Generation of 4-polyfluoroaryl pyrrolo[1,2-a]quinolines via C-H bond activation

Article abstract of DOI:10.1039/c2cc31301d

A novel and efficient preparation of 4-polyfluoroaryl pyrrolo[1,2-a] quinolines via a palladium-catalyzed reaction of 1-[2-(2,2-dibromoethenyl) phenyl]-1H-pyrrole with polyfluoroarene is described. This transformation is efficient, leading to the correspo

Full text of DOI:10.1039/c2cc31301d

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COMMUNICATION
Generation of 4-polyfluoroaryl pyrrolo[1,2-a]quinolines via C–H bond
activationw
Shengqing Ye,a Jianping Liu*b and Jie Wu*ac
Received 21st February 2012, Accepted 22nd March 2012
DOI: 10.1039/c2cc31301d
A novel and efficient preparation of 4-polyfluoroaryl pyrrolo-
[1,2-a]quinolines via a palladium-catalyzed reaction of 1-[2-(2,2-
dibromoethenyl)phenyl]-1H-pyrrole with polyfluoroarene is described.
This transformation is efficient, leading to the corresponding products
in good yields.
It is well known that polyfluorinated compounds have an
important role in medicinal chemistry1 and material science.2
Continuous efforts have been devoted to the generation of
molecules containing the polyfluoroarene structure. Recently,
we have focused on fluorinated natural product-like compounds
due to their remarkable effects on biological activities. As a
part of our research in the construction of natural product-
like compounds,3 we are interested in the preparation of
polyfluoroaryl substituted pyrrolo[1,2-a]quinolines. Pyrrolo[1,2-a]-
quinoline and its derivatives are found in a wide variety of
biologically important molecules,4 and their applications with
electron transport properties have been reported.5 We anticipated
that the polyfluoroaryl substituted pyrrolo[1,2-a]quinolines would
be beneficial for various biological evaluations. Therefore, we
initiated a program for rapid access to polyfluoroaryl pyrrolo-
[1,2-a]quinolines.
Scheme 1 Proposed synthetic route for the generation of polyfluoroaryl-
substituted pyrrolo[1,2-a]quinolines.
bond in one step would be a good vehicle for the efficient
assembly of pyrrolo[1,2-a]quinolines 3. Herein, we describe the
results of an investigation that has led to the discovery of a novel
route to 4-polyfluoroaryl pyrrolo[1,2-a]quinolines via a palladium-
catalyzed C–H bond activation of 1-[2-(2,2-dibromoethenyl)-
phenyl]-1H-pyrrole with polyfluoroarene.
Conditions for the palladium-catalyzed C–H bond activation
were explored using 1-[2-(2,2-dibromoethenyl)phenyl]-1H-pyrrole
1a and perfluoroarene 2a as substrates. Initially, the reaction
was carried out with Pd(OAc)2 (5 mol%), S-Phos (10 mol%),
and Cs2CO3 (3.0 equiv.) in 1,4-dioxane at 100 1C under a
nitrogen atmosphere (Table 1, entry 1). Gratifyingly, the
expected 4-(perfluoroaryl)pyrrolo[1,2-a]quinoline 3a was
formed and isolated in 45% yield. With this promising result
in hand, we then focused on the selection of solvent. The yield
was increased to 58% when toluene was used (Table 1, entry 2).
We further screened different ligands. No desired product was
detected without the addition of a phosphine ligand in a control
experiment (data not shown in Table 1). The reaction gave rise
to the best result when Ru-Phos was employed as the ligand
(Table 1, entry 8). Switching the ligand to others proved to be
unfruitful. Only a trace amount of product was observed
when the ligand was replaced by Xant-Phos or DPPF (Table 1,
entries 5 and 9). We were pleased to discover that the yield was
increased to 90% when the temperature was lowered to 90 1C
(Table 1, entry 11), while the yield was inferior when the reaction
was performed at 110 1C or 80 1C. Screening other bases and
palladium sources revealed that the combination of Cs2CO3 and
Pd(OAc)2 gave the best yield (Table 1, entries 13–17).
Recent work on the synthesis of polyfluorinated aromatic
compounds via direct coupling reactions of C–H bonds6 of
polyfluoroarenes with aryl and alkenyl halides has been
attractive in organic synthesis.7,8 In the meantime, Lautens
and others reported9–12 the formation of heterocycles using
gem-dihalovinyl systems. The reactivity of gem-dihalovinyl
systems and the efficiency of C–H activation of polyfluorinated
aromatic compounds prompted us to consider the synthetic
feasibility of the reaction of 1-(2-(2,2-dibromovinyl)phenyl)-1H-
pyrrole 1 with polyfluoroarene 2 (Scheme 1). We envisaged that
an intermolecular alkenylation of a polyfluoroarene C–H bond
and an intramolecular alkenylation of a pyrrole or indole C–H
a Department of Chemistry, Fudan University, 220 Handan Road,
Shanghai 200433, China. E-mail: jie_wu@fudan.edu.cn;
Fax: +86 21 6564 1740; Tel: +86 21 6510 2412
b EENT Hospital, Fudan University, 83 Fenyang Road,
Shanghai 200031, China
c State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, China
The generality of this process was explored under the
optimal reaction conditions involving 5 mol% of Pd(OAc)2,
10 mol% of Ru-Phos, 3.0 equiv. of Cs2CO3 in toluene at 90 1C
(Table 2).13 Various 1-[2-(2,2-dibromoethenyl)phenyl]-1H-
pyrrole 1 and polyfluoroarenes 2 were evaluated. A wide range
w Electronic supplementary information (ESI) available: Experimental
procedure, characterization data, 1H, 19F and 13C NMR spectra of
compounds 3. See DOI: 10.1039/c2cc31301d
c
5028 Chem. Commun., 2012, 48, 5028–5030
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Table
1
Initial studies for the palladium-catalyzed reaction of
Table 2 Generation of 4-polyfluoroaryl pyrrolo[1,2-a]quinolines via a
palladium-catalyzed reaction of 1-[2-(2,2-dibromoethenyl)phenyl]-1H-
pyrrole with polyfluoroarenea
1-[2-(2,2-dibromoethenyl)phenyl]-1H-pyrrole 1a with perfluoroarene 2aa
Entry [Pd]
Ligand
Base
Solvent
Yieldb (%)
1
2
3
4
Pd(OAc)2 S-Phosf
Pd(OAc)2 S-Phos
Pd(OAc)2 S-Phos
Pd(OAc)2 S-Phos
Cs2CO3 Dioxane 45
Cs2CO3 Toluene 58
Cs2CO3 MeCN
Cs2CO3 DMF
49
14
5
Pd(OAc)2 Xant-Phosg Cs2CO3 Toluene Trace
6
7
8
9
Pd(OAc)2 DavePhosh
Pd(OAc)2 X-Phosi
Pd(OAc)2 Ru-Phosj
Pd(OAc)2 DPPFk
Pd(OAc)2 Ru-Phos
Pd(OAc)2 Ru-Phos
Pd(OAc)2 Ru-Phos
Pd(OAc)2 Ru-Phos
Pd(OAc)2 Ru-Phos
Pd(OAc)2 Ru-Phos
Cs2CO3 Toluene 21
Cs2CO3 Toluene 58
Cs2CO3 Toluene 77
Cs2CO3 Toluene Trace
Cs2CO3 Toluene 75
Cs2CO3 Toluene 90
Cs2CO3 Toluene 67
10c
11d
12e
13d
14d
15d
16d
17d
K2CO3
Ag2CO3 Toluene Trace
K3PO4 Toluene 48
Toluene Trace
PdCl2 Ru-Phos
Pd2(dba)3 Ru-Phos
Cs2CO3 Toluene 31
Cs2CO3 Toluene 52
a
Reaction conditions (unless otherwise specified): 1a (0.4 mmol), 2a
(3 equiv.), [Pd] (5 mol%), ligand (10 mol%), and base (3 equiv.) in
b
solvent (2.0 mL), at 100 1C. Isolated yield based on 1-[2-(2,2-
dibromoethenyl)phenyl]-1H-pyrrole 1a. c The reaction was performed at
110 1C. d The reaction occurred at 90 1C. e The reaction occurred at 80 1C.
f
g
Dicyclohexyl(20,60-dimethoxy-[1,10-biphenyl]-2-yl)phosphine. (9,9-
h
Dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine). 20-(Dicyclohexyl-
phosphino)-N,N-dimethyl-[1,10-biphenyl]-2-amine. i Dicyclohexyl(20,40,60-
triisopropyl-[1,10-biphenyl]-2-yl)phosphine. Dicyclohexyl(20,60-diiso-
propoxy-[1,10-biphenyl]-2-yl)phosphine. 1,10-Bis(diphenylphosphino)-
ferrocene.
j
k
of polyfluoroarenes were employed and tolerated in the reaction.
For example, 1-[2-(2,2-dibromoethenyl)phenyl]-1H-pyrrole 1a
underwent the reaction with 1,2,4,5-tetrafluoro-3-methoxy-
benzene leading to the expected product 3b in 80% yield.
Compound 3c was obtained in 68% yield when 1,2,4,5-tetra-
fluoro-3-methylbenzene was used as a reactant. 1,2,4,5-Tetra-
fluoro-3-(trifluoromethyl)benzene was a good partner as well,
which afforded the desired product 3d in 82% yield. Further
investigation revealed that reaction of 1-[2-(2,2-dibromoethenyl)-
phenyl]-1H-pyrrole 1a with cyano or nitro-substituted polyfluoro-
arene also worked well to furnish the corresponding product in
good yields. Interestingly, incorporation of 2,3,5,6-tetrafluoro-
pyridine in the transformation did not hamper the efficiency
of the process, which generated pyrrolo[1,2-a]quinoline 3h
in 86% yield. Additionally, we found that the reaction of
1-[2-(2,2-dibromoethenyl)phenyl]-1H-indoles with polyfluoro-
arenes 2 proceeded smoothly, giving rise to the 4-polyfluoroaryl
indolo[1,2-a]quinolines 3l–3o in good yields. The reaction of
1-[2-(2,2-dibromoethenyl)phenyl]-1H-pyrrole 1a with perfluoroarene
2a in a 10 mmol scale was performed in the meantime, which
afforded the corresponding product 3a in 88% yield.
a
Isolated yield based on 1-(2-(2,2-dibromovinyl)phenyl)-1H-pyrrole 1.
1-[2-(2,2-dibromoethenyl)phenyl]-1H-pyrroles with polyfluoro-
arenes. This transformation incorporates an intermolecular alkenyl-
ation of a polyfluoroarene C–H bond and an intramolecular
alkenylation of a pyrrole or indole C–H bond in one step.
Financial support from the National Natural Science
Foundation of China (No. 21032007, 21172038) is gratefully
acknowledged.
Notes and references
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efficient assembly of 4-polyfluoroaryl pyrrolo[1,2-a]quinolines
and their derivatives via a palladium-catalyzed reaction of
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13 General experimental procedure for the palladium-catalyzed
reaction of 1-[2-(2,2-dibromoethenyl)phenyl]-1H-pyrrole 1 with
polyfluoroarene 2: polyfluoroarene 2 was added to a solution of
1-(2-(2,2-dibromovinyl)phenyl)-1H-pyrrole
1
(0.4
mmol),
Pd(OAc)2 (5 mol%), Ru-Phos (10 mol%), and Cs2CO3 (3.0 equiv.)
in toluene (2.0 mL). The mixture was stirred at 90 1C for 12 hours.
After completion of the reaction as indicated by TLC, the residue
was purified directly by flash chromatography on silica gel to
afford products 3. For details, please see the ESIw.
9 For reviews of gem-dihaloolefins, see: (a) in Handbook of
Organopalladium Chemistry for Organic Synthesis, ed. E. Negishi,
c
5030 Chem. Commun., 2012, 48, 5028–5030
This journal is The Royal Society of Chemistry 2012