Iodine-mediated divergent synthesis of fused aza-heterocycles via allylamines derived from Morita-Baylis-Hillman chemistry Harikrishna Batchu,† Soumya Bhattacharyya† and Sanjay Batra* Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow, India E-mail:
[email protected],
[email protected] .
Iodine which is a mild Lewis acid and electrophilic in nature is known to promote several chemical transformations.1 Amongst such reactions, the ones involving activation of π-system are of significant interest as they complement metal-catalyzed processes and lead to formation of useful products. Such reactions proceeds either through formation of a charge transfer complex or via an iodoiranium/iodoirenium intermediate followed by attack of a nucleophile either in an endo or exo fashion (Figure 1). We have been involved in exploring the synthetic applications of Morita-Baylis-Hillman (MBH) derivatives for the generation of heterocyclic scaffolds of biological significance. In this context, we have been interested in utilizing the primary allylamine prepared from MBH adducts, for the synthesis of aza-heterocycles. In one of such works it was envisaged that an aromatic system bearing a 2-ethynyl functionality at ortho-position to the carbon bearing the allyamine subunit upon treatment with iodine may offer a facile route to benzazepines via exo-trig cyclization. However it was discovered that treating the allylamine prepared from the MBH adduct of 2(phenylethynyl)benzaldehyde with alkylacrylate with iodine resulted into formation of quinolone instead of the expected benzazepine (Figure 2). Given the relevance of quinoline motif in natural products and bioactive compounds, we were encouraged to study the reaction in greater details. It was found that suitably substituted primaryallylamines undergo intramolecular electrophilic aromatic cyclization under mild conditions. protocol was sucessfully extended to hetroaromatic substrates to prepare pyrazolo[4,3-b]pyridines and thieno-[3,2b]pyridines.2 The success of the reaction relied on the presence of a free C-H group ortho to the carbon bearing the allylamine chain. Conversely it was anticipated that if there was no free C–H available at the designated position then the intramolecular cyclization would occur to afford the azepine ring instead of the pyridine ring. Expectedly it was discovered that when the allylamines prepared from 4-alkynyl-3pyrazolecarbaldehyde were treated with iodine, dihydropyrazolo[4,3c]azepines were formed via intramolecular hydrative cyclization (Figure 3).3
Substrate scope
Optimization of reaction conditions
Introduction
Entrya
Base (equiv)
Iodine source (equiv)
1
Na2CO3 (3)
I2 (3)
MeCN
24 h
-
2
K2CO3 (3)
I2 (3)
MeCN
30 min
80
3
K2CO3 (2)
I2 (3)
MeCN
12 h
58
4
K2CO3 (1)
I2 (3)
MeCN
12 h
10
5
Cs2CO3 (3)
I2 (3)
MeCN
24 h
-
6
NaHCO3 (3)
I2 (3)
MeCN
12 h
10
7
Et3N (3)
I2 (3)
MeCN
24 h
-
8
DBU (3)
I2 (3)
MeCN
24 h
-
9
K2CO3 (3)
ICl (3)
MeCN
15 h
35
10
K2CO3 (3)
NIS (3)
MeCN
15 h
39
11
K2CO3 (3)
I2 (2)
MeCN
12 h
40
12
K2CO3 (3)
I2 (1)
MeCN
12 h
15
13
K2CO3 (3)
I2 (3)
CH2Cl2
5h
39
14
K2CO3 (3)
I2 (3)
CHCl3
30 min
84
15
K2CO3 (3)
I2 (3)
H2O
24 h
19
Solvent
Time
Yield (%)b
aAll
reactions were performed using 0.1 g (0.52 mmol) of the allylamine at room temperature in 5 mL of solvent, bYield of chromatographically pure product.
Plausible Reaction Mechanism
Substrate scope
Figure 1.
Summary
Attempted Iodocyclization of alkyne in allylamines
A novel synthesis of quinoline, thienopyridine and pyrazolopyridine was achieved via unprecedented intramolecular electrophilic aromatic substitution in primary allylamines obtained from MBH chemistry. The cyclization is essentially assisted by carboxylate group present in the allylamine. The cyclization is possible only if a free C-H group is present adjacent to the carbon bearing the allylamine subunit. If the adjacent carbon is substituted then iodine induces exo-dig intramolecular cyclization. This has been demonstrated by synthesis of dihydropyrazolo[4,3c]azepines from suitably substituted pyrazole-based allylamines via iodine mediated hydrative cyclization
Acknowledgments Figure 2
Plausible Reaction Mechanism
Iodine-mediated intramolecular hydrative cyclization
Figure 3
Financial support to HB and SB from CSIR, New Delhi in the form of fellowship is gratefully acknowledged. This work was funded by the DST, New Delhi. The authors also acknowledge the SAIF Division of CDRI for the spectroscopic data.
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