Visible-Light-Mediated Photocatalytic Difunctionalization of Olefins by Radical Acylarylation and Tandem Acylation/Semipinacol Rearrangement

Article abstract of DOI:10.1002/chem.201504985

A novel method for the mild photoredox-mediated tandem radical acylarylation and tandem acylation/semipinacol rearrangement has been developed. The synthesis of highly functionalized ketones bearing all-carbon α- or β-quaternary centers has been achieved

Full text of DOI:10.1002/chem.201504985

DOI: 10.1002/chem.201504985
Communication
&
Photocatalysis |Hot Paper|
Visible-Light-Mediated Photocatalytic Difunctionalization of
Olefins by Radical Acylarylation and Tandem Acylation/
Semipinacol Rearrangement
Giulia Bergonzini, Carlo Cassani, Haldor Lorimer-Olsson, Johanna Hçrberg, and
Carl-Johan Wallentin*[a]
addition of acyl radicals generated from the electrochemical or
chemical reduction of anhydrides to activated olefins
(Scheme 1a).[7] However, the need for controlled potential elec-
Abstract: A novel method for the mild photoredox-medi-
ated tandem radical acylarylation and tandem acylation/
semipinacol rearrangement has been developed. The syn-
thesis of highly functionalized ketones bearing all-carbon
a- or b-quaternary centers has been achieved using easily
available symmetric aromatic carboxylic anhydrides as the
acyl radical source. The method allows for a straightfor-
ward introduction of the keto functionality and concomi-
tant construction of molecular complexity in a single oper-
ation.
The development of novel catalytic, mild, and efficient genera-
tion of acyl radicals and their application in CÀC bond forming
reactions represents a fundamental goal in organic synthe-
sis.[1,2] A variety of procedures have been achieved to access
such radical species.[3] Despite the remarkable advances (typi-
cally involving UV irradiation, high temperature, high CO pres-
sure, tin reagents or peroxides), the development of novel cat-
alytic protocols to access acyl radicals for further transforma-
tions under environmentally friendly and sustainable condi-
tions have proven to be challenging.
Scheme 1. Symmetric carboxylic anhydrides as acyl radical precursors:
a) Cobalt-catalyzed hydrocarbonylation of activated olefins; b) acylarylation
of N-arylacrylamides and acylation/semipicanol rearrangement by visible-
light photoredox catalysis.
trolysis or stoichiometric amount of activated zinc dust as elec-
tron source represent major drawbacks of these protocols.
Herein, we describe a novel, mild, and efficient method for the
synthesis of high-value 3,3-disubstituted 2-oxindoles and 1,4-
diketones initiated by a single-electron reduction of symmetric
aromatic carboxylic anhydrides by means of photoredox catal-
ysis (Scheme 1b).
In the last decade, visible-light photoredox catalysis has
emerged as a powerful entry to highly reactive radical inter-
mediates under very mild and operationally accessible condi-
tions.[4] In this context, we became interested in the activation
of aromatic carboxylic acids and their use as acyl radical pre-
cursors under visible-light photoredox-catalyzed conditions.[5]
Further exploring complementary methods towards acyl radi-
cals generation, we sought to employ easily available symmet-
ric carboxylic anhydrides as the acyl radical source. In radical
chemistry, symmetric anhydrides have been utilized as acyl
radical source for spectroscopic and mechanistic studies.[6] In
1983, Scheffold and Orlinski reported on the cobalt-catalyzed
The 3,3-disubstituted 2-oxindole framework containing the
carbonyl functionality is a privileged heterocyclic motif found
in many pharmaceutical and bioactive natural products.[8]
Moreover, due to the innate reactivity of the carbonyl function-
al group, 3,3-disubstituted 2-oxindoles represent versatile inter-
mediates in organic synthesis. Owing to the importance and
versatility of this class of compounds, much effort has gone
into the development of novel approaches for their prepara-
tion.[8c,9] Among these, the tandem radical acylarylation of N-ar-
ylacrylamides has recently emerged as a powerful approach.[10]
However, new strategies to provide access to valuable carbon-
yl containing 3,3-disubstituted 2-oxindoles that proceed under
mild conditions without the requirement for external oxidants,
high temperature, or high-energy UV light still remains elusive.
Here we report an operationally simple redox-neutral protocol
for the mild visible-light-mediated tandem radical acylarylation
and tandem acylation/semipinacol rearrangement of olefins
[a] Dr. G. Bergonzini, Dr. C. Cassani, H. Lorimer-Olsson, J. Hçrberg,
Dr. C.-J. Wallentin
Department of Chemistry and Molecular Biology
Gothenburg University, 412 58, Gothenburg (Sweden)
E-mail: carl.wallentin@chem.gu.se
Supporting information and the ORCID identification number for the
author of this article can be found under http://dx.doi.org/10.1002/
chem.201504985.
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building structural diversity, we next turned to the synthesis of
versatile 1,4-diketones and 1,4-ketoaldehydes by a tandem acy-
lation/semipinacol rearrangement of allylic alcohol derivatives
(Scheme 2). The semipinacol rearrangement of allylic alcohols
is of high importance in natural product synthesis for the for-
mation of a-quaternary carbonyl structures.[13] Taking advant-
age of the ability of photoredox catalysis to facilitate radical–
polar crossover reactions,[14] we envisioned that after the addi-
tion of the photogenerated acyl radical and subsequent single-
electron oxidation, the resulting carbocation would undergo
1,2-migration (Scheme 2a).[15] This transformation would consti-
tute the first visible-light photoredox-catalyzed tandem acyla-
tion/semipinacol rearrangement initiated by acyl radicals.
Table 1. Selected optimization studies.[a]
Entry
Photocatalyst
Solvent
Yield 3a [%][b]
1
2
3
4
5[c]
6
7[c,e]
[Ir(ppy)2(dtbbpy)]BF4
[Ru(bpy)3]Cl2
fac-[Ir(ppy)3]
fac-[Ir(ppy)3]
fac-[Ir(ppy)3]
–
CH3CN
CH3CN
CH3CN
DMA
DMA
DMA
0
0
38
>95
>95 (94)[d]
0
0
fac-[Ir(ppy)3]
DMA
Table 2. Tandem radical cyclization: carboxylic anhydride scope.[a,b]
[a] Reactions performed on 0.1 mmol scale using 2 equiv of 1a. [b] Deter-
mined by 1H NMR using 2,5-dimethylfuran as internal standard. [c] Performed
with 1 mol% of fac-[Ir(ppy)3]. [d] Isolated yield. [e] Reaction carried out in the
dark. DMA=N,N-dimethylacetamide.
using readily available and inexpensive carboxylic anhydrides
as acyl radical source.
We began our investigation using benzoic anhydride (1a)
and N-methyl-N-phenylmethacrylamide (2a) as the model sub-
strates in the presence of a photocatalyst under visible-light ir-
radiation at room temperature in acetonitrile (Table 1). The
evaluation of different photocatalysts showed that although
no product was observed using [Ir(ppy)2(dtbbpy)]+ and
[Ru(bpy)3]2+ (entries 1 and 2), strongly reducing fac-[Ir(ppy)3]
was able to promote the desired acylarylation reaction
(entry 3). When N,N-dimethylacetamide (DMA) was used as sol-
vent, 3a was obtained in quantitative yield (entry 4). Moreover,
it was possible to lower the catalyst loading to 1 mol% with-
out affecting the reaction efficiency (entry 5). Control experi-
ments indicated that both the photocatalyst and visible light
were essential in this acylarylation protocol (entries 6 and 7).
Having identified the optimal reaction conditions, we next
turned our attention to the scope of the symmetric carboxylic
anhydride (Table 2). As shown, differently substituted aromatic
as well as heteroaromatic carboxylic anhydrides were applica-
ble to this transformation. Anhydrides bearing electron-defi-
cient arenes could be readily employed, providing the corre-
sponding products in good to excellent yields (3a–c and 3 f).
Pleasingly, the Lewis acid activation of more challenging elec-
tron-rich aromatic and heteroaromatic carboxylic anhydrides
allowed for the generation of the corresponding carbonyl radi-
cals and the efficient synthesis of products 3d, 3e and 3g–
j.[11,12] As a limitation, hydrocinnamic anhydride was found to
be unreactive under these conditions.
[a] Reactions performed on 0.1 mmol scale using 2 equiv of 1. [b] Isolated
yield. [c] [2a]0 =0.05m. [d] Reaction performed by adding 1 equiv of
MgCl2; reaction time=60 h. [e] Photocatalyst loading=2.5 mol%.
As shown in Scheme 2b, subjecting olefin 4a to our opti-
mized conditions, ring expanded product 5a was obtained as
the major product together with epoxide 5b. Upon trimethyl-
silyl (TMS) protection of the hydroxyl group, we were pleased
to find that compound 5a could be generated as the exclusive
reaction product in excellent yield. Furthermore, the less strain-
ed five-membered carbacycle derivative 4c also provided the
corresponding ring expanded cyclohexanone 5c in almost
quantitative yield. Acylation/aryl 1,2-migration was achieved
utilizing 1,1,2-triphenylprop-2-en-1-ol (4d). Also in this case,
the rearranged product 5d was obtained along with epoxide
5e. Decreasing the nucleophilicity of the hydroxyl group
through TMS protection (4e) allowed for the formation of 5d
as the sole reaction product. Remarkably, when TMS-protected
secondary allylic alcohol 4 f was used as reaction partner, good
yield of densely functionalized aldehyde 5 f was obtained. This
With respect to the olefin reaction partner (Table 3), the pro-
tocol could be applied to differently substituted N-phenylacryl-
amides, obtaining products 3k and 3l in excellent yields.
Moreover, olefins bearing electron-withdrawing as well as -do-
nating groups on the phenyl ring were highly compatible with
the optimized conditions (3m–o).
To further extend the utility of this visible-light-mediated
method for the introduction of the carbonyl functionality while
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Table 3. Tandem radical cyclization: olefin scope.[a,b]
[a] Reactions performed on 0.1 mmol scale using 2 equiv of 1. [b] Isolated
yield.
example illustrates that the protocol is competent for the for-
mation of both diketones and ketoaldehydes.
A plausible reaction mechanism for the tandem radical acyl-
arylation reaction and the tandem acylation/semipinacol rear-
rangement is shown in Scheme 3. Photoexcitation of fac-
[IrIII(ppy)3] (depicted as IrIII) under visible light generates fac-
[*IrIII(ppy)3], which is a strong reductant (E1/2 [IrIV/*IrIII]=À1.73 V
versus SCE).[4] Thermodynamically favorable single-electron re-
duction of symmetric carboxylic anhydride 1 (benzoic anhy-
dride 1a, E1/2red =À1.13 V versus SCE)[6b] by fac-[*IrIII(ppy)3]
would generate fac-[IrIV(ppy)3] and radical anion I, which after
fragmentation delivers acyl radical II. At this stage, acyl radical
II might undergo a selective radical addition to olefin 2, giving
radical intermediate III.[10] Upon intramolecular cyclization, the
oxidation of intermediate IV by fac-[IrIV(ppy)3] would provide
final product 3 along with the ground state of the photocata-
lyst. In the presence of protected allylic alcohols 4, acyl radical
Scheme 2. a) Visible-light-mediated tandem acylation/semipinacol rearrange-
ment of allylic alcohols by a radical–polar crossover mechanism; b) scope of
the reaction. [a] Reactions performed on 0.1 mmol scale using 2 equiv of 1a;
[b] isolated Yield; [c] reaction time=60 h. TMS=trimethylsilyl.
II may undergo a radical addition to generate benzylic radical
V. Single-electron transfer (SET) from V to fac-[IrIV(ppy)3] regen-
Scheme 3. Proposed mechanism.
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erates the photocatalyst and delivers carbocation VI.[16] A 1,2-
alkyl or -aryl migration would form product 5 upon loss of the
silyl protecting group.[15] As a support for the proposed initial
SET event between the photocatalyst and the symmetric anhy-
dride 1, Stern–Volmer fluorescence quenching studies showed
that the emission intensity of the excited state of fac-[Ir(ppy)3]
was significantly quenched by symmetric benzoic anhydride
1a.[17]
In conclusion, we have developed a photoredox-mediated
method for the tandem radical acylarylation and tandem acyl-
ation/semipinacol rearrangement of olefins. The method repre-
sents a mild and powerful entry to the synthesis of highly
functionalized carbonyl compounds bearing all-carbon a- or b-
quaternary centers using easily available symmetric aromatic
carboxylic anhydrides as the acyl radical source. The method
allows for the sustainable, mild, and straightforward introduc-
tion of the keto functionality and concomitant construction of
molecular complexity in a single operation.
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Acknowledgements
The authors thank the Olle Engkvist Byggmästare foundation,
the Wilhelm and Martina Lundgren research foundation, the
Ollie and Elof foundation, the Magnus Bergvall foundation, the
Adlerbertska foundation and the Swedish Research Council.
C.C. is grateful to the European Commission for a Marie Skło-
dowska-Curie fellowship (H2020-MSCA-IF-2014 n: 660668). The
Swedish NMR Centre at the University of Gothenburg is ac-
knowledged for instrument access and support.
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Keywords: acylation · cyclization · oxindole · photoredox
catalysis · synthetic methods
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part of a radical chain propagation.
[17] See the Supporting Information for details on fluorescence quenching
studies.
Received: December 11, 2015
Published online on February 2, 2016
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