Copper-catalyzed C-N bond formation with N-heterocycles and aryl halides

Article abstract of DOI:10.1055/s-0031-1290827

The microwave-assisted, cuprous oxide catalyzed coupling of aryl bromides and iodides with imidazole, benzimidazole, pyrazole, or triazole was found to give a wide range of N-aryl heteroaromatic products in good to high yields. Aryl dibromides undergo sel

Full text of DOI:10.1055/s-0031-1290827

1240▌
LETTER
lCettoerpper-Catalyzed C–N Bond Formation with N-Heterocycles and Aryl
Halides
Heterocycle Cross-Coupling
Mikki G. Boswell, Fanny G. Yeung, Christian Wolf*
Department of Chemistry, Georgetown University, Washington, DC 20057, USA
Fax +1(202)6876209; E-mail: cw27@georgetown.edu
Received: 04.01.2012; Accepted after revision: 07.03.2012
this reaction furnishes a wide range of aniline and anilide
Abstract: The microwave-assisted, cuprous oxide catalyzed cou-
pling of aryl bromides and iodides with imidazole, benzimidazole,
pyrazole, or triazole was found to give a wide range of N-aryl het-
1
1
analogues from aryl iodides, bromides, and chlorides.
Since then, we have found that Cu O also catalyzes the C–
2
eroaromatic products in good to high yields. Aryl dibromides un- N bond formation of aryl halides with imidazole, benz-
dergo selective monosubstitution even in the presence of large imidazole, pyrazole, and triazole. Interestingly, aryl di-
excess of N-heterocyclic nucleophiles which leaves the second aryl
bromide functionality intact for further derivatization.
bromides show remarkable selectivity, and we have been
able to develop a protocol that gives monosubstitution
Key words: copper, cross-coupling, N-heterocycles, aryl halides, products in high yields. We now wish to present the gen-
microwave
eral substrate scope of this reaction and the possibility of
discrete aryl halide transformation.
During the optimization of typical reaction parameters
The transition-metal-catalyzed cross-coupling of aryl ha-
(
temperature, base, catalyst loading, etc.) for the coupling
lides with amines, amides, and N-heterocyclic nucleo-
philes has become a powerful strategy for the synthesis of
pharmaceuticals, natural products, and other important
of 1,3- or 1,4-dibromobenzene with either imidazole or
pyrazole, we found that heating of a solution of the aryl di-
halide and two equivalents of the N-heterocycle in the
1
compounds. To date, many efficient palladium and cop-
presence of 10 mol% of Cu O and two equivalents of so-
2
per complexes have been introduced to carbon–nitrogen
dium tert-butoxide in NMP at 100 °C in the microwave
oven gives the monoamination products 1–3 in high yields
within 15 hours (Table 1, entries 1–3). The second aryl
bromide bond proved significantly less reactive and only
small amounts of the corresponding disubstituted prod-
ucts were obtained even when the reaction mixture was
charged with up to eight equivalents of the heterocyclic
2
,3
bond formation with ammonia, amines, and anilines.
Similarly, palladium-catalyzed halide replacement with
amides, ureas, and other nitrogen-containing reagents has
4
5
7
provided invaluable access to anilides, imidazolones,
oxazolidinones,6 quinolinones, and naphthyridinones,
and many examples of copper variants are known. Re-
cently, the cross-coupling of aryl halides with N-hetero-
cyclic nucleophiles has received increasing attention
8
12
nucleophile. The second bromide was also not replaced
when 2 or 3 were isolated and then employed in the same
procedure or when N,N-diethyl-3-bromoaniline was used.
By contrast, attempts to produce the monosubstitution
product of 1,2-diiodobenzene were not successful even
when pyrazole was used in equimolar amounts at lower
temperatures. The lack of selectivity in this case can prob-
ably be attributed to the inherently high reactivity of aryl
iodides. Accordingly, 1,2-di(N-pyrazolyl)benzene (4) was
obtained in 96% yield using our general reaction proce-
dure (Table 1, entry 4). We generally observed that a re-
duction of the catalyst loading and of the reaction
temperature as well as the replacement of sodium tert-but-
(
Scheme 1).9
X
Z
H
N
Y
Y
Cu catalyst
base
N
R +
Z
R
X = Br, I
Y, Z = CH or N
Scheme 1 Copper-catalyzed C–N bond formation with N-hetero-
cycles
The use of copper catalysts appears to be particularly at- oxide with weak bases such as tertiary amines and cesium
tractive for large-scale industrial applications because of carbonate resulted in decreased conversion. The same
the relatively low cost and toxicity in comparison to pal- trend was obtained when the reactions were carried out
ladium complexes. We previously reported the cuprous with conventional heating. Apparently, the cuprous oxide
oxide catalyzed amination of aryl halides with primary catalyzed cross-coupling of aqueous ammonia, amines,
1
0
and secondary amines, amides, and ammonia. Using in- and anilines with aryl halides occurs under milder condi-
expensive Cu O as catalyst, two equivalents of the amine tions with lower catalyst loading and can also be extended
2
or amide and N-methylpyrrolidinone (NMP) as solvent, to aryl chlorides while the variant with N-heterocycles re-
quires microwave heating and slightly higher tempera-
1
0
tures to give the coupling products in comparable yields.
SYNLETT 2012, 23, 1240–1244
Advanced online publication: 26.04.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
We then tested the microwave-assisted coupling of imid-
azole, benzimidazole, pyrazole, and triazole with several
DOI: 10.1055/s-0031-1290827; Art ID: ST-2012-S0006-L
Georg Thieme Verlag Stuttgart · New York
©

LETTER
Heterocycle Cross-Coupling
1241
aryl halides. The corresponding N-aryl heterocycles 5–11 corresponding N-aryl imidazoles 6 and 7 in 83% and 86%
were produced in good to high yields, in particular when yield, respectively. Importantly, this reaction also affords
1
3
pyrazole or imidazole were used (Table 1, entries 5–11).
excellent results with sterically hindered aryl halides, and
In light of the deactivating effect of the imidazole or pyr- 12–15 were obtained in 71–92% yield (Table 1, entries
azole moiety in 1–3 or the amino group in N,N-diethyl-3- 12–16). For example, the coupling of 1-iodo-2-isopropyl-
bromoaniline on the aryl bromide bond discussed above, benzene or 1-bromo-2-isopropylbenzene with pyrazole
we were pleased to find that other electron-rich substrates afforded 12 in 91–92% yield while less than 10% conver-
such as 2-bromoanisole and 4-bromothioanisole gave the sion was observed with triazole and benzimidazole.
Table 1 Microwave-Assisted Copper-Catalyzed C–N Bond Formationa
X
Z
H
Cu2O (10 mol%)
NaOt-Bu (2 equiv)
N
Y
Y
N
R +
Z
NMP, MW (100–120 °C)
15 h
R
X = Br, I
Y, Z = CH or N
Yield (%)b
Entry
Substrate
Heterocycle
Product
N
N
Br
H
N
91c
1
2
N
Br
Br
1
N
Br
N
H
N
84c
N
Br
Br
2
H
N
N
Br
N
94c
96
3
4
Br
Br
N
3
N
N
I
N
N
H
N
I
N
4
N
N
I
H
N
5
6
75
83
N
5
N
Br
N
H
N
OMe
OMe
N
6
©
Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1240–1244

1242
M. G. Boswell et al.
LETTER
a
Table 1 Microwave-Assisted Copper-Catalyzed C–N Bond Formation (continued)
X
Z
H
Cu2O (10 mol%)
NaOt-Bu (2 equiv)
N
Y
Y
N
R +
Z
NMP, MW (100–120 °C)
15 h
R
X = Br, I
Y, Z = CH or N
Yield (%)b
Entry
Substrate
Heterocycle
Product
H
N
N
MeS
N
7
MeS
Br
86
N
7
H
N
N
8
9
Br
N
N
98
95
70
8
9
H
N
N
N
N
Br
Br
N
H
N
N
1
0
1
N
N
N
1
1
1
1
0
1
2
2
N
N
N
Br
N
N
N
H
N
1
N
73
92
91
I
H
N
1
1
1
1
2
3
4
5
N
Br
H
N
N
N
Br
N
H
N
Ph
Ph
81
71
N
1
1
3
4
N
Br
N
H
N
Ph
Ph
N
Synlett 2012, 23, 1240–1244
© Georg Thieme Verlag Stuttgart · New York

LETTER
Heterocycle Cross-Coupling
1243
a
Table 1 Microwave-Assisted Copper-Catalyzed C–N Bond Formation (continued)
X
Z
H
Cu2O (10 mol%)
NaOt-Bu (2 equiv)
N
Y
Y
N
R +
Z
NMP, MW (100–120 °C)
15 h
R
X = Br, I
Y, Z = CH or N
Yield (%)b
Entry
Substrate
Heterocycle
Product
N
Br
N
H
N
16
78
N
1
5
a
The reaction was performed with aryl halide (2.0 mmol), Cu O (10 mol%), N-heterocycle (4.0 mmol), NaOt-Bu (4.0 mmol) in NMP (1.5 mL),
2
microwave irradiation (150 W), 120 °C, 15 h.
b
Isolated yields based on the aryl halide.
c
1
00 °C.
In summary, we have developed a synthetically useful 7.36 (d, J = 8.1 Hz, 1 H), 7.58 (dd, J = 1.2, 8.1 Hz, 1 H), 7.70 (d,
J = 1.3 Hz, 1 H), 7.86 (d, J = 2.5 Hz, 1 H), 7.88 (dd, J = 1.9, 1.9 Hz,
procedure for the microwave-assisted, cuprous oxide cat-
1
3
1
1
H). C NMR: δ = 108.1, 117.4, 122.2, 123.1, 126.7, 129.2, 130.7,
41.1, 141.5.
alyzed coupling of aryl bromides and iodides with several
N-heterocycles. Good to high yields were obtained with
electron-rich and sterically hindered aryl halides and ex-
cess of imidazole, benzimidazole, pyrazole, and triazole. Acknowledgment
The selective monosubstitution of aryl dibromides is par-
Funding from the National Science Foundation (CHE-0910604) is
ticularly interesting because it leaves the second aryl bro-
mide functionality intact for further derivatization, for
example via Suzuki, Stille, or Sonogashira cross-cou-
plings. The use of this cross-coupling method for the syn-
thesis of axially chiral receptors with chiroptical sensing
applications is currently investigated in our laboratory. It
gratefully acknowledged.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.onmornifIatngonimSorfniturItagponiSutpor
is noteworthy that C–N bond formation with N-heterocy- References and Notes
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©
Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1240–1244

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M. G. Boswell et al.
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