Metal-Free Photocatalyzed Cross Coupling of Bromoheteroarenes with Pyrroles

Article abstract of DOI:10.1021/acscatal.6b01452

The excited radical anion of rhodamine 6G reduces heteroaryl bromides and chlorides to generate heteroaryl radicals that were successively trapped by pyrroles for the synthesis of heteroaromatic biaryls in moderate to excellent yields. The synthetically important photoredox catalytic C-H heteroarylation reaction works for a broad range of brominated electron-rich heteroarenes and chlorinated heteroarenes bearing electron withdrawing groups. In addition, this methodology was applied to the formal synthesis of a benzimidazole derivative II with interesting pharmacological properties.

Full text of DOI:10.1021/acscatal.6b01452

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Article
Metal-Free Photocatalyzed Cross Coupling
of Bromo-Heteroarenes with Pyrroles
Leyre Marzo, Indrajit Ghosh, Francisco Esteban, and Burkhard König
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b01452 • Publication Date (Web): 30 Aug 2016
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Metal‐Free Photocatalyzed Cross Coupling of Bromo‐Heteroarenes
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with Pyrroles
Leyre Marzo,† Indrajit Ghosh,† Francisco Esteban,‡ and Burkhard König*†
†Institute of Organic Chemistry, University of Regensburg, D‐93040 Regensburg, Germany.
‡Department of Organic Chemistry (Modulo I), Universidad Autónoma de Madrid, Cantoblanco, 28049, Madrid,
Spain.
ABSTRACT: The excited radical anion of rhodamine 6G
(Rh‐6G) reduces heteroaryl bromides and chlorides to gen‐
erate heteroaryl radicals that were successively trapped by
pyrroles for the synthesis of heteroaromatic biaryls in mod‐
erate to excellent yields. The synthetically important photo‐
redox catalytic C–H heteroarylation reaction works for a
broad range of brominated electron rich heteroarenes and
chlorinated heteroarenes bearing electron withdrawing
groups. In addition, this methodology was applied to the formal synthesis of a benzimidazole derivative II with interest‐
ing pharmacological properties.
KEYWORDS: Photoredox catalysis, visible light, C–H heteroarylation, metal free reaction, pyrrole
1. INTRODUCTION
The abundance of the bi‐heteroaryl moiety in many in‐
teresting compounds triggered the development of effi‐
cient methods for their synthesis. The typical preparation
involves transition‐metal catalyzed arylation reactions
using pre‐functionalized substrates. Palladium catalyzed
C–C coupling starting form heteroaryl halides and organ‐
ometallic species yields C2–C2´ and C2–C3´cross coupled
diheteroarenes (eq. A, Scheme 1).6 On the other hand,
palladium catalyzed C–H bond arylation has emerged as a
more direct and atom‐economic alternative for the for‐
mation of such C–C bonds, because it avoids the use of
pre‐functionalized starting materials, and therefore, re‐
duces the number of steps for the synthesis (eq. B,
Scheme 1).7 However, the use of transitions metals as
catalyst of the reaction, and the use of high temperatures
still remain a disadvantage.8 As an alternative, visible light
photoredox catalysis may provide an efficient method for
the formation of C–C bonds.9 Aryl halides (Ar–X) are
activated by photoinduced electron transfer yielding the
corresponding radical anions (Ar–X–), which upon frag‐
mentation (and by releasing halide anions) generate the
corresponding aryl radicals that could be used for subse‐
quent coupling reactions. However, the scope of such
reactions is limited by the available reduction power of
commonly known photocatalytic systems.9c Rhodamine
6G10(Rh‐6G) has recently been reported by us as a visible
light photoredox catalyst with a high reduction poten‐
tial.11 The reduction potential of the radical anion, gener‐
ated in situ, in its excited state reaches a value of ca.–2.4V
vs SCE,12 and has been applied for C–H arylation reactions
using substituted aryl bromides.11 We now apply the rho‐
Heteroaromatic biaryls are an important structural motif
in organic synthesis. They are present in polymers, ad‐
vanced materials, liquid crystals, ligands, and molecules
of medicinal interest.1 For example, DB320 is a chemo‐
therapeutic agent for Trypanosomaevansi, which causes
surra, an animal pathogenic infection (Figure 1).2 Ben‐
zafuranolderivative I acts as a potent retinoic acid recep‐
tor α antagonist,3 while Wakayin is an alkaloid with anti‐
cancer activity (Figure 1).4 Prodigiosin is a bright red tri‐
pyrrole pigment isolated from Serratia marcescens, show‐
ing biological activities such as antibacterial, anticoccidi‐
al, antimalarial and antifungal, and is often used as a
biochemical tool (Figure 1).5
Figure 1. Bioactive compounds containing bi‐
heteroaryl moieties.
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damine 6G catalytic system for the photocatalytic genera‐
redox catalytic chemical reactions, the faster quenching of
Rh‐6G in ACN cannot fully account for the better isolated
yields of compounds 3b, 3d and 3n–pin DMSO.
tion of heteroaryl radicals from commercially available,
and bench‐stable brominated and chlorinated substrates
using DIPEA as a sacrificial electron donor under blue
light (Ex = 455 nm) irradiation at room temperature (25
C). Subsequent trapping of heteroaryl radicals with a
second heteroarene under C–H cross coupling conditions
gives bi‐heteroaryls in good to excellent yields (eq. C,
Scheme 1).
Then the reaction was examined in the presence of 20
mol% catalyst loading, affording a 71% conversion in
DMSO (45% isolated yield) and 92% conversion in ACN
(65% isolated yield, see also the discussion below) (entries
8 and 9, Table 1). Control experiments without light,
without catalyst or without DIPEA confirmed that all the
components are necessary for the photoredox catalytic
reaction to take place (entries 10–12).
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Scheme 1. Synthesis of bi‐heteroaryls.
Table1. Optimization of the reaction conditions for
the photocatalyzed C–H heteroarylation.a
Entry
Rh‐6G
(mol%)
Solvent DIPEA Time Conv.b
(eq.)
1.5
1.0
2.0
2.5
1.5
1.5
1.5
1.5
1.5
(h)
48
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(%)
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59
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20
20
20
‐‐
DMSO
DMSO
DMSO
DMSO
DMF
ACN
NMP
DMSO
ACN
ACN
ACN
ACN
23
71 (45)f
92 (65)f
10c
11d
12e
1.5
1.5
‐‐
0
0
0
20
a The reactions were performed with 0.1 mmol of 2‐bromothiophene 1a,
1.8 mmol of N‐methylpyrrole2a, and 1.5 mL of solvent. b Conversion to the
final product determined by GC analysis after 48h. c Reaction in the dark.
2. RESULTS AND DISCUSSION
d
e
Reaction with blue LED light, without catalyst. Reaction without
f
Synthesis: The optimization of the reaction conditions
was carried out by irradiating a mixture of 2‐bromo‐
thiophene (1a, test substrate), N‐methylpyrrole (2a), rho‐
damine 6G, and DIPEA, under nitrogen atmosphere using
blue LEDs (Table 1).
DIPEA. In parenthesis is given the isolated product yield after flash
chromatography.
With the optimized reaction conditions in hand (entry 8
or 9, Table 1), the reaction scope was explored with a
range of substituted thiophenes and different pyrroles as
radical trapping reagents (Table 2).
Using 10 mol% catalyst, 1.5 equivalent of DIPEA in
DMSO, 35% conversion to the final product was observed
by GC (entry 1, Table 1). Different amounts of the sacrifi‐
cial electron donor (i.e., DIPEA) did not affect the reac‐
tion outcome (entries 2–4, Table 1). Then the reaction was
carried out using 10 mol% catalyst in different solvents.
DMF and NMP as solvent gave lower conversions than
DMSO, while the reaction in acetonitrile afforded better
result, with a 59% conversion of the bromide substrate
giving the desired product (entries 5–7, Table 1).13 The role
of solvent in determining the yields of the photoredox
catalytic chemical reaction is not fully understood at
present. The Stern‐Volmer quenching analysis demon‐
strates that quenching of Rh‐6G excited states by DIPEA
is faster in ACN than in DMSO (see Figure S2 in the Sup‐
porting Information). However, knowing that solvents
also a play a crucial role in determining the stability and
reactivity of radical intermediates (including the radical
anion of rhodamine 6G), generated in situ during photo‐
The reaction between 2‐bromothiophene 1a and pyrrole
2a gave excellent conversion to the desired product 3a, as
monitored by GC, with 20 mol% catalyst in 48h using
ACN as solvent of the reaction, but the high volatility of
the final product allowed its isolation only in 65% yield
(entry 1, Table 2). In the case of pyrrole 2b, better results
were obtained by carrying out the reaction in DMSO as
solvent, but again the high volatility of 3b allowed its
isolation only in moderate yield (entry 2, Table 2). A simi‐
lar situation was found for 3‐bromothiophene 1b in its
reaction with pyrroles 2a and 2b. Although good conver‐
sion to the final products were observed by GC, the high
volatility of 3c and 3d, only allowed their isolation in
moderate yields (entries 3 and 4, Table 2). Thiophenes 1c
and 1d bearing electron withdrawing substituents gave
full conversion with 10 mol% catalyst loading in 24h in
ACN or DMSO with pyrroles 2a–2d. However, reactions
in ACN allowed an easier isolation of the final products
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final product after purification using flash column chromatography, and
hence we give the range for the isolated chemical yield.
3e–3j, that were obtained in excellent yields (entries 5–10,
Table 2). The brominated pyrrol 2c is an excellent trap‐
ping reagent in the reaction with 1c, affording 3g in good
yield, that can be used as starting material for further
functionalizations (entry 7, Table 2). Other heterocycles
such as (benzo)furan or(benzo)thiophene do not act as
radical trapping reagents and the radical coupling step
with 2‐bromothiophene 1a does not occur (entry 11, Table
2). 14
Next, the reaction scope was investigated with different
electron‐rich heterocycles, 1e–1j, using N‐methylpyrrole
2a as a trapping reagent (Table 3 and Scheme 2). For
compounds 1e–1g, best results were obtained in ACN,
whereas for compounds 1h–1j, DMSO provided slightly
better yields. Substituted thianaphthene 1e and substitut‐
ed furfural 1f gave products 3k (80%) and 3l (81%) in very
good isolated yields in the presence of 20 and 10 mol%
catalyst, respectively (Table 3). Indole derivative 1g gave
90% conversion to a mixture of Boc‐deprotected indole,
the dehalogenated reduced form (via hydrogen atom
abstraction either from the radical cation of DIPEA or
from the solvent),11 and the desired product 3m (isolated
in 49% yield, Table 3). For the reaction of 1h–1j 20 mol%
catalyst loading was necessary for the complete conver‐
sion of the starting materials. Compounds 3n and 3p were
isolated in good yields(87% and 79%,respectively, Table
3). However, compound 1i gave the coupled product 3o in
moderate yield (51%) due to the formation of the dehalo‐
genated reduced byproduct.
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Table2. Scope of bromothiophenes used in the pho‐
tocatalyzed C–H heteroarylation.a
Entry Thio‐
Reac‐
tant
Product
Yieldb
(%)
phene
1c
65c,e
2
3
41±15d,e,
Table 3. Scope of bromo‐heteroarenes for the photo‐
g
catalyzed C‐H heteroarylation.a
Me
N
62c,e
S
3c
Entry Hetero‐
T.R.
Product
Yieldb
(%)
4
49±15d,
arene
e, g
1
80 c, e
5
6
7
96 c, f
2
3
81c,f
72c, f
70 c, f
49c, e
5
8
9
87d, e
84c,f
79c,f
6
51d, e
10
11
91c,f
0 c, e
7
79d,e
a
Reaction conditions: Bromoheteroarene (0.1 mmol), N‐methylpyrrole
a Reaction conditions: Bromoheteroarene (0.1 mmol), pyrrole (1.8 mmol),
b
(1.8 mmol), Rh‐6G (10 or 20 mol%), DIPEA (0.15 mmol), 1,5 mL solvent.
Isolated yield after flash chromatography. c Reaction carried out in ACN. d
Reaction carried out in DMSO. e Yield after 48h, with 20 mol% catalyst
loading. f Yield after 24h, with 10 mol% catalyst loading.
b
Rh‐6G (10 or 20 mol%), DIPEA (0.15 mmol), 1.5 mL solvent. Isolated
d
yield after flash chromatography. c Reaction carried out in ACN. Reac‐
tion carried out in DMSO. e Yield after 48h, with 20 mol% catalyst load‐
ing. f Yield after 24h, with 10 mol% catalyst loading. g As this compound is
quite volatile we were not able to remove the residual solvent form the
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Notably, the regioselectivity of the reaction is controlled
The dehalogenated reduced byproduct, which is formed
by the stability of the radical intermediates. Under the
catalytic reaction conditions, in all cases, single regioiso‐
mers were obtained.
in notable amounts in some cases (e.g., for substrate 1i),is
formed by hydrogen atom transfer from the radical cation
of DIPEA or from the solvent to the aryl radical.11
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Scheme 4. Mechanistic proposal
Although chloro‐heteroarenes have higher reduction
potentials than the corresponding brominated com‐
pounds, approaching the limits of the available reduction
power byRh‐6G,15 the presence of electron withdrawing
substituents decrease this reduction potential. Thus, the
reaction of 1k with 2a in the presence of 10 mol% catalyst
afforded 3q in good yield after 48h (Scheme 2).
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Scheme 2. Photocatalytic heteroarylation of chloro‐
heteroarene.
The methodology was also applied for the formal syn‐
thesis of compounds with biological activity. Starting
from brominated imidazole 1l and using N‐methylpyrrole
2a as radical trapping reagent, 20 mol% catalyst in DMSO
in 48 h, product 3r was obtained in 84% isolated yield
(Scheme 3). Compound 3r is an intermediate in the syn‐
thesis of the benzimidazole derivative II that is an MCH‐
R1 antagonist,16 known to be involved in the control of
food intake and body weight,17 being one of the promising
lead structures for obesity treatment (Scheme 3).
3. CONCLUSSION
Photocatalytic cross–coupling of five membered bromin‐
ated and chlorinated heteroarenes with pyrroles yields
biheteroaryls. The strong reductive power of the excited
radical anion of rhodamine 6G allows the reduction of a
variety of heteroaryl bromides, and heteroaryl chlorides
bearig electron withdrawing groups, giving the corre‐
sponding aryl radical, which is subsequently trapped by a
pyrrol derivative present in the solution affording the
target biaryls in good to excellent isolated yields. The
simple photocatalytic protocol may be useful as metal–
free alternative to the transition metal catalyzed cross
coupling methods.
Scheme 3. Formal synthesis of the benzimidazole
derivative II.
ASSOCIATED CONTENT
Supporting Information
Supporting Information Available:
[Full experimental data (PDF)]
This material is available free of charge via the Internet at
http://pubs.acs.org.
Mechanistic proposal: We assume the same catalytic
cycle as reported previously for Rh‐6G photocatalytic
systems.11 The catalytic cycle starts with the photoexcita‐
tion of Rh‐6G with blue LEDs. Rh‐6G in its excited state is
able to accept an electron from a sacrificial electron donor
(i.e., DIPEA), yielding the radical anion of the Rh‐6G (Rh‐
AUTHOR INFORMATION
Corresponding Author
E‐mail: Burkhard.Koenig@ur.de
*Fax: (+49)‐941‐943‐1717. Phone: (+49)‐941‐943‐4575.

–

+
6G ) and the radical cation of the DIPEA (DIPEA
)
(Scheme 4). The generated radical anion of Rh‐6G ab‐
sorbs a second photon (upon blue light irradiation) to
reach its excited state that has a higher reduction poten‐
tial and is therefore able to reduce the heteroaryl bro‐
mides by electron transfer, returning to its ground state,
and yielding the heteroaryl radical by scission of the C–Br
bond. Finally, this heteroaryl radical is trapped by pyrrole
derivatives present in the media, yielding the biheteroaryl
products after oxidation and rearomatization (Scheme 4).
Funding Sources
Deutsche Forschungsgemeinschaft (DFG, GRK 1626, Chemi‐
cal Photocatalysis).
ACKNOWLEDGMENT
This work was supported by the Deutsche Forschungsge‐
meinschaft DFG; GRK 1626, Chemical Photocatalysis). F.E.
thanks the Spanish government for a FPI fellowship. We
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