Synthesis of pyrrolo[1,2-a] quinolines and ullazines by visible light mediated one- and twofold annulation of N-arylpyrroles with arylalkynes

Article abstract of DOI:10.1039/c6cc04366f

1-(2-Bromophenyl)-1H-pyrrole and 1-(2,6-dibromophenyl)-1H-pyrrole react in the presence of catalytic amounts of rhodamine 6G (Rh-6G) and N,N-diisopropylethylamine (DIPEA) under blue light irradiation with aromatic alkynes and subsequently cyclize intramol

Full text of DOI:10.1039/c6cc04366f

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DOI: 10.1039/C6CC04366F
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Synthesis of Pyrrolo[1,2‐a]quinolines and Ullazines by Visible Light
mediated one‐ and twofold Annulation of N‐Arylpyrroles with
Arylalkynes†
Received 00th January 20xx,
Accepted 00th January 20xx
Amrita Das,a Indrajit Ghosha* and Burkhard Königa*
DOI: 10.1039/x0xx00000x
www.rsc.org/
direct arylation of geminal dibromo‐olefins with a boronic acid via
tandem Suzuki‐Miyura coupling reaction.23 Larock et al. reported a
copper catalyzed tandem synthetic methodology for the synthesis
of pyrrolo‐ and indolo[2,1‐a]isoquinolines.24 Recently, Baxendale et
1‐(2‐Bromophenyl)‐1H‐pyrrole and 1‐(2,6‐dibromophenyl)‐
1
H
‐pyrrole react in the presence of catalytic amounts of
rhodamine 6G (Rh‐6G) and ‐diisopropylethylamine
N,N
(DIPEA) under blue light irradiation with aromatic alkynes
and subsequently cyclize intramolecularly to form
al.
developed
a
method
for
the
synthesis
of
pyrrolo[1,2‐a]‐quinolines based on an allene cascade reaction in
batch and flow mode.25 Miyura et al. described the coupling of
phenylazoles with internal alkynes in the presence of a rhodium
catalyst and a copper oxidant.26 Also, the same group reported the
formation of indolo[1,2‐a][1,8]naphthyridines by rhodium catalyzed
dehydrogenative coupling via rollover cyclometallation27.
Dumitrescu et al. developed the synthesis of pyrrolo[2,1‐
a]isoquinolines by multicomponent 1,3‐dipolar cycloaddition.28
However, all the current synthetic methods require base, specific
ligands, high temperature and transition metal catalysts, multi‐step
processes, and in some cases both cyclized and non‐cyclized
products are formed, which are difficult to separate. Transition
metal free visible light photoredox catalysis is an attractive mild,
selective and efficient alternative for the synthesis of pyrrolo[1,2‐
a]quinolines, pyrazolo[1,5‐a]quinolines, and ullazines by one and
two fold annulation of N‐aryl pyrroles/pyrazoles with aryl alkynes.
We report here a one‐step visible light mediated metal free direct
arylation of 1‐(2‐bromophenyl)‐1H‐pyrrole, 1‐(2‐bromophenyl)‐1H‐
pyrrolo[1,2‐a]quinoline and ullazines. The reactions proceed
at room temperature, avoid transition metal catalysts, and
provide the target compounds in one pot in moderate to
good yields. Mechanistic investigations suggest that the
photo excited Rh‐6G is reduced by DIPEA to form the
corresponding radical anion Rh‐6G•–, which is again excited
by 455 nm light. The excited radical anion of Rh‐6G donates
an electron to the aryl bromide giving an aryl radical that is
trapped by aromatic alkynes. The intermediate vinyl radical
cyclizes intramolecularly and yields the product after
rearomatization.
Fused nitrogen containing heterocycles are structural elements
of biologically active natural products1 or active pharmaceutical
ingredients (APIs) and find applications in organic materials.2
Among them, pyrrolo[1,2‐a]quinolines, pyrazolo[1,5‐a]quinolines,
and ullazines are of particular importance. Some of their derivatives
show antitumor,3 antibacterial4 or antimicrobial5 activities; they
activate caspases or induce apoptosis6 and are used as organic
semiconductors,7 in host–guest chemistry8, 9 or as liquid crystals.10,
pyrazole,
3‐bromo‐2‐(1H‐pyrrol‐1‐yl)pyridine
and
1‐(2,6‐
dibromophenyl)‐1H‐pyrrole with simple aromatic alkynes providing
pyrrolo[1,2‐a]quinolines, pyrazolo[1,5‐a]quinolines, pyrrolo[1,2‐
a][1,8]naphthyridine and ullazine compounds, respectively. This
method utilizes blue light, the organic dye rhodamine 6G (Rh‐6G) as
photocatalyst and N,N‐diisopropylethylamine (DIPEA) as electron
donor.
11
Also, the pyrazolo derivatives, e.g.; 4‐phenylpyrazolo[1,5‐
a]quinoline show anti reproductive utility.12 Ullazines have found
applications in optoelectronics, as organic sensitizer for solar‐cell
and show very good electron transport properties.13
Several methods for the synthesis of fused nitrogen‐containing
heterocycles have been reported; many apply direct arylation
15, 16, 17
reactions. These include palladium‐catalyzed reactions,14,
1,2‐alkyl migration,18 DDQ‐mediated intramolecular cyclizations,19
flash vacuum pyrolysis,20 photosubstitution reactions,21 and alkyne‐
carbonyl metathesis.22 Lautens et al. reported a palladium catalyzed
a. Institut für Organische Chemie, Universität Regensburg, Universitätsstraße 31, D‐
93053 Regensburg.
†Electronic Supplementary Information (ESI) available: Supplementary figures,
materials, methods and analytical data. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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slow reaction rates owing to the high reduction potentials of the
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substrates36 representing the limit of the DphOoI:t1o0c.a10ta3l9y/sCt6CscCo0p4e3,66oFr
due to the competing light absorption (i.e., the inner filter effect) of
the colored products with the catalyst and/or its radical anion (see
Fig. 2). In addition, trace amount of dehalogenated starting material
was isolated as by‐product.34, 35
Table 1 Synthesis of Pyrrolo[1,2‐a]quinoline.
Entry
Aryl
R1
Alkynea
R
Product Yieldb,c
Bromidea
Scheme 1 Pyrrolo[1,2‐a]quinoline syntheses.
1
2
1ad
1ad
1ad
1ad
1bd
1bd
1bd
1bd
1bd
1cd
1cd
1cd
1cd
1de
1de
1ef
1ef
H
H
2a
2b
2c
2d
2a
2b
2c
2d
2e
2a
2b
2c
2d
2a
2c
2a
2b
H
CH3
OCH3
F
3a
3b
3c
3d
3e
3f
60
51
50
48
56
54
75
50
50
52
56
41
41
39
35
49
50
First, the annulation reaction of aryl halide 1a with aryl alkyne
2a (entry 1) in the presence of Rh‐6G (20 mol%) as the
photocatalyst in DMSO at 25 C under visible light irradiation (blue
o
LEDs: λmax = 455 ± 15nm) was investigated. Under the reaction
conditions Rh‐6G photo‐bleaches and 20 mol% catalyst loading was
required. The annulated pyrrolo[1,2‐a]quinoline 3a was obtained in
60% yield in 24 hours. This synthetic approach uses the high
3
H
4
H
30
reduction power of the excited stable radical anion Rh‐6G•–29,
5
COCH3
COCH3
COCH3
COCH3
COCH3
CF3
CF3
CF3
CF3
H
H
obtained upon photoirradiation of the xanthene dye under nitrogen
with visible light in the presence of N,N‐diisopropylethylamine
(DIPEA). Our photocatalytic method allows the activation of
electron rich heteroarenes with a redox potential up to ca. –2.4 V vs
SCE, which is not accessible using common photocatalysts,31, 32 for
C–C bond formation. The synthesis of fused heterocycles combines
an intermolecular radical addition to alkynes with an intramolecular
cyclization reaction. To improve the efficiency of this method, the
reaction conditions were optimized trying various solvents, electron
donors, varying the amount of catalyst and of the starting materials.
DMSO was found to be the best solvent for the photoreaction using
0.07 mol/L substrate concentrations, 20 equiv. of the alkyne and 2.2
equiv. of DIPEA. Notably, excess amount of alkynes (unreacted
6
CH3
OCH3
F
7
3g
3h
3i
8
9
Cl
10
11
12
13
14
15
16
H
3j
CH3
OCH3
F
3k
3l
alkynes were recovered during isolation) were used to avoid the
33
dehalogenated byproduct30,
formed upon hydrogen atom
abstraction of the generated aryl radical from the radical cation of
DIPEA or from the solvent.34, 35 The cyclized product was obtained in
good yield with 20 mol% of the photocatalyst. We used a thin layer
(1.0 mm) glass reactor with 1.5 ml volume to have an optimal
exposure of the reaction mixture for irradiation (for details see ESI).
Control reactions confirmed that light, the photocatalyst, and an
electron donor are needed for the reaction to occur. Having
identified the optimized reaction conditions, we examined the
scope of the reaction with substituted aryl halides and alkynes. The
products were obtained in moderate to good yields (Table 1). It is
observed that the reaction is much faster with neutral and electron
rich alkynes, and comparatively slower in the presence of electron
withdrawing alkynes. The products (entry 5‐13) in Table 1 were
obtained in shorter time, but the reaction stops before full
conversion. Adding one extra nitrogen to the system increases the
redox potential of the aryl halide, hence, slows down the reaction.
1‐(2‐Bromophenyl)‐1H‐pyrazole (1d) has a redox potential of ~ –2.4
V vs SCE (Table 1, entry 14–15) and 3‐bromo‐2‐(1H‐pyrrol‐1‐
yl)pyridine (1e) has a redox potential of ~ –2.1 V vs SCE (Table 1,
entry 16–17). The observed low yields may be attributed to the
3m
3n
3o
3p
3q
H
H
OCH3
H
H
17
H
CH3
a
The reaction was performed with 1(a–e) (0.1 mmol), 2(a–e) (20
equiv.), DIPEA (2.2 equiv.), and Rh‐6G (20 mol%) in 1.5 mL of DMSO.
b
Isolated yields after purification by flash column chromatography
using silica gel. for the reaction times see ESI. d X, Y = C (entry 1‐
c
13), e X = N, Y = C (entry 14 and 15), f X = C, Y = N (entry 16 and 17).
2 | J. Name., 2012, 00, 1‐3
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Table 2 Synthesis of ullazines.
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DOI: 10.1039/C6CC04366F
Rh-6G
Br
Br
DIPEA, DMSO
LED 455nm
24h, 25°C
N
N
R
R
R
Entry
Substrate
Alkyne
R
Product
Yieldb
3e
3i
1
2
3
1f
1f
1f
H
2a
2b
2c
3r
3s
3t
45
30
30
Fig. 1 Crystal structures of compounds 3e and 3i.
CH3
OCH3
Extending the scope of the reaction by replacing the pyrrole
moiety by indole resulted in low yields for the transformation. A
likely rational for the lower reactivity and yields of indoles in the
cyclization reaction is the enforced unfavourable substitution at the
2 position.37
The reaction was performed with 1f (0.1 mmol), 2(a–c) (20 equiv.),
DIPEA (2.2 equiv.), and Rh‐6G (0.2 equiv.) in 1.5 mL of DMSO.
b Isolated yields after purification by flash column chromatography
using silica gel.
R
R
Based on previous results,30 spectroscopic investigations, and
our experimental observations we propose the following
mechanism (Scheme 3) for the cyclization reaction. Upon
photoexcitation with blue light (max = 455nm),41 Rh‐6G is
photoreduced in the presence of DIPEA to the stable radical anion
Rh‐6G•–, which is again excited by blue light and transfers an
electron to the N‐aryl bromide 1a forming Ar‐Br•– while
regenerating the neutral Rh‐6G. While the radical anion of
rhodamine 6G (Rh‐6G•–) can also be generated with green light, the
blue light excitation is required to photoexcite it again. Using blue
light for both steps simplifies the experimental set up. The
reduction potential of Rh‐6G•– (ca. –1.0) is not sufficient to reduce
the N‐aryl bromide substrates investigated here. Fragmentation of
the radical anion Ar‐Br•– generates the aryl radical, which reacts
intermolecularly with the alkyne 2a to form the vinyl radical A. This
vinyl radical cyclizes intramolecularly giving the annulated product
3a after oxidation and rearomatization. The formation of the
dehalogenated product is due to hydrogen atom abstraction by the
R1
i)
N
N
Br
ii) Rh-6G (20 mol%)
III) DIPEA (2.2 equiv.)
DMSO, 455nm LED,
25°C, 24h
R = H, R1 = H, 30%
R = CH3, R1 = H, 20%
R = H, R1 = OCH3, < 10%
Scheme 2 Indolo[1,2‐a]quinoline syntheses.
Next, we explored the photocatalytic synthesis of ullazines. First
derivatives of these class of compounds were prepared in 1983 by
38
Balli et al.
in 9 steps with very poor yields. Takahasi’s route39
showed no regioselectivity and required harsh conditions. Grätzel's
synthesis40 uses InCl3 and requires four steps. The photoredox
reaction yields ullazines in one pot. Using the optimized reaction
condition, the annulation reaction was carried out between the
dibromo compound 1d and aryl alkynes. The results are
summarized in Table 2. The observed low yields are due to the
extremely high reduction potentials of quinoline intermediates and
intensively colored products that inhibit the reaction by competing intermediate aryl radical either from the radical cation of DIPEA or
in absorption with the catalyst and/or it’s radical anion (see Fig. 2).
Although not quantified, most of the unreacted starting materials
could be recovered during the purification process.
from the solvent.
Fig. 2 Stern‐Volmer quenching plot of Rh‐6G in the presence of
DIPEA and 1b (test substrate). In the inset, absorption spectra of
compounds 3e, and 3o are shown.
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Scheme 3 Proposed reaction mechanism.
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In conclusion, the first photocatalytic synthesis of pyrrolo[1,2‐
a]quinolines and ullazines was accomplished starting from N‐aryl
halides and aryl alkynes. This method provides in a single step mild
and efficient access to different types of substituted pyrrolo[1,2‐
a]quinolines,
pyrazolo[1,5‐a]quinolines,
pyrrolo[1,2‐
a][1,8]naphthyridine and ullazines avoiding transition metal
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We thank the Deutsche Forschungsgemeinschaft (GRK 1626)
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and Dr. R. Vasold and Ms. R. Hoheisel for GC–MS and CV
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