Cu(TFA)2-catalyzed oxidative tandem cyclization/1,2-alkyl migration of enamino amides for synthesis of pyrrolin-4-ones

Article abstract of DOI:10.1021/ol4022222

A novel Cu(TFA)₂-catalyzed oxidative tandem cyclization/1,2- alkyl migration of readily available enamino amides for the synthesis of pyrrolin-4-ones has been developed. The reaction tolerates a wide range of functional groups and is a reliable method for the rapid synthesis of substituted pyrrolin-4-ones in high yields under mild conditions.

Full text of DOI:10.1021/ol4022222

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Cu(TFA)2‑Catalyzed Oxidative Tandem
Cyclization/1,2-Alkyl Migration of
Enamino Amides for Synthesis of
Pyrrolin-4-ones
Zhi-Jing Zhang, Zhi-Hui Ren, Yao-Yu Wang, and Zheng-Hui 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
guanzhh@nwu.edu.cn
Received August 5, 2013
ABSTRACT
A novel Cu(TFA)2-catalyzed oxidative tandem cyclization/1,2-alkyl migration of readily available enamino amides for the synthesis of pyrrolin-4-
ones has been developed. The reaction tolerates a wide range of functional groups and is a reliable method for the rapid synthesis of substituted
pyrrolin-4-ones in high yields under mild conditions.
The tandem reaction is an active area of research in
organic chemistry and is a powerful and versatile synthetic
tool for the construction of complex molecules from simple
starting materials.1 Over the past decades, transition-metal
catalyzed tandem reactions have been developed for the
efficient synthesis of many heterocycles, polycycles, and
natural products;2 however, most of these reactions pro-
ceeded under redox-neutral conditions.3 Oxidative cou-
pling has recently emerged as an atom-economical and
high-efficiency protocol for organic synthesis.4 Accord-
ingly, the oxidative tandem reaction is a promising avenue
for the further extension of traditional tandem reactions.5
1,2-Alkyl migration is one of the most fundamental
reactions. Classic 1,2-alkyl migration reactions, such as
pinacol rearrangement and R-ketol rearrangement, are
well established in organic synthesis.6 Recently, transition-
metal catalyzed tandem reactions along with 1,2-alkyl
migration have been found to be a powerful strategy for
the rapid construction of complex molecules.7 Our interest
in the cyclization of enamines or enamides for the synthesis
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r
10.1021/ol4022222
XXXX American Chemical Society

Table 1. Optimization of the Reaction Conditionsa
Scheme 1. Oxidative Tandem Cyclization/1,2-Alkyl Migration
of Enamino Amide
entry
catalyst
oxidant additive
solvent
yield (%)
1
Cu(TFA)2
Cu(TFA)2
Cu(TFA)2
Cu(TFA)2
Cu(TFA)2
Cu(TFA)2
Cu(TFA)2
Cu(TFA)2
Cu(TFA)2
Cu(TFA)2
Cu(OAc)2
Cu(OTf)2
Cu(TFA)2
Cu(TFA)2
Cu(TFA)2
Cu(TFA)2
AgOAc
Ag2CO3
BQ
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
1,4-dioxane
toluene
CH3OH
DCE
12
0
2
3
0
4
DDQ
0
of azaheterocycles8 prompted us to study the oxidative
cyclization of enamines. Unexpectedly, pyrrolin-4-one was
observed when the cyclization of enamino amides was
conducted in the presence of a Cu(TFA)2 catalyst
(Scheme 1). We assumed that it was generated from the
intermolecular oxidative cyclization of enamino amide 1a
subsequent to 1,2-methyl migration. The pyrrolin-4-one
scaffold is a class of valuable azaheterocycles that is
prevalent in many pharmaceuticals and biologically active
compounds.9 Despite a few synthetic methods that have
been recently developed for the synthesis of pyrrolin-4-
ones,10 versatile and efficient methods for the direct con-
struction of pyrrolin-4-one scaffolds that are compatible
with various functional groups and use readily available
starting materials are rare. In this paper, we report a
Cu(TFA)2-catalyzed oxidative tandem cyclization/1,2-al-
kyl migration of enamino amides that we developed for the
synthesis of pyrrolin-4-ones.
5
DTBP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
23
36
31
29
11
26
8
6
7
8
9
10
11
12
13
14
15
16b
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
0
TBHP
TBHP
TBHP
TBHP
TBHP
AcOH
PivOH
TFA
35
33
49
57
65
71
52,e
(39)f
0
TFA
17b,c Cu(TFA)2
TFA
18c,d Cu(TFA)2 TBHP
TFA
TFA
19c
Cu(TFA)2
TBHP
20
ꢀ
TBHP
TFA
CH3CN
a Reaction conditions: (Z)-3-amino-N-phenylbut-2-enamide 1a
(0.4 mmol), [Cu] (10 mol %), oxidant (0.5 equiv), additive (0.5 equiv)
in solvent (3 mL) at 80 °C for 2 h; isolated yields. b Cu(TFA)2 (5 mol %).
c TBHP (0.25 equiv) (70% in water). d Cu(TFA)2 (2.5 mol %). e Cu-
(TFA)2 (1.0 mol %). f Cu(TFA)2 (0.5 mol %).
We began our study by investigating the copper-cata-
lyzed oxdative cyclization of 3-amino-N-phenylbut-2-en-
amide 1a in the presence of AgOAc under a balloon
pressure of O2.11 Unexpectedly, pyrrolin-4-one, which
may be from intermolecular oxidative cyclization of
enamino amide 1a subsequent to 1,2-methyl migration,
was obtained at a yield of 12%.10c The structure of product
2a was confirmed by X-ray diffraction analysis (Scheme 1).
This result promoted us to optimize reaction conditions
in order to develop a synthetically useful process for the
synthesis of substituted pyrrolin-4-ones.
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Then, a series of oxidants, such as Ag2CO3, BQ, DDQ,
DTBP, and TBHP, were screened to determine if they
improved the reaction efficiency (Table 1, entries 2ꢀ6).
TBHP was found to be the most effective of the screened
oxidants. By screening various solvents, such as 1, 4-diox-
ane, toluene, CH3OH, and DCE, we found that CH3CN is
the most effective at increasing the reaction yield (Table 1,
entries 7ꢀ10). In contrast, no reaction was observed in the
presence of the Cu(OTf)2 catalyst, and only an 8% yield of
2a was obtained when Cu(OAc)2 was used as the catalyst
(Table 1, entries 11ꢀ12). To further improve the reaction
outcome, acid additives were screened. TFA proved to be
an active additive in the reaction and resulted in a 49%
yield of 2a (Table 1, entries 13ꢀ15). Finally, we found that
the catalyst loading as well as TBHP loading play an
important role in the reaction (Table 1, entries 16ꢀ18).
2.5 mol % of Cu(TFA)2 and 0.25 equiv of TBHP give the
highest yields of 2a (Table 1, entry 18). However, further
decreasing of the catalyst loading resulted in a long
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B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Cu(TFA)2-Catalyzed Oxidative Tandem Cyclization/
1,2-Alkyl Migration of Enaminesa
Scheme 2. Cu(TFA)2-Catalyzed Oxidative Tandem Cycliza-
tion/1,2-Alkyl Migration of Enamino Amides for Synthesis of
Pyrrolin-4-onesa,b
a Reaction conditions: 1 (0.4 mmol), Cu(TFA)2 (2.5 mol %), TBHP
b
(0.25 equiv), TFA (0.5 equiv) in CH3CN (3 mL) at 80 °C for 2 h.
Isolated yields.
a Reaction conditions: 2 (0.4 mmol), Cu(TFA)2 (2.5 mol %), TBHP
(0.25 equiv), and TFA (0.5 equiv) in CH3CN (3 mL) at 80 °C for 2 h.
b Isolated yields.
enamino amides. Ethyl- and propyl-substituted enamino
amides 1fꢀ1g proceeded smoothly and resulted in the
corresponding pyrrolin-4-ones 2fꢀ2g in 63ꢀ68% yields
(Table 2, entries 6ꢀ7). Enaminone 1h tolerated the condi-
tions as well. Acetyl-substituted pyrrolin-4-one 2h was
obtained at a yield of 62% (Table 2, entry 8); however,
enaminoester 1i was unable to induce the reaction.
Encouraged by the above results, further extension of
the reaction scope of the enamino amides was conducted
(Scheme 2). Enamino amides with a series of substituents,
such as methyl, methoxyl, fluoro, chloro, bromo, sensitive
functional groups such as iodo, and strong electron-with-
drawing groups such as cyano, acetyl, and ester, all gave
the corresponding substituted pyrrolin-4-ones in good to
high yields. These results indicate that the reaction was
unaffected by the electronic effects of the substituents on the
reaction time and low yield (Table 1, entry 19). And no
reaction occurred in the absence of the copper catalyst
(Table 1, entry 20).
With the optimized conditions in hand, we investigated
the scope of the reaction (Table 2). This new cyclization
reaction displayed high functional-group tolerance and
proved to be a general protocol for the synthesis of
substituted pyrrolin-4-ones. Enamino amides with methyl,
ethyl, phenyl, and benzyl substitutents on the nitrogen
atom (1bꢀ1e) were well tolerated and exhibited slightly
higher reactivity compared to N-unsubstituted enamino
amide 1a and gave the corresponding pyrrolin-4-ones
2bꢀ2e in 77ꢀ86% yields (Table 2, entries 2ꢀ5). We also
examined alkyl substituents on the olefin skeleton of the
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 3. Plausible Mechanisms of the Reaction
Scheme 4. Experiments To Elucidate the Reaction Mechanism
(TEMPO), was added to the reaction. However, the reaction
was not influenced by TEMPO (Scheme 4, eq 1), indicating
that the radical pathway (pathway a) is less likely. To confirm
that the mechanism follows pathway b, acetoacetyl aniline G
(1.0 equiv) was added to the reaction under the aforemen-
tioned conditions. Pyrrolin-4-one 2b was obtained in 0.12
mmol (>0.10 mmol), implying that acetoacetyl aniline G
was a reactant in the reaction (Scheme 4, eq 2). Therefore, the
reaction probably proceeds through pathway b.
In summary, we have developed a novel and highly
efficient copper-catalyzed oxidative tandem cyclization/
1,2-alkyl migration of readily available enamino amides
for the synthesis of pyrrolin-4-ones. This general reaction
tolerates a wide range of functional groups and is a reliable
method for the rapid synthesis of substituted pyrrolin-4-
ones in high yields under mild conditions. Our preliminary
mechanistic studies indicate that the mechanism of the
reaction likely proceeds through nucleophilic attack of an
acetoacetyl aniline intermediate to a nitrenium ion. Further
investigation of the reaction scope and mechanistic studies
are underway.
aryl ring of the amide group. Meanwhile, ortho-Me-, MeO-,
Cl-, and Br- substituted substrates reacted smoothly and
resulted in the desired pyrrolin-4-ones (2ea, 2ed, 2ee, 2eg,
2ek, 2en) in 65ꢀ82% yields, implying that steric hindrance
of the substrates has little influence on the reaction.
The tentative mechanisms are proposed in Scheme 3 on
the basis of the aforementioned observations. One pro-
posed mechanism is that the reaction starts from a single-
electron-transfer oxidation of enamino amide 1 by Cu2þ to
generate amino radical A and alkyl radical B.12 Then,
radical coupling of A and B leads to the intermediate C.
Hydrolysis of C gives intermediate D. Intramolecular
cyclization of intermediate D leads to intermediate E.8d
Tautomerization followed by oxidation by Cu2þ then
generates the 3H-pyrrol-1-ium intermediate F. Finally,
R-hydroxy imine rearrangement of the intermediate F pro-
duces pyrrolin-4-one 2 (pathway a).6,13 Alternatively, two
steps of a single-electron-transfer oxidation of enamino
amide 1 by Cu2þ to generate nitrenium ion G could occur.10c
Meanwhile, hydrolysis of enamino amide 1 would generate
acetoacetyl aniline H. Then, the nucleophilic attack of H to
nitrenium ion G produces the intermediate D (pathway b).14
To gain more insight into the reaction mechanism, a radical-
trapping reagent, (2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl
Acknowledgment. We thank the National Natural
Science Foundation of China (NSFC-21272183, 21002077)
and the Rising Scientific Stars Foundation of Shanxi Pro-
vince (2012KJXX-26) for financial support.
Supporting Information Available. Experimental pro-
cedures, spectral data for all products, and X-ray data of
2a. This material is available free of charge via the
Internet at http://pubs.acs.org.
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The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX