CeCl3·7H2O catalyzed C-C and C-N bond-forming cascade cyclization with subsequent side-chain functionalization and rearrangement: A domino approach to pentasubstituted pyrrole analogues

Article abstract of DOI:10.1021/jo301796r

CeCl₃·7H₂O is found as an efficient catalyst for new intermolecular domino reactions of three-, four- and seven-component assemblies of common precursors under benign reaction conditions. Generation of enaminioesters from β-keto esters and primary amines, activation of their allylic sp³ C-H, vinylic sp² C-H and N-H bonds, multi C-C and C-N bond-forming cascade cyclization with 1,2-diketones and subsequent side-chain alkylation have been developed to construct functionalized pentasubstituted pyrroles and their chiral analogues. The scope of the domino reaction is successfully explored toward synthesis of highly aryl-substituted pyrroles, pentasubstituted pyrroles bearing C2-olefinic side-chain and spiro-2-pyrrolinones and their chiral analogues via unusual side-chain amination, elimination and ring contraction. The new domino reaction is operationally simple, robust, substrate specific, selective and high yielding.

Full text of DOI:10.1021/jo301796r

Note
pubs.acs.org/joc
CeCl3·7H2O Catalyzed C−C and C−N Bond-Forming Cascade
Cyclization with Subsequent Side-Chain Functionalization and
Rearrangement: A Domino Approach to Pentasubstituted Pyrrole
Analogues
Dipankar Dhara, Krishnanka S. Gayen, Saikat Khamarui, Palash Pandit, Sukla Ghosh, and Dilip K. Maiti*
Department of Chemistry, University of Calcutta, University College of Science, 92, A. P. C. Road, Kolkata-700009, India
S
* Supporting Information
ABSTRACT: CeCl3·7H2O is found as an efficient catalyst for new
intermolecular domino reactions of three-, four- and seven-component
assemblies of common precursors under benign reaction conditions. Generation
of enaminioesters from β-keto esters and primary amines, activation of their
allylic sp3 C−H, vinylic sp2 C−H and N−H bonds, multi C−C and C−N bond-
forming cascade cyclization with 1,2-diketones and subsequent side-chain
alkylation have been developed to construct functionalized pentasubstituted
pyrroles and their chiral analogues. The scope of the domino reaction is
successfully explored toward synthesis of highly aryl-substituted pyrroles,
pentasubstituted pyrroles bearing C2-olefinic side-chain and spiro-2-pyrroli-
nones and their chiral analogues via unusual side-chain amination, elimination
and ring contraction. The new domino reaction is operationally simple, robust,
substrate specific, selective and high yielding.
syntheses, cycloaddition, and metal-catalyzed cyclization,7
ubstituted pyrrole and pyrrolinone derivatives are highly
Scited heterocyclic moieties and key skeletons of many using new building blocks and multistep processes.8 Enamines
are important intermediates for organic synthesis9 and also
natural products including hemoglobin, chlorophylls, vitamin
B12, lukianols and tetrapentalones.1,2 Functionalized pyrroles
have found widespread applications as pharmaceuticals (e.g.,
Lipitor), agrochemicals, flavor additives, antiport agents,
efficiently used for the synthesis of substituted pyrroles by
transition metal-catalyzed C−H activation,10 and intra- and
intermolecular cyclization (eq i, ii, Scheme 1).11 In this regard,
FeCl3-catalyzed four component cyclization reaction of
aldehydes, amines, nitroalkenes and 1,3-dicarbonyl compounds
to pentasubstituted pyrroles is encouraging.11b However,
predesigned precursors, stoichiometric amount of unsafe metals
as a copromotor and/or high temperature are employed in
most of these approaches. Substrate scope of the reaction
becomes very limited under the reaction conditions. We have
successfully developed a new domino reaction (eq iii) at
ambient temperature by direct C−C and C−N bond-forming
cascade cyclization involving vinylic sp2 C−H, allylic sp3 C−H
organoleptics, synthetic building blocks, and materials for
molecular sensors and high-tech devices.1,3 Recent medicinal
research on heterocyclic scaffolds has recognized them as
inhibitors for histone deacetylase, monoamine oxidase, FGFR1
and aurora kinase, antimalarial and anticancer agents.4 The
synthesis of a wide variety of such multifunctionalized
molecules by a new intermolecular domino reaction is an
important addition to the existing robust synthetic approaches
in organic chemistry. Domino reactions5 feature the synthesis
of functional molecules by executing all chemical trans-
formations in a single operation. This approach avoids
undesirable reaction steps, including the protection, depro-
tection, and activation of precursors, the isolation and
purification of the intermediates, and the use of different
catalysts and reaction conditions. This manuscript presents a
benign, eco-friendly and practical intermolecular domino
reaction that utilizes common precursors and an inexpensive
metal catalyst to access multifunctionalized pyrrole analogues
involving a new multi C−C and C−N bond-forming cascade
cyclization6 under benign reaction conditions.
and a N−H of enaminioesters on use of acetylene-equivalent
13
1,2-diketone12 and rare-earth metal catalyst CeCl3
.
We were unsuccessful in applying various transition and rare-
earth metal Lewis acids to the initial multicomponent domino-
strategy utilizing common precursor ethyl acetoacetate (1a),
benzylamine (2a), diacetyl (3a) and tert-butyl acetoacetate (4a,
entries 1−12, Table 1). To remove the additional preparation
of enaminioesters and their purification step, we were also
searching for a protocol that could generate enaminioesters in
situ from a β-keto ester (1) and primary amine (2). To our
The usefulness of the ubiquitous N-heterocycles has led to
the development of a large number of new methods in recent
years, including the Paal−Knorr, Hantzsch, and Schmidt
Received: August 24, 2012
Published: October 31, 2012
© 2012 American Chemical Society
10441
dx.doi.org/10.1021/jo301796r | J. Org. Chem. 2012, 77, 10441−10449

The Journal of Organic Chemistry
Note
delight, use of environmentally safe and inexpensive metal
catalyst CeCl3 (5 mol %) had successfully performed the four-
component cascade cyclization reaction with side-chain
alkylation to afford pentasubstituted pyrrole 5a (Scheme 2)
in 45% yield (entry 13). Surprisingly, the new domino reaction
proceed smoothly to completion under the catalytic influence
of hepta-hydrated Cerium(III) chloride (CeCl3·7H2O) and
MgSO4 with enhancement of yield up to 79% after purification
by silica-gel column chromatography (entry 14). Herein, water
molecule-coordinated metal ion might play a vital role during
organization of the precursors, their cascade cyclization and/or
side-chain alkylation process leading to completion of the
reaction. MgSO4 was used as a desiccant to remove water
generated during course of the reaction. Despite its suitability
for other systems, NaI13c was not a good activator for this
catalyst to accelerate the reaction convergence (entry 15). THF
is a good solvent for the catalytic process (entries 16−18). Our
attempt to enhance the reaction convergence by heating (70
°C) was unsuccessful (entry 19). The role of the CeCl3·7H2O
catalyst in promoting generation of enaminioester intermediate
was experimentally verified utilizing a β-keto ester (1a) and a
primary amine (2a) to afford corresponding enaminioester. We
had also verified that the presence of the catalyst was essential
for the cascade cyclization with side-chain alkylation reaction
among the enaminioester, 1,2-diketone (3a) and tert-butyl
acetoacetate (4a) toward construction of 5a.
Scheme 1. Transition Metal Catalyzed C−H Activated
Cyclization vs Rare-Earth Metal Catalyzed Cascade
Cyclization
Table 1. Development and Optimization of Intermolecular
Domino Reaction to 5a
This report presents the synthesis of pentasubstituted
functionalized pyrroles 5a−d involving various substrates (1−
4) under mild reaction conditions and at high yield (81−87%).
Chiral pyrroles, an important class of N-heterocycles, are
usually synthesized by the regioselective transformation of
pyrroles via catalytic approaches.14 Herein, the development of
a new domino reaction under benign reaction conditions has
improved the substrate scope toward the direct synthesis of
valuable chiral pyrroles (5e−h; dr: 39:61 and 44:56) utilizing
optically pure amino acid derivatives. The structure of the
pentasubstituted pyrroles is determined by single crystal X-ray
diffraction (XRD) for 5b and spectral analysis of all new
compounds (5a−h). Interestingly, the methyl groups at C4 and
C5 are not alkylated.
The exact mechanism of the reaction is unknown to us.
However, it is expected to proceed through generation of
enaminioesters (Ia) from a β-keto ester (1), and primary amine
(2: R3 = alkyl), N−H insertion of CeIII with deprotonation
using KI (Ib), activation of vinylic sp2 C−H bond of the
enaminioester (Ic), subsequent CC bond formation with
strongly electrophilic 1,2-diketone (3; R4 = alkyl) and activation
of sp3 C−H to provide intermediate II. Putative intermediate II
undergoes N−C bond-forming cascade cyclization under the
influence of the powerful Lewis acid to generate III.
Simultaneous displacement of the hydroxyl group and side-
chain alkylation with compound 4 of the intermediate III
affords the desired heterocycle 5. KI may have important role in
the deprotonation and protonation process to execute the
domino cyclization reaction.
yield
a
b
entry
1
catalyst
reaction conditions
conversion
(%)
c
VO(acac)2
CH3CN, MgSO4, rt,
36 h
nd
2
TiCl4
CH3CN, MgSO4, rt,
35 h
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
3
Ti(OBu)4
ZrCl4
CH3CN, MgSO4, rt,
48 h
4
CH3CN, MgSO4, rt,
47 h
5
FeCl3
CH3CN, MgSO4, rt,
32 h
6
Cu(OAc)2
Cu(OTf)
AuCl3
CH3CN, MgSO4, rt,
48 h
7
CH3CN, MgSO4, rt,
42 h
8
CH3CN, MgSO4, rt,
45 h
9
Ni(OAc)2·2H2O
Pd(OAc)2
IrCl3
CH3CN, MgSO4, rt,
36 h
10
11
12
CH3CN, MgSO4, rt,
24 h
CH3CN, MgSO4, rt,
45 h
(NH4)2Ce(NO3)6 CH3CN, MgSO4, rt,
45 h
13
14
15
CeCl3
MeCN, KI, MgSO4, 48 h
MeCN, KI, MgSO4, 48 h
75
45
79
41
CeCl3·7H2O
CeCl3·7H2O
100
60
MeCN, NaI, MgSO4,
48 h
16
CeCl3·7H2O
CH2Cl2, KI, MgSO4,
48 h
80
64
17
18
CeCl3·7H2O
CeCl3·7H2O
THF, KI, MgSO4, 45 h
100
90
81
73
Aryl-substituted pyrroles are commonly synthesized by
metal-catalyzed regioselective coupling of bromopyrroles.15
Pentasubstituted pyrroles bearing a large number of aromatic
rings with π−π stacking and other weak interactions are
potential candidates for fabrication of organic nanostructured
materials.13b,16 To achieve the direct synthesis of highly aryl-
substituted pyrroles, we had further screened (path b, Scheme
3) the domino reaction with a new set of primary amines (2: R3
Me2CO, KI, MgSO4,
48 h
d
19
CeCl3·7H2O
THF, KI, MgSO4, 70 °C,
90
35
24 h
a
b
c
Catalyst (5 mol %). KI or NaI (15 mol %). Not detected.
Decomposition.
d
10442
dx.doi.org/10.1021/jo301796r | J. Org. Chem. 2012, 77, 10441−10449

The Journal of Organic Chemistry
Note
Scheme 2. Four Component Domino Reaction with Side-Chain Alkylation
= aryl) and 1,2-diketone (3: R4 = aryl). Surprisingly, under the
optimized reaction conditions (entry 17, Table 1) novel bis-
aminomethyl pyrroles (6) bearing a number of aromatic
moieties were obtained. Herein, aryl amine was involved in
amination reaction to the C2 side-chain of two putative
intermediates (III) successively with expulsion of hydroxyl
groups to result compound 6. Traces of corresponding side-
chain alkylation products (5) are also generated in some of the
reactions. This reaction is quite substrate specific. Aromatic-
ring-substituted 1,2-diketone (3) and aromatic amine (2)
precursors were essential for this reaction to proceed. Various
substituted aromatic amines (2), diaryl-1,2-diketones (3) and 3-
ketoesters (1) are tolerated in this seven-component domino
reaction approach to afford highly substituted aminomethyl
pyrroles 6a−g with a high yield (79−92%). The structures are
confirmed by X-ray single crystal analyses of compound 6a and
recording spectra (Supporting Information) of all new
compounds (6a−g).
Interestingly, upon the placement of an alkyl group (Et) on
the side-chain of β-keto ester [R1, R2 = Et, ethyl 3-
oxohexanoate (1d)] a three-component domino reaction
(path c, Scheme 4) occurred with primary amines (2: R3 =
alkyl) and 1,2-diketones (3: R4 = alkyl or aryl) to afford the
pentasubstituted pyrrole 7 bearing a C2-olefinic side-chain.
Surprisingly, the sp3 Cβ−H of enamine intermediate underwent
an elimination reaction to install a double bond with absolute
trans-selectivity. Herein, cyclized intermediate III is expected to
undergo simultaneous removal of Cβ−H side-chain proton and
hydroxyl group under the catalytic conditions. Various achiral
and chiral multifunctionalized pyrroles were synthesized by this
robust protocol with high yield (76−82%). XRD structure of 7e
is presented in Scheme 4.
Pyrrolinones have found widespread applications as universal
peptidomimetics and highly selective inhibitors of VEGF R2/3,
HIV-1 integrase, HIF-2 and phosphodiesterase.2,17 Spirocyclic
heterocycles are common in nature and play an important role
10443
dx.doi.org/10.1021/jo301796r | J. Org. Chem. 2012, 77, 10441−10449

The Journal of Organic Chemistry
Note
Scheme 3. Three Component Domino Reaction with Side-Chain Amination
in biochemical transformations.18 To determine the reaction
specificity and scope of the new intermolecular domino
reaction process, synthesis of pentasubstituted spiro-2-pyrroli-
nones19 was successfully investigated (path d, Scheme 5).
Herein, first one-step synthesis of spiro-2-pyrrolinone (8)
involving ring contraction was devised under benign reaction
conditions in high to excellent yields (74−92%). Herein, the
use of cyclic 1,2-diketone [3: R4, R4 = (CH2)4] led to formation
of corresponding intermediate II, which on cascade cyclization
produced intermediate III. The metal Lewis acid stabilized
ionic intermediate involved in migration of the alkyl chain
furnished rearranged pentasubstituted spiro-2-pyrrolinones
(8a−e). Interestingly, the domino reaction was unsuccessful
when the reaction was carried out using aromatic amines (2: R3
= aryl). The X-ray single crystal structure of the optically pure
N-heterocycle 8e is displayed in Scheme 5.
unusual side-chain alkylation, amination, elimination and ring
contraction. We have demonstrated three-, four- and seven-
component coupling of β-keto esters, primary amines and 1,2-
diketones to valuable pentasubstituted pyrroles bearing various
functional groups, a large number of aromatic moieties, and
trans-selective olefin substituent, and spiro-2-pyrrolinones and
their chiral analogues. Environmentally benign hepta-hydrated
CeCl3 is found as an efficient catalyst for the multistep domino
process under mild reaction conditions. Structures of the new
and novel N-heterocycles are established by means of X-ray
single crystal diffraction analyses. Excellent catalytic activity of
the inexpensive rare-earth metal salt and synthesis of such a
diverse class of highly functionalized pentasubstituted pyrroles
by this simple and robust domino reaction are expected to find
immense application in organic synthesis, medicinal chemistry
and material sciences.
In conclusion, we have devised a new intermolecular domino
reaction of easily availabe precursors involving generation of
enaminioesters, triple activation of their allylic sp3 C−H, vinylic
sp2 C−H, and N−H bonds, a multi C−C and C−N bond-
forming cascade cyclization with 1,2-diketones and subsequent
EXPERIMENTAL SECTION
General Procedure A for Synthesis of 5. β-Ketoester (1, 1.25
mmol), aliphatic amine (2, 1.25 mmol), CeCl3·7H2O (70 mg, 5 mol
%), KI (100 mg, 15 mol %) and anhydrous MgSO4 were taken in dry
■
10444
dx.doi.org/10.1021/jo301796r | J. Org. Chem. 2012, 77, 10441−10449

The Journal of Organic Chemistry
Note
Scheme 4. Three Component Domino Reaction with Side-Chain Elimination
THF (30 mL) and stirred for 24 h at room temperature. 1,2-Diketone
(3, 1 mmol) and β-keto ester (4, 1.25 mmol) were added to it and
stirred at room temperature for 43−48 h. After removal of the solvent,
the reaction mixture was diluted with ethyl acetate (25 mL). The
organic layer was washed with water (3 × 10 mL), dried on anhydrous
Na2SO4 and evaporated under reduced pressure in a rotary evaporator
at room temperature. The residue was then subjected to column
chromatography over silica gel (60−120 mesh) and eluted with 3%
(5a−c,e−h) and 5% (5d) ethyl acetate in petroleum ether (v/v).
1-Benzyl-2-(2-tert-butoxycarbonyl-3-oxo-butyl)-4,5-dimeth-
yl-1H-pyrrole-3-carboxylic acid ethyl ester (5a). 346 mg (81%
yield); pale yellow liquid: 1H NMR (300 MHz, CDCl3) δ 1.19 (3H, t,
J = 7.2 Hz), 1.38 (3H, s), 1.56 (9H, s), 1.98 (3H, s), 2.21 (3H, s),
3.21−3.30 (2H, m), 4.06−4.19 (3H, m), 5.19 (2H, dd, J = 17.4 Hz),
6.82 (2H, d, J = 6.9 Hz), 7.20−7.30 (3H, m); 13C NMR (75 MHz,
CDCl3) δ 9.7, 11.6, 13.9, 23.9, 27.8, 28.5, 30.1, 46.7, 59.0, 61.3, 79.3,
116.3, 125.4, 125.5, 127.1, 128.7, 134.6, 137.8, 165.4, 169.4, 203.8; FT-
IR (neat, cm−1) 1178, 1282, 1367, 1682, 1714, 1732, 2978; HR-MS
(m/z) for C25H34NO5 (M + H) calculated 428.2437, found 428.2439.
1-Benzyl-2-(2-methoxycarbonyl-3-oxo-butyl)-4,5-dimethyl-
1H-pyrrole-3-carboxylic acid methyl ester (5b). 322 mg (87%
yield); pale yellow solid: mp 62−64 °C; 1H NMR (300 MHz, CDCl3)
δ 1.93 (3H, s), 2.11 (3H, s), 2.15 (3H, s), 3.11−3.18 (1H, dd, J= 7.8
and 14.7 Hz), 3.23−3.28 (1H, dd, J = 6.6 and 14.7 Hz), 3.58 (3H, s),
3.82 (3H, s), 4.09−4.14 (1H, dd, J = 6.6 and 7.8 Hz), 5.08−5.14 (1H,
d, J = 17.7 Hz), 5.20−5.26 (1H, d, J= 17.7 Hz), 6.72−6.74 (2H, d, J=
6.9 Hz), 7.14−7.26 (3H, m); 13C NMR (75 MHz, CDCl3) δ 9.73,
11.47, 24.13, 30.04, 46.8, 50.48, 52.36, 58.98, 111.10, 116.60, 125.40,
125.83, 127.17, 128.78, 135.57, 137.75, 166.41, 169.86, 203.40; FT-IR
(KBr, cm−1) 729.7, 782.6, 825.1, 1027.7, 1113.3, 1149.6, 1236.3,
1276.6, 1359.9, 1440.4, 1513.7, 1684.5, 1744.2, 2943.7, 3411.6, 3754.0;
HR-MS (m/z) for C21H26NO5 (M + H) calculated 372.1811, found
372.1815.
1-Ethoxycarbonylmethyl-2-(2-ethoxycarbonyl-3-oxo-butyl)-
4,5-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (5c). 343
1
mg (87% yield), pale yellow liquid: H NMR (300 MHz, CDCl3) δ
1.13−1.38 (9H, m), 1.95 (3H, s), 2.08 (3H, s), 2.20 (3H, s), 3.09−
3.16 (1H, dd, J = 7.5 and 15.0 Hz), 3.21−3.28 (1H, dd, J = 6.6 and
15.0 Hz), 3.99−4.23 (6H, m), 4.63−4.69 (1H, d, J = 18.3 Hz), 4.65−
4.81 (1H, d, J = 18.3 Hz); 13C NMR (75 MHz, CDCl3) δ 9.57, 11.45,
13.87, 14.03, 14.37, 23.86, 30.18, 45.24, 59.05, 59.10, 61.36, 61.54,
111.47, 116.47, 125.54, 135.69, 165.78, 168.67, 169.28; FT-IR (neat,
cm−1) 731.2, 787.0, 858.9, 963.9, 1027.2, 1118.7, 1204.6, 1269.6,
1381.1, 1444.4, 1516.3, 1594.6, 1741.8, 2981.3, 3123.9, 3430.8; HR-
MS (m/z) for C20H30NO7 (M + H) calculated 396.2022, found
396.2018.
1-Dodecyl-2-(2-ethoxycarbonyl-3-oxo-butyl)-4,5-dimethyl-
1H-pyrrole-3-carboxylic acid ethyl ester (5d). 391 mg (82%
yield); pale yellow liquid: 1H NMR (300 MHz, CDCl3) δ 0.87 (2H, t,
J = 7.2 Hz), 1.17−1.34 (26H, m), 1.42−1.55 (2H, m), 2.08 (3H, s),
2.14 (3H, s), 2.21(3H, s), 3.27−3.34 (2H, m), 3.77−3.98 (2H, m),
4.07−4.19 (2H, m), 4.21−4.28 (3H, m); 13C NMR (75 MHz, CDCl3)
δ 9.98, 11.1, 14.4, 14.7, 22.6, 24.1, 26.8, 29.3, 29.5, 29.6, 30.2, 31.3,
31.9, 43.5, 59.0, 61.3, 110.5, 116.3, 124.8, 134.7, 166.0, 169.4, 203.7;
FT-IR (neat, cm−1) 1111, 1258, 1444, 1513, 1683, 1716, 1744, 2854,
2926; HR-MS (m/z) for C28H48NO5 (M + H) calculated 478.3532,
found 478.3535.
1-(1-Ethoxycarbonyl-2-phenylethyl)-2-(2-methoxycarbonyl-
3-oxo-butyl)-4,5-dimethyl-1H-pyrrole-3-carboxylic acid meth-
yl ester (5e and 5f). dr 39:61; 416 mg (91% yield); pale yellow
1
liquid: H NMR (300 MHz, CDCl3) δ 1.21 (3H, t, J = 7.2 Hz), 1.99
(3H, s), 2.03 (2H, s), 2.08 (3H, s), 2.12 (3H, s), 2.81−3.03 (2H, m),
3.54 (3H, s), 3.57 (1H, s), 3.65 (3H, s), 3.67−3.71 (2H, m), 4.14−
4.21 (1H, m), 6.74−6.78 (2H, m), 7.07−7.10 (3H, m); 13C NMR (75
MHz, CDCl3) δ 11.29, 13.92, 23.02, 28.96, 31.00, 37.49, 50.27, 52.26,
58.98, 59.36, 61.74, 110.59, 117.97, 124.71, 128.44, 128.93, 129.52,
136.49, 136.96, 166.10, 169.94, 202.51, 203.66; FT-IR (neat, cm−1)
10445
dx.doi.org/10.1021/jo301796r | J. Org. Chem. 2012, 77, 10441−10449

The Journal of Organic Chemistry
Note
Scheme 5. Three Component Domino Reaction with Ring Contraction
702.4, 753.0, 785.6, 859.3, 1030.4, 1116.5, 1226.0, 1260.8, 1364.7,
1439.9, 1512.9, 1592.0, 1701.7, 1737.4, 2951.3, 3442.8; HR-MS (m/z)
for C25H32NO7 (M + H) calculated 458.2179, found 458.2176.
2-(2-Methoxycarbonyl-3-oxo-butyl)-1-(methoxycarbonyl-
phenylmethyl)-4,5-dimethyl-1H-pyrrole-3-carboxylic acid
methyl ester (5g and 5h). dr 44:56; 348 mg (81% yield); pale
yellow liquid: 1H NMR (300 MHz, CDCl3) δ 2.15 (3H, s), 2.22 (3H,
s), 2.26 (3H, s), 3.38−3.45 (2H, m), 3.55 (1H, s), 3.67 (3H, s), 3.80
(3H, s), 3.89 (3H, s), 4.05−4.13 (2H, m), 6.99−7.03 (2H, m), 7.26−
7.35 (3H, m); 13C NMR (75 MHz, CDCl3) δ 11.35, 11.41, 23.94,
29.37, 30.47, 50.59, 52.47, 52.84, 59.89, 111.77, 117.68, 126.79,
127.10, 127.90, 128.42, 134.96, 136.21, 166.30, 169.44, 170.00, 202.59,
203.42; FT-IR (neat, cm−1) 699.5, 745.5, 790.1, 832.3, 1003.0, 1116.8,
1209.3, 1267.2, 1358.1, 1443.8, 1514.1, 1586.5, 1684.1, 1741.0, 2371.5,
2952.5, 3437.4.; HR-MS (m/z) for C23H28NO7 (M + H) calculated
430.1866, found 430.1865.
General Procedure B for Synthesis of 6. β-Ketoester (1, 1.25
mmol), aromatic amine (2, 1.25 mmol), CeCl3·7H2O (70 mg, 5 mol
%), KI (100 mg, 15 mol %) and anhydrous MgSO4 were taken in dry
THF (30 mL) and stirred for 24 h at room temperature. Aromatic 1,2-
diketone (3, 1.0 mmol) and aromatic amine (2, 1 mmol) were added
to it and stirred at room temperature for 43−52 h. The reaction was
monitored by TLC. After evaporation of the solvent, the reaction
mixture was diluted with ethyl acetate (25 mL). This organic layer was
washed with water (3 × 10 mL) and dried on anhydrous Na2SO4. The
solvent was evaporated under reduced pressure in a rotary evaporator
at room temperature. The residue was then subjected to column
chromatography over silica gel (60−120 mesh) and eluted with 2%
(6a,f) 3% (6b−d,g) and 5% (6e) ethyl acetate in petroleum ether (v/
v).
4′-tolyl-amino-bis[(2-methyl)-4,5-diphenyl-1-4′-tolyl-1H-
pyrrole-3-carboxylic acid ethyl ester] (6a). 383 mg (86% yield);
colorless solid: mp 220−221 °C; 1H NMR (300 MHz, CDCl3) δ 0.89
(6H, t, J = 7.2 Hz), 2.12 (3H, s), 2.18 (6H, s), 3.98 (4H, q, J = 7.2
Hz), 4.14 (4H, s), 6.31(2H, d, J = 8.4 Hz), 6.64−7.18 (30 H, m); 13C
NMR (75 MHz, CDCl3) δ 13.7, 20.4, 21.1, 45.4, 59.4, 114.1, 117.0,
123.5, 125.6, 126.4, 127.0, 127.1, 128.0, 128.4, 129.0, 130.7, 131.2,
131.4, 132.8, 135.2, 136.0, 137.6, 145.0, 165.8; FT-IR (KBr, cm−1)
1173, 1276, 1514, 1692, 2978, 3032; HR-MS (m/z) for C61H56N3O4
(M + H) calculated 894.4271, found 894.4277.
4′-Bromophenylamino-bis[(2-methyl)-4,5-di(4′-bromophen-
yl)-1-4′-bromophenyl-1H-pyrrole-3-carboxylic acid ethyl
ester] (6b). 576 mg (82% yield); yellow liquid: 1H NMR (300
MHz, CDCl3) δ 1.04 (6H, t, J = 7.2 Hz), 4.13 (4H, q, J = 7.2 Hz), 4.31
(4H, s), 6.42 (2H, d, J = 8.7 Hz), 6.65 (4H, d, J = 8.4 Hz), 7.03 (6H,
dd, J = 8.4, 1.8 Hz), 7.16−7.26 (8H, m), 7.35 (4H, d, J = 8.4 Hz), 7.47
(4H, d, J = 8.7 Hz); 13C NMR (75 MHz, CDCl3) δ 13.9, 39.9, 60.2,
114.3, 116.0, 120.7, 121.8; 123.0, 123.9, 129.2, 130.0, 130.5, 131.2,
131.7, 131.9, 132.3, 132.5, 132.6, 133.6, 135.7, 136.5, 145.7, 165.2. FT-
IR (neat, cm−1) 1182, 1494, 1694, 2853, 2923, 3382; HR-MS (m/z)
for C58H43Br7N3O4 (M + H) calculated 1397.7537, found 1397.7534
(one of the peaks).
4′-Chlorophenylamino-bis[(2-methyl)-4,5-diphenyl-1-4′-
chlorophenyl-1H-pyrrole-3-carboxylic acid methyl ester] (6c).
426 mg (92%, yield); colorless solid: mp 122−124 °C; 1H NMR (300
MHz, CDCl3) δ 3.61 (6H, s), 4.31 (4H, s), 6.46 (4H, d, J = 8.7 Hz),
6.78 (4H, dd, J = 8.1 and 1.8 Hz), 6.97−7.09 (8H, m), 7.18−7.24
(16H, m); 13C NMR (75 MHz, CDCl3) δ 40.2, 51.1, 113.9, 115.7,
124.6, 126.3, 127.2, 127.7, 129.0, 129.2, 129.8, 130.6, 130.8, 131.0,
133.1, 134.5, 134.7, 135.6, 136.0, 166.2; FT-IR (KBr, cm−1) 1078,
10446
dx.doi.org/10.1021/jo301796r | J. Org. Chem. 2012, 77, 10441−10449

The Journal of Organic Chemistry
Note
1174, 1277, 1495, 1694, 2359, 3369; HR-MS (m/z) for
C56H43Cl3N3O4 (M + H) calculated 926.2319, found 926.2325 (one
of the peaks).
125.6, 125.8, 127.0, 127.5, 127.9, 128.5, 130.5, 131.2, 131.5, 132.0,
132.8, 135.4, 138.1, 165.9; FT-IR (KBr, cm−1) 701, 767, 1035, 1159,
1232, 1303, 1406, 1689, 2975; HR-MS (m/z) for C29H28NO2 (M +
H) calculated 422.2120, found 422.2120.
4′-Methoxyphenylamino-bis[(2-methyl)-4,5-diphenyl-1-4′-
methoxyphenyl-1H-pyrrole-3-carboxylic acid ethyl ester] (6d).
4,5-Bis-(4-bromo-phenyl)-1-ethoxycarbonylmethyl-2-pro-
1
367 mg (78% yield); yellow liquid: H NMR (300 MHz, CDCl3) δ
penyl-1H-pyrrole-3-carboxylic acid ethyl ester (7b). Yield: 454
1
1.02 (6H, t, J = 7.2 Hz), 3.74 (6H, s), 3.80 (3H, s), 4.13 (4H, q, J = 7.2
Hz), 4.32 (4H, s), 6.50 (4H, d, J = 9.0 Hz), 6.73 (4H, d, J = 8.7 Hz),
6.80−6.86 (8H, m), 6.92−7.10 (16H, m); 13C NMR (75 MHz,
CDCl3) δ 13.8, 40.8, 55.4, 55.7, 59.7, 113.4, 113.8, 114.0, 114.6, 115.6,
124.3, 126.0, 126.7, 127.1, 127.5, 129.2, 129.7, 129.9, 130.3, 131.0,
131.3, 132.8, 135.4, 137.4, 142.1, 152.6, 159.2, 163.4, 165.7; FT-IR
(neat, cm−1) 698, 828, 1027, 1075, 1176, 1244, 1458, 1510, 1608,
1691, 2847, 2924, 3373; HR-MS (m/z) for C61H56N3O7 (M + H)
calculated 942.4118, found 942.4123.
mg (79% yield); colorless solid; mp 102−104 °C; H NMR (300
MHz, CDCl3) δ 1.04 (3H, t, J = 7.2 Hz), 1.25 (3H,t, J = 6.9 Hz), 1.94
(3H, dd, J = 1.5 Hz, 6.9 Hz), 4.08 (2H, q, J = 6.9), 4.20 (2H, q, J = 7.2
Hz), 4.49 (2H, s), 5.94−6.06 (1H, m), 6.62 (1H, dd, J = 1.5 Hz, 16.2
Hz), 6.96−7.00 (4H, m), 7.29 (2H, d, J = 8.4 Hz), 7.39 (2H, d, J = 8.4
Hz); 13C NMR (75 MHz, CDCl3) δ 13.9, 14.1, 19.1, 47.4, 59.6, 61.8,
112.6, 120.2,120.3, 122.6, 123.5, 129.9, 130.4, 131.7, 131.9, 132.2,
132.6, 133.1, 134.1, 137.0, 165.0, 168; FT-IR (KBr, cm−1) 826, 1012,
1153, 1214, 1300, 1432, 1507, 1704, 1742, 2981; HR-MS (m/z) for
C26H26Br2NO4 (M + H) calculated 574.0230, found 574.0229 (one of
the peaks).
2′-Naphthylamino-bis[(2-methyl)-4,5-di(2′-naphthyl)-1-2′-
naphthyl-1H-pyrrole-3-carboxylic acid ethyl ester] (6e). 415 mg
1
(83% yield); yellow liquid: H NMR (300 MHz, CDCl3) δ 1.11 (6H,
1-(1-Ethoxycarbonyl-2-phenyl-ethyl)-4,5-dimethyl-2-pro-
penyl-1H-pyrrole-3-carboxylic acid ethyl ester (7c). 292 mg
(76% yield); yellow liquid: 1H NMR (300 MHz, CDCl3) δ 1.23−1.33
(6H, m),1.76 (3H, dd, J = 1.5 Hz, 6.6 Hz), 2.03 (3H, s), 2.15 (3H, s),
3.09 (1H, dd, J = 9.6 Hz, 14.1 Hz), 3.53(1H, dd J = 4.8 Hz, 13.8 Hz),
4.16−4.27 (4H, m), 5.12−5.16 (1H, m), 5.43−5.50 (1H, m), 6.05
(1H, dd, J = 1.5 Hz, 15.9 Hz), 6.86−6.89 (2H, m), 7.15−7.19 (3H,
m); 13C NMR (75 MHz, CDCl3) δ 10.6, 11.1, 14.1, 14.3, 18.6, 37.5,
59.0, 61.8, 111.7, 117.6, 121.4, 125.5, 126.8, 128.3, 128.6, 129.9, 132.7,
136.5, 137.0, 166.0, 170.5; FT-IR (neat, cm−1) 964, 1029, 1113, 1248,
1411, 1454, 1497, 1604, 1695, 1739, 2933, 2979; HR-MS (m/z) for
C23H30NO4 (M + H) calculated 384.2175, found 384.2174.
1-Benzyl-4,5-bis-(4-bromo-phenyl)-2-propenyl-1H-pyrrole-
3-carboxylic acid ethyl ester (7d). 474 mg (82% yield); colorless
solid: mp 126−130 °C; 1H NMR (300 MHz, CDCl3) δ 1.05 (3H, t, J
= 7.2 Hz), 1.83 (3H, dd, J = 1.5 Hz, J = 6.6 Hz), 4.09 (2H, dd, J = 7.2
Hz, J = 14.4 Hz), 5.06 (2H, s), 6.06−6.11 (1H, m), 6.54 (1H, dd, J =
1.8 Hz, J = 14.4 Hz), 6.79−6.88 (4H, m), 6.97−6.99 (2H, m), 7.24−
7.30 (7H, m); 13C NMR (75 MHz, CDCl3) δ 13.8, 19.1, 48.6, 59.7,
112.5, 119.8, 120.1, 122.2, 125.7, 127.3, 128.7, 130.2, 130.4, 131.3,
131.6, 132.2, 132.9, 134.3, 136.3, 137.7, 165.5; FT-IR (KBr, cm−1)
1009, 1095, 1146, 1229, 1305, 1493, 1691, 2959; HR-MS (m/z) for
C29H25Br2NO2 (M + H) calculated 578.0332, found 578.0329 (one of
the peaks).
t, J = 6.9 Hz), 4.29 (4H, q, J = 7.2 Hz), 4.42 (2H, d, J = 14.1 Hz), 4.72
(2H, d, J = 14.1 Hz), 6.37 (2H, s), 6.89−7.08 (8H, m), 7.18 (2H, t, J =
7.5 Hz), 7.30−7.68 (23H, m), 7.81 (2H, d, J = 7.5 Hz), 7.92−7.94
(4H, m); 13C NMR (75 MHz, CDCl3) δ 13.8, 40.0, 60.0, 113.9, 120.4,
122.6, 124.1, 124.5, 124.6, 124.9, 125.5, 126.1, 126.7, 126.9, 127.2,
127.3, 127.5, 127.6, 127.9, 128.2, 128.3, 129.4, 130.6, 131.0, 131.5,
133.7, 134.1, 134.2, 135.3, 166.1; FT-IR (neat, cm−1) 1275, 1402,
1511, 1610, 1668, 1737, 2927, 3427; HR-MS (m/z) for C70H56N3O4
(M + H) calculated 1002.4271, found 1002.4270.
Phenylamino-bis[(2-methyl)-4,5-diphenyl-1-phenyl-1H-pyr-
role-3-carboxylic acid tert-butyl ester] (6f). 364 mg (79% yield);
colorless solid: mp 124−126 °C; 1H NMR (300 MHz, CDCl3) δ 1.30
(18H, s), 4.40 (4H, s), 6.46 (4H, d, J = 7.5 Hz), 6.69 (2H, t, J = 7.2
Hz), 6.85 (4H, dd, J = 7.5 and 1.8 Hz), 6.96−7.38 (25H, m); 13C
NMR (75 MHz, CDCl3) δ 27.9, 39.0, 80.2, 113.6, 115.5, 117.6, 124.2,
125.9, 126.7, 127.2, 127.4, 128.3, 128.7, 128.9, 129.0, 130.9, 131.0,
131.2, 132.3, 135.7, 136.5, 137.4, 147.9, 165.0; FT-IR (KBr, cm−1)
695, 752, 1156, 1253, 1290, 1501, 1597, 1679, 2928, 2974, 3383; HR-
MS (m/z) for C62H58N3O4 (M + H) calculated 908.4427, found
908.4429.
4′-Tolylamino-bis[(2-methyl)-4,5-di(4′-bromophenyl)-1-4′-
tolyl-1H-pyrrole-3-carboxylic acid ethyl ester] (6g). 530 mg
1
(88% yield); yellow liquid: H NMR (300 MHz, CDCl3) δ 1.05 (6H,
t, J = 7.2 Hz), 2.21 (3H, s), 2.37 (6H, s), 4.13 (4H, q, J = 6.9 Hz), 4.33
(4H, s), 6.39 (2H, d, J = 8.4 Hz), 6.65 (2H, d, J = 8.4 Hz), 6.91 (3H, d,
J = 8.1 Hz), 7.04 (3H, d, J = 8.1 Hz), 7.13 (4H, d, J = 8.4 Hz), 7.34
(2H, d, J = 8.1 Hz); 13C NMR (75 MHz, CDCl3) δ 13.9, 20.3, 21.1,
39.7, 59.9, 113.4, 114.0, 120.4, 121.3, 123.5, 127.1, 128.2, 129.5, 129.7,
129.9, 130.4, 130.9, 131.4, 132.4, 134.2, 138.0, 145.5, 156.6, 165.1; FT-
IR (neat, cm−1) 729, 1181, 1283, 1514, 1683, 3390; HR-MS (m/z) for
C61H52Br4N3O4 (M + H) calculated 1206.0693, found 1206.0690.
(one of the peaks).
General Procedure C for Synthesis of 7. Ethyl 3-oxohexanoate
(1, 1.25 mmol), aliphatic amine (2, 1.25 mmol), CeCl3·7H2O (70 mg,
5 mol %), KI (100 mg, 15 mol %) and anhydrous MgSO4 were taken
in dry THF (30 mL) and stirred for 24 h at room temperature. Aryl-
1,2-diketone (3, 1 mmol) was added to it and stirred for 72 h at room
temperature for completion of the reaction. After evaporation of the
solvent, the reaction mixture was diluted with ethyl acetate (25 mL).
This organic layer was washed with water (3 × 10 mL) and dried on
anhydrous Na2SO4. The solvent was evaporated under reduced
pressure in a rotary evaporator at room temperature. The residue was
then subjected to column chromatography over silica gel (60−120
mesh) and eluted with 1% (7a), 3% (7b,d,e) and 5% (7c) ethyl
acetate−petroleum ether (v/v).
1-tert-Butoxycarbonylmethyl-4,5-diphenyl-2-propenyl-1H-
pyrrole-3-carboxylic acid ethyl ester (7e). 361 mg (81% yield);
colorless solid: mp 102−106 °C; 1H NMR (300 MHz, CDCl3) δ 0.99
(3H, t, J = 7.2 Hz), 1.42 (9H, s), 1.94 (3H, dd, J = 1.8 Hz, 6.6 Hz),
4.05 (2H, q, J = 7.2 Hz), 4.43 (2H, s), 5.99−6.06 (1H, m), 6.68 (1H,
dd, J = 1.8 Hz, 16.2 Hz), 7.09−7.17(7H, m), 7.22−7.26 (3H, m); 13C
NMR (75 MHz, CDCl3) δ 13.8, 19.2, 27.8, 48.2, 59.4, 82.4, 112.5,
120.6, 124.2, 125.7, 127.0, 127.8, 128.2, 130.6, 131.2, 131.4, 132.1,
133.2, 135.5, 136.4, 165.6, 168.0; FT-IR (KBr, cm−1) 963, 1150, 1232,
1307, 1433, 1603, 1695, 1737, 2974; HR-MS (m/z) for C28H32NO4
(M + H) calculated 446.2331, found 446.2328.
General Procedure D for Synthesis of 8. Ethyl 3-oxohexanoate
(1d, 1.25 mmol), aliphatic amine (2, 1.25 mmol), CeCl3·7H2O (70
mg, 5 mol %), KI (100 mg, 15 mol %) and anhydrous MgSO4 were
taken in dry THF (30 mL) and stirred for 24 h at room temperature.
1,2-Cyclohexadione (3d, 1 mmol) was added to it and stirred at room
temperature for 40−48 h toward completion of the domino reaction.
The reaction was monitored by TLC. After evaporation of the solvent,
the postreaction mixture was extracted with ethyl acetate (25 mL).
This organic layer was washed with water (3 × 10 mL) and dried on
anhydrous Na2SO4. The solvent was removed under reduced pressure
in a rotary evaporator at room temperature. The residue was then
subjected to column chromatography over silica gel (60−120 mesh)
and eluted with 1% (8a), 2% (8b,c) and 3% (8d,e) ethyl acetate in
petroleum ether (v/v).
1-Benzyl-4,5-diphenyl-2-propenyl-1H-pyrrole-3-carboxylic
acid ethyl ester (7a). 346 mg (82% yield); colorless solid: mp 92−93
°C; 1H NMR (300 MHz, CDCl3) δ 1.12 (3H, t, J = 7.2 Hz), 1.95 (3H,
dd, J = 6.6, 1.5 Hz), 4.21 (2H, q, J = 7.2 Hz), 5.22 (2H, s), 6.16−6.28
(1H, m), 6.67 (1H, dd, J = 16.2, 1.5 Hz), 7.02 (2H, d, J = 7.2 Hz),
7.10−7.13 (2H, m), 7.21−7.26 (7H, m), 7.28−7.48 (4H, m); 13C
NMR (75 MHz, CDCl3) δ 13.7, 19.1, 48.5, 59.5, 112.7, 119.9, 124.5,
2-Benzyl-3-methyl-1-oxo-2-aza-spiro[4.4]non-3-ene-4-car-
boxylic acid ethyl ester (8a). 266 mg (85% yield); yellow liquid: 1H
NMR (300 MHz, CDCl3) δ 1.10−1.3 (5H, m), 1.68−2.05 (5H, m),
2.25−2.40 (4H, m), 4.12 (2H, q, J = 7.2 Hz), 4.84 (2H, s), 7.06−7.14
10447
dx.doi.org/10.1021/jo301796r | J. Org. Chem. 2012, 77, 10441−10449

The Journal of Organic Chemistry
Note
(2H, m), 7.17−7.26 (3H, m); 13C NMR (75 MHz, CDCl3) δ 12.8,
14.3, 27.4, 35.9, 43.1, 54.7, 59.4, 113.0, 126.6, 127.5, 128.8, 136.9,
152.5, 164.2, 184.9; FT-IR (neat, cm−1) 700, 734, 951, 1082, 1214,
1309, 1384, 1447, 1619, 1690, 2945; HR-MS (m/z) for C19H24NO3
(M + H) calculated 314.1756, found 314.1757.
AUTHOR INFORMATION
Corresponding Author
*E-mail: dkmchem@caluniv.ac.in.
Notes
■
2,3-Dimethyl-1-oxo-2-aza-spiro[4.4]non-3-ene-4-carboxylic
The authors declare no competing financial interest.
1
acid ethyl ester (8b). 176 mg (74% yield); yellow liquid: H NMR
(300 MHz, CDCl3) δ 1.23 (3H, t, J = 7.2 Hz), 1.69−1.87 (8H, m),
2.36 (3H, s), 2.98 (3H, s), 4.13 (2H, q, J = 7.2 Hz); 13C NMR (75
MHz, CDCl3) δ 12.6, 14.3, 26.2, 27.3, 35.7, 54.7, 59.3, 112.6, 152.6,
164.2, 184.8; FT-IR (neat, cm−1) 801, 1068, 1151, 1210, 1257, 1381,
1449, 1624, 1687, 2927, 3445; HR-MS (m/z) for C13H20NO3 (M +
H) calculated 238.1443, found 238.1442.
ACKNOWLEDGMENTS
■
Financial support from DST (SR/S1/OC-5/2012 and SR/
NM/NS-29/2010), India, and research fellowships from CSIR,
India, is gratefully acknowledged. SG thanks UGC, India, for
the MR Project (F.PSW-121/10-11; Gobardanga Hindu
College).
2-Ethoxycarbonylmethyl-3-methyl-1-oxo-2-aza-spiro[4.4]-
non-3-ene-4-carboxylic acid ethyl ester (8c). Yield: 241 mg (78%
1
yield); yellow liquid; H NMR (300 MHz, CDCl3) δ 1.17−1.35 (6H,
REFERENCES
m), 1.73−2.01 (6H, m), 2.05−2.10 (2H, m), 2.34 (3H, s), 4.07−4.22
(4H, m), 4.25 (2H, s); 13C NMR (75 MHz, CDCl3) δ 12.3, 14.0, 14.3,
14.4, 27.2, 35.6, 40.9, 54.7, 59.4, 61.7, 113.1, 151.2, 164.1, 168.0, 184.5;
FT-IR (neat, cm−1) 770, 956, 1088, 1206, 1381, 1624, 1691, 2947;
HR-MS (m/z) for C16H24NO5 (M + H) calculated 310.1654, found
310.1657.
■
(1) (a) Sundberg, R. J. In Comprehensive Heterocyclic Chemistry II;
Katrizky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon Press:
Oxford, NY, 1996; Vol. 2. (b) Battersby, A. R. Nat. Prod. Rep. 2000,
17, 507−526. (c) Trofimov, B. A.; Sobenina, L. N.; Demenev, A. P.;
Mikhaleva, A. I. Chem. Rev. 2004, 104, 2481−2506. (d) Fan, H. N.;
Peng, J.; Hamann, M. T.; Hu, J. F. Chem. Rev. 2008, 108, 264−287.
(2) (a) Bellina, F.; Rossi, R. Tetrahedron 2006, 62, 7213−7256.
(b) Marcus, A. P.; Sarpong, R. Org. Lett. 2010, 12, 4560−4563.
(3) (a) Huffman, J. W. Curr. Med. Chem. 1999, 6, 705−720. (b) Xu,
H.; Yu, G.; Xu, W.; Xu, Y.; Cui, G.; Zhang, D.; Liu, Y.; Zhu, D.
Langmuir 2005, 21, 5391−5395. (c) Sessler, J. L.; Pantos, G. D.; Gale,
P. A.; Light, M. E. Org. Lett. 2006, 8, 1593−1596. (d) Zhao, Y.; Li, Y.;
Ou, X.; Zhang, P.; Huang, Z.; Bi, F.; Huang, R.; Wang, Q. J. Agric. Food
Chem. 2008, 56, 10176−10182. (e) Gale, P. A.; Tong, C. C.; Haynes,
C. J. E.; Adeosun, O.; Gross, D. E.; Karnas, E.; Sedenberg, E. M.;
Quesada, R.; Sessler, J. L. J. Am. Chem. Soc. 2010, 132, 3240−3241.
(4) (a) Pacorel, B.; Leung, S. C.; Stachulski, A. V.; Davies, J.; Vivas,
L.; Lander, H.; Ward, S. A.; Kaiser, M.; Brun, R.; O'Neill, P. M. J. Med.
Chem. 2010, 53, 633−640. (b) Chen, Z.; Wang, X.; Zhu, W.; Cao, X.;
Tong, L.; Li, H.; Xie, H.; Xu, Y.; Tan, S.; Kuang, D.; Ding, J.; Qian, X.
J. Med. Chem. 2011, 54, 3732−3745. (c) Arikawa, Y.; Nishida, H.;
Kurasawa, O.; Hasuoka, A.; Hirase, K.; Inatomi, N.; Hori, Y.;
Matsukawa, J.; Imanishi, A.; Kondo, M.; Tarui, N.; Hamada, T.;
Takagi, T.; Takeuchi, T.; Kajino, M. J. Med. Chem. 2012, 55, 4446−
4456.
2-Butyl-3-methyl-1-oxo-2-aza-spiro[4.4]non-3-ene-4-car-
boxylic acid tert-butyl ester (8d). 252 mg (74% yield); yellow
liquid: 1H NMR (300 MHz, CDCl3) δ 0.92 (3H, t, J = 7.2 Hz), 1.25−
1.39 (4H, m), 1.51 −1.54 (10H, m), 1.69−1.76 (3H, m), 1.86−2.06
(4H, m), 2.41 (3H, s), 3.46 (2H, t, J = 7.2 Hz); 13C NMR (75 MHz,
CDCl3) δ 12.4, 13.6, 19.9, 27.1, 27.7, 28.5, 31.4, 35.4, 39.4, 54.7, 79.9,
113.7, 151.8, 163.7, 184.9; FT-IR (neat, cm−1) 722, 846, 946,1062,
1145, 1255, 1367, 1452, 1617, 1686, 1715, 2937; HR-MS (m/z) for
C18H30NO3 (M + H) calculated 308.2226, found 308.2225.
(S)-2-(1-Ethoxycarbonyl-2-phenyl-ethyl)-3-methyl-1-oxo-2-
aza-spiro[4.4]non-3-ene-4-carboxylic acid ethyl ester (8e). 354
25
mg (92% yield); colorless solid: mp 158−159 °C; [α]D = −170.93°
1
[c 2.25, CHCl3]; H NMR (300 MHz, CDCl3) δ 1.18 (3H, t, J = 7.5
Hz), 1.50−1.54 (2H, m), 1.72−1.88 (6H, m), 1.90 (3H, s), 3.24−3.33
(1H,dd, J = 11.4 and 14.1 Hz), 3.39−3.45 (1H, dd, J = 4.5 and 14.1
Hz), 3.61 (3H, s), 4.08−4.24 (2H, m), 4.40−4.55 (1H, dd), 7.01 (2H,
dd, J = 7.5 and 1.5 Hz), 7.02−7.20.; 13C NMR (75 MHz, CDCl3 δ
12.4, 14.1, 27.1, 27.2, 35.0, 35.5, 35.7, 50.5, 54.2, 55.8, 61.8, 112.7,
127.0, 128.6, 129.1, 137.1, 152.2, 164.5, 169.2, 184.3; FT-IR (KBr,
cm−1) 1073, 1206, 1264, 1331, 1386, 1441, 1622, 1695, 1745, 2867,
2952; HR-MS (m/z) for C22H28NO5 (M + H) calculated 386.1967,
found 386.1969.
(5) (a) Tietze, L. F.; Brasche, G.; Gericke, K. Domino Reactions in
Organic Synthesis; Wiley-VCH: Weinheim, Germany, 2006. (b) Marigo,
Procedure E for Synthesis of Enaminioester. Ethyl acetoace-
tate (1a, 1 mmol), benzylamine (2a, 1 mmol), CeCl3·7H2O (70 mg, 5
mol %), KI (100 mg, 15 mol %) and anhydrous MgSO4 were taken in
dry THF (30 mL) and stirred for 24 h at room temperature to
complete the reaction. After evaporation of the solvent, the reaction
mixture was diluted with ethyl acetate (20 mL). This organic layer was
washed with water (3 × 10 mL) and dried on anhydrous Na2SO4. The
solvent was evaporated under reduced pressure in a rotary evaporator
at room temperature. The residue was then subjected to column
chromatography over silica gel (60−120 mesh) and eluted with 2%
ethyl acetate−petroleum ether (v/v).
́
M.; Schulte, T.; Frazen, J.; Jøgensen, K. A. J. Am. Chem. Soc. 2005, 127,
15710−15711. (c) Fillion, E.; Fishlock, D. J. Am. Chem. Soc. 2005, 127,
13144−13145.
(6) (a) Nicolaou, K. C.; Chen, J. S. Chem. Soc. Rev. 2009, 38, 2993−
3009. (b) Sengupta, T.; Gayen, K. S.; Pandit, P.; Maiti, D. K. Chem.
Eur. J. 2012, 18, 1905−1909.
(7) (a) Gorin, D. J.; Davis, N. R.; Toste, F. D. J. Am. Chem. Soc. 2005,
127, 11260−11261. (b) Binder, J. T.; Kirsch, S. F. Org. Lett. 2006, 8,
2151−2153. (c) Cyr, D. J. S.; Arndtsen, B. A. J. Am. Chem. Soc. 2007,
129, 12366−12367. (d) Lin, M.; Hao, L.; Ma, R.-d.; Zhan, Z.-p. Synlett
́ ́
2010, 2345−2351. (e) Estevez, V.; Villacampa, M.; Menendez, J. C.
3-Benzylaminobut-2-enoic acid ethyl ester. 213 mg (97%
Chem. Soc. Rev. 2010, 39, 4402−4421. (g) Auricchio, S.; Truscello, A.
M.; Lauria, M.; Meille, S. V. Tetrahedron 2012, 68, 7441−7449.
(8) (a) Freifeld, I.; Shojaei, H.; Langer, P. J. Org. Chem. 2006, 71,
4965−4968. (b) Zhang, Z.; Zhang, J.; Tan, J.; Wang, Z. J. Org. Chem.
2008, 73, 5180−5182. (c) Xin, X.; Wang, D.; Li, X.; Wan, B. Angew.
Chem., Int. Ed. 2012, 51, 1693−1697.
1
yield); yellow liquid: H NMR (300 MHz, CDCl3) δ 1.26 (3H, t, J =
7.2 Hz), 1.91 (3H, s), 4.10 (2H, q, J = 7.2 Hz), 4.42 (2H, d, J = 6.3
Hz), 4.54 (1H, s), 7.25 − 7.36 (5H, m), 8.96 (1H, bs); 13C NMR (75
MHz, CDCl3) δ 14.6, 19.3, 46.7, 58.3, 83.1, 126.7, 127.3, 128.7, 138.7,
161.8, 170.6; FT-IR (KBr, cm−1) 558, 696, 740, 785, 1028, 1064, 1121,
1178, 1242, 1449, 1505, 1610, 1659, 2986, 3298, 3686; HR-MS (m/z)
for C13H18NO2 (M + H) calculated 220.1338, found 220.1342.
(9) (a) Simon, C.; Constantieux, T.; Rodriguez, J. Eur. J. Org. Chem.
2004, 4957−4980. (b) Bonne, D.; Coquerel, Y.; Constantieux, T.;
Rodriguez, J. Tetrahedron: Asymmetry 2010, 21, 1085−1109.
(c) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev.
2007, 107, 5471−5569.
(10) (a) Willis, M. C. Chem. Rev. 2010, 110, 725−748. (b) Guin, S.;
Ghosh, T.; Rout, S. K.; Banerjee, A.; Patel, B. K. Org. Lett. 2011, 13,
5976−5979. (c) Wang, Y.-F.; Chen, H.; Zhu, X.; Chiba, S. J. Am.
Chem. Soc. 2012, 134, 11980−11983.
ASSOCIATED CONTENT
■
S
* Supporting Information
General remarks, NMR spectra and CIF data for new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
10448
dx.doi.org/10.1021/jo301796r | J. Org. Chem. 2012, 77, 10441−10449

The Journal of Organic Chemistry
Note
(11) (a) Khalili, B.; Jajarmi, P.; Eftekhari-Sis, B.; Hashemi, M. M. J.
Org. Chem. 2008, 73, 2090−2095. (b) Maiti, S.; Biswas, S.; Jana, U. J.
Org. Chem. 2010, 75, 1674−1683. (c) Rakshit, S.; Patureau, F. W.;
Glorius, F. J. Am. Chem. Soc. 2010, 132, 9585−9587. (d) Saito, A.;
Konishi, O.; Hanzawa, Y. Org. Lett. 2010, 12, 372−374. (e) Rueping,
M.; Parra, A. Org. Lett. 2010, 12, 5281−5283. (f) Toh, K. K.; Wang, Y.-
F.; Ng, E. P. J.; Chiba, S. J. Am. Chem. Soc. 2011, 133, 13942−13945.
(12) Raimondi, W.; Bonne, D.; Rodriguez, J. Angew. Chem., Int. Ed.
2012, 51, 40−42.
(13) (a) Yadav, L. D. S.; Kapoor, R. Tetrahedron Lett. 2008, 49,
4840−4844. (b) Maiti, D. K.; Halder, S.; Pandit, P.; Chatterjee, N.;
Joarder, D. D.; Pramanik, N.; Saima, Y.; Patra, A.; Maiti, P. K. J. Org.
Chem. 2009, 74, 8086−8097. (c) Bartoli, G.; Marcantoni, E.;
Marcolini, M.; Sambri, L. Chem. Rev. 2010, 110, 6104−6143.
(14) (a) Sheng, Y.-F.; Gu, Q.; Zhang, A.-J.; You, S.-L. J. Org. Chem.
2009, 74, 6899−6901. (b) Thirumalairajan, S.; Pearce, B. M.;
Thompson, A. Chem. Comm 2010, 46, 1797−1812.
(15) Handy, S. T.; Sabatini, J. J. Org. Lett. 2006, 8, 1537−1539.
(16) Che, Y.; Datar, A.; Yang, X.; Naddo, T.; Zhao, J.; Zang, L. J. Am.
Chem. Soc. 2007, 129, 6354−6355.
(17) (a) Peifer, C.; Selig, R.; Kinkel, K.; Ott, D.; Totzke, F.;
Schachtele, C.; Heidenreich, R.; Rocken, M.; Schollmeyer, D.; Laufer,
S. J. Med. Chem. 2008, 51, 3814−3824. (b) Bokesch, H. R.; Gardella,
R. S.; Rabe, D. C.; B.ottaro, D. P.; Linehan, W. M.; Mcmahon, J. B.;
Mckee, T. C. Chem. Pharm. Bull. 2011, 59, 1178−1179. (c) Raghura-
man, A.; Ko, E.; Perez, L. M.; Ioeger, T. R.; Burgess, K. J. Am. Chem.
Soc. 2011, 133, 12350−12353.
(18) Xie, J.-H.; Zhou, Q.-L. Acc. Chem. Res. 2008, 41, 581−593.
(19) (a) Schmidt, A.; Habeck, T.; Lindner, A. S.; Snovydovych, B.;
Namyslo, J. C.; Adam, A.; Gjikaj, M. J. Org. Chem. 2007, 72, 2236−
2239. (b) Saragi, T. P. I.; Spehr, T.; Siebert, A.; Fuhrmann-Lieker, T.;
Salbeck, J. Chem. Rev. 2007, 107, 1011−1065. (c) Chen, X.-H.; Wei,
Q.; Luo, S.-W.; Xiao, H.; Gong, L.-Z. J. Am. Chem. Soc. 2009, 131,
13819−13825.
10449
dx.doi.org/10.1021/jo301796r | J. Org. Chem. 2012, 77, 10441−10449