Umpolung Strategy for α-Functionalization of Aldehydes for the Addition of Thiols and other Nucleophiles

Article abstract of DOI:10.1002/anie.201911793

Nucleophile–nucleophile coupling is a challenging transformation in organic chemistry. Herein we present a novel umpolung strategy for α-functionalization of aldehydes with nucleophiles. The strategy uses organocatalytic enamine activation and quinone-promoted oxidation to access O-bound quinol-intermediates that undergo nucleophilic substitution reactions. These quinol-intermediates react with different classes of nucleophiles. The focus is on an unprecedented organocatalytic oxidative α-thiolation of aldehydes. The reaction scope is demonstrated for a broad range of thiols and extended to chemoselective bioconjugation, and applicable to a large variety of aldehydes. This strategy can also encompass organocatalytic enantioselective coupling of α-branched aldehydes with thiols forming quaternary thioethers. Studies indicate a stereoselective formation of the intermediate followed by a stereospecific nucleophilic substitution reaction at a quaternary stereocenter, with inversion of configuration.

Full text of DOI:10.1002/anie.201911793

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Accepted Article
Title: Novel Umpolung Strategy for α-Functionalization of Aldehydes for
the Addition of Thiols and other Nucleophiles
Authors: Karl Anker Jørgensen, Jakob Blom, Gabriel J. Reyes-
Rodríguez, Henriette N Tobiesen, Johannes N Lamhauge,
Marc V Iversen, Casper L Barløse, Niels Hammer, and
Matilde Rusbjerg
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201911793
Angew. Chem. 10.1002/ange.201911793
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10.1002/anie.201911793
Angewandte Chemie International Edition
RESEARCH ARTICLE
Umpolung Strategy for -Functionalization of Aldehydes for the
Addition of Thiols and other Nucleophiles
Jakob Blom,[a] Gabriel J. Reyes-Rodríguez,[a] Henriette N. Tobiesen,†,[a],[b] Johannes N. Lamhauge,†,[a]
Marc V. Iversen,†,[a] Casper L. Barløse,[a] Niels Hammer,[a] Matilde Rusbjerg,[a] and Karl Anker
Jørgensen*,[a]
Abstract: Nucleophile-nucleophile coupling is
a
challenging
evolved. In particular, umpolung of enamines has broadened the
scope of conventional enamine catalysis.[1]
Based on a single-electron transfer oxidation, MacMillan et al.
introduced the concept of SOMO activation, where an enamine is
oxidized in situ generating a radical-cation intermediate (Scheme
1c). This activation principle has provided attractive strategies for
transformation in organic chemistry. Herein we present a novel
umpolung strategy for -functionalization of aldehydes with
nucleophiles. The strategy uses organocatalytic enamine activation
and quinone-promoted oxidation to access O-bound quinol-
intermediates that undergo nucleophilic substitution reactions. These
quinol-intermediates react with different classes of nucleophiles. The
focus is on an unprecedented organocatalytic oxidative -thiolation of
aldehydes. The reaction scope is demonstrated for a broad range of
thiols and extended to chemoselective bioconjugation, and applicable
to a large variety of aldehydes. This strategy can also encompass
organocatalytic enantioselective coupling of -branched aldehydes
-alkylations, -allylations, -vinylations, -alkynylations, and
-
arylations of aldehydes.[2] However, its applicability towards
functionalizations with classical polar nucleophiles is limited.[2f]
Recently, we have turned our attention towards oxidative
umpolung strategies of enamines and dienamines and disclosed
various oxidants for such approaches.[3]
with thiols forming quaternary thioethers. Studies indicate
stereoselective formation of the intermediate followed by
a
a
stereospecific nucleophilic substitution reaction at a quaternary
stereocenter, with inversion of configuration.
Introduction
A reaction between a nucleophile and an electrophile forming a
covalent bond is a fundamental transformation in chemistry. In
contrast, the bond formation between two nucleophiles is much
more challenging as their electronic nature makes them inherently
incompatible (Scheme 1a). To overcome this, an oxidative
umpolung strategy can be applied by which an in situ oxidation
inverts the electronic properties of one of the nucleophiles
(Scheme 1b).
The reactivity of the -position of a carbonyl functionality is
typically determined by its nucleophilic nature, traditionally as an
enol/enolate intermediate, however, it can be converted into an
activated electrophile. Recently, an increasing interest in
umpolung strategies in combination with organocatalysis has
Scheme 1. a) Incompatible coupling of two nucleophiles. b) The oxidative
umpolung concept for the coupling of two nucleophiles. c) SOMO activation by
radical-cation intermediates. d) This work: Quinone-mediated oxidation of
enamines to facilitate umpolung of the -position of aldehydes.
A
particularly interesting class of oxidants are the 1,4-
benzoquinones which have been used as oxidative promoters of
both carbon-carbon and carbon-heteroatom bonds.[4,5] An
important aspect of the quinone-mediated oxidative
transformations is the formation of covalent quinone adducts,
which have been proposed as crucial intermediates in e.g.
dehydrogenation reactions.[5] A major challenge in generating
covalent quinone intermediates is the diverse reactivity of the
quinones, allowing for formation of various regioisomers. Studies
have shown that several quinone adducts can co-exist as
intermediates, each of which may give access to different reaction
pathways.[6] Mayr et al. investigated the product distribution in
reactions of -nucleophiles (primarily silyl-enol ethers) with
quinone derivatives and found that product mixtures of C- and O-
bound adducts were obtained.[7] Regiocontrol can be enforced,
but requires a perfect match between steric and electronic
properties of both quinone and nucleophile, as well as kinetic
versus thermodynamic control of the reaction. Recently List et al.
[a]
J. Blom, Dr. G. J. Reyes-Rodríguez, H. N. Tobiesen, J. N.
Lamhauge, M. V. Iversen, C. L. Barløse, Dr. N. Hammer, M.
Rusbjerg, and Prof. Dr. K. A. Jørgensen
Department of Chemistry
Aarhus University
Langelandsgade 140, 8000 Aarhus C, Denmark
E-mail: kaj@chem.au.dk
H. N. Tobiesen
Research Chemistry, Global Research Technologies
Novo Nordisk A/S
Novo Nordisk Park, 2760 Maaloev, Denmark
These authors contributed equally.
[b]
†
The data supporting the findings of this study are available in the
article and its Supporting Information. Crystallographic data for the
structures of ()-2dII and (S)-4ad are available free of charge from
the Cambridge Crystallographic Data Centre
(https://www.ccdc.cam.ac.uk/) under references CCDC 1916306
and CCDC 1916307, respectively.
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10.1002/anie.201911793
Angewandte Chemie International Edition
RESEARCH ARTICLE
disclosed an unexpected formation of O-bound quinol-adducts
resulting from a phosphoric acid catalyzed functionalization of -
substituted cyclic ketones with un-activated 1,4-benzoquinones.[8]
These O-bound quinol-adducts were found to be persistent
enough to allow for isolation and were isolated in moderate yields.
Notably, O-bound quinol-intermediates are generally considered
deleterious and of no synthetic utility due to their reported inability
to facilitate dehydrogenation transformations.[5,6] In the following,
we will demonstrate that these intermediates are more useful than
what is the general conception in quinone-mediated oxidations
and that their potential for further functionalization have been
overlooked. Furthermore, we will disclose the development of a
novel umpolung strategy for -functionalization of aldehydes
based on quinone-mediated oxidation of enamines (Scheme 1d).
Early exploration of its mechanistic aspects led to the discovery
of -substituted quinone-aldehyde adducts and allowed us to
identify O-bound quinol adducts as unprecedented reactive
intermediates in -functionalizations of aldehydes. It will be
shown that these O-bound adducts provide access to reactions
that are not possible with outer-sphere oxidants, and that -
required prolonged reaction times and provided moderate
conversions, while 2-phenylpropanal 1d, as well as the electron-
poor aldehyde 1e gave low conversion to the corresponding
quinol-intermediates (entries 2-5). Employing quinones with lower
reduction potentials, such as tetrachloro-p-benzoquinone
(chloranil) and tetrafluoro-p-benzoquinone (fluoranil) failed to
provide sufficient reactivity, even in combination with the most
reactive aldehyde 1a (entries 6,7). We were pleased to find the
application of aminocatalyst 3a promoted the oxidation of
aldehyde 1d and allowed for use of less-activated quinones as
oxidants (entries 8-10). The use of a phosphoric acid catalyst also
provided the desired quinol-intermediate from aldehyde 1d, albeit
in lower conversion (entry 11, vide infra). For the screening of
other organocatalysts, such as secondary and tertiary amines,
see Supporting Information.
Table 1. Reaction of aldehydes with quinones under various reaction conditions.
substituted
O-bound
quinol-aldehyde
adducts
present
conceivable potential as electrophilic intermediates for
substitution reactions.[9,10]
In comparison to the single-electron oxidative approach of SOMO
activation, using O-bound quinol adducts as electrophilic
intermediates offers a novel complementary reactivity. The single-
electron oxidation of the enamine in SOMO activation generates
a radical-cation as the reactive umpolung intermediate which
reacts with SOMOphiles as single-electron donors. However, with
the use of an O-bound quinol adduct, classical polar substitution
reactivity can be obtained, allowing for the use of simple and
readily available nucleophiles. The potential of these
intermediates in coupling reactions is demonstrated with thiol
nucleophiles, which are normally incompatible with oxidative
conditions. The reaction is general for a very broad range of thiols
and aldehydes forming tertiary and quaternary stereocenters, as
well as tolerant towards biologically relevant thiols such as
cysteine derivatives and a peptide. Furthermore, this novel
reactivity opens up for an enantioselective organocatalytic
protocol providing optically active -functionalized aldehydes with
thiol nucleophiles. An important aspect of the present work is the
transfer of chiral information. It has been found to occur by an
aminocatalyzed formation of an enantioenriched O-bound quinol-
intermediate, and a subsequent stereospecific nucleophilic
Entry
1
Aldehyde
Ar
6-MeO-
Naphth
(1a)
Naphth
(1b)
p-MeOPh
(1c)
Quinone
DDQ
Catalyst
(mol%)
-
Time
(h)
Conv.
(%)[a]
Yield
(%)[a]
2aI
85
1
>95
-
-
-
-
-
2bI
48
2cI
20
2dI
6
2
3[b]
4
DDQ
DDQ
DDQ
DDQ
20
20
20
20
70
64
6
Ph (1d)
p-NO2Ph
(1e)
6-MeO-
Naphth
(1a)
6-MeO-
Naphth
(1a)
2eI
6
5
8
2aII
-
6
chloranil
20
n.r.
2aIII
<5
7
8
9
fluoranil
DDQ
-
7
1
7
2dI
85
Ph (1d)
3a (10)
3a (10)
>95
>95
6-MeO-
Naphth
(1a)
6-MeO-
Naphth
(1a)
2aII
27
chloranil
23
2aIII
81
10
11
fluoranil
DDQ
3a (10)
3
>95
49
(PhO)2PO2H
(10)
2dI
34
Ph (1d)
21
displacement on
a quaternary center with inversion of
configuration.[11] Finally, some key mechanistic insights are
discussed.
Performed on 0.10 mmol scale. [a] Conversion and yields measured by 1H NMR
of the crude reaction mixture relative to an internal standard (methyl 4-methyl-
3-nitrobenzoate). [b] Performed on 0.05 mmol scale.
During the development of the reaction concept, we were pleased
to realize that we were able to isolate and characterize the O-
bound quinol-intermediates 2dI,hI,dII. The structure of the
intermediates were confirmed by X-ray analysis of (±)-2dII
(Scheme 2a, see Supporting Information). This demonstrates that
the former nucleophilic -carbon in the enamine is selectively
converted into an activated electrophile by an overall two-electron
oxidation upon reaction with the quinone.
Results and Discussion
We set out to investigate the potential formation of O-bound
quinol-intermediates generated by reaction of aldehydes 1a-e
with quinones (Table 1). 2-(6-Methoxynaphthalen-2-yl)propanal
1a underwent full conversion into the quinol-intermediate 2aI in
the presence of 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ)
and absence of benzhydrylamine 3a as the aminocatalyst (entry
1). Aldehydes which were found to be less activated, such as 1b,c,
As shown in Table 1, 2-(6-methoxynaphthalen-2-yl)propanal 1a
underwent full conversion into the O-bound quinol-intermediate
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10.1002/anie.201911793
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RESEARCH ARTICLE
2aI in the absence of benzhydrylamine 3a. Attempts to isolate 2aI
were unsuccessful due to the inherent reactivity of the compound.
Encouraged by this, 2aI was reacted with simple nucleophiles to
provide the corresponding coupling products (Scheme 2b). We
were pleased that thiophenol reacted smoothly forming 4aa in
83% yield. Introducing other nucleophiles such as water,
methanol, phenol and chloride also afforded the corresponding -
functionalized products 5,6 in moderate yields under unoptimized
reaction conditions. It is worthwhile to reiterate that oxidative
umpolung strategies are typically restricted to nucleophilic
coupling partners that are not prone to oxidation. The presented
one-pot procedure allows for coupling of nucleophiles known to
be incompatible with oxidants such as DDQ (e.g. phenols and
thiols). It is also noteworthy that the reaction concept allows the
presence of oxidant in tandem with nucleophiles that are not
prone to oxidation by DDQ. While the presented methodology
permits the coupling of several nucleophiles, we have decided to
focus on thiols. A general oxidative thiolation based on readily
available thiols is a valuable goal given the ubiquity and
importance of the thioether functionality in nature.[12] Traditionally,
organocatalytic methodologies available for the preparation of -
sulfur-functionalized carbonyl compounds have been reactions
involving electrophilic sulfenylation reagents.[12] Therefore, these
have been restricted to classical enamine-electrophile couplings,
limiting the thioether moiety to the nature of electrophilic sulfur
reagents. Thus, it has a significant impact if one can overcome
the incompatibility of thiols to oxidative conditions as this allows
the coupling of thiols inaccessible using sulfenylation strategies.
observed that the thiolation rate decreases and prolonged
reaction times are needed to ensure full consumption of the
quinol-intermediate as the steric bulk of the thiol is increased (see
Supporting Information). Substituted thiophenols afforded the
desired thioether products 4gd-pd in good to high yields (67-90%).
Ortho-, meta-, and para-substituted thiophenols were tolerated
and gave similar yields (compare 4gd-id and 4jd-ld). Both
electron-rich and electron-poor thiophenols also reacted, though
lower reactivity was observed for the more electron-poor variants
(4kd and 4md-pd), suggesting an electronic influence on the
nucleophilic displacement step. To summarize, both aliphatic and
aromatic, as well as very sterically hindered thiols reacted
smoothly under these organocatalytic oxidative coupling
conditions with aldehyde 1d.
Scheme 2. a) Isolated O-bound quinol-intermediates applying different
aldehydes and quinones in the presence of aminocatalyst, and single-crystal X-
ray structure of (±)-2dII (thermal ellipsoids drawn at 50% probability). b)
Reactions of O-bound quinol-intermediate 2aI with nucleophiles. Performed on
0.20 mmol scale.
Scheme 3. a) Oxidative coupling of 2-phenylpropanal 1d with thiols. Performed
on 0.20 mmol scale. [a] 3.0 equiv of ethylthiol were used. b) Oxidative coupling
of aldehydes 1 with thiophenol. Performed on 0.20 mmol scale. [b] 20 mol% of
3a were used. [c] (±)-3,3-Dimethyl-1-morpholinobutane-2-amine, (±)-3b, was
used as the aminocatalyst. [d] Fluoranil was used as the oxidant. [e] Thiophenol
was added in two portions. [f] 20 mol% of (±)-3b were used.
To examine the potential of quinol-intermediates as electrophilic
synthons for an -thiolation strategy, various thiols were tested
(Scheme 3a). Quinol-intermediate 2dI, derived from
aminocatalyzed DDQ-promoted oxidation of 2-phenylpropanal 1d,
was chosen as the coupling partner to generate a scope using
only commercially available reagents. Aliphatic thiols such as
ethylthiol gave thioether 4bd in 66% yield. Sterically demanding
aliphatic thiols also reacted and led to formation of 4cd-ed in
similar yields, while benzyl thiol provided 4fd in 87%. It was
Next, we turned our attention toward exploring the aldehyde
scope using thiophenol as the standard nucleophile (Scheme 3b).
Unsubstituted 2-phenylpropanal 1d smoothly provided 2-phenyl-
2-(phenylthio)propanal 4ad in 82% yield.
A library of 2-
arylpropanals containing electron-donating and withdrawing
groups was tested under the reaction conditions. Substituents in
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10.1002/anie.201911793
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mixture was concentrated and redissolved in TFA prior to addition of the
cysteine derivative; yield and d.r. were measured by 1H NMR analysis of the
crude reaction mixture relative to an internal standard (methyl 4-methyl-3-
nitrobenzoate). [d] Octapeptide was used as limiting reagent, and added after
the crude reaction mixture was redissolved in TFA.
ortho-, meta-, and para-positions were tolerated, as demonstrated
with Me-substituted aldehyde derivatives 1f-h which afforded the
thioethers 4af-ah in 67-89% yield. Both electron-poor and
electron-rich aryl substituents gave the desired products 4aa-am
in 67-94% yield. In the case of the electron-rich aldehyde
derivatives 1a-c, the DDQ quinol-intermediates were found to
undergo undesired dehydrogenations affording ,-unsaturated
aldehydes as byproducts due to their increased reactivity. This
undesired reactivity was suppressed by employing the less
activated quinone fluoranil, which still provided substitution-active
intermediates 2aIII-cIII and formation of thioethers 4aa-ac in 80-
84% yield. The -thiolation strategy can also be applied to a
broader class of acetaldehydes. 2-Phenylbutanal 1n smoothly
underwent conversion and gave thioether 4an in 75% yield.
Diaryl- and dialkyl-substituted acetaldehydes, such as
diphenylacetaldehyde 1o and isobutyraldehyde 1p, also afforded
products 4ao and 4ap in 67% and 66% yield. Furthermore,
phenylacetaldehyde 1q and 2-(3-methoxyphenyl)acetaldehyde 1r
gave the desired tertiary substituted thioethers. However, it was
necessary to implement a one-pot NaBH3CN reduction following
the thiophenol addition due to the instability of the thioethers. This
provided alcohols 4aq and 4ar in 48% and 50% yield, respectively.
In light of the developed aminocatalyzed oxidative thiolation
strategy, we aimed to demonstrate that the concept might have
the potential to also proceed as an enantioselective variant.
Nucleophilic substitution at a quaternary stereocenter is a major
synthetic challenge and only very few enantioselective examples
have been reported with thiols, despite the importance of
quaternary thioethers in biological and medicinal chemistry.[13] To
the best of our knowledge, no one-pot enantioselective -
thiolation of racemic carbonyl compounds has been
disclosed.[11,14] Screening of aminocatalysts and quinones
provided reaction conditions (see Supporting Information) that
afforded moderate to high enantioselectivities for the formation of
various thioethers 4 using aminocatalyst (S)-3,3-dimethyl-1-
morpholinobutan-2-amine, (S)-3b, chloranil as the oxidant, and a
benzoic acid additive (Scheme 5a). We were pleased to find that
aldehydes (±)-1d,j,l,n allowed for the formation of optically active
thioethers (S)-4ad,aj,al,an,fd,gd,jd in 40-81% yield and 68-84%
ee. The stereochemistry of (S)-4ad was assigned by X-ray
crystallography, and the remaining thioethers were assigned by
analogy (see Supporting Information).
As
a part of the mechanistic investigation, cyclopropyl
acetaldehyde 1s was included in the scope and tested under the
reaction conditions. It is notable, that the coupling occurred
without ring-opening of the cyclopropyl moiety to afford thioether
4as in 53% yield, indicating a non-radical intermediate (vide infra).
To summarize, both aliphatic and aromatic, as well as -branched
and linear aldehydes provided all the desired thioethers in good
to high yields under the standard reaction conditions.
Encouraged by the broad tolerance towards the various thiols, we
envisioned that the methodology might allow for functionalization
of biologically relevant thiols, such as cysteine derivatives
(Scheme 4). N-Acetyl-L-cysteine methyl ester reacted smoothly to
give the cysteine-coupled product. To ease the purification, a one-
pot NaBH3CN reduction was employed to give alcohol 4qd in an
overall 52% yield and 1:1 d.r. Inspired by this, protected and
unprotected cysteine derivatives were also tested and both N-
acetyl-L-cysteine and L-cysteine underwent the oxidative coupling
chemoselectively affording 4rd and 4sd. We were pleased, that
the reaction concept could be extended to afford bioconjugates,
as exemplified by the coupling of an octapeptide (4td).
Scheme 5. a) Enantioselective organocatalytic procedure for the synthesis of
optically active thioethers 4. Performed on 0.20 mmol scale, and ee was
determined by chiral stationary phase ultra performance convergence
chromatography (UPC2). [a] Thiol addition was performed at -25 oC. [b] Thiol
addition was performed at rt. b) Stereospecific transformation of isolated O-
bound quinol-intermediate (R)-2dII to thioether (S)-4ad. ee was determined by
chiral stationary phase UPC2.
Scheme 4. Oxidative coupling of 2-phenylpropanal 1d with cysteine derivatives
and a peptide. [a] Yield was determined after NaBH3CN reduction and
purification of the corresponding alcohol. d.r. was determined on the crude
reaction mixture prior to reduction. [b] Yield and d.r. were measured by 1H NMR
analysis of the crude reaction mixture relative to an internal standard (1,3,5-
tris(trifluoromethyl)benzene). [c] After full consumption of 1d, the reaction
In order to obtain further insight into the thiolation step, we
focused the attention on isolating the enantiomeric enriched
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RESEARCH ARTICLE
Multiple mechanistic scenarios can be envisioned. Given the
ability of bulky thiols, such as tert-butyl thiol and 1-
adamantanethiol, to displace the quinol moiety, led us to consider
a radical-type substitution reaction. These have previously been
observed for substitution of quaternary benzylic and -carbonyl
positions.[15,16] To probe for potential radical pathways, common
inhibitors of such reactivities[16] were tested by forming quinol-
intermediate 2dI under the general reaction conditions and
monitoring the thiolation in the presence of various inhibitors (see
Supporting Information). Most challenging is the inherent
reactivity of the thiols towards commonly employed radical
trapping reagents, such as 2,2,6,6-tetramethyl-1-piperidinyloxy
(TEMPO), galvinoxyl and O2, which makes in situ studies of the
thiolation event biased in their presence.
In the absence of light, the addition of thiophenol to the O-bound
quinol-intermediate 2dI underwent smoothly, thus excluding light
promoted radical propagation to account for the reactivity.
Reactions in CH2Cl2 saturated with O2 and under an O2
atmosphere proceeded well, albeit with slightly prolonged
reaction time. Addition of p-dinitrobenzene, a strong electron
acceptor, and the radical trap galvinoxyl, did not suppress the
thiolation. The thiolation also proceeded smoothly in the presence
of 3,5-di-tert-4-butylhydroxytoluene (BHT). Attempted trapping of
intermediate 2dI by addition of TEMPO, in the absence of excess
DDQ and thiophenol did not afford any consumption of 2dI.
Finally, cyclopropyl derivative 1s afforded the corresponding
quinol-intermediate 2sIII and underwent thiolation without ring-
opening of the cyclopropyl moiety (vide supra). In summary, all
attempts to trap a radical species as the reactive intermediate
proved inconclusive since no trapping adducts were observed,
and the thiolation was not inhibited by the presence of known
radical inhibitors, regardless of minor rate attenuations.
The formation of thioethers from thiol addition to the O-bound
quinol-intermediates points to a rare event: a nucleophilic
bimolecular substitution at a quaternary stereocenter with
inversion of configuration. Leaving groups at quaternary centers
adjacent to carbonyls are known to be activated and have
previously been described to undergo stereospecific nucleophilic
substitution, albeit very few examples are reported.[11,14,17] The
activation of quaternary -substituted carbonyl compounds
towards nucleophilic substitution is a fundamental discussion
addressed by several authors.[18] Based on this, several key
characteristics in the presented concept make an SN2-type
displacement feasible. The electron-withdrawing effect of the
aldehyde moiety deactivates the intermediate towards SN1
reactivity, as well as increasing the electrophilic character of the
-position, and the planarity of the carbonyl may better
accommodate the sterically demanding transition state required
for an SN2 displacement compared to classic quaternary centers.
As for the initial interaction between the thiol and quinol-
intermediate, multiple scenarios may be envisioned. Depending
on the substrate, electrostatic as well as covalent interactions with
the carbonyl substituent have been postulated to account for the
increased activation of quaternary -substituted carbonyl
compounds towards nucleophilic substitution.[18] It is uncertain if
such interactions are promoters of this unprecedented thiolation
reaction and we can not exclude, that the reaction might proceed
by a nucleophilic attack to the carbonyl carbon atom, followed by
a 1,2-shift to the achieve substitution at the quaternary carbon.[18b]
quinol-intermediates formed by chloranil promoted oxidation of
aldehydes (±)-1 in the presence of aminocatalyst (S)-3b. We were
pleased that quinol-intermediate (R)-2dII could be isolated in
practical quantities. The absolute configuration of (R)-2dII was
assigned based on calculated electronic circular dichroism (ECD)
spectra and compared with experimental results (see Supporting
Information). The reactivity of isolated quinol-intermediate (R)-
2dII was evaluated under the reaction conditions and treated with
thiophenol in the absence of catalyst (S)-3b (Scheme 5b). This
led to formation of the thioether (S)-4ad in 53% yield. Interestingly,
the substitution was stereospecific as the enantiomeric excess of
(R)-2dII (53% ee) was maintained in (S)-4ad (see Supporting
Information for specific details). This demonstrates that the
enantioselectivity originates from the formation of 2dII and is
transferred in the subsequent thiolation event, thus under these
reaction conditions, the substitution step does not involve
stereoinduction by the aminocatalyst.
In an attempt to understand the mechanism and the
stereochemical implications, further investigations were
performed. Key empirical observations reveal insights into the
reaction mechanism. Single-electron oxidation processes
accountable for previously disclosed couplings[3a,c] were limited to
electron-rich aldehydes whereas the present work also proceeds
very well for electron-poor aldehydes. For example, oxidation of
enamines
derived
from
2-arylpropanals
1d-n
and
isobutyraldehyde 1p proceeds smoothly in the presence of DDQ
and at comparable rates of formation. Thus varying the electronic
nature of the aldehyde has a limited effect on the extent of
oxidation. In fact, these aldehydes were incapable of product
formation in the aforementioned single-electron oxidation
couplings, indicating that a different oxidation pathway may be
operational when using quinones as oxidants. Evidence in favor
of a two-electron pathway includes, specifically, the formation of
covalent O-bound quinol-intermediates prior to the nucleophilic
coupling. As for the thiolation event, isolated O-bound quinol-
intermediates 2dI,hI,dII react with thiophenol to afford the
corresponding thioether products 4ad,ah in the absence of
additives. This observation suggests that the aminocatalyst is not
essential for the substitution step (Scheme 5b). In addition, as the
steric bulk of the thiol is increased, the thiolation rate decreases
and prolonged reaction times are needed to ensure full
consumption of the quinol-intermediates. Similar decrease in
reactivity is observed when comparing electron-rich thiophenols
to electron-poor analogues (vide supra). Prolonged reaction times
were also observed when decreasing the equivalents of thiol
indicating a non-zero order dependence of the thiol nucleophile
(see Figure S5, p. 36 in Supporting Information). These
observations indicate a dependence of both steric and electronic
nature, as well as concentration of thiol on the rate of substitution.
Furthermore, we have demonstrated that the conversion of
isolated quinol-intermediate (R)-2dII to thioether (S)-4ad
conserved the enantiomeric excess of the intermediate, thus
pointing to a stereospecific transformation independent of the
aminocatalyst. On the basis of these experimental results, the
thiol substitution appears to proceed via an unusual bimolecular
pathway with inversion of configuration.
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10.1002/anie.201911793
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RESEARCH ARTICLE
To account for the experimentally observed stereochemistry, a
mechanistic proposal for (S)-3b-promoted oxidation of (±)-1d to
give quinol-intermediate (R)-2dII, and sequential thiolation to
provide (S)-4ad, is outlined in Scheme 6.
functionalizations and for the development of their asymmetric
variants, as well as an alternative approach for bioconjugation.
Acknowledgements
This work was made possible by generous support from
Carlsberg Foundation “Semper Ardens”, FNU, Aarhus University.
K.A.J. was funded by a Villum Investigator grant (no. 25867) from
The Villum Foundation. H.N.T. thanks Novo Nordisk for a PhD
grant. We thank Frank Jensen for guidance on computational
ECD analysis as well as Jacob Overgaard and Mathias Kirk
Thøgersen for performing X-ray analysis.
Keywords: organocatalysis • umpolung • oxidative thiolation •
enantioselective -thiolation • bioconjugation
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Scheme 6. Proposed mechanism for the stereoselective formation of (S)-4ad.
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10.1002/anie.201911793
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RESEARCH ARTICLE
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10.1002/anie.201911793
Angewandte Chemie International Edition
RESEARCH ARTICLE
RESEARCH ARTICLE
Jakob Blom, Gabriel J. Reyes-
Rodríguez, Henriette N. Tobiesen,
Johannes N. Lamhauge, Marc V.
Iversen, Casper L. Barløse, Niels
Hammer, Matilde Rusbjerg, and Karl
Anker Jørgensen*
Page No. – Page No.
Umpolung Strategy for -
Functionalization of Aldehydes for
the Addition of Thiols and other
Nucleophiles
Table of Content text:
Discovered by oxidant. Organocatalytic umpolung of the -position of aldehydes through O-bound
quinol intermediates.
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