Minisci C?H Alkylation of Heteroarenes Enabled by Dual Photoredox/Bromide Catalysis in Micellar Solutions**

Article abstract of DOI:10.1002/chem.202002320

Aromatic heterocycles are omnipresent structural motifs in various natural products, pharmaceuticals and agrochemicals. This work describes a photocatalytic Minisci-type C?H functionalization of heteroarenes with non-activated alkyl bromides. The reaction avoids stoichiometric radical-promoters, oxidants, or acids, and is conducted using blue LEDs as the light source. The reactive carbon-centered alkyl radicals are generated by merging the photoredox approach with bromide anion co-catalysis and spatial pre-aggregation of reacting species in the micellar aqueous solutions. The obtained data highlight the critical importance of microstructuring and organization of the components in the reaction mixture.

Full text of DOI:10.1002/chem.202002320

Accepted Article
Accepted Article
Title: Minisci C-H alkylation of heteroarenes enabled by dual
photoredox/bromide catalysis in micellar solutions
Authors: Maciej Giedyk, Marilia S. Santos, Martyna Cybularczyk-
Cecotka, and Burkhard König
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.202002320
Link to VoR: https://doi.org/10.1002/chem.202002320
01/2020

10.1002/chem.202002320
Chemistry - A European Journal
FULL PAPER
Minisci C-H alkylation of heteroarenes enabled by dual
photoredox/bromide catalysis in micellar solutions
Marilia S. Santos,b† Martyna Cybularczyk-Cecotka,a† Burkhard Königb and Maciej Giedyk*a
[a]
Dr. M. Cybularczyk-Cecotka, Dr. M. Giedyk
Institute of Organic Chemistry
Polish Academy of Sciences
Kasprzaka 44/52, 01-224 Warsaw, Poland.
Email: maciej.giedyk@icho.edu.pl
[b]
Dr. M. S. Santos and Prof. B. König
Institute of Organic Chemistry, Faculty of Chemistry and Pharmacy
University of Regensburg
Universitätsstraße 31, 93053 Regensburg, Germany.
Equal contribution
†
Supporting information for this article is given via a link at the end of the document.
Abstract: Aromatic heterocycles are omnipresent structural motifs in
various natural products, pharmaceuticals and agrochemicals. This
work describes a photocatalytic Minisci-type C-H functionalization of
heteroarenes with non-activated alkyl bromides. The reaction avoids
stoichiometric radical-promoters, oxidants, or acids, and is conducted
using blue LEDs as the light source. The reactive carbon-centered
alkyl radicals are generated by merging the photoredox approach with
bromide anion co-catalysis and spatial pre-aggregation of reacting
species in the micellar aqueous solutions. The obtained data highlight
the critical importance of microstructuring and organization of the
components in the reaction mixture.
N-oxides in the presence of palladium catalyst and phosphine
ligand.23 The method was further developed by Zhou et al., who
extended the palladium-catalyzed Minisci reaction on a broad
variety of heteroarenes, including indole- and pyridine
derivatives.24 The photocatalytic alternative towards the activation
of alkyl bromides have been presented by McCallum and
Barriault.25 Using gold complexes as catalysts and UV light as the
energy source, they performed Minisci reactions with various
non-activated bromoalkanes and heteroarenes and supported
their studies by the detailed investigations of photophysical and
electrochemical properties of the photocatalyst.26 Minisci
reactions with non-activated alkyl bromides were also
investigated by the groups of Wang, ElMarrouni and Xu, who
capitalized on the joined action of the photocatalyst, acid, silyl
radical-promoters and visible light irradiation.27–29
While these pioneering methods are of unquestionable value, the
need for mild, catalytic C-H alkylation of heteroarenes with alkyl
bromides still remains. In order to address this challenge we
resorted to photocatalysis in aqueous structured solutions. We
exploited the pre-aggregation of the reacting species and merged
it with the catalytic role of bromide anions, which were generated
in situ from the starting material.30 This allowed facilitating the C-
C coupling of non-activated alkyl bromides with heteroarenes
without stoichiometric radical-promoters, in acid-free conditions
and with commercial blue LEDs as the light source.
Introduction
C-H alkylation of heteroarenes, known as Minisci reaction, is a
well-established synthetic tool for C(sp2)-C(sp3) bond formation.1
It enables direct, late-stage modification of aromatic heterocycles,
which are omnipresent structural motifs in various natural
products, pharmaceuticals and agrochemicals.2 The Minisci
reaction involves generation of carbon-centered alkyl radicals and
their addition to an electron-deficient heteroaromatic ring, which
is accompanied by a formal loss of the hydrogen atom.
Various precursors of alkyl radicals have been employed in the
Minisci reaction including amino acids,3 aldehydes,4–6 ketones,7
carboxylic acids,8–10 alkyltrifluoroborate salts,11 pyridinium
salts,12,13 boronic acids,14,15 diazonium salts,16 peroxides,17–19
alkyl halides20–27 etc. Among them, alkyl bromides are of particular
synthetic potential, as they are readily available and inexpensive
starting materials. However, the cleavage of the relatively strong
C−Br bond in alkyl bromides, which must occur in the course of
the process, presents a major challenge. As a result, only few
variants of the Minisci reaction exploiting non-activated alkyl
bromides have been reported so far.
The established strategies to overcome the challenge of C-Br
bond activation involve the use of high temperatures, strong UV-
light irradiation or the addition of stoichiometric amounts of silyl
radical-promoters (Scheme 1). Accordingly, in 2012 Hu et al.
developed an efficient method for alkylation of benzoxazoles with
secondary alkyl halides.22 The majority of presented syntheses
were realized using alkyl iodides, but few examples with bromides
have also been reported. The reaction was performed at elevated
temperatures, and with the use of copper-based catalyst. One
year later, Fu et al. demonstrated the cross-coupling of non-
activated secondary and tertiary alkyl bromides with pyridine
Scheme 1. Strategies for C-H alkylation of heteroarenes with non-activated
alkyl bromides. SDS - sodium dodecyl sulfate.
1
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Results and Discussion
upon the single-electron-reduction and fragmentation of alkyl
bromides, can be recycled and used as mediators in the Minisci
reaction - quench the excited Ir(III)-photocatalyst and thus
promote the generation of alkyl radicals.
The redox potential of typical photocatalysts in their excited state,
including strongly reducing Ir-species, precludes the direct single-
electron-transfer (SET) to alkyl bromides (-2.29 V vs. SCE for
1-bromooctane)31. However, catalytic species of a much higher
reducing power can be generated via the reductive quenching of
the catalyst followed by the subsequent excitation with a second
visible-light-photon.30,32–34 Although the typically used reductive
quenchers include tertiary amines, Hantzsch esters, alcohols,
ascorbate anions etc.,35 it has recently been shown that the
efficient quenching of excited Ir-complexes can also be achieved
using simple halide anions, leading to Ir(II)-species and halide
radicals.36–40 We decided to test, if Br- anions, which are released
Unique properties of structured solutions of surfactants, combined
with operationally simple preparation, render them advantageous
media for chemical reactions such as biocatalysis,41
polymerizations,42 transition-metal catalyzed cross-coupling
reactions,43 and organocatalytic transformations44. Recent reports
show that they may also play a vital role in photocatalysis.30,45–48
From the viewpoint of the designed Minisci reaction, structured
aqueous solution could provide the necessary pre-association of
the starting materials and the photocatalyst, improve the kinetics
of the reaction and thus eliminate the harsh reaction conditions or
stoichiometric additives, including radical promoters and acids.
In order to test the working hypothesis, we subjected
bromocyclohexane (2a) to the reaction with lepidine (1a) in the
presence of [Ir(dtbby)(ppy)2]PF6 (4) as photocatalyst, in aqueous
solution of surfactant and under irradiation with blue LEDs (Table
1). We were pleased to see that the reaction proceeded and the
desired coupling product 3a was formed in 31% yield (entry 1).
The reaction parameters were then optimized with respect to the
surfactant, photocatalyst, co-catalyst, time, as well as the ratio
and concentration of reagents (for full optimization studies see SI).
The addition of the catalytic amount of NaBr facilitated the
process and increased the yield of the compound 3a to 47% (entry
2). Further screening established CBr4 as a co-catalyst of choice
(entries 2-5).
Table 1. Optimization studies[a]
The applied conditions, which were called Procedure A, afforded
the full conversion of lepidine 1a and the desired product 3a in
91% yield. The alkylation occurred selectively at position C2.
Although the optimal reaction conditions involved 20 mol% of
CBr4 and 42 hours of irradiation, the efficient formation of the
product 3a was observed already after shorter reaction time (52%
after 18 h, 78% after 24 h) or using lower co-catalyst loading (5
mol%) (entries 6 and 7, respectively). Among various tested
photocatalysts, the highest activity was achieved using
[Ir(dtbbpy)(ppy)2]PF6 (4). Other mediators proved inefficient
(entries 8, 10-12), or provided the product 3a in low yield (entry
9). Having catalyst and co-catalyst selected, we evaluated the
influence of popular and readily available surfactants. The
superior performance of sulfate-based surfactants: sodium
dodecyl sulfate (SDS) and sodium lauryl oligoethylene glycol
sulfate (SLES) was observed (entries 1 - 13), which is in
agreement with previous reports.30 The satisfactory 41% yield of
the desired product 3a was also detected when zwitterionic
surfactant SB3-14 was used (entry 15). The application of anionic
potassium dodecanate, cationic dodecyltrimethylammonium
chloride (DTAC) or non-ionic Triton X-100 led to less efficient
product 3a formation (entries 14, 16, 17).
With the reaction conditions established, we next investigated the
scope of the developed transformation (Scheme 2). In general,
secondary bromides 2a-2d provided higher yields of the desired
products than primary ones 2e-2l, which reflects higher
thermodynamic stability of the intermediate radicals. However,
the precursors 2m, 2n of even more stabilized benzyl or tertiary
radicals proved unsuitable, presumably due to the lower reactivity
in addition processes, competing oxidation to carbocations and
hydrolysis. Several functional groups in the bromide moiety
showed good compatibility with our procedure such as free
hydroxyl group (3h), primary (3k) and secondary amides (3l),
Time
[h]
Yield
[%][b]
No.
Co-Catalyst
Photocatalyst
Surfactant
1
2
-
NaBr
NBS
[Ir] 4
[Ir] 4
42
42
42
42
42
24
42
42
42
42
42
42
42
42
42
42
42
SDS
SDS
31
47
19
85
91
78
48
0
3
[Ir] 4
SDS
4
CCl3Br
CBr4
[Ir] 4
SDS
5
[Ir] 4
SDS
6
CBr4
[Ir] 4
SDS
7
CBr4 (5 mol%)
CBr4
[Ir] 4
SDS
8
[Ir] 5
SDS
CBr4
9
[Ir] 6
SDS
16
0
10
11
12
13
14
15
16
17
CBr4
Ru(bpy)3PF6 (7)
4CzIPN (8)
Eosin Y (9)
[Ir] 4
SDS
CBr4
SDS
0
CBr4
SDS
0
CBr4
SLES
C11H23CO2K
SB3-14
Triton X-100
DTAC
48
13
41
24
16
CBr4
[Ir] 4
CBr4
[Ir] 4
CBr4
[Ir] 4
CBr4
[Ir] 4
[a] Reaction conditions: lepidine 1a (0.1 mmol), bromocyclohexane 2a (0.2
mmol), surfactant (0.25 mmol), co-catalyst (20 mol%), photocatalyst (3 mol%),
water (5 mL), 40 °C, 451 nm, 42 h. [b] Yields were calculated using GC analysis.
n-Dodecane was used as internal standard. [Ir] 4 - [Ir(dtbbpy)(ppy)2]PF6, [Ir] 5 -
Ir(ppy)3PF6, [Ir] 6 - Ir[dF(CF3)(ppy)2](dtbby)PF6.
2
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Scheme 2. Scope studies. [a] Average isolated yield obtained from two separate reactions are given. [b] Isolated in a 3:1 mixture with 2,4-dicyclohexylquinoline.
[c] Reactions were carried out for 20 h with 5 equiv. of alkyl bromide.
chlorides (3g) or CF3 function (3j). Additionally, the product 3i
possessing a terminal double bond was also isolated. Alkyl
bromides 2o decorated with acetal groups proved unstable and
alkyl chlorides 2p did not display sufficient reactivity under the
reaction conditions. Evaluation of the aromatic coupling partners
showed that the reaction is compatible not only with simple
heterocycles such as lepidine 1a, phenantridine 1b and quinoline
aldehyde or ketone groups or substrates with halogen
substituents, for which the undesired dehalogenation reactions
prevailed.
In order to gain more insights into the studied reaction, a series of
mechanistic experiments was conducted. The control reactions
showed that light, the photocatalyst and the surfactant are all
essential for this Minisci protocol (Table 2, entries 2, 3 and 4).
1c, but also derivatives, which contain ester or cyano substituents. Furthermore, the addition of CBr4 facilitates the reaction and lower
4-Phenylpyridine 1d gave a mixture of mono- and disubstituted
products 10d and di-10d, both of which could be selectively
isolated (38% and 40% respectively). In the case of nicotinonitrile
1e and methylnicotinate 1f, the increase in the amount of alkyl
bromide (from 3 to 5 equiv.) led to selective formation of
tri-substituted products 10e and tri-10f in very good yields.
Alternatively, by keeping the standard reaction conditions, the
di-substituted compound 10f was obtained as the main product.
The two alkyl groups were appended selectively at positions C4
and C6, as indicated by 2D NMR studies (see SI). Pleasingly, we
were also able to employ caffeine (1g), an important central
nervous system stimulant, as a substrate. The observed
limitations on the side of the heteroaromatic partner included the
compounds with blocked position C2, heterocycles possessing
yield (31%) of the model product 3a was obtained in its absence
(entry 5). To evaluate the impact of the micellar solution as the
reaction environment, the control reaction in acetonitrile was
performed. Although a clear solution indicated good solubility of
all of the reaction components, the formation of product 3a was
not detected (entry 6). The use of other organic solvents, as well
as hetero- or homogenous water/solvent mixtures also gave
inferior results to those obtained in the micellar system (see SI).
Additionally, no desired reaction was observed when 2,2,6,6-
tetramethylpiperidinyloxyl (TEMPO) was employed under the
optimized conditions, which indicates the presence of radical
intermediates in the reaction mechanism (entry 7).
3
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Table 2. Control experiments.
This acceleration can be explained by the accumulation of
bromide anions in the mixture, as well as a significant change in
the pH, which evolves from basic (pH = 10) to acidic (pH = 3). In
order to evaluate the impact of both these factors, we carried out
two reactions for 10 h: one with NaBr (20 mol%) added together
with CBr4 (20 mol% of), and the second in which the acidity was
initially adjusted with TFA to reach pH = 3. Both reactions
proceeded faster than under standard conditions and yielded the
desired product 3a in 47% and 52% respectively (see SI). This
reflects higher affinity of protonated pyridines towards alkyl
radicals, but also supports the concept of the catalytic role of
bromide anions. Their accumulation in the reaction mixture
increases the quenching efficiency and provides higher
concentration of the reduced form of the photocatalyst 4.
In accordance with these results, as well as the optimization
studies, we propose a mechanism of the developed Minisci
reaction (Scheme 3). The excited [Ir] 4 photocatalyst (E1/2
Ir(III)*/Ir(II) = 0.66 V vs. SCE)51 undergoes reductive quenching by
Br- anions (E1/2red = 0.80 V vs. SCE)36–39. A slight endergonicity of
this SET step is presumably compensated by a beneficial pre-
organization of the components in the reaction mixture (see SI).
Consequently, an equilibrium concentration of bromine radical
and the reduced Ir(II)-complex are generated. The latter species
can undergo consecutive absorption of a second photon, resulting
in the formation of a strongly reducing form of the iridium-
complex30,32 or a solvated electron.34 SET to alkyl bromide A
followed by fragmentation affords alkyl radical B and a bromide
anion, which participates in subsequent catalytic cycles. An
addition of alkyl radical B to pyridinium salt C provides the radical
cation D, able to undergo hydrogen-atom-transfer (HAT) with
electrophilic bromine radical. As a result, the protonated form E of
the final product is produced. Another mechanistic pathway,
which may contribute to the reaction, involves the deprotonation
of acidic radical cation D. It affords neutral radical F, which can be
further oxidized either by Br radical or CBr4 leading to the desired
product in its protonated form E.
No.
Deviation from optimized conditions[a]
Yield [%][b]
1
2
3
4
5
6
7
-
91
0
no photocatalyst 4
no light
0
no SDS
1
no CBr4
31
0
MeCN instead SDS(aq)
addition of TEMPO[c]
0
[a] Optimized conditions: lepidine (1a, 0.1 mmol), bromocyclohexane (2a, 0.2
mmol), SDS (0.25 mmol), CBr4 (20 mol%), [Ir(dtbbpy)(ppy)2]PF6 (4, 3 mol%),
water (5 mL), 40 °C, 451 nm, 42 h. [b] Yields were calculated using GC analysis.
n-Dodecane was used as internal standard; [c] 2 equiv. of TEMPO were added
to the reaction mixture.
To further examine the mechanistic pathway, we conducted a
radical-clock experiment starting from 5-bromo-1-hexene (2r)
(Figure 1a). The presence of the cyclopentane ring in the main
product 3r suggests the formation of carbon-centered radicals,
which undergo fast 5-exo-trig cyclization and subsequent addition
to the heteroarene 1a. The Stern−Volmer fluorescence quenching
experiment was performed, to examine the interactions of the
photocatalyst with other reaction components (Figure. 1b).49 It
showed that the excited state of Ir(dtbbpy)(ppy)2PF4 (4) is
quenched effectively by CBr4, while only low quenching efficiency
was observed for the lepidine (1a) or the alkyl bromide 2a. These
results are congruent with the high redox potential of alkyl
bromides and nitrogen heterocycles.50
The reaction progress was monitored over time, showing the
increasing rate during the first 10 hours of irradiation (Figure. 1c).
3,5
2,5
1,5
0,5
Tetrabromomethane
Lepidine
Bromocyclohexane
0
1
2
3
4
5
Concentration [mmol.L-1]
Tetrabromomethane
PC (50 µM)
0.25 mM
0.50 mM
0.74 mM
0.99 mM
1.2 mM
1.5 mM
1.7 mM
2.0 mM
2.2 mM
1600000
1400000
1200000
1000000
800000
600000
400000
200000
0
100
pH = 10
80
pH = 3
60
40
20
0
2.4 mM
4.8 mM
400
450
500
550
600
650
700
0
5
10
15
20
25
30
35
40
45
Wavelength / nm
Time [h]
Figure 1. Mechanistic investigations: a) radical-clock experiment with 6-bromo-1-hexene (2r); b) Stern−Volmer fluorescence quenching of Ir(dtbbpy)(ppy)2 (c = 50
μM) in aqueous SDS; c) Kinetic studies of the model reaction and the change in the pH of the reaction progress illustrated on the photos of the indicatory strips.
4
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SET to recover Ir(III) and produce CBr3 cation, which reacts with
water to give the tribromomethanol and a proton. Continuous pH
measurements strongly support such steady generation of HBr.
Upon the interaction of CBr4, water, photocatalyst and light the
reaction mixture gradually become acidic (see SI). Finally,
tetrabromomethane may contribute to the overall reaction
outcome through yet another catalytic mode. Due to the halogen
bonding with bromide anions,59,60 it may decrease their
hydrophilic character, slow down the migration to the water bulk
and, consequently, render Br- more accessible to the excited
Ir(III)* photocatalyst.
To further examine the decisive role of the solution structuring, in
particular the postulated pre-arrangement of bromide anions, we
investigated the reaction in the presence of the cationic surfactant
cetyltrimethylammonium bromide (CTAB) and catalytic amount of
NaBr instead of CBr4. The positively charged head of the
surfactant would retain the bromide counter-anion through ion-
pairing interactions and keep it in a close distance to the interface,
thus favoring the interaction with the photocatalyst. We were
pleased to find, that, under this condition, which were called
Procedure B, the compound 3a was obtained in 88% yield
(Scheme 4). Moreover, the use of CTAB as a sole source of
bromide anions, without external NaBr added, also afforded the
desired product 3a in good yield (66%). Finally, we demonstrated
that the Procedure B can be successfully implemented to obtain
alkylated heterocycles 3b, 3h and 10d from other aliphatic
bromides and heteroarenes in good efficiency.
Scheme 3. Proposed mechanistic pathway; a dotted line between Br- and CBr4
indicates a postulated halogen bonding.
Detailed mechanistic studies on the role of CBr4 co-catalyst are
ongoing, but preliminary results suggest that, through the
photosensitized hydrolysis of CBr4, it may provide the starting
concentration of bromide anions at the early stage of the process.
Although the light-induced reactivity of this compound is usually
associated with mesolytic bond cleavage,52–55 or homolytic
dissociation to CBr3 and Br radicals,56,57 it has been shown that in
the aqueous conditions the photoinduced hydrolytic pathway to
HBr prevails.58 Alternatively, the reduction of CBr4 by excited
Ir(III)*-photocatalyst can be considered, leading to Br-, the CBr3
radical and Ir(IV)-complex. The last two species may undergo
Conclusion
In summary, we have developed a new photocatalytic procedure
for Minisci-type coupling of heteroarenes with various alkyl
bromides, which exploits the combination of photoredox catalysis
with bromide anion catalysis. With the use of micellar solution as
the reaction media, it is possible to carry out the reaction in mild,
aqueous conditions, with no need for external oxidant or
stoichiometric radical promoter. The coupling products were
obtained in the absence of equimolar amounts of acid, a
requirement for standard Minisci protocols. The external additives
are simple and cost-efficient and they were used in catalytic
amounts. The obtained optimization data and mechanistic
experiments highlight the critical importance of microstructuring
and pre-organization of the components in the reaction mixture.
Experimental Section
General Procedure for Minisci Reaction mediated by CBr4 (Procedure
A): 10 mL crimp vial, equipped with a magnetic stirring bar was charged
with [Ir(dtbby)(ppy)2]PF6 (2.7 mg, 3 mol%), SDS (72 mg, 0.25 mmol) and
CBr4 (6 mg, 0.02 mmol). The vial was sealed and degassed via two pump-
argon cycles, followed by water (5 mL) addition. The resulting mixture was
degassed via five pump-argon cycles, the heterocycle (0.10 mmol) and
alkyl bromide (0.20 mmol) were added under argon and the mixture was
degassed again via two pump-argon cycles, keeping the vacuum above
50 mbar. The reaction mixture was irradiated with 800 mW 451 nm LEDs
through the plane bottom side and stirred intensely for 42 h. The
temperature was maintained at 40 °C to 42 °C by cooling with the built-in
cooling fan. Then the vial was opened and the crude reaction mixture was
transferred to a separatory funnel. Solution of KHCO3 (1 M, 5 mL) and
brine (20 mL) were added and the mixture was extracted with AcOEt (3 x
20 mL). Combined organic fractions were washed with fresh brine, dried
over Na2SO4, filtrated and concentrated in vacuo. A crude product was
purified by flash column chromatography on silica gel.
Scheme 4. The C-H alkylation of heteroarenes using cationic surfactant with
bromide counter ion. [a] Yields were calculated using NMR analysis with 1,3,5-
trimethoxybenzene as an internal standard. [b] The reaction was performed in
the absence of NaBr.
5
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General Procedure for Minisci Reaction mediated by NaBr
(Procedure B): 10 mL crimp vial, equipped with a magnetic stirring bar
was charged with [Ir(dtbby)(ppy)2]PF6 (2.7 mg, 3 mol%), CTAB (92 mg,
0.25 mmol) and NaBr (2 mg, 0.02 mmol). The vial was sealed and
degassed via two pump-argon cycles, followed by water (5 mL) addition.
The resulting mixture was degassed via five pump-argon cycles, the
heterocycle (0.10 mmol) and alkyl bromide (0.20 mmol) were added under
argon and the mixture was degassed again via two pump-argon cycles,
keeping the vacuum above 50 mbar. The reaction mixture was irradiated
with 800 mW 451 nm LEDs through the plane bottom side and stirred
intensely for 42 h. The temperature was maintained at 40 °C to 42 °C by
cooling with the built-in cooling fan. Then the vial was opened and the
crude reaction mixture was transferred to a separatory funnel. Solution of
NaHCO3 (1 M, 5 mL) and brine (20 mL) were added and the mixture was
extracted with AcOEt (3 x 20 mL). Combined organic fractions were
washed with fresh brine, dried over Na2SO4, filtrated and concentrated in
vacuo.
[22] P. Ren, I. Salihu, R. Scopelliti, X. Hu, Org. Lett. 2012, 14, 1748–1751.
[23] B. Xiao, Z. J. Liu, L. Liu, Y. Fu, J. Am. Chem. Soc. 2013, 135, 616–619.
[24] X. Wu, J. W. T. See, K. Xu, H. Hirao, J. Roger, J.-C. Hierso, J. S. Zhou,
Angew. Chemie 2014, 126, 13791–13795; Angew. Chem. Int. Ed. 2014,
53, 13573–13577.
[25] T. McCallum, L. Barriault, Chem. Sci. 2016, 7, 4754–4758.
[26] C. D. McTiernan, M. Morin, T. McCallum, J. C. Scaiano, L. Barriault,
Catal. Sci. Technol. 2016, 6, 201–207.
[27] J. Dong, X. Lyu, Z. Wang, X. Wang, H. Song, Y. Liu, Q. Wang, Chem.
Sci. 2019, 10, 976–982.
[28] J. J. Perkins, J. W. Schubert, E. C. Streckfuss, J. Balsells, A. ElMarrouni,
Eur. J. Org. Chem. 2019, 4, 2–10.
[29] R. Chang, J. Fang, J.-Q. Chen, D. Liu, G.-Q. Xu, P.-F. Xu, ACS Omega
2019, 4, 14021–14031.
[30] M. Giedyk, R. Narobe, S. Weiß, D. Touraud, W. Kunz, B. König, Nat.
Catal. 2020, 3, 40–47.
[31] P. W. Jennings, D. G. Pillsbury, J. L. Hall, V. T. Brice, J. Org. Chem. 1976,
41, 719–722.
[32] T. U. Connell, C. L. Fraser, M. L. Czyz, Z. M. Smith, D. J. Hayne, E. H.
Doeven, J. Agugiaro, D. J. D. Wilson, J. L. Adcock, A. D. Scully, D. E.
Gómez, N. W. Barnett, A. Polyzos, P. S. Francis, J. Am. Chem. Soc.
2019, 141, 17646–17658.
Acknowledgements
We gratefully acknowledge funding from the National Science
Centre, Poland (SONATA 2018/31/D/ST5/00306), Fundação de
Amparo à Pesquisa do Estado de São Paulo – FAPESP
(2018/20956-5) and the German Science Foundation (DFG, KO
1537/18-1) for the financial support.
[33] I. Ghosh, T. Ghosh, J. I. Bardagi, B. König, Science 2014, 346, 725–728.
[34] F. Glaser, C. Kerzig, O. S. Wenger, Angew. Chem. 2020, 132, 2– 23;
Angew. Chem. Int. Ed. 2020, 59, 2–21.
[35] D. Petzold, M. Giedyk, A. Chatterjee, B. König, Eur. J. Org. Chem. 2020,
1193–1244.
Keywords: photoredox catalysis • visible-light • micellar solution
• Minisci • alkyl bromide • heteroarenes • C-H functionalization
[36] P. Zhang, C. C. Le, D. W. C. MacMillan, J. Am. Chem. Soc. 2016, 138,
8084–8087.
[37] T. Kawasaki, N. Ishida, M. Murakami, J. Am. Chem. Soc. 2020, 142,
3366–3370.
[1]
[2]
R. S. J. Proctor, R. J. Phipps, Angew. Chem. 2019, 131, 13802– 13837;
Angew. Chem. Int. Ed. 2019, 58, 13666–13699.
[38] Z. Wang, X. Ji, T. Han, G.-J. Deng, H. Huang, Adv. Synth. Catal. 2019,
361, 5643–5647.
K. C. Majumdar, S. K. Chattopadhyay, Heterocycles in Natural Product
Synthesis, Wiley-VCH, Weinheim, Germany, 2011.
D. N. Mai, R. D. Baxter, Org. Lett. 2016, 18, 3738–3741.
K. Matcha, A. P. Antonchick, Angew. Chem. 2013, 125, 2136–2140;
Angew. Chemie Int. Ed, 2013, 52, 2082–2086.
[39] Z. Wang, Q. Liu, X. Ji, G.-J. Deng, H. Huang, ACS Catal. 2020, 10, 154–
159.
[3]
[4]
[40] M. Zidan, A. O. Morris, T. McCallum, L. Barriault, Eur. J. Org. Chem.
2020, 1453–1458.
[41] M. Cortes-Clerget, N. Akporji, J. Zhou, F. Gao, P. Guo, M. Parmentier, F.
Gallou, J. Y. Berthon, B. H. Lipshutz, Nat. Commun. 2019, 10, 1–10.
[42] I. Capek, T. Kocsisova, Des. Monomers Polym. 2011, 14, 327–345.
[43] S. Handa, B. Jin, P. P. Bora, Y. Wang, X. Zhang, F. Gallou, J. Reilly, B.
H. Lipshutz, ACS Catal. 2019, 9, 2423–2431.
[5]
Y. Siddaraju, M. Lamani, K. R. Prabhu, J. Org. Chem. 2014, 79, 3856–
3865.
[6]
[7]
[8]
Z. Wang, X. Ji, J. Zhao, H. Huang, Green Chem. 2019, 21, 5512–5516.
P. Liu, W. Liu, C. J. Li, J. Am. Chem. Soc. 2017, 139, 14315–14321.
W.-F. Tian, C.-H. Hu, K.-H. He, X.-Y. He, Y. Li, Org. Lett. 2019, 21, 6930–
6935.
[44] L. Baxová, R. Cibulka, F. Hampl, J. Mol. Catal. A Chem. 2007, 277, 53–
60.
[9]
F. Minisci, R. Bernardi, F. Bertini, R. Galli, M. Perchinummo, Tetrahedron
1971, 27, 3575–3579.
[45] M. Bu, G. Lu, J. Jiang, C. Cai, Catal. Sci. Technol., 2018, 8, 3728–3732.
[46] T. Kohlmann, C. Kerzig, M. Goez, Chem. Eur. J. 2019, 25, 9991–9996.
[47] C. Kerzig, M. Goez, Chem. Sci. 2016, 7, 3862–3868.
[48] R. Naumann, F. Lehmann, M. Goez, Angew. Chem. 2018, 130, 1090–
1093; Angew. Chem. Int. Ed. 2018, 57, 1078–1081.
[49] M. H. Gehlen, J. Photochem. Photobiol. C Photochem. Rev. 2020, 42,
100338.
[10] J. Kan, S. Huang, J. Lin, M. Zhang, W. Su, Angew. Chem. 2015, 127,
2227–2231; Angew. Chem. Int. Ed. 2015, 54, 2199–2203.
[11] G. A. Molander, V. Colombel, V. A. Braz, Org. Lett. 2011, 13, 1852–1855.
[12] F. J. R. Klauck, M. J. James, F. Glorius, Angew.Chem. 2017, 129,12505–
12509; Angew. Chem. Int. Ed. 2017, 56, 12336–12339.
[13] X. Ma, S. B. Herzon, J. Am. Chem. Soc. 2016, 138, 8718–8721.
[14] G. X. Li, C. A. Morales-Rivera, Y. Wang, F. Gao, G. He, P. Liu, G. Chen,
Chem. Sci. 2016, 7, 6407–6412.
[50] H. G. Roth, N. A. Romero, D. A. Nicewicz, Synlett 2016, 27, 714–723.
[51] C. K. Prier, D. A. Rankic, D. W. C. MacMillan, Chem. Rev. 2013, 113,
5322–5363.
[15] I. B. Seiple, S. Su, R. A. Rodriguez, R. Gianatassio, Y. Fujiwara, A. L.
Sobel, P. S. Baran, J. Am. Chem. Soc. 2010, 132, 13194–13196.
[16] D. Xue, Z. H. Jia, C. J. Zhao, Y. Y. Zhang, C. Wang, J. Xiao, Chem. Eur.
J. 2014, 20, 2960–2965.
[52] M. J. W. Taylor, W. T. Eckenhoff, T. Pintauer, Dalt. Trans. 2010, 39,
11475–11482.
[53] M. Pirtsch, S. Paria, T. Matsuno, H. Isobe, O. Reiser, Chem. Eur. J. 2012,
18, 7336–7340.
[17] D. A. DiRocco, K. Dykstra, S. Krska, P. Vachal, D. V. Conway, M. Tudge,
Angew. Chem. Int. Ed. 2014, 53, 4802–4806.
[54] M. N. C. Balili, T. Pintauer, Dalt. Trans. 2011, 40, 3060–3066.
[55] T. Hou, P. Lu, P. Li, Tetrahedron Lett. 2016, 57, 2273–2276.
[56] Q. Kong, M. Wulff, J. H. Lee, S. Bratos, H. Ihee, J. Am. Chem. Soc. 2007,
129, 13584–13591.
[18] F. Minisci, C. Giordano, E. Vismara, S. Levi, V. Tortelli, J. Am. Chem.
Soc. 1984, 106, 7146–7150.
[19] F. Minisci, E. Vismara, F. Fontana, G. Morini, M. Serravalle, C. Giordano,
J. Org. Chem. 1986, 51, 4411–4416.
[57] S. Tripathi, S. N. Singh, L. D. S. Yadav, RSC Adv. 2016, 6, 14547–14551.
[58] C. Zhao, X. Lin, W. M. Kwok, X. Guan, Y. Du, D. Wang, K. F. Hung and
D. L. Phillips, Chem. Eur. J. 2005, 11, 1093–1108.
[20] N. B. Bissonnette, M. J. Boyd, G. D. May, S. Giroux, P. Nuhant, J. Org.
Chem. 2018, 83, 10933–10940.
[59] G. Cavallo, P. Metrangolo, R. Milani, T. Pilati, A. Priimagi, G. Resnati, G.
Terraneo, Chem. Rev. 2016, 116, 2478–2601.
[21] P. Nuhant, M. S. Oderinde, J. Genovino, A. Juneau, Y. Gagné, C. Allais,
G. M. Chinigo, C. Choi, N. W. Sach, L. Bernier, Y. M. Fobian, M. W.
Bundesmann, B. Khunte, M. Frenette, O. O. Fadeyi, Angew. Chem. 2017,
129, 15511–15515; Angew. Chem. Int. Ed. 2017, 56, 15309–15313.
[60] T. Brinck, A. N. Borrfors, J. Mol. Model. DOI:10.1007/s00894-019-4014-
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10.1002/chem.202002320
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The combination of microstructured aqueous solution and photoredox catalysis allowed us to develop a new approach for Minisci
reaction. The smooth C-H alkylation of the heterocycles was achieved employing non-activated alkyl bromides and without the use of
stoichiometric amounts of radical promoters. The biologically useful products were generated under neutral and basic conditions under
commercially available blue LEDs.
7
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