Light-Driven Vitamin B12-Catalysed Generation of Acyl Radicals from 2-S-Pyridyl Thioesters

Article abstract of DOI:10.1002/adsc.201700913

Acyl radicals are invaluable intermediates in organic synthesis, however their generation remains challenging. Herein, we present an unprecedented light-driven, cobalt-catalysed method for the generation of acyl radicals from readily available 2-S-pyridyl thioesters. The synthetic potential of this methodology was demonstrated in the Giese-type acylation of activated olefins in the presence of heptamethyl cobyrrinate. This vitamin B₁₂ derivative proved to be the most efficient catalyst in the studied process. The developed method features broad substrate scope (38 examples), good functional group tolerance, and mild reaction conditions. Moreover, it is easily scalable (illustrated on a 20-fold scale-up procedure), enabling its preparative use. Mechanistic studies revealed that the reaction proceeds via a radical pathway with the key steps involving the formation of an acyl-vitamin B₁₂ complex and subsequent photolysis of the Co?C bond. (Figure presented.).

Full text of DOI:10.1002/adsc.201700913

Title: Light-Driven Vitamin B12-Mediated Generation of Acyl Radicals
from 2-S-Pyridyl Thioesters
Authors: Michał Ociepa, Oskar Baka, Jakub Narodowiec, and Dorota
Gryko
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201700913
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10.1002/adsc.201700913
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Light-Driven Vitamin B12-Catalysed Generation of Acyl
Radicals from 2-S-Pyridyl Thioesters
Michał Ociepa,a Oskar Baka,a,b Jakub Narodowiec,a and Dorota Grykoa*
a
Institute of Organic Chemistry Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
E-mail: dorota.gryko@icho.edu.pl
Warsaw University of Technology, Faculty of Chemistry, Noakowskiego 3, 00-664 Warsaw, Poland
b
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. Acyl radicals are invaluable intermediates in reaction conditions. Moreover, it is easily scalable
organic synthesis, however their generation remains (illustrated on 20-fold scale-up procedure), enabling its
challenging. Herein, we present an unprecedented light- preparative use.
driven, cobalt-catalysed method for generation of acyl Mechanistic studies revealed that the reaction proceeds via
radicals from readily available 2-S-pyridyl thioesters. The a radical pathway with the key steps involving the
synthetic potential of this methodology was demonstrated in formation of acyl-vitamin B12 complex and subsequent
the Giese-type acylation of activated olefins in the presence photolysis of the Co-C bond.
of heptamethyl cobyrrinate. This vitamin B12 derivative
proved the most efficient catalysts in the studied process.
The developed method features broad substrate scope (38
examples), good functional group tolerance, and mild
Keywords: cobalt • catalysis • acyl radicals • cobalamin•
Giese-type acylation
while Co(I)-porphyrinoids react with acyl surrogates
as nucleophiles.[11,12] This unique reactivity allows to
access acyl radicals from electrophilic derivatives
with redox potentials beyond the scope of commonly
used photoredox catalysts. In this line, light-driven
cobalt catalysis may provide an alternative to current
photocatalytic methods.
There are only few reports on cobalt-promoted
generation of acyl radicals. Under light irradiation
acyl-cobalt salophen complexes obtained from acyl
chlorides react with olefins furnishing ketones.[11]
Scheffold developed the electrochemical method for
the acylation of double bonds with acid anhydrides
involving acylcobalamin as an intermediate.[12]
Notwithstanding, catalytic method for cobalt-
mediated generation of acyl radicals remains
unexplored.
Introduction
In the past few decades, transition-metal catalysis
has emerged as a powerful tool for C-C bond forming
reactions. Although, 4d and 5d transition metals have
been mainly used, cobalt-catalysis provides an
environmentally benign and inexpensive alternative
to numerous noble metal catalysed transformations.[1]
In addition to its wide application in C-H activation[2]
and cross-coupling[3] reactions, it also gives a
practical access to alkyl radicals via homolytic
cleavage of weak Co-C bonds.[4] On the other hand,
generation of acyl radicals via cobalt-catalysis
remains challenging since the requirement for
reductive conditions (i.e. NaBH4, Zn, to generate
supernucleophilic Co(I)) precludes the use of
common acyl precursors (acyl chlorides, carboxylic
acid anhydrides).
Acyl radicals are of particular interest as their
nucleophilic character renders them exceptional acyl
anion equivalents.[5] Their significance is emphasized
by many applications in Giese-type additions to
activated olefins[6] and Minisci-type acylations of
heterocycles.[7] These reactive species are mainly
formed via: a) homolytic rupture of a RCO-(X)
bond,[8] b) carbonylation of carbon-centered radicals
with CO,[9] and c) decarboxylation of α-ketocarbonyl
compounds.[10] Recently, photocatalytic methods
attracted a lot of attention.[8,10] Such processes enable
to generate radical species via single-electron transfer,
Scheme 1. Co(I)-catalysed generation of acyl radicals from
2-S-pyridyl thioesters.
Herein, we demonstrate an unprecedented
application of 2-S-pyridyl thioesters as acyl-radicals
precursors in Co- catalysis (Scheme 1). To the best of
our knowledge this is also the first report featuring
the use of thioesters to generate acyl-cobalt
complexes.
1
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10.1002/adsc.201700913
Advanced Synthesis & Catalysis
Results and Discussion
Higher efficiency of porphyrinoid-type complexes
can be ascribed to their ability to stabilize radicals via
persistent radical effect.[4a,17] The higher reactivity of
thioesters (1e, 1h) compared with active esters (1c,
1d and 1f) resulted from the stronger electrophilic
character of the carbonyl group. On the basis of
background studies (for detailed optimization studies
see SI) all reaction components (catalyst, light and
reducing agent) were identified as essential.
The potential of 2-S-pyridyl thioesters as an acyl
chloride surrogates had been explored before in
Grignard reactions,[18] Ni-catalysis,[19] or SmI2
mediated generation of acyl radical anions.[20]
Nevertheless, to the best of our knowledge, this is the
first report on their use to generate acyl-cobalt
complexes and acyl radicals. The presented procedure
utilizing 2-S-pyridyl thioesters, easily accessible form
carboxylic acids, and the abundant metal-based
catalyst provides viable alternative to the previously
published Ru- and Ir-catalysed methods for the
generation of acyl radicals from α-oxocarboxylic
acids.[10] Moreover, this mode of acyl-group
activation in the Giese-type acylation is superior to
the homolytic cleavage of the C-S bond, as it
circumvents the lingering problems of competing
couplings with sulfur-centered radicals.[5,21]
Model studies
Our and others previous studies proved that vitamin
B12 - a natural Co-complex can serve as an
environmentally benign, efficient catalyst for many
types of reactions.[4b,13,14] In its Co(I)-form it reacts
with various electrophiles. Therefore, we anticipated
that nucleophilic Co(I) complexes would react with
acyl derivatives via the addition-elimination
mechanism giving acyl-cobalt derivatives, hence
providing a straightforward access to acyl radicals via
subsequent photolytic cleavage of the Co-C bond. To
this end the replacement of commonly used acyl
chlorides with their reduction stable surrogates
should facilitate an efficient, cobalt-catalysed access
to acyl radicals. Our choice of acyl derivatives was
inspired by a number of stable acylating agents
routinely used in the amide bond formation, easily
prepared from carboxylic acid, including active esters
and thioesters.[15]
Table 1. Co-catalysed reactions of acrylate 2 with various
precursors of acyl radicals.a)
Entry
Acyl
Catalyst
Yield of 3
[%]b)
reagent
-
1
2
3
4
5
6
7
8
9
(H2O)Cby+ClO4 (4a)
0
0
5
0
73
7
11
57
45
37
9
1a
1b
1c
1d
1e
1f
1g
1h
1e
1e
1e
1e
-
(H2O)Cby+ClO4 (4a)
-
(H2O)Cby+ClO4 (4a)
-
(H2O)Cby+ClO4 (4a)
-
(H2O)Cby+ClO4 (4a)
-
(H2O)Cby+ClO4 (4a)
-
(H2O)Cby+ClO4 (4a)
-
(H2O)Cby+ClO4 (4a)
(CN)Cby
Co(II)(TPP)
Co(dmgH)2(py)Cl (4d)
Co(acac)3 (4e)
(4b)
(4c)
10
11
12
0
a)
Reaction conditions: alkene 2 (0.25 mmol), acyl
derivative (1.4 equiv), catalyst (5 mol %), Zn (3 equiv),
NH4Cl (1.5 equiv), MeCN (2.5 mL), light source: blue
LEDs tape, 16 h at room temperature (19-25 ˚C) under
argon atmosphere (for more details see SI).b) Isolated yields.
TPP – tetraphenylporphyrin, dmgH – dimethylglyoxime,
acac – acetylacetonate.
Scheme 2. Investigation of acyl derivatives and catalysts.
Due to their nucleophilic character, acyl radicals
react with electrophiles, hence electron deficient
alkenes were chosen as coupling partners.[5,16]
Initially, a series of acyl derivatives (1a-1h) and
cobalt catalysts (4a-4e) were tested in the acylation of
n-butyl acrylate (2) (Scheme 2, Table 1). The
reactions with thioesters 1e and 1h furnished desired
product 3 in satisfactory yields in the presence of
porphyrin-type Co catalysts (4a, 4b, 4c, Table 1,
entries 5-8). Unsurprisingly, acyl chloride 1a and
anhydride 1b did not facilitated the formation of the
product 3.
Scope and Limitations
Using our optimized conditions, the scope and
limitations of the studied reaction were investigated.
Alkenes bearing various electron-withdrawing groups
such as esters, nitriles, sulfones, amides, and ketones
provided products (6-13) in good to excellent yields
(Scheme 3). Gratifyingly, even the electron-deficient
styrenes were reactive enough to furnish β-aryl
2
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10.1002/adsc.201700913
Advanced Synthesis & Catalysis
Scheme 3. Scope of the Co(I)-catalysed radical acylation of electron-deficient olefins. Reaction conditions: alkene (0.25
mmol), thioester 5 (1.4 equiv.), catalyst 4a (5 mol %), Zn (3 equiv.), NH4Cl (1.5 equiv.), MeCN (2.5 mL, c = 0.1 M), light
source: blue LEDs tape, rt (19-25 ˚C), 16 h, under argon atmosphere. All reported yield values are mean value of isolated
yields from at least two independent experiments. a) From dimethyl fumarate. b) From dimethyl maleate.
Scheme 4. Scope of thioesters. Reaction conditions: acrylonitrile (0.25 mmol), thioester (1.4 equiv.), catalyst 4a (5 mol %),
Zn (3 equiv.), NH4Cl (1.5 equiv.), MeCN (2.5 mL, c = 0.1 M), light source: blue LEDs tape, rt (19-25 ˚C), 16 h, under
argon atmosphere. All reported yield values are mean value of isolated yields from at least two independent experiments.
ketones (14, 15). Although the reaction is reagents.[22] Aryl, heteroaryl, and alkyl derivatives
unencumbered by the presence of substituents at the reacted equally well, affording acylated products
α-position to the electron withdrawing group (20, 21), (Scheme 4). Aryl thioesters with a range of electron-
substitution by an alkyl or aryl group at the β-position donating (23-27) as well as mildly electron-
(16, 17) led to a decrease in the product yield. This withdrawing substituents (30, 31) generated acyl
effect is not only of steric origins as the reaction with radical efficiently. While those with electron-
dimethyl fumarate afforded desired product 18 in withdrawing furnished products 32, 33 but with
excellent yields. The geometry of the double bond did diminished yield, presumably due to their higher
not influence the outcome of the reaction, since both susceptibility to reduction (for -Me Epc = -1.77 V, -
dimethyl fumarate (isomer E) and maleate (isomer Z) CF3 Epc = -1.49 V, -CN Epc = -1.36 V vs. Ag/AgCl,
provided product 18 in comparable yields.
see SI). Additionally, substitution at the ortho-
To examine the scope of thioesters, several position of the aryl ring led to a significant decrease
thioesters were prepared from the corresponding acyl in the product yield (compare products 23 and 25),
chlorides
chromatography-free
Lindsey[18b] or directly from acids using coupling
via
an
operationally
method developed
simple, presumably because of a steric hindrance imposed by
by catalyst 4a. Interestingly, even notoriously
challenging electron rich heterocycles performed
3
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10.1002/adsc.201700913
Advanced Synthesis & Catalysis
remarkably well, providing desired products in very we assume that the acylation occurs via complex C
good yields (34-36). generated in the reaction of supernucleophilic Co(I)-
It is well documented that vitamin B12 derivatives complex with thioester A, which upon light
(such as complex 4a) exhibit exquisite reactivity in irradiation undergoes homolytic cleavage, furnishing
dehalogenation
reactions,[4b,13]
thus
utilizing acyl radical D and Co(II)-complex. Subsequently,
halogenated derivatives in B12-catalyzed reactions is nucleophilic radical D reacts with electron-deficient
often plagued by the formation of a significant olefin, providing radical E, while the Co(II)-catalyst
amount of dehalogenated products. Notwithstanding, is reduced back to its Co(I)-form by Zn to maintain
in the studied reaction products bearing both bromo- the catalytic cycle.
and chloro- substituents (30, 31) were obtained
To corroborate the aforementioned mechanism
selectively. To the best of our knowledge this is the several experiments were performed. Firstly, Co(III)-
first example of such selective vitamin B12 derivative- and Co(II)-forms of catalyst 4a were tested in the
catalysed reaction with no dehalogenation being absence of the reducing agent, and in both cases
observed.
formation of product 6 was not observed. Secondly,
Furthermore, primary alkyl thioesters regardless of the presence of acyl-cobalt complex C in the reaction
the substituent tethered to the alkyl chain reacted mixture was confirmed by ESI(+) LR-MS (m/z =
equally well with acrylonitrile (37-42). Even complex 1155.7). Furthermore, the experiment with the
molecules such as a dehydrocholic acid derivative addition
of
a
radical
trap,
(2,2,6,6-
afforded compound 43 in good yield. tetramethylpiperidin-1-yl)oxyl (TEMPO, 44), led to
During our study we encountered examples of the formation of acylated TEMPO derivative 45 along
substrates being beyond the reach of the developed with traces of product 6 (Scheme 6A). Finally, when
method. The use of reductive conditions precludes the the reaction was performed with the addition of
use of compounds bearing reduction-sensitive groups ND4Cl, the deuterium incorporation occurred only at
[-CHO, -SO2F, -P(O)(OMe)2]. Moreover, sterically the α position to the electron withdrawing group
demanding substrates were found to be unreactive originating from compound 2, despite the presence of
under the developed conditions. Due to the competing two enolizable positions in the product 3 (Scheme
decarbonylation of acyl radicals,[5] thioesters with 6B).
highly electron-deficient aromatic rings or those
derived from secondary or tertiary carboxylic acids
did not give desired products.
The reaction was easily scalable and could be run
on a preparative scale (5 mmol), giving product 6 in
79% yield (Scheme 3). A 20-fold increase in the scale
of the model reaction required only prolongation of
the reaction time (40 h).
Mechanistic considerations
Scheme 6. Mechanistic studies.
The Co-C bond in alkyl and acyl vitamin B12
derivatives undergoes homolytic cleavage under
photolytic, electrolytic, or thermolytic conditions.[13]
To assess if in the studied reaction acyl radicals are
generated via the photolytic pathway, the light
ON/OFF experiment was performed (Figure 1). The
generation of product 6 only during periods of
constant irradiation supports our mechanism. The
reaction conducted in darkness for seven days
afforded product 6 in only 21% yield, suggesting
some contribution from the thermolytic pathway.
Nevertheless, all attempts to perform the reaction at
elevated temperatures with no light irradiation (40
and 60 °C) gave only traces of the acylated olefin,
mainly due to the accelerated reduction of the
thioester (see SI).
Scheme 5. Proposed mechanism of the Co(I)-catalysed
acylation of olefins.
Scheme 5 outlines the proposed mechanism of the
investigated reaction. Based on experimental
evidences, Pattenden’s[11] and Scheffold’s[12] studies,
4
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10.1002/adsc.201700913
Advanced Synthesis & Catalysis
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Conclusion
In summary, light-driven vitamin B12-mediated
reaction enabled to generate acyl radicals from
thioesters. Their stability under reductive conditions
renders them suitable electrophilic partners for the
catalytically active, supernucleophilic Co(I)-corrin.
Under light irradiation the obtained acylated Co-
complex furnishes acyl radicals that react with
electron deficient olefins via the Giese-type acylation.
Hence, vitamin B12 and its derivatives can be
considered ‘reversible carriers’ for acyl groups.
Accordingly, we hope that this research will serve as
an inspiration for further developments in vitamin
B12-catalysis.
[11] D. J. Coveney, V. F. Patel, G. Pattenden, D. M.
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Experimental Section
General procedure for the Co(I)-catalysed acylation of
electron-deficient alkenes
A glass reaction tube equipped with a magnetic element
and sealed with septum was charged with activated zinc
(50 mg, 0.75 mmol, 3 equiv.), NH4Cl (20 mg, 0.38 mmol,
1.5 equiv.) and catalyst 4a (14.5 mg, 0.0125 mmol, 5
mol%). MeCN (2.5 mL) was added and the resulting
mixture was degassed by purging the solution with argon
for 15 min with simultaneous sonication using ultrasonic
bath (solution turned from red to dark green/brown).
Subsequently, an alkene (0.25 mmol, 1.0 equiv.) and a
thioester (0.35 mmol, 1.4 equiv.) were added and the
reaction vessel was placed in a photoreactor and irradiated
with blue LED light (see SI) for 16 h under argon
atmosphere. After that time, the mixture was quenched
with Et2O, filtered through a cotton pad, and concentrated
in vacuo. A crude product was purified using column
chromatography.
Acknowledgements
Financial support for this work was provided by the Ministry of
Science
and
Higher
Education
(M.O.,
grant
no.
0141/DIA/2015/44) and National Science Foundation (D.G.,
SYMFONIA grant no. DEC 2014/12/W/ST5/00589).
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5
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10.1002/adsc.201700913
Advanced Synthesis & Catalysis
[22] B. Neises, W. Steglich, Angew. Chem. Int. Ed. 1978,
17, 522-524.
6
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Advanced Synthesis & Catalysis
FULL PAPER
Title Text
Adv. Synth. Catal. Year, Volume, Page – Page
Michał Ociepa, Oskar Baka, Jakub Narodowiec,
Dorota Gryko*
7
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