. At lower temperatures (50 and 80 °C),
the reaction totally fails and with lower reaction time (6 and
12 h) only low to moderate yield is obtained (entries 15 to 18).
These preliminary results reveal that per-6-ABCD acts as a good
ligand with optimum conditions such as the presence of mild
base (K2CO3) and CuI as the copper source in DMSO solvent
at 100-110 °C for 24 h.
The scope of this coupling reaction is further expanded to
diverse aryl bromides (2b-r) with 3 and the results are listed
in Table 2.
The results indicate clearly that this protocol is general and
is applicable for reactions of a wide variety of electron-rich and
electron-deficient aryl bromides with 3 and the yields are also
good. Substrates possessing electron-rich groups such as p-
bromotoluene, o-bromotoluene, and m-bromoanisole afford
coupling products in good yield, but with long reaction time
(up to 24 h). In contrast, bromoarenes having electron-
withdrawing groups (such as p-COCH3, p-NO2, p- and m-CN,
p-CF3 and p-OCF3 groups) proceed faster to give excellent
yields. It is noteworthy that the present protocol also tolerates
many other functional groups including nitrile and amino groups
as hydrolyzed products are not observed with 2l (entry 12).
Imidazole 3 can be selectively arylated in the presence of a free
amino group (entry 13). And also this reaction is less sensitive
to steric factors and gives good yield as is evident in all ortho-
substituted bromoarenes. However, with increasing steric crowd-
ing, as in 2-bromomesitylene, the reaction fails. Fused ring
compounds such as 1-bromo and 2-bromonaphthalenes react
smoothly with 3 giving excellent yields. Among the aryl halides,
the coupling proceeds very readily with aryl bromides giving
excellent yield of the corresponding N-aryl derivative. Heteroaryl
bromides, namely 2-bromopyridine, 2-bromothiophene, and
5-bromopyrimidine (entries 16, 17, and 18), react smoothly
giving an excellent yield. Control experiments suggest that
among aryl halides, the coupling proceeds readily with aryl
chlorides also (in addition to bromides and iodides), but is inert
with aryl fluorides.
To expand the scope of this protocol further, other nitrogen-
containing heterocycles such as pyrrole, pyrazole, triazole,
indole, benzimidazole, and hindered imidazoles like 2-meth-
ylimidazole are coupled with bromobenzene to give the corre-
sponding N-arylated products in good yield (Table 3). Among
the heterocycles, indole reacts slowly and requires a longer
reaction time. All other N-heterocycles and sterically hindered
2-methylimidazole give excellent yields.
a General reaction conditions: imidazole (1 mmol), ArBr (1.2 mmol),
CuI (0.2 mmol), per-6-ABCD (0.1 mmol), and K2CO3 (2.1 mmol) in
DMSO (2 mL) at 110 °C. b Isolated yield.
hydrophobic interaction leads to intermediate II. Treatment of
imidazole with II in presence of potassium carbonate generates
complex III. Subsequent reductive elimination of III gives
N-arylated product 4 regenerating the active Cu(I) species. The
catalytic role of 1, i.e., the inclusion of bromoarene within the
CD cavity, and reaction taking place inside the cavity is also
evidenced by carrying out control experiments on the same
A plausible three-step mechanism for the copper-catalyzed
N-arylation of 3 (Scheme 1) is proposed in accordance with
previous reports.23,26b,29,38 per-6-ABCD reacts with CuI to
produce a Cu-chelated complex (I) via interaction between
amino groups of per-6-ABCD and CuI. Subsequent oxidative
addition of aryl bromide bound inside the CD cavity via
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J. Org. Chem. Vol. 73, No. 22, 2008 9123

TABLE 3. CuI/per-6-ABCD Catalyzed N-Arylation of Various
Nitrogen Heterocycles
In summary, we have demonstrated that per-6-amino-ꢀ-
cyclodextrin (per-6-ABCD), a natural sugar derivative, acts as
an efficient ligand for the cheapest and commercially viable
CuI as catalyst in N-arylation of imidazole with a wide range
of aryl and heteroaryl bromides providing excellent yields under
milder conditions. per-6-ABCD also functions as an excellent
supramolecular host facilitating inclusion of aryl halide and
imidazole cooperatively. This procedure is not only capable of
coupling hindered substrates, but also tolerates an array of other
functional groups such as nitrile, nitro, and free amines present
in aryl bromide. This methodology avoids an inert atmosphere,
which is a common requisite with earlier works. This protocol
thus may find widespread use for the preparation of N-arylated
products and, despite the limiting use of DMSO as solvent, will
be a great value addition in the pharmaceutical industry.
Experimental Section
General Prodedure for N-Arylation of Imidazole with
Aryl Bromides. A Schlenk tube equipped with a Teflon stopcock
are charged with a magnetic stir bar, K2CO3 (572 mg, 2.1 mmol),
CuI (0.38 mg, 0.20 mmol, 20 mol %), and per-6-amino-ꢀ-
cyclodextrin (100 mg, 0.08 mmol, 8 mol %). DMSO (1 mL) was
added at room temperature. Then a solution of bromobenzene (188
mg, 1.2 mmol) and imidazole (68 mg, 1.0 mmol) in DMSO (1
mL) was added. The tube was sealed and the mixture was allowed
to stir for 24 h at 110 °C. Water (5 mL) was added to the reaction
mixture after completion of the reaction. Then it was extracted with
ethyl acetate (3 × 20 mL) and the combined organic layers were
dried with anhydrous Na2SO4 and concentrated by vacuum. The
residue was purified by column chromatography on silica gel, using
hexane/ethyl acetate (1:3) as eluant, to give an oil of 1-phenylimi-
dazole 4a (164 mg, 98%)
a General reaction conditions: N-heterocycle (1 mmol), ArBr (1.2
mmol), CuI (0.2 mmol), per-6-ABCD (0.1 mmol), and K2CO3 (2.1
mmol) in DMSO (2 mL) at 110 °C. b Isolated yields.
SCHEME 1. Proposed Mechanism for CuI Catalyzed
N-Arylation of Imidazole 3 in Presence of per-6-ABCD 1
1
1-Phenyl-1H-imidazole (4a): H NMR (300 MHz, CDCl3) δ
7.87(s, 1H), 7.51-7.46 (m, 2H), 7.40 -7.34 (m, 3H), 7.29 (br s,
1H), 7.21 (br s, 1H); 13C NMR (75 MHz) δ 137.1, 135.5, 130.1,
129.7, 127.4, 121.3, 118.2. GC-MS m/z 144.0 (M+).
Acknowledgement. Financial assistance from the Department
of Science and Technology (DST), New Delhi, India is
gratefully acknowledged.
Supporting Information Available: Characterization for
products (1H and 13C NMR). This material is available free of
charge via the Internet at http://pubs.acs.org.
JO801811W
reaction in the presence of adamantane (which forms a more
stronger inclusion complex with CD).39 As adamantane com-
petes with aryl bromide to complex with CD, a decrease in
conversion (40%) is noticed.
(39) (a) Gody´nez, L. A.; Schwartz, L.; Criss, C. M.; Kaifer, A. E. J. Phys.
Chem. B 1997, 101, 3376. (b) Liu, J.; Ong, W.; Roman, E.; Lynn, J. M.; Kaifer,
A. E. Langmuir 2000, 16, 3000. (c) Palaniappan, K.; Hackney, S. A.; Liu, J.
Chem. Commun. 2004, 2704.
9124 J. Org. Chem. Vol. 73, No. 22, 2008