Bioinspired Radical Stetter Reaction: Radical Umpolung Enabled by Ion-Pair Photocatalysis

Article abstract of DOI:10.1002/anie.201809601

A bioinspired, intermolecular radical Stetter reaction of α-keto acids and aldehydes is disclosed that is contingent on a formal “radical umpolung” concept. Enabled by secondary amine activation, electrostatic recognition ensures that the α-ketocarboxylic acids, which function as latent acyl radicals, are proximal to the in situ generated iminium salts. This photoactive contact ion pair is an electron donor–acceptor (EDA) complex, and undergoes facile single electron transfer (SET) and rapid decarboxylation prior to radical–radical recombination. Importantly, decarbonylation is mitigated by this strategy. The initial computational validation on which the process is predicated matches closely with experiment. Synergising organo- and photocatalysis activation principles finally expands the mechanistic and synthetic scope of the classic Stetter reaction to include α,β-unsaturated aldehydes as acceptors.

Full text of DOI:10.1002/anie.201809601

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Accepted Article
Title: Bioinspired Radical Stetter Reaction: Radical Umpolung Enabled
by Ion-Pair Photocatalysis
Authors: Tobias Morack, Christian Mück-Lichtenfeld, and Ryan Gilmour
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201809601
Angew. Chem. 10.1002/ange.201809601
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10.1002/anie.201809601
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Bioinspired Radical Stetter Reaction: Radical Umpolung Enabled by Ion-
Pair Photocatalysis
Tobias Morack, Christian Mück-Lichtenfeld, Ryan Gilmour*
Dedicated to Prof. Dr. Dieter Seebach
formation by virtue of electrostatic recognition.[13] The close proximity
Abstract: A bioinspired, intermolecular radical Stetter reaction of α-keto
of this ion pair would allow for Electron-Donor-Acceptor complex
(EDA-complex) formation,[14] which upon light excitation would
rapidly decarboxylate (-CO2) prior to radical-radical recombination
(RR). This design is conditional on radical-radical recombination out-
competing decarbonylation of the acyl radical (-CO),[15] to mitigate by-
product formation [ν(-CO2) > νRR > ν(-CO)].
acids and aldehydes is disclosed that is contingent on a formal “radical-
Umpolung” concept. Enabled by secondary amine activation, electrostatic
recognition ensures that the α-ketocarboxylic acids, which function as
latent acyl radicals, are proximal to the in-situ generated iminium salts.
This photoactive contact ion-pair is an electron-donor-acceptor (EDA)
complex, which undergoes facile single electron transfer (SET) and rapid
decarboxylation prior to radical-radical recombination. Importantly,
decarbonylation is mitigated via this strategy. The initial computational
validation on which the process is predicated matches closely with
experiment. Synergising organo- and photo-catalysis activation principles
finally expands the mechanistic and synthetic scope of the classic Stetter
reaction to include α,β-unsaturated aldehydes as acceptors.
Since its inception in 1970’s, the venerable Stetter reaction has been
synonymous with reactivity Umpolung,[1] and constitutes a powerful
approach for the construction of 1,4-dicarbonyl motifs from aldehydes
and Michael acceptors.[2] Efficient, catalysis-based strategies to
generate these versatile scaffolds are essential for downstream
heterocycle synthesis. Indeed, the prominence of Paal-Knorr routes to
furans, thiophenes and pyrroles, often in complex molecules and
pharmaceuticals,[3,4] is predicated on effective routes to the requisite
substrates. Contingent on the generation of a nucleophile from a
carbonyl source via polarity reversal (a1 → d1), the original cyanide-
catalysed transformation has been superseded by advances in N-
heterocyclic carbene catalysis (Scheme 1, top).[5] This has enabled the
development of efficient, enantioselective variants together with a
notable expansion in substrate scope. Despite this, employing α,β-
unsaturated aldehydes (e.g. cinnamaldehyde) as Michael acceptors
remains an intractable problem in Stetter chemistry.[6] Compromised by
a general lack of chemoselectivity, this problem is particularly acute in
intermolecular transformations.[7] To address this conspicuous absence,
it was envisaged that translating the conventional polar Umpolung
process to a Giese-type radical Umpolung paradigm[8] would mitigate
the intrinsic chemoselectivity challenges. This would require a formal
substitution of the anionic (a1) intermediate and Michael acceptor with
a proximal radical pair. As a conceptual blueprint, the pyruvate
dehydrogenase complex (PDC)[9] (Scheme 1, middle) provided
inspiration and recent advances in photocatalysis[10] encouraged the use
of pyruvic acid derivatives as bioinspired, acyl radical precursors.[11] In
view of the acidic nature and electron donor ability of this substrate
class, merger with iminium ion activation of cinnamaldehydes was
envisaged to enable the desired reactivity. Recent studies have
demonstrated that excited iminium ions are excellent electron
acceptors,[12] and thus pyruvic acids would play a dual role in (i)
facilitating iminium ion condensation and (ii) ensuring contact ion-pair
Scheme 1. Top: The Stetter reaction as a powerful tool for 1,4-dicarbonyl
synthesis. Centre: Pyruvate decarboxylation and acetyl-CoA synthesis in the
PDC as an inspiration for this study. Bottom: Conceptual blueprint for a radical
Stetter reaction exploiting the radical Umpolung concept.
Reaction Design: Computational Validation of the Radical
Stetter Reaction. In order to translate the design considerations for a
radical Stetter reaction into an effective protocol a model system was
conceived for theoretical and experimental validation. To satisfy
absorption requirements, cinnamaldehyde was employed as a model
acceptor together with pyrrolidine as a small molecule organocatalyst.
This would ensure that the transient photoactive iminium complex
contains a suitably extended π-system that may also favour π,π-
interactions in the EDA complex.
[a]
M.Sc. T. Morack, Dr. C. Mück-Lichtenfeld, Prof. Dr. R. Gilmour
Organisch Chemisches Institut, Westfälische Wilhelms-Universität
Münster, Corrensstraße 40, 48149 Münster, Germany.
E-mail: ryan.gilmour@uni-muenster.de
Commercially available phenylglyoxylic acid was selected as a
d1 radical source. Prior to catalysis, the system was investigated
computationally at the DFT level of theory (Scheme 2). This study
Homepage: www.uni-muenster.de/Chemie.oc/gilmour/
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indicated that the close ion pair I exhibits a vertical excitation energy
(S0 → S1 transition) of 78.5 kcal/mol for the charge transfer band (the
calculated HOMO and LUMO structures of I are shown in Scheme 2,
lower). This corresponds to an excitation wavelength of 365 nm (The
measured and computed absorption spectra are provided in the
Supporting Information). Upon excitation, the photoactive EDA
complex can undergo single electron transfer (SET) followed by
intersystem crossing (ISC, S1→T0, II). Concomitant release of CO2
generates complex III with a relative triplet energy of 19.1 kcal/mol.
Collapse of the radical pair ensures productive C(sp3)-C(sp3) bond
formation, whilst hydrolysis of the iminium ion enables catalytic
turnover.
the amount of the acid substrate marginally improved the reaction
outcome (65%, entry 6).
Next, the influence of reaction medium was investigated,
revealing that aprotic solvents generally furnish higher yields with
dichloromethane being superior to acetonitrile (55%, entry 7) and
toluene (57%, entry 8). Employing polar protic solvents, such as
methanol shuts down the reaction, presumably by compromising the
close ion pair. The postulated involvement of a close ion pair, required
for facile electron transfer, was further supported by the enhanced
yields at higher concentrations (entry 10 + 11). Indeed, performing the
reaction at 1 M led to the highest yields of the study (78%).
Consequently, the conditions described in entry 11 with CH2Cl2
(1 mol/L) were adopted for the remainder of the study.
Table 1: Reaction optimisation and identification of a suitable
secondary amine organocatalyst.[a]
Entry
Catalyst
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
Toluene
CH3OH
CH2Cl2
CH2Cl2
Equiv. of acid
c [mol/L]
0.2
Yield[a]
26%
40%
53%
63%
60%
65%
55%
57%
>5%
76%
78%
1
2
1
2
3
4
4
4
4
4
4
4
4
2
2
2
2
2
3
3
3
3
2
2
0.2
3
0.2
4
0.2
5[b]
6
0.2
0.2
7
0.2
8
0.2
9
0.2
Scheme 2: Postulated catalytic cycle based on a computation validation of the
elementary steps using pyrrolidine as the organocatalyst. Full details are
provided in the SI. Lower: Frontier orbitals of complex I (Lower left: HOMO I;
Lower right: LUMO I).
10
11
0.5
1.0
[a] Reactions were performed on a 0.1 mmol scale under UV-light irradiation at
[b]
Encouraged by these theoretical data, a model reaction was
explored under irradiation at 402 nm using a commercial LED (Table
1). Upon dissolving phenylglyoxylic acid, trans-cinnamaldehyde and
pyrrolidine (cat 1) in degassed CH2Cl2, the solution immediately
turned yellow. The reaction mixture was irradiated for 6 h at ambient
temperature. Gratifyingly, the desired 4-ketoaldehyde 1 was isolated in
26% yield (entry 1). Bolstered by this preliminary finding, a short
catalyst optimisation was initiated. The venerable MacMillan
imidazolidinones[16] (cat 2-4) were investigated (entries 2-4). The
MacMillan 1st generation catalyst proved to be most efficient yielding
the product in 63% (entry 4). It was observed that using non-degassed
solvent had a minor impact on yield (60%, entry 5), whereas increased
402 nm at ambient temperature in degassed solvents.
performed in non-degassed solvent.
Reaction was
Having established a set of general conditions for the radical
Stetter reaction, substrate scope and limitations were explored. To
establish the effect of structural modifications of the α-ketocarboxylic
acids on reaction efficiency, a variety of substrates were exposed to the
standard conditions (Scheme 3). Introduction of para-substituents on
the aryl ring was generally well tolerated (Scheme 2, 1-7, up to 71%).
Furthermore, p-alkyl derivatives were also processed smoothly to the
desired 4-ketoaldehydes 2 (p-Me, 66%) and 3 (p-tBu, 71%).
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Indeed, in the case of substrate 21, moving the methoxy substituent
from the para- to ortho-position had a beneficial effect on yield (75%).
Scheme 3. Reaction scope of the Radical Stetter Reaction: Exploring the α-
keto acid. Reactions were performed on a 0.1 mmol scale under UV-light
irradiation at 402 nm at ambient temperature in degassed CH2Cl2. Reported
yields are isolated and the average of two experiments. Selected examples on
a 0.25 mmol scale are provided in the SI. Compound 1 was prepared on a 1
mmol scale (50%).
Scheme 4. Establishing α,β-unsaturated aldehyde scope in the Radical Stetter
Reaction. Reactions were performed on a 0.1 mmol scale under UV-light
irradiation at 402 nm at ambient temperature in degassed CH2Cl2. Reported
yields are isolated and the average of two experiments. Selected examples on
a 0.25 mmol scale are provided in the SI.
Importantly, the C(sp2)-Br bond was tolerated under the reaction
conditions. Product 4 was isolated in 51% yield and offers a platform
for subsequent structural modification. The corresponding p-Cl (5), p-F
(6) and p-OMe (7) derivatives were isolated in 61%, 66% and 61%,
respectively. Next, more elaborate substitution patterns were examined.
Employing the meta-chloro regioisomer 8 was unproblematic (60%),
and substitution of hydrogen by deuterium had a negligible influence
on the yield (9, 74%). Moreover, electron-rich systems were tolerated
10 (56%) and the introduction of an ortho-substituent gave one of the
highest yields of the study (11, 79%). It was also gratifying to note that
α-oxo-2-furanacetic acid could successfully be converted to product 12
in 51%. Furthermore, simple pyruvic acid proved to be a competent
substrate for the transformation (13, 57%), thus underscoring the
tolerance of the protocol to a variety of acyl radical sources.
Whereas the o-Br substituted derivative 22 was isolated in 49%,
a reduction in yield was observed for the o-NO2 substrate 23 (26%).
This may be attributed to alteration of the photochemical properties of
the starting material. Finally, crotonaldehyde was employed in order to
establish the necessity of an extended π-system. Although 24 was
isolated in a lower yield of 25%, this example is persuasive evidence
that sufficient absorption also occurs with shorter π-systems in the
close ion-pair/EDA-complex that is key to catalysis.
To lend further support to the mechanistic hypothesis delineated
in the computational validation, a series of controls were conducted
(Scheme 5). Initially, two control experiments were sequentially
performed in (i) the absence of the secondary amine organocatalyst,
and (ii) in the absence of light. In both cases no reaction was observed
supporting the involvement of photo-excitation of the transient
iminium salt. A light on/off experiment and determination of quantum
yield Φ = 0.01 is in line with the involvement of a closed catalytic
cycle (for details and reaction progress monitoring see Supporting
Information).[17]
Crucial to the success of the study was validation of the α,β-
unsaturated aldehyde scope (Scheme 4). The effect of variation in the
para-substituent is reflected in entries 14 – 19. Halide substituted
substrates proved to be competent acceptors and were efficiently
converted to the respective 4-ketoaldehydes [61% (p-Br, 14), 69% (p-
Cl, 15) and 56% (p-F, 16)]. Whilst p-CF3 derivative 19 was isolated in
a moderate yield of 45%, more electron rich p-OCH3 (17, 65%) and p-
CH3 (18, 56%) substrates were isolated in higher yields. Disubstituted
cinnamaldehydes containing the m-OCH3 and p-OAc groups were also
smoothly processed (20, 71%). Despite the proximity to the site of
addition, ortho-substitution had little impact on the reaction outcome.
In an attempt to demonstrate the involvement of a radical
pathway, two radical clock experiments were conceived. In both cases,
one might deduce a high reaction rate of the post-decarboxylation
radical-radical recombination. Indeed, both experiments afforded a
mixture of the expected Stetter adducts (25 and 27) and the
decarbonylated, alkylation products (26 and 28). Consequently, the rate
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this manuscript to Prof. Dr. Dieter Seebach on his award of the
Arthur C. Cope Award 2019.
of radical-radical recombination must be of similar magnitude to that
of decarbonylation (5.2·107 s-1 for the formation of the benzyl radical)
of the radical clock.[15] It follows that the proximity of both reacting
partners ensures that fast recombination occurs prior to
decarbonylation.
Keywords: electrostatic • ion pair • radical • Stetter reaction •
Umpolung
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In conclusion, translation of the celebrated Stetter reaction to a
radical paradigm has enabled the selective conversion of α,β-
unsaturated aldehydes to 4-ketoaldehydes, thereby providing a solution
to a long-standing chemoselectivity problem. Diverse substitution
patterns on both reacting partners are tolerated, ranging from alkyl
groups to multi-substituted aryl groups. Informed by computational
insights, and supported by mechanistic probes, the radical Stetter
reaction is postulated to proceed via a photoactive EDA complex that
is generated by electrostatic recognition of the α-ketoacid with a
transient iminium ion. The rapid rate of radical-radical recombination
out-competes decarbonylation thereby providing a solution to the
application of α,β-unsaturated aldehydes as acceptors in this classic
transformation. Efforts to render the transformation enantioselective
are ongoing and will be reported in due course.
10.1002/ange.201803102.
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Acknowledgements
We acknowledge financial support from the WWU Münster,
Deutsche Forschungsgemeinschaft (SFB 858) and Verband der
Chemischen Industrie (Kekulé Fellowship to TM). We dedicate
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Entry for the Table of Contents
Tobias Morack, Christian Mück-
Lichtenfeld, and Ryan Gilmour*
Page No. – Page No.
Bioinspired Radical Stetter Reaction:
Radical Umpolung Enabled by Ion-
Pair Photocatalysis
Text for Table of Contents
Radical Umpolung! A bioinspired, radical Stetter reaction of α-keto acids and aldehydes is disclosed that is contingent on a formal “radical-
Umpolung” concept. Enabled by secondary amine activation, electrostatic recognition ensures that the α-ketocarboxylic acids, which function as
latent acyl radicals, are proximal to the in-situ generated iminium salts. Synergising organo- and photo-catalysis activation principles finally
expands the mechanistic and synthetic scope of the classic Stetter reaction to include α,β-unsaturated aldehyde acceptors.
This article is protected by copyright. All rights reserved.