LETTER
▌2497
lAettcercess to Ynamides via CuO-Mediated Oxidative Amidation of Alkynes
Synthesis of Ynamides
Xiaogang Tong,a,b Guanghui Ni,a,b Xu Deng,a Chengfeng Xia*a
a
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences,
Yunnan 650201, P. R. of China
Fax +86(871)5223354; E-mail: xiachengfeng@mail.kib.ac.cn
b
Graduate University of Chinese Academy of Sciences, Beijing 100049, P. R. of China
Received: 31.07.2012; Accepted after revision: 23.08.2012
combination of CuI and DMEDA (N,N′-dimethylethyl-
diamine) could directly convert 1,1-dibromo-1-alkenes
into the corresponding ynamides.22 More recently, Jiao
developed the copper-catalyzed aerobic oxidative amida-
Abstract: Copper(II) oxide mediated the direct coupling of termi-
nal alkynes and amides by way of C–H functionalization to afford
ynamides as useful building blocks. Some alkali halides such as
KCl were discovered to play a key role as additive in the coupling
reaction, while other salts could suppress the formation of products. tion of propiolic acids via decarboxylation under air to
synthesize various ynamides.23 However, the direct for-
Key words: alkylation, amides, copper, cross-coupling, oxidation
mation of ynamides by coupling unactivated alkynes and
amides was still full of challenge. In 2008, Stahl docu-
mented the first copper-catalyzed aerobic oxidative ami-
The nitrogen-substituted alkyne ynamines are versatile
dation of terminal alkynes and proposed a mechanism for
synthons for organic synthesis while being featured with
the functionalized C–H reaction catalyzed by CuCl2.24 As
instability and sensitivity. To improve the stability and ex-
part of developing methodologies for efficient natural
pand the utility of ynamines, the electron-deficient yn-
products synthesis, herein, we report another observation
amides were created by some distinguished chemists.1,2 In
of a C–H functionalization method for the synthesis of yn-
1972, Viehe and his co-workers generated the first yn-
amides via a CuO-mediated direct coupling of terminal al-
kynes with nitrogen nucleophiles in the presence of alkali
halide.
amide by elimination of HCl from the corresponding α-
chloroenamide which was obtained from benzylic amide.3
Due to the excellent balance between stability and reactiv-
ity, ynamides rapidly received considerable attention
from the synthetic community and became useful and ver-
R
Nu (E)
O
R'
satile tools in organic synthesis in the following decades
( )n = 1–4
R
R
EWG
N
(Scheme 1).4–11 More importantly, it is worthy to mention
that some ynamides were also employed as an unparal-
leled building block in the total synthesis of natural prod-
ucts, which showed great potentialities in building some
unusual skeletons.12–15
N
EWG
R'
N
E (Nu)
O
R'
EWG
addition
reactions
cycloadditions
oxidations
EWG
EWG
R'
With regard to the development of methodologies for yn-
amide synthesis, the copper-catalyzed cross-coupling re-
action is among the most efficient and economic methods
for the formation of the ynamide C–N bond.1,16 In 2003,
Hsung and co-workers developed the pioneering copper-
catalyzed C–N bond formation in ynamide synthesis. Ac-
cording to his study, a catalytic amount of CuCN or CuI
could catalyze the oxazolidinone-based amide coupling
with alkynyl bromide to form the corresponding yn-
amides.17 Meanwhile, Danheiser reported a general ami-
nation strategy for the N-alkynylation of carbamates,
sulfonamides, chiral oxazolidinones, and imidazoli-
dinones via deprotonation of amides with KHMDS fol-
lowed by reaction with stoichiometric CuI and an alkynyl
bromide.18 Inspired by Hsung’s compelling results,
Skrydstrup,19 Urable,20 and Kerwin21 modified the
Hsung’s system to discover some new copper sources,
ligands, and bases, respectively. Evano reported that the
N
R
N
R
R'
metal-catalyzed
cycloisomerizations
( )n
reductions
R
coupling reactions
GWE
EWG
R'
N
N
N
EWG
N
R'
R1
R'
EWG
R
Scheme 1 Representative reactions of ynamides
We discovered that CuO could couple alkynes with 2-
oxazolidinone to generate the corresponding ynamides
without the assistance of oxygen and base. When 2.5
equivalents of CuO were added to the mixture of p-anisyl-
acetylene and 2-oxazolidinone in toluene at 80 °C, we ob-
served the formation of ynamide 3 in around 38% yield,
together with trace amount of homocoupled dimer 4 (Ta-
ble 1, entry 1). To improve the coupling yield, we opti-
mized the reaction conditions by screening the solvents,
temperature, as well as the ratio of substrates. But all these
efforts did not considerably increase the yield, and the
SYNLETT 2012, 23, 2497–2500
Advanced online publication: 21.09.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1290464; Art ID: ST-2012-W0645-L
© Georg Thieme Verlag Stuttgart · New York