Visible light photoredox catalyzed cascade cyclizations of α-bromochalcones or α-bromocinnamates with heteroarenes

Article abstract of DOI:10.1002/adsc.201301069

Vinyl radicals were generated from α-bromochalcones or a-bromocinnamate ethyl ester under visible light photoredox catalyzed conditions via an oxidative quenching cycle of the iridium complex [Ir{d(CF ₃)ppy}₂(dtbbpy)]PF6 and subjected to cascade cyclizations with heteroarenes entailing two consecutive C-C bond formations and three C-H activations. The process is amenable to furans, benzofurans, pyrroles, and indoles, giving rise to a broad variety of novel polycyclic frameworks in high yields under mild and environmentally benign reaction conditions.

Full text of DOI:10.1002/adsc.201301069

FULL PAPERS
DOI: 10.1002/adsc.201301069
Visible Light Photoredox Catalyzed Cascade Cyclizations of a-
Bromochalcones or a-Bromocinnamates with Heteroarenes
Suva Pariaa and Oliver Reisera,*
a
Institut fꢀr Organische Chemie, Universitꢁt Regensburg Universitꢁtsstrasse 31, 93053 Regensburg, Germany
Fax : (+49)-941-943-4121; phone: (+49)-941-943-4631; e-mail: Oliver.Reiser@chemie.uni-regensburg.de
Received: November 29, 2013; Published online: February 2, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201301069.
Abstract: Vinyl radicals were generated from a-bro- zofurans, pyrroles, and indoles, giving rise to a broad
mochalcones or a-bromocinnamate ethyl ester under variety of novel polycyclic frameworks in high yields
visible light photoredox catalyzed conditions via an under mild and environmentally benign reaction con-
oxidative quenching cycle of the iridium complex ditions.
[Ir{dF
ACHTUNGTRENNUNG(CF3)ppy}2ACHTUNGTRENNUNG(dtbbpy)]PF6 and subjected to cas-
cade cyclizations with heteroarenes entailing two
À
À
consecutive C C bond formations and three C H Keywords: cascade cyclization; heteroarenes; iridi-
activations. The process is amenable to furans, ben- um; vinyl radicals; visible-light photocatalysis
Introduction
tions if the elimination pathway to alkynes is not pos-
sible. Indeed, we found that a highly efficient photo-
Cascade cyclizations[1,2] are a powerful tool in organic redox catalyzed tandem cyclization between a broad
chemistry for the synthesis of polycyclic compounds, variety of heteroarenes[10] and a-bromochalcones or
being characterized by high efficiency and operational a-bromocinnamates (employed as an E/Z-mixture,
simplicity. A particularly well-explored strategy is the see the Supporting Information for details) can be
cyclization of 1,6-enynes, and only recently, an elegant achieved, in which the latter both serve as precursors
example for the coupling of this structural element
with aryl sulfonyl chlorides by a visible-light driven
process to arrive at polycyclic aromatic compounds
was demonstrated.[3] We report here an alternative
strategy by coupling photochemically generated vinyl
radicals with heteroarenes in an intermolecular pro-
À
cess involving a threefold C H activation to give rise
to novel scaffolds such as naphtho
A
benzo[e]indoles and related heterocycles (Scheme 1).
Despite an astonishing resurrection[4] of visible light
photocatalysis[5] demonstrating impressively the syn-
thetic potential of such processes, there are only few
examples for the formation of vinyl radicals by photo-
2
À
redox activation of C
N
recently Stephenson et al. reported vinyl radicals ob-
tained by photoredox catalysis from vinyl iodides, en-
gaging them in reductions or cyclizations.[6] In our
previous report[7] of visible-light mediated dehaloge-
nations[8] we showed that vicinal dibromo carbonyl
compounds can be used as a source for a-keto vinyl
radicals, giving rise to the formation of alkynes. Given
the high reactivity of such radicals,[9] we questioned
À
Scheme 1. Photoredox catalyzed cascade cyclization be-
whether those could engage in C C coupling reac- tween a-bromochalcones or a-bromocinnamates.
Adv. Synth. Catal. 2014, 356, 557 – 562
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Suva Paria and Oliver Reiser
À
for vinyl radicals and provide ortho-Caryl H bonds for [91% (NMR), 85% isolated; Table 1, entry 7 and
the cyclization (Scheme 1).
Table 2, entry 1]. DMF proved to be essential as sol-
vent, for example, when acetonitrile (Table 1, entry 8)
was used no conversion of 1a was observed. Likewise,
both light (Table 1, entry 9) and catalyst (Table 1,
entry 10) were essential for the reaction to take place.
Having found suitable reaction conditions we ex-
Results and Discussion
We began our investigation with the reaction between
a-bromochalcone 1a and furan 4a (Table 1). Employ- amined the scope of the process. The chalcone 1 can
ing Ru(bpy)3Cl2 (bpy=bipyridine) (1 mol%) as the be varied with electron-donating and electron-accept-
ACHTUNGTRENNUNG
photocatalyst in the presence of an amine, conditions ing substituents in either ring (Table 2). Especially,
typical for a reductive quenching cycle (Table 1, en- halides in the arene rings did not show any cross-reac-
tries 1 and 2), gave rise to dehalogenation of 1a with- tivity with the vinyl bromide that is activated in the
out formation of a coupling product with 4a. In con- photochemical key step. Limitations were observed
trast, on attempting to utilize the oxidative quenching with substrates having an ortho-substituent as R2
cycle of RuACHTUNGTRENNUNG(bpy)3Cl2, being operationally and eco- (Table 2, entries 6 and 10) thus blocking one possible
nomically advantageous since there is no need for the reaction site for cyclization. Products 5fa and 5ja
addition of a sacrificial electron donor, indeed a cou- were still formed in a clean reaction, but conversion
pling between the chalcone 1a and furan (4a) took of the starting material was incomplete. Substrates
place (Table 1, entry 3) to give rise to 5aa. Product with nitro groups either as R1 (Table 2, entry 12) or
5aa was formed in a clean reaction and especially no R2 (Table 2, entry 13) did not give any conversion of
competing dehalogenation of the starting material the starting materials, which is surprising since the ini-
took place, nevertheless, the low conversion of 1a re- tial photoreduction should be facile (E0 =À1.0 V for
sulting in a yield of ꢀ5% made optimization of the 1l and 1m, see the Supporting Information) as was,
process necessary.
Turning to Cu
1,10-phenanthroline],
(dtbbpy)]PF6 (ppy=2-phenylpyridine, dtbbpy=4,4’- of these substrates at 420 nm that was used for irradi-
for example, proven in ATRA reactions with nitro-
(dap)2Cl [dap=2,9-bis(para-anisyl)- benzyl bromides.[11h] Examination of the UV spectra
Eosin or Ir[(ppy)2 of 1l and 1m also proved that there is no absorption
AHCTUNGTRENNUNG
Y
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
di-tert-butyl-2,2’-dipyridyl), which all have been suc- ation. Other furans such as 2-methylfuran (Table 2,
cessfully utilized in coupling reactions via an oxidative entries 14 and 15) and benzofuran (Table 2, entry 16)
quenching cycle,[11] did not result in any conversion of were also found to be excellent reaction partners for
1a (Table 1, entries 4–6). Gratifyingly, when using chalcones 1.
[Ir{dF
(CF3)ppy}
E
G
N-Heteroaromatic systems such as pyrroles and in-
(2,4-difluorophenyl)-5-trifluoromethylpyridine]
at doles, either in N-protected or N-unprotected form,
a catalyst concentration of only 1 mol%, 1a was fully proved to be even better coupling partners for chal-
consumed after 12 h, giving rise to 5aa in high yield cones 1 (Table 3). Functional group tolerance of
Table 1. Optimization of the reaction conditions – screening of different photocatalysts and solvents.[a]
Entry
Photocatalyst
Solvent
Yield [%][b]
1
2
3
4
5
6
7
Ru
Ru
Ru
U
DMF
MeCN
DMF
DMF
DMF
DMF
DMF
MeCN
DMF
DMF
dehalogenation,>95
dehalogenation, 70
ꢀ 5
Cu
A
no reaction
no reaction
no reaction
91
N
CHTUNGTRENNUNG
[Ir{dF
[Ir{dF
[Ir{dF
N
R
A
CHTUNGTRENNUNG
C
CHTUNGTRENNUNG
8
no reaction
no reaction
no reaction
9[c]
10
no photocatalyst, 420 nm
[a]
Reaction conditions: 1a (1 equiv.), furan 4a (5 equiv.), photocatalyst (1 mol%).
Yields were determined by H NMR analysis.
Without light irradiation
[b]
[c]
1
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Visible Light Photoredox Catalyzed Cascade Cyclizations
Table 2. Reaction of a-bromochalcones with furans.[a]
Entry
R1
R2
1
Furan (4)
Product (5)
Yield [%][b]
1
2
3
4
5
6
7
8
H
H
H
4-Cl
H
4-Br
4-Me
2-Me
4-Me
H
4-F
2-F
H
H
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1d
1b
1d
furan (4a)
furan (4a)
furan (4a)
furan (4a)
furan (4a)
furan (4a)
furan (4a)
furan (4a)
furan (4a)
furan (4a)
furan (4a)
furan (4a)
5aa
5ba
5ca
5da
5ea
5fa
5ga
5ha
5ia
5ja
5ka
–
85
82
91
80
80
32
83
60
Cl
Cl
Cl
Cl
Me
OMe
H
H
F
NO2
H
Cl
H
9
82
42
78
10
11
12
13
14
15
16
no reaction
no reaction
65
78
85
4-NO2
4-Br
4-Cl
4-Br
furan (4a)
–
2-methylfuran (4b)
2-methylfuran (4b)
benzofuran (4c)
5db
5bb
5dc
Cl
[a]
Reaction conditions: 1 (0.5 mmol), 4 (5 equiv.) and photocatalyst (1 mol%) in dry DMF (2.0 mL) were irradiated for 12 h
with an LED light source (420 nm).
Yield of isolated product.
[b]
Table 3. Reaction of a-bromochalcones with other heteroarenes.[a]
Entry
R1
R2
1
Heteroarene (6)
Product (7)
Yield [%][b]
1
2
3
4
5
6
7
8
H
H
Cl
Cl
OMe
H
H
F
NO2
H
Cl
H
H
1a
1b
1e
1f
1h
1i
1j
1k
1l
1m
1c
1a
1c
1n
1c
1a
pyrrole (6a)
pyrrole (6a)
pyrrole (6a)
pyrrole (6a)
pyrrole (6a)
pyrrole (6a)
pyrrole (6a)
pyrrole (6a)
pyrrole (6a)
pyrrole (6a)
N-Boc-pyrrole (6b)
N-Boc-pyrrole (6b)
indole (6c)
indole (6c)
5-methoxyindole (6d)
N-methylindole (6e)
7aa
7ba
7ea
7fa
7ha
7ia
7ja
7ka
–
89
95
91
78
80
87
83
84
4-Cl
4-Me
2-Me
H
4-F
2-F
H
H
NO2
H
H
H
4-Me
H
H
9
no reaction
no reaction
10
11
12
13
14
15
16
–
7cb
7ab
7cc
7nc
7cd
7ae
92
85
87
72
70
70
Cl
H
Cl
H
[a]
Reaction conditions: 1 (0.5 mmol), 6 (5 equiv,) and photocatalyst (1 mol%) in dry DMF (2 mL) were irradiated for 12 h
with an LED light source (420 nm).
Yield of isolated product.
[b]
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Suva Paria and Oliver Reiser
Figure 1. X- ray crystal structures of 5ga and 7ba.
Scheme 3. Allylation and reduction of a-bromochalcone 1a.
To further prove the formation of vinyl radical 14
1 was similar as found in coupling with furans, but
noteworthy, an ortho-substituent in the arene ring of in the photochemical key step of the anellation pro-
1 that is involved in the cyclization process, although cess, the coupling of 1a was carried out with allylstan-
somewhat lower than the para-substituted analogues, nane 13, which is a known radical allylating agent.[14]
gives rise to 7 in much higher yields compared to the Indeed, the expected allylated compound 15 was iso-
coupling with furans (Table 3, entries 4–7; Table 1, en- lated in high yield.
tries 5, 6 and 9,10). Again, nitro substituents in either
arene ring of 1 did not lead to any conversion of the (Table 1, entries 1 and 2), by switching to the reduc-
starting materials (Table 3, entries 9 and 10). tive quenching cycle by adding triethylamine as sacri-
Furthermore, as already observed for RuACTHGNUTERN(NUG bpy)3Cl2
The structural assignments of products 5 and 7 ficial electron donor a clean reduction of 1a to 16 is
were confirmed unambiguously by single-crystal X- observed with the iridium catalyst in high yields,
ray analyses of 5ga and 7ba (Figure 1).[12]
being also consistent with the formation of a vinyl
Replacement of the arene ring in 1 being not in- radical 14 (Scheme 3).
volved in the cyclization process was also possible
A plausible reaction mechanism (Scheme 4) for the
(Scheme 2). Besides the thiophene derivative 8, espe- above anellation reaction should therefore involve
cially useful from a preparative point of view appears the initial photoredox catalyzed formation of vinyl
to be cinnamate 10 as coupling partner, leading to radical 14 with concurrent oxidation of excited *Ir3+.
benzoanellated 1H-indole-7-carboxylates 11. Such The radical 14 then adds to the heteroarene 2 to form
1H-indole-7-carboxylates have been recognized to the radical 17, which subsequently adds chemoselec-
display manifold biological activities and have been tively to the arene ring of chalcone bearing the vinyl,
identified as EP4 receptor antagonists and PPAR but not the carbonyl group. The observed chemose-
active compounds.[13]
lectivity might be a consequence of the known prefer-
ence of a-bromochalcones to reside in the s-cis-con-
formation.[15] The resulting 18 undergoes back elec-
tron transfer to Ir4+, thus regenerating the catalyst
with formation of the cation 20. Alternatively, inter-
mediate 17 could be oxidized with concurrent reduc-
tion of Ir4+, followed by electrophilic ring closure to
20. We assume that the back electron transfer step
(17 to 19 or 18 to 20) to the iridium catalyst is respon-
sible for the fact that other catalysts such as
CuACTHUNTRGENNG(U dap)2Cl (cf. Table 1, entry 4) are not active in the
process: While the initial vinyl radical formation (re-
duction potentials of 1a–1j, 8 and 10 are in the range
of À0.59 to À0.97 V, see the Supporting Information)
should easily proceed also with the copper
catalyst {Cu
[Ir{dF(CF3)ppy}
À0.89 V}, the oxidation potential of Cu
ACHTUNGTRENNUNG
N
G
ACHTUNGTRENNUNG
Scheme 2. Photocyclization of chalcone 8 or ethyl a-bromo-
cinnamate (10) with pyrrole (6a).
AHCTUNGTRENNUNG
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Visible Light Photoredox Catalyzed Cascade Cyclizations
functional group tolerance, and proceeds in high
yields, giving a rapid access to polycyclic heteroarenes
with novel connection patterns.
Experimental Section
Typical Procedure for the Photoredox Catalyzed
Cascade Cyclization
An oven-dried 10-mL vial equipped with a plastic septum
and magnetic stir bar was charged with [Ir{dF
ACHTUGNERTN(NUNG CF3)ppy}2
AHCTUNGTRENN(GUN dtbbpy)]PF6 (1 mol%) and the a-bromochalcone 1a
(143 mg, 0.5 mmol, 1 equiv.). The flask was purged with
a stream of nitrogen and 2.0 mL of dry dimethylformamide
were added. The resultant mixture was degassed for 5 min
by nitrogen sparging and furan (4a) (5 equiv.) was added to
the vial. The vial was placed at a distance of ~0.5–1.0 cm
from a blue LED lamp (420 nm) and irradiated for 12 h at
room temperature. After completion of the reaction (as
judged by TLC analysis), the mixture was transferred to
a separating funnel, diluted with ethyl acetate (15 mL) and
washed with water. The aqueous layer was extracted 3 times
with ethyl acetate (3ꢃ10 mL), and the combined organic
layers were dried (anhydrous sodium sulfate) and concen-
trated under vacuum. The residue was purified on silica,
using hexane/ethyl acetate as solvent system to afford 5aa as
a yellow solid; yield: 116 mg (85%); Rf (EtOAc/hexane 1:9):
0.38; mp 147–1498C; IR (neat): n=3057, 1658, 1598, 1293,
Scheme 4. Proposed reaction mechanism for the photoredox
catalyzed cascade cyclization between chalcones and hetero-
arenes.
1
1265,734, 632 cmÀ1; H NMR (300 MHz, CDCl3): d=8.19 (d,
J=8.3 Hz, 1H), 8.01 (d, J=10.2 Hz, 2H), 7.95–7.89 (m,
2H), 7.82 (d, J=2.1 Hz, 1H), 7.70 (m, 1H), 7.67–7.61 (m,
1H), 7.59–7.47 (m, 3H), 7.33 (d, J=2.1 Hz, 1H); 13C NMR
(75 MHz, CDCl3): d=193.95, 145.32, 137.95, 133.02, 130.23,
129.95, 129.43, 129.37, 128.61, 128.41, 125.39, 124.25, 123.77,
123.48, 105.40; HR-MS (ESI): m/z=272.0837, calcd. for
C19H12O2 [M+]+: 272.0837.
[Cu(II)/Cu(I)= +0.62 V vs. Ir(IV)/IrACTHNUGRTENUNG(III)= +1.69 V]
appears to be not sufficient to close the catalytic
cycle.
Carbocation 20 then finally forms product 3, in
which overall one molecule of hydrogen is lost, driven
by the aromatization of the final product. The mecha-
nism for this dehydrogenation is still elusive but has
been reported in the literature before in different
processes.[11g,16] We have performed the reaction of a-
bromochalcone 1a with pyrrole 6a in DMF-d7 under
deaerated conditions: NMR analysis showed that the
dehydrogenation giving rise to 7aa indeed takes place
during the reaction and is not a consequence of oxida-
tion during the work-up procedure (see the Support-
ing Information for details). Iridium catalysts are well
known for their power to catalyze hydrogenation/de-
hydrogenation processes, and we therefore assume
that also here the iridium photocatalyst employed can
take on such a role.
Acknowledgements
This work was supported by GRK 1626-Chemical Photoca-
talysis. We thank Dr. Bodensteiner and Ms. Stempfhuber, De-
partment of Crystallography, Universitꢀt Regensburg for car-
rying out the X-ray crystal structure analyses.
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À
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