Photoredox and weak Br?nsted base dual catalysis: Alkylation of α-thio alkyl radicals

Article abstract of DOI:10.1021/acscatal.0c03851

We report the C?H activation of thioethers to α-thio alkyl radicals and their addition to electron-deficient olefins to afford alkylated products through dual photoredox and weak Br?nsted base catalysis. Mechanistic studies are consistent with a two-step activation mechanism, where oxidation of thioethers to their corresponding sulfide radical cations by an acridinium photoredox catalyst is followed with deprotonation by trifluoroacetate to generate α-thio alkyl radicals and trifluoroacetic acid (TFA). Experimental studies support the involvement of TFA in all subsequent steps leading to product formation.

Full text of DOI:10.1021/acscatal.0c03851

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Letter
Photoredox and Weak Brønsted Base Dual Catalysis: Alkylation of
α‑Thio Alkyl Radicals
Edwin Alfonzo* and Sudhir M. Hande*
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ABSTRACT: We report the C−H activation of thioethers to α-thio
alkyl radicals and their addition to electron-deficient olefins to afford
alkylated products through dual photoredox and weak Brønsted base
catalysis. Mechanistic studies are consistent with a two-step
activation mechanism, where oxidation of thioethers to their
corresponding sulfide radical cations by an acridinium photoredox
catalyst is followed with deprotonation by trifluoroacetate to
generate α-thio alkyl radicals and trifluoroacetic acid (TFA). Experimental studies support the involvement of TFA in all
subsequent steps leading to product formation.
KEYWORDS: photoredox, Brønsted base, dual catalysis, C−H activation, thioethers
hioethers and their higher oxidation state congeners S(II)
(sulfoxide) and S(IV) (sulfones, sulfoximines, and others)
C−H deprotonation was recognized as a significant pathway, but
overoxidation precluded synthetic use.19
T
are pervasive in pharmaceuticals, natural products, materials, and
agrochemicals.1−3 In drug design, the low-lying σ* orbitals of
thioethers can be strategically engaged intramolecularly with n
and π donors to bias confirmation and enhance ligand-target
interactions (1) (Scheme 1A).4 Higher-order S(II) and S(IV),
which are typically prepared from thioethers, can modulate
solubility (2), hydrogen bond donor/acceptor count, and
provide new vectors for analogue synthesis.5−7 New methods
that can leverage the sulfur atom’s innate reactivity for bond
construction offer unique opportunities to attune the cohort of
exceptional properties of thioethers and their derivatives.
Owingtocontinualprogressinradical-basedreactions, theC−
H activation of thioethers to α-thio alkyl radicals is an attractive
strategy for derivatization. α-Thio alkyl radicals have been
previously generated from single electron transfer (SET)
oxidation and fragmentation of thioethers comprising an α-
electrofuge group (Scheme 1B).8 In this vein, Mariano’s studies
first demonstrated that α-silyl thioethers can undergo
fragmentation through oxidation with a photoredox catalyst,
and work since has shown that other functional groups, like
carboxylic acids and trifluoroborates, are also viable.9−13
MacMillan and co-workers demonstrated that α-thio alkyl
radicals could be generated from thioethers using a hydrogen
atom transfer (HAT) catalyst, which were then leveraged in a
nickel-mediated cross-coupling reaction.14
The advantage of generating α-thio alkyl radicals in a two-step
approach is twofold. First, thioethers are ubiquitous, commer-
cially available materials, and functionalization with an electro-
fuge group would not be necessary. Second, a stepwise approach
can lead to greater site selectivity than HAT methodologies,
especially when engaging substrates with multiple hydridic C−H
bonds.
The oxidationpotentialsofthioethers (Ep/2 =+2.14to+0.85 V
vs saturated calomel electrode (SCE) in acetonitrile (MeCN))20
are only slightly more positive than their amine counterparts,
placing them in a range accessible by conventional photoredox
catalysts.21,22 We hypothesized that an appropriate photoredox
catalyst (PC) and base (B−) could generate α-thio alkyl radicals
from thioethers(Scheme 1C). Thoughweenvisionedthat α-thio
alkyl radicals could participate in many reactions, we decided to
explore addition to polarity-matched,23 electron-deficient
olefins, which would complement the well-known thiol−ene
reaction in the synthesis of alkylated thioethers.24 Akin to
previous efforts in photoredox-catalyzed radical addition to
electron-deficient olefins, we posited that a PC could mediate
oxidation of the thioether and reduction of an α-EWG (EWG =
electron withdrawing group) alkyl radical, affording a redox-
neutral transformation.25−27
We sought to develop a general method to generate α-thio
alkyl radicals from thioethers. Studies in photoredox generation
ofα-aminoalkylradicalsfromaminesthroughSEToxidationand
α-C−H deprotonation inspired us to consider generating the
isoelectronic α-thio alkyl radical in a similar fashion.15−18
Credence for this mode of activation was found in anodic
oxidation studies of thioethers to sulfide radical cations, where α-
Received: September 3, 2020
Revised: October 7, 2020
https://dx.doi.org/10.1021/acscatal.0c03851
© XXXX American Chemical Society
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a
Scheme 1. Strategy for C−H Activation of Thioethers
Table 1. Control Reactions of Optimized Conditions
b
entry
conditions
yield (%)
1
2
as above
no CF3CO2Na
55 (50)
15
3
4
5
TFA (20 mol %) as cocatalyst
DCM or MeOH
8:1 DCM/MeOH
19
<5
22
6
1:1 DCM/MeOH
14
7
7 as PC
20
8
9
10
TTMS, Hantzsch ester, or L-ascorbic acid
no degassing
no Mes-Acr+ or blue LEDs
0
18
0
a
Reaction conditions: olefin (0.5 mmol, 1 equiv), thioether (3
equiv), Mes-Acr+ (5 mol %), CF3CO2Na (20 mol %), 3:1 DCM/
b
MeOH [0.1 M], 34 W blue LEDs, Ar, 30 °C. 1HNMR obtained
Ourstudiesbeganbyprobingthereactionofthioanisole3(E=
+1.21VvsSCEinH2O)28 towardadditionwithmethylacrylate4
(Table 1). After the reaction conditions and optimization had
been scouted, it was found that an acridinium catalyst, Mes-
Acr+(6) (E*red = +2.10 V vs SCE in MeCN),29 and a weak
Brønsted base, sodium trifluoroacetate (CF3CO2Na), could
cocatalyze the reaction and afford 5 in 50% isolated yield (entry
1). Surprisingly, stronger bases surveyed generated poor yields,
whereas other weak Brønsted bases showed similar results.
Additionally, a countercation effect on CF3CO2Na was not
observed.30 In the absence of CF3CO2Na, the reaction
proceeded in 15% yield (entry 2). The surprising effectiveness
of CF3CO2Na led us to probe its conjugate acid, trifluoroacetic
acid (TFA), which showed a reproducible, but marginal, positive
effect (19% yield) on the reaction (entry 3). Critical to the
reaction’s success was identifying a mixed solvent system of
dichloromethane (DCM) and methanol (MeOH). When DCM
orMeOHwasomitted, thereactionfailed(entry4),andasolvent
ratioof3:1 wasrequiredfor optimumefficiency(entries5and6).
Other than Mes-Acr+, a pyrylium catalyst, MD(p-tol)PT (7)
(E*red = +2.27 V vs SCE in MeCN), showed promising results
(entry 7).31 Close examination of the reaction mixture showed
the accumulation of oligomeric products. This observation led us
tohypothesizethattheputativeα-EWGalkylradical(E≈−0.7to
−0.6 V vs SCE in MeCN)32 was not reduced efficiently by
reduced 6 (Ep/2 = −0.56 V vs SCE in MeCN),29 allowing these
side reactions to compete. Unfortunately, efforts to suppress
oligomerformationwithknownhydrogenatomdonorsinhibited
the reaction (entry 8). Lastly, control experiments indicated that
the reaction was sensitive to oxygen (entry 9) and that Mes-Acr+
andvisiblelightwereneededforasuccessfuloutcome(entry10).
yield. Yield in parentheses refer to isolated yield. Abbreviations:
TTMS = tris(trimethylsilyl)silane; Ar = argon.
With established reaction conditions, the olefin scope was
evaluated with three structurally different thioethers (Table 2A).
Acrylates containing methyl (5), 1,1,1,3,3,3-hexafluoroisopropyl
(8), 2,2,2-trifluoroethyl (9), propargyl (10), allyl (11), and
amide groups (12) reacted in good yields with thioanisole.
Example 8 was synthesized on a 1 g scale, and the reaction
showed an improved outcome (87% vs 71%). Notably,
dehydroalanine (13 and 14) derivatives participated in the
reaction with high efficiency, providing nonproteinogenic
methionine-like amino acids. Other olefins that could participate
include diethyl maleate (15), α-methylene-γ-butyrolactone
(16), and diethyl methylene malonate (17). The latter example
is an advanced intermediate en route to sulfinpyrazone, a known
uricosuric used to treat gout.1 Given the broad scope of this
reaction, establishing a structure−activity relationship for
sulfinpyrazone and other sulfur-containing drugs could be
streamlined. Using tert-butyl methyl sulfide, acrylates containing
anilide (18), α-phenyl (19), and α-trifluoromethyl (20) were
addressed. Radical acceptors with phenyl (21) and methyl (22)
β-groups were also tolerated. Lastly, a dehydroalanine with
orthogonal protecting groups (23) and maleimide (24) reacted
with good yields. With tetrahydrothiophene, a wide selection of
acrylatescontainingmethyl(25), ethyl(26), t-butyl(27), phenyl
(28), and benzyl (29) groups were effective coupling partners.
To probe the diastereoselectivity of the reaction, olefins
containing α- and β-groups were tested (30 and 31), but no
selectivity was observed in either case (1:1 diastereomeric ratio
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a
Table 2. Scope of Alkylation of Thioethers
a
Reaction conditions: olefin (0.5 mmol, 1 equiv), thioether (3 equiv), Mes-Acr+ (5 mol %), CF3CO2Na (20 mol %), 3:1 DCM/MeOH [0.1 M],
b
c
Ar, 30 °C, blue LEDs. thioether (2 equiv). thioether (5 equiv).
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Figure 1. (A) Stern−Volmer quenching studies of Mes-Acr+ in the presence of thioanisole and CF3CO2Na. (B) A thermochemical analysis of
thioanisole radical cation can predict its α-C−H pKa value. (C) A competition experiment was used to determine the primary KIE. (D) A radical clock
experiment implicated α-thio alkyl radicals as a reactive intermediate. (E) Deuterium labeling experiments were used to determine whether HAT or
reduction leads to product formation. (F) TFA had a positive influence on the success of the reaction.
(dr)). Methyl vinyl ketone (32), 2-vinylpyridine (33), and
phenyl vinyl sulfone (34) reacted in modest to good yields.
Unreactive examples include tetrasubstituted olefins and
acrylonitrile.
oatoms (S, N, and O) provided the desired product (59−61)
with site selectivity. Lastly, biotin 62 was alkylated in excellent
yield, underscoring the potential for late-stage diversification of
thioethers within complex molecules.
On account of their high yield and synthetic versatility, methyl
2-acetamidoacrylate and phenyl and 1,1,1,3,3,3-hexafluoroiso-
propyl acrylate were chosen to evaluate the scope of thioethers
(Table 2B). Aryl thioethers with substitution in the ortho, meta,
and para positions were suitable for this reaction. These include
methyl- (35), bromo- (36 and 40), fluoro- (37), cyano- (38),
trifluoromethyl- (39), methoxy- (41), and chloro- (42)
substituted aryl sulfides. Electron-rich sulfides generally showed
poor levels of conversion (e.g., 41). We attribute this lack of
reactivity to preferential formation of an aryl radical cation
insteadoftherequisite sulfideradicalcation.33 Heterocycles such
as pyridine (43), quinoline (44), pyrimidine (45), and
benzothiazole (46) were tolerated. Tertiary substituted aryl
thioethers were accessible as showcased by 47. Interestingly, a
tethered nucleophile can be introduced to realize intramolecular
cyclization to the nascent pendant ester, as illustrated by lactone
48. Additionally, an alkyl chloride was recovered from the
reaction as the methyl ether 49. Other medicinally relevant
building-blocks that were incorporated include tetrahydropyran
50, N-Boc-piperidine 51, and adamantine 52, which were
obtained in excellent yields.
Aliphatic thioethers with two sites for C−H activation
produced regioisomeric products with no selectivity (63−65).
This was especially surprising for 65, where deprotonation from
methyl would be kinetically more facile than from isopropyl.
Symmetrical aliphatic thioethers with varying chain length and
substitution (ethyl, butyl, and isopropyl) were alkylated
efficiently (66−68). Lastly, C−H activation of methionine
residue 69 gave good yield but poor selectivity (1:2 (1:1 dr)
regioisomeric ratio (rr)). However, this activation mode holds
potential as a bioconjugation strategy, which has been of recent
interest.34,35
Though the exquisite site selectivity observed supports a two-
step activation mechanism, we set out to find evidence for the
proposed reaction. To support the involvement of sulfide radical
cations, we performed luminescence quenching studies (Figure
1A). Stern−Volmer (SV) analysis revealed that thioanisole (E =
+1.21 V vs SCE) quenches (Ksv = 175 M−1) the luminescence of
Mes-Acr+ (E*red = +2.10 V vs SCE) almost 4 times faster than
CF3CO2Na (Ksv = 46.8 M−1), consistent with the proposed
electron transfer event. Additionally, using a thermochemical
cycle, we estimated the pKa of thioanisole radical cation (pKa ≈
2.1)30 and found that it was nearly 40 orders of magnitude more
acidic than thioanisole (pKa = 42 in dimethyl sulfoxide
(DMSO)),36 supporting the view that a deprotonation event
leads to α-thio alkyl radicals (Figure 1B).37 Though CF3CO2Na
(pKa = 0.23 in H2O)38 is not a strong base, it is clear from control
studies that deprotonation happens even in its absence,
suggesting that the pKa might be lower than predicted. A
Cyclic thioethers, which are ubiquitous in drugs, participated
in this reaction on average with excellent yields. These include
four (53), five (54), and six-membered (55) cyclic thioethers.
Substitution on tetrahydrothiopyran at the four position was well
tolerated, providing access to ketone (56), alcohol (57), and
carboxylic acid (58) containing products with high selectivity
(>10:1 dr). Saturated heterocycles possessing multiple heter-
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competition experiment between thioanisole and deuterated
thioanisole (thioanisole-d3) was undertaken, and a primary
kinetic isotope effect (KIE) of 3.8 was observed (Figure 1C),
implicating deprotonation in the product-determining step.39
Similarly, we monitored the progress of reactions with
thioanisole and thioanisole-d3 in parallel and found a KIE of
3.3, indicating that deprotonation is also involved in the rate-
limitingstep.29 Lastly, wantingtoassociateα-thioalkylradicalsin
the reaction, a radical clock experiment was undertaken (Figure
1D). When 70 was submitted to the developed reaction a formal
(3 + 2) cycloaddition product 71 was isolated. We propose that
71 forms through α-thio alkyl radical generation, cyclopropyl
ring-opening, sequentialolefinadditions, andaHATthatleadsto
product formation, which most likely occurs through a radical
process. Collectively, these data support oxidation to a sulfide
radical cation and α-C−H deprotonation as gateway events
toward α-thio alkyl radicals.
Scheme 2. Proposed Dual Catalytic Cycle
We then focused our attention on understanding how the
product is generated. Specifically, we questioned whether α-
EWG alkyl radical intermediates terminate through a radical
propagating HAT or reduction to an enolate equivalent (Figure
1E). To this end, thioanisole-d3 was submitted to the developed
reactionwiththeexpectationthat, ifHATweretheprimarymode
of termination, substantial deuterium incorporation would be
identified in the product. However, only 12% deuterium
incorporation was observed (eq 1), suggesting that a radical
propagating HAT is a minor pathway.40 With the same design
approach, but with thioanisole and D-methanol (CH3OD), 90%
deuterium incorporation was observed (eq 2). This suggests that
the main path to product formation involves reduction to an
enolate equivalent and protonation from the solvent cage.
Lastly, we sought to understand all the possible roles
CF3CO2Na could play in the reaction. We posited that TFA,
which is produced in situ after deprotonation of sulfide radical
cations, might serve to activate radical acceptors toward addition
and, in some cases, increase the thermodynamic driving force to
reduction of the α-EWG alkyl radical intermediate. This view
finds context in Yoon’s work, where TFA was noted to promote
α-amino alkyl radical addition to electron-deficient olefins.16
Additionally, the groups of Yoon and Knowles have documented
that Brønsted acids can increase the thermodynamic driving
force to reduction of carbonyl motifs.41,42 These precedents led
us to revisit the additive effect observed with TFA with a well-
behaved olefin (Figure 1F). Surprisingly, when TFA (20 mol %)
was used as the cocatalyst, the reaction went to near completion
after 24 h (entry 2), affording the desired product in 70% yield.
This is a considerable increase in yield compared to the control
reaction (entry 1) but not superior to that of CF3CO2Na (entry
3). These results implicate TFA as an active, noninnocent agent
in the developed reaction and suggest that CF3CO2Na plays
multiple roles in leading to product formation.
This reduction ultimately regenerates both catalytic cycles and
produces an enolate equivalent that after protonation affords the
alkylated products.
ASSOCIATED CONTENT
* Supporting Information
The SupportingInformationisavailablefree ofchargeathttps://
pubs.acs.org/doi/10.1021/acscatal.0c03851.
■
sı
Experimental procedures and data (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Edwin Alfonzo − Medicinal Chemistry, Research and Early
Development, Oncology R&D, AstraZeneca, Waltham,
Massachusetts 02451, United States; orcid.org/0000-0002-
4112-8751; Email: edwinalfonzo@live.com
Sudhir M. Hande − Medicinal Chemistry, Research and Early
Development, Oncology R&D, AstraZeneca, Waltham,
Massachusetts 02451, United States; Email: sudhir.hande@
astrazeneca.com
Complete contact information is available at:
https://pubs.acs.org/10.1021/acscatal.0c03851
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. S. Tentarelli for high-resolution mass spectrometry
data and analyses. We gratefully acknowledge Dr. A. J. Metrano
and Dr. J. W. Johannes for proofreading and insightful
discussions. E.A. thanks Dr. J. J. Beiger, Dr. K. D. Reichl, Dr. R.
A. Escobar, Dr. L. Yan, and Dr. R. E. Ziegler for training and
discussions.
To summarize, a combination of experimental results and
literature precedents supports the mechanism depicted in
Scheme 2. Upon irradiation with visible light, Mes-Acr+ can
access its excited state and reductively quench thioethers,
furnishing reduced Mes-Acr· and sulfide radical cations.
−
Deprotonation of the latter by CF3CO2 affords α-thio alkyl
REFERENCES
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barrier of addition by nucleophilic, α-thio alkyl radicals. The
resulting activated α-EWG alkyl radical is expected to be reduced
at potentials more positive than its nonactivated counterpart.
Therefore, reduction by Mes-Acr· would be more exergonic.
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