Acyl Radicals from Terminal Alkynes: Photoredox-Catalyzed Acylation of Heteroarenes

Article abstract of DOI:10.1002/chem.201801628

A photoredox-mediated acylation reaction of electron deficient heteroarenes with terminal alkynes is reported. The method relies on oxidative cleavage of phenylacetylenes for generation of acyl radicals as a key enabling feature. The reaction is regiosele

Full text of DOI:10.1002/chem.201801628

A Journal of
Accepted Article
Title: Acyl radicals from terminal alkynes: Photoredox-catalyzed
acylation of heteroarenes
Authors: Bhahwal Ali Shah
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10.1002/chem.201801628
Chemistry - A European Journal
COMMUNICATION
Acyl radicals from terminal alkynes: Photoredox-catalyzed
acylation of heteroarenes
Shaista Sultan,[a] Masood Ahmad Rizvi,[b] Jaswant Kumar[a] and Bhahwal Ali Shah*[a]
incomplete conversion of starting materials. Additionally, the
reaction is regioselective with broad substrate scope, excellent
functional group tolerance and short reaction times.
Abstract: A photoredox-mediated acylation reaction of electron
deficient heteroarenes with terminal alkynes is reported. The
method relies on oxidative cleavage of phenylacetylenes for
generation of acyl radicals as a key enabling advance. The
reaction is regioselective with broad substrate scope. Quantum
yield investigations support a radical chain mechanism.
Acyl radicals are one of the most investigated synthetic
organic building blocks owing to their application in the synthesis
of multitude of natural/medicinally important molecules.[1] These
radicals are conventionally generated via C-X bond cleavage
involving the use of toxic organotin reagents, carbonylation of C-
X bond and fragmentation of C-C bond in ketones and α-
ketoacids/esters.[1] Recently, some milder photocatalytic
approaches have also emerged to produce these radicals,
involving the use of aldehydes,[2] acid chlorides,[3] anhydrides[4]
and acyl silanes (Figure 1).[5] Among these use of α-ketoacid
presents most attractive and widely used synthon to make acyl
radical, because of the fact that its anionic form easily oxidises
in presence of catalysts such as Eosin, Ir(III) complexes,
acridinium salts, Ru(II) complexes via elimination of carbon
dioxide.[6] Also, recently Zang et al.,[6k] developed an
electrochemical method of generating acyl radical from α-
ketoacid. The α-ketoacids in turn are commonly sourced from
acetophenones using strong oxidizing agents like selenium
dioxide.[7]
In this regard, the oxidative reactions of alkynes offers an
interesting proposition,[8] however, their use in the generation of
acyl radicals and its subsequent applications in acylation
reactions are hitherto unreported. This intrigued us to develop a
direct and facile protocol for the generation of acyl radicals from
terminal alkynes via glyoxylic acid and their subsequent use in
acylation reactions. Thus, in continuation of our interests,[9]
herein we present a novel photoredox catalysed oxidative
cleavage of terminal arylacetylenes, enabling their use as acyl
precursors for acylation of heteroarenes (Scheme 1). Notably,
acylated heterocycles are present in myriad drugs/naturally
occurring molecules of pharmacological significance, generally
accessed through Minisci reaction.[10,11] The appeal of the
present method also lies in obviating the traditional requirements
of Minisci acylation reaction such as high temperatures or harsh
reaction conditions with excess amounts of radical precursors,
low site selectivity, longer reaction times (around 20 h) and
Figure 1. Acyl radical sources
Our studies initiated with the reaction of isoquinoline 1 and
phenylacetylene 2 as model substrates (Table 1). The reaction
was irradiated under a 27 W CFL bulb in presence of potassium
persulfate (K2S2O8) and trifluoroacetic acid (TFA) with Eosin-Y
as photocatalyst using MeCN/H2O as solvent (Table 1, entry 1).
The reaction led to the formation of product 3a in 40% yields in
18 h. We next screened different photocatalysts to improve
reaction yields. The use of 9-mesityl-10-methylacridinium
tetrafluoroborate (Mes-Acr+BF4 ) resulted in no product formation,
-
whereas, 9-fluorenone and Rose Bengal produced 3a in 55 and
46% yields, respectively (Table 1, entries 2-4). Remarkably, the
use of Ru(bpy)3Cl2.6H2O as a photocatalyst resulted in an
improved yield of 81% with quantitative consumption of starting
materials and considerably reduced reaction time (Table 1, entry
5). Notably, the reaction returned lower yields and took longer
time when irradiated under blue LEDs (Table 1, entry 6) possibly
because of faster oxidative cleavage of phenylacetylene to acyl
radicals in blue light resulting in the formation of benzaldehyde
as a by-product. We also screened various solvents to study
their impact on reaction yields. The use of CH2Cl2/H2O led to a
decrease in the product yields, while no product formation was
observed in MeOH/H2O (Table 1, entries 7 and 8). Solvents
such as DCE, DMF and DMSO were also screened; however,
they did not result in the product formation (Table 1, entries 9-
11). Also, control experiments revealed light source to be critical
for the reaction as trace amounts of 3a were obtained in its
absence (Table 1, entry 12). The reaction at 55 oC in absence of
photocatalyst and light led to the formation of desired product in
20% yields (Table 1, entry 13).
[a]
S. Sultan, J. Kumar, Dr. B.A. Shah
Natural Product Microbes and ACSIR
CSIR-Indian Institute of Integrative Medicine, Jammu-180001
E-mail: bashah@iiim.ac.in
Home page: http://www.iiim.res.in/People/CV/cv_bhahwal.php
Orcid ID: 0000-0001-6629-0002
[b]
Dr. M.A. Rizvi
Department of Chemistry, University of Kashmir, Srinagar, 190006
Supporting information for this article is given via a link at the end of the
document.
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Notably, the reaction with aliphatic alkynes did not yield the
desired product.
Table 1. Optimization of the reaction conditions.[a]
Scheme 1. Substrate Scope with different phenylacetylenes
entry
photocatalyst
light
source
CFL
CFL
CFL
CFL
CFL
Blue
LEDs
CFL
CFL
CFL
CFL
CFL
-
solvent
time
(h)
18
18
18
18
4
yield
(%)
40
traces
55
46
81
53
1
2
3
4
5
6
Eosin-Y#
MeCN/H2O
MeCN /H2O
MeCN /H2O
MeCN /H2O
MeCN /H2O
MeCN /H2O
-#
Mes-Acr+BF4
9-fluorenone#
Rose Bengal#
Ru(bpy)3Cl2
#
Ru(bpy)3Cl2
18
#
7
8
9
10
11
12
13ǁ
Ru(bpy)3Cl2
CH2Cl2/H2O
MeOH/H2O
DCE
DMF
DMSO
18
18
18
18
18
18
18
43
traces
Nd
Nd
Nd
#
Ru(bpy)3Cl2
#
Ru(bpy)3Cl2
#
Ru(bpy)3Cl2
#
Ru(bpy)3Cl2
#
Ru(bpy)3Cl2
MeCN /H2O
MeCN /H2O
Traces
20
-
-
[a]Reaction conditions: 1 (1.0 mmol), 2 (1.2 mmol), photocatalyst (2 mol %),
persulfate salt (3 mmol), trifluoroacetic acid (TFA, 1 mmol), solvent (2-3 mL), rt
= 25-30 oC. #Note: These reactions were not monitored beyond 18 h. ǁThe
reaction was carried out at 55oC in the absence of photocatalyst and light.
To demonstrate the functional group tolerance and
applicability of this method further, we examined the scope of
this reaction with different electron-deficient heteroarenes
(Scheme 2). As demonstrated by the reaction with simple
phenylacetylene, a range of substituted quinolines served as
suitable substrates, generating the corresponding acylated
products as single regioisomers in good yields (4a-4d). Similarly,
quinoxaline and its methyl derivative underwent coupling with
phenylacetylenes to produce acylated products in good yields
(4e-4g). The reaction also works well with polycyclic
heteroarene benzo[h]quinoline to give the corresponding product
(4h) in 78% yield. Benzothiazole was also found to be a suitable
substrate for acylation utilizing phenylacetylene, thereby
generating the corresponding product (4i) in 60% yield.
Phenanthridine was also observed to participate in the acylation
producing 4j in 75% yields.
Having conditions optimized, we turned our attention
towards expanding the scope of the reaction to various
substituted phenylacetylenes (Scheme 1). A range of alkyl-
substituted phenylacetylenes viz., methyl, ethyl, propyl, tert-
butyl, 2,4,5-trimethyl and pentyl phenylacetylene reacted
efficiently with the model substrate isoquinoline to generate the
corresponding products (3b-3g) in good yields. The electron-rich
alkoxy-substituted phenylacetylenes 4-phenoxy and 3-methoxy
phenylacetylene were also found to participate in the reaction
smoothly to give products 3h and 3i in 79 and 75% yields,
respectively. Furthermore, the scope of acylation of
heteroarenes
was
extended
to
halo-substituted
phenylacetylenes, which can offer the possibility of further
functionalization. The reaction with 4-fluoro, 4-bromo and 3-
fluoro phenylacetylene was amenable to reaction with
isoquinoline, producing the corresponding products (3j-3l) in
good yields. The reaction with electron deficient 4-
trifluoromethoxy phenylacetylene also proceeded efficiently to
give corresponding acylated heteroarenes 3m in 71% yield.
The reaction possibly proceeds via photo-excitation of
Ru(bpy)3Cl2, which is known to undergo single electron transfer
(SET) in the presence of persulfate salt, thereby, generating
sulphate radical anion (SO4−•) and Ru(III).[12] On the other hand,
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phenylglyoxylic acid A generated in-situ from phenylacetylene[8a-
range of heteroarenes and arylacetylenes to afford structurally
diverse acylated nitrogen heteroarenes as single regioisomers in
good yields. Stoichiometric use of acyl precursor and shorter
reaction times are some of the advantages of the protocol. This
study opens a new way of utilizing terminal alkynes as a source
of acyl groups which can find application in multitude of synthetic
reactions. The further reactivity and applicability of this reaction
system is currently under investigation in our laboratory.
c]
undergoes decarboxylation followed by hydrogen atom
transfer (HAT) with sulphate radical anion (SO4−•) to produce
acyl radical B,[13] and subsequently couples with protonated
heteroarene C to give intermediate D. The final product 3a is
produced as a result of an SET reaction between intermediate D
and Ru(III), which also completes the photoredox catalytic cycle
of Ru catalyst and hence its regeneration (Scheme 3). The
reaction under standard conditions in presence of radical
quencher viz., TEMPO failed to give desired product and instead
lead to the trapping of acyl radical to give its radical adduct. The
role of phenylglyoxylic acid as an intermediate was
unambiguously proved by the reaction of isoquinoline with
phenylglyoxylic acid under the stipulated conditions to give the
final product 3a in 45% yields (Scheme 3). Furthermore, in the
absence of heteroarene as a reactant under standard conditions,
the reaction led to the formation of phenylglyoxylic acid from
phenylacetylene. Notably, in both the cases benzaldehyde
accompanied as a side product, which explains lower than
expected yields. We also studied the emission profile of
[Ru(bpy)3]2+ fluorophore with the increasing concentration of
potassium persulfate as quencher (see supporting information).
The Stern−Volmer analysis revealed that the photoluminescence
of Ru(bpy)3Cl2 was quenched by K2S2O8 in MeCN/H2O at 25 °C
and the results are well in accordance with the literature
reports.[14] Furthermore, reaction quantum yield of 7.2 show that
reaction propagates via a radical chain mechanism.
Scheme 2. Substrate Scope with different heteroarenes
Scheme 3. Plausible mechanism
ACKNOWLEDGMENT
BAS thank CSIR for Young Scientist Award Grant (P-81-113)
and DBT (1151/2016), New Delhi for financial assistance. SS
and JK thank CSIR for Fellowship. IIIM communication No. 2200
Keywords: phenylacetylene • acyl radical • photoredox •
heteroarene • acylation
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Entry for the Table of Contents
COMMUNICATION
Ms. Shaista Sultan[a], Dr. Masood
Ahmad Rizvi,[b] Mr. Jaswant Kumar[b]
and Dr. Bhahwal Ali Shah*[a]
Page No. – Page No.
Acyl radicals from terminal alkynes:
Photoredox-catalyzed acylation of
heteroarenes
A
photoredox-mediated acylation reaction of electron deficient heteroarenes with
terminal alkynes is reported. The method relies on oxidative cleavage of
phenylacetylenes for generation of acyl radicals as a key enabling advance. The
reaction is regioselective with broad substrate scope.
This article is protected by copyright. All rights reserved.