Synthesis of 5-azaspiro[2.4]heptan and penta-substituted pyrrole derivatives via pd-catalyzed intramolecular cyclization reaction of alkynyl carboxamides

Article abstract of DOI:10.1080/00397911.2010.535944

Penta-substituted pyrrole derivatives, including a three-membered ring (5-azaspir-o[2.4]heptan), were readily prepared in moderate to excellent yields by the Pd-catalyzed intramolecular cyclization reaction of alkynyl carboxamide compounds. When an excess

Full text of DOI:10.1080/00397911.2010.535944

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Synthesis of 5-Azaspiro[2.4]heptan and
Penta-Substituted Pyrrole Derivatives via
Pd-Catalyzed Intramolecular Cyclization
Reaction of Alkynyl Carboxamides
Jian-Ye Hou a , Dan-Zhu Wang a , Fei Li b , Ze-Yi Yan b , Yong-Min
Liang a & Ying-Qian Liu c
a State Key Laboratory of Applied Organic Chemistry, Lanzhou
University, Lanzhou, China
b Laboratory of Radiochemistry, School of Nuclear Science and
Technology, Lanzhou University, Lanzhou, China
c School of Pharmacy, Lanzhou University, Lanzhou, China
Accepted author version posted online: 07 Oct 2011.Published
online: 16 Dec 2011.
To cite this article: Jian-Ye Hou , Dan-Zhu Wang , Fei Li , Ze-Yi Yan , Yong-Min Liang & Ying-Qian
Liu (2012) Synthesis of 5-Azaspiro[2.4]heptan and Penta-Substituted Pyrrole Derivatives via Pd-
Catalyzed Intramolecular Cyclization Reaction of Alkynyl Carboxamides, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 42:7, 1070-1084,
DOI: 10.1080/00397911.2010.535944
To link to this article: http://dx.doi.org/10.1080/00397911.2010.535944
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Synthetic Communications1, 42: 1070–1084, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.535944
SYNTHESIS OF 5-AZASPIRO[2.4]HEPTAN AND
PENTA-SUBSTITUTED PYRROLE DERIVATIVES VIA
Pd-CATALYZED INTRAMOLECULAR CYCLIZATION
REACTION OF ALKYNYL CARBOXAMIDES
Jian-Ye Hou,1 Dan-Zhu Wang,1 Fei Li,2 Ze-Yi Yan,2
Yong-Min Liang,1 and Ying-Qian Liu3
1State Key Laboratory of Applied Organic Chemistry, Lanzhou University,
Lanzhou, China
2Laboratory of Radiochemistry, School of Nuclear Science and Technology,
Lanzhou University, Lanzhou, China
3School of Pharmacy, Lanzhou University, Lanzhou, China
GRAPHICAL ABSTRACT
Abstract Penta-substituted pyrrole derivatives, including a three-membered ring (5-azaspir-
o[2.4]heptan), were readily prepared in moderate to excellent yields by the Pd-catalyzed
intramolecular cyclization reaction of alkynyl carboxamide compounds. When an excess
amount of ZnCl2 acted as a Lewis acid and a source of halide, the one-pot bi-metallic sys-
tem could afford more valuable penta-substituted chloroethyl pyrrole products under similar
conditions. This indicates that the present method is a powerful tool for the preparation of a
wide range of functionalized and polysubstituted pyrroles.
Keywords Alkynyl carboxamide; 5-azaspiro[2.4]heptan; Pd-catalyzed; penta-substituted;
pyrrole derivatives
INTRODUCTION
Transition metal–catalyzed cyclization reactions represent an effective and
straightforward methodology for the synthesis of cyclic and polycyclic structures,
which have attracted much attention.[1] Among these methods, palladium catalysis
has attracted great interest. During recent decades, palladium catalysts have emerged
as extremely powerful tools for the construction of carbocyclic and heterocyclic
Received May 7, 2010.
Address correspondence to Ze-Yi Yan, Laboratory of Radiochemistry, School of Nuclear Science
and Technology, Lanzhou University, Lanzhou 730000, China. E-mail: yanzeyi@lzu.edu.cn
1070

PENTA-SUBSTITUTED PYRROLE DERIVATIVES
1071
compounds.[2] Because the Pd-catalyzed procedure can tolerate many active groups,
such as carbonyl and hydroxyl groups, and it can be employed in the synthesis of
highly complex molecules.[3] Pd-catalyzed reactions have been expanded to generate
pyridines,[4] oxazoles,[5] thiazoles,[5,6] thiophenes,[7] benzothiophenes,[8] pyrazines,[9]
furans,[10] isoquinolines,[11] indoles,[12] and benzofurans[13] under various conditions.
Pyrroles and their derivatives occur in numerous pharmacologically active
natural and synthetic products and display a variety of physiological activities.[14]
Consequently, many methods for syntheses of diversely substituted pyrroles have
been reported, and numerous references can be found.[15] Classic methods for syn-
thesis of pyrrole derivatives have been developed (1) the Paal–Knorr reaction,[16]
one of the most attractive methods in which 1,4-diketones and primary amines are
converted to various pyrrole derivatives; (2) the Knorr reaction,[17] which assembles
pyrroles by the reaction of a-aminoketones and b-ketoesters; (3) the Hantzsch
reaction,[18] which is condensation of a-haloketones with 1,3-dicarbonyl compounds
in the presence of ammonia; and (4) other methods[19] including conjugate addition
reactions,[19h] transition metal–mediated reactions,[19i,j] reductive couplings,[19k]
aza-Wittig reactions,[19l] and other multi–step operations.[19m,n] Although numerous
strategies for synthesis of di-, tri-, and tetra-substituted pyrrole derivatives have been
widely reported, access to penta-substituted pyrroles is somewhat limited.[20] It has
been reported that penta-substituted pyrrole derivatives are potent hypocholestero-
lemic agents through the inhibition of HMG-CoA reductase, a key enzyme in the de
novo synthesis of cholesterol.[21] On the other hand, 5-azaspiro[2,4]heptane substitu-
ents could enhance the activity of quinolone antibiotics, especially against both
Gram-positive and Gram-negative bacteria.[22] The hydroxamate-spirocyclopropyl
compounds are potent inhibitors of TNF-a convertase (TACE).[23] Therefore, the
development of alternative strategies for synthesis of penta-substituted pyrrole and
5-azaspiro[2,4]heptane derivatives is of considerable importance.
Very recently, we reported synthesizing the polysubstituted 3-iodopyrans by
electrophilic cyclization of alkynyl carboxamides with ICl, I2, and N-iodosuccini-
mide (NIS).[24] In addition, we have also demonstrated that palladium-catalyzed
reactions of propargylic compounds with soft nucleophiles can serve as a useful
method for the construction of versatile carbon–carbon and carbon–heteroatom
bonds such as furans,[25] indenes,[26] benz[a]anthracene,[27] and benzo[b]furan.[26c]
In connection with our ongoing project on the Pd-catalyzed annulation reaction,
we expected that alkynyl carboxamides would afford polysubstituted heterocyclic
compounds via palladium catalysis (Scheme 1). Herein, we report our results on
the cyclization reaction of these substrates to unusual penta-substituted pyrroles.
Scheme 1. Cyclization reaction of alkynyl carboxamides.

1072
J.-Y. HOU ET AL.
RESULTS AND DISCUSSION
Based on the typical reaction condition explored in our earlier palladium-
catalyzed synthesis of indenes,[26a] we started our investigation by using 0.3 equiva-
lent of 1-(2-hydroxy-4-phenylbut-3-yn-2-yl)-N-phenylcyclopropanecarboxamide 1a,
5mol% of Pd(PPh3)4, and 0.45 equivalent of K2CO3 in refluxing tetrahydrofuran
(THF) under an argon atmosphere (Table 1, entry 1). Thin-layer chromatography
(TLC) showed that the reaction was complete after 8 h under these conditions.
The structure of the product was discerned by spectroscopic analysis and confirmed
to be penta-substituted pyrrole derivative 2a, rather than the pyran derivatives
obtained by the previous electrophilic iodocyclization.[24] This prompted us to exam-
ine optimal conditions of the cyclization reaction of substrate 1a to obtain more sat-
isfactory results. The first investigation demonstrated that the base played an
important role in this process. Although other common bases such as Et3N, Cs2CO3,
Na2CO3, and KOt-Bu were effective as well (entries 2–5), the weaker base NaOAc
could not promote the hydroamination reaction (entry 6). The best result was
obtained in the presence of Cs2CO3 (entry 2). Changing the solvent to toluene and
CH3CN failed to improve the yield of the product 2a (entries 7 and 8). Subsequently,
different palladium species such as Pd2(dba)3 ꢀ CHCl3, PdCl2=PPh3, Pd(OAc)2=PPh3,
and Pd(PPh3)2Cl2 were also tested (entries 9–12). Pd(PPh3)4 proved to be the more
efficient catalyst in this reaction. To exclude the possibility of base-mediated cycliza-
tion, the reaction was investigated in the absence of palladium catalyst. The reaction
failed to proceed and nearly quantitative 1a was recovered (entry 13), although
Jacobi et al.[28] reported the N-benzyl acetylenic amides related the present substrates
underwent cyclization to cyclic enamides using stoichiometric to excess amount of n-
Bu4NF (TBAF). By way of comparison, for the present substrate, at best the
Table 1. Optimization of the Pd-catalyzed intramolecular hydroamination procedure of alkynyl
carboxamides 1aa
Entry
Catalysts
Base
Solvent
Yield (%)b
1
2
Pd(PPh3)4
Pd(PPh3)4
K2CO3
Cs2CO3
Et3N
THF
THF
THF
THF
THF
THF
Toluene
CH3CN
THF
THF
THF
THF
THF
THF
53
71
3
Pd(PPh3)4
Pd(PPh3)4
62
46
4
Na2CO3
KOt-Bu
NaOAc
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
—
5
Pd(PPh3)4
Pd(PPh3)4
61
No reaction
6
7
Pd(PPh3)4
Pd(PPh3)4
36
53
8
9
Pd2(dba)3 ꢀ CHCl3
PdCl2=PPh3
Pd(OAc)2=PPh3
Pd(PPh3)2Cl2
Free-catalyst
n-Bu4NF
48
10
11
12
13
14
24
55
60
No reaction
<20c
aReactions were carried out on a 0.3 mmol scale in 3.0 mL of solvent under argon atmosphere with 1.0
equivalent of 1a, 1.5 equivalents of base, and 0.05 equivalent of catalyst at reflux for 8 h.
bIsolated yields.
c1.0 eq TBAF was used.

PENTA-SUBSTITUTED PYRROLE DERIVATIVES
1073
reaction afforded only 20% of product 2a after heating 24 h with 1.0 eq tetrabuty-
lammonium fluoride (TBAF) (entry 14). Thus, we chose the following reaction con-
ditions as optimum for all subsequent cyclization: 0.3 mmol of 1a, 5 mol%
Pd(PPh3)4, and 0.45 mmol Cs2CO3 in 3.0 mL THF were stirred at refluxing for 8 h.
With these evaluations in mind, we therefore proceeded to examine the scope
of this procedure by studying other alkynyl carboxamides bearing different substitu-
ents on either the nitrogen atom or the carbon–carbon triple bond. The Pd-catalyzed
hydroamination of both N-phenylcyclopropanecarboxamide 1a and 2-methyl-N-
phenylcyclopropanecarboxamide 1b generated the corresponding polysubstituted
5-azaspiro[2.4]heptan-4-one in 71% and 68% yields, respectively, with only a trace
amount of side products (Table 2, entries 1 and 2). It seems to indicate that the sub-
stituents in the a-position of carbonyl group have negligible effect on reactivity. Sub-
sequently, the effect of substitution on the aniline ring has also been examined. In
general, electron-donor substituents on the aniline ring played a positive role in
the hydroamination process; when a methyl occurred on the aniline ring (in ortho-,
meta-, or para-position), satisfactory results have been obtained (entries 3–5).
Introduction of methoxy in para- and ortho-position gave different result: The for-
mer proceeded smoothly in good yield, and the latter gave only poor yield of desired
product likely due to the steric hindrance of methoxy group in the para-position
Table 2. Pd-catalyzed cyclization of alkynyl carboxamides to 1,2,3,4,5-substituted pyrrole derivativesa
Entry
R1
R2
R3
Product
Time (h)
Yield (%)b
1
2
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
n-Propyl
n-Pentyl
Phenyl
H
CH3
H
H
H
2a
2b
2c
2d
2e
2f
8
8
71
68
81
77
83
<5
73
78
75
82
78
79
49
53
90
3
2-CH3
3-CH3
4-CH3
2-OCH3
4-OCH3
2-Cl
11
10
8
4
H
5
H
6
H
20
8
7
H
2g
2h
2i
8
H
12
8
9
H
3-Cl
4-Cl
10
11
12
13
14
15
H
2j
8
H
3-Br
4-Br
2k
2l
9
H
9
H
4-Cl
4-Cl
2m
2n
2o
20
20
8
H
H
2,4-Dimethyl
aReactions were carried out on a 0.3 mmol scale in 3.0 mL of THF under argon with 1.0 equivalent of
1a, 1.5 equivalents of Cs2CO3, and 0.05 equivalent of Pd(PPh3)4 at reflux for an appropriate time.
bIsolated yields.

1074
J.-Y. HOU ET AL.
(entries 6 and 7). In contrast, introducing electron-withdrawing groups on the aniline
ring did not remarkably improve the reactivity of the present cyclization (entries
8–12). In general, substrates with Cl- substituents on the aniline ring were slightly
less reactive than those bearing Br-substituents (to compare entries 9 and 11, 10
and 12). We next examined the effect of various substituents on the alkyne terminus.
The results demonstrated that this cyclization was not limited to aryl substituted
alkynes, and the reaction of alkyl substituted alkynes could also proceed smoothly
(entries 13 and 14). However, the terminal alkyne in which the phenyl has been
replaced by a hydrogen atom failed to give any recognizable products. Finally, we
examined the possibility of introducing two substituents on the aniline ring under
the same conditions. Penta-substituted pyrrole 2o bearing two electron-donating
methyl substituents on the aromatic ring was obtained in the best yield (entry 15).
All of the pyrrole derivatives were identified by spectroscopic methods. The
stereochemistry of the products was further established by single-crystal x-ray analysis.
Using this technique, the structure of product 2h was unambiguously confirmed to
be (Z)-6-benzylidene-5-(2-chlorophenyl)-7-hydroxy-7-methyl-5-azaspiro[2.4]heptan-
4-one (Fig. 1). The atomic coordinates for 2h have been deposited at the Cambridge
Crystallographic Data Centre. CCDC-760179 contains the supplementary crystallo-
graphic data for this article. These data can be obtained free of charge from the
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Having developed a useful method for the synthesis of the penta-substituted
pyrroles bearing an active three-membered ring, we next examined the transforma-
tions of the three-membered ring moiety because ring-opening products were con-
sidered more valuable molecules (Scheme 2). Accordingly, 2a was treated with an
excess amount of ZnCl2 in refluxing THF to give the chloroethyl compound 3a in
Figure 1. Structure of product 2h by X-ray. (Figure is provided in color online.)

PENTA-SUBSTITUTED PYRROLE DERIVATIVES
1075
good yield. It was noteworthy that the zinc salts acted not only as Lewis acid but also
as a source of halide in this transformation. Encouraged by this result, we attempted
to carry out the one-pot transformation of 1a to 3a by using 0.3 equivalent of alkynyl
carboxamides, 0.6 equiv. of ZnCl2, 5 mol % of Pd(PPh3)4 and 0.45 equivalent of
Cs2CO3 in refluxing toluene. As shown in Table 3, all tested N-phenylcyclopropane-
carboxamides bearing both electron-withdrawing and electron-donor groups on the
Table 3. One-pot bimetallic-promoted cyclization of alkynyl carboxamides to polysubstituted chloroethyl
pyrrole derivativesa
Entry
Adducts
Products
Time (h)
Yield (%)b
1
12
66
2
3
16
12
75
77
4
5
12
19
62
66
aReactions were carried out in 3.0 mL of refluxing toluene under argon with 0.3 equivalent of 1a, 0.45
equivalent of Cs2CO3, 0.6 equivalent of ZnCl2, and 5 mol% of Pd(PPh3)4 for an appropriate time.
bIsolated yields.

1076
J.-Y. HOU ET AL.
aniline ring afforded target chloroethylpyrroles in good overall yield (Table 3, entries
1–5). This study demonstrated that alkynyl carboxamides used in this reaction could
be further employed for the synthesis of more advanced intermediates.
In summary, we have developed a new approach to the synthesis of 5-azaspiro
[2.4]heptan and penta-substituted pyrrole derivatives by palladium-catalyzed cycliza-
tion of alkynyl carboxamides. A variety of N-phenylcyclopropane-carboxamides
underwent this process to give the desired products in good to excellent yields. As
the zinc salts acted as Lewis acids and a source of halides, the extended Pd-Zn bimet-
allic system afforded the penta-substituted chloroethylpyrroles and proved that the
present method is a powerful tool for the preparation of a wide range of functiona-
lized and polysubstituted pyrroles. Further extension of the substrate for synthesis of
more valuable penta-substituted chloroethylpyrrole or bromoethylpyrrole deriva-
tives are under way in our laboratory and will be reported in the near future.
EXPERIMENTAL
Commercially available reagents and solvents were used without further puri-
fication. Alkynyl carboxamide compounds were prepared according to the literature
procedures.[24] Melting points were determined with a microscopic apparatus and are
1
uncorrected. Column chromatography was carried out on silica gel. H NMR spec-
tra were recorded with a 400-MHz spectrometer in CDCl3 by using tetramethylsilane
(TMS) as the internal standard. 13C NMR spectra were recorded with a 100-MHz
spectrometer in CDCl3. Infrared (IR) spectra were recorded with a Fourier trans-
form (FT)–IR spectrometer, and only the major peaks are reported. All new
compounds were further characterized by elemental analysis.
General Procedure for the Preparation of
5-Azaspiro[2.4]heptan-4-one 2
A mixture of alkynyl carboxamide 1 (0.30 mmol), Cs2CO3 (0.45 mmol),
Pd(PPh3)4 (5 mol %), and THF (3.0 mL) was placed under an argon atmosphere in
a 25-mL flask. The resulting mixture was then heated at 80 ꢁC. When the reaction
was considered complete as determined by TLC analysis, the reaction mixture was
allowed to cool to room temperature, quenched with a saturated aqueous solution
of ammonium chloride, and extracted with EtOAc. The combined organic extracts
were washed with water and saturated brine. The organic layers were dried over
Na2SO4 and filtered. Solvents were evaporated under reduced pressure. The residue
was purified by chromatography on silica gel to afford the corresponding
5-azaspiro[2.4]heptan-4-one 2.
General Procedure for the Preparation of Penta-Substituted
Chloroethylpyrrole Derivatives 3
Cs2CO3 (0.45 mmol), Pd(PPh3)4 (5 mol%), and ZnCl2(0.6 mmol) were added to
a solution of alkynyl carboxamide 1 (0.30 mmol) in toluene (3.0 mL). The resulting
mixture was then heated under an argon atmosphere until reflux. When the reaction
was considered complete, as determined by TLC analysis, the reaction mixture was

PENTA-SUBSTITUTED PYRROLE DERIVATIVES
1077
allowed to cool to room temperature, quenched with a saturated aqueous solution of
ammonium chloride, and extracted with EtOAc. The combined organic extracts were
washed with water and saturated brine. The organic layers were dried over Na2SO4
and filtered. Solvents were evaporated under reduced pressure. The residue was pur-
ified by chromatography on silica gel to afford the corresponding penta-substituted
chloroethylpyrrole derivatives 3.
(Z)-6-Benzylidene-7-hydroxy-7-methyl-5-phenyl-5-azaspiro[2.4]heptan-4-
one 2a. Colorless solid; mp 115–116 ꢁC. IR (KBr): 3414, 1713, 1661, 1496, 1387,
1341, 1174, 696 cmꢂ1
.
1H NMR (400 MHz, CDCl3): d ¼ 1.01–1.06 (m, 1H),
1.14–1.20 (m, 1H), 1.22–1.27 (m, 1H), 1.35–1.40 (m, 1H), 1.49 (s, 3H), 2.41 (br s,
1H), 6.13 (s, 1H), 6.69–6.71 (t, J ¼ 1.6 Hz, 2H), 6.83–6.88 (q, 3H), 6.95–7.01 (m,
5H) ppm.13C NMR (100 MHz, CDCl3): d ¼ 10.18, 12.16, 26.31, 33.27, 73.60,
104.09, 125.26, 125.60, 126.20, 126.93, 127.95, 128.14, 134.16, 135.36, 146.35,
175.27 ppm. Anal. calcd. for C20H19NO2: C, 78.66; H, 6.27, N, 4.59. Found: C,
78.34; H, 6.29; N, 4.54.
(Z)-6-Benzylidene-7-hydroxy-1,7-dimethyl-5-phenyl-5-azaspiro[2.4]-heptan-
4-one 2b. Colorless solid; mp 135–136 ꢁC. IR (KBr): 3421, 2929, 1710, 1661, 1387,
1336, 1180, 696 cmꢂ1. 1H NMR (400 MHz, CDCl3): d ¼ 1.12–1.15 (q, 1H), 1.39–1.40
(m, 4H) 1.48 (s, 3H), 1.51–1.56 (m, 1H), 2.08 (brs, 1H), 6.09 (s, 1H), 6.72–6.74 (m,
2H), 6.83–6.88 (m, 3H), 6.95–7.04 (m, 5H) ppm. 13C NMR (100 MHz, CDCl3):
d ¼ 11.86, 17.98, 20.47, 24.72, 36.68, 74.57, 103.91, 125.47, 125.64, 126.14, 126.96,
127.95, 128.21, 134.22, 135.57, 145.54, 174.36 ppm. Anal. calcd. for C21H21NO2:
C, 78.97; H, 6.63; N, 4.39. Found: C, 79.24; H, 6.67, N, 4.42.
(Z)-6-Benzylidene-7-hydroxy-7-methyl-5-o-tolyl-5-azaspiro[2.4]heptan-
4-one 2c. Colorless solid; mp 99–100 ꢁC. IR (KBr): 3398, 1707, 1642, 1405, 1184,
1
910, 730 cmꢂ1. H NMR (400 MHz, CDCl3): d ¼ 1.05–1.10 (m, 1H), 1.17–1.29 (m,
2H), 1.35–1.40 (m, 1H), 1.53 (s, 3H), 1.96 (s, 3H), 2.19 (brs, 1H), 6.11 (s, 1H),
6.64–6.66 (m, 2H), 6.77–6.86 (m 5H), 6.91–7.02 (m, 2H) ppm. 13C NMR
(100 MHz, CDCl3): d ¼ 10.32, 11.51, 17.77, 26.70, 32.69, 73.45, 103.58, 125.45,
125.95, 126.70, 127.07, 127.85, 128.16, 129.52, 130.48, 134.00, 134.77, 146.25,
175.15 ppm. Anal. calcd. for C21H21NO2: C, 78.97; H, 6.63; N, 4.39. Found: C,
78.57; H, 6.60; N 4.35.
(Z)-6-Benzylidene-7-hydroxy-7-methyl-5-m-tolyl-5-azaspiro[2.4]heptan-4-
one 2d. Colorless solid; mp 125–126 ꢁC. IR (KBr): 3413, 2924, 1713, 1663, 1386,
1
1340, 1171, 733, 697 cmꢂ1. H NMR (400 MHz, CDCl3): d ¼ 1.02–1.07 (m, 1H),
1.15–1.20 (m, 1H), 1.23–1.28 (m, 1H), 1.36–1.41 (m, 1H), 1.51 (s, 3H), 2.04 (s,
3H), 2.21 (brs, 1H), 6.13 (s, 1H), 6.70–6.77 (m, 4H), 6.95 (m, 5H) ppm. 13C NMR
(100 MHz, CDCl3): d ¼ 10.23, 12.09, 20.87, 26.39, 33.26, 73.61, 103.94, 122.57,
125.61, 126.09, 126.82, 126.95, 127.81, 127.98, 134.39, 135.09, 137.82, 146.52,
175.17 ppm. Anal. calcd. for C21H21NO2: C, 78.97; H, 6.63; N, 4.39. Found: C,
78.62; H, 6.56; N, 4.33.
(Z)-6-Benzylidene-7-hydroxy-7-methyl-5-p-tolyl-5-azaspiro[2.4]heptan-4-
one 2e. Colorless solid; mp 105–106 ꢁC. IR (KBr): 3395, 2925, 2252, 1709, 1392,
1157, 910, 734 cmꢂ1
.
1H NMR (400 MHz, CDCl3): d ¼ 1.00–1.16 (m, 1H),

1078
J.-Y. HOU ET AL.
1.18–1.25 (m, 2H), 1.36–1.39 (m, 1H), 1.51 (s, 3H), 2.07 (brs, 1H), 2.16 (s, 3H), 6.12
(s, 1H), 6.65–6.74 (m, 2H), 6.81–6.89 (m, 7H) ppm. 13C NMR (100 MHz, CDCl3):
d ¼ 10.16, 12.08, 20.85, 26.38, 33.24, 73.69, 103.82, 125.15, 125.49, 126.89, 128.30,
128.55, 132.88, 134.24, 136.11, 146.66, 175.20 ppm. Anal. calcd. for C21H21NO2:
C, 78.97; H, 6.63; N, 4.39. Found: C, 78.43; H, 6.66; N, 4.35.
(Z)-6-Benzylidene-7-hydroxy-5-(4-methoxyphenyl)-7-methyl-5-azaspir-o
[2.4]heptan-4-one 2g. Colorless solid; mp 113–114 ꢁC. IR (KBr): 3406, 2929, 1710,
1
1661, 1512, 1341, 1249, 1178, 910, 830, 733 cmꢂ1. H NMR (400 MHz, CDCl3):
d ¼ 1.01–1.07 (m, 1H), 1.14–1.19 (m, 1H), 1.22–1.27 (m, 1H), 1.34–1.40 (m, 1H),
1.49 (s, 3H), 2.49 (brs, 1H), 3.65 (s, 3H), 6.11 (s, 1H), 6.53 (d, J ¼ 9.2 Hz, 2H),
6.69–6.71 (m, 2H), 6.87–6.90 (m, 5H) ppm. 13C NMR (100 MHz, CDCl3):
d ¼ 10.24, 12.04, 26.43, 33.09, 55.37, 73.51, 103.64, 113.29, 125.52, 126.55, 126.88,
128.29, 128.41, 134.19, 146.72, 157.76, 175.40 ppm. Anal. calcd. for C21H21NO3:
C, 75.20; H, 6.31; N, 4.18. Found: C, 74.88; H, 6.26; N, 4.16.
(Z)-6-Benzylidene-5-(2-chlorophenyl)-7-hydroxy-7-methyl-5-azaspiro-[2.4]
heptan-4-one 2h. Colorless solid; mp 138–139 ꢁC. IR (KBr): 3437, 2924, 2854,
1
1721, 1664, 1343, 1174, 764, 706 cmꢂ1. H NMR (400 MHz, CDCl3): d ¼ 1.10–1.14
(m, 1H), 1.19–1.32 (m, 2H), 1.39–1.43 (m, 1H), 1.57 (s, 3H), 2.25 (brs, 1H), 6.16
(s, 1H), 6.74–7.25 (m, 9H) ppm. 13C NMR (100 MHz, CDCl3): d ¼ 10.44, 11.86,
26.46, 32.65, 73.54, 103.99, 125.62, 126.67, 126.82, 128.10, 128.81, 128.97, 129.75,
131.31, 133.23, 133.76, 145.50, 174.50 ppm. Anal. calcd. for C20H18ClNO2: C,
70.69; H, 5.34; N, 4.12. Found: C, 70.93; H, 5.37; N, 4.13.
(Z)-6-Benzylidene-5-(3-chlorophenyl)-7-hydroxy-7-methyl-5-azaspiro-[2.4]
heptan-4-one 2i. Colorless solid; mp 137–138 ꢁC. IR (KBr): 3415, 1714, 1664, 1408,
1
1338, 1173, 911, 701 cmꢂ1. H NMR (400 MHz, CDCl3): d ¼ 1.04–1.11 (m, 1H),
1.18–1.31 (m, 2H), 1.36–1.43 (m, 1H), 1.50 (s, 3H), 2.21 (s, 1H), 6.19 (s, 1H),
6.71–6.74 (m, 2H), 6.84–6.98 (m, 7H) ppm. 13C NMR (100 MHz, CDCl3):
d ¼ 10.51, 12.28, 26.22, 33.35, 73.62, 104.61, 123.49, 125.65, 126.12, 126.26, 127.19,
128.01, 128.90, 133.72, 133.99, 136.31, 145.99, 175.07 ppm. Anal. calcd. for
C20H18ClNO2: C, 70.69; H, 5.34; N, 4.12. Found: C, 70.87; H, 5.33; N, 4.09.
(Z)-6-Benzylidene-5-(4-chlorophenyl)-7-hydroxy-7-methyl-5-azaspiro-[2.4]
heptan-4-one 2j. Colorless solid; mp 121–122 ꢁC. IR (KBr): 3413, 1714, 1663, 1493,
1
1387, 1339, 1173, 1091, 910, 733, 702 cmꢂ1. H NMR (400 MHz, CDCl3): d ¼ 1.05–
1.10 (m, 1H), 1.17–1.22 (m, 1H), 1.25–1.30 (m, 1H), 1.37–1.42 (m, 1H), 1.50 (s, 3H),
2.21 (brs, 1H), 6.17 (s, 1H), 6.70–6.72 (d, J ¼ 7.2 Hz, 2H), 6.89–6.99 (m, 7H) ppm.
13C NMR (100 MHz, CDCl3): d ¼ 10.47, 12.22, 26.23, 33.32, 73.64, 104.38, 126.05,
126.47, 127.18, 128.05, 128.15, 128.28, 131.68, 133.95, 146.13, 175.15 ppm. Anal.
calcd. for C20H18ClNO2: C, 70.69; H, 5.34; N, 4.12. Found: C, 70.57; H, 5.39; N,
4.17.
(Z)-6-Benzylidene-5-(3-bromophenyl)-7-hydroxy-7-methyl-5-azaspiro-
[2.4]heptan-4-one 2k. Colorless solid; mp 135–136 ꢁC. IR (KBr): 3415, 1713,
1664, 1384, 1338, 1176, 911, 734, 699 cmꢂ1
.
1H NMR (400 MHz, CDCl3):
d ¼ 1.03–1.09 (m, 1H), 1.15–1.21 (m, 1H), 1.24–1.29 (m, 1H), 1.35–1.40 (m, 1H),
1.48 (s, 3H), 2.40 (brs, 1H), 6.17 (s, 1H), 6.71–6.73 (m, 2H), 6.86–6.93 (m, 4H),

PENTA-SUBSTITUTED PYRROLE DERIVATIVES
1079
6.99 (d, J ¼ 7.6 Hz, 1H), 7.00–7.09 (m, 2H) ppm. 13C NMR (100 MHz, CDCl3):
d ¼ 10.54, 12.24, 26.19, 33.29, 73.50, 104.60, 121.40, 123.98, 126.09, 127.16, 127.96,
128.48, 129.11, 129.12, 133.97, 136.37, 145.90, 175.13 ppm. Anal. calcd. for
C20H18BrNO2: C, 62.51; H, 4.72; N, 3.65. Found: C, 62.29; H, 4.62; N, 3.75.
(Z)-6-Benzylidene-5-(4-bromophenyl)-7-hydroxy-7-methyl-5-azaspiro-
[2.4]heptan-4-one 2l. Colorless solid; mp 111–112 ꢁC. IR (KBr): 3417, 1715, 1662,
1
1489, 1386, 1340, 1171, 910, 733, 701 cmꢂ1. H NMR (400 MHz, CDCl3): d ¼ 1.04–
1.09 (m, 1H), 1.16–1.21 (m, 1H), 1.23–1.29 (m, 1H), 1.36–1.41 (m, 1H), 1.48 (s, 3H),
2.35 (brs, 1H), 6.16 (s, 1H), 6.69 (d, J ¼ 7.2 Hz, 2H), 6.86–7.01 (m, 5H), 7.11 (d,
J ¼ 8.4 Hz, 2H) ppm. 13C NMR (100 MHz, CDCl3): d ¼ 10.47, 12.23, 26.20, 33.30,
73.58, 104.42, 119.54, 126.02, 126.77, 127.17, 128.19, 130.98, 133.91, 134.41,
145.99, 175.12 ppm. Anal. calcd. for C20H18BrNO2: C, 62.51; H, 4.72; N, 3.65.
Found: C, 62.69; H, 4.70; N, 3.61.
(Z)-6-Butylidene-5-(4-chlorophenyl)-7-hydroxy-7-methyl-5-azaspiro-[2.4]
heptan-4-one 2m. Colorless solid; mp 99–110 ꢁC. IR (KBr): 3396, 2959, 2928,
1
1709, 1674, 1493, 1394, 1091, 911, 826, 734 cmꢂ1. H NMR (400 MHz, CDCl3):
d ¼ 0.70–0.73 (t, J ¼ 7.2 Hz, 3H), 0.86–0.88 (m, 1H), 1.00–1.02 (m, 1H), 1.11–1.32
(m, 9H), 1.99 (brs, 1H), 4.91 (t, J ¼ 7.2 Hz, 1H), 7.21 (d, J ¼ 4.2 Hz, 2H), 7.38 (d,
J ¼ 4.2 Hz, 2H) ppm. 13C NMR (100 MHz, CDCl3): d ¼ 10.56, 11.46, 13.53, 22.76,
25.83, 28.25, 33.21, 73.21, 105.01, 127.82, 128.99, 132.77, 135.67, 145.37,
175.07 ppm. Anal. calcd. for C17H20ClNO2: C, 66.77; H, 6.59; N, 4.58. Found: C,
66.50; H, 6.54; N, 4.55.
(Z)-5-(4-Chlorophenyl)-6-hexylidene-7-hydroxy-7-methyl-5-azaspiro-[2.4]
heptan-4-one 2n. Colorless solid; mp 64–65 ꢁC. IR (KBr): 3410, 3096, 2855, 1712,
1668, 982, 826 cmꢂ1. 1H NMR (400 MHz, CDCl3): d ¼ 0.80–0.83 (m, 3H), 0.97–1.45
(m, 15H), 2.02 (brs, 1H), 4.91 (t, J ¼ 7.2 Hz, 1H), 7.21 (d, J ¼ 8.8 Hz, 2H), 7.37 (d,
J ¼ 8.8 Hz, 2H) ppm. 13C NMR (100 MHz, CDCl3): d ¼ 10.55, 11.44, 13.93, 20.19,
22.30, 26.28, 29.25, 31.23, 33.20, 73.19, 105.24, 127.79, 128.98, 132.76, 135.69,
145.18, 175.06 ppm. Anal. calcd. for C19H24ClNO2: C, 68.35; H, 7.25; N, 4.20.
Found: C, 68.07; H, 7.29; N, 4.19.
(Z)-6-Benzylidene-5-(2,4-dimethylphenyl)-7-hydroxy-7-methyl-5-azasp-
iro[2.4]heptan-4-one 2o. Colorless solid; mp 101–102 ꢁC. IR (KBr): 3405, 3020,
2976, 1712, 1664, 1394, 1341, 1187, 911, 732, 701 cmꢂ1. 1H NMR (400 MHz, CDCl3):
d ¼ 0.99–1.40 (m, 4H), 1.47 (s, 3H), 1.89 (s, 3H), 2.11 (s, 3H), 2.51 (brs, 1H), 6.05 (s,
1H), 6.61–6.65 (m, 2H), 6.78–6.87 (m, 6H) ppm. 13C NMR (100 MHz, CDCl3):
d ¼ 10.16, 11.45, 17.56, 20.72, 26.73, 32.56, 73.20, 103.36, 125.09, 126.49, 126.58,
126.77, 128.12, 130.91, 131.92, 133.81, 134.06, 137.48, 146.35, 175.01 ppm. Anal.
calcd. for C22H23NO2: C, 79.25; H, 6.95; N, 4.20. Found: C, 79.07; H, 6.91; N, 4.23.
(Z)-5-Benzylidene-3-(2-chloroethyl)-4-methyl-1-phenyl-1H-pyrrol-2(5H)
one 3a. Yellowish oil. IR (KBr): 2923, 1699, 1497, 1391, 697 cmꢂ1 1H NMR
.
(400 MHz, CDCl3): d ¼ 2.29 (s, 3H), 2.92 (t, J ¼ 6.8 Hz, 2H), 3.80 (t, J ¼ 6.8 Hz,
2H), 6.42 (s, 1H), 6.50 (d, J ¼ 7.2 Hz, 2H), 6.90 (t, J ¼ 7.6 Hz, 3H), 6.95–7.05 (m,
5H) ppm. 13C NMR (100 MHz, CDCl3): d ¼ 10.63, 27.74, 43.11, 111.44, 126.14,
126.69, 126.75, 126.92, 127.20, 128.05, 129.23, 133.55, 135.94, 138.82, 145.68,

1080
J.-Y. HOU ET AL.
170.92 ppm. Anal. calcd. for C20H18ClNO: C, 78.14; H, 5.60; N, 4.33. Found: C,
78.44; H, 5.66; N, 4.30.
(Z)-5-Benzylidene-3-(2-chloroethyl)-4-methyl-1-o-tolyl-1H-pyrrol-2(5H)-
1
one 3c. Yellowish oil. IR (KBr): 2924, 1698, 1494, 1390, 1130, 756, 701 cmꢂ1. H
NMR (400 MHz, CDCl3): d ¼ 2.10 (s, 3H), 2.27 (s, 3H), 2.92 (t, J ¼ 6.8 Hz, 2H),
3.76–3.83 (m, 2H), 6.38 (s, 1H), 6.77 (d, J ¼ 7.6 Hz, 2H), 6.81–6.96 (m, 7H) ppm.
13C NMR (100 MHz, CDCl3): d ¼ 10.60, 18.09, 27.69, 43.10, 111.34, 125.89,
126.70, 126.99, 127.79, 128.39, 128.67, 129.84, 130.33, 133.19, 135.69, 135.92,
139.10, 145.15, 170.40 ppm. Anal. calcd. for C21H20ClNO: C, 74.66; H, 5.97; N,
4.15. Found: C, 74.24; H, 5.93; N, 4.20.
(Z)-5-Benzylidene-3-(2-chloroethyl)-4-methyl-1-p-tolyl-1H-pyrrol-2(5H)-
1
one 3e. Yellowish oil. IR (KBr): 1699, 1514, 1391, 1125, 813, 702 cmꢂ1. H NMR
(400 MHz, CDCl3): d ¼ 2.19 (s, 3H), 2.27 (s, 3H), 2.91 (t, J ¼ 6.8 Hz, 2H), 3.79 (t,
J ¼ 6.8 Hz, 2H), 6.39 (s, 1H), 6.84–6.90 (m, 6H), 6.93 (t, J ¼ 8.0 Hz, 2H), 6.96–6.99
(m, 1H) ppm. 13C NMR (100 MHz, CDCl3): d ¼ 10.58, 20.86, 27.72, 43.14, 111.28,
126.48, 126.73, 127.11, 128.64, 129.29, 133.33, 133.56, 135.95, 136.13, 138.95,
145.48, 170.96 ppm. Anal. calcd. for C21H20ClNO: C, 74.66; H, 5.97; N, 4.15. Found:
C, 74.91; H, 6.02; N, 4.10.
(Z)-5-Benzylidene-3-(2-chloroethyl)-1-(4-methoxyphenyl)-4-methyl-1H-
1
pyrrol-2(5H)-one 3g. Yellowish oil. IR (KBr): 1695, 1512, 1247 cmꢂ1. H NMR
(400 MHz, CDCl3): d ¼ 2.29 (s, 3H), 2.93 (t, J ¼ 6.8 Hz, 2H), 3.70 (s, 3H), 3.80 (t,
J ¼ 6.8 Hz, 2H), 6.41 (s, 1H), 6.58–6.60 (q, 2H), 6.87–6.90 (m, 3H), 6.92–7.03 (m,
4H) ppm. 13C NMR (100 MHz, CDCl3): d ¼ 10.57, 27.74, 43.11, 55.44, 111.17,
113.50, 126.77, 126.83, 127.16, 127.87, 128.95, 129.28, 133.54, 139.13, 145.33,
157.89, 171.04 ppm. Anal. calcd. for C21H20ClNO2: C, 71.28; H, 5.70; N, 3.96.
Found: C, 71.04; H, 5.62; N, 3.97.
(Z)-5-Benzylidene-3-(2-chloroethyl)-1-(3-chlorophenyl)-4-methyl-1H-
pyrrol-2(5H)-one 3i. Yellowish oil. IR (KBr): 1703, 1592, 1482, 1388, 1123, 782,
1
699 cmꢂ1. H NMR (400 MHz, CDCl3): d ¼ 2.28 (s, 3H), 2.91 (t, J ¼ 6.8 Hz, 2H),
3.78 (t, J ¼ 6.8 Hz, 2H), 6.46 (s, 1H), 6.87–7.02 (m, 9H) ppm. 13C NMR (100 MHz,
CDCl3): d ¼ 10.63, 27.64, 43.00, 111.81, 124.83, 126.16, 126.71, 126.98, 127.33,
127.39, 128.87, 129.02, 133.36, 133.60, 136.89, 138.48, 146.04, 170.65 ppm. Anal.
calcd. for C20H17Cl2NO: C, 67.05; H, 4.78; N, 3.91. Found: C, 67.28; H, 4.77; N, 3.95.
ACKNOWLEDGMENTS
The authors thank the National Natural Science Foundation of China
(30800720) and China Postdoctoral Science Foundation (20090450843) for the finan-
cial support of this work.
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