A domino copper-catalyzed C-N and C-O cross-coupling for the conversion of primary amides into benzoxazoles

Article abstract of DOI:10.1002/adsc.200404182

Benzoxazoles can be efficiently prepared in a single step and in good yield from primary amides and o-dihalobenzenes using Cu catalysis. Starting from substituted o-bromochlorobenzenes this unusual domino reaction allows the regioselective formation of benzoxazoles.

Full text of DOI:10.1002/adsc.200404182

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A Domino Copper-Catalyzed C N and C O Cross-Coupling for
the Conversion of Primary Amides into Benzoxazoles
Gereon Altenhoff, Frank Glorius*
Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany
Fax: (þ49)-208-306-2994, e-mail: glorius@mpi-muelheim.mpg.de
Received: Received: June 16, 2004; Accepted: September 27, 2004
Supporting Information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Benzoxazoles can be efficiently prepared
in a single step and in good yield from primary
amides and o-dihalobenzenes using Cu catalysis.
Starting from substituted o-bromochlorobenzenes
this unusual domino reaction allows the regioselec-
tive formation of benzoxazoles.
try could potentially fill this gap. Our ultimate goal was
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the formation of benzoxazoles by the domino C N and
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C O bond formation under the same reaction condi-
tions (1þ2!4).
The starting point of our investigation was the cycliza-
tion of 2-bromobenzene amide 3a (Y¼Br, R¼Me,
R’¼H) to the corresponding benzoxazole 4a.[12] Despite
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Keywords: benzoxazoles; C N and C O cross-cou-
pling; copper; cyclization; domino reactions; hetero-
cycles
many Pd catalysts being known to catalyze C N and
C O bond formations,[13] all palladium catalysts tested
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failed to produce the desired product.[14] Since the pio-
neering work of Ullman and Goldberg on Cu-catalyzed
cross-coupling reactions, many efficient protocols for
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otherwise difficult C N and C O bond formations
have been developed.[15] Fortunately, Cu catalysis under
Benzoxazoles are an important subunit of many com- conditions developed by Buchwald for the amidation of
pounds from different areas of chemistry, like natural aryl halides[16] resulted in the formation of significant
products,[1] biologically active compounds,[2] fluorescent amounts of 4a, although the conversion was not com-
probes[3] or heat-resistant polymers.[4] However, where- plete. Screening of different conditions led to the identi-
as many different strategies for the synthesis of related fication of an optimal protocol (5 mol % CuI, 10 mol %
oxazoles exist, the 2-substituted benzoxazole ring sys- dmeda, K2CO3, toluene, 1108C) for the complete con-
tem is mostly built up by classical approaches as shown version of 3a, resulting in the formation of 4a in 81%
in Scheme 1.[5] In these classical syntheses of benzoxa- yield (Scheme 3). The use of K3PO4 instead of K2CO3
zoles, 2-aminophenols are coupled with aldehydes un-
der oxidative conditions[6] or with carboxylic acid deriv-
atives,[7] either sequentially or in a one-step process.[5] In
many cases rather harsh reaction conditions (oxidative,
acidic or high temperature) are needed for these trans-
formations. In addition, these approaches are limited
by the availability of the properly substituted o-amino-
phenols. Different strategies for the synthesis of the ben-
zoxazole ring system should significantly increase the at-
tractivity of this important entity. Herein, we report an
efficient Cu-catalyzed formation of benzoxazoles from
o-dihaloaromatic compounds and primary amides in a
single step (Scheme 1).
Scheme 1. Retrosynthetic analysis of benzoxazole formation.
The cyclization of o-halobenzeneamides 3 to benzox-
azoles 4 has been reported several times,[8,9] including
two copper-mediated transformations (Scheme 2).[10]
However, these methods were hampered by the use of
stoichiometric amounts of catalyst, harsh reaction con-
ditions, low yields or limited substrate scope. Because
of our interest and experience in Pd- and Cu-catalyzed
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Scheme 2. Sequential C N and C O couplings in the forma-
coupling reactions[11] we felt that cross-coupling chemis- tion of benzoxazoles (X, Y¼halides).
Adv. Synth. Catal. 2004, 346, 1661–1664
DOI: 10.1002/adsc.200404182
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Gereon Altenhoff, Frank Glorius
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Table 1. Cu-catalyzed formation of 2-phenyl benzoxazoles.[a]
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Scheme 3. Cu-catalyzed C O bond formation of 2-bromo-
benzene amides 3; dmeda¼N,N’-dimethylethylenediamine.
Entry
o-Dihalo
substrate
Product
Isolated
yield [%]
1
4c
4c
4d
4c
4c
4c
4e
4c
4e
4f
90
95
88
65
89
0
2[b]
3
4
5[c]
6
Figure 1. Amide substrates 2 that do not result in benzoxa-
zole formation.
as a base resulted in comparable results. Acetamides 3b
and 3c were also cyclized in good yields.
7
0
Encouraged by these results we decided to investigate
the one-step synthesis of benzoxazoles 4 from o-dihalo-
benzene derivatives 1 and primary amides 2 (Scheme 2).
The amidation of halobenzenes is a well known reaction
and several protocols for this transformation have been
developed in recent years.[18] We were pleased to find
that under Cu catalysis, benzoxazoles were formed
from primary amides and o-dihalobenzene derivatives.
An extensive screening of the reaction conditions was
performed for the reaction of 1,2-dibromobenzene
with benzamide.[19] Under optimized conditions
(5 mol % CuI, 10 mol % dmeda, 3 equivs. K2CO3, tol-
uene, 1108C) the desired benzoxazole was smoothly
formed and isolated in 90% yield (Table 1, entry 1).
This reaction can also be run on a 20 mmol scale without
any problems (entry 2). Even a sensitive acetal moiety is
well tolerated under the reaction conditions (entry 3).
Furthermore, the reaction of benzamide with several
other o-dihaloaromatic substrates was investigated.
Whereas standard conditions result in incomplete con-
version of 1,2-diiodobenzene, the use of more catalyst
8[c]
9
95
77
75
10
11
12
4g
4h
59
72
[a]
General conditions: o-dihaloaromatic substrate (1 mmol),
amide (1.1 mmol), CuI (5 mol %), N,N’-dimethylethylene-
diamine (10 mol %), K2CO3 (3 mmol), toluene (3 mL),
1108C, 24h.
[b]
[c]
20 mmol scale.
CuI (10 mol %), N,N’-dimethylethylenediamine (20 mol %).
(10 mol % CuI and 20 mol % dmeda) results in a high served. These high levels of regioselectivity nicely dem-
yield (entries 4and 5). Even though the Cu-catalyzed
onstrate the utility of this method by expanding the
amidation of aryl chlorides has been reported,[16] no ami- scope of benzoxazole synthesis. From the outcome of
dation or benzoxazole formation was observed with 1,2- these reactions of 1-bromo-2-chlorobenzenes it is obvi-
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dichlorobenzene under our standard conditions (en- ous that the amidation occurs selectively at the C Br po-
try 6). Interestingly, whereas 1,2-dichlorobenzene and sition followed by the subsequent cyclization and C O
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2,3-dichloropyridine result in no product formation (en- bond formation with the C Cl moiety (Scheme 2, X¼
tries 6 and 7), 1-bromo-2-chlorobenzene and 2-chloro- Br, Y¼Cl). Furthermore, whereas iodides or bromides
3-bromopyridine smoothly react with benzamide to are required as coupling partners for the amidation
yield 4c and 4e (entries 8 and 9). Moreover, differently step (entries 6 and 7), chlorides are sufficiently reactive
substituted benzoxazoles can regioselectively be formed for the final cyclization step (entries 8–12).
from the corresponding 1-bromo-2-chlorobenzenes (en-
Some primary amides did not react with 1,2-dibromo-
tries 10–12).[20] The other regioisomers were not ob- benzene to give the desired benzoxazoles (Figure 1).
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Adv. Synth. Catal. 2004, 346, 1661–1664

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Domino Copper-Catalyzed C N and C O Cross-Coupling
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Table 2. Cu-catalyzed formation of differently 2-substituted
In conclusion, we have developed an efficient Cu-cat-
alyzed method for the single-step synthesis of benzoxa-
zoles from readily available primary amides and o-diha-
lobenzene derivatives. To the best of our knowledge this
is the first benzoxazole synthesis of this type.[21] While
some limitations were found the scope of this transfor-
mation seems to be rather broad. It is hoped that this
non-classical synthetic approach will increase the popu-
larity of the versatile benzoxazole moiety in all areas of
chemistry.
benzoxazoles.[a]
Entry Amide
substrate
Product
Isolated
yield [%]
1
2
3
4
4i
86
67
72
78
Experimental Section
4j
4k
4l
Representative Procedure for the Synthesis of
Benzoxazoles (Tables 1 and 2)
1,2-Dibromobenzene (120 mL, 1.0 mmol), benzamide (133 mg,
1.1 mmol), K2CO3 (414 mg, 3.0 mmol) and CuI (10 mg,
0.05 mmol) were weighed into a vial under air. The vial was
evacuated and filled with argon, followed by the addition of
N,N’-dimethylethylenediamine (11 mL, 0.1 mmol) and toluene
(3 mL). The vial was closed and the reaction mixture stirred at
1108C for 24h. After cooling to room temperature the reaction
mixture was poured into 25% aqueous NH4OH, extracted with
EtOAc, dried over Na2SO4, filtered and concentrated. Chro-
matography over silica gel (EtOAc/hexane¼1/10) yielded 4c
as a white powder; yield: 176 mg (90%).
5
6
4m 77
4b
4n
4o
92
68
68
7[b]
8[b]
Acknowledgements
[a]
General conditions: o-dihaloaromatic substrate (1 mmol),
amide (1.1 mmol), CuI (5 mol %), N,N’-dimethylethylene-
diamine (10 mol %), K2CO3 (3 mmol), toluene (3 mL),
1108C, 24h.
CuI (10 mol %), N,N’-dimethylethylenediamine (20 mol %),
K2CO3 (4.3 mmol).
We thank Prof. A. Fürstner for generous support, as well as the
Bundesministerium für Bildung und Forschung and the Fonds
der Chemischen Industrie (Liebig scholarship to F. G.) for fi-
nancial support. We also thank Dr. R. Mynott for in-depth
NMR analyses and M. Rusek for experimental support.
[b]
However, the broad scope of this synthetic method was
showcased by the successful variation of the primary
amide coupling partner (Table 2). Several aromatic
and aliphatic amides are good substrates, resulting in
product formation in yields ranging from 67 to 92%.
Even an aniline derivative is tolerated under the reac-
tion conditions (entry 2). It is important to note that
small variations can have a profound effect. For exam-
ple, while 4-aminobenzamide is a good substrate (en-
try 2), no reaction is seen with 2-aminobenzamide. Fur-
thermore, whereas 3-pyridylamide (nicotinic acid
amide) leads to the formation of the desired product
(entry 4), the regioisomeric 2-pyridylamide does not.
In some cases, astonishing volatility of the product can
complicate the efficient purification and may result in
a loss in yield (entries 7 and 8). These results demon-
strate that the o-dihalobenzene derivative as well as
the primary amide can be varied over a wide range al-
lowing the formation of numerous differently substitut-
ed benzoxazoles.
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COMMUNICATIONS
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CuOTf, Cu(CN)4PF6; ligands: 1,2-diaminocyclohexane,
N,N’-dimethylethylenediamine, phenanthroline, proline.
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