the allylamine carrying a meta substituted phenyl ring, no
regioselectivity was observed, and the product although
obtained in good yields was a 1:1 mixture of 6- and
8-substituted quinolines (entry 11). On the other hand, the
allylamine synthesized from MBH adduct of 2-naphthalde-
hyde resulted in regioselective cyclization at 1-position albeit
in low yields (entry 15). Changing the methyl ester to ethyl
ester or tert-butyl ester in the allylamine did not influence
the formation of the product (entries 16À18).
Scheme 2. Proposed Reaction Mechanism
Following successful synthesis of quinolines from the
substrates prepared from benzaldehydes, we decided to
examine the substituted primary allylamines generated
from heterocyclic aldehydes in order to enhance the
scope of our methodology. Therefore appropriate pri-
mary allylamines were prepared from the MBH adducts
of 3-pyrazolecarbaldehydes, 2-thiophenecarbaldehydes and
4-chloro-3-quinolinecarbaldehyde and were treated with
iodine under the optimized conditions. It was pleasing to
note that the pyrazole and the thiophene derivatives gave
the expected products in good yields (entries 19À24). Inter-
estingly however the quinoline derivative, instead of the
expected product, afforded a naphthyridine derivative pre-
sumably via SNAr reaction (entry 25). As a consequence, we
considered investigating the reaction of allylamine prepared
from the MBH adduct of 2,6-dichlorobenzaldehyde with
iodine. But we found that this allylamine failed to afford the
expected product even after 12 h of reaction time (entry 26).
In order to rationalize these results, we propose a
plausible mechanism summarized in Figure 1, wherein
the iodine initially activates the carbonyl group to form
intermediate A (Scheme 2). This initiates an electrophilic
cyclization via a nucleophilic attack of the amino group
onto the aromatic ring leading to a zwitterionic intermedi-
ate B, which may stabilize to C. Subsequently in the
presence of iodine and base, the iodinated intermediate D
is formed, which is then deiodinated to furnish the dihy-
droquinoline. Oxidation of the dihydroquinoline under
reaction conditions yield the quinoline. Since we were
unable to isolate any intermediate, we presume that the
product is formed via a concerted mechanism.9 To man-
ifest the essentiality of alkoxycarbonyl group for the
protocol, we considered probing similar reaction with the
allylamine 3 bearing E-stereochemistry. The required ally-
lamine 3 prepared by the reported method10 on treatment
with iodine failed to yield the required quinoline (Scheme 3).
Scheme 3. Unsuccessful Attempt to Cyclize Allylamine 3 via the
Optimized Protocol
In conclusion, we have developed a unique route to the
synthesis of aromatic ring annulated pyridines via an
unprecedented intramolecular electrophilic aromatic cycli-
zation in suitably substituted primary allylamines. This
method not only allows installing desired functional
groups at C-5 and C-7 in quinoline, but also gives the
option to readily prepare C-5ÀC-6, C-5ÀC-7 and C-5ÀC-
8 disubstituted quinolines with preferred substitutions.
Further, the versatility of the protocol is evident from the
synthesis of substituted pyrazolo[4,3-b]pyridines and thieno-
[3,2-b]pyridines. The readily available starting reagents, no
use of metal catalyst, and mild conditions are some of the
additional features of this protocol.
(8) (a) Alajarın, R.; Burgos, C. In Modern Heterocyclic Chemistry;
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Alvarez-Builla, J., Vaquero, J., Barluenga, J., Eds.; Wiley-VCH: Weinheim,
Germany, 2011; pp1527À1630. (b) Michael, J. P. Nat. Prod. Rep. 2008,
25, 166–187. (c) Wagman, A. S.; Wentland, M. P. In Comprehensive
Medicinal Chemistry II; Taylor, J. B., Triggle, D. J., Eds.; Elsevier, Ltd.:
Oxford, UK: 2006; Vol. 7, pp 567À596. (d) Goncalves, V.; Brannigan,
J. A.; Whalley, D.; Ansell, K. H.; Saxty, B.; Holder, A. A.; Wilkinson,
A. J.; Tate, E. W.; Leatherbarrow, R. J. J. Med. Chem. 2012, 55, 916–
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Ciulli, A.; Munro, A. W.; Abell, C. Angew. Chem., Int. Ed. 2012, 51,
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(9) A successful iodine-mediated cyclization of (E)-methyl 2-(amino-
methyl)-3-phenylacrylate to corresponding quinoline in the presence of
radical scavengers including chloranil, benzoquinone or oxygen (balloon)
ruled out the possibility of a radical mechanism. Unfortunately, however, the
starting amine was decomposed, and no product could be isolated when the
similar reaction was attempted in the presence of TEMPO.
Acknowledgment. Two of the authors (HB and SB)
gratefuly acknowledge the financial support from the
CSIR, New Delhi, in the form of fellowships. The authors
are thankful for the financial support from the DST, New
Delhi. The authors acknowledge the SAIF Division of
CDRI for providing the spectroscopic and analytical data.
CDRI Comm. No. 8368.
Supporting Information Available. Experimental pro-
cedures and spectroscopic data for new compounds and
1
copies of H and 13C NMR spectra for representative
compounds. This material is available free of charge via
(10) Li, M.-B.; Wang, Y.; Tian, S.-K. Angew. Chem., Int. Ed. 2012,
51, 2968–2971.
The authors declare no competing financial interest.
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