FeCl3·6H2O-Catalyzed Intermolecular-Cascade Cyclization
COMMUNICATION
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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.
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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
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1907