Coupling of enamides with alkynes or arynes for synthesis of substituted pyridines and isoquinolines via amide activation

Article abstract of DOI:10.1039/c2cc33768a

A novel and general procedure for Cu-catalyzed coupling of enamides with alkynes to synthesize substituted pyridines was developed. The chemistry was allowed to extend to the synthesis of substituted isoquinolines by coupling of enamides with arynes under transition-metal-free conditions.

Full text of DOI:10.1039/c2cc33768a

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COMMUNICATION
Coupling of enamides with alkynes or arynes for synthesis of substituted
pyridines and isoquinolines via amide activationw
Mi-Na Zhao, Zhi-Hui Ren, Yao-Yu Wang and Zheng-Hui Guan*
Received 25th May 2012, Accepted 26th June 2012
DOI: 10.1039/c2cc33768a
A novel and general procedure for Cu-catalyzed coupling of
enamides with alkynes to synthesize substituted pyridines was
developed. The chemistry was allowed to extend to the synthesis
of substituted isoquinolines by coupling of enamides with arynes
under transition-metal-free conditions.
We began our study by investigating the coupling of
N-acetyl enamide 1a with dimethyl acetylenedicarboxylate
(DMAD) 2a. Delightedly, dimethyl 2-methyl-6-phenylpyridine-
3,4-dicarboxylate 3a was observed in 23% yield in the presence
of CuI in DMSO, with 60% recovery of enamide 1a (Table 1,
entry 1). The high chemoselectivity of this pyridine formation
reveals that the vinyl anion, which was generated from
nucleophilic addition of enamide to dimethyl acetylenedi-
carboxylate (DMAD) 2a, directly attacked the amide carbonyl
group in the transformation (Scheme 1). There are only a few
examples of amide activation using Grignard or organolithium
reagents as the nucleophiles.14 Although the triflic anhydride/
pyridine system3,15 shows an efficient protocol for amide
activation, the nucleophilic attack to the amide carbonyl
group by a vinyl anion is unprecedented. This interesting
result encouraged us to optimize the reaction conditions to
give a general protocol for this new reaction.
The prevalence of substituted pyridines in bioactive molecules,
natural products, pharmaceuticals and functional materials
has promoted the development of many useful methods for
their preparation.1 Condensation of amines with carbonyl
compounds and cycloaddition reactions2 allow construction
of many substituted pyridines. Recently, a few elegant methods,
such as triflic anhydride/2-Cl-pyridine-promoted pyridine
synthesis,3 coupling of ketoxime esters with alkenylboronic
acids,4 coupling of alkynes with unsaturated imines or oximes5
and Mn-mediated cyclization of cyclopropanols with vinyl
azides,6 have been developed for the synthesis of unsymme-
trical substituted pyridines. Despite these advances, versatile
and efficient methods for the direct construction of pyridine
rings that are compatible with various functional groups and
use readily available starting materials remain highly desirable.7
Enamides and their derivatives are a class of powerful
building blocks and have been widely used in asymmetric
reactions.8 However, transition metal catalyzed couplings of
enamides have still been rarely explored. Recently, a few
elegant Pd- or Rh-catalyzed coupling reactions of enamides
have been developed by Loh,9 Bergman and Ellman,10
Stuart and Fagnou,11 and Glorius.12 In connection with our
Cu-catalyzed synthesis of enamides,13 we have studied the
coupling reaction of enamides and alkynes. Interestingly, a
substituted pyridine was observed in the transformation which
involved amide activation in the presence of a copper catalyst
(Fig. 1). In this communication, we report a novel and efficient
cross-coupling of enamides with alkynes or arynes for synth-
esis of substituted pyridines and isoquinolines.
Therefore, different solvents and copper catalysts were screened
for improving the reaction efficiency (Table 1, entries 2–8). It
was found that the coupling of enamide 1a and DMAD 2a
proceeded smoothly with CuI as the catalyst in 1,4-dioxane at
140 1C (Table 1, entry 9). Other solvents and catalysts are less
effective. Also, it should be noted that the CuI did indeed
improve the reaction efficiency; only 20% yield of the 3a was
achieved in the absence of CuI (Table 1, entries 5 and 8). To
further improve the reaction outcome, various ligands were
Key Laboratory of Synthetic and Natural Functional Molecule
Chemistry of Ministry of Education, Department of Chemistry &
Materials Science, Northwest University, Xi’an 710069, P. R. China.
E-mail: guanzhh@nwu.edu.cn
w Electronic supplementary information (ESI) available: All spectro-
scopic data and procedures for novel compounds. CCDC 876059. For
ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c2cc33768a
Fig. 1 Strategies for transition-metal-catalyzed couplings of enamides.
Chem. Commun., 2012, 48, 8105–8107 8105
c
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Table 1 Optimization of reaction conditionsa
Table 2 Cu-catalyzed coupling of enamides and alkynes for synthesis
of substituted pyridinesa
Entry
Catalyst
Ligand
Solvent
Tb (1C)
Yield (%)
1
2
3
4
5
6
7
8
9
10
CuI
CuI
CuI
CuI
CuI
CuBr
CuCl
—
DMSO
DMF
DCE
THF
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
120
120
120
120
120
120
120
120
140
140
23
31
40
68
70
54
38
20
76
88
CuI
CuI
glycine
a
Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), catalysts
(10 mol%) and ligand (20 mol%) in solvent (3 mL); isolated yields.
b
Oil bath temperature.
a
Reaction conditions: 1 (0.3 mmol), 2a (0.45 mmol), CuI (10 mol%)
and glycine (20 mol%) in 1,4-dioxane (3 mL) at 140 1C (oil bath
temperature); isolated yields. Diethyl acetylenedicarboxylate 2b
(0.45 mmol).
b
Scheme 1 Construction of pyridines by amide activation.
cross-coupling reactions20 and/or transition-metal-free reac-
tions.21 A multicomponent coupling of arynes, isocyanides and
terminal alkynes has been developed for synthesis of poly-
substituted pyridines and isoquinolines by Sha and Huang.20b
Insertion of arynes into the CQO double bond of aldehydes22
and esters23 has been developed in three-component coupling
strategies by several groups. A common feature of these reac-
tions is nucleophilic attack to arynes by a nucleophile and
subsequent trapping of the aryl anion intermediate with an
electrophile. Based on the aforementioned results, we envision
that the coupling of arynes and enamides may make it possible
to construct substituted isoquinolines24 directly (Scheme 2).
Further experiments were conducted for optimization of the
reaction conditions (Table 3). However, the triphenylene 5,
which was generated from the cyclotrimerization of benzyne in
the presence of CuI catalyst, was observed as the major
product (Table 3, entry 1).16b After several attempts, it was
found that significant improvement was achieved by using
18-crown-625 as the additive in the absence of CuI catalyst
(Table 3, entry 3). CsF shows more reactivity than KF
(Table 3, entry 4). The reaction temperature was also manipulated
and 80 1C was the best choice (Table 3, entries 6–8).
screened. We were pleased to find that glycine gave the best
results and the pyridine 3a was obtained in 88% yield (Table 1,
entry 10). Other ligands, such as N-methyl glycine, N,N-dimethyl
glycine, phenanthroline, L-proline and 2,20-dipyridine showed no
overall improvement (see supporting information, Table S1w). It
is noteworthy that other transition-metal catalyst (Pd(OAc)2) or
Lewis acids (FeCl3, ZnBr2, ZnCl2) resulted in decomposition of
enamide 1a to give acetophenone as the main product.
With the optimized reaction conditions established, the
scope of the reaction was investigated (Table 2). This trans-
formation displayed high functional group tolerance and
proved to be a quite general methodology for preparation of
multisubstituted pyridines. Enamides with methyl, methoxyl,
fluoro, chloro and bromo groups on aryl rings all gave the
corresponding pyridines 3b–3j in good to excellent yields. The
o-Me phenyl-substituted pyridine 3j was achieved in 71%
yield, suggesting that the transformation was insensitive to
steric hindrance of enamides. Both electron-rich and electron-
deficient enamides showed similar efficiency. The 2-ethyl
pyridine 3m was obtained in 82% yield when N-(1-phenylvinyl)-
propionamide 1m was used as the substrate. The diethyl
acetylenedicarboxylate 2b shows similar reactivity with
DMAD, the pyridine diethyl 2-methyl-6-phenylpyridine-3,4-
dicarboxylate 3n was obtained in 68% yield. However, tricyclic
pyridine 3o was not achieved by using cyclic enamide 1o as the
substrate.
Next, the transition-metal-free coupling of various enamides
1
and 2-(trimethylsilyl)phenyl triflate 2c were explored
(Table 4). Satisfactorily, the transformation displayed good
functional group tolerance and great efficiency; a series of
Arynes are highly reactive intermediates, which have been
utilized extensively in transition-metal-catalyzed carbon–
carbon and carbon–heteroatom bond formation reactions.16
The highly electrophilic character of arynes makes it possible
to insert into C–C,17 C–X18 s bonds or a CQO19 double
bond. Recently, efforts have been devoted to multicomponent
Scheme 2 Construction of isoquinolines by amide activation.
c
8106 Chem. Commun., 2012, 48, 8105–8107
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Table 3 Optimization of reaction conditionsa
rapid elaboration of the readily available enamides into a
variety of substituted pyridines and isoquinolines. Current
research is focused on extending the scope of the reaction.
This research was supported by National Natural Science
Foundation of China (NSFC-21002077) and Fund of New
Scientific Stars of Shanxi Province (2012KJXX-26).
Entry
Fluoride
Solvent
T/1C
Yield (%)
1b
2d
3
4
5
6
7
8
KF
KF
KF
CsF
CsF
CsF
CsF
CsF
THF
THF
THF
THF
CH3CN
THF
THF
60
60
60
60
60
40
80
100
trace (78)c
Notes and references
n.r.
55
65
60
61
71
66
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Reaction conditions: 1 (0.2 mmol), 2c (0.3 mmol), CsF (0.3 mmol)
and 18-crown-6 (0.3 mmol) in THF (3 mL) at 80 1C (oil bath
temperature); isolated yields.
isoquinolines 4 were synthesized in good yields (60–75%). It is
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In summary, we have developed a novel and general method
for Cu-catalyzed coupling of enamides with alkynes for the
synthesis of functionalized pyridines. The chemistry was
allowed to extend to coupling of enamides and arynes for
the synthesis of substituted isoquinolines under transition-
metal-free conditions. These novel methods tolerate a wide
range of functional groups and show reliable procedures for
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´
nguez
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This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 8105–8107 8107