Efficient synthesis of highly substituted pyrrolin-4-ones via PIFA-mediated cyclization reactions of enaminones

Article abstract of DOI:10.1021/ol702362n

A convenient and efficient synthesis of highly substituted pyrrolin-4-ones is developed via the PIFA-mediated cyclization reactions of readily available enaminones, and a mechanism involving sequential cleavage of N - C bond, formation of new N - C bond, intramolecular addition reaction, and benzilic acid type rearrangement is proposed.

Full text of DOI:10.1021/ol702362n

ORGANIC
LETTERS
2007
Vol. 9, No. 26
5345-5348
Efficient Synthesis of Highly Substituted
Pyrrolin-4-ones via PIFA-Mediated
Cyclization Reactions of Enaminones
Jie Huang,† Yongjiu Liang,† Wei Pan,† Yang Yang,† and Dewen Dong*,†,‡
Department of Chemistry, Northeast Normal UniVersity, Changchun 130024, China,
and Changchun Institute of Applied Chemistry, Chinese Academy of Sciences,
Changchun 130022, China
dongdw663@nenu.edu.cn
Received July 19, 2007
ABSTRACT
A convenient and efficient synthesis of highly substituted pyrrolin-4-ones is developed via the PIFA-mediated cyclization reactions of readily
available enaminones, and a mechanism involving sequential cleavage of N−C bond, formation of new N−C bond, intramolecular addition
reaction, and benzilic acid type rearrangement is proposed.
Due to their promising structural feature, enaminones have
emerged as versatile synthetic intermediates that combine
the ambident nucleophilicity of enamines with the ambident
electrophilicity of enones.1,2 Their chemistry has been the
focus of intense research for decades, particularly in het-
erocyclic synthesis, and continues to be an active area of
research today.
On the other hand, hypervalent iodine reagents have been
extensively used as the oxidation reagents in synthetic
organic chemistry.3 One such reagent, phenyliodine(III) bis-
(trifluoroacetate) (PIFA) has attracted considerable attention
recently due to its ready availability, low toxicity, easy
handling, and reactivity similar to that of heavy metal
reagents.4 Its efficient utilization in the metal-free transfor-
mations relies on both the extremely mild reaction conditions
required and its ability to oxidize chemoselectively a wide
range of functionalities such as phenols, amines, sulfides,
and carbonyl compounds. Recently, Tellitu and co-workers
developed novel metal-free approaches to the synthesis of
nitrogen-containing heterocycles using properly substituted
amides and amines as synthetic precursors in which an
intramolecular N-N, N-S, or N-C bond is formed through
a PIFA-mediated oxidization process.5
During the course of our studies on â-oxo amide deriva-
tives in the synthesis of carbo- and heterocycles,6 we
successfully developed an efficient one-pot synthesis of
substituted isothiazol-3(2H)-ones from readily available
R-carbamoyl ketene (S,S)-acetals in the presence of PIFA.7
Thus, in connection with this previous work and following
† Northeast Normal University.
‡ Chinese Academy of Sciences.
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10.1021/ol702362n CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/30/2007

on from our research on the synthesis of highly valuable
heterocycles through oxidative processes, we have prepared
a series of enaminones from 1,3-dicarbonyl compounds and
examined their reactivity toward the environmentally friendly
reagent PIFA. As a result of these studies, we have developed
a simple and efficient synthesis of highly substituted pyrrolin-
4-ones via the PIFA-mediated cyclization of readily available
enaminones.
alkylation reaction of 3-hydroxy pyrroles.16 In the present
paper, we provide a novel and alternative access route to
substituted pyrrolin-4-ones through a PIFA-mediated oxida-
tive cyclization.
Substrate enaminones 3 were prepared from 1,3-dicarbonyl
compounds 1 with various amines 2 in very high yields
according to the reported procedure (Scheme 1).17 We
Pyrrolin-4-one derivatives are an important class of
functionalized nitrogen-containing heterocycles along with
useful biological activities and widely used as key building
block for the development of anticancer, antithrombotic, and
antimicrobial agents.8 Smith and Hirschmann have defined
a pyrrolin-4-one-based scaffold that mimics peptide â-sheet
backbone hydrogen-bonding donors, acceptors, and side
chains9 and extended that to the design of substrate mimetics
of HIV-1 protease10 and ligands of MHC class II proteins.11
So far, extensive research has generated many procedures
for the synthesis of pyrrolin-4-ones, such as formal [2 + 3]
cycloaddition reaction of cyclopropenones with imine deriva-
tives containing the CdN moiety,12 cyclocondensation reac-
tions of R-amino ester derivatives with aldehydes13 and
vicinal tricarbonyls with enamines or amines,14 intramolecu-
lar cyclization of 2-azabutadienes,15 and intramolecular
Scheme 1. Preparation of Substrates Enaminones 3
selected 3-(benzylamino)-N-phenylbut-2-enamide 3a from a
series of substrates 3, see Table 1, as the model compound
to examine its behavior under different conditions.
Table 1. The Cyclization Reactions of Enaminones 3a
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I.; Dom´ınguez, E.; Moreno, I.; SanMart´ın, R. Org. Lett. 2005, 7, 3073-
3076. (f) Correa, A.; Tellitu, I.; Dom´ınguez, E.; SanMart´ın, R. J. Org. Chem.
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R. Org. Lett. 2006, 8, 4811-4813.
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2007, 2791-2796.
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entry
3
R1
PhNH
4-MePhNH
4-MeOPhNH Bn
4-ClPhNH
2-MePhNH
2-MeOPhNH Bn
2-ClPhNH
PhNH
4-MePhNH
4-MeOPhNH Me
R2
time (h)
4
yieldc (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17b
18b
19
20
3a
3b
3c
3d
3e
3f
3g
3h
3i
Bn
Bn
4.5
5.0
4.0
5.0
4.0
4.5
5.0
4.0
4.0
4.0
4.5
4.0
4.0
4.5
4.0
4.5
3.0
2.5
3.5
3.0
4a
4b
4c
4d
4e
4f
4g
4h
4i
65
60
61
59
64
58
62
68
65
69
75
63
61
66
77
71
Bn
Bn
Bn
Me
Me
3j
3k
3l
4j
4k
4l
4-ClPhNH
2-MePhNH
Me
Me
3m 2-MeOPhNH Me
4m
4n
4o
4p
4q
4r
4s
4t
3n
3o
3p
3q
3r
3s
3t
2-ClPhNH
PhNH
2-MePhNH
OEt
OEt
Me
Me
Ph
Ph
Bn
Me
Bn
Me
68
59
23 (52)d
0 (67)d
Me
a Reagents and conditions: 3 (1.0 mmol), PIFA (1.0 mmol), TFA (2.0
mmol), CH2Cl2 (100 mL), rt. b The concentration of PIFA is 0.1 M.
c Isolated yields. d The data in parentheses is for compounds 5.
(11) Smith, A. B., III; Benowitz, A. B.; Guzman, M. C.; Sprengeler, P.
A.; Hirschmann, R.; Schweiger, E. J.; Bolin, D. R.; Nagy, Z.; Campbell,
R. M.; Cox, D. C.; Olson, G. L. J. Am. Chem. Soc. 1998, 120, 12704-
12705.
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(13) (a) Smith, A. B., III; Guzman, M. C.; Sprengeler, P. A.; Keenan,
T. P.; Holcomb, R. C.; Wood, J. L.; Carroll, P. J.; Hirschmann, R. J. Am.
Chem. Soc. 1994, 116, 9947-9962. (b) Smith, A. B., III; Liu, H.;
Hirschmann, R. Org. Lett. 2000, 2, 2041-2044. (c) Kakehi, A.; Ito, S.;
Yotsuya, T. Chem. Pharm. Bull. 1986, 34, 2435-2443. (d) Kakehi, A.;
Ito, S.; Nakanishi, K.; Watanabe, K.; Kitagawa, M. Bull. Chem. Soc. Jpn.
1980, 53, 1115-1120.
Upon treatment of 3a with PIFA (1.0 equiv, 0.05 M) and
trifluoroacetic acid (TFA, 3.0 equiv) in CH2Cl2 at room
temperature for 4.5 h, the reaction furnished a product after
(14) (a) Wasserman, H. H.; Ennis, D. S.; Vu, C. B.; Schulte, G. K.
Tetrahedron Lett. 1991, 32, 6039-6042. (b) Wasserman, H. H.; Frechette,
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5346
Org. Lett., Vol. 9, No. 26, 2007

workup and purification (column chromatography) of the
resulting mixture, which was characterized as a substituted
pyrrolin-4-one 4a (57% yield) on the basis of its spectral
and analytical data (Scheme 2). Meanwhile, compound 1a,
3a was performed with PIFA (1.0 equiv, 0.01 M) in CH2Cl2
at room temperature in the presence of TFA (2.0 equiv),
whereby the yield of 4a reached 65% (Table 1, entry 1).
Having established the optimal conditions for the key cy-
clization process, we aimed to determine its scope with re-
spect to the amide moiety and amine functionality of sub-
strates 3. Thus, a series of enaminones 3b-p were subjected
to PIFA/TFA under the optimized conditions. As shown in
Table 1 (entries 2-7), the PIFA-mediated cyclization reaction
proved to be suitable for 3b-g with varied aryl amide
groups, affording the corresponding substituted pyrrolin-4-
ones 4b-g in moderate to good yields. The versatility of
this pyrrolin-4-one synthesis was further evaluated by per-
forming 3h-p bearing methylamino or phenylamino groups
under the identical conditions (entries 8-16). The results
shown above demonstrate the efficiency and synthetic value
of the cyclization reaction of variable enaminones 3. It should
be noted that the richness of the functionality of substituted
pyrrolin-4-ones 4 may render them versatile as synthons in
further synthetic transformations, for example, upon hydro-
genation to their pyrrolidinone and pyrrolidine analogues.18
It is worth mentioning that in Tellitu’s recent work on a
novel N-N bond formation for the synthesis of indazol-3-
ones, the key cyclization step is assumed to involve the
formation of an N-acylnitrenium ion,19 mediated by PIFA,
and its subsequent intramolecular trapping by the amine
moiety.5d In contrast, our results suggested that a nitrenium
ion was generated at alkylamino group of substrate 3 instead
of aryl amide moiety. These findings encouraged us to extend
the scope of the cyclization protocol to other types of
enaminones. Thus, we examined the reactions of enaminones
3q and 3r, prepared from â-oxo esters, under the same
conditions. Unfortunately, it was found that the reactions
proceeded sluggishly with much lower conversions and
yields. However, with increase of the concentration of
PIFA to 0.1 M, the reactions could afford the corre-
sponding pyrrolin-4-ones 4 in good yields (entries 17 and
18). Interestingly, when subjecting 3s, prepared from acetyl-
acetone, to the identical conditions as for 4a, the reaction
furnished two products, which were characterized as pyrrolin-
4-ones 4s (23%) and 5s (52%) on the basis of their spectra
and analytical data (entry 19, Scheme 3). Apparently,
Scheme 2. Reaction of Enaminone 3a in the Presence of
PIFA/TFA
the precursor of 3a, was obtained as a byproduct in 21%
yield. The structure of 4a was further confirmed by the X-ray
single-crystal analysis (Figure 1).
Figure 1. ORTEP drawing of 4a.
The optimization of the reaction conditions, including
reaction temperature, solvents, concentration of PIFA, and
feed ratio of PIFA, TFA, and 3a, were then investigated.
Variation of the reaction temperature in the range 0-40 °C
has no significant influence on the reaction. The reaction
also proceeds in other polar solvents, such as DMF, THF,
and acetonitrile, although CH2Cl2 proved to be the most
efficient medium for the cyclization reaction. The concentra-
tion of PIFA plays an important role in the reaction. A high
concentration of PIFA, more than 0.1 M, for example, results
in a low yield. In the absence of TFA, the reaction proceeded
sluggishly, and as indicated by TLC compound 1a was
formed and accumulated. A series of experiments revealed
that the optimal results were obtained when the reaction of
Scheme 3. Reactions of Enaminones 3s/3t
compound 5s is formed by the deacylation of the corre-
sponding 4s under the acidic conditions. As indicated by
(15) (a) Palacios, F.; Alonso, C.; Legido, M.; Rubiales, G.; Villegas, M.
Tetrahedron Lett. 2006, 47, 7815-7818. (b) Erden, I.; Ozer, G.; Hoarau,
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31, 4945-4948.
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Chem. Soc. 1986, 108, 3443-3452. (c) Deli, N. S.; Perumal, S. Tetrahedron
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Org. Lett., Vol. 9, No. 26, 2007
5347

TLC, 4s could be converted completely into 5s by further
stirring (8.0 h) at room temperature. In the case of 3t, only
the corresponding deacylation product 5t was obtained in
67% yield (entry 20, Scheme 3).
Scheme 5. Proposed Mechanism of the Cyclization of 3
Further experiments were conducted in order to gain
insight into the mechanism of the cyclization reaction. In
the absence of PIFA, the reaction of 3h with 2.0 equiv of
TFA was performed at room temperature for 30 min and
then quenched with saturated aqueous NaHCO3. Compound
1h was obtained in 93% yield. This result implied that the
above cyclization reaction of 3 might take place between
compounds 3 and 1 instead of two molecules of compound
3. Thus, we examined the reaction of 3h and 1d under the
same conditions as for 4h in Table 1. After workup and
purification, to our delight, compounds 4hd and 4h were
obtained in 19% and 43% yields, respectively (Scheme 4).
Scheme 4. Reaction between 3h and 1d
ion F, which finally undergoes a benzilic acid type rear-
rangement affording the product 4.14a,20 If R1 of 4 is a methyl
group, a deacylation reaction of 4 easily takes place to give
the corresponding pyrrolin-4-one of type 5.
In summary, a convenient and efficient synthesis of highly
substituted pyrrolin-4-ones 4 is developed via the PIFA-
mediated cyclization reactions of readily available enami-
nones 3, which involves sequential cleavage of N-C bond,
new N-C bond formation, intramolecular C-C bond forma-
tion, and benzilic acid type rearrangement processes. This
protocol is associated with readily available starting materials,
mild conditions, good yields, and broad range of synthetic
potential of the products. Further work on the scope of the
cyclization protocol and its application is currently underway
in our laboratory.
The structure of compound 4hd was confirmed by its
elemental analyses and NMR spectra in comparison to that
of 4h and 4k. The mass spectra of 4hd (398.1 [M + 1]+)
are consistent with the NMR results. All of the results reveal
that TFA is a useful additive assisting the cleavage of
enaminone 3 and provides the acidic conditions promoting
the novel cyclization to 4.
A plausible mechanism for the synthesis of substituted
pyrrolinones 4 based on the results obtained is presented in
Scheme 5. The overall transformation commences from the
cleavage of enaminone 3 (at least 0.5 equiv) in the presence
of TFA yielding 1, and the simultaneous formation of
nitrenium ion A generated from 3 (less than 0.5 equiv) by
the action of the mild oxidant PIFA. The nitrenium ion A
reacts with B, the tautomer of 1, to give intermediates C
and D. Then an intramolecular addition reaction of D via
the enamine chemistry occurs under acidic conditions to give
E, followed by a PIFA-mediated oxidation to form iminium
Acknowledgment. Financial support of this research by
the NNSFC (20572013 and 20711130229) is greatly ac-
knowledged.
Supporting Information Available: Experimental de-
1
tails, spectral data, and copies of H NMR and 13C NMR
spectra for compounds 3-5. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL702362N
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