Copper-Catalyzed Carbonylative Coupling of Cycloalkanes and Amides

Article abstract of DOI:10.1002/anie.201603235

Carbonylation reactions are a most powerful method for the synthesis of carbonyl-containing compounds. However, most known carbonylation procedures still require noble-metal catalysts and the use of activated compounds and good nucleophiles as substrates.

Full text of DOI:10.1002/anie.201603235

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International Edition: DOI: 10.1002/anie.201603235
German Edition: DOI: 10.1002/ange.201603235
Carbonylation Very Important Paper
Copper-Catalyzed Carbonylative Coupling of Cycloalkanes and
Amides
Yahui Li, Kaiwu Dong, Fengxiang Zhu, Zechao Wang, and Xiao-Feng Wu*
Abstract: Carbonylation reactions are a most powerful
method for the synthesis of carbonyl-containing compounds.
However, most known carbonylation procedures still require
noble-metal catalysts and the use of activated compounds and
good nucleophiles as substrates. Herein, we developed
a copper-catalyzed carbonylative transformation of cyclo-
carbonylated and gave the desired products in good yields.
A few rare examples of the directing-group-assisted carbon-
3
À
ylation of C(sp ) H bonds with palladium or ruthenium
catalysts have been reported[3] whereas directing-group-free
variants are without precedence.[4] On the other hand, the free
radical carbonylation of (cyclo)alkanes in the presence of
radical initiators has been well established.[1f–i]
alkanes and amides. Imides were prepared in good yields by
3
À
carbonylation of a C(sp ) H bond of the cycloalkane with the
Among all transitional-metal catalysts, copper salts are
particularly inexpensive and benefit from their low toxicity.[5]
The use of copper catalysts in carbonylative transformations
is thus attractive for both academic and industrial purposes.
However, to our surprise, only few examples of copper-
catalyzed carbonylative coupling reactions with aryl iodides
or diaryliodonium salts have been reported.[6]
On the other hand, amides occur frequently in nature, and
they are also important intermediates and building blocks in
organic synthesis.[7] Based on the diversity of available
amides, the development of new reactions that employ
amides as reactants is a worthwhile pursuit. However,
compared with alcohols and amines, the low nucleophilicity
of amides has hindered their application in carbonylative
coupling reactions.[8] On the other hand, owing to the
comparatively high stability of amides towards oxidants,
suitable conditions for the use of amides as coupling partners
should be easily found.
amides acting as weak nucleophiles. Notably, this is the first
À
report of copper-catalyzed carbonylative C H activation.
T
ransition-metal-catalyzed carbonylative reactions are pow-
erful methods for the synthesis of carbonyl-containing com-
pounds.[1] Through carbonylation, the carbon chain of
a parent molecule can be easily elongated with carbon
monoxide (CO) as one of the cheapest and most abundant C1
building blocks. However, most of the known procedures
require either noble-metal catalysts, activated substrates, and/
or sufficiently reactive nucleophiles (Scheme 1a). More
specifically, catalysts based on palladium, ruthenium, and
rhodium are frequently explored. Aryl halides and analogues
thereof are commonly applied reactants whereas alcohols,
amines, and organometallic reagents are usually employed as
the nucleophiles. Hence, these methods suffer from some
common limitations, such as expensive catalysts and tedious
substrate preparation.
With all of these considerations in mind, we herein report
À
À
Various carbonylative C H activation reactions of arenes
that benefit from the assistance of directing groups have been
the first copper-catalyzed carbonylative C H activation of
cycloalkanes. With amides as the reaction partners, the
reported.[2] In the presence of a noble-metal catalyst and
a suitable oxidant, the C(sp ) H bonds of arenes were
C(sp ) H bond of simple cycloalkanes were carbonylated to
finally provide the corresponding imides in good yields
(Scheme 1b).
3
À
2
À
Initially, we chose cyclohexane (both as reagent and
solvent) and N-methylacetamide as the model substrates to
establish this carbonylation reaction (Table 1). Among vari-
ous metal catalyst precursors (entries 1–10), CuBr(Me2S)
gave the best result (80% GC yield, product isolated in 75%
yield; entry 6). Notably, the decreased reaction efficiency
with Pd(OAc)2, PdCl2, Mn2(CO)10, and Co(acac)2 excludes
the possibility that such metal impurities in the copper salt
play a role in the overall reaction (entries 7–10).
Scheme 1. Carbonylation reactions.
Next, various ligands were studied (entries 11–20). L2, L6,
and L7 achieved similar results to 1,10-phenanthroline
hydrate (entries 12, 16, and 17) whereas other ligands were
less effective. Subsequently, the CO pressure was varied. To
our surprise, the yield of 3a improved with a decrease in the
CO pressure (entries 21 and 22). Other additives, such as I2
and KI, were also tested, but led to decreased reaction
efficiency (entries 23 and 24). Furthermore, in the absence of
catalyst or ligand, only trace amounts of the desired product
were observed (entries 25 and 26). Overall, it was found that
[*] Y. Li, Dr. K. Dong, F. Zhu, Z. Wang, Prof. Dr. X.-F. Wu
Leibniz-Institut für Katalyse e.V. an der Universität Rostock
Albert-Einstein-Strasse 29a, 18059 Rostock (Germany)
E-mail: Xiao-Feng.Wu@catalysis.de
Prof. Dr. X.-F. Wu
Department of Chemistry, Zhejiang Sci-Tech University
Xiasha Campus, Hangzhou 310018 (P.R. China)
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201603235.
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Table 1: Catalyst screen.[a]
Table 2: Copper-catalyzed carbonylative imide synthesis.[a]
Entry
Catalyst
Ligand
Yield[b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21[d]
22[e]
23[f]
24[g]
25
26
CuI
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
L1
L2
L3
L4
L5
L6
L7
L8
L9
40%
22%
15%
23%
Cu(CH3CN)4BF4
Cu(CH3CN)4SO3CF3
Cu(CH3CN)4PF6
Cu(CF3CO2)2
CuBr(Me2S)
PdCl2
Pd(OAc)2
Mn2(CO)10
Co(acac)2
CuBr(Me2S)
CuBr(Me2S)
CuBr(Me2S)
CuBr(Me2S)
CuBr(Me2S)
CuBr(Me2S)
CuBr(Me2S)
CuBr(Me2S)
CuBr(Me2S)
CuBr(Me2S)
CuBr(Me2S)
CuBr(Me2S)
CuBr(Me2S)
CuBr(Me2S)
–
17%
80% (75%)[c]
34%
trace
0%
6%
54%
74%
62%
45%
33%
72%
71%
29%
64%
L10
27%
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
–
88% (84%)
89% (88%)
13%
74%
0%
CuBr(Me2S)
trace
[a] Reaction conditions: N-Methylacetamide (0.5 mmol), catalyst
(10 mol%), ligand (10 mol%), DTBP (0.75 mmol), CO (50 bar), cyclo-
hexane (1.5 mL), 24 h. [b] Determined by GC analysis. [c] Yields of
isolated products given in parentheses. [d] Catalyst (5 mol%), ligand
(5 mol%), CO (30 bar). [e] Catalyst (5 mol%), ligand (5 mol%), CO
(20 bar). [f] I2 (10 mol%). [g] KI (10 mol%). acac=acetylacetonate,
DTBP=di-tert-butylperoxide, 1,10-phen=1,10-phenanthroline hydrate.
[a] 2 (0.5 mmol), CuBr(Me2S) (5 mol%), 1,10-phen (5 mol%), DTBP
(0.75 mmol), CO (20 bar), cyclohexane (1.5 mL), 24 h. [b] Yields of
isolated products.
sponding products in very good yields (3j and 3k, 91% and
85%, respectively). Interestingly, these products belong to
a family of proinflammatory mediators that promote the
recruitment and activation of leukocytes (e.g., monocytes,
lymphocytes, and granulocytes). The reactions between
phenyl-substituted amides (2l, 2m, and 2n) and cyclohexane
gave the desired products in yields of 85%, 86%, and 69%,
respectively. Whereas N-methylbenzamide gave the desired
coupling product in 61% yield, with N-phenylacetamide and
N-phenylformamide, only the corresponding amides were
obtained rather than the desired imides. This may due to the
low stability of the imides, which decompose immediately to
give these amides. Furthermore, benzamide and acetamide, as
exemplary primary amides, were reacted with cyclohexane
under the standard reaction conditions, but the desired imides
were not detected.
the use of 5 mol% of CuBr(Me2S) and 1,10-phen together
with DTBP (1.5 equiv) under CO atmosphere (20 bar) gave
3a in 89% yield (determined by GC analysis; entry 22).
With the optimized reaction conditions in hand, we
examined the scope of the reaction with a range of amides.
As shown in Table 2, the desired imides were formed in good
yield when N-ethylacetamide or N-butylpropionamide was
used in combination with cyclohexane (yield of isolated 3b
and 3c: 69% and 74%, respectively). Long-chain imides were
also formed in good to excellent yields (such as 3e, 3 f, 3g, and
3h).
Different cyclic amides were also tested (Table 3).
Azepan-2-one (2j) and azocan-2-one (2k) gave the corre-
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Table 3: Copper-catalyzed carbonylation with lactams and amides.[a]
worked well under the standard reaction conditions
(entries 1–3), and the corresponding imides were isolated in
moderate to good yields (3q, 3r, and 3s). With adamantane as
the reactant, the desired imide was formed in 31% when
(trifluoromethyl)benzene was used as the solvent (entry 4).
The use of pentane under the standard reaction conditions
resulted in a mixture of two products.
To gain insight into the reaction mechanism, we con-
ducted some control experiments (Scheme 2). When 2 equiv
of TEMPO were added to the standard reaction conditions,
the desired product was only formed in 30% yield (deter-
mined by GC). The yield further decreased to 10% in the
presence of 4 equiv of TEMPO.
Scheme 2. Control experiments.
Based on our results, a possible reaction mechanism is
proposed (Scheme 3). The reaction is initiated by the copper-
(I)-catalyzed or thermal homolytic cleavage of the peroxide
to generate a tert-butoxy radical, which reacts with cyclohex-
ane; sequential oxidation of the copper(I) species gives the
CuIII–cyclohexane intermediate D. Then, complex D reacts
with the amide to yield CuIII intermediate E. Subsequent CO
insertion forms intermediate F or G, which then affords the
final carbonylation product after reductive elimination while
the active CuI species is regenerated for the next catalytic
cycle.
In conclusion, we have developed a copper-catalyzed
carbonylation reaction of cycloalkanes with amides as the
nucleophiles. Various imides were prepared in good yields by
3
À
carbonylation of a C(sp ) H bond of the cycloalkane.
[a] 2 (0.5 mmol), CuBr(Me2S) (5 mol%), 1,10-phen (5 mol%), DTBP
(0.75 mmol), CO (20 bar), cyclohexane (1.5 mL), 24 h. [b] Yields of
isolated products.
Furthermore, several cycloalkane derivatives were tested
(Table 4). Cyclopentane, cycloheptane, and cyclooctane
Scheme 3. Proposed reaction mechanism.
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Table 4: Copper-catalyzed synthesis of imides with various alkanes.[a]
(LIKAT) for general support and Dr. W. Baumann, Dr. C.
Fisher, S. Buchholz, and S. Schareina for analytical support.
Keywords: amides · carbonylation · copper catalysis ·
cycloalkanes · imides
How to cite: Angew. Chem. Int. Ed. 2016, 55, 7227–7230
Angew. Chem. 2016, 128, 7343–7346
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À
ylative C H activation.
Experimental Section
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General procedure: A 4 mL screw-cap vial was charged with CuBr-
(Me2S) (5.1 mg, 5 mol%), 1,10-phenanthroline hydrate (5 mg,
5 mol%), cyclohexane (1.5 mL), and an oven-dried stir bar. The
vial was closed with a Teflon septum and cap and connected to the
atmosphere via a needle. After cyclohexane (1.5 mL) and DTBP
(0.75 mmol) had been added with a syringe, the vial was moved to an
alloy plate and put into a Paar 4560 series autoclave (500 mL) under
argon atmosphere. At room temperature, the autoclave was flushed
with CO three times and then subjected to 20 bar of CO. The
autoclave was placed on a heating plate equipped with a magnetic
stirrer and an aluminum block. The reaction mixture was heated to
1208C for 24 h. Afterwards, the autoclave was cooled to room
temperature, and the pressure was carefully released. After solvent
removal under reduced pressure, the product was isolated by column
chromatography on silica gel (pentane/ethyl acetate = 20:1).
3
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Acknowledgements
We acknowledge financial support from the Chinese Scholar-
ship Council, the NSFC (21472174), and the Zhejiang Natural
Science Fund for Distinguished Young Scholars
(LR16B020002). We thank Professor Matthias Beller
Received: April 2, 2016
Published online: May 11, 2016
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