Copper catalysed amidation of aryl halides through chelation assistance

Article abstract of DOI:10.1039/c4cc09940k

A copper mediated C-N bond formation for the amidation of aryl halides using 8-aminoquinoline has been developed. This strategy provides efficient access to amides bearing two contiguous heterocyclic moieties and does not require the presence of additiona

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Copper catalysed amidation of aryl halides through
chelation assistance
Cite this: DOI: 10.1039/x0xx00000x
a
b
b
a,c*
Subban Kathiravan, Shishir Ghosh, Graeme Hogarth, and Ian A. Nicholls
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
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A copper mediated C-N bond formation for the amidation of substituted amides without any the use of either noble metal catalysts
aryl halides using 8-aminoquinoline has been developed. This or ligands. To the best of our knowledge chelationꢀassisted copper
strategy provides efficient access to amides bearing two catalysed amidation of aryl halides has not been yet reported
contiguous heterocyclic moieties and does not require the (Scheme 1).
presence of additional ligands.
The selective construction of CꢀN bonds continues to be an
important goal in organic synthesis and is extensively utilized in
1
medicinal chemistry and industrial processes. Among the different
types of CꢀN bond forming reactions, the synthesis of N-substituted
amides is of crucial importance due to the prevalence of this
structural motif in pharmaceuticals, agrochemicals and biologically
active natural products as well as in biological and synthetic
2
polymers, i.e. proteins and nylons. Traditionally amides have been
3
prepared by the reaction of amines with carboxylic acid derivatives,
4
5
6
alcohols, or aldehydes, hydroamination of alkynes, and hydration
of nitriles. Further, a number of methodologies for the synthesis of
7
amides and related compounds by the palladiumꢀcatalysed amidation
of arylhalides have been presented in pioneering studies by the
8
research groups of Buchwald and Hartwig. Milstein and coꢀworkers
introduced the dearomatized Ruꢀpincer complex for the direct
9
synthesis of amides from esters and amines. Beller has explored the
transamidation of nonꢀactivated primary carboxamides and ureas
1
0
with amines in the presence of copper catalysts. Fu et. al. described
the photoinduced copper catalysed amidation of secondary alkyl
1
1
halides under mild conditions. Despite notable progress in this
area, the establishment of a general intermolecular process with Scheme 1. Transition metal catalysed amidation reactions
amides remains a challenge. The development of innovative
Initial model reaction studies were conducted using carboxamide 1a,
chelating groups that enable transformations through CꢀN bond
phenyl bromide 2a and 10 mol% of Cu(SO CF ) , and different
3 3 2
formation under mild and simple conditions is highly desirable.
The recent seminal work on the use of 8ꢀaminoquinoline as a
bidentate directing group in the transformation of C−H bonds by
0
bases in toluene at 120 C for 24h in the presence of different ligands
L1-L14) (For detailed optimization studies see supporting
(
12
information). With the best reaction conditions in hand we next
examined the scope of aryl bromides 2a-2o amenable to reaction
with 1a to test the feasibility of preparing a variety of corresponding
carboxamides 3a-3o (Table 2). We established that this method
could be applied to the amidation of an array of unactivated NꢀH
bonds, generating the desired C−N bonds in good yield (Table 2).
Daugulis has led to a number of developments including the report
2
by Kanai et al. of a copper catalysed intramolecular C(sp )ꢀH and
3
13
C(sp )ꢀH amidations by oxidative cyclization. We envisioned that
the copper catalysed reaction of readily available amides derived
from 8ꢀaminoquinoline and various commercial aryl halides would
constitute a new complementary route for the facile synthesis of
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The reactions were successful for both electronꢀrich (3b-3e) and 8ꢀ9). Pivalimide (4j) also afforded the desired regioselective product
electronꢀpoor (3f-3j) arylbromides. Various functionalities, such as 5j in 69% yield (entry 10). In addition 2ꢀphenylbutanamide (4k)
sterically hindered 3,5ꢀdimethyl groups (3d), chloride (3f), fluoride gave the corresponding product 5k in 60% yield (entry 11). A
(
(
3g), and trifluoromethyl (3h) are tolerated. 5ꢀbromoꢀNꢀmethylindole substrate containing the hydrocinnamoyl group was also readily
3k), 2ꢀpyridine (3l), 2ꢀthiophene (3m) bromides are reactive, thus employed, furnishing 5l in 59% yield (entry 12).
showing the compatibility of reaction conditions with heterocycles.
Interestingly, the catalytic reaction proceeded very well with 4ꢀ The value of this method was further emphasised through the
bromo diphenylether (3n), which afforded the amidation product preparation of arylated adamantanyl amides derived from (6a), a
16
(
3n) in 80% yield. Moreover, we were pleased to find that 2ꢀ motif found in number of pharmaceuticals (scheme 2).
bromonaphthalene (2o) could also be used in this reaction with the Table 2. Copper catalysed amidation of aryl halides: Substrate scope
corresponding NꢀH functionalized product (3o) being obtained in with respect to amides
very good yield 86%. Further the structures of 3m and 3o were
1
4
unambiguously confirmed through xꢀray crystallographic analysis.
Table 1. Copper catalysed amidation of aryl halides: Substrate scope
a
with respect to arylbromides
a
Reaction conditions: 1a (1.0 equiv.), 2a-2p (2.0 equiv.), Cu(SO
3
CF
3 2
) (10
0
b
mol%), CS
2
CO
3
(3.0 equiv.) toluene 1 mL, at 120 C, 24h; isolated yield.
The versatility of the copper catalyst was not limited to carboxamide
a, as seen in its catalysis of amidations with challenging
1
carboxamides 4a-4k, highlighting the scope of the reaction as
presented in Table 3 (entry 1ꢀ11). Thus, propionoyl (4a), valeroyl
(
(
(
4b), and octanoyl (4c), 3ꢀmethyl butanoyl (4d) and 2ꢀethyl butanoyl
4e) carboxamides were efficiently arylated with 2ꢀbromopyridine
2l) and furnished the products (5a-5e) in 80, 75, 85, and 68% yields,
respectively (entry 1ꢀ5). Functionalization with cyclopropanyl
moieties was then explored due to the utility of this structural motif
in medicinal chemistry and as scaffolds for other chemical
transformations; here using the arylation of aminoquinoline
cyclopropylamide (4f) with 2ꢀbromopyridine (2l) which resulted in
a
1
5
Reaction conditions : 4aꢀ4m (1.0 equiv.), 2l (2.0 equiv.) Cu(SO
3
CF ) (10
3 2
5
f in moderate yield (60%) (entry 6). Aminoquinoline cyclopentyl
0
b
mol%), CS CO (3.0 equiv.) toluene 1 mL, at 120 C, 24h; isolated yield.
2 3
actamide (4g) was also reacted with 2ꢀbromopyridine (2l) under
standard conditions to afford 5g in 82% yield (entry 7). Cyclopentyl
and cyclohexyl carboxamides (4h & 4i) also proving to be effective
coupling partners and furnishing their corresponding arylated
derivatives 5h and 5i in good yields 80 and 69%, respectively (entry
2
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Scheme 2. Reaction with adamantanyl amides
We also explored the reactivity of more challenging aminoquinoline
vinylamides (8a). These were also found to be reactive and provided
9
a in 63% yield (scheme 3)
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2
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Importantly, the chelating group could be efficiently removed by
treatment with methyl trifluoromethanesulfonate followed by
2
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Scheme 5. Removal of chelating group
Conclusions
In conclusion, we have developed a general and straightforward
chelationꢀassisted, copperꢀmediated amidation of weakly activated
arylbromides with 8ꢀaminoquinoline. This catalytic protocol
facilitates the synthesis of variety of disubstituted amides (e.g.
5
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primary carboxamides in good to excellent yields. Interestingly, this
amidation procedure is user friendly as it does not required external
ligands to promote CꢀN bond formation. More detailed
investigations of the mechanism are currently underway in our
laboratory including exploring the use of alternative chelating
amides. We believe that this novel procedure is and will be of
significant value in the synthesis of substituted peptides and other
bioactive molecules.
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The financial support from Linnaeus University, KK foundation
(Grant 2010ꢀ0223) is gratefully acknowledged. Sofia Essen (Lund
University, Sweden) is thanked for HRMS analysis. We thank the
Commonwealth Scholarship Commission for the award of a
Commonwealth Scholarship to SG.
9
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Notes and references
a
Bioorganic & Biophysical Chemistry Laboratory, Linnaeus University
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Sweden, Fax: (+) 46 0480-446244, E-mail: ian.nicholls@lnu.se
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Crystallographic Data Centre. For compounds 3m and 3o the data have
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Graphical Abstract
Copper catalysed amidation of
aryl halides through chelation
assistance
Subban Kathiravan, Shishir Ghosh, Graeme Hogarth,
*
and Ian A. Nicholls
Using 8ꢀaminoquinolineꢀbased alkyl and aryl carboxamides, the direct Nꢀ
arylation was achieved in good yields in the presence of a copper catalyst
via chelationꢀassisted reaction.
4
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