Design and evolution of copper apatite catalysts for N-arylation of heterocycles with chloro- and fluoroarenes

Article abstract of DOI:10.1021/ja0436594

We report the preparation of recyclable heterogeneous catalysts, copper-exchanged fluorapatite, and copper-exchanged tert-butoxyapatite by incorporating basic species F^-/^tBuO^- in apatite in situ by coprecipitation and subsequent exchange with Cu(II). These basic copper catalysts catalyzed N-arylation of imidazoles and other heterocycles with chloroarenes and electron-poor fluoroarenes in good to excellent yields. Synthesis and characterization of some of the intermediates of the catalytic cycle gave some insight into the mechanism of the very important organic transformation. The necessity of basic sites for the activation of C-Cl and C-F bonds in the N-arylation of heterocycles with haloarenes is well-established. Copyright

Full text of DOI:10.1021/ja0436594

Published on Web 06/22/2005
Design and Evolution of Copper Apatite Catalysts for N-Arylation of
Heterocycles with Chloro- and Fluoroarenes
Boyapati M. Choudary,*,† Chidara Sridhar, Mannepalli L. Kantam, Gopaldasu T. Venkanna, and
Bojja Sreedhar
Inorganic Chemistry DiVision, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received October 19, 2004; E-mail: bmchoudary@yahoo.com
Scheme 1. Preparation of Catalysts 1 and 2
N-Arylheterocycles are common motifs in pharmaceutical re-
search.1 Arylation of heterocyclic nitrogen is a long-standing
problem, which is far from being satisfactorily solved. The
discovery and development of the catalytic path for N-arylation of
heterocycles by Buchwald2 and Taillefer3 with bromo- and
iodoarenes using copper in the presence of basic ligands generated
greater interest in industry. The N-arylation of heterocycles using
chloro- and fluoroarenes is of importance, since this reaction
involving C-Cl and C-F activation contributes to the fundamental
understanding of the reactivity of such very stable bonds. In this
direction, N-arylation of heterocycles with chloroarenes containing
electron-withdrawing groups (EW) by using copper oxide coated
copper nanoparticles and electron-donating groups (ED) by Pd
catalysts in the presence of strong bases are performed.4 Although
C-N and C-C coupling reactions with fluoroarenes (EW) are
realized using Pd(0) catalysts, the scope is severely restricted to
fluoroarenetricarbonylchromium(0) or 2-nitrofluoroarene only.5
We conceived the use of strong basic support to make electron-
rich copper catalyst that activates C-Cl and C-F bonds in
haloarenes for N-arylation of heterocycles.6 We chose weakly
amphoteric apatites as supports, since various kinds of cations and
anions can be readily introduced into their framework due to their
large ion exchange ability, and such exchanged apatites are already
in use in several organic transformations.7
Table 1. N-Arylation of Imidazole with Chloro- and Fluoroarenesa
entry
Ar-X
time (h)
yield (%)b
1
2
3
4
1-chloro-4-nitrobenzene
1-chloro-2-nitrobenzene
4-chlorobenzonitrile
2-chloro-5-(trifluoromethyl)
benzonitrile
1
3
6
3
100 (90) 90c 0d
100 (88)
98 (95)
100 (92)
5
6
4-chlorobenzaldehyde
2-chloropyridine
10
7
88 (82)
96 (92)
100 (90)
96 (88)
72 (60) 85e
65 (55)
62 (52)
95 (82)
92 (80)
100 (85)f
95 (85)g
7
8
9
10
11
12
13
14
15
2-chloropyrimidine
4-chlorobenzophenone
chlorobenzene
4-chlorotoluene
4-chloroanisole
2-fluorobenzonitrile
4-fluorobenzaldehyde
1-fluoro-4-nitrobenzene
3-chloro-4-fluoronitrobenzene
1
6
36
36
36
1
1
0.5
1
In this communication, we report the preparation of recyclable
heterogeneous catalysts, copper-exchanged fluorapatite (1), and
copper-exchanged tert-butoxyapatite (2) by incorporating basic
species F-/tBuO- in apatite in situ by coprecipitation and subsequent
exchange with Cu(II) (Scheme 1) for N-arylation of imidazoles and
other heterocycles with chloroarenes and fluoroarenes (EW), which
gave good to excellent yields for the first time. We also present
the synthesis and characterization of some of the intermediates of
the catalytic cycle8 to understand the mechanistic aspects of the
very important organic transformation, hitherto confined to specula-
tions only. These catalysts were well-characterized by XRD, TPD,
XPS, IR, ICP-MS, and DTA-MS (see the Supporting Information,
SI).
To identify the best system for N-arylation of imidazole with
chlorobenzene, a variety of copper catalysts in conjunction with
different bases were screened, and we found that 1, 2 with K2CO3
(2 equiv) and KOtBu (10 mol %) as additive in DMF at 120 °C
afforded the optimum yield (85%). The decreased order of activity
1 + KOtBu (10 mol %) > 2 + KOtBu (10 mol %) > 1 > 2 is in
accordance to their decreased basicity, while a simple weakly basic
copper hydroxyapatite (CuHAP), Cu(OAc)2, CuI, and Cu powder
are essentially inactive (see SI).
a ArX (1 mmol), imidazole (1.2 mmol), catalyst (100 mg), K2CO3 (2
mmol), DMF (4 mL), 120 °C. b Yields refer to GC yields, and yields in
parentheses refer to isolated yields. c GC yield after fourth recycle. d Yield
without copper. e GC yield obtained by using 10 mol % of KOtBu. f Yield
with CuHAP and CuFAP. g Selective C-F coupling product.
catalyst 1, and the results are described in Table 1. As illustrated
in Table 1, chloroarenes (EW), 2-chloropyridine, and 2-chloropy-
rimidine provide excellent yields in shorter reaction times than
chlorobenzene and chloroarenes (ED) (entries 1-11). Cyano, nitro,
and trifluromethyl groups are well-tolerated (entries 1, 3, and 4).
These N-arylation results of deactivated chloroarenes using K2CO3
as a base are quite impressive over the unreactive system using
nanocopper and Cs2CO3 base4a (see SI). Another significant feature
is that, under similar conditions, the N-arylation of imidazole with
chlorobenzene affords moderate yields, which could be further
improved by the addition of KOtBu (entry 9 and SI). N-Arylation
of heterocycles developed here using the cheaper chloroarenes is
more attractive than the one using the expensive bromo- and
iodoarenes in terms of economic feasibility. The catalyst is recycled
four times with a slight decrease in activity (entry 1). Interestingly,
fluoroarenes composed of several o- or p-EW groups (entries 12-
15) are also coupled with imidazole to afford the corresponding
N-arylated products in excellent yields. Faster reactivity over the
chloroarenes (entries 1, 5, 13, and 14) and selective coupling
involving C-F activation only in chlorofluoroarene (entry 15) are
Our hypothesis was successfully amenable to the N-arylation of
the imidazole with a wide range of chloro- and fluoroarenes using
† Current address: Ogene Systems (I) Pvt. Ltd., #11-6-56, GSR Estates, 1st
Floor, Near IDPL, Moosapet, Hyderabad 500037, India.
9
9948
J. AM. CHEM. SOC. 2005, 127, 9948-9949
10.1021/ja0436594 CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 2. N-Arylation of Various Nitrogen Heterocycles
in normal conditions and Cu(I) in nitrogen atmosphere (see SI).
The FTIR spectrum of the used catalyst 1 obtained in normal
conditions (see SI) shows the disappearance of the P-OH bond,
indicating the regeneration of 1 to initiate another cycle. Although
we are unable to isolate any intermediate complex, the identification
of Cu(I) complex in nitrogen atmosphere presumes copper-assisted
nucleophilic displacement of X- of the arene by N--Het, providing
coupling product via transient 4. In normal conditions, the formed
Cu(I) may be reoxidized to 1. Similarly, in a reaction with the
chloroarene, the deep blue complex 3 obtained from 2 also provides
coupling product. The deep blue complex formed on the treatment
of a simple copper hydroxyapatite with imidazole is inert in the
coupling reaction with the chlorobenzaldehyde. The above results
and the identification of intermediates provide better comprehension
on the mechanism and the necessity of strong basic sites in the
apatite for the transformation of 3 to give the coupling product.
In conclusion, newly designed and developed copper basic
apatites are found to be potential candidates for N-arylation of
heterocycles of both chloroarenes (EW and ED) and fluoroarenes
(EW).
X
)
Cl
X
)
F
entry
Het-NH
time (h)
yield (%)a
time (h)
yield (%)a
1
2
3
4
pyrrole
pyrazole
benzimidazole
piperidine
4
3
12
5
90 (80) 0b
95 (85)
85 (72)
90 (80)
2
1
9
1
95 (85) 0b
90 (80)
85 (75)
95 (85)
a Yields refer to GC yields, and yields in parentheses refer to isolated
yields. b Without Cu, reaction with ArX and ArX(ED).
Scheme 2. Possible Mechanism for the N-Arylation of
Heterocycles
Acknowledgment. Ch.S. and G.T.V. thank the CSIR, India,
for SRF and JRF, respectively.
Supporting Information Available: Full characterization of all
catalysts with detailed experimental procedures. This material is
available free of charge via the Internet at http://pubs.acs.org.
References
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other attributes of this innovative coupling. Such precedence of
higher reactivity of C-F over C-Cl for fluoroarenes (EW) in
Suzuki reaction is recorded.5b In N-arylation of heterocycles with
fluoroarenes (EW), even CuHAP showed good performance (entry
14). On detailed examination, the in situ formed catalyst 1 as
indicated by XPS and FTIR (see SI) is indeed found to be the real
catalyst. However, there was no N-arylation reaction with fluo-
robenzene by catalyst 1. As shown in Table 2, benzimidazole,
pyrrole, pyrazole, and piperidine are also coupled with 1-chloro-
4-nitrobenzene and 1-fluoro-4-nitrobenzene to give the correspond-
ing N-arylated products in very excellent yields.
To understand the mechanism of the N-arylation of imidazole,
a series of experiments were conducted. The reaction of catalyst 1
with imidazole gives a deep blue Cu-imidazole complex (3), which
is considered to be the first step of the catalytic cycle as described
in Scheme 2, since there was no reaction between catalyst 1 and
chloro- or fluorobenzaldehyde. The XPS of N 1s (3) lines appears
at 401.8 and 399.6 eV (see SI), which are assigned to Cu-N and
CdN bonds, respectively.9 The FTIR of 3 indicates P-OH (see
SI), which is in consonance to the identical hydride(enolato)-
ruthenium(II)apatite complex reported earlier.7c Subsequent reaction
of complex 3 with chloro- or fluorobenzaldehyde affords the final
product N-arylimidazole instantly and leaves the 1 [Cu(II)] catalyst
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X-ray Photoelectron Spectroscopy; Perkin-Elmer Corp.: Eden Prairie, MN,
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