Photoredox-Catalyzed Generation of Acetonyl Radical in Flow: Theoretical Investigation and Synthetic Applications

Article abstract of DOI:10.1021/acscatal.8b03875

A hydrogen atom transfer (HAT) step from acetone allowed the smooth generation of acetonyl radical that was then exploited as synthon in the mild formation of C-C bonds under flow conditions. The process was promoted by aryl radicals photocatalytically generated via single-electron transfer (SET) reduction of arenediazonium salts. The mechanism has been investigated by a combined experimental and computational approach and further supported by deuterium labeling experiments.

Full text of DOI:10.1021/acscatal.8b03875

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Article
Photoredox catalyzed generation of acetonyl radical in
flow: theoretical investigation and synthetic applications
Manuel Anselmo, Andrea Basso, Stefano Protti, and Davide Ravelli
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b03875 • Publication Date (Web): 01 Feb 2019
Downloaded from http://pubs.acs.org on February 1, 2019
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Photoredox Catalyzed Generation of Acetonyl Radical in Flow:
Theoretical Investigation and Synthetic Applications
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a
,a
b
,b
Manuel Anselmo, Andrea Basso,* Stefano Protti, Davide Ravelli*
a
Department of Chemistry and Industrial Chemistry, University of Genova, Via Dodecaneso 31,
16100 Genova, Italy. *E-mail: andrea.basso@unige.it
b
PhotoGreen Lab, Department of Chemistry, University of Pavia, Viale Taramelli 12, 27100 Pavia,
Italy. *E-mail: davide.ravelli@unipv.it
ABSTRACT
A Hydrogen Atom Transfer (HAT) step from acetone allowed the smooth generation of acetonyl
radical, that was then exploited as synthon in the mild formation of C–C bonds under flow
conditions. The process was promoted by aryl radicals photocatalytically generated via Single
Electron Transfer (SET) reduction of arenediazonium salts. The mechanism has been investigated
by a combined experimental and computational approach and further supported by deuterium
labelling experiments.
KEYWORDS
Photocatalysis, Hydrogen Atom Transfer (HAT), Aryl radicals, Arenediazonium salts, Acetonyl
radical.
INTRODUCTION
Arenediazonium salts are raising considerable interest as substrates in visible-light photoredox
1
2
catalyzed processes in view of the smooth preparation and the use as precursors of aryl radicals. A
few years ago, König reported the efficient use of arenediazonium salts in photo-Meerwein
3
4
reactions with styrenes, yielding amides (Scheme 1, path a) or esters (Scheme 1, path b) in a
5
multi-component fashion, depending on the nature of the adopted solvent. The methodology was
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later extended and applied to the preparation of isochromanones, via the photocatalyzed arylation
of styrene derivatives by 2-carboxy substituted arenediazonium salts (Scheme 1, path c). Shortly
after, some of us reported that similar results can be smoothly obtained starting from 2-
alkoxycarbonyl arenediazonium salts (Scheme 1, path d).7
0
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0
R1
Ru(bpy) 2
+
3
R2
(
0.5 mol%)
Ar
Ar
H
N
O
3
R2
R1
R CN / H O
2
Ar R3
a (G = H)
R1
Ru(bpy)32+
R2
h (VIS) (2 mol%)
a
G
DMF / H O
O
O
2
R2
N2+ BF4-
b (G = H)
Ar
H
Ru(bpy) 2
+
R1
3
(
1-2 mol%)
Ar
O
a
dry MeCN
O
c (G = COOH)
d (G = COOR)
Ar
Scheme 1. Photocatalyzed Meerwein reactions for the arylation of styrenes.
RESULTS AND DISCUSSION
Pursuing the studies along this line, we found that the irradiation of arenediazonium salts (e.g. the
4
-methoxybenzenediazonium tetrafluoroborate salt 1a) under analogous conditions in the presence
7
of ethyl 2-vinylbenzoate 2 (Scheme 2, path a) afforded isobenzofuranone 3. Notably, the reaction
was successfully carried out under both batch and continuous flow conditions. In this report,
however, we describe a different outcome, since batch irradiation of an equimolar mixture of 1a and
–
2
2
in acetone under dilute conditions (down to 10 M), in the presence of [Ru(bpy) ]Cl (1 mol%) as
3 2
the photoredox catalyst, does not lead to the formation of expected 3, but affords compound 4
instead (Scheme 2, path b), a known natural metabolite of cardiovascular drug n-butylphthalide,8
where a molecule of the solvent has been incorporated in the final product. Notably, we improved
the yield of 4 (up to 88% yield) by performing the reaction under continuous flow conditions (flow
rate of 10 mL·h–1).9
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O
O
a
N2+ BF -
4
Acetone
1a (0.1 M)
h
OMe
1a
MeO
(Blue LED)
3, 40%
[
Ru(bpy) ]Cl
3 2
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(
1 mol%)
O
O
b
EtO C
2
O
2
(1 equiv.)
Acetone
a (0.01 M)
1
4
, 60% (batch)
8% (flow)
8
Scheme 2. Concentration-dependent synthesis of isobenzofuranones 3 and 4.
This result convinced us to investigate more deeply into the nature of the product obtained and, on
1
0
the basis of the reactivity of aryl radicals, we reasoned that an indirect photocatalytic Hydrogen
Atom Transfer (HAT)11 mechanism could be operative.12 In our scenario, acetonyl radical
•
CH C(=O)CH2 could be generated from an acetone solvent molecule via hydrogen atom
3
•
abstraction operated by the aryl radical Ar (Scheme 3, path a) obtained from the photocatalytic
•
reduction of the corresponding arenediazonium salt (path a'). The species CH C(=O)CH could
3
2
•
•
then be trapped by the styrene moiety in 2, to form benzyl radical 5 (path b). Oxidation of 5 then
+
afforded benzyl cation 5 (path c) while restoring the photocatalyst, then ensuing intramolecular
cyclization onto the carboxylic group (path d) and elimination of the ethyl group (possibly favored
1
3
by adventitious water) gave the final product 4.
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O
O
II
2+
[
Ru (bpy) ]
3
5+
H O
OEt
2
-
EtOH
O
h
VIS)
d
O
(
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SET
c
O
O
II
2+
II
2+
[
Ru (bpy) ]
*
[Ru (bpy) ]
*
3
3
4
SET
EtO C
2
a'
- N2
ArN +
2
5
Ar
b
O
Ar H
a
CH2
EtO C
2
O
2
H
Scheme 3. Proposed mechanism for the formation of 4.
With the final aim of verifying the suggested mechanism, we supplemented the data available in the
literature with a combined theoretical and experimental investigation. The idea was that of
analyzing the key steps involved in the proposed mechanism, namely: i) the quenching of the
excited state of Ru(bpy)32+ by arenediazonium salts, ii) the hydrogen atom abstraction from the
solvent promoted by the aryl radical and iii) the addition of the photogenerated radicals, either the
original aryl radical or that deriving from the solvent, onto methyl 2-vinylbenzoate 2' (a convenient
computational model of 2).
At first, the reaction was performed, alternatively, in the absence of the diazonium salt or the Ru(II)
catalyst, as well as in the dark (irradiation omitted). In all such cases, no traces of product 4 were
detected, thus confirming that all the reaction components play a key role in the reaction and that
light is mandatory for the desired process to occur. Next, we evaluated the possibility to adopt
differently substituted arenediazonium salts in the formation of 4 (Table 1). Noteworthily, we found
that the 4-methoxy derivative 1a was the best in the series, followed by the 4-methyl one (1b),
yielding 4 in around 90 and 70% isolated yield, respectively, and with a good overall mass balance
(
see the recovery of 2). On the other hand, both the 4-fluoro (1c) and the 4-chloro (1d) derivatives,
as well as the parent benzenediazonium salt (1e), failed to give 4 in a satisfactory yield (< 50%).
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Table 1. Experimental data for the synthesis of 4 promoted by differently substituted
arenediazonium salts under optimized flow conditions (see Scheme 2).a
N2+ BF4-
EtO C
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
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0
FG
1a-e
2 (1 equiv.)
h
Blue LED)
10 mL h-1
[
Ru(bpy) ]Cl
3
2
(
(1 mol%)
Acetone
a-e (0.01M)
1
4
+ recovered 2
Diazonium salt, Yield of
Recovery
Entry
FG =
4 (%)
88
of 2 (%)
1
2
3
4
5
1a (FG = OMe)
1b (FG = Me)
1c (FG = F)
7
68
18
82
51
41
5
1d (FG = Cl)
1e (FG = H)
47
39
a
Yields are referred to isolated products after column silica gel chromatography.
Furthermore, we also repeated the reaction between 1a and 2 in acetonitrile (instead of acetone)
under otherwise identical reaction conditions (both batch and flow). Thus, we observed the
formation of isobenzofuranone 3, although in a low yield (23% under flow conditions), while only
trace amounts of the compound incorporating the solvent (6) were detected by GC-MS analysis
(Scheme 4).
h
(
Blue LED)
0 mL h-1
1
NC
N2+ BF4-
3
(23%)
EtO C
[Ru(bpy) ]Cl2
O
2
3
MeO
1a
2 (1 equiv.)
(1 mol%)
O
Acetonitrile
1a (0.01M)
6, traces
revealed by GC-MS)
(
Scheme 4. Attempts to use acetonitrile under the same reaction conditions.
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Excited photocatalyst quenching by arenediazonium salts. We initially verified the possibility
for the excited Ru(bpy)32+ photocatalyst to be oxidatively quenched by arenediazonium salts. Thus,
3
+
2+
the excited state redox potential of the photocatalyst E(Ru(bpy) /Ru(bpy) *) is largely negative,
3
3
1
4
namely – 0.86 V vs SCE. On the other hand, arenediazonium salts are known to be easily reduced
+
•
0
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0
and redox potentials E(ArN /ArN ) < + 0.5 V vs SCE have been measured, where the ease of
2
2
reduction largely depends on the electronic effect of the substituent present on the aromatic ring
(e.g. the reduction potential for the 4-nitrobenzenediazonium salt is ca. + 0.46-0.50 V vs SCE, while
15
that for the 4-methoxybenzenediazonium salt is ca. + 0.18-0.19 V vs SCE). Accordingly, in all the
examined cases the photocatalyst should be competent in triggering the desired mono-electronic
reduction step, suggesting that this step cannot be responsible for the differences in reactivity
reported in Table 1.
Hydrogen abstraction from the solvent by aryl radicals. Next, we pursued to collect evidences
of the HAT step occurring between the proposed aryl radical intermediates and the solvent. Thus,
we undertook a theoretical investigation employing the Density Functional Theory (DFT) approach.
In particular, the relevant geometries have been optimized adopting the (unrestricted) B97XD
functional with the 6-31G(d,p) basis set in the gas phase. Careful inspection of the frequency
calculations performed on the optimized geometries at the same level of theory allowed to identify
the stationary points either as minima or transition states. In the latter case, it was verified as well
that the only imaginary frequency described the motion along the desired reaction coordinate.
Finally, solvent effects were included via single point calculations adopting the implicit SMD
model and either acetone or acetonitrile as the reaction medium (see Section S4 in the Supporting
Information for further details).
Table 2. Computational data for relevant H-abstraction processes promoted by differently
substituted aryl radicals.a
O
O
H
H
H2C
H
or
+
+
FG
FG
or
H C
CN
2
Aryl Radical
CN
Solvent
G‡
Aryl Radical
FG =
G
Entry
Solvent
–
1
–1
[kcal·mol ] [kcal·mol ]
10.49 -16.68
1
4-OMe
Acetone
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4-Me
4-F
Acetone
Acetone
10.55
10.94
10.95
11.24
10.69
10.68
-15.93
-16.83
-16.69
-15.63
-16.64
-16.66
4-Cl
Acetone
H
Acetone
1
1
1
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0
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0
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0
1
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3
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9
0
1
2
3
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7
8
9
0
2-COOMe
4-OMe
Acetone
Acetonitrile
a
–1
Energy values expressed in kcal·mol at the SMD-B97XD/6-31G(d,p) level of theory in bulk acetone or
acetonitrile (see the “Solvent” column) have been reported (see Table S1 in the SI for details).
As reported in Table 2, the efficiency of (substituted) aryl radicals in promoting the HAT step from
acetone depends on the nature of the aromatic substituent, if any. Whereas all the examined
processes occur with a largely negative Gibbs free energy change (G), different trends can be
‡
identified in terms of Gibbs free energy barriers (G ). Thus, while the 4-methyl and the 4-methoxy
‡
–1
substituted aryl radicals show G values around + 10.5 kcal·mol (entries 1, 2), the 4-halogen
substituted and the unsubstituted derivatives (entries 3-6) show higher barriers, around + 11.0
–
1
kcal·mol , with the species bearing a 2-methoxycarbonyl group ranking in between (ca. + 10.7
–
1
kcal·mol ). As indicated in Table 2, entry 7, we also verified computationally the possibility to
cleave the C–H bond in acetonitrile by taking the p-methoxy aryl radical as model H-abstracting
‡
–1
species. The latter process was predicted to occur with a G value around + 10.7 kcal·mol , a
‡
–1
slightly higher barrier if compared with that of acetone (G ca. + 0.20 kcal·mol ).
Interestingly, the reaction profile of the model reaction describing the hydrogen atom abstraction
from acetone promoted by the 4-methoxyphenyl radical is reported in Figure 1, along with the
structure of the involved transition state (TS). Indeed, it is apparent that the reaction occurs with an
…
early TS, as highlighted by the shorter CH C(=O)CH H distance (1.24 Å, blue color in Figure 1)
3
2
…
than the Ar H distance (1.46 Å, orange color), a typical case of largely exergonic processes.
‡
‡
–1
Accordingly, even if small differences in G values (G < 1 kcal·mol ) have been observed
when considering the H-abstraction operated by different aryl radicals, these values can still be
considered as indicative of a different reactivity and the small gaps can be related to the intrinsic
character of the modeled processes. As a matter of fact, there is a close agreement between the
experimental data gathered in Table 1 and the computational ones in Table 2, showcasing the
importance of this H-abstraction step for the occurrence of the investigated reaction.
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Figure 1. Reaction profile of the hydrogen atom abstraction process from acetone by the 4-
methoxyphenyl radical, along with the structure of the transition state (TS, highlighted in the green
circle) and a few relevant geometric parameters.
Deuterium labelling experiments. To further confirm the role of the HAT step promoted by the
aryl radical, the reaction was carried out by using the 2-(4-methoxybenzyloxy)carbonyl
benzenediazonium salt 1f, since the 4-methoxybenzyloxycarbonyl substituent facilitated TLC
detection and chromatographic purification of the corresponding reduced derivative, while
remaining inert during the reaction. Furthermore, according to the computational data reported
above, the presence of a -COOMe group ortho- to the aryl radical site should not hamper the HAT
reactivity of this intermediate (see Table 2, entry 6). Accordingly, irradiation of 1f in acetone under
the conditions described above gave equimolar amounts of 4-methoxybenzyl benzoate 7 (73%) and
product 4 (73%; Scheme 5, upper part). On top of that, when the reaction was carried out in
–
1
hexadeuteroacetone, the process required a longer irradiation time (5 mL·h flow rate adopted) and
yielded 4-methoxybenzyl 2-deuterobenzoate 7-d and pentadeuterated product 4-d , again in
1
5
comparable yields (83 and 90%, respectively; Scheme 5, lower part). Taken together, these
experiments confirm the need to use a stoichiometric amount of the starting arenediazonium salt for
the desired process to take place, further corroborating the proposed mechanism. The kinetic
isotope effect (KIE) of the reaction was measured as well by running the same experiment in a 1:1
–
1
mixture of acetone and hexadeuteroacetone with a flow rate of 5 mL·h : the ratio of 7 and 7-d was
1
found to be 6.5:1, as determined by GC-MS analysis (a similar ratio of 4 and 4-d was found, viz.
5
7
:1), pointing out a primary kinetic isotope effect for the investigated process.
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H
O
O
10 mL h-1
CO R
2
+
+
O
N2+ BF -
2
CO R
7, 73%
4
Acetone
1f (0.01 M)
4
, 73%
1f
h (VIS)
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
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5
5
5
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0
1
2
3
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5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
D
3
(1 mol%)
D
D
D
O
O
5
mL h-1
EtO C
2
O
D D
4-d , 83%
CO R
2 (1 equiv.)
Acetone-d6
1f (0.01 M)
2
7-d , 90%
5
1
R =
O
Scheme 5. Experiments carried out to demonstrate the role of arenediazonium salts in the reaction
mechanism.
Addition of the photogenerated radicals onto 2-vinylbenzoate ester. As hinted above, we also
modeled the addition of the photogenerated radicals onto the olefinic reaction partner present in
solution, viz. methyl 2-vinylbenzoate 2', taken as a computational model of 2 (Table 3). Also, in this
case, the investigated processes can be grouped according to two different categories. The first one
describes the addition of the p-methoxyphenyl radical onto 2', a process that occurs with a very
‡
–1
small Gibbs free energy barrier (G ca. + 6.00 kcal·mol ), independently from the adopted
solvent (acetone or acetonitrile; see entries 1, 2). At the same time, the process is accompanied by a
–
1
largely negative Gibbs free energy change, around – 40 kcal·mol . By contrast, the addition of the
•
•
acetonyl radical CH C(=O)CH or the cyanomethyl radical NCCH occurs with less favorable
3
2
2
‡
–1
parameters (entries 3, 4), as highlighted by the more positive G (ca. + 10.9 and + 11.5 kcal·mol ,
–
1
respectively) and less negative G values (ca. – 20.2 and – 19.1 kcal·mol , respectively). Indeed,
these data confirm the lower tendency of the cyanomethyl radical towards the addition onto 2
‡
–1
compared to the acetonyl radical, with a G value around + 0.60 kcal·mol .
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1
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2
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2
2
2
2
2
2
3
3
3
3
3
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3
3
3
3
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4
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5
5
5
6
Table 3. Computational data for relevant radical addition processes onto methyl 2-vinylbenzoate
2'.a
R
COOMe
COOMe
+
R
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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1
2
3
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7
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9
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2
3
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7
8
9
0
2'
G‡
G
Radical
Entry
Solvent
•
[kcal·mol–1]
[kcal·mol–1]
R =
•
1
2
3
4
4-MeOC H
Acetone
Acetonitrile
Acetone
6.02
5.96
-39.27
-39.21
-20.24
-19.14
6
4
•
4-MeOC H
6
4
•
CH COCH
10.89
11.52
3
2
NCCH2•
Acetonitrile
a
-1
Energy values expressed in kcal·mol at the SMD-B97XD/6-31G(d,p) level of theory in bulk acetone or
acetonitrile (see the “Solvent” column) have been reported (see Table S2 in the SI for details).
Taken together, the computational evidences well match with the experimental outcome reported in
Table 1. First, the simulations clearly highlight the fundamental role of generating a good H-
•
abstracting species (4-MeOC H ) for the desired process to take place satisfactorily. When the 4-F,
6
4
4-Cl or 4-H aryl radicals are involved, on the other hand, the occurrence of undesired side processes
partially inhibits the reaction, probably due to a poor turnover of the catalytic system.
Furthermore, the experimental results obtained when running the reaction in acetonitrile (see
Scheme 4) can be ascribed to two main reasons, namely: i) HAT step from acetonitrile is not
occurring or ii) the cyanomethyl radical is indeed generated, but does not add to the double bond,
again inhibiting the turnover of the catalytic system and leading to poor results. Thus, the
computational analysis seems to point towards the second hypothesis, since a marked difference
between the behavior of acetone vs acetonitrile has been observed only in the second step (with a
‡
–1

G value around + 0.60 kcal·mol ). Furthermore, this is also in accordance with previous reports
in the literature, that highlighted the possibility to generate and trap both acetonyl and cyanomethyl
1
6
radicals with a methacrylamide reaction partner under similar reaction conditions. Accordingly,
we do believe that the 4-methoxyphenyl radical is indeed capable to cleave the C–H bond both in
acetone and acetonitrile, but in the latter case the radical trap employed here is not suitable for
intercepting the cyanomethyl radical, triggering the occurrence of parasite pathways that shut down
the catalytic cycle.
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Overall, provided that the optimal reaction partners are chosen, the computational work
corroborates the fundamental role of the concentration parameter. Thus, the high reactivity of aryl
radicals towards olefins can be prevented only under highly diluted conditions, in order to minimize
the chance for the aryl radical to interact and add onto the -bond trap, in turn shifting the reactivity
towards the desired HAT from the solvent.
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Intrigued therefore by the novelty of our findings and specifically by the mildness of the conditions
employed to generate the acetonyl radical, we extended this strategy to other substrates able to
undergo a similar radical cyclization. Accordingly, we tested the reactivity of ethyl
propenylbenzoate 8 (displaying a more challenging internal double bond), N-methyl-N-phenyl
methacrylamide 10 (recently employed as trap of acetonyl and cyanomethyl radicals)16,17 and
phenylpropiolate 12 under optimized reaction conditions. Indeed, the desired products, including
isobenzofuranone 9, oxindole 11 and coumarin 13 (already prepared through a similar cascade
1
8
process using excess peroxides at high temperature), were obtained in decent yields (Scheme 6).
Thus, 9 was isolated in 25% yield (55% based on the consumption of 8) in a process involving a
rather unusual (for this kind of reactions) -substituted styrene as the starting substrate. On the other
hand, irradiation of 1a in acetone in the presence of 10 afforded the desired oxindole 11 in 50%
yield (93% based on the consumption of the starting substrate), whereas ketocoumarin 13 was
isolated in discrete yield via an acetonyl radical induced cyclization of 12.
O
O
O
EtO C
2
8
(1 equiv)
1
a (0.01M)
9
, 25%
flow rate: 10 mL.h-1
(
55% based on
recovered 8)
h
N
(Blue LED)
Ph
N2+ BF -
4
O
O
10 (1 equiv)
O
1a (0.005M)
[
Ru(bpy) ]Cl2
3
N
11, 50%
flow rate: 1 mL.h-1
(1 mol%)
OMe
(93%, based on
recovered 10)
O
1a
OPh
2 (1 equiv)
O
O
Ph
1
O
1
3, 39%
1a (0.01M)
flow rate: 2 mL.h-1
Ph
Scheme 6. Acetonyl radical induced synthesis of heterocycles 9, 11 and 13.
1
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19
However, the electrophilic nature of the acetonyl radical suggested that reaction with electron-rich
olefins, such as silyl enol ethers, could be a favorable process, in turn able to afford valuable 1,4-
dicarbonyl derivatives. The photocatalytic addition of acetonyl radical to enol ether derivatives
under flow conditions could represent a mild and valuable alternative to existing procedures to
assemble such compounds.20
0
1
2
3
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7
8
9
0
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9
0
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0
To this aim, we reacted arenediazonium salt 1a with silyl enol ether 14a (derived from
acetophenone) in acetone, under the optimized continuous flow conditions described above, using a
–1
flow rate of 10 mL·h . The desired product 15a was isolated in 91% yield. The same reaction
under batch conditions afforded only 17% of the desired product after 24 hrs. On the other hand,
when acetophenone was used in place of 14a, no acetonyl radical addition occurred, as expected.
h
(Blue LED)
O
O
OTBDMS
R2
R1
R1
[Ru(bpy) ]Cl
R2
3
2
O
O
(solvent)
14a-g
(1 mol%)
1
5a-g
1a (0.01M)
O
O
O
O
O
O
O
15a (91%)
15b (79%)
15c (79%)
15d (61%)
O
O
O
O
O
O
N
H
N
O
H
1
5e (70%)
d:r 4:1
O
15g (75%)
15f (58%)
Scheme 7. Photocatalytic synthesis of 1,4-diketones via acetonyl radical.
The versatility of the proposed methodology was further demonstrated by extending the protocol to
other silyl enol ethers (14b-g), and the results are reported in Scheme 7. Noteworthy, products 15f-g
were synthesized from silyl enol ethers prepared according to a photoinduced silylative-ketene-
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three-component-reaction recently disclosed by some of us.21 Accordingly, the synthesis of
compound 15g was also optimized in a one-pot fashion. Thus, diazoketone 16, silanol 17 and
isocyanide 18 were irradiated in toluene (0.5 M) to induce the formation of the silyl enol ether 14g.
Upon consumption of the diazoketone, the solution was diluted with acetone (up to 0.01 M, based
on a theoretical 100% yield for 14g), then diazonium salt 1a and the photocatalyst [Ru(bpy)3]2+
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
–
1
were added and the resulting mixture flown through the flow apparatus at a 3 mL·h flow rate.
Compound 15g was successfully isolated, after chromatographic purification, in 40% overall yield,
thus demonstrating that the present acetonylation methodology is also compatible with crude
mixtures deriving from a multi-component process (Scheme 8). Finally, since 1,4-dicarbonyls are
extensively used in organic synthesis, for example in the Paal-Knorr reaction towards five-
2
2
membered heteroarenes, compound 15g was reacted with benzylamine in the presence of acetic
acid, giving highly functionalized pyrrole 19 in 59% yield (Scheme 8).
N2
O
OSiPh3
O
16
h (300 nm)
Ph
HN
Ph Si OH
Ph
Toluene (0.5 M)
14g
1
7
1
a (1 equiv.)
NC
18
h (Blue LED)
mL h-1 [Ru(bpy) ]Cl (1 mol%)
3
3
2
Acetone (0.01 M)
15g (40% over two steps)
Benzylamine (1 equiv.)
AcOH (1 equiv.)
MeOH, reflux
Ph
O
N
N
H
19 (59%)
Ph
Scheme 8. One-pot synthesis of 1,4-dicarbonyl 15g via silylative-ketene-three-component-reaction
and acetonylation of the resulting silyl enol ether, followed by Paal-Knorr process to give pyrrole
1
9.
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Acetonyl radical has recently attracted the scientific community for his surprisingly high
2
3
concentration in the troposphere and its role in affecting NO , HO and O cycling. However, its
X
X
3
application in synthesis is rather limited and not exempt from drawbacks. For example, its
generation is usually accomplished by employing an excess of an oxidant (hydroperoxides, MnO2)
and high temperatures as well as prolonged reaction times are commonly required.16-18,24 On the
other hand, the reaction conditions presented here require only 1 mol% of a photoredox catalyst,
together with a stoichiometric amount of a diazonium salt as the aryl radical precursor. The
generation of the acetonyl radical proceeds at room temperature in diluted solutions, and application
of a flow system, whose advantages in photocatalysis are well recognized,25 allows also for
overcoming the safety issues related to the use of diazonium salts. Furthermore, our conditions have
been proven compatible with a wide variety of (relatively unstable) silyl enol ethers.
0
1
2
3
4
5
6
7
8
9
0
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2
3
4
5
6
7
8
9
0
1
2
3
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5
6
7
8
9
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
CONCLUSIONS
In conclusion, we have reported that acetonyl radical can be generated from the combination of
arenediazonium salts and the well-known [Ru(bpy)3]2+ photocatalyst dissolved in acetone under
blue LED irradiation. The reaction proceeds via the formation of an aryl radical and subsequent
HAT from the solvent. Diluted conditions have shown to prevent the typical addition of aryl
radicals to C=C bonds and the application of a flow system has been beneficial for the reaction,
overcoming safety issues usually associated with the handling of diazonium salts and improving
reaction yields compared to the batch processes. The optimized methodology has been exploited to
highlight the synthetic relevance of this investigation, since acetonyl radical can be efficiently used
as synthon to prepare 1,4-dicarbonyl derivatives through a formal umpolung reactivity mode.
ASSOCIATED CONTENT
General experimental methods, details on experimental procedures, analytical data, computational
1
13
analyses and copies of H and C NMR spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
ACKNOWLEDGEMENTS
D.R. thanks the MIUR for financial support (SIR Project “Organic Synthesis via Visible Light
Photocatalytic Hydrogen Transfer”; Code: RBSI145Y9R). Calculations were carried out at the
CINECA Supercomputer Center (Italy), with computer time granted by ISCRA projects (code:
HP10CSWOH1).
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References
(
4
5
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7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
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2
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5
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5
6
1) For a review, see: (a) Mo, F.; Dong, G.; Zhang, Y.; Wang, J. Recent Applications of Arene
Diazonium Salts in Organic Synthesis. Org. Biomol. Chem. 2013, 11, 1582-1593; for recent
examples, see: (b) Majek M.; von Wangelin A. J. Metal-free Carbonylations by Photoredox
Catalysis. Angew. Chem. Int. Ed. 2015 54, 2270-2274; (c) Akram, M. O.; Mali, P. S.; Patil, N.
T. Cross-Coupling Reactions of Aryldiazonium Salts with Allylsilanes under Merged
Gold/Visible-Light Photoredox Catalysis. Org. Lett. 2017, 19, 3075-3078; (d) Tlahuext-Aca,
A.; Hopkinson, M. N.; Daniliuc, C. G.; Glorius, F. Oxidative Addition to Gold(I) by
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Complexes. Chem. Eur. J. 2016, 22, 11587-11592; (e) Xia, Z.; Khaled, O.; Mouriès-Mansuy,
V.; Ollivier, C.; Fensterbank, C. Dual Photoredox/Gold Catalysis Arylative Cyclization of o-
Alkynylphenols with Aryldiazonium Salts: A Flexible Synthesis of Benzofurans. J. Org. Chem.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
016, 81, 7182-7190; (f) Tlahuext-Aca, T.; Hopkinson, M. N.; Sahoo, B.; Glorius, F. Dual
Gold/Photoredox-Catalyzed C(sp)–H Arylation of Terminal Alkynes with Diazonium Salts.
Chem Sci. 2016, 7, 89-93; (g) Bottecchia, C; Rubens, M.; Gunoo, S. B.; Hessel, V.; Madder,
A.; Noël, T. Visible‐Light‐Mediated Selective Arylation of Cysteine in Batch and Flow.
Angew. Chem. Int. Ed. 2017, 56, 12701-12707.
(2) Ghosh, I.; Marzo, L.; Das, A.; Shaikh, R.; König, B. Visible Light Mediated Photoredox
Catalytic Arylation Reactions. Acc. Chem. Res. 2016, 49, 1566-1577.
(3) (a) Hari, D. P.; König, B. The Photocatalyzed Meerwein Arylation: Classic Reaction of Aryl
Diazonium Salts in a New Light. Angew. Chem. Int. Ed. 2013, 52, 4734-4743; (b) Hari, D. P.;
Hering, T.; König, B. The Photoredox‐Catalyzed Meerwein Addition Reaction: Intermolecular
Amino‐Arylation of Alkenes. Angew. Chem. Int. Ed. 2014, 53, 725-728.
(4) Yao, C.-J.; Sun, Q.; Rastogi, N.; König, B. Intermolecular Formyloxyarylation of Alkenes by
Photoredox Meerwein Reaction. ACS Catal. 2015, 5, 2935-2938.
(5) For a review on photocatalyzed multicomponent reactions, see: Garbarino S.; Ravelli, D.;
Protti, S.; Basso, A. Photoinduced Multicomponent Reactions. Angew. Chem. Int. Ed. 2016, 55,
1
5476-15484.
(6) Crespi, S.; Jäger, S.; König, B.; Fagnoni, M. A Photocatalytic Meerwein Approach to the
Synthesis of Isochromanones and Isochromenones. Eur. J. Org. Chem. 2017, 2017, 2147-2153.
(7) Anselmo, M.; Moni, L.; Ismail, H.; Comoretto, S.; Riva, R.; Basso, A. Photocatalyzed
Synthesis of Isochromanones and Isobenzofuranones under Batch and Flow Conditions.
Beilstein J. Org. Chem. 2017, 13, 1456-1462.
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(
8) Diao, X.; Deng, P.; Xie, C.; Li, X.; Zhong, D.; Zhang Y.; Chen, X. Metabolism and
Pharmacokinetics of 3-n-Butylphthalide (NBP) in Humans: The Role of Cytochrome P450s
and Alcohol Dehydrogenase in Biotransformation. Drug Metab. Dispos. 2013, 41, 430-444.
9) The in-house made flow apparatus has already been described in Ref. 7.
(
(
0
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2
3
4
5
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9
0
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2
3
4
5
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7
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9
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9
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
10)For a review, see: (a) Galli, C. Radical Reactions of Arenediazonium Ions: An Easy Entry into
the Chemistry of the Aryl Radical. Chem. Rev. 1988, 88, 765-792; for a recent example, see:
(b) Majek, M.; Filace, F.; Jacobi von Wangelin, A. Visible Light Driven
Hydro‐/Deuterodefunctionalization of Anilines. Chem. Eur. J. 2015, 21, 4518-4522.
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Complexity of the Simplest Atom Transfer Reaction. Acc. Chem. Res. 2018, 51, 2601-2602.
(
12)(a) Capaldo, L.; Ravelli, D. Hydrogen Atom Transfer (HAT): A Versatile Strategy for
Substrate Activation in Photocatalyzed Organic Synthesis. Eur. J. Org. Chem. 2017, 2017,
2056-2071; (b) Protti, S.; Fagnoni, M.; Ravelli, D. Photocatalytic C–H Activation by
Hydrogen‐Atom Transfer in Synthesis. ChemCatChem 2015, 7, 1516-1523.
(
13)The elimination of the alkyl group during the cyclization step was already discussed in Ref. 7.
14)Narayanam, J. M. R.; Stephenson, C. R. J. Visible Light Photoredox Catalysis: Applications in
Organic Synthesis. Chem. Soc. Rev. 2011, 40, 102-113.
(
(
15)(a) Koval'chuk, E. P.; Obushak, N. D.; Ganushchak, N. I.; Yanderka, P. Polarographic
Investigation of the Reduction of para-Substituted Arenediazonium Salts. J. Gen. Chem. USSR
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