Photoredox-enabled 1,2-dialkylation of α-substituted acrylatesviaIreland-Claisen rearrangement

Article abstract of DOI:10.1039/d0sc06385a

Herein, we report the 1,2-dialkylation of simple feedstock acrylates for the synthesis of valuable tertiary carboxylic acids by merging Giese-type radical addition with an Ireland-Claisen rearrangement. Key to success is the utilization of the reductive radical-polar crossover concept under photocatalytic reaction conditions to force the [3,3]-sigmatropic rearrangement after alkyl radical addition to allyl acrylates. Using readily available alkyl boronic acids as radical progenitors, this redox-neutral, transition-metal-free protocol allows the mild formation of two C(sp³)-C(sp³) bonds, thus providing rapid access to complex tertiary carboxylic acids in a single step. Moreover, this strategy enables the efficient synthesis of highly attractive α,α-dialkylated γ-amino butyric acids (GABAs) when α-silyl amines are used as radical precursors - a structural motif that was still inaccessible in related transformations. Depending on the nature of the radical precursors and their inherent oxidation potentials, either a photoredox-induced radical chain or a solely photoredox mechanism is proposed to be operative.

Full text of DOI:10.1039/d0sc06385a

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Photoredox-enabled 1,2-dialkylation of a-
substituted acrylates via Ireland–Claisen
rearrangement†
Cite this: Chem. Sci., 2021, 12, 2816
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
*
Roman Kleinmans, Leon E. Will, J. Luca Schwarz and Frank Glorius
Herein, we report the 1,2-dialkylation of simple feedstock acrylates for the synthesis of valuable tertiary
carboxylic acids by merging Giese-type radical addition with an Ireland–Claisen rearrangement. Key to
success is the utilization of the reductive radical-polar crossover concept under photocatalytic reaction
conditions to force the [3,3]-sigmatropic rearrangement after alkyl radical addition to allyl acrylates.
Using readily available alkyl boronic acids as radical progenitors, this redox-neutral, transition-metal-free
protocol allows the mild formation of two C(sp3)–C(sp3) bonds, thus providing rapid access to complex
tertiary carboxylic acids in a single step. Moreover, this strategy enables the efficient synthesis of highly
attractive a,a-dialkylated g-amino butyric acids (GABAs) when a-silyl amines are used as radical
precursors – a structural motif that was still inaccessible in related transformations. Depending on the
nature of the radical precursors and their inherent oxidation potentials, either a photoredox-induced
radical chain or a solely photoredox mechanism is proposed to be operative.
Received 20th November 2020
Accepted 7th January 2021
DOI: 10.1039/d0sc06385a
rsc.li/chemical-science
tandem Michael addition of carbon-nucleophiles to allyl acrylates
with a subsequent Ireland–Claisen rearrangement forms two new
Introduction
C–C bonds at once, which generates more complexity in one step
(Fig. 1B).10 However, these reactions oen suffer from low func-
tional group tolerance, limited substrate scope and produce stoi-
chiometric quantities of metal waste (Mg, Zn, Cu). Furthermore,
Carboxylic acids and their derivatives are among the most
common structural motifs in natural products, biologically active
compounds and materials science.1 In addition, carboxylic acids
play an important role in organic synthesis owing to their high
diversiability.1,2 Nowadays, especially decarboxylative approaches
for functional group interconversion or cross-coupling reactions
are of great importance.3 The coupling of tertiary carboxylic acids
to obtain otherwise difficult-to-access quaternary centers has
recently gained signicant attention.4 The synthesis of tertiary
carboxylic acids, however, is still challenging and oen requires
harsh reaction conditions.5 An easy and mild access to complex
tertiary carboxylic acids from readily available and simple starting
materials is therefore highly desirable.
A classical method is the a-alkylation of secondary carboxylic
acids via Ireland–Claisen rearrangement (Fig. 1A).6,7 In this reac-
tion, allyl esters are treated with strong bases such as LDA (lithium
diisopropylamide) or n-BuLi under cryogenic conditions to form an
ester enolate. This enolate is converted to the respective silyl ketene
acetal, which can undergo a [3,3]-sigmatropic rearrangement at
ambient temperature. Although this method is highly valuable
from a synthetic point of view,8 the incompatibility with base-
sensitive functional groups is adversely.9 Moreover, the main
skeleton of the carboxylic acid has to be preset. Alternatively, the
¨
¨
¨
Organisch-Chemisches Institut, Westfalische Wilhelms-Universitat Munster,
¨
Corrensstraße 40, 48149 Munster, Germany. E-mail: glorius@uni-muenster.de
Fig. 1 Background, motivation, and features of the current work. LG ¼
leaving group, RRPCO ¼ reductive radical-polar crossover.
† Electronic supplementary information (ESI) available. CCDC 2033245–2033247.
For ESI and crystallographic data, see DOI: 10.1039/d0sc06385a
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none of these methods could be applied to synthesize tertiary substrate under visible-light-mediated photocatalytic reaction
carboxylic acids.10
conditions in the presence of trimethylsilyl chloride (TMSCl).
In contrast, a modern strategy for forming C–C bonds in the b- Unfortunately, most of the common radical precursors11d did
position of electron withdrawing groups is the photoredox- not provide the desired product. Carboxylates and alkyl tri-
mediated Giese-type radical addition to Michael acceptors.11,12 uoroborates, for example, were incompatible under the reac-
The product radical can further be reduced to the corresponding tion conditions because of side reactions with TMSCl, while
carbanion, which is known as reductive radical-polar crossover halogen atom abstraction (XAT)17 approaches or the use of
(RRPCO).13 In most cases these carbanions are simply proton- Hantzsch esters almost exclusively resulted in the formation of
ated,14 and there are only a few examples, in which carbon- the respective Giese-type side product (see ESI†). Pleasingly,
electrophiles were employed to trap the anion, resulting in the utilization of the recently introduced, easily oxidizable aryl-
formation of two new C–C bonds.15,16 With that in mind, we boronates15d,18 yielded the carboxylic acid product 3a when
questioned whether it would be possible to merge photoredox- using cyclohexylboronic ester (1a) as radical progenitor and
mediated RRPCO with a subsequent Ireland–Claisen rearrange- 4CzIPN as photocatalyst (Table 1).19 The corresponding aryl-
ment using allyl acrylates as Michael acceptors (Fig. 1C). This boronates were preformed in situ by treating the readily avail-
strategy would lead to an underexplored but highly desirable 1,2- able boronic esters20 with phenyllithium (PhLi). Extensive
dialkylation of a-substituted acrylates. Owing to the typically mild optimization led to the conditions shown in entry 1, which
nature of photoredox catalysis,11 this approach was expected to afforded the desired product in 76% 1H NMR yield. Interest-
tolerate a wide range of functional groups allowing an efficient ingly, performing the reaction in solely THF signicantly
synthesis of valuable tertiary carboxylic acids.
diminished the product yield (entry 2). The use of Ir-based
photocatalysts instead of 4CzIPN decreased the yield of the
desired product (entries 3 and 4).19 In contrast to other proto-
cols employing arylboronate complexes as radical pre-
cursors,15d,18 excess PhLi was adversely (entry 5). The addition of
TMSCl is crucial for this reaction (entry 6), and even the change
to the sterically more hindered tert-butyldimethylsilyl chloride
(TBSCl) inhibited the reaction entirely (entry 7). Control exper-
iments revealed that the reaction does not proceed in the
absence of light, photocatalyst or PhLi (entry 8). For a conve-
nient and simple applicability of this transformation even on
a larger scale, conditions were sought where no solvent has to
be removed in vacuo during the reaction set-up. Nevertheless,
changing the solvent to exclusively MeCN gave the product in
83% 1H NMR and 77% isolated yield (entry 9). Furthermore,
a reaction-condition-based sensitivity screen was applied to
facilitate high reproducibility (Table 1, see ESI for more
details†).21 Apart from the expected moisture and air sensitivity,
other parameters (concentration, light intensity, temperature,
scale) had a negligible effect on the reaction outcome.
Results and discussion
We began our investigation with the evaluation of a suitable
alkyl radical precursor using allyl methacrylate (2a) as standard
Table 1 Deviation from standard reaction conditionsa
With these optimized reaction conditions in hand, we pro-
ceeded to investigate the substrate scope of this methodology
(Table 2), starting with the boronic esters. Besides the cyclo-
hexane moiety (3a), smaller and larger carbocycles could be
installed in moderate to excellent yields (3b and 3c). Up-scaling
of the reaction by a factor of 20 had only a minor effect on the
product yield (3a, and compare sensitivity assessment). Func-
tional groups, such as protected secondary amines (3d), ethers
(3e), and diuoromethylene (3f) groups were well tolerated. In
addition, a boronic ester with an indane scaffold was success-
fully tested (3g), albeit giving a lower yield. Acyclic secondary
boronic esters are also competent as demonstrated by product
3h. Tertiary boronic esters such as 1-adamantyl and a gem-
brozil (Gevilon) derivative reacted in good yields to the products
3i and 3j, respectively. Notably, this leads to two all-carbon
Entry
Deviation from standard conditions
% yield 3a
1
2
3
4
5
6
7
8
9
None
76 (74)
57
68
59
51
n.d.
n.d.
n.d.
83 (77)
THF instead of MeCN/THF (1:1)
(Ir-1) (2 mol%) instead of 4CzIPN
(Ir-2) (2 mol%) instead of 4CzIPN
2.2 equiv. PhLi
No TMSCl
TBSCl instead of TMSCl
No light (40 ꢀC), no PC or no PhLi
MeCN instead of MeCN/THF (1:1)
a
Reactions were performed on
a 0.20 mmol scale. Yields were
determined by 1H NMR spectroscopy using 1,3,5-trimethoxybenzene quaternary centers in a 1,3-distance. Primary boronic esters
as internal standard. Isolated yields are given in parentheses. n.d. ¼
not detected. See ESI for specied reaction conditions regarding the
sensitivity assessment.
are currently a limitation, presumably owing to faster decom-
position of the arylboronate complex with TMSCl (see ESI†).
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Next, we examined the allyl acrylate scope. This method not advantage of this protocol is the rapid access to highly
only allows the setting of quaternary centers in a 1,3-distance, substituted olens (3n and 3o) from simple tertiary allylic
but also in a vicinal fashion in good yields (3k and 3l). The alcohol-derived acrylate esters. Even an electron-withdrawing
construction of contiguous, all-carbon quaternary centers still chloro-substituent in the 2-position of the allyl alcohol was
remains extremely challenging, and the occurrence of this tolerated to give the desired product 3p in moderate yield.
structural motif in various natural products underpins the Additionally, an E-substituted allylic alcohol-derived acrylate
synthetic value of this transformation.22 In addition, 3l shows ester was tested. The respective product 3q was afforded in good
that ketones, as an example of base-sensitive functional groups yield, but unfortunately no diastereoselectivity was observed,
which pose a challenge in traditional Ireland–Claisen rear- which indicates that there is no geometry control during the
rangements, are well tolerated. Furthermore, this trans- silyl ketene acetal formation.7 As the next part of the allyl
formation offers highly diastereoselective access to E-olens acrylate scope, different substituents in the a-position of the
(3m) in high yield when secondary allylic alcohols are acrylate were tested. Pleasingly, a uoro-substituent was toler-
employed. This stereocontrol arises from the chair-like transi- ated, allowing the synthesis of a-uoro tertiary carboxylic acid
tion state of the Ireland–Claisen rearrangement, in which the 3r in a synthetically useful yield. These motifs are highly
substituent prefers the pseudo-equatorial position.7 Another attractive, because they can be easily converted into a variety of
Table 2 Scope of the 1,2-dialkylation of acrylatesa
a
Standard reaction conditions: 1 (2.0 equiv.), PhLi (1.9 M in dibutyl ether, 1.8 equiv.), THF (0.2 M) at 0 ꢀC to rt for 1 h, then solvent exchange to
MeCN (0.05 M), 2 (0.20 mmol, 1.0 equiv.), 4CzIPN (5 mol%), TMSCl (3.0 equiv.) at rt for 20 h under irradiation with blue LEDs (lmax ¼ 450 nm).
Isolated yields are given. 1H NMR yields were determined with 1,3,5-trimethoxybenzene as internal standard and are given in parentheses. See
b
c
ESI for full experimental details. Performed in THF/MeCN (1:1, 0.05 M). Diastereomeric ratio (d.r.) was determined by 1H NMR spectroscopy
of the crude reaction mixture. Alkyl-B(pin) ¼ alkylboronic acid pinacol ester, X-ray ¼ see ESI for the crystal structure.
2818 | Chem. Sci., 2021, 12, 2816–2822
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valuable, uorinated building blocks.23 Aryl substituents were
also tolerated and the products (3s–3v) were obtained in good to
high yields. Moreover, acyclic ethers (3w), sterically demanding
alkyl groups (3x) and also an unsubstituted a-position (3y) were
tolerated in moderate to good yields. The functional group
tolerance of this methodology was additionally demonstrated
by an additive-based robustness screen (Table 2).24 The results
show a generally high tolerance towards many functional
groups (see ESI for more details†).
Table 3 a-Silyl amine scope for the synthesis of g-amino butyric acids
(GABAs)a
To further illustrate the potential of this reaction concept, we
investigated the use of a-silyl amines25 as radical precursors for
the synthesis of tertiary g-amino butyric acids (GABAs).26 GABAs
are of broad interest because of their biological relevance as
neuromodulators and their physicochemical properties.27
Importantly, these structural motifs would be extremely diffi-
cult to access via the tandem Michael addition/Ireland–Claisen
strategy, owing to the challenging generation of unstabilized a-
amino carbanions.28 Aer optimizing the reaction conditions
with a-silyl amine 4a and allyl methacrylate (2a) as standard
substrates (see ESI†), we continued with the exploration of the
a-silyl amine scope (Table 3). In addition to morpholine (5a),
other important N-heterocycles such as thiomorpholine (5b),
and various N-substituted piperazines (5c, 5d and 5g) were
successfully tested in good to excellent yields. Besides N-
heterocycles, acyclic a-silyl amines also reacted in good yields
to the desired products 5e and 5f. A complex uoxetine (Prozac)
derivative could be installed as well (5h), highlighting the
potential of this method. Even a N-[a-(silyl)ethyl]-substituted
piperidine was suitable in this transformation and gave the
branched product 5i in moderate yield. Overall, many func-
tional groups including ethers (5a, 5g and 5h), thioethers (5b),
tertiary amines (5c, 5d and 5g), bromo-substituted pyrimidines
(5d) and amides (5g) were tolerated, making this method
applicable for the synthesis of a wide range of diverse a,a-dia-
lkylated GABAs. It is worth noting that most other methods for
the synthesis of GABAs by radical addition to acrylates are either
limited to anilines or protected amines.29
a
Standard reaction conditions: 2 (0.30 mmol, 1.0 equiv.), 4 (1.1 equiv.),
4CzIPN (5 mol%), TMSCl (0.5 equiv.), DCE (0.20 M) at rt for 14 h under
irradiation with blue LEDs (lmax ¼ 450 nm). Isolated yields are given. 1H
NMR yields were determined with 1,3,5-trimethoxybenzene or
mesitylene as internal standard and are given in parentheses.
b
c
d
Isolated as methyl ester (see ESI). Performed in THF. Performed
on
a 0.10 mmol scale with 1.7 equiv. of a-silyl amine 4h.
e
Diastereomeric ratio was determined by 1H NMR spectroscopy of the
isolated product. X-ray ¼ see ESI for the crystal structure.
reductive quenching pathway. The quantum yield of this
transformation, however, was determined to be F ¼ 2.27,31
which is not explained by a solely photoredox mechanism and
hints towards a radical chain mechanism. Comparison of the
redox potentials shows that a direct oxidation of arylboronate
complex I by the respective a-acyl radical IIc is thermodynami-
cally unfavorable (E1/2(IIc/IIꢁ) ¼ approx. ꢁ0.6 V vs. SCE in
MeCN).32 However, Lewis-acid activation of the a-acyl radical IIc
with a TMS+ species has a dramatic effect on its oxidation
potential (see species II-TMSc+, E1/2(II-TMSc+/II-TMS) ¼ +0.46 V
vs. SCE in MeCN).33 This opens up the possibility of direct
oxidation of the arylboronate complex I by the activated a-acyl
radical II-TMSc+ (Fig. 2B). We propose that in this reaction
system both, the photoredox and the radical chain mechanism,
are simultaneously operative (see ESI for more details†).
Considering the higher oxidation potentials of a-silyl amines
(E1/2(4c+/4) ¼ approx. +0.7 V vs. SCE in MeCN)25c compared to
arylboronates,15d a radical chain mechanism is thermodynam-
ically not feasible for these. The quantum yield of this reaction
variant was determined to be F ¼ 0.09,31 suggesting that
a photo-independent radical chain process is negligible,
although an inefficient chain cannot be excluded in principle.
Furthermore, different behaviors of the two reaction systems
were observed in TEMPO trapping and light on/off experiments,
Mechanistic studies
Aer demonstrating the substrate scope of this protocol, we
turned our attention towards the reaction mechanism (Fig. 2).
Based on previous reports,15d,18 the following photoredox
mechanism was proposed for the transformation with arylbor-
onates as radical precursors (Fig. 2A). Reductive quenching of
the excited photocatalyst (E1/2(PC*/PCcꢁ) ¼ +1.35 V vs. SCE in
MeCN)30 by arylboronate complex I (for R ¼ cyclohexyl, E1/2(Ic+/I)
¼ +0.31 V vs. SCE in MeCN)15d generates an alkyl radical and
PhB(pin). The alkyl radical then adds to the allyl acrylate and
reduction of the formed a-acyl radical IIc regenerates the pho-
tocatalyst (E1/2(PC/PCcꢁ) ¼ ꢁ1.21 V vs. SCE in MeCN).30 Trap-
ping of the ester enolate by TMSCl affords the silyl ketene acetal
II-TMS, which nally undergoes the desired [3,3]-sigmatropic
rearrangement. To test this hypothesis, various experiments
were conducted. First, Stern–Volmer luminescence quenching
studies revealed that only arylboronate complex I quenches the
excited photocatalyst, which is consistent with the proposed
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Fig. 2 Proposed reaction mechanisms for the two reactions systems. (A) Photoredox mechanism and (B) radical chain mechanism with aryl-
boronates as radical precursors. (C) Photoredox mechanism with a-silyl amines as radical precursors.
hinting towards a difference in the reaction mechanism (see
ESI†). Based on these results, a solely photoredox mechanism is
Acknowledgements
proposed (Fig. 2C). The a-silyl amine quenches the excited
photocatalyst reductively (see Stern–Volmer quenching studies
in the ESI†) and the resulting radical cation furnishes TMS+ and
an a-amino alkyl radical aer fragmentation.25c This nucleo-
philic radical adds to the allyl acrylate in the presence of TMS+
to generate the rst C(sp3)–C(sp3) bond. The formed a-acyl
radical is reduced by the reduced state of the photocatalyst to
afford the silyl ketene acetal intermediate. Subsequent [3,3]-
sigmatropic Ireland–Claisen rearrangement gives the desired
a,a-dialkylated g-amino butyric acid product.
´
We thank the Fonds der Chemischen Industrie (R. K., Kekule
Scholarship No.: 106151) and the Deutsche For-
schungsgemeinscha (Leibniz Award) for generous nancial
support. We also thank Frederik Sandfort, Tobias Pinkert,
Toryn Dalton, Felix Strieth-Kalthoff, Malte Schrader, and Dr
Jiajia Ma for helpful discussions, Dr Klaus Bergander for the
NMR analysis, and Dr Constantin G. Daniliuc (all WWU
¨
Munster) for the X-ray crystallographic analysis.
Notes and references
Conclusions
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carboxylic acids, by combining modern photocatalytic-enabled
RRPCO with the established [3,3]-sigmatropic Ireland-Claisen
rearrangement. This transition-metal-free and redox-neutral
protocol is especially efficient for the construction of tertiary
carboxylic acids. Owing to the mild generation of the silyl
ketene acetal intermediate, this protocol outperforms the clas-
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radical progenitors, a-silyl amines were also compatible, which
led to the formation of valuable a,a-disubstituted g-amino
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There are no conicts to declare.
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