Photocatalytic Reductive Radical-Polar Crossover for a Base-Free Corey–Seebach Reaction

Article abstract of DOI:10.1002/chem.202003000

A metal-free generation of carbanion nucleophiles is of prime importance in organic synthesis. Herein we report a photocatalytic approach to the Corey–Seebach reaction. The presented method operates under mild redox-neutral and base-free conditions giving the desired product with high functional group tolerance. The reaction is enabled by the combination of photo- and hydrogen atom transfer (HAT) catalysis. This catalytic merger allows a C?H to carbanion activation by the abstraction of a hydrogen atom followed by radical reduction. The generated nucleophilic intermediate is then capable of adding to carbonyl electrophiles. The obtained dithiane can be easily converted to the valuable α-hydroxy carbonyl in a subsequent step. The proposed reaction mechanism is supported by emission quenching, radical–radical homocoupling and deuterium labeling studies as well as by calculated redox-potentials and bond strengths.

Full text of DOI:10.1002/chem.202003000

Accepted Article
Accepted Article
Title: Photocatalytic Reductive Radical‑Polar Crossover for a
Base‑Free Corey‑Seebach Reaction
Authors: Karsten Donabauer, Kathiravan Murugesan, Urša Rozman,
Stefano Crespi, and Burkhard König
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
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To be cited as: Chem. Eur. J. 10.1002/chem.202003000
Link to VoR: https://doi.org/10.1002/chem.202003000
01/2020

10.1002/chem.202003000
Chemistry - A European Journal
COMMUNICATION
Photocatalytic Reductive Radical-Polar Crossover for a Base-Free
Corey-Seebach Reaction
Karsten Donabauer,[a] Kathiravan Murugesan,[a] Urša Rozman,[a] Stefano Crespi[b] and Burkhard
König*[a]
Abstract: A metal-free generation of carbanion nucleophiles is of
prime importance in organic synthesis. Herein we report
a
photocatalytic approach to the Corey-Seebach reaction. The
presented method operates under mild redox-neutral and base-free
conditions giving the desired product with high functional group
tolerance. The reaction is enabled by the combination of photo- and
hydrogen atom transfer (HAT) catalysis. This catalytic merger allows
a C-H to carbanion activation by the abstraction of a hydrogen atom
followed by radical reduction. The generated nucleophilic
intermediate is then capable of adding to carbonyl electrophiles. The
obtained dithiane can be easily converted to the valuable α-hydroxy
carbonyl in a subsequent step. The proposed reaction mechanism is
supported by emission quenching, radical-radical homocoupling and
deuterium labeling studies as well as by calculated redox-potentials
and bond strengths.
Ketones bearing a hydroxy group in alpha position are a common
structural moiety in several natural products and potential drugs.[1]
A classical method to synthesize this class of compound is the
well-known Corey-Seebach umpolung first reported in 1965.[2] In
their seminal and subsequent work, they describe the
deprotonation of dithianes by a strong base, yielding an acyl anion
equivalent. This intermediate is capable of reacting with various
electrophiles, including carbonyl compounds opening easy
access to α-hydroxy ketones upon deprotection (Scheme 1A).[3]
A more novel approach to generate acyl anion equivalents is
N-heterocyclic carbene (NHC) catalysis.[4] However, the benzoin
self-condensation is, in some cases, a severe side reaction,
especially when a ketone is the targeted electrophile and so far,
only specific activated ketones could be used in an intermolecular
reaction using NHC catalysis.[5] Thus, the Corey-Seebach
umpolung is still widely applied for the synthesis of natural
products[6] as well as for the construction of smaller molecules
today.[7] Accordingly, over the last two decades, significant efforts
have been made to advance the dithiane method introduced by
Corey and Seebach. Among others,[8] an anion relay strategy[9]
and the combination with metal-[10] and organocatalysis[11]
(Scheme 1B) have been developed. Additionally, specific
dithianes could be used as radical precursors in photocatalytic
transformations for an addition to double bonds (Scheme 1C).[12]
Scheme 1. Corey-Seebach reaction and the use of dithianes as substrate in
different catalytic systems.
Despite the advances mentioned above, the deprotonation of
aliphatic dithianes still requires strong organometallic bases (e.g.
n-BuLi), as the masked acyl anion exhibits a pKa value of approx.
40 (1,3-dithiane in DMSO).[13] This limitation prohibits the
presence of base- and nucleophile-sensitive functional groups
such as halides, esters and nitriles. Likewise, the stoichiometric
use of an organometallic reagent generates undesired waste
including metal salts.
In order to circumvent these issues, the dithiane would need to be
activated by other means than direct deprotonation. With the C-H
bond being in alpha position to two sulfur atoms it should be
susceptible to a facile hydrogen atom transfer (HAT) opening an
alluring alternative activation pathway.[14] This solution is
especially attractive, as in recent years, the combination of photo-
and HAT-catalysis enabled the development of several novel
reactions and allowed the use of catalytic amounts of a hydrogen
abstracting reagent (HAT-catalyst) instead of a stoichiometric
quantity.[15]
[a]
K.Donabauer, Dr. K. Murugesan, U. Rozman, Prof. Dr. B. König
Department of Organic Chemistry
University of Regensburg
Universitätsstraße 31, 93053 Regensburg (Germany)
E-mail: burkhard.koenig@chemie.uni-regensburg.de
Dr. S. Crespi
[b]
Stratingh Institute for Chemistry
University of Groningen
Nijenborgh 4, 9747 AG Groningen (The Netherlands)
Last year, we reported that radicals generated by the combination
of photo- and HAT-catalysis can be reduced to render an anionic
intermediate capable of reacting with electrophiles.[16] So far, this
method was limited to substrates stabilizing the radical and the
Supporting information for this article is given via a link at the end of
the document.
1
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Table 1. Reaction optimization.[a]
anion intermediate by an aromatic group. We wondered if this
concept is applicable to aliphatic dithianes for a base-free
Corey-Seebach reaction, hence featuring a novel and improved
approach for a classic and established strategy (Scheme 1D).
Other photocatalytic methods to access carbon nucleophiles from
sp3 C-H bonds are rare, and require
a
catalytic[17] or
stoichiometric[18] amount of a chromium source. To the best of our
knowledge, the here presented method is the first example for a
photocatalytic Corey-Seebach reaction via a carbon nucleophile
under metal- and base-free reaction conditions.
Conc. 1a
[mM]
Temp.
[°C]
Yield[b] [%]
Conv.[b] [%]
Entry
Additive
3aa
1a
1
2
–
100
200
200
200
200
200
200
200
25
25
0
32
39
48
59
76
79
87
3
–
The investigation was started employing 2-methyl-1,3-dithaine
(1a) and acetone (2a) as simple model substrates (Table 1).
Gratifyingly, with 3DPA2FBN as photocatalyst and iPr3SiSH as
HAT-catalyst the product was obtained in 32% GC-yield (entry 1)
using DMF as solvent in the presence of 4 Å molecular sieve at
25 °C. Increasing the concentration (entry 2) improved the
reaction outcome slightly, while lowering the temperature to 0 °C
proved to be crucial (entry 3). The presence of bis(neopentyl
glycolato)diboron (B2neop2) as mild Lewis acid was beneficial as
well (entry 4). After completion of the reaction, degradation
products of the HAT-catalyst were observed by GC-MS. Thus, the
addition of a second catalyst loading was tested as well, resulting
in a modest yield gain (entry 5). Overall, an almost full conversion
with a good GC-yield of 73% translating into an isolated yield of
65% was achieved. Control experiments revealed the necessity
of the combination of light, photo- and HAT-catalyst (entries 6-8).
The full detailed optimization process is given in the SI.
3
–
59
4
B2neop2
B2neop2
B2neop2
B2neop2
B2neop2
0
65
5[c]
6[d]
7[e]
8[f]
0
73 (65)
n.d.
n.d.
n.d.
0
0
1
0
1
[a] Reactions were performed with 1a (200 μmol, 1 eq.) and 2a (2.00 mmol,
10 eq.) in degassed dry DMF (1-2 mL) in the presence of 4 Å molecular sieve
(50 mg) and a reaction time of 16 h. [b] Determined by GC-FID with n-decane
as internal standard. [c] After 4 h 3DPA2FBN (2 mol%) and iPr3SiSH (10 mol%)
were added, the reaction time was prolonged to 19 h. [d] Reaction stirred in the
dark. [e] In absence of 3DPA2FBN. [f] In absence of iPr3SiSH.
With the optimized conditions, the substrate scope was
established (Table 2).
Table 2. Substrate Scope.[a]
[a] Reactions were run with 1 eq. set to 200 μmol in degassed dry DMF (1 mL) in presence of 4 Å molecular sieve (50 mg). The reaction was started with 3DPA2FBN
(3 mol%) and iPr3SiSH (10 mol%). After 4 h, 3DPA2FBN (2 mol%) and iPr3SiSH (10 mol%) were added; total reaction time 19 h. [b] Acetone (2a) (10 eq.) as
electrophile. BoR-StM: Based on recovered starting material. [c] 1a (1 eq.) as nucleophile precursor. [d] 1a (3 eq.) as nucleophile precursor with the aldehyde set
to 1 eq.
2
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The reaction was successful with unsubstituted 1,3-dithiane (1b)
as the nucleophile, the alkyl chain could be prolonged (1c) and an
additional heteroatom giving rise to other potentially cleavable
C-H bonds did not hamper the reaction (1d). Indeed, the reaction
tolerates base or nucleophile sensitive cyano- (1e) and ester
functionalities (1g) as well as halogen substituted aromatic
moieties (1h-j) and an unsubstituted phenyl ring (1f).
The yield generally improves when increasing the equivalents of
the electrophile. However, a maximum yield is reached at a
specific concentration, which cannot be increased by raising the
electrophile concentration any further. Thus, evaluating the
electrophile scope, the optimal amount of reactant for every
substrate was tested. Prolonging the alkyl chain was viable (2b),
while an additional substituent in α-position decreased the yield
due to an increased steric hindrance (2c). Cyclic Ketones (2d-f)
and the presence of a heteroatom (2f) were both well accepted.
A double bond within the electrophile (2g) gave the desired
product despite a potential radical addition as side reaction and
ketones bearing a phenyl ring with various substituents (2h-k)
were all tolerated. An exception is the presence of a free –OH
group (2l), as the anionic dithiane intermediate is likely to be
protonated by the fairly acidic alcohol (pKa = 18.0 for phenol in
DMSO)[19] rather than adding to its ketone moiety. Accordingly, a
protected alcohol yielded the wanted product (2k). In terms of
nitrogen containing functionalities, a Boc-protected secondary
amine (2m), a tertiary amine (2n) and an amide (2o) were viable
electrophiles. A CF3-substituted cyclohexane (2p) gave rise to a
diastereomeric product mixture separable by chromatography. An
X-ray crystal structure could verify the structure of the syn-isomer
(syn-3ap). With a substrate containing both, an electrophilic
ketone and ester group (2q) the nucleophilic addition proceeded
exclusively at the more reactive ketone moiety, yielding the
corresponding lactone product (3aq) resulting from an attack of
the formed alcohol to the ester. Aldehydes were suitable
electrophiles as well (2r-t). In this case, an excess of dithiane was
required, due to a competing hydrogen atom abstraction at the
carbonyl group[20] leading to side reactions. (Tested low- and
non-yielding substrates are listed in section 5 of the SI).
Scheme 3. Selective functionalization of dithianes with two reactive sites.
Scheme 4. Dithiane deprotection.
The same was observed with a phenyl ring as substituent (1l). We
reasoned, that adding an electron donating methoxy substituent
(1m) should increase the reactivity of the formed nucleophilic
intermediate and indeed isolatable amounts of product 3ma were
formed in this case.
Consequently, we tested aldehydes as sterically more accessible
and reactive electrophiles for 1k-m, due to their ineffective
addition to ketones. As expected, the desired products for all three
nucleophile precursors (3kr-3mr) could be isolated in moderate
to good yields. With the reactive C-H bond of 1l and 1m being in
a benzylic position and alpha to both sulfur atoms, it is highly
susceptible to HAT and the aldehyde could be added in slight
excess. In contrast, an excess of dithiane 1k was required to
arrive at a reasonable yield of 3kr, however, most of the surplus
starting material could be recovered after completion of the
reaction (Scheme 2).
We decided to exploit these findings testing the selectivity of the
reaction (Scheme 3). A substrate bearing both, a sterically
demanding and an open dithiane site was selectively
functionalized at the more accessible position (3na). A substrate
bearing a benzylic as well as an aliphatic dithiane moiety could be
selectively functionalized at the benzylic position (3or), as the
HAT activation step is likely to occur at the C-H bond with a lower
BDE. However, an aldehyde is required as reaction partner in this
case. No product could be isolated with acetone as electrophile.
Lastly, the dithiane deprotection to valuable α-hydroxy ketones
was investigated for selected examples. Among others,
photocatalytic oxidations,[21] as well as an elegant Bi(NO3)3•5H2O
catalyzed method[22] have already been developed by other
groups. After a preliminary optimization (see SI), both strategies
afforded the desired product in good yields, with the
Bi(NO3)3•5H2O method being more efficient (Scheme 4). A
one-pot procedure starting with the photocatalytic Corey-Seebach
reaction followed by the deprotection as the second step is
possible, yet low yielding (see SI Scheme S3).
The described transformation is sensitive to steric hindrance,
especially regarding the nucleophile (Scheme 2). A sterically
demanding dithiane bearing a cyclohexyl ring (1k) could not be
added to acetone giving the desired product 3ka.
In the proposed mechanism, the oxidation of the HAT-catalyst by
the excited photocatalyst is the first step. This hypothesis was
supported by emission quenching studies indicating an interaction
between the excited 3DPA2FBN and iPr3SiSH in the presence of
4 Å molecular sieve (Figure 1A, left).
Scheme 2. Sterically hindered dithianes as nucleophile precursors.
3
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c(3DPA2FBN) = 37.5 mM
c(1a) = 5.56 mM
c(1a) = 16.7 mM
c(1a) = 27.7 mM
c(1a) = 44.3 mM
c(1a) = 71.7 mM
c(1a) = 99.0 mM
c(1a) = 153 mM
c(3DPA2FBN) = 37.5 mM
1,00
1,00
0,75
0,50
0,25
0,00
c (iPr3SiSH) = 3.10 mM
c (iPr3SiSH) = 9.30 mM
c (iPr3SiSH) = 15.5 mM
c (iPr3SiSH) = 24.7 mM
0,75
0,50
0,25
0,00
450
500
550
600
450
500
550
600
Wavelength [nm]
Wavelength [nm]
Scheme 5. Proposed mechanism.
radical anion of 3DPA2FBN and the iPr3SiS• radical after
deprotonation. The thus activated HAT catalyst abstracts a
hydrogen atom from the most labile C-H bond, which is in alpha
position to both sulfur atoms within the dithiane 1, regenerating
the HAT-catalyst and forming the corresponding radical species
1•. The photocatalytic cycle is then closed by reduction of 1•,
yielding anionic key intermediate 1-. This carbanion nucleophile is
capable to attack non-activated ketones (2) to furnish the desired
Corey-Seebach product 3 after protonation of the alcoholate.
Figure 1. A: Emission quenching of 3DPA2FBN by addition of iPr3SiSH (left)
and 1a (right). B: Radical-radical homocoupling of 1m. The reaction was
conducted in 200 μmol scale. C: Deuterium labeling experiments. Reactions run
with 1 eq. set to 200 μmol.
The same effect was not observed using 1a (Figure 1A, right) or
2a (Figure S5). The activated HAT catalyst (S-H BDE:
88.9 kcal/mol)[23] should then abstract a hydrogen atom from the
In summary, we have developed a photocatalytic Corey-Seebach
reaction operating under mild metal- and base-free conditions,
employing solely catalytic additives. Base- and nucleophile
sensitive functional groups are tolerated and ketones as well as
aldehydes are viable electrophiles giving the desired product in
moderate to good yields. The reaction is enabled by the
combination of photo- and hydrogen atom transfer catalysis. This
catalytic merger allows the activation of suitable C-H bonds to
carbanions capable of reacting with carbonyl electrophiles, the
mechanism of which is supported experimentally as well as by
calculated redox potentials and bond strengths. The anionic
intermediate seems to be less reactive than the classical lithiated
species, allowing regio- and chemo-selective transformations.
However, the exact nature of the carbanion species remains as of
now unknown and is under current investigation by time resolved
spectroscopy and in-situ NMR studies.
dithiane
substrate.
The
corresponding
radical-radical
homocoupling side product 5 could be detected by HRMS for 1m
as a selected example after the reaction reached completion. A
higher quantity could be detected by NMR when omitting the
electrophile (Figure 1B).
Ultimately,
the
reduced
photocatalyst
(E1/2 (3DPA2FBN/3DPA2FBN•–) = -1.92 V vs SCE)[24] should be
capable to transfer an electron to the dithiane radical
(E1/2 (1a•/1a•–) = -1.87 V vs SCE),[23] giving rise to the carbanion
nucleophile. Deuterium labeling studies could experimentally
support this step. With deuterated tert-butanol (tert-BuOD) as
electrophile, the expected deuterated dithiane (d-1d) could be
isolated under the standard reaction conditions with a deuterium
incorporation of approx. 70% (Figure 1C). No deuterium
incorporation was observed in absence of the photocatalyst. The
dithiane radical (C-H BDE 1a: 88.2 kcal/mol)[23] should not be
reactive enough to abstract the deuterium from tert-BuOD (O-H
BDE: 106.3 kcal/mol),[20a, 25] whereas an anionic intermediate
(pKa 1,3-dithiane approx. 40 in DMSO)[13] is expected to do so
(pKa tert-BuOH = 32.2 in DMSO[26]), clearly indicating its
formation. The generation of an ionic species from a radical
intermediate can be dubbed as radical-polar crossover and the
application of this strategy in photocatalysis is a currently growing
field in interest of several research groups.[27] As shown in
Scheme 2, the active nucleophilic species is highly sensitive to
steric hindrance and thus less reactive than expected for a
classical lithiated dithiane. Therefore, the exact nature of the
anionic intermediate is so far unknown and subject of current
investigations.
Acknowledgements
This work was supported by the German Science Foundation
(DFG, KO 1537/18-1). This project has received funding from the
European Research Council (ERC) under the European Union's
Horizon 2020 Research and Innovation Programme (grant
agreement No. 741623). We thank Dr. Rudolf Vasold for GC-MS
Measurements, Clara Scheelje for experimental assistance and
the X-Ray department for crystal structure analysis.
Keywords: Corey-Seebach • Photocatalysis • HAT-catalysis •
Radical-polar crossover • Carbanion
Based on the mechanistic studies and previous reports, following
mechanism is proposed (Scheme 5): the excited 3DPA2FBN
photocatalyst oxidizes the iPr3SiSH HAT catalyst giving rise to the
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10.1002/chem.202003000
Chemistry - A European Journal
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A photocatalytic approach for the Corey-Seebach reaction is presented. This base- and metal-free reaction exploits the combination of
photo- and HAT-catalysis furnishing the desired product under mild conditions with a high functional group tolerance. The reactive
intermediate is generated by hydrogen atom abstraction followed by radical reduction rendering a carbanion nucleophile capable of
adding to aldehydes and ketones.
6
This article is protected by copyright. All rights reserved.