α-Heteroarylation of Thioethers via Photoredox and Weak Br?nsted Base Catalysis

Article abstract of DOI:10.1021/acs.orglett.1c02151

We report the C-H activation of thioethers to α-thio alkyl radicals and their addition to N-methoxyheteroarenium salts for the redox-neutral synthesis of α-heteroaromatic thioethers. Studies are consistent with a two-step activation mechanism, where oxidation of thioethers to sulfide radical cations by a photoredox catalyst is followed by α-C-H deprotonation by a weak Br?nsted base catalyst to afford α-thio alkyl radicals. Further, N-methoxyheteroarenium salts play additional roles as a source of methoxyl radical that contributes to α-thio alkyl radical generation and a sacrificial oxidant that regenerates the photoredox catalytic cycle.

Full text of DOI:10.1021/acs.orglett.1c02151

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Letter
α‑Heteroarylation of Thioethers via Photoredox and Weak Brønsted
Base Catalysis
Edwin Alfonzo* and Sudhir M. Hande*
Cite This: Org. Lett. 2021, 23, 6115−6120
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ABSTRACT: We report the C−H activation of thioethers to α-thio alkyl
radicals and their addition to N-methoxyheteroarenium salts for the redox-
neutral synthesis of α-heteroaromatic thioethers. Studies are consistent with a
two-step activation mechanism, where oxidation of thioethers to sulfide radical
cations by a photoredox catalyst is followed by α-C−H deprotonation by a weak
Brønsted base catalyst to afford α-thio alkyl radicals. Further, N-methoxyheter-
oarenium salts play additional roles as a source of methoxyl radical that
contributes to α-thio alkyl radical generation and a sacrificial oxidant that
regenerates the photoredox catalytic cycle.
inhibition of gastric H+/K+-ATPase.3 Ceralasertib (2), an ATR
kinase inhibitor being investigated in clinical trials, has an α-
heteroaromatic sulfoximine indispensable for bioavailability.4
Compound 3 is a VEGF inhibitor leveraging an intramolecular
chalcogen bond that improves ligand-target contact.5 Despite
their success and diversity of function, methods for the synthesis
of these motifs are scant. Generally, entry to these has relied on
displacement reactions, for example, with a thiolate and
heterobenzylic electrophile. New reactions for the synthesis of
α-heteroaromatic thioethers and their derivatives that can
expand their accessible chemical space are desired.6−8
α-Heteroaromatic thioethers and their higher oxidation state
congeners, typically derived from the former, are essential
structures that confer function to pharmaceuticals, clinical
candidates, and agrochemicals (Scheme 1A).1,2 For instance, the
sulfoxide in Omeprazole (1) serves as an electrophile for
Scheme 1. Strategy for α-Heteroarylation of Thioethers
Given their availability and structural diversity, the Minisci
reaction of thioethers is an attractive strategy for synthesizing α-
heteroaromatic thioethers.9 Hitherto, this reaction has been
seldom documented and is limited to few examples.10 This
stands in stark contrast with recent developments in Minisci-
type reactions, where the coupling of the isoelectronic amine
and ether are much more well established.11−17 The challenge in
developing a Minisci reaction with thioethers lies in the redox
activity of sulfur, making them labile to oxidation by the requisite
oxidant needed in the reaction (Scheme 1B). We sought to
overcome this by employing N-methoxyheteroarenium salts.
Seminal work by Mitchell18 and contemporary studies by
Herzon,19,20 Hong,21−23 and Lakhdar24,25 provide background
into the capabilities and creative uses of these salts. Notably,
these carry an added oxidation state, obviating the need for
oxidants. Additionally, they are activated toward a single radical
Received: July 1, 2021
Published: July 23, 2021
https://doi.org/10.1021/acs.orglett.1c02151
© 2021 American Chemical Society
Org. Lett. 2021, 23, 6115−6120
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Letter
addition, precluding acid additives that limit scope and promote
overalkylation. Studies by Strekowski on N-fluoropyridinium
salts as heteroarylation reagents of sulfides provided further
impetus to pursue the envisioned transformation.26
relevant for scale-up procedures in flow,36 which necessitate
homogeneous conditions, but because CF3CO2Na is inex-
pensive it was used to explore the scope of the reaction. Control
studies showed a background reaction in the absence of Mes-
Acr+ and CF3CO2Na (entries 4−6), though inefficient
compared to the optimized conditions. This was attributed to
an observed charge-transfer (CT) complex between 4 and 5
(Figure S3). The reaction is tolerant of ambient oxygen (entry
7), but we opted for degassed conditions as oxidation products
were observed during prolonged irradiation. No reaction
occurred in the absence of visible light (entry 8).
Pyridinium salts with substitution in the ortho, meta, and para
positions were suitable for this reaction (Table 2A). These
include methyl- (6), benzyloxy- (11 and 23), trifluoromethyl-
(12 and 24), phenyl- (13), cyano-(14), chloro- (15), fluoro-
(16), and alkyl- (17) substituted pyridines. Interestingly, the
fluoro group in 16 appears to be ortho-activating the pyridinium
salt, parallel to general trends of protonated pyridines.37
Substituted quinolinium salts performed well, providing access
to methoxy- (18), bromo- (19), and methyl- (20) substituted α-
quinoline thioethers. Pyridine (25), quinoline (21), and
isoquinoline (22) products were also accessed. In general,
when the C2 and C4 positions of N-methoxyheteroarenium salts
are both available, C2 addition is favored in a 3:1 regioisomeric
ratio (rr) or greater, except for 13. The observed selectivity is
consistent with the anticipated nucleophilicity of α-thio alkyl
radicals, which are known to add preferably to the more
electrophilic C2 position.9,12
We recently established that thioethers can be activated
toward α-thio alkyl radicals via a two-step approach, where
oxidation of thioethers to sulfide radical cations by a photoredox
catalyst is followed by α-C−H deprotonation by a weak
Brønsted base catalyst.27 Activating thioethers in this manner
offers two advantages over previous strategies to generate α-thio
alkyl radicals: (1) site selectivity, compared to hydrogen atom
transfer (HAT) methodologies in the cases where multiple
hydridic C−H bonds are available,28 and (2) entry to an
abundant, yet underutilized, source of α-thio alkyl radicals,
which are more typically generated from thioethers comprising
an α-proradical group.29−33 Here, we wed these two
technologies, the dual catalytic generation of α-thio alkyl
radicals and N-methoxyheteroarenium salts in Minisci reactions,
for the synthesis of α-heteroaromatic thioethers (Scheme 1C).
Our studies began by evaluating thioanisole (4) (E = +1.21 V
vs SCE)34 toward addition with 1-methoxy-4-methylpyridin-1-
ium methyl sulfate (5) (Table 1). Similar to our previous
a
Table 1. Control Reactions of Optimized Conditions
Aryl sulfides with substitution in the ortho, meta, and para
positions reacted in good to excellent yields (Table 2B). These
include cyano- (26), bromo- (27 and 33), chloro- (34), fluoro-
(28), trifluoromethyl- (29), methyl- (30), methoxy- (31 and
44), acetamide- (32), ester- (35), 2-naphthyl- (36), and anilide-
(38) substituted aryl sulfides. An α-heteroaromatic sulfide
containing orthogonal halogen groups (37) and a β-ketonitrile
(39) were accessible using this method. Heterocycles, such as
pyridine (40 and 41), 2-chloropyridine (42), and N-Boc-indole
(43), were also tolerated. Secondary α-thio alkyl radicals can be
coupled to produce methyl- (45 and 46) and methanol- (47)
branched α-heteroaromatic thioethers. Cyclic sulfides reacted
on average with good yields. These include five- (48) and six-
(50) membered sulfides. Biotin 49 was functionalized with site
selectivity, albeit affording a 1:1 diastereomeric ratio (dr).
Substitution on tetrahydrothiopyran (THTP) at the four
position was amenable, providing entry to ketone- (51),
alcohol- (52), and methanol- (53) containing products.
Saturated heterocycles possessing multiple heteroatoms (S, N,
and O) afforded the desired product with site selectivity (54−
56). In 55, a trace amount of an undesired regioisomer was
isolated, pertinent to the reaction mechanism. Lastly, aliphatic
sulfides containing adamantyl- (57), tert-butyl- (58), ethyl-
(59), cyclohexyl- (60), isopropyl- (61), and methyl- (62)
substitution participated in the reaction. We observed no
reaction with thioethers that could only generate tertiary α-thio
alkyl radicals, explaining the regioselectivity observed with 60
and 61. To showcase further the use of this reaction, we engaged
THTP in sequential C−H activation (Table 2C). Hetero-
arylation of THTP at C2 was followed by alkylation at C6, using
our previously developed alkylation method, affording 63.
Additionally, we executed a two-step synthesis of potent VEGF
inhibitor 3 (Table 2D).5
a
5 (0.5 mmol, 1 equiv), 4 (3 equiv), Mes-Acr+ (5 mol %), CF3CO2Na
b
(20 mol %), DCM [0.2 M], blue LEDs, Ar, 30 °C. 1H NMR yield.
Yield in parentheses refer to isolated yield. 24 h irradiation.
c
studies, an acridinium catalyst, Mes-Acr+ (8) (E*red = +2.10 V vs
SCE in MeCN),35 and a weak Brønsted base, sodium
trifluoroacetate (CF3CO2Na), were found to cocatalyze the
reaction and afford 6 in 61% isolated yield (entry 1). The
remaining mass balance was attributed to 4-methylpyridine (7),
presumed to arise through single electron transfer (SET)
reduction of 5. We posited that fully homogeneous weak
Brønsted bases could increase the rate of deprotonation of
sulfide radical cations and found these could be generated in situ
from their corresponding acid and 2,6-di-tert-butylpyridine.
Improved results were obtained using trifluoroacetate 9 and
diphenyl phosphate 10 (entries 2 and 3). These conditions are
We sought to study the mechanism of this reaction. To
support the involvement of sulfide radical cations, we performed
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a
Table 2. Scope of α-Heteroarylation of Thioethers
a
Reaction conditions: N-methoxyheteroarenium salt (0.5 mmol, 1 equiv), thioether (3 equiv), Mes-Acr+ (5 mol %), CF3CO2Na (20 mol %), DCM
b
c
d
e
[0.2 M], Ar, 30 °C, blue LEDs. Thioether (2 equiv). Thioether (5 equiv). Thioether (10 equiv). 1-g scale.
luminescence quenching studies. Stern−Volmer (SV) analysis
revealed thioanisole quenches (Ksv = 214 M−1) the lumines-
cence of Mes-Acr+ four times more efficiently than N-
methoxypyridinium salt (Ksv = 51 M−1) and CF3CO2Na (Ksv
= 47 M−1).38 The pKa of the α-C−H bonds in the thioanisole
and dimethyl sulfide radical cations have been previously
estimated to be pKa ≈ 2.1 and 0, respectively, lending credence
to the hypothesized deprotonation.27,39 Though CF3CO2Na
(pKa = 0.23 in H2O)40 is a weak base, its catalytic role was
confirmed by observing that the rate of the model reaction is
nearly tripled (KB /Kw/o B = 2.8) in its presence.38 Kinetic
isotope effect (KIE) experiments conducted with thioanisole
and thioanisole-d3 revealed C−H bond cleavage is both product-
(KIE = 4.9) and rate-determining (KIE = 2.5).38 We have
−
−
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Figure 1. (A) Mechanistic probes. (B) Proposed mechanism.
previously demonstrated an olefin can capture a thioether
radical clock in a formal (3 + 2) cycloaddition under analogous
conditions, providing evidence for the intermediacy of α-thio
alkyl radicals.27 Together, these data support oxidation and α-
C−H deprotonation of thioethers as a working mechanism for
α-thio alkyl radical formation.
was found to be optimal to promote the reaction. Under these
reductive conditions (Figure 1A, eq 1), the reaction with 1,4-
oxathiane afforded 55 with little selectivity (1.42:1 rr), providing
evidence that, in the developed reaction, formation of α-thio
alkyl radicals via a stepwise approach is critical for the observed
efficiency and selectivity.
We then focused on understanding how the product is
generated. Studies using N-methoxyheteroarenium salts in
Minisci-type reactions propose the following mechanism for
product formation: (1) radical addition, forming an N-methoxy
radical cation; (2) subsequent α-C−H deprotonation to afford
an N-methoxy α-amino alkyl radical; and (3) homolytic
fragmentation, which generates methoxyl radical (MeO•) and
the Minisci product.22,25 We conducted a competition experi-
ment with 1-methoxypyridin-1-ium sulfate and 1-methoxypyr-
idin-1-ium-d5 sulfate, but a KIE was not observed, signifying α-
C−H bond cleavage of the N-methoxy radical cation is fast.38
MeO• can serve as a latent electrophilic HAT agent and
propagate a radical chain. In our system, HAT of a hydridic α-
C−H bond from a thioether, for example, thioanisole (BDE = 93
kcal mol−1),41 by MeO• (BDE = 104 kcal mol−1)42 is likely to be
exergonic and kinetically favored by polar effects.43 When
measuring the quantum yield of the reaction with thioanisole, a
value above unity (Φ = 1.14) was observed. In contrast, the
quantum yield of the reaction with 1,4-oxathiane, the parent
thioether to 55, was below unity (Φ = 0.22). It appeared that
radical chains are occurring in the reaction, but their extent is
substrate dependent.
Instead, isolation of trace amounts of an undesired
regioisomer of 55 provided convincing evidence for the
intermediacy of MeO•. We wondered whether we could use
1,4-oxathiane and its observed regioselectivity (>20:1 rr) as a
probe to gain insights into the extent that HAT from MeO• is
responsible for generating α-thio alkyl radicals. We posited that
the high selectivity observed in our system could not be
recapitulated by a reaction chiefly operating through MeO•
HAT. To test this hypothesis, we turned to conditions recently
developed by Lakhdar and co-workers for C−H alkylation of N-
methoxyheteroarenium salts.44 Important here is that fac-
Ir(ppy)3, a strongly reducing (E*ox = −1.73 vs SCE)45 but
weakly oxidizing (E*ox = +0.31 V vs SCE)45 photoredox catalyst,
Lastly, we wanted to understand how both catalysts turnover.
It was thought that the background reduction of N-methoxy-
heteroarenium salts (Ep/2 ≈ −0.6 − −0.7 V vs SCE)22,46 to their
corresponding heteroarene arose from competitive SET from
Mes-Acr• (Ep/2 = −0.56 V vs SCE in MeCN), renewing the
photoredox catalytic cycle.35 To test this, we submitted di-tert-
butyl sulfide (Ep/2 = +1.42 V vs SCE in MeCN),47 which is
excluded from generating α-thio alkyl radicals but capable of
reductively quenching excited Mes-Acr+*, to the developed
reaction (Figure 1A, eq 2). Indeed, quantitative reduction of the
N-methoxyheteroarenium salt was observed. Control studies
implicated Mes-Acr+, di-tert-butyl sulfide, and visible light as
necessary for this reaction.38 In the case of CF3CO2 , 1H NMR
−
time course analysis demonstrated α-heteroaromatic thioethers
become protonated as they appear in solution (Figure S9). This
data support deprotonation of in situ generated trifluoroacetic
acid (TFA) by α-heteroaromatic thioethers as the turnover step
−
to regenerate CF3CO2 .
The discovery that Mes-Acr+ is regenerated by reduction of
an N-methoxyheteroarenium salt led us to hypothesize that the
reaction yield could be improved by identifying a sacrificial
heteroarenium salt. In a preliminary study, we identified 64 as a
candidate since it was observed to be quantitatively reduced,
despite having the C4 position accessible for addition (Figure
1A, eq 3). When we probed 64 as an additive in our model
reaction an improved yield of 75% (previously 61%) was
observed. This preliminary study provides proof-of-concept for
further refining of this reaction.
The existing experimental studies and literature precedent
support the mechanism depicted in Figure 1B. Catalysis is
initiated through visible light irradiation of Mes-Acr+, which
promotes it to its excited state. This species can be reductively
quenched by thioethers, furnishing reduced Mes-Acr• and
−
sulfide radical cations. Deprotonation of the latter by CF3CO2
produces α-thio alkyl radicals and TFA. Addition of α-thio alkyl
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ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c02151.
Experimental procedures and data (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Edwin Alfonzo − Medicinal Chemistry, Research and Early
Development, Oncology R&D, 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, Waltham, Massachusetts
02451, United States; Email: sudhir.hande@
astrazeneca.com
(16) Huang, C.-Y.; Li, J.; Liu, W.; Li, C.-J. Diacetyl as a “Traceless”
Visible Light Photosensitizer in Metal-Free Cross-Dehydrogenative
Coupling Reactions. Chem. Sci. 2019, 10, 5018−5024.
(17) Grainger, R.; Heightman, T. D.; Ley, S. V.; Lima, F.; Johnson, C.
N. Enabling Synthesis in Fragment-Based Drug Discovery by Reactivity
Mapping: Photoredox-Mediated Cross-Dehydrogenative Heteroaryla-
tion of Cyclic Amines. Chem. Sci. 2019, 10, 2264−2271.
(18) Katz, R. B.; Mistry, J.; Mitchell, M. B. An Improved Method for
the Mono-Hydroxymethylation of Pyridines. A Modification of the
Minisci Procedure. Synth. Commun. 1989, 19, 317−325.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c02151
(19) Ma, X.; Herzon, S. B. Intermolecular Hydropyridylation of
Unactivated Alkenes. J. Am. Chem. Soc. 2016, 138, 8718−8721.
(20) Ma, X.; Dang, H.; Rose, J. A.; Rablen, P.; Herzon, S. B.
Hydroheteroarylation of Unactivated Alkenes Using N -Methoxyheter-
oarenium Salts. J. Am. Chem. Soc. 2017, 139, 5998−6007.
(21) Jung, S.; Lee, H.; Moon, Y.; Jung, H.-Y.; Hong, S. Site-Selective
C−H Acylation of Pyridinium Derivatives by Photoredox Catalysis.
ACS Catal. 2019, 9, 9891−9896.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Sharon Tentarelli for high-resolution mass
spectrometry data and analyses, Dr. A. J. Metrano and Dr. A.
J. Chinn for proofreading, and Dr. J. J. Beiger for discussions. All
acknowledged are affiliated with AstraZeneca.
(22) Kim, I.; Kang, G.; Lee, K.; Park, B.; Kang, D.; Jung, H.; He, Y.-T.;
Baik, M.-H.; Hong, S. Site-Selective Functionalization of Pyridinium
Derivatives via Visible-Light-Driven Photocatalysis with Quinolinone.
J. Am. Chem. Soc. 2019, 141, 9239−9248.
(23) Lee, W.; Jung, S.; Kim, M.; Hong, S. Site-Selective Direct C−H
Pyridylation of Unactivated Alkanes by Triplet Excited Anthraquinone.
J. Am. Chem. Soc. 2021, 143, 3003−3012.
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