Amide to Alkyne Interconversion via a Nickel/Copper-Catalyzed Deamidative Cross-Coupling of Aryl and Alkenyl Amides

Article abstract of DOI:10.1021/acs.orglett.7b01194

A nickel-catalyzed deamidative cross-coupling reaction of amides with terminal alkynes as coupling partners was disclosed. This newly developed methodology allows the direct interconversion of amides to alkynes and enables a facile route for C(sp2)-C(sp) bond formation in a straightforward and mild fashion.

Full text of DOI:10.1021/acs.orglett.7b01194

Letter
pubs.acs.org/OrgLett
Amide to Alkyne Interconversion via a Nickel/Copper-Catalyzed
Deamidative Cross-Coupling of Aryl and Alkenyl Amides
Watchara Srimontree,† Adisak Chatupheeraphat,† Hsuan-Hung Liao,† and Magnus Rueping*,†,‡
†Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
‡King Abdullah University of Science and Technology (KAUST), KAUST Catalysis Center (KCC), Thuwal 23955-6900, Saudi
Arabia
S
* Supporting Information
ABSTRACT: A nickel-catalyzed deamidative cross-coupling
reaction of amides with terminal alkynes as coupling partners
was disclosed. This newly developed methodology allows the
direct interconversion of amides to alkynes and enables a facile
route for C(sp2)−C(sp) bond formation in a straightforward
and mild fashion.
tertiary alcohols through addition of copper acetylide to the
amide substrate has to be prevented (Scheme 1).
ransition-metal-catalyzed cross-coupling reactions repre-
Tsent one of the most successful domains in modern
organic chemistry. Among the developed transformations, the
Sonogashira reaction has emerged as one of the most
straightforward and powerful methods to facilitate linkages
between carbon atoms.1 Although this well-known reaction
shows a superior ability to incorporate alkynyl units into
organic molecules and has found applications in industrial and
laboratory settings, the electrophilic coupling partners for the
Sonogashira reactions are often limited to aryl and vinyl halides.
Recently, increasing emphasis on the development of environ-
mentally friendly synthetic protocols has stimulated research
aimed at finding alternative cross-coupling partners that avoid
corrosive halide-containing waste production in transition-
metal-catalyzed reactions. The establishment of decarbonylative
transformations2 making use of carboxylic acids, anhydrides,
acid chlorides, esters, and amides is significant in realizing this
concept. With these considerations in mind, our attention was
drawn to the cross-coupling reaction of amide derivatives with
silylated acetylenes as nucleophilic coupling partners. If
successful, this protocol would allow the synthesis of alkynes
which are versatile intermediates in organic synthesis and
important structural motifs of various biologically active
molecules.3 Besides their capacity to undergo subsequent
transformations,3 silylated alkynes can undergo protodesilyla-
tion to afford terminal alkynes that hold great potential for
further functional group interconversion.4 In addition, sila-
Sonogashira reaction5 provides an ideal protocol to convert
silylated alkynes into internal alkynes.6
Scheme 1. Cross-Coupling Alkynylation Reactions
Given the above considerations, we started to investigate a
deamidative cross-coupling reaction with amide 1a and
(triisopropylsilyl)acetylene (2a) as reaction partners (Table
1). Among the different metal catalysts tested, nickel
complexes7−12 were found to activate the amide in the
alkynylation reaction.13 Subsequently, different ligands were
evaluated (Table 1, entries 1−10). Monodentate phosphine
However, in order to develop a successful catalytic amide to
alkyne interconversion procedure, there are several challenges
that need be to addressed: (1) the formation of alkyne
homocoupling products (Glaser−Hey coupling) as well as
enyne formation has to be suppressed; (2) the use of strong
bases which limits functional group tolerance needs to be
avoided; and (3) the undesired formation of ketones and
Received: April 20, 2017
Published: June 5, 2017
© 2017 American Chemical Society
3091
DOI: 10.1021/acs.orglett.7b01194
Org. Lett. 2017, 19, 3091−3094

Organic Letters
Letter
Initially, a number of different amide substrates 1b−q
bearing a broad range of substituents were studied, and the
results are summarized in Scheme 2.16 Regarding the
Table 1. Optimization of the Nickel-Catalyzed Deamidative
a
C(sp2)−C(sp) Coupling
Scheme 2. Scope of Nickel-Catalyzed Sonogashira Cross-
a b
,
Coupling with Aryl Amides
entry
ligand
PCy3
base
solvent
yield (%)
1
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
CsF
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
60
55
67
<5
58
60
51
46
34
42
16
0
2
PnBu3
dcype
3
4
dcypf
5
dcypp
6
dcypm
dcypb
7
8
dtbbpy
SIPr · HCl
IMes · HCl
dcype
9
10
11
12
13
dcype
Cs2CO3
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
dcype
70
73
44
0
b
14
dcype
b
b
b
e
,
c
15
16
17
18
19
20
21
22
dcype
,
d
dcype
0
dcype
dcype
dcype
PCy3
PCy3
30
99
99
86
80
b
b
b
b
,
,
f
f
a
Reaction conditions: 1a (0.2 mmol), 2a (0.6 mmol), Ni(cod)2 (20
mol %), ligand (40 mol %), CuI (10 mol %), base (2.0 equiv), solvent
b
(1 mL), 150 °C, 16 h, yield after isolation. Using 2a (1.0 mmol).
c
d
e
f
Using dcype (20 mol %). Without Ni(cod)2. Without CuI. Using
Ni(cod)2 (5 mol %) and dcype (20 mol %).
ligands PCy3 and PnBu3 afforded the expected alkynylation
product 3a in moderate yield (Table 1, entries 1 and 2). A
slightly higher yield was obtained using the bidentate
phosphine ligand dcype [1,2-bis(dicyclohexylphosphino)-
ethane] (Table 1, entry 3). Evaluation of further ligands did
not improve the yield of the reaction (Table 1, entries 4−10).14
The use of different bases such as Cs2CO3 or CsF provided
unsatisfactory results (Table 1, entries 11 and 12). Changing
the solvent to 1,4-dioxane resulted in an increased yield of 70%
(Table 1, entry 13). Changing the catalyst to ligand ratio
resulted in a considerably lower yield (Table 1, entry 15). A
control experiment showed that no desired product was formed
in the absence of the nickel catalyst and dcype ligand (Table 1,
entries 16 and 17).
Furthermore, the copper iodide is essential for achieving
good yields of the desired product (Table 1, entry 18 vs 13).
Notably, when the reaction was performed in the absence of
base, the desired product was obtained in an excellent yield of
99% (entry 19). In addition, performing the reaction with a
lower catalyst loading also resulted in an excellent yield of 99%
for the desired product (entry 20). We have also tested CuCl2
and Cu(OAc)2; however, the yields obtained are lower (59%,
56%) when compared with the yield obtained with CuI (99%).
With the optimized reaction conditions in hand, we further
investigated the scope of this newly developed nickel catalyzed
Sonogashira cross-coupling reaction with a variety of amides
and terminal alkynes.
a
Reaction conditions: 1 (0.2 mmol), 2a (1.0 mmol), Ni(cod)2 (20 mol
%), dcype (40 mol %), CuI (10 mol %) in dioxane (0.2 M) at 150 °C,
b
16 h. Using Ni(cod)2 (5 mol %) and dcype (20 mol %). Yields for
c
isolated products. Reactions performed with Ni(acac)2 (5 mol %) and
dcype (20 mol %).15
application of phenyl derivatives, electron-neutral as well as
electron-rich and -poor phenyl-derived amides 1c−l were
alkynylated, providing products 3c−l with excellent yields. In
addition, substrates bearing methoxy, fluorine, and methyl ester
groups underwent reaction without affecting the substituents.
The latter observation is interesting as methoxy as well as
fluorine substituents have been reported as coupling partners in
nickel-catalyzed reactions. Furthermore, heterocyclic amides
including furan, thiophene, benzofuran, benzothiophene, and
pyridine derivatives 1m−q are also tolerated under our reaction
conditions and provided the products 3m−q in high yields. We
next examined the scope of the reaction with respect to alkynes
bearing different silyl groups (Scheme 3).17 Trimethylsilyl and
triethylsilyl alkynes 2b,c performed smoothly in the cross-
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DOI: 10.1021/acs.orglett.7b01194
Org. Lett. 2017, 19, 3091−3094

Organic Letters
Letter
Scheme 3. Scope of Nickel-Catalyzed Cross-Coupling of
Amides with Terminal Silyl Alkynes
Scheme 6. Proposed Mechanism for the Nickel-Catalyzed
Deamidative Alkynylation Reaction
a
a
Reaction conditions: 1a (0.2 mmol), 2b−d (1.0 mmol), Ni(cod)2 (20
mol %), dcype (40 mol %), CuI (10 mol %) in dioxane (0.2 M) at 150
°C, 16 h, yields for isolated products 3r−t.
coupling with 2-naphthylamide 1a to provide the correspond-
ing products 3r,s in 91% and 95% yield, respectively. The steric
effect of the tert-butyldimethylsilyl group had a detrimental
impact on the rate of the reaction, and the product 3t was
obtained in moderate yield.
To show the applicability of the method, the synthesis of
conjugated enynes 3u and 3v starting from unsaturated amides
1u and 1v and alkyne 2a was attempted. Pleasingly, by applying
our developed protocol, enynes 3u and 3v were obtained in
90% and 69% yield, respectively (Scheme 4).18
complete the catalytic cycle. The role of copper cocatalyst is to
activate the terminal alkyne, and the glutarimide moiety
stemming from the substrate acts as a base and removes a
proton.
In summary, we have developed a new and selective cross-
coupling reaction of amides with terminal alkynes as coupling
partners. The direct, one-step transformation of an aryl or
alkenlyl amide to the corresponding alkyne was previously not
known and is, with conventional methods, difficult to achieve.
Thus, the newly developed methodology enables a facile route
for C(sp2)−C(sp) bond formation in a straightforward fashion
by successful suppression of the undesired homocoupling
process. Various terminal silyl alkynes and a wide range of
aromatic amides bearing various substituents are tolerated in
this process, which afforded products in good to excellent
yields. The utility of this newly developed protocol has been
demonstrated in the synthesis of enynes as well as large-scale
synthesis of silylated alkynes. Given the simplicity and
generality of the protocol, it is anticipated that it should find
application in synthesis, retrosynthesis, and late-stage mod-
ification.
Scheme 4. Preparation of Enynes via Nickel-Catalyzed
Sonogashira Cross-Coupling
Furthermore, a gram-scale reaction was carried out in order
to demonstrate the scalability of our method. Importantly, the
inexpensive and air-stable Ni(acac)2 was found to provide the
alkynyl arene 3a in 75% yield,15 which offers a great
opportunity for further applications in the industry (Scheme 5).
ASSOCIATED CONTENT
* Supporting Information
■
S
Scheme 5. Gram-scale Nickel-Catalyzed Sonogashira Cross-
Coupling
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01194.
Detailed experimental procedures, spectral data for all
1
compounds, and H, 13C, and 19F NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: magnus.rueping@rwth-aachen.de.
ORCID
A proposed mechanism for this new nickel-catalyzed
alkynylation of amides is depicted in Scheme 6. Oxidative
addition of nickel into the C(acyl)−N amide bond generates Ni
complex A. Transmetalation provides the corresponding nickel
complex B, which undergoes CO extrusion to form Ni
intermediate C. Lastly, selective cross-coupling via reductive
elimination delivers alkynylation product 3 and nickel(0) to
Magnus Rueping: 0000-0003-4580-5227
Notes
The authors declare no competing financial interest.
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DOI: 10.1021/acs.orglett.7b01194
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Organic Letters
Letter
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■
H.-H.L. acknowledges the DAAD for a doctoral fellowship.
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