Palladium-Catalyzed Decarbonylative Alkynylation of Amides

Article abstract of DOI:10.1021/acs.orglett.8b00949

A palladium-catalyzed decarbonylative alkynylation of amides via C-N bond activation is developed. Compared with the reported Ni/Cu catalyzed reaction, which only proceeded well with silylacetylenes, this transformation was also applicable to both aromatic and aliphatic terminal alkynes, including those bearing functional groups, and thus provided a general and straightforward access to diverse internal alkynes.

Full text of DOI:10.1021/acs.orglett.8b00949

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Palladium-Catalyzed Decarbonylative Alkynylation of Amides
Long Liu,†,‡ Dan Zhou,‡ Min Liu,‡ Yongbo Zhou,‡ and Tieqiao Chen*,†,‡
†Key Laboratory of Ministry of Education for Advanced Materials in Tropical Island Resources, College of Materials and Chemical
Engineering, Hainan University, Haikou 570228, China
‡State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University,
Changsha 410082, China
S
* Supporting Information
ABSTRACT: A palladium-catalyzed decarbonylative alkyny-
lation of amides via C−N bond activation is developed.
Compared with the reported Ni/Cu catalyzed reaction, which
only proceeded well with silylacetylenes, this transformation
was also applicable to both aromatic and aliphatic terminal
alkynes, including those bearing functional groups, and thus provided a general and straightforward access to diverse internal
alkynes.
Scheme 1. Internal Alkyne Construction via C−N Bond
nternal alkynes are fundamental structural motifs found in
numerous bioactive compounds and functional materials.1
Activation of Amide
I
Because of the flexible reactivity of the unsaturated CC triple
bond, internal alkynes are also widely applied in organic
synthesis.1,2 In this context, the development of efficient
methods for preparing those compounds is very important.
Among the existing synthetic methods,3−6 transition-metal
catalyzed Sonogashira coupling of terminal alkynes with aryl
halides represents a powerful and convenient access to internal
alkynes.4 During the past decades, this reaction has been
extensively studied and many novel electrophilic reagents such
as arenediazonium salts, sodium sulfonates, arylhydrazines,
arylsulfonyl hydrazides, etc. have been successfully developed as
the coupling partners instead of halides.5 Despite the high
efficiency of those coupling reagents, from economic and
environmental points of view, the ideal ones would be naturally
abundant and less pollutant.6
Rueping’s catalytic system; all three kinds of terminal alkynes,
i.e. aryl, alkyl, and silyl acetylenes, were applicable, and thus
provided a general and straightforward method for the
synthesis of internal alkynes.
Initially, N-acyl-glutarimides16 1a reacted with phenyl-
acetylene 2a (3.0 equiv) in the presence of Pd(OAc)2 (5 mol
%), 1,1-bis(diphenylphosphino)methane (dppm, 10 mol %),
and Na2CO3 (1.0 equiv) in dioxane at 150 °C under N2 for 16
h. To our delight, the decarbonylative alkynylation product 2-
(phenylethynyl)naphthalene 3a was generated in 26% yield
(Table 1, entry 1). It should be noted that no trace amount of
this internal alkyne was produced in the previous Ni/Cu
catalytic system.14 This result encouraged us to further screen
the reaction conditions. Among the ligands investigated, 1,3-
bis(diphenylphosphanyl)propane (dppp) provided the best
result, and 3a was given in 79% yield (Table 1, entries 1−5). A
phosphine ligand was essential in this reaction; no desired
product was detected in its absence. Only a 28% yield of 3a was
obtained when 5 mol % dppp was loaded, whereas further
increasing the loading of dppp to 15 mol % also did not
improve the reaction efficiency (Table 1, entries 6−8). Other
bases such as NaOAc, NaHCO3, Li2CO3, K2CO3, and K3PO4
Amides are widespread raw materials.7 In the past three
years, transition-metal catalyzed C−N activation has emerged
as a powerful strategy for amide conversions. By using this
strategy, a series of excellent coupling reactions for constructing
carbon−carbon and carbon−heteroatom bonds were reported
by Garg,8 Szostak,9 Shi,10 Zeng11 et al.,12,13 making amides a
promising electrophilic reagent in coupling chemistry. Very
recently, an efficient Ni/Cu-catalyzed decarbonylative cross-
coupling of amides with terminal alkynes was developed by
Rueping (Scheme 1).14 However, probably due to the quick
polymerization of other aromatic and aliphatic terminal
acetylenes under the Ni-catalyzed reaction conditions, this
reaction was only applicable to silylacetylenes.15 Despite the
fact that other internal alkynes could be prepared from the
silylated alkynes through further sequential protodesilylation
and Sonogashira reaction or sila-Sonogashira reaction, a more
general and straightforward method was highly desirable.
Herein, we report a palladium-catalyzed decarbonylative
alkynylation of amides with terminal alkynes via C−N bond
activation. This reaction overcame the substrate limitation of
Received: March 23, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00949
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a b
,
ditions, indicating that this catalyst system bears high capability
in facilitating decarbonylation.
Table 1. Optimization of the Reaction Conditions
With the optimized reaction conditions in hand, the substrate
scope and generality of this decarbonylative alkynylation
reaction were investigated, and the results are summarized in
Scheme 2. Diverse terminal alkynes including aryl, alkyl, and
a b
,
Scheme 2. Substrate Scope
a
Reaction conditions: 1a (0.2 mmol), 2a (3.0 equiv), [Pd] (5 mol %),
ligand (10 mol %), and base (1.0 equiv) in the solvent (2 mL) at 150
a
Reaction conditions: amides 1 (0.2 mmol), terminal alkynes 2 (3.0
b
°C under N2 for 16 h. GC yield using tridecane as an internal
equiv), Pd(OAc) (3 mol %), dppp (6 mol %), Na2CO3 (1.0 equiv) in
dioxane (2 mL) at 150 °C under N2 for 16 h. Isolated yields.
c
d
e
standard. dppp (5 mol %). dppp (15 mol %). base (2.0 equiv).
b
f
g
h
Na2CO3 (0.5 equiv). Na2CO3 (1.5 equiv). Pd2(dba)3 (2.5 mol %).
Pd(OAc)2 (3 mol %), dppp (6 mol %). Pd(OAc)2 (1 mol %), dppp
(2 mol %). 160 °C. 130 °C. 2a (1.0 equiv), 24 h. 2a (2.0 equiv).
i
j
k
l
m
n
silyl acetylenes were good substrates, giving the corresponding
internal alkynes in good to excellent yields. Under the
optimized conditions, 3a was obtained in 78% isolated yield.
Other aromatic terminal alkynes, bearing electronic-donating
groups such as 4-Me (3b), 3-Me (3g), OMe (3c, 3f), tBu (3d),
and NMe2 (3e); halo groups such as F (3h), 4-Cl (3j), and 3-
Cl (3k); and the electron-withdrawing group CF3 (3i) on the
benzene ring all served well under the reaction conditions,
furnishing the desired products in 53−90% yields. Worth
noting is that a sterically hindered terminal alkyne was
transformed into the expected internal alkyne in a comparable
yield (3c vs 3f). The heteroaromatic alkynes were workable
under the reaction conditions. When 2-ethynylthiophene or 3-
ethynylthiophene reacted with 1a, the corresponding hetero-
cycle-containing internal alkynes were produced in 75% and
76% yields, respectively (3l and 3m). In addition, silylated
alkynes were also successfully constructed in this catalytic
system (3n and 3o). Aliphatic alkynes such as oct-1-yne also
worked well, generating the expected product in 86% yield
(3p).
could also promote the reaction, despite the fact that relatively
low yields of 3a were afforded (Table 1, entries 9−13). The
loading of base was also screened. A low yield was given with
0.5 equiv of Na2CO3, while increasing the amount of base did
not enhance the reaction efficiency (Table 1, entries 14 and
15). As for the solvents, dioxane was the best choice (Table 1,
entries 16−18). PdCl2, Pd(dppf)Cl2, and Pd2(dba)3 were also
effective under similar reaction conditions (Table 1, entries
19−21). When 3 mol % Pd(OAc)2 was used, a slightly higher
yield of 3a (82%) was obtained; however, further reduction of
the catalyst to 1 mol % led to the decrease in yield (Table 1,
entries 22 and 23). Reaction temperature was also investigated.
Elevating the reaction temperature did enhance the yield,
whereas a low yield was afforded at 130 °C (Table 1, entries 24
and 25). It seems that excessive 2a was necessary, since
decreasing the loading of 2a led to a decrease in the yield
(Table 1, entries 26 and 27). It should be mentioned that no
alkynone product was detected under those reaction con-
B
DOI: 10.1021/acs.orglett.8b00949
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Letter
As for the amides’ applicability, 1-(1-naphthoyl)piperidine-
2,6-dione was a good substrate for this reaction; the
corresponding product 3q was isolated in 80% yield. Phenyl
derivatives including those with 4-Ph and 4-F substituents were
suitable to this transformation, giving the corresponding
internal alkynes in 60−68% yields (3r−t). However, substrates
bearing an electron-donating group such as 4-Me and 4-OMe
on the benzene ring gave a low yield under the reaction
conditions (3u and 3v). Delightfully, heteroaromatic amides
such as benzofuran-2-carboxamide and benzo[b]thiophene-2-
carboxamide worked well, furnishing the valuable heteroaryl-
containing internal alkynes in 76% and 83% yields, respectively
(3w and 3x). The effect of different N-substituents on amides
was investigated next. As shown in Scheme 3, the less distorted
In conclusion, we have developed a Sonogashira-type cross-
coupling reaction of amides with terminal alkynes via
palladium-catalyzed C−N bond activation. In addition to the
high capability of decarbonylation, this reaction overcame the
substrate limitation of the Ni/Cu catalytic system and provided
a straightforward access to diverse internal alkynes, including
aryl, alkyl, and silyl substituents in good to excellent yields,
which, to some extent, broadened the utility of the abundant
and readily available amides for chemical synthesis.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00949.
a
Scheme 3. Effect of Different N-Substituents
Experimental procedures, full spectroscopic data, and
1
copies of H and 13C spectroscopies (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: chentieqiao@hnu.edu.cn.
ORCID
Yongbo Zhou: 0000-0002-3540-8618
Tieqiao Chen: 0000-0002-9787-9538
Notes
a
GC yield using tridecane as an internal standard.
The authors declare no competing financial interest.
amide 1f was feasible,17 producing 3a in 80% yield. A promising
yield of 3a was also obtained by the reaction of N-acylsaccharin
1g18 with terminal alkyne 2a. Consistent with metal insertion
into the neutral amide C−N bond,9d,19 amides 1h and 1i
resulted in low yields of 3a.
ACKNOWLEDGMENTS
■
Financial support by the National NSF of China (Grant Nos.
21373080, 21403062, and 21273067) and the NSF of Hunan
Province (Grant No. 2016JJ1007) is appreciated.
Although the specific mechanism remains unclear, a tentative
pathway was proposed based on the previous literature.8−14 As
shown in Scheme 4, the in situ formed Pd(0) species undergoes
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