Direct oxidative coupling of enamides and 1,3-dicarbonyl compounds: A facile and versatile approach to dihydrofurans, furans, pyrroles, and dicarbonyl enamides

Article abstract of DOI:10.1021/ol503009f

An efficient manganese(III)-mediated oxidative coupling reaction between α-aryl enamides and 1,3-dicarbonyl compounds has been developed. A series of dihydrofurans and dicarbonyl enamides were synthesized in moderate to good yields. Moreover, these dihydrofurans could be readily transformed into the corresponding furans and pyrroles via the Paal-Knorr reaction.

Full text of DOI:10.1021/ol503009f

Letter
pubs.acs.org/OrgLett
Direct Oxidative Coupling of Enamides and 1,3-Dicarbonyl
Compounds: A Facile and Versatile Approach to Dihydrofurans,
Furans, Pyrroles, and Dicarbonyl Enamides
Pan Li,†,‡ Jingjing Zhao,† Chungu Xia,† and Fuwei Li*,†
†State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of
Sciences, Lanzhou 730000, P. R. China
‡Graduate University of Chinese Academy of Sciences, Beijing 100049, P. R. China
S
* Supporting Information
ABSTRACT: An efficient manganese(III)-mediated oxidative coupling
reaction between α-aryl enamides and 1,3-dicarbonyl compounds has
been developed. A series of dihydrofurans and dicarbonyl enamides were
synthesized in moderate to good yields. Moreover, these dihydrofurans
could be readily transformed into the corresponding furans and pyrroles
via the Paal−Knorr reaction.
heterocycles is highly interesting and desirable. As part of our
continuing interest in free radical chemistry and the synthesis of
heterocyclic compounds,12 we herein report a Mn(OAc)3-
mediated direct oxidative coupling of 1,3-dicarbonyl com-
pounds to versatile enamides to readily yield three kinds of
heterocycle and dicarbonyl enamides.
C−C Bond formation via direct oxidative coupling of two
different C−H bonds is of great significance and a challenge.1
The radical-driven process has recently provided an important
approach by which to realize these oxidative coupling reactions,
and the addition of free radicals to olefins has attracted
particular attention.2 Enamides are versatile and powerful
building blocks in organic synthesis.3,4 However, the oxidative
coupling of free radicals and enamides has been rarely
reported.5 The electron-rich character of enamides could be
expected to promote their reactivity with electron-deficient
radicals.
Five-membered heterocycles (dihydrofurans, furans, and
pyrroles) are important scaffolds and building blocks in natural
products, pharmaceuticals, and functional materials.6 1,3-
Dicarbonyl compounds are usually utilized to build five-
membered heterocycles,7 prepare dihydrofurans from olefins,8
and create furans from alkynes or functional olefins.9,10 They
can also be used to synthesize pyrroles from vinyl azides11
(Scheme 1). Although preparations of dihydrofurans, furans,
and pyrroles have been separately developed, a simple and mild
strategy for realizing the diverse synthesis of all these
Considering that enamides are electron-rich and versatile,
our initial investigations focused on the reaction of N-(1-
phenylvinyl)acetamide (1a) with ethyl 3-oxobutanoate (2a).
Gratifyingly, the desired dihydrofuran 3aa was isolated in 69%
yield in the presence of 3 equiv of Mn(OAc)3 (Table 1, entry
1), which is usually considered to be a good single-electron
oxidant in the field of free radical chemistry.13 The present
reaction also proceeded smoothly in other solvents, such as
DMF, MeCN, EtOAc, and MeOH (Table 1, entries 2−5).
MeCN was the most suitable solvent, giving the desired
product 3aa in 80% yield (Table 1, entry 3). However, the
reaction did not occur in H2O (Table 1, entry 6). In addition,
temperature variation only slightly affected the reaction
efficiency (Table 1, entries 7 and 8). By reducing the amount
of Mn(OAc)3 to 2.5 equiv, the yield of 3aa dropped to 68%
(Table 1, entry 9). Running the reaction under an argon
atmosphere increased the yield of 3aa to 87% (Table 1, entry
10).
Scheme 1. Synthesis of Five-Membered Heterocycles from
1,3-Dicarbonyl Compounds
In order to test the practicality of this approach, a gram-scale
synthesis of 3aa (2.37 g, 82% yield) was successfully performed
(Table 1, entry 11).
With these optimized conditions in hand (Table 1, entry 10),
we turned to examining the scope and limitations of this
method (Scheme 2). The unsymmetrical 1,3-dicarbonyl
compounds gave the corresponding products (3ab and 3ac)
Received: October 13, 2014
© XXXX American Chemical Society
A
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Letter
a
(3bd and 3cd) showed higher yields than those with
withdrawing groups (3dd−3fd) when reacted with pentane-
2,4-dione 2d. In addition, the aromatic enamides substituted
with electron-withdrawing groups (Cl and NO2) at the ortho-
or meta-positions could also be efficiently converted to the
expected dihydrofurans in 86−58% yields (3ga−3ia and 3gd−
3id). To our delight, other representative enamides derived
from heteroaromatic ethanone (1-(thiophen-2-yl)ethanone)
and cyclic ketone (α-tetralone) were also found to be suitable
for this transformation (3ja and 3jd, 3ka and 3kd).
Replacing 1,3-dicarbonyl compounds with the 2-substituted
1,3-dicarbonyl compounds in the reaction with enamides can
selectively produce the (Z)-dicarbonyl enamides 4 through
direct oxidative coupling (Scheme 3). The stereochemistry of
Table 1. Reaction Optimization
entry
solvent
temp (°C)
yield (%)
1
2
3
4
5
6
7
8
DMSO
DMF
80
80
80
80
80
80
100
50
80
80
80
69
62
80
72
69
0
MeCN
EtOAc
MeOH
H2O
MeCN
MeCN
MeCN
MeCN
MeCN
74
66
68
87
82
b
9
a
c
Scheme 3. Synthesis of Dicarbonyl Enamides
10
cd
,
11
a
All reactions were carried out on a 0.2 mmol scale in 2 mL of solvent
b
c
for 6 h. Isolated yield. 2.5 equiv of Mn(OAc)3·2H2O. Under argon.
d
The reaction was carried out on a 10 mmol scale in 100 mL of
MeCN under argon in 250 mL Schlenk tubes for 24 h.
Scheme 2. Synthesis of Dihydrofurans from Enamides and
a
1,3-Dicarbonyl Compounds
a
A mixture of enamides (0.2 mmol), 1,3-dicarbonyl compounds (0.3
mmol), and Mn(OAc)3·2H2O (0.6 mmol) in 2 mL of MeCN was
stirred under argon in 50 mL Schlenk tubes at 80 °C for 6 h. Isolated
yields.
dicarbonyl enamides 4 was further unambiguously confirmed
by the X-ray diffraction (XRD) analysis of a representative
product 4a (CCDC 1026793) (Figure 1). The aromatic
a
A mixture of enamides (0.2 mmol), 1,3-dicarbonyl compounds (0.3
mmol), and Mn(OAc)3·2H2O (0.6 mmol) in 2 mL of MeCN was
stirred under argon in 50 mL Schlenk tubes at 80 °C for 6 h. Isolated
yields.
in good yield, and the yield of 3ac was lower than that of 3ab,
owing to the steric hindrance. The symmetrical 1,3-dicarbonyl
compounds with an alkyl substituent afforded the desired
products (3ad and 3af) in 87% and 80% yields, respectively.
Unfortunately, the aryl substituted 1,3-dicarbonyl compounds
gave a much lower yield of 3ae (30% yield), and the larger sized
dipivaloylmethane even failed to give the corresponding
dihydrofuran.14 Fortunately, various aromatic enamides with
electron-donating (Me and OMe) and electron-withdrawing
groups (Br, Cl, F, and NO2) all worked well with unsym-
metrical and symmetrical 1,3-dicarbonyl compounds, affording
the desired dihydrofurans in 88% to 46% yields, respectively
(3ba−3ka and 3bd−3kd). With ethyl 3-oxobutanoate 2a, the
para-substituted aromatic enamides with electron-withdrawing
groups (3da−3fa) gave rise to better results than electron-
donating groups (3ba and 3ca). Contrastingly, the para-
substituted aromatic enamides with electron-donating groups
Figure 1. Single crystal structure of 4a.
enamides with electron-withdrawing groups (F) or electron-
donating groups (OMe) gave the corresponding products in
moderate-to-good yield (4b and 4c). The oxidative coupling
reactions of heteroaromatic enamides or cyclic 1,3-dicarbonyl
compounds also proceeded smoothly, yielding, for example, the
corresponding 4d and 4e.
Owing to the versatility of amide groups, the above
dihydrofurans 3 could be easily transformed into the
corresponding furans by using amide as an easy leaving group
in the presence of p-toluenesulfonic acid (Scheme 4). As
expected, the dihydrofurans (3aa and 3ad) converted into the
B
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a
Scheme 4. Synthesis of Furans from Dihydrofurans
Scheme 6. Radical Trapping Experiments
However, 1,1-diphenylethylene, as another radical scavenger,
could not stop this reaction, indicating that enamides show
higher activity than 1,1-diphenylethylene in reacting with the
radical species of 1,3-dione. We have also demonstrated that
enamides are good alternatives to alkenes for reactions with the
radical species (Scheme 6c).
a
A mixture of dihydrofurans (0.2 mmol) and TsOH (0.22 mmol) in 2
mL of toluene was stirred in 15 mL pressure tubes at 100 °C for 2 h.
Isolated yields.
corresponding furans (5aa and 5ad) in 95% and 85% yields,
respectively.15 Dihydrofurans with electron-withdrawing groups
(Cl) at the ortho- or para-position afforded corresponding
furans in 99% to 64% yield (5ea and 5ed, 5ia and 5id). To our
delight, the typical heteroaromatic dihydrofurans also gave the
desired products in excellent yields (87% of 5ja and 85% of
5jd). In addition, other representative dihydrofurans derived
from cyclic 1,3-dicarbonyl compounds or cyclic enamides all
worked efficiently in the transformation from dihydrofuran to
furan (5af and 5ka).
Based on the above control experiments, a proposed
mechanism is shown in Scheme 7. Initially, the 1,3-dicarbonyl
Scheme 7. A Plausible Mechanism
Encouraged by the above results in the Paal−Knorr reaction,
we decided to react these dihydrofurans with amines to obtain
the corresponding pyrroles. To our delight, both aromatic and
aliphatic amines were suitable for this transformation (Scheme
5). The aromatic amines afforded the desired pyrroles in 83%
to 68% yield (6a−6c), and aliphatic amines also gave the
corresponding product in 73% to 65% yield (6d and 6e).
Scheme 5. Synthesis of Pyrroles from Dihydrofurans and
a
Amines
compound generates an electron-deficient radical A in the
presence of Mn(OAc)3. A then adds to the electron-rich
enamides to afford radical B which can be further oxidized by
Mn(OAc)3 into carbocation C or iminium ion C′, which
undergoes cyclization/deprotonation to give the desired
dihydrofurans 3. It can be seen from the reaction pathway
that oxidative coupling theoretically needs 2 equiv of
Mn(OAc)3. With the help of acid, the dihydrofuran 3 goes
through ring cleavage to generate imine D or enamide D′,
which can further hydrolyze to afford another versatile 1,4-
dione E intermediate that can be isolated.15 Eventually, E
would then afford the corresponding furan 5 and pyrrole 6 via
the Paal−Knorr reaction.16
a
A mixture of dihydrofurans (0.2 mmol), TsOH (0.22 mmol), and
aromatic amines (0.3 mmol) or aliphatic amines (0.6 mmol) in 2 mL
of toluene was stirred in 15 mL pressure tubes at 100 °C for 2 h.
Isolated yields.
In summary, we have developed a versatile approach to
dihydrofurans and dicarbonyl enamides. Notably, these trans-
formations can be efficiently scaled up. In addition, these
unique dihydrofurans with amide substituents can smoothly
transform into furans and pyrroles via another versatile 1,4-
dione intermediate. Other diverse syntheses through the
addition of different radical partners with enamides are under
investigation in our laboratory.
To validate the original design of the present radical process
involving a Mn-initiated single electron transfer, a series of
control experiments were carried out. The oxidative coupling
reaction could be very effectively prevented by the addition of
the radical inhibitors TEMPO (2,2,6,6-tetramethylpiperidino-
oxy) or BHT (butylated hydroxytoluene) (Scheme 6a and b).
C
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Letter
(11) (a) Chiba, S.; Wang, Y.-F.; Lapointe, G.; Narasaka, K. Org. Lett.
2008, 10, 313. (b) Wang, Y.-F.; Toh, K. K.; Chiba, S.; Narasaka, K.
Org. Lett. 2008, 10, 5019.
ASSOCIATED CONTENT
* Supporting Information
Experimental details, compound characterization data. This
material is available free of charge via the Internet at http://
pubs.acs.org.
■
S
(12) (a) Zhao, J.; Li, P.; Xia, C.; Li, F. Chem. Commun. 2014, 50,
4751. (b) Li, P.; Zhao, J.; Xia, C.; Li, F. Tetrahedron Lett. 2014, 55,
390. (c) Xue, L.; Shi, L.; Han, Y.; Xia, C.; Huynh, H. V.; Li, F. Dalton
Trans. 2011, 40, 7632. (d) Li, Z.; Liu, J.; Huang, Z.; Yang, Y.; Xia, C.;
Li, F. ACS Catal. 2013, 3, 839. (e) Shi, L.; Xue, L.; Lang, R.; Xia, C.;
Li, F. ChemCatChem 2014, 6, 2560. (f) Wang, W.; Wu, J.; Xia, C.; Li,
F. Green Chem. 2011, 13, 3440. (g) Sun, P.; Long, X.; He, H.; Xia, C.;
Li, F. ChemSusChem 2013, 6, 2190.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: fuweili@licp.cas.cn.
(13) For selected reviews on the manganese(III) acetate mediated
reaction, see: (a) Mondal, M.; Bora, U. RSC Adv. 2013, 3, 18716.
(b) Demir, A. S.; Emrullahoglu, M. Curr. Org. Synth. 2007, 4, 223.
(14) The 2,2,6,6-tetramethyl-4-(2-oxo-2-phenylethyl)heptane-3,5-
dione (3ag) was obtained in 20% yield. The progress could only
occur by oxidative coupling of enamide (1a) and the 1,3-dicarbonyl
compound (2g), followed by the hydrolysis itself.
(15) The corresponding 1,4-diones were detected using a catalytic
amount of TsOH. These results indicated that furans generated from
dihydrofurans could undergo the Paal−Knorr mechanism.
(16) Zheng, X.; Lu, S.; Li, Z. Org. Lett. 2013, 15, 5432.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the Chinese Academy of Sciences
and the National Natural Science Foundation of China
(21133011 and 21373246) for generous financial support.
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