Copper-promoted oxidative coupling of enamides and alkynes for the synthesis of substituted pyrroles

Article abstract of DOI:10.1002/chem.201304565

An efficient copper-promoted oxidative coupling of enamides with alkynes has been developed for the synthesis of substituted pyrroles. The reaction proceeded through C-H and N-H bond functionalization of enamides under mild conditions.

Full text of DOI:10.1002/chem.201304565

DOI: 10.1002/chem.201304565
Communication
&
Synthetic Methods
Copper-Promoted Oxidative Coupling of Enamides and Alkynes
for the Synthesis of Substituted Pyrroles
Mi-Na Zhao, Zhi-Hui Ren, Yao-Yu Wang, and Zheng-Hui Guan*[a]
Abstract: An efficient copper-promoted oxidative cou-
pling of enamides with alkynes has been developed for
the synthesis of substituted pyrroles. The reaction pro-
ceeded through CÀH and NÀH bond functionalization of
enamides under mild conditions.
The construction of pyrrole rings is a hot topic in organic syn-
thesis owing to the prevalence of pyrrole motifs in countless
natural products, materials, and pharmaceuticals.[1] Apart from
the well-documented traditional approaches,[2] recently, new
strategies, such as cycloaddition reactions,[3] multicomponent
couplings,[4] dehydrogenative cyclization reactions,[5] and the
oxidative cyclization of N-allylimines[6] have been developed
for the synthesis of substituted pyrroles. We have previously
developed a copper-catalyzed homocoupling of ketoxime car-
boxylates to synthesize symmetrical pyrroles.[7] Although chem-
ical strategies exist, novel and efficient methods for the synthe-
sis of multisubstituted pyrroles that are compatible with vari-
ous functional groups and use readily available starting materi-
als remain highly desirable.[8]
Enamides are valuable building blocks in organic synthesis.[9]
The importance of enamide chemistry has been illuminated by
transition-metal-catalyzed coupling reactions[10] and Lewis acid
catalyzed 1,2-nucleophilic addition reactions.[11] In this respect,
the seminal work by the research groups of Glorius[12] and
Stuart and Fagnou[13] revealed that Rh-catalyzed oxidative cou-
pling of enamides with internal alkynes could be used to syn-
thesize multisubstituted pyrroles. Ru-catalyzed oxidative cou-
plings of enamides with internal alkynes for the synthesis of
substituted pyrroles have been developed, simultaneously, by
the groups of Ackermann[14] and Wang.[15] Recently, we have
discovered a copper-catalyzed cross-coupling reaction be-
tween enamides and electron-deficient alkynes, for the synthe-
sis of di-ester substituted pyridines, by means of activation of
the amide carbonyl functionality (Scheme 1, [Eq. (1)]).[16] This
reaction occurred with intramolecular nucleophilic attack of
Scheme 1. Coupling reactions of enamides and activated alkynes.
the amide carbonyl group by the highly active vinyl anion in-
termediate, which was stabilized under neutral conditions. We
hypothesized that the active vinyl anion intermediate might
be quenched by the rapid proton transfer in the reaction
system under basic conditions. Therefore, a dehydrogenative
cyclization might occur, producing di-ester substituted pyrroles
in the presence of a suitable oxidant (Scheme 1). As part of
our continuous interest in the synthesis of pyrroles,[7] we
report herein a copper-promoted oxidative coupling of enam-
ides with electron-deficient alkynes to synthesize di-ester sub-
stituted pyrroles (Scheme 1, [Eq. (2)]).
We commenced our investigation with the oxidative cou-
pling of enamide 1a and diethyl but-2-ynedioate 2a, in the
presence of K2CO3 and a stoichiometric amount of Cu(OAc)2, in
toluene. A pyridine product[16] was completely suppressed, and
NH pyrrole 3aa was observed as the sole product, in 37%
yield (Table 1, entry 1). Screening of various solvents, such as
1,2-dichloroethane (DCE) and 1,4-dioxane, showed that DCE
was the most suitable solvent for this reaction (Table 1, en-
tries 2 and 3). Experiments suggest that the choice of base
also plays an important role in this oxidative coupling reaction;
[a] M.-N. Zhao, Z.-H. Ren, Prof. Y.-Y. Wang, Prof. Dr. Z.-H. Guan
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
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201304565.
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Communication
Table 1. Optimization of reaction conditions.[a]
Scheme 2. Coupling reaction of enamide 1a with ethyl 3-phenylpropiolate
2c.
Entry
Base
Additive
Solvent
Yield [%]
1
2
3
4
5
6
7
8
K2CO3
K2CO3
K2CO3
Cs2CO3
Na2CO3
K2CO3
K2CO3
K2CO3
K2CO3
–
–
–
–
–
toluene
DCE
1,4-dioxane
DCE
DCE
DCE
DCE
DCE
DCE
DCE
37
44
12
17
0
63
25
20
In addition, when ethyl 3-phenylpropiolate 2c was em-
ployed as the substrate, pyrrole 3ac was obtained as single re-
gioisomer, albeit in low yield (Scheme 2). The structure of 3ac
was unambiguously confirmed by X-ray diffraction analysis.
To gain insight into the reaction mechanism, the reactions
were quenched at 3 h and at 24 h. Pyrrole 3aa was obtained
as the sole product, in 75% yield, at 24 h. However, N-acetyl
pyrrole 4aa was isolated, in 50% yield, at 3 h (Scheme 3,
–
Et3N
DABCO[b]
DBU[c]
DIPEA[d]
Et3N
Et3N
Et3N
9
58
10
11[f]
12[f,g]
10 (43)[e]
75
K2CO3
K2CO3
DCE
DCE
45
[a] Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), Cu(OAc)2
(2.0 equiv), base (2.0 equiv), additive (1.0 equiv), solvent (3 mL), at 1208C
for 24 h; isolated yields. [b] DABCO=1,4-diazobicyclo[2.2.2]octane.
[c] DBU=1,8-diazabicyclo[5.4.0]undec-7-ene. [d] DIPEA=N,N-diisopropyle-
thylamine. [e] Diethyl 1-acetyl-5-phenyl-1H-pyrrole-2,3-dicarboxylate 4aa
(43%) was isolated. [f] Reaction performed under O2 balloon. [g] Cu(OAc)2
(50 mol%).
Cs2CO3 and Na2CO3 were found to be inferior to K2CO3 (Table 1,
entries 4 and 5). The yield of pyrrole 3aa was further improved
by adding an organic base (Table 1, entries 6–9). Of the organic
bases screened, Et3N proved to be the most effective, provid-
ing 3aa in 63% yield. Notably, control experiments confirmed
that N-acetyl pyrrole 4aa was isolated as the major product in
the absence of K2CO3 (Table 1, entry 10). Finally, the yield of
pyrrole 3aa was improved to 75% when the reaction was per-
formed under balloon pressure of oxygen (Table 1, entry 11).
However, decreasing the Cu(OAc)2 loading resulted in a low
yield of pyrrole 3aa (Table 1, entry 12).
With the optimized conditions in hand, we then investigated
the reaction scope (Table 2). This transformation displayed
high functional-group tolerance and proved to be a reasonably
general methodology. Enamides with electron-neutral or elec-
tron-donating groups, such as alkyl, phenyl, methoxyl, [1,3]di-
oxole, and amino groups gave the corresponding NH pyrroles,
3ba–3ka, in good to high yields. The ortho-methyl substituted
enamide, 1e, was smoothly transformed into the desired pyr-
role, 3ea, in 76% yield, indicating that the transformation was
insensitive to steric hindrance from the enamides. Enamides
with an electron-withdrawing group, such as fluoro, chloro,
bromo, and sensitive iodo functionalities, were well tolerated
in the reaction and afforded desired NH pyrroles 3la–3oa in
70–80% yield. The strong electron-withdrawing NO2-substitut-
ed pyrrole 3pa was obtained in 50% yield, with 32% recovery
of para-NO2-substituted enamide 1p. 2-Naphthyl enamide 1q
also proceeded smoothly to give the corresponding naphthyl
substituted pyrrole 3qa in 65% yield. Moreover, cyclic enamide
1r was tolerated in the reaction and 1,4-dihydroindeno[1,2-
b]pyrrole 3ra was obtained in 34% yield.
Scheme 3. Control experiments.
[Eq. (1)]). These results suggest that the reaction proceeds
through cyclization of the enamides and alkynes, followed by
deacetylation of the N-acetyl pyrroles that are generated in
situ. The deacetylation step of N-acetyl pyrrole 4aa was then
investigated (Scheme 3, [Eq. (2)]). Control experiments indicat-
ed that K2CO3 was essential for the deacetylation of 4aa.
Furthermore, when the reaction was performed in the ab-
sence of Cu(OAc)2, diethyl 2-(N-(1-phenylvinyl) acetamido)ma-
leate 5a was formed in 52% yield. However, compound 5a
cannot undergo the cyclization to give the pyrrole product
under the standard conditions (Scheme 4). These results indi-
Scheme 4. Investigation of the mechanism.
cate that the coupling reaction is not initiated by nucleophilic
addition of the amide group to the electron-deficient alkyne.
On the basis of the aforementioned results and previous re-
ports,[17] a tentative mechanism of the reaction is proposed in
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Single-electron oxidation of intermediate B, in the
presence of Cu(OAc)2, can then generate radical inter-
mediate D.[17a] Radical cyclization of intermediate D
followed by a second single-electron oxidation, of
the intermediate E, by Cu(OAc)2 gives N-acetyl pyr-
role 4.[8e,17c] Finally, deacetylation of N-acetyl pyrrole 4
in the presence of K2CO3 affords pyrrole 3.
Table 2. Oxidative coupling of enamides and alkynes for the synthesis of substituted
pyrroles.[a]
In summary, a novel copper-promoted oxidative
coupling of enamides with electron-deficient alkynes
has been developed for the synthesis of multisubsti-
tuted NH pyrroles. This reaction tolerates a wide
range of functional groups and is a reliable proce-
dure for the rapid elaboration of readily available en-
amides into a variety of di-ester substituted NH pyr-
roles, under mild conditions. Further studies on oxi-
dative coupling of enamides are ongoing in our labo-
ratory.
Experimental Section
Typical Procedure for the Synthesis of Pyrroles
In a 25 mL round-bottomed flask, enamide 1 (0.3 mmol),
alkyne 2 (0.45 mmol), Cu(OAc)2 (0.6 mmol, 108.7 mg),
K2CO3 (0.6 mmol, 82.9 mg), and Et3N (0.3 mmol, 30.6 mg)
were stirred in 1,2-dichloroethane (DCE, 3 mL) at 1208C,
under an O2 balloon, for 24 h. After completion of the re-
action (detected by TLC), the reaction mixture was
cooled to room temperature, extracted with ethyl ace-
tate (20 mL) and washed with dilute NH3·H2O (5 mL) and
brine (20 mL). The organic layer was dried over anhy-
drous Na2SO4 and evaporated in vacuo. The desired pyr-
role, 3, was obtained after purification by flash chroma-
tography on silica gel with hexanes/ethyl acetate (8:1) as
the eluent.
Acknowledgements
This work was supported by generous grants from
the National Natural Science Foundation of China
(21272183 and 21002077) and the Fund of the Rising
Stars of Shanxi Province (2012KJXX-26).
[a] Reaction conditions: 1a (0.3 mmol), 2a (0.45 mmol), Cu(OAc)2 (2.0 equiv), K2CO3
(2.0 equiv), Et3N (1.0 equiv), DCE (3 mL), O2 balloon, 24 h; isolated yields. Boc=tert-bu-
toxycarbonyl.
Keywords: alkynes · copper · enamides · methodology ·
pyrroles
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Received: November 21, 2013
Revised: December 19, 2013
Published online on January 22, 2014
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