Highly efficient and expedient synthesis of 5-hydroxy-1 H-pyrrol-2-(5 H)-ones from FeCl3-catalyzed tandem intramolecular enaminic addition of tertiary enamides to ketones and 1,3-hydroxy rearrangement

Article abstract of DOI:10.1021/ol101607z

Catalyzed by FeCl₃ under very mild conditions, tertiary enamides underwent a highly efficient intramolecular enaminic addition reaction to the ketonic carbonyls followed by 1,3-hydroxy rearrangement to produce 5-hydroxy-1H-pyrrol-2(5H)-ones in

Full text of DOI:10.1021/ol101607z

ORGANIC
LETTERS
2010
Vol. 12, No. 17
3918-3921
Highly Efficient and Expedient Synthesis
of 5-Hydroxy-1H-pyrrol-2-(5H)-ones from
FeCl3-Catalyzed Tandem Intramolecular
Enaminic Addition of Tertiary Enamides
to Ketones and 1,3-Hydroxy
Rearrangement
Luo Yang,† Chuan-Hu Lei,† De-Xian Wang,† Zhi-Tang Huang,† and
Mei-Xiang Wang*,†,‡
Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of
Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of
Sciences, Beijing 100190, China, and The Key Laboratory of Bioorganic Phosphorus
Chemistry & Chemical Biology (Ministry of Education), Department of Chemistry,
Tsinghua UniVersity, Beijing 100084, China
wangmx@mail.tsinghua.edu.cn
Received July 12, 2010
ABSTRACT
Catalyzed by FeCl3 under very mild conditions, tertiary enamides underwent a highly efficient intramolecular enaminic addition reaction to the
ketonic carbonyls followed by 1,3-hydroxy rearrangement to produce 5-hydroxy-1H-pyrrol-2(5H)-ones in excellent yields.
5-Hydroxy-1H-pyrrol-2(5H)-ones 1 are important N-hetero-
cyclic compounds in organic chemistry. Not only is the
heterocyclic structure found in natural products such as
oteromycin,1 a microbial metabolite acting as an antagonist of
endothelin receptor, but also some synthetic 5-hydroxy-1H-
pyrrol-2(5H)-one derivatives have been shown to possess
interesting pharmacological properties2 and neuritogenic activ-
ity.3 In addition, 5-hydroxy-1H-2(5H)-ones are useful interme-
diates in synthesis.4-6 For example, 5-allyl-5-hydroxy-3-iodo-
1H-pyrrol-2(5H)-one has been used as a key intermediate
in the total synthesis of natural product lucilactaene, a cell
cycle inhibitor active in p53-inactive cells.4 A few synthetic
approaches to 5-hydroxy-1H-pyrrol-2(5H)-one skeletons have
been reported in the literature (Figure 1). They mainly
include: (1) the condensation reaction between R,ꢀ-diketones
with acetamides bearing a strong electron-withdrawing group
in the R-position;3,7 (2) selective reduction of maleimide
derivatives6,8 and addition of an organometallic agent to
† Chinese Academy of Sciences.
‡ Tsinghua University.
(1) Singh, S. B.; Goetz, M. A.; Jones, E. T.; Bills, G. F.; Giacobbe,
R. A.; Herranz, L.; Stevens-Miles, S.; Williams, D. L., Jr. J. Org. Chem.
1995, 60, 7040.
(4) (a) Coleman, R. S.; Walczak, M. C.; Campbell, E. L. J. Am. Chem.
Soc. 2005, 127, 16038. (b) Uno, H.; Yayamn, A.; Suzuki, H. Tetrahedron
(2) Toja, E.; Gorini, C.; Barzaghi, F.; Galliani, G. U.S. Patent 4885307,
1989.
1992, 48, 8353
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(5) Snider, B. B.; Neubert, B. J. J. Org. Chem. 2004, 69, 8952
(6) Pin, F.; Comesse, S.; Garrigues, B.; Marchalin, S.; Da¨ıch, A. J. Org.
Chem. 2007, 72, 1181
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(3) Kakeya, H.; Onozuka, C.; Sato, M.; Arai, K.; Osada, H. J. Med.
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10.1021/ol101607z  2010 American Chemical Society
Published on Web 08/10/2010

enantioenriched R-amino acid derivatives.18 In recent years,
Kobayashi19 has shown that secondary enamides, the ena-
mide species bearing an N-H moiety (Figure 2), are able
Figure 2. Enamine, tertiary enamide, and secondary enamide.
to react with different electron-deficient reactants in the
presence of a Lewis acid catalyst. These secondary enamides
behave actually as the aza-ene components to undergo the
aza-ene reactions.19,20 The enaminic (nucleophilic) reactions
of tertiary enamides (Figure 2) are very rare.16,21 Only very
strong electrophiles such as acid chlorides, acid anhydrides,
and iminium salts (the Vilsmeier reagent) are reported to
react with tertiary enamides or enecarbamates.21 In the study
of the synthesis of clausena alkaloids, however, we22 found
that tertiary enamides can act as good nucleophiles to react
with epoxide to form homoclausenamide alkaloids. This led
us to explore the enaminic reactions of enamides. We
envisioned that the ready availability of various enamides23
and their good stability would render enamides as valuable
and unique nucleophilic reagents in organic synthesis. We
report herein highly efficient FeCl3-catalyzed intramolecular
nucleophilic addition of enamides to ketones followed by
1,3-hydroxy shift reaction. The reaction provided a very
convenient and expedient access to 5-hydroxy-1H-pyrrol-
2(5H)-one derivatives in excellent yields.
Figure 1. Reported synthetic approaches to 5-hydroxy-1H-pyrrol-
2(5H)-one derivatives.
maleimide derivatives;4 (3) oxidation of pyrrolinones;5,9 (4)
reaction of isonitriles with chalcones;10 (5) a Pd(0)-catalyzed
coupling reaction of 2,3-allenamides with aryl iodide;11 and
(6) ceric ammonium nitrate (CAN) mediated oxidative
5-endo-cyclization of enamides.12 These methods however
suffer from drawbacks such as low chemical yield, poor
regioselectivity, or substrate limitations. The development
of new synthetic methods is therefore highly desirable.
Enamines13 are very useful intermediates in organic
synthesis.14 The importance of enamine chemistry has been
illuminated recently by asymmetric organocatalysis using
chiral amine derivatives.15 As the enamine variant, enamides
are, however, stable and show diminished nucleophilic
reactivity because of the electron-withdrawing effect of the
N-acyl group which alleviates the delocalization of the lone-
pair electrons on nitrogen into the carbon-carbon double
bond.16 The stability of enamides has been exemplified by
the observation of many enamide natural products.17 The
majority of the synthetic application of enamides is their
catalytic hydrogenation reactions for the preparation of
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Shin-ya, K.; Furihata, K.; Hayakawa, Y.; Seto, H. J. Org. Chem. 1999, 64,
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Boyd, M. R. J. Org. Chem. 1997, 62, 8968. (c) McKee, T. C.; Galinis,
D. L.; Pannell, L. K.; Cardellina II, J. H.; Laakso, J.; Ireland, C. M.; Murray,
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K. L.; Beutler, J. A.; Cardellina, J. H., II; Boyd, M. R. J. Org. Chem. 1997,
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Inagaki, T.; Sakakibara, T.; Suzuki, Y.; Thompson, J. F.; Yamauchi, Y.;
Kojima, N. J. Antibiot. 1998, 51, 14. (g) Jansen, R.; Kunze, B.; Reichenbach,
H.; Ho¨fle, G. Eur. J. Org. Chem. 2000, 913. (h) Milner, P. H.; Costes,
N. J.; Gilpin, M. L.; Spear, S. R. J. Nat. Prod. 1996, 59, 400. (i) Shiomi,
K.; Hatae, K.; Yamaguchi, Y.; Masuma, R.; Tomoda, H.; Kobayashi, S.;
Omura, S. J. Antibiot. 2002, 11, 952. (j) Su, S.; Kayeya, H.; Osada, H.;
Porco, J. A., Jr. Tetrahedron 2003, 59, 8931, and references cited therein.
(18) Gridnev, I. D.; Imamoto, T. Acc. Chem. Res. 2004, 37, 633.
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S. V. J. Am. Chem. Soc. 1988, 110, 4017. (b) Mase, N.; Nishi, T.; Hiyoshi,
M.; Ichihara, K.; Bessho, J.; Yoda, H.; Takabe, K. J. Chem. Soc., Perkin
Trans. 1 2002, 707. (c) Coleman, R. S.; Liu, P.-H. Org. Lett. 2004, 6, 577
(9) (a) Rudler, H.; Parlier, A.; Ousmer, M.; Vaissermann, J. Eur. J. Org.
Chem. 1999, 3315. (b) Clayden, J.; Turnbull, R.; Pinto, I. Tetrahedron:
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Asymmetry 2005, 16, 2235
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(19) (a) Matsubara, R.; Kobayashi, S. Acc. Chem. Res. 2008, 41, 292,
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enamides with imines was also known. Terada, M.; Machioka, K.;
Sorimachi, K. Angew. Chem., Int. Ed. 2006, 45, 2254. (c) Terada, K.;
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(10) Adib, M.; Mahdavi, M.; Noghani, M. A.; Bijanzadeh, H. R.
Tetrahedron Lett. 2007, 48, 8056.
(11) Ma, S.; Xie, H. J. Org. Chem. 2002, 67, 6575.
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Shono, T.; Matsumura, Y.; Tsubata, K.; Sugihara, Y.; Yamane, S.-i.;
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Org. Lett., Vol. 12, No. 17, 2010
3919

We started our study with a catalytic reaction of
enamide 2a which was obtained readily from the reaction
of imine with 2-oxo-2-phenylacetyl chloride (see Sup-
porting Information). Having considered the natural
abundance, cost, environmental impact, and convenience
of handling, Lewis acids derived from zinc, copper, and
iron were chosen as catalysts (Table 1). In the presence
3, Table 1), Cu(OTf)2 was able to catalyze the reaction
of 2a efficiently to produce 4a as the sole product in
almost quantitative yield (entry 4, Table 1). Both AlCl3
and Sn(OTf)2 were effective catalysts for the transforma-
tion of 2a into 4a, albeit the former catalyst was less active
than the latter (entries 5 and 6, Table 1). To our delight,
FeCl3 was found to be a very active Lewis acid catalyst.
It catalyzed the reaction of enamide 2a very rapidly to
give quantitative yield of product 4a (entry 7, Table 1).
FeCl3·6H2O also catalyzed the reaction but with diminished
efficiency (entry 8, Table 1). It is noteworthy that
transformation of 2a into 4a proceeded equally efficiently
with the use of a decreased catalyst loading (entry 9, Table
1), and rapid and quantitative conversion of 2a into 4a
was achieved even with the use of 0.5 mol % of catalyst
(entry 10, Table 1). The efficient FeCl3-catalyzed reaction
also took place in other solvents such as CHCl3 (entry
11, Table 1) and toluene (entry 12, Table 1). However, a
polar solvent such as acetonitrile slowed down the
transformation of 2a (entry 13, Table 1), whereas methanol
completely inhibited the reaction (entry 14, Table 1). It
should be addressed that compound 3a was the precursor
of product 4a, as the treatment of isolated 3a with a
catalytic amount of FeCl3 (2 mol %) in CH2Cl2 at room
temperature led to the exclusive formation of 4a.
Table 1. Optimization of Catalytic Reaction of Enamide 1aa
entry
cat. (mol %)
ZnCl2 (10)
Zn(OTf)2 (10)
[Cu(CH3CN)4]PF6 (10) CH2Cl2 46.5 h
Cu(OTf)2 (10)
AlCl3 (10)
Sn(OTf)2 (10)
FeCl3 (10)
FeCl3·6H2O (10)
FeCl3 (2)
solvent
time
3a (%)b 4a (%)b
1
2
3
4
5
6
7
8
9
CH2Cl2 47 h
CH2Cl2 47.5 h
53
22
54
-
-
-
-
-
-
-
-
-
-
-
34
48
26
98
97
95
99
98
100
100
100
100
100
-
CH2Cl2 5 h
CH2Cl2 60 h
CH2Cl2 20 min
CH2Cl2 15 min
CH2Cl2 2 h
CH2Cl2 15 min
CH2Cl2 20 min
CHCl3 15 min
toluene 30 min
CH3CN 6 days
CH3OH 7 days
10 FeCl3 (0.5)
The structures of 3a and 4a were established on the basis
of spectroscopic data and elemental analysis. It should be
noted that that the vinyl proton of 3a gave its resonance peak
at 5.58 ppm, while compound 4a showed its vinyl proton
11 FeCl3 (2)
12 FeCl3 (2)
13 FeCl3 (2)
14 FeCl3 (2)
1
signal at 7.01 ppm in their H NMR spectra. The huge
a A mixture of reactant 2a (0.3 mmol) and catalyst in dry solvent (15
mL) was stirred at room temperature. The reaction was stopped when
reactant was consumed. b Isolated yield.
difference in chemical shift (∆δ ) 1.43 ppm) between two
proton signals in 1H NMR spectra reflected different
structural features of two compounds. In the case of 3a,
because of the delocalization of nitrogen lone pair electrons
into the carbon-carbon double bond, the electron density
of C-3 was increased, leading to a shielding effect on the
vinyl proton. On the contrary, the R,ꢀ-unsaturated system
in compound 4a resulted in the decrease of electron density
of C-3, causing its vinyl proton signal to be downfield shifted.
This difference was actually used as a diagnostic tool to
differentiate these two products. To prove the structures
beyond doubt, compound 3a was converted into its O-
methylated derivative 5 (Scheme S1, Supporting Information
(SI)), and single-crystal molecular structures of 4a and 5 were
determined unambiguously by X-ray crystallography (Figure
S1, SI).
of a catalytic amount of ZnCl2 (10 mol %), enamide 2a
was found to undergo reaction smoothly at room temper-
ature. After about two days, 1-benzyl-3-hydroxy-3,5-
diphenyl-1H-pyrrol-2(3H)-one 3a, the product resulting
from direct intramolecular nucleophilic addition of ena-
mide to ketone carbonyl, was obtained in 53% yield.
Surprisingly, the reaction also produced a moderate yield
of 1-benzyl-5-hydroxy-3,5-diphenyl-1H-pyrrol-2(5H)-one
4a (entry 1, Table 1). The use of Zn(OTf)2 as a catalyst
gave a similar result but with a slight preference for the
formation of product 4a (entry 2, Table 1). While
[Cu(CH3CN)4]PF6-catalyzed reaction proceeded slowly to
afford a mixture of products 3a (54%) and 4a (26%) (entry
Under the optimized reaction conditions, the scope of
the reaction was explored. As indicated by the results in
Table 2, all enamides tested underwent highly efficient
intramolecular reaction to give 5-hydroxy-3,5-diaryl-1H-
pyrrol-2(5H)-one products in excellent yields. The reaction
was accelerated when ketone moiety was substituted by
a 4-chlorophenyl group (entry 8, Table 2). The change of
the substituent on nitrogen from benzyl (entries 1-9,
Table 2) and allyl (entry 10, Table 2) to methyl and phenyl
led to a decrease of reaction rate (entries 11 and 12, Table
2). It was noticeable that the stronger the nucleophilicity
(23) For examples of the synthesis of enamides, see: (a) Boeckman,
R. K., Jr.; Goldstein, S. W.; Walters, M. A. J. Am. Chem. Soc. 1988, 110,
8250. (b) Hosokawa, T.; Takano, M.; Kuroki, Y.; Murahashi, S.-I.
Tetrahedron Lett. 1992, 33, 6643. (c) Zezza, C. A.; Smith, M. B. Synth.
Commun. 1987, 17, 729. (d) Kiefel, M. J.; Maddock, J.; Pattenden, G.
Tetrahedron Lett. 1992, 33, 3227. (e) Kondo, T.; Tanaka, A.; Kotachi, S.;
Watanabe, Y. J. Chem. Soc., Chem. Commun. 1995, 413. (f) Brettle, R.;
Mosedale, A. J. J. Chem. Soc., Perkin Trans. 1 1988, 2185. (g) Cuevas,
J.-C.; Patil, P.; Snieckus, V. Tetrahedron Lett. 1989, 30, 5841. (h) Palomo,
C.; Aizpurua, J. M.; Legido, M.; Picard, J. P.; Dunogues, J.; Constantieux,
T. Tetrahedron Lett. 1992, 33, 3903. (i) Couture, A.; Deniau, E.;
Grandclaudon, P. Tetrahedron Lett. 1993, 34, 1479. (j) Yang, L.; Deng,
G.; Wang, D.-X.; Huang, Z.-T.; Zhu, J.-P.; Wang, M.-X. Org. Lett. 2007,
9, 1387.
3920
Org. Lett., Vol. 12, No. 17, 2010

(nucleophilic) reaction of enamide to the Lewis acid-activated
ketone carbonyl to form a cyclic iminium intermediate B.
Deprotonation of iminium afforded 3-hydroxy-3,5-diaryl-1H-
pyrrol-2(3H)-one product 3. Dehydration of 3 led to the
formation of 2-oxo-2H-pyrrolium intermediate C which
reacted with a water molecule to furnish the final 5-hydroxy-
3,5-diaryl-1H-pyrrol-2(5H)-one products 4 (Scheme 2). It
Table 2. FeCl3-Catalyzed Reaction of Enamides 2
entry
2
R1
R2
R3
t (min)
4 (%)a
1
2
3
4
6
7
8
9
2a Bn
2b Bn
2c Bn
2d Bn
2e Bn
2f Bn
2g Bn
2h PMB Ph
2i Allyl Ph
2j Me
2k Ph
Ph
Ph
15
45
30
40
40
40
5
30
30
120
60
4a (100)
4b (100)
4c (96)
4d (99.5)
4e (100)
4f (99)
4g (98)
4h (100)
4i (99)
Scheme 2. Mechanism of FeCl3-Catalyzed Reaction
4-Me-C6H4 Ph
4-Cl-C6H4 Ph
4-Br-C6H4 Ph
Ph
Ph
Ph
4-Me-C6H4
4-F-C6H4
4-Cl-C6H4
Ph
Ph
Ph
10
11
12
Ph
Ph
4j (94)
4k (94)
Ph
a Isolated yield.
of enamide and electrophilicity of the carbonyl, the faster
the reaction.
The method was also applicable to other substrates.
Scheme 1 illustrates, for example, the synthesis of a tricyclic
should be addressed that the activation of ketone carbonyl
occurred via a monocoordination fashion. The chelation of
R-oxo amide to iron is not beneficial or responsible for the
intramolecular enaminic reaction because the rigid geometry
of the chelation structure does not bring the proximity of
enaminic carbon to ketone carbonyl carbon. Polar solvents
such as acetonitrile and methanol compete with substrate to
interact with iron catalyst, leading to a very slow reaction.
The driving force of the rearrangement of the hydroxy group
from C-3 to C-5 was most likely due to the stability gained
from the formation of the 2-oxo-2H-pyrrolium intermediate
and of an R,ꢀ-conjugation system in the final products.
In summary, we have provided a highly efficient and
expedient access to 5-hydroxy-1H-pyrrol-2(5H)-ones. The
synthesis involves FeCl3-catalyzed intramolecular enaminic
addition of tertiary enamides to a ketonic carbonyl followed
by 1,3-hydroxy rearrangement. The study of reactions of
tertiary enamides with various electrophiles is being actively
pursued in this laboratory.
Scheme 1. Synthesis of Tricyclic Compound 9
compound with the FeCl3-catalyzed cyclization reaction as
a key step. Thus, reaction of R-tetralone 6 with benzylamine
gave a quantitative yield of imine 7 that underwent N-acylation
using 2-oxo-2-phenylacetyl chloride to afford enamide 8 in 79%.
FeCl3-catalyzed reaction of enamide 8 produced 1-benzyl-9b-
hydroxy-3-phenyl-4,5-dihydro-1H-benzo[g]indol-2(9bH)-one 9
in a very high yield (Scheme 1).
Acknowledgment. We thank NNSFC, MOST, and CAS
for financial support.
Supporting Information Available: Synthesis and char-
acterization of products, 1H and 13C NMR spectra, and X-ray
structure of 4a and 5 (cifs). This material is available free
of charge via the Internet at http://pubs.acs.org.
The FeCl3-catalyzed intramolecular reaction of enamides
2 proceeded most probably through the direct enaminic
OL101607Z
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