Alkynylation of Csp2 (O)–H Bonds Enabled by Photoredox-Mediated Hydrogen-Atom Transfer

Article abstract of DOI:10.1002/anie.201708037

The development of new hydrogen-atom transfer (HAT) strategies within the framework of photoredox catalysis is highly appealing for its power to activate a desired C?H bond in the substrate leading to its selective functionalization. Reported here is the first photoredox-mediated hydrogen-atom transfer method for the efficient synthesis of ynones, ynamides, and ynoates with high regio- and chemoselectivity by direct functionalization of C_sp² (O)?H bonds. The broad synthetic application of this method has been demonstrated by the selective functionalization of C(O)?H bonds within complex molecular scaffolds.

Full text of DOI:10.1002/anie.201708037

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Accepted Article
Title: Alkynylation of sp2 C(O)−H Bonds Enabled by Photoredox-
Mediated Hydrogen Atom Transfer
Authors: Satobhisha Mukherjee, Aleyda Garza-Sanchez, Adrian
Tlahuext Aca, and Frank Glorius
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201708037
Angew. Chem. 10.1002/ange.201708037
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http://dx.doi.org/10.1002/ange.201708037

10.1002/anie.201708037
Angewandte Chemie International Edition
COMMUNICATION
Alkynylation of sp2 C(O)−H Bonds Enabled by Photoredox-
Mediated Hydrogen Atom Transfer
Satobhisha Mukherjee, R. Aleyda Garza-Sanchez,+ Adrian Tlahuext-Aca,+ and Frank Glorius*
Abstract: The development of new Hydrogen Atom Transfer (HAT)
strategies within the framework of photoredox catalysis is highly
appealing for its power to activate a desired C−H bond in the
substrate leading to its selective functionalization. Reported here, is
the first photoredox mediated Hydrogen Atom Transfer protocol for
the efficient synthesis of ynones, ynamides and ynoates with high
regio- and chemoselectivity by direct functionalization of sp2 C(O)–H
bonds. The broad synthetic application of this method has been
demonstrated by the selective functionalization of C(O)–H bonds
within complex molecular scaffolds.
The growing interest in visible-light mediated photoredox
catalysis stems from its ability to promote bond formation under
mild reaction conditions. Despite considerable advances in the
field of HAT mediated photocatalytic activation of different
C(sp3)–H bonds,1,2 the corresponding protocols for the selective
activation of sp2 C(O)–H bonds has remained comparatively
Scheme 1. Synthesis of ynones, ynamides and ynoates via carbonyl
radical intermediates. EBX, ethynylbenziodoxolone.
underdeveloped.3 Aldehydes are cheap and commercially
available, which makes them abundant surrogates for the facile
relative bond dissociation energies (BDE) of these C−H bonds
[BDE for C(sp3)−H= 96.5 kcal/mol vs BDE for sp2 C(O)–H= 89.4
kcal/mol]10 would impart kinetic selectivity in such an abstraction
generation of acyl radicals. The strategies, reported to date,
utilize either superstoichiometric amounts of strong oxidant4 or
harsh reaction conditions such as high temperatures,5 or UV-
event leading to the selective generation of an acyl radical.
light irradiation,6 in order to generate acyl radical by direct
Ynones, ynamides and ynoates are important structural motifs,
homolysis of the C(O)–H bond, thereby limiting such processes
that occur in various biologically active molecules and serve as
mainly to the aromatic aldehydes (Scheme 1a). These major
useful synthons for the synthesis of various natural products and
drawbacks have prompted the development of a catalytic
heterocycles.11 Traditional methods for the synthesis of such
system that would enable the generation of acyl radicals under
compounds often suffer from low functional group tolerance,
milder reaction conditions, hence providing a versatile platform
limited substrate scope, and in some cases practical
that can be extended also to the branched aliphatic aldehydes
inconvenience.12-14 With the genesis of single electron transfer
and other XC(O)–H (X= N, O) bonds, which are known to
undergo facile decarbonylation under harsh reaction conditions.7
catalysis in recent years, new strategies have been delineated
for the effective synthesis of these compounds in which the
The success of such protocol primarily relies on the choice of a
carbonyl radical is generated either by decarboxylation of alpha
proper HAT catalyst, that could chemoselectively abstract
keto acid,15,16 or OC–alkyl bond cleavage of β carbonyl alcohols
(Scheme 1a).17 However, such methodologies require prior
hydrogen from a C(O)–H bond over a multitude of other C–H
bonds present in the molecule.8 In this context, our laboratory
substrate functionalization, thereby displaying low atom and step
has recently demonstrated that benzoate can serve as a HAT-
economy. Herein, we report photoredox mediated HAT strategy
catalyst upon oxidation by a photoredox catalyst, leading to the
selective functionalization of the unactivated C(sp3)–H bonds.9
direct C(O)–H bond alkynylation with electrophilic EBX
On basis of this observation, we wondered, whether it would be
for the efficient synthesis of ynones, ynamides and ynoates by
(ethynylbenziodoxolone) reagents which are known to serve as
possible for such a benzoyloxy radical to selectively abstract
facile radical acceptors.18, 15d (Scheme 1b).
hydrogen from C(O)–H bond in the presence of other C(sp3)–H
To test our hypothesis, we took cyclohexanecarbaldehyde (A)
bonds in the molecule. We envisioned that the exploitation of the
as our test substrate, and subjected it to an analogous catalytic
system that was reported in our previous work9 −10 mol% of
sodium
2-iodobenzoate19
and
2
mol%
=
of
[Ir(dF(CF3)ppy)2(dtbbpy)]PF6 (Ir-F, (dF(CF3)ppy)
2-(2,4-
[*]
S. Mukherjee, R. A. Garza-Sanchez,[+] A. Tlahuext-Aca,[+] Prof. Dr.
F. Glorius
difluorophenyl)-5-(trifluoromethyl)pyridine, dtbbpy = 4,4’- di-
tertbutyl-2,2’-bipyridine) PC I (IrIII*/IrII = 1.21 V vs SCE) in the
presence of EBX reagent (B). The desired product was formed
in only 10% yield (Table 1, entry 1). After a solvent screen, we
switched to 1,2-dichloroethane (entry 2) and an improved yield
was observed at higher concentration (entry 3).
Organisch-Chemisches Institut
Westfälische Wilhelms-Universität Münster
Corrensstrasse 40, 48149 Münster (Germany)
E-mail: glorius@uni-muenster.de
[+]
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201708037
Angewandte Chemie International Edition
COMMUNICATION
Table 1: Optimization of reaction conditions.
Entry
1
Photocatalyst
PC I
Solvent
MeCN
Conc.
0.2 M
0.2 M
0.4 M
0.4 M
0.4 M
0.4 M
0.4 M
0.4 M
Yield(%)d
10
15
18
45
85
−
2
PC I
DCE
DCE
3
PC I
DCE
DCE
DCE
DCE
DCE
4
PC II
PC II
PC II
−
5a
6b
7
trace
−
8c
PC II
General reaction conditions: A (0.15 mmol), B (0.10 mmol), photocatalyst (2
mol%), sodium 2-iodobenzoate (10 mol%), additive (30 mol%), in DCE (0.4 M)
under Ar with 5W blue LED irradiation at room temperature for 24 h, unless
otherwise noted. Reaction conditions: a) in presence of 30 mol% of BIOAc, b)
in absence of light, c) in absence of sodium 2-iodobenzoate, d) Isolated yield.
BI, benziodoxolone; LED, light-emitting diode; DCE, 1,2-dichloroethane;
Conc., Concentration.
A
more oxidizing photocatalyst [Ir(dF(CF3)ppy)2(5, 5′-
dCF3bpy)]PF6 (bpy = 2,2’-bipyridine) (IrIII*/IrII = 1.68 V vs SCE)
PC II1f was found to be superior, which resulted in a substantial
improvement of the yield to 45% (entry 4). Addition of BIOAc
(BI= benziodoxolone) as an additive gave 85% (entry 5) of the
desired product (vide infra).
Scheme 2. Scope of the alkynylation reaction. A) Alkynylation of the aliphatic
aldehydes. B) Alkynylation of the benzaldehyde with various EBX reagents. C)
Alkynylation of XC(O)–H (X= N, O) bonds. General reaction conditions: A
(0.45 mmol), B (0.30 mmol), photocatalyst (2 mol%), sodium 2-iodobenzoate
(10 mol%), BIOAc (30 mol%), in 1,2-dichloroethane (0.4 M) under Ar with 5W
blue LED irradiation at room temperature for 24 h, unless otherwise noted. a)
reaction time was 48 h. EBX, ethynylbenziodoxolone; TIPS, triisopropylsilyl.
With the optimized conditions in hand, we sought to explore
the generality of this alkynylation reaction (Scheme 2A). The
reaction was tested with respect to other aliphatic aldehydes,
they gave the alkynyltation products 2-10 in decent yields.
Gratifyingly, the tertiary aldehyde gave the corresponding
alkynylated product 11 exclusively in 90% yield, and
decarbonylated side product was not observed.20 Aromatic
aldehydes were also found to be compatible under the reaction
conditions giving the alkynylated products 12−18 in decent
yields.
The TIPS protected alkyne is of particular importance as it
provides a versatile synthetic platform for further modifications
(Scheme 3). The corresponding products 29–33 were isolated in
decent yields.
The utility of our mild synthetic strategy was next
demonstrated by its successful application in late-stage
fuctionalization of complex molecules via selective alkynylation
of the C(O)−H bonds of various biologically active molecules
using the EBX-TIPS reagent. Cholesterol derivative and the
lithocholic acid derivative were selectively alkynylated to give the
products 34 and 35 in high yields of 78% and 72%, respectively.
The pharmaceuticals probenecid, and adapalene derivative
when subjected to the alkynylation reaction, they gave the
products 36 and 37 in 56% and 48% yields, respectively. The
robustness and functional group tolerance of this reaction was
additionally studied by performing an additive based robustness-
screen (See SI).
The substrate scope was also explored with respect to the
EBX reagents (Scheme 2B). Various aryl-substituted EBX
reagents worked well under the reaction condition. Giving the
corresponding products 19−22 in 67−75% yields. The EBX-TIPS
reagent gave the corresponding acylated product 23 in 70%
yield.
The potential of this synthetic method was further
demonstrated by the selective functionalization of other
XC(O)−H (X= N, O) bonds, which is not well explored in
synthetic radical chemistry (Scheme 2C). The facile formation of
ynamides 24, 25, and 26 in 56−67% yields was achieved.
Additionally, the oxygen analogoues 27 and 28 were also
formed, albeit in lower yields.
To gain mechanistic insight into the above transformation, a
luminescence-quenching experiment was carried out (see SI).
The 2-iodobenzoate was found to be the only reaction
component that was quenching the excited photocatalyst. Next,
a radical trap experiment with TEMPO was carried out. In this
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10.1002/anie.201708037
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COMMUNICATION
Scheme 5: Plausible mechanism.
In conclusion, we succeeded in develop a mild photoredox
mediated Hydrogen Atom Transfer strategy for the successful
generation of carbonyl radicals by direct homolysis of C(O)−H
bonds and their subsequent trapping with electrophilic EBX
reagents. The method exhibits excellent substrate scope and
functional group tolerance and has been successfully extended
to secondary and tertiary aldehydes and to other XC(O)–H (X=
N, O) bonds.The amenability of this method to be used as a late-
stage functionalization tool has been shown by selective
functionalization of C(O)−H bonds in complex molecules. We
hope, that the strategy will find further applications in the field of
organic synthesis.
Scheme 3: Alkynylation of complex molecules. General reaction conditions:
aldehyde (0.30 mmol), TIPS reagent (0.45 mmol), photocatalyst (2 mol%),
sodium 2-iodobenzoate (10 mol%), BIOAc (30 mol%), in 1,2-dichloroethane
(0.4 M) under Ar with 5W blue LED irradiation at room temperature for 48 h,
unless otherwise noted. Reaction Conditions: a) reaction carried out in 0.1
mmol scale, b) 0.2 M reaction concentration.
case, the formation of the alkynylated product was completely
inhibited and the TEMPO adduct 38 was observed by high
resolution mass spectrometry (Scheme 4).
Acknowledgements
We thank Dr. Lisa Candish, Dr. A. Gómez-Suaréz and Michael
Teders for helpful discussions. Generous financial support from the
NRW Graduate School of Chemistry (A.T.A.) and the Deutsche
Scheme 4: Mechanistic experiment.
Forschungsgemeinschaft
acknowledged.
(Leibniz
Award)
are
gratefully
Based on the above results, we propose the following
mechanism (Scheme 5). The 2-iodobenzoate (A) is reductively
quenching the excited photocat-alyst IrIII* to IrII, with concomitant
oxidation to the 2-iodobenzoyloxyl radical (B). At room
temperature the 2-iodobenzoyloxyl radical (B) can undergo
hydrogen atom abstraction from the C(O)−H bond, thereby
forming the carbonyl radical (C), which adds to the EBX reagent
to give the product with simultaneous elimination of
benziodoxolonyl radical (D).15a At this stage, two pathways are
possible, the benziodoxolonyl radical (D) can either accept an
electron from the reduced photocatalyst and regenerating both
Keywords: • carbonyl radicals • C-H activation • Hydrogen Atom
Transfer • hypervalent compounds • photocatalysis
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Entry for the Table of Contents
COMMUNICATION
S. Mukherjee, R. A. Garza-Sanchez,[+]
A. Tlahuext-Aca,[+] Prof. Dr. F.
Glorius*
Page No. – Page No.
Alkynylation of sp2C(O)–H Bonds
Enabled by Photoredox-Mediated
Hydrogen Atom Transfer
Tip your HAT to light: Photoredox catalysed Hydrogen Atom Transfer (HAT)
mediated protocol has been developed for the successful generation of carbonyl
radicals from aldehydes and analogous compounds with XC(O)–H (X= N, O) group.
The successful trapping of the carbonyl radicals with ethynylbenziodoxolone (EBX)
reagents provides a route for the synthesis of ynone, ynamides and ynoates from
readily available starting material.
I
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