FeCl3·6H2O-catalyzed intermolecular-cascade cyclization of acetoacetanilide: Aldehyde-tuned synthesis to valuable 2-pyridone analogues

Article abstract of DOI:10.1002/chem.201103354

The first ever breakthrough toward activation of β-ketoacetanilide and subsequent C-C and C-N bond-forming intermolecular-cascade cyclization processes is demonstrated by development of the unprecedented Lewis acid property of non-toxic FeCl₃·6

Full text of DOI:10.1002/chem.201103354

COMMUNICATION
DOI: 10.1002/chem.201103354
FeCl3·6H2O-Catalyzed Intermolecular-Cascade Cyclization of
Acetoacetanilide: Aldehyde-Tuned Synthesis to Valuable 2-Pyridone
Analogues
Tista Sengupta, Krishnanka S. Gayen, Palash Pandit, and Dilip K. Maiti*[a]
2-Pyridones[1] and their tetrahydro[2] and bridged[3] ana-
logues have wide occurrence in Nature and have found a
broad range of applications in the chemical, medical, and
material sciences.[1–6] For example, 2-pyridone-unit-contain-
ing alkaloids are available in halotolerant fungus Penicillum
chrysogenum, bioactive tenellin, and related metabolites.[4]
The ubiquitous N-heterocycles are known as antihepatitis B
viral agents, non-steroidal tissue-selective androgen receptor
modulators, human rhinovirous 3C protease, Met kinase,
5a-reductase inhibitors, and antimycobacterium tuberculosis
agents.[5] From a synthetic point of view, the heterocyclic
scaffolds are important synthons for construction of novel
pyridine, piperidine, quinolizi-
zation involving anilide N H and a-C H remains a difficult
task for chemists. Generation of a substrate–metal-chelated
À
À
À
reactive species offers a facile regio- and stereoselective C
N and C C bond-forming cyclization process towards the
À
construction of a wide range of interesting nitrogen-contain-
ing frameworks. Contributing to the progress of synthesizing
2-pyridone analogues pioneered by Bardhan in 1929,[12b] and
from the same department, we report our preliminary obser-
vation on development of C N and C C bond-forming in-
termolecular cyclization process to a number of valuable
compounds by the discovery of unprecedented diverse cata-
lytic activities of FeCl3·6H2O (6–9, Scheme 1).
À
À
dine, and indolizidine alka-
loids.[6] Despite its tremendous
importance, tetrahydro-2-pyri-
dones are less studied.[2]
Transition-metal-catalyzed se-
lective functionalization and
cyclization are emerging as the
major solution for atom- and
step economical direct organic
synthesis.[7] Recently, iron com-
plexes, especially FeCl3, have
been rightly employed as useful
À
green catalysts for selective C
H functionalization,[8] C C and
À
C N bond formation,[9] and
À
cyclization[10,11] processes. How-
ever, the cyclization reactions
are limited to intramolecular
processes,
requirement
of
halide synthons, difficultly ac-
cessible predesigned precursors,
and/or harsh reaction condi-
tions. In general, cascade cycli-
Scheme 1. Acetoacetanilide activated intermolecular cyclization.
We have successfully utilized the common laboratory
compounds, acetoacetanilides (1), aromatic aldehyde, and
FeCl3·6H2O (2) to afford the highly functionalized 1,2,3,4-
tetrahydro-2-pyridone core (6, path a) at room temperature.
To develop and optimize the reaction, acetoacetanilide (1a)
and m-nitrobenzaldehyde (2a) were taken as the model
system and a series of metal catalysts, Brønsted acid, ligands,
and solvents were screened (Table 1). FeCl3·6H2O (5 mol%)
is proved to be the most efficient one (entry 7, Table 1) with
[a] T. Sengupta, K. S. Gayen, Dr. P. Pandit, Dr. D. K. Maiti
Department of Chemistry
University of Calcutta, University College of Science
92, A. P. C. Road, Kolkata-700009 (India)
Fax : (+91)33-2351-9755
E-mail: dkmchem@caluniv.ac.in
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201103354.
Chem. Eur. J. 2012, 18, 1905 – 1909
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1905

Table 1. Development and optimization of the reaction.
Entry Catalyst[a]
Reaction Conditions Conversion Yield
[%]
6a[%]
1
CeCl3
InCl3
2a, CH2Cl2,
MgSO4, RT, 24 h
2a, CH2Cl2,
MgSO4, RT, 24 h
2a, CH2Cl2,
MgSO4, RT, 24 h
2a, CH2Cl2,
MgSO4, RT, 24 h
2a, CH2Cl2,
MgSO4, RT, 24 h
2a, CH2Cl2,
MgSO4, RT,48 h
2a, CH2Cl2,
MgSO4, RT, 10 h
2a, THF,
0
nd[b]
2
0
0
nd
nd
18
12
73
87
nd
64
nd
nd
nd
nd
67
nd
3
AgOTf
4
Sc
A
30
20
90
100
0
5
Yb
ACHTUNGTRENNUNG
6
FeCl3
7
FeCl3·6H2O
FeCl3·6H2O
8
MgSO4, RT, 24 h
2a, CH2Cl2,
MgSO4, RT, 24 h
2a, CH2Cl2,
9
Fe
N
75
0
10
11
12
13
14
15
FeCl3·6H2O, Phen[c]
MgSO4, RT, 24 h
FeCl3·6H2O, DPPE[d] 2a, CH2Cl2,
0
MgSO4, RT, 24 h
2a, CH2Cl2,
MgSO4, RT, 24 h
2a, CH2Cl2,
MgSO4, RT, 24 h
2a, CH2Cl2,
MgSO4, RT, 24 h
2a, EtOH,
Fe
Fe
U
0
0
FeCl2·XH2O
80
0
HCl
RT, 24 h
[a] Catalyst loading: 5 mol%. [b] nd: Not detected. [c] Phen: 1,10-Phe-
nanthroline. [d] DPPE: 1,2-Bis(diphenylphosphine)ethane.
dichloromethane as the most suitable solvent. With THF as
a solvent (entry 8, Table 1), chelating ligands (entries 10 and
11) and bulky ligand-iron complex (entries 12 and 13), the
reaction is completely blocked. We presume that acetoaceta-
nilides are activated first by a metal Lewis acid and succes-
sive cascade cyclization leading to construction of the rare
class of N-heterocycle (6). On treatment of acetoacetanilide
and the catalyst generates a new spot in TLC that may be
due to formation of the acetoacetanilide–FeCl3 activated
complex.
The tetrahydropyridone motif is found in bioactive natu-
ral products, and has tremendous utility as synthons toward
synthesis of pharmaceuticals, alkaloids, heterocycles, and
natural products.[2] Under the identical reaction conditions
(entry 7, Table 1), a wide range of aromatic aldehydes were
examined to establish the scope and generality of the
method (Scheme 2). The reaction proceeds smoothly with
benzaldehyde (6b), naphthaldehyde (6c) and heterocyclic
thiophene aldehyde (6d). Functionalized benzaldehyde pos-
sessing varied electron-withdrawing functionalities (6a and
6e–j), highly reactive aldehyde (6k), triple bond (6l), phe-
nolic OH (6m) and several electron-donating groups (6n–q)
are tolerated in this robust intermolecular cyclization. Yields
are generally high with electron-withdrawing substituents
(78–90%). However, the reaction is unsuccessful with alde-
Scheme 2. Cyclization with aromatic aldehydes (2).
hydes possessing an ortho-hydroxyl group and pyridine alde-
hydes. Acetoacetanilide-bearing OMe (6 f), Me (6h), Cl (6i
and 6o), and Br (6j and 6p) moieties are suitable for the cy-
clocondensation processes. However, the reaction does not
perform with the electron-withdrawing substituent (4’-nitro-
acetoacetanilide); this demonstrates that the electronic
effect of the N-aryl substituent is crucial for execution of
1906
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Chem. Eur. J. 2012, 18, 1905 – 1909

FeCl3·6H2O-Catalyzed Intermolecular-Cascade Cyclization
COMMUNICATION
À
the reaction. The electron-donating substituent tends to in-
crease the electron density over the anilide N-atom to facili-
tate the reaction, whereas the electron-withdrawing substitu-
ent decreases it toward failure. From our experimental re-
sults (entries 9–13, Table 1), ClÀ is found as the optimum
ligand to execute the intermolecular-cascade cyclization pro-
cess. Exclusive formation of trans-6 isomer can be rational-
ized by comparing the stability of the corresponding transi-
tion states during C3–C4 bond-forming cyclization process.
A large steric and electronic repulsion between R2 and
COMe is expected in the putative cis-6 transition state. The
structure is determined by means of X-ray diffraction analy-
ses (6q, Scheme 2)[13] and spectroscopic measurement (see
the Supporting Information).
By the treatment of two different acetoacetanilide deriva-
tives we have found two major regioisomers 6r and 6e from
the post-reaction mixture (Scheme 3). Herein, the electron-
donating substituent (OMe) on Ar2 plays important role to
form the FeCl3–acetoacetanilide activated complex, which is
reflected in the product ratio (6r/6e=52:37).
toward formation of double bond between C2 C3 accounting
for better stability of the olefin-like transition state.
Regio- and stereoselective coupling of p systems of heter-
ocyclic units to various bridged architectures has drawn sig-
nificant interest of organic chemists.[3,15] The reactions gener-
ally proceed with highly regio- and stereoselective fashion.
Pyridone skeletons are the important partner especially in
photocycloaddition.[16] Another interesting and unprecedent-
ed observation is noticed when the reaction between b-ke-
toanilide and acetonide protected glyceraldehydes is stud-
ied. Under the benign reaction conditions, the optically pure
sugar-based
2-oxa-5-aza-bicyclo
[2.2.2]-type
interesting
moiety (8a–c, entries 6–8) is obtained (path c) in moderate
yields (60–68%). It is well suited for installation of a wide
variety of functional groups in a highly dense array. A
double cyclization process occurs to construct N- and O-con-
taining bridged architecture. X-ray diffraction analyses of
8b[16] (Scheme 4) confirms its structure and also orientation
of the groups present in the optically pure compound.
Acetoacetanilide is a common laboratory compound but
it has not found significant ap-
plication in organic synthesis.[17]
However, prefunctionalized de-
rivatives are utilized for intra-
molecular cyclization to 2-pyri-
done and its fused analogue by
using a large excess of trifluoro-
sulfonic acid and SnCl4.[18] The
2-pyridone skeleton offers easy
Scheme 3. Cross-coupling of acetoacetanilides.
functionalization to furnish val-
uable pharmaceuticals and bio-
active natural products.[19] Tre-
mendous application of the key
structural motif[1,4–6] leads to the
development of several ap-
proaches. For instance, SN2 dis-
placement of Baylis–Hilman
adducts,
cycloaddition
ap-
proaches,
cyclocondensation,
Blaise and metathesis reac-
tions.[3c,6b,10a,12,20] In our experi-
ments FeCl3·6H2O shows re-
markable versatility when we
have shifted our attention to
the chromone aldehyde system
(5, Scheme 5). Interestingly,
Scheme 4. Reaction with non-aromatic aldehydes.
À
By using non-aromatic aldehydes (Scheme 4), the reaction
rate is enhanced (4.0 h) to furnish the corresponding trans-
1,2,3,4-tetrahydro-2-pyridone (6s and 6t) in good yields (78–
80%, entries 1 and 2, Table 2). Surprisingly, a trace amount
of activated methylene-aldehyde-condensed corresponding
olefins are detected (7, Scheme 4, path b), which are not iso-
lated. On treatment of conjugated aldehyde (3) the reaction
follows completely path b to afford valuable trans-selective
1,3-diene[14] possessing carbonyl and anilide functionalities
(7c–e, entries 3–5, Table 2). Herein, the incorporated alde-
hyde having an olefinic double bond guides the reaction
acetoacetanilides are coupled with the enal unit (C=C CH=
O) of the chromone aldehyde with opening of the ether
linkage. The unprecedented catalytic property of
FeCl3·6H2O leads to a rapid (4–6 h) bimolecular cascade
cyclization to furnish functionalized 2-pyridone (9a–f). The
role of Cs2CO3 is not just that of a proton sponge because
the reaction does not proceed on its replacement by K2CO3.
Herein, the nitro-group-bearing acetoacetanilide reacts
smoothly to give the desired N-heterocycle (9 f). The X-ray
diffraction structure of 9c[21] is displayed in Scheme 5.
Chem. Eur. J. 2012, 18, 1905 – 1909
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1907

D. K. Maiti et al.
Table 2. Experimental data utilizing non-aromatic aldehydes (2–4).
diverse Lewis acid activities of
non-toxic FeCl3·6H2O. Aromat-
ic, aliphatic, a,b-unsaturated,
sugar-based chiral and chro-
mone aldehydes are regio- and
stereoselectively cyclized with
b-keto anilide systems toward
construction of trans-1,2,3,4-tet-
rahydro-2-pyridone, trans-diene,
Entry
b-Keto amide
Aldehyde
Product
t
Yield
[%]
[h]
R2-CHO
1
2
1a: R1 =H
2l: R2 =n-propyl
4
6
6s, 78
6t, 80
2m: R2 =n-isobutyl
sugar-based
2-oxa-5-aza-
3a
bicyclo[2.2.2] and 2-pyridones.
AHCTUNGTRENNUNG
We are currently investigating
the reaction mechanism to es-
tablish the reaction path of the
robust catalytic process by ex-
perimental evidence as well as
theoretical studies by DFT cal-
culations, which will be report-
ed in due course. We believe
that the novel catalytic property
of the environmentally safe and
inexpensive catalyst will find
wide spread application in
chemistry and its allied branch-
es of science and technology.
3
4
1a: R1 =H
3a
3a
4
3
7a, 88
7b, 90
1e: R1 =OMe
5
1a: R1 =H
3b
X=Ph and Me
3
7c, 87
4a
6
7
8
1a: R1 =H
4a
4a
4a
36
32
30
8a, 60
8b, 68
8c, 62
1 f: R1 =Me
1e: R1 =OMe
Experimental Section
General procedure for synthesis of
1,2,3,4-tetrahydro-2-pyrridone: A solu-
tion of b-ketoanilide (1, 1.0 mmol) and
aromatic/aliphatic
aldehyde
(2,
1.5 mmol) in CH2Cl2 (10 mL) was
added to
(25 mL).
a
round-bottom flask
FeCl3·6H2O (13.5 mg,
0.05 mmol) and anhydrous MgSO4
were added after cooling at 08C. Prog-
ress of the reaction was monitored by
TLC and the reaction was complete
after 6–18 h depending on the sub-
strates used. The post-reaction mixture
was filtered, washed with saturated
sodium bicarbonate solution (2ꢁ
10 mL) and brine solution (1ꢁ10 mL),
dried by using activated sodium sul-
fate, and concentrated in
a rotary
evaporator under reduced pressure at
room temperature. Thus, the reaction
with acetoacetanilide (1a, 177 mg,
1.0 mmol) and m-nitrobenzaldehyde
(2a, 225 mg, 1.5 mmol) afforded 5-
acetyl-2-methyl-4-(3-nitro-phenyl)-6-
oxo-1-phenyl-1,4,5,6-tetrahydro-pyri-
dine-3-carboxylic acid phenylamide
(6a) after purification by column chro-
matography on silica gel (60–120
mesh) with ethyl acetate/petroleum
ether (1:13, v/v) as an eluent to give an
87% yield of isolated product (408 mg,
Scheme 5. Bimolecular cascade cyclization.
In conclusion, we have demonstrated the activation of
acetoacetanilides and the subsequent intermolecular C C
0.87 mmol). The trans-1,2,3,4-tetrahydro-2-pyridones (6a–6t) were char-
acterized by X-ray diffraction analysis and measurement of the NMR
spectrum, FT-IR and MS (EI-MS and HR-MS).
À
À
and C N-bond-forming cascade cyclization process by the
1908
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Chem. Eur. J. 2012, 18, 1905 – 1909

FeCl3·6H2O-Catalyzed Intermolecular-Cascade Cyclization
COMMUNICATION
Compound 6a: Isolated as a white solid. M.p: 136–1388C; 1H NMR
(300 MHz, CDCl3): d=1.76 (3H, s), 2.44 (3H, s), 3.88 (1H, s), 4.45 (1H,
s), 7.03 (3H, d, J=7.2 Hz), 7.16–7.49 (6H, m), 7.53 (2H, d, J=7.8 Hz),
7.63 (1H, d, J=7.2 Hz), 8.05 (1H, d, J=7.8 Hz), 8.21 (1H, s), 8.68 ppm
(1H, s); 13C NMR (75 MHz, CDCl3): d=17.8, 28.1, 39.8, 63.9, 115.2,
119.5, 119.5, 122.2, 122.9, 124.3, 129.0, 129.6, 130.2, 133.5, 136.7, 138.0,
139.3, 140.0, 148.8, 164.0, 166.0, 202.6 ppm; IR (KBr): 697, 1075, 1166,
1312, 1348, 1437, 1524, 1596, 1666, 2976, 3065, 3329; EI-MS (m/z): 469
[M+], 416, 370, 311, 281, 207, 148, 139, 118, 103, 96, 77; HR-MS (m/z):
for C27H23N3O5 469.1638 [M+H]+; found: 469.1642.
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Received: October 25, 2011
Published online: January 20, 2012
Chem. Eur. J. 2012, 18, 1905 – 1909
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