Acyl Radicals from Aromatic Carboxylic Acids by Means of Visible-Light Photoredox Catalysis

Article abstract of DOI:10.1002/anie.201506432

Simple and abundant carboxylic acids have been used as acyl radical precursor by means of visible-light photoredox catalysis. By the transient generation of a reactive anhydride intermediate, this redox-neutral approach offers a mild and rapid entry to hi

Full text of DOI:10.1002/anie.201506432

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Communications
International Edition: DOI: 10.1002/anie.201506432
German Edition: DOI: 10.1002/ange.201506432
Acyl Radicals
Acyl Radicals from Aromatic Carboxylic Acids by Means of Visible-
Light Photoredox Catalysis
Giulia Bergonzini, Carlo Cassani, and Carl-Johan Wallentin*
Abstract: Simple and abundant carboxylic acids have been
used as acyl radical precursor by means of visible-light
photoredox catalysis. By the transient generation of a reactive
anhydride intermediate, this redox-neutral approach offers
a mild and rapid entry to high-value heterocyclic compounds
without the need of UV irradiation, high temperature, high CO
pressure, tin reagents, or peroxides.
C
arboxylic acids are abundant and inexpensive starting
materials readily available in great structural diversity. For
this reason, continuous efforts have been made to engage this
class of compounds in novel catalytic organic transforma-
tions.[1] In more recent years, visible-light photoredox catal-
ysis has emerged as a benign and powerful tool in organic
synthesis, and novel strategies targeting carboxylic acids as
building blocks have been developed.[2] Those methods rely
on photo-induced oxidation of carboxylates to generate, after
CO2 extrusion, reactive alkyl radical intermediates (Sche-
me 1a).[3] Capitalizing upon the high synthetic potential of
visible-light photoredox catalysis, we questioned whether
carboxylic acids might be used for the generation of acyl
radicals by single-electron reduction (Scheme 1b).[4] This
would offer an unprecedented synthetic method that extends
beyond the existing routes to access acyl radicals, which are
often characterized by harsh conditions (UV irradiation, high
temperature, high CO pressure, tin reagents, or peroxides) or
the need of pre-generated acyl radical precursors such as
telluroesters, selenoesters, and thioesters.[3j,5]
Scheme 1. a,b) Generation of reactive radical species from simple
carboxylic acids by means of visible-light photoredox catalysis. c) Pho-
tocatalyzed redox-neutral acylarylation of methacrylamides using ben-
zoic acids as starting material. DMDC=dimethyl dicarbonate.
ditions and a novel entry to a broader spectrum of accessible
products.
At the onset of our investigation, we tested our idea for
the formation of 3,3-disubstituted 2-oxindoles by 1,2-acylar-
ylation of alkenes (Scheme 1c). The 3,3-disubstituted 2-
oxindoles containing the carbonyl functionality are common
structural motifs in pharmaceutical and bioactive natural
products, and represent versatile intermediates in organic
synthesis.[9]
Consequently, in the last few years, the development of
efficient synthetic methods for the synthesis of 3,3-disubsti-
tuted 2-oxindoles has received increased interest. Among
these, 1,2-acylarylation of methacrylamides has emerged as
a particularly interesting approach.[10] However, the use of
stoichiometric amounts of external oxidants, high temper-
ature, or high-energy UV light represent considerable dis-
advantages of the procedures.
Herein we report the first redox-neutral approach for the
mild visible-light-mediated tandem acylarylation of olefines
using carboxylic acids as an acyl radical source. We first
explored the proposed acylarylation reaction using benzoic
acid 1a and N-methyl-N-phenylmethacrylamide 2a as the
model substrates in the presence of the photocatalyst,
DMDC, and 2,6-lutidine under visible-light irradiation
(Table 1). We were pleased to find that the strongly reducing
fac-Ir(ppy)3 provided the desired product 3a in excellent yield
(entry 1). In contrast, much weaker reductants such as
[Ir(ppy)2(dtbbpy)]+ and [Ru(bpy)3]2+ were unable to promote
the reaction (Supporting Information, Table S1, entries 1 and
We envisioned that transient mixed anhydride intermedi-
ates, obtained from simple carboxylic acids in the presence of
dimethyl dicarbonate (DMDC),[6] could be engaged as
oxidative quenchers of a photocatalyst to generate the desired
acyl radical species, along with CO2 and methanoate as the
only byproducts.[7,8] This would provide carboxylic acids with
orthogonal redox reactivity under mild photocatalytic con-
[*] Dr. G. Bergonzini,[+] Dr. C. Cassani,[+] Dr. C.-J. Wallentin
Department of Chemistry and Molecular Biology,
Gothenburg University
41258 Gothenburg (Sweden)
E-mail: carl.wallentin@chem.gu.se
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201506432.
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co.
KGaA. This is an open access article under the terms of the Creative
Commons Attribution Non-Commercial NoDerivs License, which
permits use and distribution in any medium, provided the original
work is properly cited, the use is non-commercial and no modifica-
tions or adaptations are made.
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Table 1: Selected optimization studies.[a]
Table 2: Carboxylic acid scope.[a]
Entry
fac-Ir(ppy)3
[mol%]
DMDC
[equiv]
2,6-lutidine Solvent Yield [%][b]
[equiv]
1
1
4
3
3
3
2
DMA
DMF
DMF
DMF
>95
>95
<5
2[c,d]
3[c,e]
4[c,e,f]
0.5
0.5
0.5
0.5
0.5
0.5
88
[a] Reactions performed on 0.1 mmol scale using 2 equiv of 1a.
[b] Determined by 1H NMR using 2,5-dimethylfuran as internal standard.
[c] Performed with 1.5 equiv of 1a; [2a]0 =0.05m. [d] Reaction
time=6 h; [e] Reaction performed with 3 equiv of Boc2O instead of
DMDC; [f] Addition of 1 equiv of MgCl2. DMA=N,N-dimethylaceta-
mide; DMF=N,N-dimethylformamide.
2). Control experiments performed in the absence of the
photocatalyst, the dicarbonate or the light source completely
impeded any reactivity (Supporting Information, Table S1,
entries 4–6). Fine tuning of the reaction conditions provided
the desired product quantitatively while also decreasing
reaction time and catalyst loading (Table 1, entry 2, Meth-
od A). When di-tert-butyl dicarbonate (Boc2O) was used
instead of DMDC to generate the corresponding mixed
anhydride, only traces of product 3a were found (entry 3).
However, upon Lewis acid activation of Boc2O with the
addition of MgCl2 the product was obtained in high yield
(entry 4).[11]
[a] Reactions performed on 0.2 mmol scale. Yield of isolated product.
[b] Reaction performed using 0.5 mol% of fac-Ir(ppy)3 and 3 equiv of
DMDC over 6 h (Method A). [c] Method A using 2.5 mol% of fac-Ir(ppy)3
over 14 h. [d] Reaction performed with 2.5 mol% of fac-Ir(ppy)3, 3 equiv
of Boc2O and 1 equiv of MgCl2 over 48 h (Method B). [e] 4 equiv of
Boc2O were used. [f] Reaction carried out with Method A on 1 mmol
scale; reaction time=10 h. [g] See the Supporting Information for
details.
phenylacetic acid was also tolerated as a substrate, giving 3a
in 30% yield.[15] However, when aliphatic carboxylic acids
such as 1-phenylcyclopentanecarboxylic acid, 2-methoxy-2-
phenylacetic acid, and N-Boc-glycine were employed under
the optimized conditions, no formation of the corresponding
products was observed.[16]
We next turned to evaluate the scope of the olefin
(Table 3). A range of methacrylates successfully gave access
to the corresponding products in good to excellent yields (74–
95%). Differently N-substituted phenylmethacrylamide
could be used without loss of efficiency (3t, 3u).
With the optimized conditions in hand (Method A), we
examined the scope of the acid component.
As shown in Table 2, the reaction proceeds in good to
excellent yield with a broad range of benzoic acids bearing
different substituents in the para-, meta-, and ortho-position
as well as carboxylic acids with extended aromatic systems
(3a–3n). Ortho- and para-methyl, as well as para-hydroxy and
para-trifluoromethyl benzoic acid, performed poorly under
the optimized conditions, and fast conversion of these acids
into the corresponding unreactive methyl esters was
observed.[12] However, they could be efficiently employed
(3e–3g, 3m) by replacing DMDC with Boc2O together with
the use of 1 equiv of MgCl2 and 2.5 mol% of fac-Ir(ppy)3 over
48 h (Method B).[13] Electron-rich carboxylic acids, expected
to be more difficult to reduce, can also serve to generate acyl
radicals by simply increasing catalyst loading and reaction
time (3d, 3i–k). Notably, carboxylic acids bearing free
hydroxy and amino groups smoothly furnished oxindoles 3g
and 3j as carbonate and carbamate derivatives, providing an
efficient and mild acylarylation/protection procedure in one-
pot. Heteroaromatic substrates such as 2-thiophene, 2-furoic,
nicotinic, and 1-methylindole-2-carboxylic acid proved to be
valuable reaction partners, generating products 3o–3r in
moderate to good yields. Isophtalic acid could also be
employed as a substrate furnishing product 3s by a consec-
utive difunctionalization. Furthermore, the optimized method
was successfully applied to five-fold scale-up of the reaction
providing product 3a in excellent yield (97%).[14] 2-Oxo-2-
Table 3: Olefin scope.[a,b]
[a] Reactions performed on 0.2 mmol using Method A. [b] Yield of
isolated product. [c] Reaction performed using 2.5 mol% of fac-Ir(ppy)3
over 14 h.
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Substrates bearing electron-donating groups reacted
smoothly and furnished the products in excellent yields (3w,
3y). Electron poor substrates reacted slower under the
optimized conditions, and higher catalyst loading and reaction
times were needed to obtain good yields (3v, 3x).
To showcase the generality and synthetic utility of this
method, we sought to employ a range of olefins beyond
methacrylamides (Scheme 2).
Pleasantly, we found that the procedure can be applied to
styrene-type substrates 4a–c to readily build high molecular
complexity accessing diverse heterocyclic motifs 5a–c in
promising yields (Scheme 2).
Figure 1. a) Proposed mechanism. b) Reaction performed using
0.1 mmol of 2a and 1.5 equiv of 7. Yield determined by 1H NMR using
2,5-dimethylfuran as internal standard.
ing studies clearly revealed that 7 is the only molecular entity
in the reaction mixture that efficiently quenches fac-*IrIII-
(ppy)3.[15] Together, these experiments strongly support the
proposed mechanism delineated in Figure 1a.
Scheme 2. Acylarylation of styrene-type olefins for the generation of
In conclusion, we have developed an operationally con-
venient visible-light photocatalytic tandem acylarylation of
olefins using available aromatic carboxylic acids as starting
material. The protocol presents a mild and energy-efficient
system which offers a viable method for the generation of acyl
diverse heterocyclic scaffolds.
A further demonstration of the synthetic value of the
method is given by the straightforward preparation of
compound 6, which features the hexahydropyrrolo[2,3-
b]indole unit found in many natural products (Scheme 3).[17]
A plausible reaction mechanism (Figure 1a) begins with
the photoexcitation of fac-IrIII(ppy)3 (depicted as IrIII in
À
radicals and their employment in C C bonding reactions.
Acknowledgements
The Olle Engkvist Byggmästare foundation, the Wilhelm and
Martina Lundgren research foundation, the Ollie and Elof
foundation, the Magnus Bergvall foundation, the Adlerbert-
ska foundation, and the Swedish Research Council are
gratefully acknowledged for financial support. C.C. is grateful
to the European Commission for a Marie Skłodowska-Curie
fellowship (H2020-MSCA-IF-2014 n: 660668). The authors
thank Pegah Sadat Nabavi Zadeh and Dr. Gert Gçransson for
their generous assistance with fluorescence and cyclic vol-
tammetry experiments. The Swedish NMR Centre at the
University of Gothenburg is acknowledged for instrument
access and support.
Scheme 3. Preparation of derivative 6 bearing the hexahydropyrrolo-
[2,3-b]indole core.
Figure 1a) under visible light, to generate fac-*IrIII(ppy)3,
which is a strong reductant (E1/2 [IrIV/*IrIII] = À1.73 V vs
SCE).[2] Single-electron reduction of mixed anhydride I
(generated in situ from carboxylic acid 1 in the presence of
DMDC under basic conditions) by fac-*IrIII(ppy)3 provides
fac-IrIV(ppy)3 and radical anion II that, after fragmentation,
delivers acyl radical III along with CO2 and methanoate.
Subsequently, acyl radical III undergoes selective radical
addition to olefin 2 giving radical intermediate IV.[10b–g] Upon
intramolecular cyclization, intermediate V is oxidized by fac-
IrIV(ppy)3 providing final product 3 along with the ground-
state of the photocatalyst. To verify the proposed role of I in
the catalytic cycle, we reacted isolated mixed anhydride 7
(E1/2red = À1.74 V vs SCE)[15] with olefin 2a in the presence of
the photocatalyst under visible-light (Figure 1b) and as
expected, smooth conversion into product 3a was observed.
Furthermore, a series of Stern–Volmer fluorescence quench-
Keywords: acyl radicals · acylarylation · carboxylic acids ·
oxindoles · photoredox catalysis
How to cite: Angew. Chem. Int. Ed. 2015, 54, 14066–14069
Angew. Chem. 2015, 127, 14272–14275
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Received: July 13, 2015
Revised: August 26, 2015
Published online: September 25, 2015
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