Synthesis of bis-exocyclic conjugated diene containing 1,2,3,4-tetrahydroquinoline derivatives via palladium-catalyzed intramolecular Heck cyclization

Article abstract of DOI:10.1039/c4ra05900j

An efficient method has been developed for the synthesis of bis-exocyclic conjugated diene containing 1,2,3,4-tetrahydroquinoline derivatives via palladium-catalyzed intramolecular Heck cyclization of (2-bromo-allyl)-(2-phenylethynyl-phenyl)-amines. The r

Full text of DOI:10.1039/c4ra05900j

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Synthesis of bis-exocyclic conjugated diene
containing 1,2,3,4-tetrahydroquinoline derivatives
via palladium-catalyzed intramolecular Heck
cyclization†
Cite this: RSC Adv., 2014, 4, 41561
Received 18th June 2014
Accepted 27th August 2014
*
Munmun Ghosh, Shubhendu Dhara, Yasin Nuree and Jayanta K. Ray
DOI: 10.1039/c4ra05900j
www.rsc.org/advances
An efficient method has been developed for the synthesis of bis- enantioselectivities upto 94% using (S)- and (R)-9-NapBNs as
exocyclic conjugated diene containing 1,2,3,4-tetrahydroquinoline chiral ligands.5 Jorgensen's group reported synthesis of opti-
derivatives via palladium-catalyzed intramolecular Heck cyclization of (2- cally active tetrahydroquinolines via enantioselective Michael
bromo-allyl)-(2-phenylethynyl-phenyl)-amines. The reaction followed addition of malonates to acyclic enones using an imidazolidine
6-exo-dig cyclization to yield the desired products in moderate to good catalyst easily prepared from phenylalanine.6 Thomson and co-
yields.
workers reported asymmetric synthesis of 2-aryl-4-
aminotetrahydroquinoline-3-carboxylic acid derivatives in
>98% de, >98% ee where lithium (R)-N-benzyl-N-(a-methyl-
benzyl) amide undergoes tandem conjugate addition-
cyclization to aromatic imines bearing an electron-decient
1,2,3,4-Tetrahydroquinoline has been found to be present as an
important structural framework in numerous naturally occur-
ring and biologically active compounds.1 Substituted tetrahy-
droquinoline derivatives exhibit a wide range of biochemical
and pharmaceutical activities.2 They are also important in terms
of industrial applications.3 Some pharmacologically active
compounds with tetrahydroquinoline as the basic moiety are
shown in Fig. 1.4
Table 1 Synthesis of Heck precursor amines (2a–2m)
Such potential and versatile applications of tetrahy-
droquinoline derivatives in chemistry, biology, as well as in
industry resulted in a number of successful novel synthetic
strategies towards its synthesis. Hamada et al. reported
synthesis of tetrahydroquinolines via Pd-catalyzed intra-
molecular asymmetric allylic alkylation reaction achieving
Fig.
1
Tetrahydroquinoline-based
therapeutically
promising
compounds.
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India.
E-mail: jkray@chem.iitkgp.ernet.in; Fax: +91 3222282252; Tel: +91 3222283326
a
Isolated yield (aer purication through column chromatography)
† Electronic supplementary information (ESI) available: For experimental details
and characterization of compounds 2a–2m and 3a–3m. See DOI:
10.1039/c4ra05900j
b
aer 10 h.
Isolated yield (aer purication through column
chromatography) aer 12 h.
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alkene substituent in the ortho position.7 Recently Bao et al. reuxing Et3N (6 mL) for 4–5 h (ref. 12) followed by mono-
reported one pot synthesis of ring-fused tetrahydroquinoline allylation of the aromatic amines using K2CO3 (2 mmol) and
derivatives from arylamines and N-substiuted lactams via FeCl3- 2,3-dibromopropene (1 mmol) in reuxing CH3CN (5 mL) for
catalyzed cascade cyclization.8 All these methodologies avail- 10–12 h (Table 1).13 Di-allylation was prevented probably by the
able so far aim at the synthesis of various substituted tetrahy- bulky phenyl group at the ortho position.
droquinolines. There are also some reports available in the
The Heck precursor 2a was then subjected to intramolecular
literature for the synthesis of 3-methylene as well as 4-methy- cyclization under Heck reaction conditions. Aer screening
lene tetrahydroquinoline derivatives.9,10 However, no such novel through a number of catalysts, ligands, bases, and solvents, the
work has been reported for the synthesis of 3,4-diene cyclization step was found to be most effective with Pd(OAc)2
substituted tetrahydroquinolines till date. So, we targeted (5 mol%), PPh3 (0.5 mmol), and HCOONa (1.5 mmol) in DMF
towards the synthesis of 3, 4-disubstituted tetrahydroquinolines (5 mL) at 80 ꢀC resulting in the formation of 82% of
applying intramolecular Heck cyclization.
4-benzylidene-3-methylene-1,2,3,4-tetrahydroquinoline as the
Following several interesting synthetic methodologies on only isolable product (Table 2, Entry 7). No further cyclization
palladium catalyzed intramolecular Heck cyclization,11 herein occurred even aer 9 h. As evident from NMR spectral data,
we report an efficient method for the synthesis of 4-benzylidene- stereoselectively only one isomer was isolated. However,
3-methylene (or, 4-trimethylsilanylmethylene)-1,2,3,4-tetra- stereochemistry of the product could not be rigorously estab-
hydroquinolines (3a–3m) via palladium catalyzed 6-exo-dig lished but based on the literature report available on the
cyclization of (2-bromo-allyl)-(2-phenylethynyl-phenyl) or, (2- mechanism of palladium-catalyzed exo-dig cyclization,14 the
bromo-allyl)-(2-trimethylsilanylethynyl-phenyl)-amines
(2a– stereochemistry of the product is expected to be the E-isomer
2m). The Heck precursors (2a–2m) were synthesized in good (Table 3).
yield from the corresponding 2-iodoanilines (1 mmol) by
As a course of mechanistic explanation, it can be postulated
Sonogashira coupling with ethynyl benzene and its derivatives that Pd(II) is initially reduced by PPh3 to Pd (0) which then enters
(1.1 mmol) (for 2a–2j, 2l and 2m) or with (trimethylsilyl)acety- the catalytic cycle by oxidative addition to the sp2-C-Br bond of
lene (for 2k) using PdCl2(PPh3)2 (5 mol%) and CuI (5 mol%) in the ‘ene–yne’system leading to the formation of the
Table 2 Optimization studiesa
Entry
Catalyst
Ligand
Base
Solvent
Temp. (ꢀC)
Yielda (%)
1
2
3
4
5
6
7
8
Pd(OAc)2 (5 mol%)
Pd(OAc)2 (5 mol%)
Pd(OAc)2 (5 mol%)
Pd(OAc)2 (5 mol%)
Pd(OAc)2 (5 mol%)
Pd(OAc)2 (5 mol%)
Pd(OAc)2 (5 mol%)
Pd(OAc)2 (5 mol%)
Pd(OAc)2 (2 mol%)
Pd(OAc)2 (5 mol%)
—
PPh3 (0.5 mmol)
PPh3 (0.5 mmol)
PPh3 (0.5 mmol)
PPh3 (0.5 mmol)
PPh3 (0.5 mmol)
PPh3 (0.5 mmol)
PPh3 (0.5 mmol)
PPh3 (0.5 mmol)
PPh3 (0.5 mmol)
PPh3 (0.2 mmol)
—
Cs2CO3 (1.5 mmol)
Cs2CO3 (1.5 mmol)
Cs2CO3 (1.5 mmol)
Na2CO3 (1.5 mmol)
K2CO3 (1.5 mmol)
NaOAc (1.5 mmol)
HCOONa (1.5 mmol)
HCOONa (1 mmol)
HCOONa (1.5 mmol)
HCOONa (1.5 mmol)
HCOONa (1.5 mmol)
HCOONa (1.5 mmol)
HCOONa (1.5 mmol)
HCOONa (1.5 mmol)
HCOONa (1.5 mmol)
HCOONa (1.5 mmol)
HCOONa (1.5 mmol)
HCOONa (1.5 mmol)
HCOONa (1.5 mmol)
HCOONa (1.5 mmol)
HCOONa (1.5 mmol)
HCOONa (1.5 mmol)
Et3N (7 mmol)
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
1,4-Dioxane
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
DMA
DME
DMF
DMF
25
60
80
80
85
80
80
80
80
80
85
85
85
80
85
85
85
85
85
85
80
85
85
85
0
10
42
40
37
47
82
62
42
46
0
53
49
75
65
55
67
32
43
56
72
42
0
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
Pd(OAc)2 (5 mol%)
Pd(OAc)2 (5 mol%)
PdCl2 (5 mol%)
—
PPh3 (0.5 mmol)
PPh3 (0.5 mmol)
—
—
—
PCy3 (0.5 mmol)
(R)-(+)-BINAP (0.5 mmol)
PPh3 (0.5 mmol)
PPh3 (0.5 mmol)
PPh3 (0.5 mmol)
PdCl2(PPh3)2 (0.5 mmol)
PPh3 (0.5 mmol)
Pd(PPh3)4 (5 mol%)
PdCl2(CH3CN)2 (5 mol%)
PdCl2(PPh3)2 (5 mol%)
Pd(OAc)2 (5 mol%)
Pd(OAc)2 (5 mol%)
Pd(OAc)2 (0.5 mol%)
Pd(OAc)2 (0.5 mol%)
Pd(OAc)2 (0.5 mol%)
CuI (0.5 mol%)
ZnCl2 (0.5 mol%)
Et3N (7 mmol)
0
a
Yields refer to the isolated yields aer purication through column chromatography.
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Table 3 Synthesis of 1,2,3,4-tetrahydroquinolinesa (3a–3m)
diene fragment via Pd-catalyzed intramolecular Heck cycliza-
tion. Our synthetic strategy is advantageous with respect to high
yield, stereoselectivity, substrate versatility, and easily acces-
sible ‘ene–yne’ moiety. This novel methodology may be
successfully applied towards the stereoselective synthesis of bis-
exocyclic conjugated diene containing tetrahydroquinoline-
based natural products demonstrating important pharmaco-
logical effects.
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a
Reagents and conditions: all the reactions were carried out under the
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PPh3 (0.5 mmol), HCOONa (1.5 mmol), DMF (5 mL), 80–85 ꢀC, 4–5 h.
b
Isolated yield (aer purication through column chromatography)
c
aer
4
h.
Isolated yield (aer purication through column
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undergoes carbopalladation to the triple bond forming another
alkenylpalladium intermediate B which is reduced by HCOONa
to give the desired product 3a (Scheme 1).
Conclusions
In short we have developed an efficient strategy for the
construction
of
4-benzylidene-3-methylene-1,2,3,4-
tetrahydroquinolines containing bis-exocyclic conjugated
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