Metallaphotoredox-Catalyzed C-S Cross-Coupling between Heteroaryl Bromides and α-Thioacetic Acids to Access Biaryl Thioethers

Article abstract of DOI:10.1021/acs.joc.1c01309

Metallaphotoredox-catalyzed C-S cross-coupling between heteroaryl bromides and α-thioacetic acids to form biaryl thioethers is described herein. This transformation allows for cross-coupling between building blocks containing reactive functional groups, nitrogen heterocycles, and pharmaceutically relevant scaffolds. Mechanistic experiments indicate a unique means by which this C-S cross-coupling occurs.

Full text of DOI:10.1021/acs.joc.1c01309

pubs.acs.org/joc
Note
Metallaphotoredox-Catalyzed C−S Cross-Coupling between
Heteroaryl Bromides and α‑Thioacetic Acids to Access Biaryl
Thioethers
Alec H. Christian*
Cite This: J. Org. Chem. 2021, 86, 10914−10920
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: Metallaphotoredox-catalyzed C−S cross-coupling
between heteroaryl bromides and α-thioacetic acids to form biaryl
thioethers is described herein. This transformation allows for cross-
coupling between building blocks containing reactive functional
groups, nitrogen heterocycles, and pharmaceutically relevant
scaffolds. Mechanistic experiments indicate a unique means by
which this C−S cross-coupling occurs.
Scheme 1. Metal-Mediated Approaches to C−S Bond
Formation
n nature, sulfur plays a major role in biosynthesis, oxidative
1−4 Introduction of C−
Istress protection, and redox signaling.
S bonds into pharmaceuticals, agrochemicals, and materials can
be used to modulate different aspects of the molecule, such as
bond length, bond angle, and lipophilicity. In addition, the
oxidation state of sulfur is readily tuned, enabling further
modification of physicochemical properties.5−7 The presence of
sulfur in marketed drug molecules such as amoxicillin
(antibacterial), esomeprazole (proton pump inhibitor), quetia-
pine (antipsychotic), and axitinib (cancer) highlights the
importance of being able to readily access a variety of C−S
bonds (Figure 1).7,8
utilization of thiyl radicals in metallaphotoredox catalysis with
the hypothesis that the thiyl radical could lead to broader
functional group tolerance and circumvent catalyst deactivation
compared to thiolates.16 However, while coupling of alkyl and
aryl thiols with aryl iodides proceeded in good yields, coupling
with aryl bromides was not sufficiently effective to stand as a
versatile synthetic method. In 2017, Miyake and co-workers
Figure 1. Sulfur-containing pharmaceuticals.
Aryl C−S bonds are of particular importance in a
pharmaceutical context and are frequently formed by
nucleophilic aromatic substitution or metal-mediated cross-
coupling.9−15 Typically, transition-metal-catalyzed C−S cross-
coupling protocols involve the formation of a thiolate
nucleophile and have been shown to have good functional
group tolerance (Scheme 1a).10−15 In 2016, Oderinde and co-
workers took a different mechanistic approach and reported the
Received: June 4, 2021
Published: July 14, 2021
https://doi.org/10.1021/acs.joc.1c01309
J. Org. Chem. 2021, 86, 10914−10920
© 2021 American Chemical Society
10914

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
described the formation of aryl thioethers from aryl and alkyl
thiols and aryl bromides by using a nickel catalyst in conjunction
with a phenoxazine-based photocatalyst.17 Although high
yielding, their scope was narrow and limited to nonheteroarenes.
More recently, Nocera and co-workers capitalized on mecha-
nistic insights to identify C−S cross-coupling conditions that
could be applied to a small selection of (hetero)aryl bromides
(Scheme 1b).18 Herein is reported a mechanistically distinct
approach toward the formation of biarylthioethers from a broad
set of heteroaryl bromides and α-thioacetic acids using
metallaphotoredox catalysis. This mechanistically differentiated
method toward C−S bond formation expands the scope of sulfur
and heteroaryl coupling partners and complements the methods
developed by Oderinde, Miyake, and Nocera (Scheme 1c).
Initial interest was in developing a method for the synthesis of
heterobenzylic thioethers from the corresponding heteroaryl
halide and α-thioacetic acids. Seminal work from the MacMillan
and Doyle laboratories demonstrated the use of decarboxylative
arylation, via the formation of an α-amino or α-oxy radical using
nickel and iridium catalysts, to form benzylic amines and
benzylic ethers.19 Hopkins and co-workers expanded on this
approach, forming benzylic amines from electron-deficient α-
amino acids.20 Dolbier and co-workers reported the use of S-
methylthioacetic acid and electron-deficient aryl bromides for
the formation of heterobenzylic thioethers and the synthesis of
Sulfoxaflor.21 Inspired by these reports, initial conditions to
form heterobenzylic thioethers from 3-bromoquinoline (1a)
and 2-((4-methoxyphenyl)thio)acetic acid (2a) gave the desired
C−C cross-coupled product 3a in 17% isolated yield and
unexpectedly, the direct C−S cross-coupled product 4a was
isolated as the major product in 63% yield with loss of the
methylene unit (Scheme 2a). Interestingly, this C−S side
C−S coupled product.22,23 Three photocatalysts, two nickel
catalysts, two solvents, and two bases were screened (see
Supporting Information Table S1). It was found that swapping
the solvent from dimethylformamide (DMF) to acetonitrile
(MeCN) and switching the iridium catalyst from Ir-1
(Ir[dF(CF3)ppy]2(dtbbpy))PF6 to Ir-2 (Ir[dF(Me)ppy]2-
(dtbbpy))PF6 afforded C−S coupled product 4a in 86% isolated
yield (79% isolated yield on 1 mmol scale) and the C−C
coupled product 3a in only 8% isolated yield (Scheme 2b).
Control experiments showed that all reaction components are
necessary for high-yielding product formation (see Supporting
Information Table S2).
The scope of the α-thioacetic acid partner used in the reaction
was investigated (Table 1). Phenylthioacetic acid gave product
Table 1. α-Thioacetic Acid Scope
Scheme 2. Optimization of C−S Cross-Coupling with α-
(4b) in 40% yield. Methyl substitution at the para (4c, 27%
yield) and ortho (4d, 35% yield) positions as well as fluoro
substitution (4e, 40% yield) were reasonably well tolerated.
However, the presence of the more electron-withdrawing
trifluoromethyl group resulted in a significant decrease in yield
(17% yield). Switching to the more electron-rich N-Boc amine
(4g) afforded a significant boost in yield (81% yield).
Heteroaromatic α-thioacetic acids were also explored. N-Me-
indole-derived product 4h was formed in 25% yield, while the 4-
pyridyl (4i) and benzoxazole (4j) products were obtained in low
yield (8% and 4% yield, respectively). When the sulfone-derived
acid (5) was attempted, no product was observed, suggesting
that the lone pairs on the thioacetic acid are necessary for the
formation of a thio-centered radical for reaction to proceed.
Benzyl thioacetic acid and tert-butyl thioacetic acid were also
tested but did not lead to detectable product formation,
presumably due to the lack of stabilization of the thiyl-radical
intermediate by the alkyl groups (see Supporting Information
Figure S2 for a comprehensive list of unreactive coupling
partners that were investigated). When a methyl group was
added to the α-position of the 2-((4-methoxyphenyl)thio)acetic
acid (2b), product 4a was observed in 56% yield. Increasing the
steric bulk at the α-position by adding a phenyl (2c) or geminal
dimethyl substitution (2d) had a deleterious impact on yield,
with 4b isolated in only 6% and 7% yields, respectively,
suggesting that the increase in sterics could inhibit product
formation (see Supporting Information Figure S6 for prelimi-
nary proposed mechanism).
Thioacetic Acid
product was also previously observed by Dolbier and co-workers
as a low-yielding side product during their α-thio C−C cross-
coupling chemistry. The observation of the C−S product in
good yield was seen as an opportunity to expand the scope of
metallaphotoredox-mediated C−S cross-couplings to more
complex heterocycles utilizing a mechanistically distinct path-
way.
This intriguing observation prompted further studies using a
photoredox high-throughput screening kit to optimize for the
The heteroaryl bromide scope was also examined (Table 2).
Substituted 3-bromoquinolines led to moderate to good yields
10915
https://doi.org/10.1021/acs.joc.1c01309
J. Org. Chem. 2021, 86, 10914−10920

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
yield), while the thiophene pharmacophore 4x was synthesized
in 25% yield.
Table 2. Heteroaryl Bromide Scope
Next, preliminary mechanistic experiments were conducted to
probe if the reaction occurs by the formation of free thiol/
thiolate, which then enters the catalytic cycle similar to the
mechanisms proposed by Oderinde, Nocera, and Guan.16,18,25
One hypothesis is the 4 equivalents of water from the nickel
catalyst displace the thiol/thiolate from the glycolic acid.
However, when the nickel catalyst was formed in situ under
anhydrous conditions, product 4a was produced in 83% yield,
demonstrating that water is not necessary for product formation
(Scheme 3a). Next, different combinations of the substrates and
Scheme 3. Mechanistic Experiments for C−S Cross-Coupling
with α-Thioacetic Acid
with the −OMe substituted quinoline (4k) obtained in 78%
yield and the −CF3 substituted quinoline (4l) in 39% yield.
Aldehydes were tolerated under the reaction conditions with the
C−S product (4m) being formed in 35% yield. Interestingly, the
chloro-substituted quinoline (4n, 55% yield) was tolerated
under the reaction conditions, allowing for further functional-
ization/derivatization of the quinoline. Pyrimidine 4o and
alcohol 4p were also tolerated under the reaction conditions,
albeit in low yields for the alcohol (9% yield). 2-Bromoheter-
oaryls were also explored, with 2-bromopyridine and 2-bromo-
6-methoxyquinoline affording C−S coupled products 4q and 4r
in 59% and 54% yield, respectively. Finally, imidazopyridine 4s
was isolated in 26% yield, while the sulfonamide-containing
arene 4t was produced in 67% yield, demonstrating the
tolerability of acidic protons by this system.
base in MeCN-d3 were analyzed by 1H NMR spectroscopy for
the presence of thiol/thiolate. Thiol/thiolate was not observed
under the reaction conditions, further suggesting that this
reaction does not proceed via thiol/thiolate formation
(Supporting Information Figure S5). When 4-methoxythiophe-
nol (6) was directly used as the nucleophile, 4a was formed in
only 11% yield, indicating that thiol/thiolate is not a significant
intermediate in the formation of the C−S coupled product. This
is in stark contrast to the methodologies reported by Oderinde,
Miyake, and Nocera where thiol is used directly in their C−S
cross-coupling reactions (Scheme 3b).16−18 Another possibility
is decarboxylation of the acid, followed by quenching to form the
thioanisole, which then acts as the S-aryl nucleophile in the
cross-coupling reaction. Indeed, recent reports by Oderinde and
MacMillan have demonstrated the use of thioanisoles for direct
C−C cross-couplings. Under the standard reaction conditions
with 4-methoxylthioanisole (7) replacing 2-((4-methoxy-
phenyl)thio)acetic acid (2), only trace C−S cross-coupled
product 4a was observed by LCMS with no detection of the C−
C cross-coupled product 3a (Scheme 3c). Taken together, these
mechanistic data strongly suggest this reaction does not proceed
through the formation of a thiol or a thioanisole and is therefore
mechanistically distinct from previously reported metallapho-
toredox catalyzed C−S cross-couplings.
To further test the utility of this transformation, pharmaceuti-
cally relevant heteroaryl bromides were explored to determine if
the C−S bond can be formed in a late-stage manner (Table 3).
Table 3. Late-Stage C−S Cross-Coupling on
Pharmaceutically Relevant Heteroaryl Bromides
Various MSD informer halides were selected and tested under
the reaction conditions to probe functional group tolerance.24
Imidazole-containing pharmacophore 4u was isolated in 57%
yield, while the chloro-containing pyridine product (4v) was
formed in 94% yield. As demonstrated previously, the aryl
chloride remained untouched. The unsaturated lactone-
containing pyridyl scaffold 4w was formed in low yield (12%
In conclusion, a metallaphotoredox-catalyzed C−S cross-
coupling between heteroaryl bromides and α-thioacetic acids
was developed. A variety of thioacetic acids and heteroaryl
bromides were tolerated in the reaction. The reaction could also
be applied to pharmaceutically relevant drug scaffolds, affording
products in a range of yields. Finally, mechanistic experiments
suggest that the reaction does not proceed through a thiol/
10916
https://doi.org/10.1021/acs.joc.1c01309
J. Org. Chem. 2021, 86, 10914−10920

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
per dose) for use in wells with Cs2CO3 as base. The reaction block was
then sealed and illuminated under constant flow of nitrogen gas for 12 h
with stirring. After 12 h, each well was quenched with a solution of
biphenyl in MeOH (250 μL, 1 equiv), followed by taking a 50 μL
aliquot and diluting it in 450 μL of MeOH, which was analyzed by
LCMS at 210 nm.
thiolate or thioanisole species, indicating a unique mechanism
that is currently under further investigation.
EXPERIMENTAL SECTION
■
General Considerations. Reactions were monitored by liquid
chromatography/mass spectrometry (LCMS). Flash chromatography
was performed using prepacked RediSep Rf silica gel columns on a
Teledyne Isco CombiFlash Rf automated chromatography system.
Organic solutions were concentrated under reduced pressure on a
Heidolph rotary evaporator or Biotage V-10 Touch evaporator.
Reversed-phase high-performance liquid chromatography was carried
out using an Agilent 1100 HPLC-MSD system consisting of a 6130B
single quadrupole mass-selective detector (MSD), G1315B diode array
detector, G2258A autosampler, two G1361A preparative pumps, one
G1379A quaternary pump with degasser, one G1312A binary pump,
and three G1364B fraction collectors from Agilent Technologies.
System control and data analysis were performed using Agilent’s
ChemStation software, revision B.03.01-SR.1. A Waters XBridge C18
OBD Prep Column, 100 Å, 5 μm, 19 mm × 150 mm, was used as the
stationary phase (Waters Corporation). Gradient elution was carried
out using water and acetonitrile as the mobile phase. An aqueous 10%
ammonium hydroxide solution was teed into the mobile phase as a
modifier using a static mixer prior to the column, pumped at 1% of the
total mobile phase flow rate. The ESI mass-triggered fraction collected
was employed using positive ion polarity scanning to monitor for the
target mass. Aqueous fractions were concentrated using an SP
Industries, Inc. Genevac HT-12 Series 3i instrument. All reagents (α-
thioacetic acids, aryl halides, photoredox catalysts) and solvents are
known and were purchased from commercial sources (Sigma-Aldrich,
Enamine, AstaTech, CombiBlocks, AmBeed, and Pharmablocks) and
used without further purification unless otherwise specified. Deuterated
solvents were purchased from Cambridge Isotope Laboratories and
used without further purification unless otherwise specified. All NMR
spectra were recorded at 298 K on a Bruker AVANCE NEO NMR
Initial Procedure for C−S Cross-Coupling. 2-((4-Methoxy-
phenyl)thio)acetic acid (60 mg, 0.30 mmol, 1.5 equiv), (Ir[dF(CF3)-
ppy]2(dtbbpy))PF6 (2.2 mg, 0.002 mmol, 0.01 equiv), and [Ni-
(dtbbpy)(OH2)4]Cl2 (9.4 mg, 0.02 mmol, 0.1 equiv) were added to a 2
dram vial. N,N-Dimethylformamide (2 mL, 0.1 M) was added, followed
by 3-bromoquinoline (27 μL, 0.20 mmol, 1 equiv) and 1,8-
diazabicyclo[5.4.0]undec-7-ene (45 μL, 0.30 mmol, 1.5 equiv). The
reaction mixture was capped and bubble degassed with argon for 5 min.
The vial was parafilmed, placed in the Penn PhD Photoreactor M2, and
irradiated with 450 nm light for 15 h with settings set at 4700 fan rpm,
500 stirring rpm, and 100% light irradiation. The reaction was
concentrated and purified by column chromatography (0−100%
EtOAc in hexanes) to afford 3-((4-methoxybenzyl)thio)quinoline
(3a) (9.6 mg, 0.03 mmol, 17% yield) as a colorless oil and 3-((4-
methoxyphenyl)thio)quinoline (4a) (33.8 mg, 0.13 mmol, 63% yield)
as a colorless solid.
General Procedure for C−S Cross-Coupling. Aryl halide (0.20
mmol, 1 equiv), α-thio acetic acid (0.30 mmol, 1.5 equiv),
(Ir[dF(Me)ppy]2(dtbbpy))PF6 (2.2 mg, 0.002 mmol, 0.01 equiv),
and [Ni(dtbbpy)(OH2)4]Cl2 (9.4 mg, 0.02 mmol, 0.1 equiv) were
added to a 2 dram vial. Acetonitrile (2 mL, 0.1 M) was added, followed
by 1,8-diazabicyclo[5.4.0]undec-7-ene (0.045 mL, 0.30 mmol, 1.5
equiv). The reaction mixture was capped and bubble degassed with
argon for 5 min. The vial was parafilmed, placed in the Penn PhD
Photoreactor M2, and irradiated with 450 nm light for 15 h with settings
set at 4700 fan rpm, 500 stirring rpm, and 100% light irradiation. The
reaction was concentrated and, unless otherwise noted, purified by
column chromatography (0−100% EtOAc in hexanes).
3-((4-Methoxybenzyl)thio)quinoline (3a). Purified by column
chromatography (0−100% EtOAc in hexanes). Isolated as a colorless
oil (4.7 mg, 0.02 mmol, 8% yield). 1H NMR (600 MHz, Chloroform-d)
δ 8.75 (d, J = 1.9 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.80 (s, 1H), 7.73−
7.63 (m, 2H), 7.51 (t, J = 7.5 Hz, 1H), 7.24 (d, J = 8.6 Hz, 2H), 6.76 (d,
J = 8.6 Hz, 2H), 4.12 (s, 3H), 3.76 (s, 3H). 13C{1H} NMR (151 MHz,
Chloroform-d) δ 159.8, 151.7, 147.2, 135.3, 135.1, 131.4, 129.4, 129.3,
127.84, 127.7, 126.9, 124.8, 114.8, 55.4, 39.0. HRMS (ESI-TOF) m/z:
[M + H]+ calcd for C17H15NOS 282.0952; found 282.0960.
3-((4-Methoxyphenyl)thio)quinoline (4a). Purified by column
chromatography (0−100% EtOAc in hexanes). Isolated as a colorless
solid (46.2 mg, 0.17 mmol, 86% yield). 1H NMR (600 MHz,
Chloroform-d) δ 8.73 (d, J = 2.2 Hz, 1H), 8.04 (d, J = 8.8 Hz, 1H),
7.81 (d, J = 1.9 Hz, 1H), 7.65−7.59 (m, 2H), 7.51−7.39 (m, 3H), 6.92
(d, J = 8.8 Hz, 2H), 3.82 (s, 3H). 13C{1H} NMR (151 MHz,
Chloroform-d) δ 160.3, 150.6, 146.3, 135.5, 134.0, 132.8, 129.3, 129.1,
128.3, 127.3, 127.1, 123.0, 115.4, 55.5. HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C16H13NOS 268.0796; found 268.0802.
1
spectrometer (600 MHz for H, 151 MHz for 13C, and 564 MHz for
19F) equipped with a room temperature BBO SmartProbe probe. All
chemical shifts (δ) are reported in parts per million (ppm). Proton
resonances are referenced to residual protium in the NMR solvent.
Carbon resonances are referenced to the carbon resonances of the
NMR solvent. Data are represented as follows: chemical shift,
multiplicity (br = broad, s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet), coupling constants (J) in hertz (Hz),
integration. LCMS samples were run on an Agilent 1100 or 1200
system. High-resolution mass spectrometry (HRMS) data were
recorded on a Waters Xevo G2 QTof instrument in either ESI+ or
ESI− (electrospray) ionization mode. All reactions were conducted
using Penn PhD Photoreactor M2 with a 450 nm light module (spectral
distribution ∼415−495 nm with max intensity at 450 nm; average
power output is 2.1 W).26,27 The [Ni(dtbbpy)(OH2)4]Cl2 and
[Ni(4,4′-OMebpy)(OH2)4]Cl2 nickel precatalyst were made according
to literature precedent.28
HTE Screening Procedure. Twenty-four reaction conditions were
examined through a high-throughput screen on 10 μmol scale using a
Lumidox Gen II LED array (470 nm) as the light source. Three
photoredox catalysts (Ir[dF(CF3)ppy]2(dtbbpy))PF6, (Ir[dF(Me)-
ppy]2(dtbbpy))PF6, and 4-DPA-IPN (5 mol %) were predosed and
dried down in each well. Finely ground Cs2CO3 (2 equiv) was dosed
into 12 wells (see Supporting Information Table S1). Eight stock
solutions were prepared. Two vials were charged with [Ni(dtbbpy)-
(OH2)4]Cl2 (5 mol %), one vial being diluted with DMF and the other
being diluted with MeCN (20 μL per dose). Two vials were charged
with [Ni(4,4′-OMebpy)(OH2)4]Cl2 (5 mol %), one vial being diluted
with DMF and the other being diluted with MeCN (20 μL per dose).
Two vials were charged with 3-bromoquinoline (1 equiv), 2-((4-
methoxyphenyl)thio)acetic acid (1.5 equiv), and DBU (2 equiv), one
vial being diluted with DMF and the other being diluted with MeCN
(40 μL per dose). Two vials were charged with 3-bromoquinoline (1
equiv) and 2-((4-methoxyphenyl)thio)acetic acid (1.5 equiv), one vial
being diluted with DMF and the other being diluted with MeCN (40 μL
For a second example, 2-((4-methoxyphenyl)thio)propanoic
acid29,30 (63.7 mg, 0.30 mmol, 1.5 equiv) (synthesized using ref 29,
NMR spectra in agreement with ref 30) was used as the acid instead of
2-((4-methoxyphenyl)thio)acetic acid. All NMR spectra are in
agreement. Isolated as a colorless solid (30.0 mg, 0.11 mmol, 56%
yield).
C−S Coupling on 1 mmol Scale. 3-Bromoquinoline (208 mg,
1.00 mmol, 1 equiv), [(4-methoxyphenyl)thio] acetic acid (297 mg
1.50 mmol, 1.5 equiv), (Ir[dF(Me)ppy]2(dtbbpy))PF6 (10.1 mg, 0.010
mmol, 0.01 equiv), and [Ni(dtbbpy)(OH2)4]Cl2 (47.0 mg, 0.10 mmol,
0.1 equiv) were added to a 20 mL vial. Acetonitrile (10.0 mL, 0.1 M)
was added, followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (0.224 mL,
1.50 mmol, 1.5 equiv). The reaction mixture was capped and bubble
degassed with argon for 5 min. The vial was parafilmed, placed in the
Penn PhD Photoreactor M2, and irradiated with 450 nm light for 15 h
with settings set at 4700 fan rpm, 500 stirring rpm, and 100% light
irradiation. The reaction was concentrated and purified by colmn
10917
https://doi.org/10.1021/acs.joc.1c01309
J. Org. Chem. 2021, 86, 10914−10920

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
chromatography (0−100% EtOAc in hex) to afford 3-((4-methoxy-
phenyl)thio)quinoline (4a) as a colorless solid (211 mg, 79% yield).
3-(Phenylthio)quinoline (4b). Purified by column chromatog-
raphy (0−100% EtOAc in hexanes). Isolated as a colorless oil (19.1 mg,
0.08 mmol, 40% yield). 1H NMR (600 MHz, Chloroform-d) δ 8.81 (s,
1H), 8.10 (m, 2H), 7.76−7.67 (m, 2H), 7.56 (t, J = 7.5 Hz, 1H), 7.41
(d, J = 7.2 Hz, 2H), 7.38−7.28 (m, 3H). 13C{1H} NMR (151 MHz,
Chloroform-d) δ 152.2, 146.7, 137.2, 134.4, 131.5, 130.2, 129.8, 129.7,
129.4, 128.4, 127.9, 127.4, 127.4. HRMS (ESI-TOF) m/z: [M + H]+
calcd for C15H11NS 238.0690; found 238.0700.
For a second example, 2-phenyl-2-(phenylthio)acetic acid (73.3 mg,
0.30 mmol, 1.5 equiv) was used as the acid instead of 2-(phenylthio)-
acetic acid. All NMR spectra are in agreement. Isolated as a colorless oil
(3.0 mg, 0.01 mmol, 6% yield).
For a third example, 2-methyl-2-(phenylthio)propanoic acid (58.9
mg, 0.30 mmol, 1.5 equiv) was used as the acid instead of 2-
(phenylthio)acetic acid. All NMR spectra are in agreement. Isolated as a
colorless oil (3.3 mg, 0.01 mmol, 7% yield).
3-(p-Tolylthio)quinoline (4c). Purified by column chromatog-
raphy (0−100% EtOAc in hexanes). Isolated as a colorless oil (13.3 mg,
0.05 mmol, 27% yield). 1H NMR (600 MHz, Chloroform-d) δ 8.77 (d, J
= 2.1 Hz, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.98 (s, 1H), 7.71−7.65 (m,
2H), 7.53 (t, J = 7.5 Hz, 1H), 7.35 (d, J = 8.1 Hz, 2H), 7.18 (d, J = 8.0
Hz, 2H), 2.37 (s, 3H). 13C{1H} NMR (151 MHz, Chloroform-d) δ
151.6, 146.5, 138.5, 135.8, 132.6, 131.4, 130.5, 130.0, 129.5, 129.4,
128.4, 127.4, 127.3, 21.3. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C16H13NS 252.0847; found 252.0849.
linear gradient). Isolated as a light yellow oil (14.6 mg, 0.05 mmol, 25%
yield). 1H NMR (600 MHz, Chloroform-d) δ 8.76 (d, J = 2.2 Hz, 1H),
8.00 (d, J = 8.4 Hz, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.61 (d, J = 7.9 Hz,
1H), 7.59−7.55 (m, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.42 (d, J = 6.1 Hz,
3H), 7.32 (t, J = 7.6 Hz, 1H), 7.17 (t, J = 7.5 Hz, 1H), 3.88 (s, 3H).
13C{1H} NMR (151 MHz, Chloroform-d) δ 149.1, 146.0, 137.8, 135.3,
133.8, 131.3, 129.6, 129.3, 128.5, 128.4, 127.1, 126.9, 123.0, 121.0,
119.6, 110.1, 99.1, 33.4. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C18H14N2S 291.0956; found 291.0958.
3-(Pyridin-4-ylthio)quinoline (4i). Purified by column chroma-
tography (0−100% EtOAc in hexanes). Isolated as a colorless solid (3.9
mg, 0.02 mmol, 8% yield). 1H NMR (600 MHz, Chloroform-d) δ 8.93
(s, 1H), 8.42 (s, 1H), 8.39 (d, J = 5.0 Hz, 2H), 8.18 (d, J = 8.4 Hz, 1H),
7.88−7.81 (m, 2H), 7.65 (t, J = 7.4 Hz, 1H), 7.02 (d, J = 5.1 Hz, 2H).
13C{1H} NMR (151 MHz, Chloroform-d) δ 154.4, 149.9, 149.3, 148.0,
142.9, 131.3, 129.7, 128.3, 128.0, 127.9, 123.5, 121.3. HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C14H10N2S 239.0643; found 239.0650.
2-(Quinolin-3-ylthio)benzo[d]oxazole (4j). Purified by column
chromatography (0−100% EtOAc in hexanes). Isolated as a colorless
solid (2.1 mg, 0.008 mmol, 4% yield). 1H NMR (600 MHz,
Chloroform-d) δ 9.11 (d, J = 2.1 Hz, 1H), 8.60−8.57 (m, 1H), 8.19
(d, J = 8.5 Hz, 1H), 7.88 (d, J = 8.1 Hz, 1H), 7.85−7.80 (m, 1H), 7.65
(t, J = 7.5 Hz, 1H), 7.62−7.57 (m, 1H), 7.44−7.39 (m, 1H), 7.28 (m,
2H). 13C{1H} NMR (151 MHz, Chloroform-d) δ 162.1, 153.8, 152.2,
142.6, 141.9, 131.4, 129.5, 128.3, 128.1, 127.9, 124.8, 124.8, 121.4,
119.3, 110.3 HRMS (ESI-TOF) m/z: [M + H]+ calcd for C16H10N2OS
279.0592; found 279.0600.
3-(o-Tolylthio)quinoline (4d). Purified by column chromatog-
raphy (0−100% EtOAc in hexanes). Isolated as a colorless oil (17.6 mg,
0.07 mmol, 35% yield). 1H NMR (600 MHz, Chloroform-d) δ 8.74 (d, J
= 1.9 Hz, 1H), 8.09 (d, J = 7.7 Hz, 1H), 7.88 (s, 1H), 7.70−7.64 (m,
2H), 7.53 (t, J = 7.5 Hz, 1H), 7.36 (d, J = 7.7 Hz, 1H), 7.33−7.27 (m,
2H), 7.19 (t, J = 7.4 Hz, 1H), 2.43 (s, 3H). 13C{1H} NMR (151 MHz,
Chloroform-d) δ 151.2, 146.4, 140.2, 135.2, 133.4, 132.2, 131.0, 130.5,
129.3, 129.3, 128.6, 128.4, 127.3, 127.1, 20.7. HRMS (ESI-TOF) m/z:
[M + H]+ calcd for C16H13NS 252.0847; found 252.0855.
7-Methoxy-3-((4-methoxyphenyl)thio)quinoline (4k). Puri-
fied by column chromatography (0−100% EtOAc in hexanes). Isolated
1
as a colorless solid (46.6 mg, 0.16 mmol, 78% yield). H NMR (600
MHz, Chloroform-d) δ 8.70 (d, J = 2.1 Hz, 1H), 7.86 (d, J = 1.9 Hz,
1H), 7.53 (d, J = 9.0 Hz, 1H), 7.39 (d, J = 8.8 Hz, 2H), 7.36 (d, J = 2.2
Hz, 1H), 7.15 (dd, J = 9.0, 2.4 Hz, 1H), 6.88 (d, J = 8.8 Hz, 2H), 3.92 (s,
3H), 3.79 (s, 3H). 13C{1H} NMR (151 MHz, Chloroform-d) δ 160.7,
159.9, 151.7, 148.2, 135.6, 134.5, 129.3, 128.3, 124.5, 123.6, 120.4,
115.3, 107.4, 55.6, 55.5. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C17H15NO2S 298.0902; found 298.0901.
3-((4-Methoxyphenyl)thio)-7-(trifluoromethyl)quinoline
(4l). Purified by column chromatography (0−100% EtOAc in hexanes).
Isolated as a colorless oil (26.3 mg, 0.08 mmol, 39% yield). 1H NMR
(600 MHz, Chloroform-d) δ 8.76 (d, J = 2.3 Hz, 1H), 8.32 (s, 1H),
7.74−7.69 (m, 2H), 7.64 (dd, J = 8.6, 1.4 Hz, 1H), 7.53−7.48 (m, 2H),
7.00−6.94 (m, 2H), 3.86 (s, 3H). 13C{1H} NMR (151 MHz,
Chloroform-d) δ 160.9, 151.0, 144.9, 136.6, 136.5, 131.8, 130.5 (q,
3-((4-Fluorophenyl)thio)quinoline (4e). Purified by column
chromatography (0−100% EtOAc in hexanes). Isolated as a colorless
oil (20.3 mg, 0.08 mmol, 40% yield). 1H NMR (600 MHz, Chloroform-
d) δ 8.77 (s, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.99 (d, J = 1.7 Hz, 1H), 7.70
(t, J = 7.8 Hz, 2H), 7.55 (t, J = 7.3 Hz, 1H), 7.47−7.42 (m, 2H), 7.07 (t,
J = 8.6 Hz, 2H). 13C{1H} NMR (151 MHz, Chloroform-d) δ 165.7 (d, J
C−F = 278.9 Hz), 151.5, 146.7, 136.2, 134.3 (d, J C−F = 8.3 Hz), 130.9,
129.7, 129.5, 128.9 (d, J C−F = 3.3 Hz), 128.3, 127.3 (d, J = 29.6 Hz),
116.8 (d, J
= 22.1 Hz). 19F NMR (564 MHz, Chloroform-d) δ
JC−F = 32.7 Hz), 129.8, 127.2 (q, J C−F = 4.3 Hz), 124.0 (q, J C−F = 272.4
C−F
−112.76. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C15H10FNS
256.0596; found 256.0603.
Hz), 123.0 (q, J C−F = 2.9 Hz), 121.2, 115.8, 55.6. 19F NMR (564 MHz,
Chloroform-d) δ −62.54. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C17H12F3NOS 336.0670; found 336.0666.
3-((4-(Trifluoromethyl)phenyl)thio)quinoline (4f). Purified by
column chromatography (0−100% EtOAc in hexanes). Isolated as a
3-((4-Methoxyphenyl)thio)quinoline-7-carbaldehyde (4m).
Purified by column chromatography (0−100% EtOAc in hexanes).
Isolated as a colorless solid (20.9 mg, 0.07 mmol, 35% yield). 1H NMR
(600 MHz, Chloroform-d) δ 10.16 (s, 1H), 8.76 (d, J = 2.2 Hz, 1H),
8.46 (s, 1H), 7.96 (dd, J = 8.5, 1.2 Hz, 1H), 7.73−7.59 (m, 2H), 7.51 (d,
J = 8.7 Hz, 2H), 6.99 (d, J = 8.7 Hz, 2H), 3.86 (s, 3H). 13C{1H} NMR
(151 MHz, Chloroform-d) δ 191.9, 161.0, 150.6, 145.5, 137.7, 136.7,
136.3, 135.3, 132.0, 131.4, 128.1, 124.1, 120.7, 115.8, 55.6. HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C17H13NO2S 296.0745; found
296.0752.
1
colorless oil (10.6 mg, 0.04 mmol, 17% yield). H NMR (600 MHz,
Chloroform-d) δ 8.88 (d, J = 2.1 Hz, 1H), 8.29 (d, J = 1.8 Hz, 1H), 8.14
(d, J = 8.4 Hz, 1H), 7.81−7.75 (m, 2H), 7.61 (t, J = 7.5 Hz, 1H), 7.53
(d, J = 8.3 Hz, 2H), 7.34 (d, J = 8.3 Hz, 2H). 13C{1H} NMR (151 MHz,
Chloroform-d) δ 153.2, 147.1, 141.2, 140.6, 131.0, 130.8, 129.4, 129.1,
129.1 (q, J C−F = 32.8 Hz), 128.4, 127.9, 127.69, 127.1, 126.3 (q, J C−F
=
3.6 Hz), 124.0 (q, J C−F = 272.0 Hz). 19F NMR (564 MHz, Chloroform-
d) δ −62.59. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C16H10F3NS
306.0564; found 306.0569.
tert-Butyl (4-(Quinolin-3-ylthio)phenyl)carbamate (4g). Pu-
rified by column chromatography (0−100% EtOAc in hexanes).
Isolated as a colorless foam (57.3 mg, 0.16 mmol, 81% yield). 1H NMR
(600 MHz, Chloroform-d) δ 8.75 (d, J = 2.0 Hz, 1H), 8.04 (d, J = 8.5
Hz, 1H), 7.88−7.83 (m, 1H), 7.63 (t, J = 7.6 Hz, 2H), 7.49 (t, J = 7.5
Hz, 1H), 7.41 (s, 4H), 7.04 (s, 1H), 1.50 (s, 9H). 13C{1H} NMR (151
MHz, Chloroform-d) δ 152.7, 150.8, 146.3, 139.2, 134.7, 134.2, 132.0,
129.3, 129.2, 128.3, 127.3, 127.1, 125.8, 119.5, 80.9, 28.3. HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C20H20N2O2S 353.1323; found
353.1328.
6-Chloro-3-((4-methoxyphenyl)thio)quinoline (4n). Purified
by column chromatography (0−100% EtOAc in hexanes). Isolated as a
pale yellow oil (33.3 mg, 0.11 mmol, 55% yield). 1H NMR (600 MHz,
Chloroform-d) δ 8.67 (d, J = 2.2 Hz, 1H), 7.95 (d, J = 8.9 Hz, 1H), 7.59
(dd, J = 9.9, 2.1 Hz, 2H), 7.53 (dd, J = 8.9, 2.3 Hz, 1H), 7.50−7.44 (m,
2H), 6.97−6.91 (m, 2H), 3.84 (s, 3H). 13C{1H} NMR (151 MHz,
Chloroform-d) δ 160.7, 150.1, 136.2, 134.9, 133.1, 131.8, 130.9, 129.8,
129.0, 125.7, 121.8, 115.6, 55.6. HRMS (ESI-TOF) m/z: [M + H]+
calcd for C16H12ClNOS 302.0406; found 302.0405.
5-((4-Methoxyphenyl)thio)pyrimidine (4o). Purified by column
chromatography (0−100% EtOAc in hexanes). Isolated as a colorless
oil (24.9 mg, 0.11 mmol, 57% yield). 1H NMR (600 MHz, Chloroform-
3-((1-Methyl-1H-indol-3-yl)thio)quinoline (4h). Purified by
reverse phase HPLC (MeCN/water with 0.1% NH4OH modifier,
10918
https://doi.org/10.1021/acs.joc.1c01309
J. Org. Chem. 2021, 86, 10914−10920

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
d) δ 8.94 (s, 1H), 8.45 (s, 2H), 7.45 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.8
Hz, 2H), 3.83 (s, 3H). 13C{1H} NMR (151 MHz, Chloroform-d) δ
160.9, 155.6, 155.3, 136.3, 135.5, 120.6, 115.7, 55.6. HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C11H10N2OS 219.0592; found 219.0594.
2-(3-((4-Methoxyphenyl)thio)pyridin-2-yl)propan-2-ol (4p).
Purified by reversed phase HPLC (MeCN/water with 0.1% NH4OH
modifier, linear gradient). Isolated as a colorless solid (5.0 mg, 0.02
mmol, 9% yield). 1H NMR (600 MHz, Chloroform-d) δ 8.28−8.25 (m,
1H), 7.40−7.36 (m, 2H), 7.27 (d, J = 6.5 Hz, 2H), 7.06−7.00 (m, 1H),
6.93 (d, J = 8.7 Hz, 2H), 3.84 (s, 3H), 1.78 (s, 6H). 13C{1H} NMR (151
MHz, Chloroform-d) δ 161.4, 160.5, 143.5, 138.6, 136.1, 133.3, 123.3,
122.9, 115.6, 72.4, 55.6, 28.5. HRMS (ESI-TOF) m/z: [M + H]+ calcd
for C15H17NO2S 276.1058; found 276.1057.
2-((4-Methoxyphenyl)thio)pyridine (4q). Purified by column
chromatography (0−100% EtOAc in hexanes). Isolated as a colorless
oil (25.7 mg, 0.12 mmol, 59% yield). 1H NMR (600 MHz, Chloroform-
d) δ 8.39 (d, J = 4.6 Hz, 1H), 7.53 (d, J = 8.7 Hz, 2H), 7.41 (td, J = 8.1,
1.6 Hz, 1H), 6.97−6.92 (m, 3H), 6.78 (d, J = 8.1 Hz, 1H), 3.84 (s, 3H).
13C{1H} NMR (151 MHz, Chloroform-d) δ 162.9, 160.8, 149.5, 137.6,
136.8, 121.2, 120.5, 119.6, 115.4, 55.5. HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C12H11NOS 218.0640; found 218.0640.
(dddd, J = 33.7, 13.5, 8.9, 4.5 Hz, 2H), 2.15 (ddt, J = 13.6, 9.5, 5.4 Hz,
2H), 1.16 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (151 MHz, DMSO-d6) δ
159.8, 154.5, 154.5, 145.4, 140.2, 137.8, 137.2, 137.1, 135.1, 133.9,
132.7, 131.7, 130.6, 128.8, 125.8, 122.2, 115.5, 60.7, 55.3, 44.3, 30.6,
30.6, 30.3, 30.2, 14.6. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C29H29ClN2O3S 521.1666; found 521.1660.
3-((5-((4-Methoxyphenyl)thio)pyridin-2-yl)oxy)-5,5-dimeth-
yl-4-(4-(methylsulfonyl)phenyl)furan-2(5H)-one (4w). Purified
by reversed phase HPLC (MeCN/water with 0.1% NH4OH modifier,
linear gradient). Isolated as a tan solid (12.4 mg, 0.03 mmol, 12% yield).
1H NMR (600 MHz, DMSO-d6) δ 8.06 (d, J = 2.4 Hz, 1H), 8.01 (d, J =
8.4 Hz, 2H), 7.84 (d, J = 8.4 Hz, 2H), 7.73 (dd, J = 8.6, 2.3 Hz, 1H), 7.42
(d, J = 8.6 Hz, 2H), 7.15 (d, J = 8.6 Hz, 1H), 6.99 (d, J = 8.6 Hz, 2H),
3.76 (s, 3H), 3.25 (s, 3H), 1.69 (s, 6H). 13C{1H} NMR (151 MHz,
DMSO-d6) δ 165.1, 159.8, 159.7, 149.1, 147.4, 142.0, 141.7, 136.3,
134.6, 133.4, 129.5, 128.9, 127.6, 123.3, 115.4, 111.8, 84.6, 55.3, 43.2,
25.8. HRMS (ESI-TOF) m/z: [M
+
H]+ calcd for
C25H23NO6S2498.1045; found 498.1045.
tert-Butyl (S,Z)-(4-(4-((4-Methoxyphenyl)thio)thiophen-2-
yl)-1,4-dimethyl-6-oxotetrahydropyrimidin-2(1H)-ylidene)-
carbamate (4x). Purified by reversed phase HPLC (MeCN/water
with 0.1% NH4OH modifier, linear gradient). Isolated as a colorless
solid 23.1 mg, 0.05 mmol, 25% yield). 1H NMR (600 MHz, DMSO-d6)
δ 9.98 (s, 1H), 7.30 (d, J = 8.7 Hz, 2H), 7.24 (d, J = 1.3 Hz, 1H), 6.97−
6.93 (m, 3H), 3.75 (s, 3H), 3.20−3.10 (m, 2H), 3.02 (s, 3H), 1.67 (s,
3H), 1.43 (s, 9H). 13C{1H} NMR (151 MHz, DMSO-d6) δ 167.5,
163.0, 159.1, 156.7, 150.0, 132.8, 131.5, 126.0, 124.6, 124.0, 115.2, 78.6,
55.3, 53.0, 44.2, 29.2, 27.9, 27.9. HRMS (ESI-TOF) m/z: [M + H]+
calcd for C22H27N3O4S2 462.1521; found 462.1521.
6-Methoxy-2-((4-methoxyphenyl)thio)quinoline (4r). Puri-
fied by column chromatography (0−100% EtOAc in hexanes). Isolated
1
as a colorless solid (32.1 mg, 0.11 mmol, 54% yield). H NMR (600
MHz, Chloroform-d) δ 7.88 (bs, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.62−
7.54 (m, 2H), 7.32 (d, J = 8.6 Hz, 1H), 7.01−6.96 (m, 3H), 6.89 (d, J =
8.7 Hz, 1H), 3.90 (s, 3H), 3.87 (s, 3H). 13C{1H} NMR (151 MHz,
Chloroform-d) δ 160.7, 159.8, 157.3, 144.2, 137.3, 135.5, 129.8, 126.7,
122.4, 121.6, 119.4, 115.3, 105.5, 55.6, 55.5. HRMS (ESI-TOF) m/z:
[M + H]+ calcd for C17H15NO2S 298.0902; found 298.0897.
5-((4-Methoxyphenyl)thio)-2-methylimidazo[1,2-a]-
vpyridine (4s). Purified by column chromatography (0−100% EtOAc
in hexanes). Isolated as a colorless oil (13.9 mg, 0.05 mmol, 26% yield).
1H NMR (600 MHz, Chloroform-d) δ 7.47 (d, J = 8.9 Hz, 1H), 7.32 (s,
1H), 7.23 (d, J = 8.8 Hz, 2H), 6.96 (dd, J = 8.8, 7.2 Hz, 1H), 6.89 (d, J =
8.8 Hz, 2H), 6.58 (d, J = 7.0 Hz, 1H), 3.80 (s, 3H), 2.87 (s, 3H).
13C{1H} NMR (151 MHz, Chloroform-d) δ 160.1, 147.3, 134.7, 133.4,
132.8, 123.9, 123.8, 123.6, 118.4, 117.1, 115.7, 55.5, 14.1. HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C15H14N2OS 271.0905; found
271.0911.
5-((4-Methoxyphenyl)thio)-2,3-dihydrobenzo[d]isothiazole
1,1-dioxide (4t). Purified by column chromatography (0−100%
EtOAc in hexanes). Isolated as a colorless solid (41.4 mg, 0.14 mmol,
67% yield). 1H NMR (600 MHz, Chloroform-d) δ 7.55 (d, J = 8.3 Hz,
1H), 7.46 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.2 Hz, 1H), 6.97 (d, J = 8.4
Hz, 2H), 6.92 (s, 1H), 4.99 (bs, 1H), 4.37 (s, 2H), 3.85 (s, 3H).
13C{1H} NMR (151 MHz, Chloroform-d) δ 161.0, 147.7, 138.0, 137.1,
132.1, 126.9, 121.5, 121.4, 120.8, 115.7, 55.6, 45.6. HRMS (ESI-TOF)
m/z: [M − H]− calcd for C14H13NO3S2 306.0258; found 306.0250.
Ethyl 8-((4-Methoxyphenyl)thio)-5-methyl-6-oxo-5,6-dihy-
dro-4H-benzo[f ]imidazo[1,5-a][1,4]diazepine-3-carboxylate
(4u). Purified by reversed phase HPLC (MeCN/water with 0.1%
NH4OH modifier, linear gradient). Isolated as a colorless solid (48.4
mg, 0.11 mmol, 57% yield). 1H NMR (600 MHz, DMSO-d6) δ 8.31 (s,
1H), 7.65 (d, J = 8.5 Hz, 1H), 7.55−7.50 (m, 2H), 7.48 (d, J = 2.2 Hz,
1H), 7.41 (dd, J = 8.5, 2.3 Hz, 1H), 7.11−7.06 (m, 2H), 4.93 (s, 1H),
4.47 (s, 1H), 4.30 (s, 2H), 3.82 (s, 3H), 3.05 (s, 3H), 1.32 (t, J = 7.1 Hz,
3H). 13C{1H} NMR (151 MHz, DMSO-d6) δ 165.1, 162.3, 160.4,
139.1, 136.5, 136.3, 135.2, 130.3, 129.5, 129.1, 128.8, 127.6, 123.8,
120.8, 115.7, 60.1, 55.4, 41.9, 35.1, 14.2. HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C22H21N3O4S 424.1331; found 424.1341.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c01309.
Experimental procedures, control experiments, mecha-
nistic experiments, and spectroscopic data for all new
compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
Alec H. Christian − Discovery Chemistry, Merck & Co., Inc.,
Boston, Massachusetts 02115, United States; orcid.org/
0000-0002-7032-230X; Email: alec.christian@merck.com
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c01309
Notes
The author declares no competing financial interest.
ACKNOWLEDGMENTS
■
Dr. Katrina Mennie, Dr. Andrew Neel, Dr. Cynthia Hong, Dr.
Duane DeMong, Dr. Umar Faruk Mansoor, Dr. Eric Phillips,
and Dr. Andrew Musacchio are thanked for helpful discussions
and editing of the manuscript. Dr. Brandon Vara is thanked for
initial samples of catalysts.
Ethyl 4-(8-Chloro-3-((4-methoxyphenyl)thio)-5,6-dihydro-
11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-
piperidine-1-carboxylate (4v). Purified by column chromatography
(0−100% EtOAc in hexanes). Isolated as a brown foam (97.7 mg, 0.19
mmol, 94% yield). 1H NMR (600 MHz, DMSO-d6) δ 8.13 (d, J = 2.0
Hz, 1H), 7.42 (d, J = 8.7 Hz, 2H), 7.38 (d, J = 2.0 Hz, 1H), 7.30 (d, J =
1.9 Hz, 1H), 7.20 (dd, J = 8.1, 2.0 Hz, 1H), 7.06 (d, J = 8.2 Hz, 1H), 6.99
(d, J = 8.8 Hz, 2H), 4.03 (q, J = 7.1 Hz, 2H), 3.77 (s, 3H), 3.63−3.55
(m, 2H), 3.30−3.10 (m, 4H), 2.76 (dtt, J = 14.2, 9.4, 5.0 Hz, 2H), 2.28
REFERENCES
■
(1) Shi, L.; Tu, B. P. Acetyl-CoA and the Regulation of Metabolism:
Mechanisms and Consequences. Current Opinion in Cell Biology;
Elsevier Ltd.: April 1, 2015; pp 125−131. DOI: 10.1016/
j.ceb.2015.02.003.
(2) Levine, R. L.; Mosoni, L.; Berlett, B. S.; Stadtman, E. R.
Methionine Residues as Endogenous Antioxidants in Proteins. Proc.
Natl. Acad. Sci. U. S. A. 1996, 93 (26), 15036−15040.
10919
https://doi.org/10.1021/acs.joc.1c01309
J. Org. Chem. 2021, 86, 10914−10920

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
(3) Paulsen, C. E.; Carroll, K. S. Cysteine-Mediated Redox Signaling:
Chemistry, Biology, and Tools for Discovery. Chem. Rev. 2013, 113 (7),
4633−4679.
(4) Lin, S.; Yang, X.; Jia, S.; Weeks, A. M.; Hornsby, M.; Lee, P. S.;
Nichiporuk, R. V.; Iavarone, A. T.; Wells, J. A.; Toste, F. D.; Chang, C. J.
Redox-Based Reagents for Chemoselective Methionine Bioconjuga-
tion. Science 2017, 355 (6325), 597−602.
(5) Beno, B. R.; Yeung, K.-S.; Bartberger, M. D.; Pennington, L. D.;
Meanwell, N. A. A Survey of the Role of Noncovalent Sulfur
Interactions in Drug Design. J. Med. Chem. 2015, 58 (11), 4383−4438.
(6) Zhao, C.; Rakesh, K. P.; Ravidar, L.; Fang, W. Y.; Qin, H. L.
Pharmaceutical and Medicinal Significance of Sulfur (SVI)-Containing
Motifs for Drug Discovery: A Critical Review. European Journal of
Medicinal Chemistry; Elsevier Masson s.r.l.: January 15, 2019; pp 679−
734. DOI: 10.1016/j.ejmech.2018.11.017.
Heteroaryl Bromides: Short Synthesis of Sulfoxaflor and Its SF5
Analog. Chem. - Eur. J. 2017, 23 (32), 7677−7681.
(22) Buitrago Santanilla, A.; Regalado, E. L.; Pereira, T.; Shevlin, M.;
Bateman, K.; Campeau, L.-C.; Schneeweis, J.; Berritt, S.; Shi, Z.-C.;
Nantermet, P.; Liu, Y.; Helmy, R.; Welch, C. J.; Vachal, P.; Davies, I. W.;
Cernak, T.; Dreher, S. D. Nanomole-Scale High-Throughput
Chemistry for the Synthesis of Complex Molecules. Science 2015, 347
(6217), 49−53.
(23) Mennen, S.; Alhambra, C.; Allen, C.; Barberis, M.; Berritt, S.;
̃
Brandt, T.; Campbell, A.; Castanón, J.; Cherney, A.; Christensen, M.;
Damon, D.; Eugenio de Diego, J.; García-Cerrada, S.; García-Losada,
P.; Haro, R.; Janey, J.; Leitch, D.; Li, L.; Liu, F.; Lobben, P.; MacMillan,
D.; Magano, J.; McInturff, E.; Monfette, S.; Post, R.; Schultz, D.; Sitter,
B.; Stevens, J.; Strambeanu, I.; Twilton, J.; Wang, K.; Zajac, M. The
Evolution of High-Throughput Experimentation in Pharmaceutical
Development and Perspectives on the Future. Org. Process Res. Dev.
2019, 23 (6), 1213−1242.
(7) Feng, M.; Tang, B.; Jiang, S. H. L.X. Sulfur Containing Scaffolds in
Drugs: Synthesis and Application in Medicinal Chemistry. Curr. Top.
Med. Chem. 2016, 16, 1200−1216.
(24) Kutchukian, P. S.; Dropinski, J. F.; Dykstra, K. D.; Li, B.;
DiRocco, D. A.; Streckfuss, E. C.; Campeau, L.-C.; Cernak, T.; Vachal,
P.; Davies, I. W.; Krska, S. W.; Dreher, S. D. Chemistry Informer
Libraries: A Chemoinformatics Enabled Approach to Evaluate and
Advance Synthetic Methods. Chem. Sci. 2016, 7 (4), 2604−2613.
(25) Ren, H.; Li, G.-F.; Zhu, B.; Lv, X.-D.; Yao, L.-S.; Wang, X.-L.; Su,
Z.-M.; Guan, W. How Does Iridium(III) Photocatalyst Regulate
Nickel(II) Catalyst in Metallaphotoredox-Catalyzed C−S Cross-
Coupling? Theoretical and Experimental Insights. ACS Catal. 2019, 9
(5), 3858−3865.
(26) Le, C.; Wismer, M.; Shi, Z.-C.; Zhang, R.; Conway, D.; Li, G.;
Vachal, P.; Davies, I.; MacMillan, D. A General Small-Scale Reactor To
Enable Standardization and Acceleration of Photocatalytic Reactions.
ACS Cent. Sci. 2017, 3 (6), 647−653.
(27) Svejstrup, T. D.; Chatterjee, A.; Schekin, D.; Wagner, T.; Zach, J.;
Johansson, M. J.; Bergonzini, G.; König, B. Effects of Light Intensity and
Reaction Temperature on Photoreactions in Commercial Photo-
reactors. ChemPhotoChem. 2021. DOI: 10.1002/cptc.202100059.
(28) Wang, X.; Davies, G.; Koschitzky, A.; Wisniewski, S.; Kelly, C.;
Molander, G. Photoredox Catalysis Enables Access to N-Function-
alized 2,1-Borazaronaphthalenes. Org. Lett. 2019, 21 (8), 2880−2884.
(29) Yeh, P.-P.; Daniels, D.; Cordes, D.; Slawin, A.; Smith, A.
Isothiourea-Mediated One-Pot Synthesis of Trifluoromethyl Sub-
stituted 2-Pyrones. Org. Lett. 2014, 16 (3), 964−967.
(30) Ple, P.; Marnett, L. J. Alkylaryl Sulfides as Peroxidase Reducing
Substrates for Prostaglandin H Synthase. Probes for the Reactivity and
Environment of the Ferryl-Oxo Complex. J. Biol. Chem. 1989, 264 (24),
13983−13993.
(8) McGrath, N. A.; Brichacek, M.; Njardarson, J. T. A Graphical
Journey of Innovative Organic Architectures That Have Improved Our
Lives. J. Chem. Educ. 2010, 87 (12), 1348−1349.
(9) Maķ osza, M. Electrophilic and Nucleophilic Aromatic Sub-
stitutions Are Mechanistically Similar with Opposite Polarity. Chem. -
Eur. J. 2020, 26 (67), 15346−15353.
(10) Xu, J.; Liu, R. Y.; Yeung, C. S.; Buchwald, S. L. Monophosphine
Ligands Promote Pd-Catalyzed C−S Cross-Coupling Reactions at
Room Temperature with Soluble Bases. ACS Catal. 2019, 9 (7), 6461−
6466.
(11) Sikari, R.; Sinha, S.; Das, S.; Saha, A.; Chakraborty, G.; Mondal,
R.; Paul, N. D. Achieving Nickel Catalyzed C−S Cross-Coupling under
Mild Conditions Using Metal−Ligand Cooperativity. J. Org. Chem.
2019, 84 (7), 4072−4085.
(12) Uyeda, C.; Tan, Y.; Fu, G. C.; Peters, J. C. A New Family of
Nucleophiles for Photoinduced, Copper-Catalyzed Cross-Couplings
via Single-Electron Transfer: Reactions of Thiols with Aryl Halides
Under Mild Conditions (O °C). J. Am. Chem. Soc. 2013, 135 (25),
9548−9552.
(13) Alvaro, E.; Hartwig, J. F. Resting State and Elementary Steps of
the Coupling of Aryl Halides with Thiols Catalyzed by Alkylbi-
sphosphine Complexes of Palladium. J. Am. Chem. Soc. 2009, 131 (22),
7858−7868.
(14) Xu, X.-B.; Liu, J.; Zhang, J.-J.; Wang, Y.-W.; Peng, Y. Nickel-
Mediated Inter- and Intramolecular C−S Coupling of Thiols and
Thioacetates with Aryl Iodides at Room Temperature. Org. Lett. 2013,
15 (3), 550−553.
(15) Kwong, F. Y.; Buchwald, S. L. A General, Efficient, and
Inexpensive Catalyst System for the Coupling of Aryl Iodides and
Thiols. Org. Lett. 2002, 4 (20), 3517−3520.
(16) Oderinde, M. S.; Frenette, M.; Robbins, D. W.; Aquila, B.;
Johannes, J. W. Photoredox Mediated Nickel Catalyzed Cross-
Coupling of Thiols With Aryl and Heteroaryl Iodides via Thiyl
Radicals. J. Am. Chem. Soc. 2016, 138 (6), 1760−1763.
(17) Du, Y.; Pearson, R. M.; Lim, C.-H.; Sartor, S. M.; Ryan, M. D.;
Yang, H.; Damrauer, N. H.; Miyake, G. M. Strongly Reducing, Visible-
Light Organic Photoredox Catalysts as Sustainable Alternatives to
Precious Metals. Chem. - Eur. J. 2017, 23 (46), 10962−10968.
(18) Qin, Y.; Sun, R.; Gianoulis, N. P.; Nocera, D. G. Photoredox
Nickel-Catalyzed C−S Cross-Coupling: Mechanism, Kinetics, and
Generalization. J. Am. Chem. Soc. 2021, 143 (4), 2005−2015.
(19) Zuo, Z.; Ahneman, D. T.; Chu, L.; Terrett, J. A.; Doyle, A. G.;
MacMillan, D. W. C. Merging Photoredox with Nickel Catalysis:
Coupling of α-Carboxyl sp3-Carbons with Aryl Halides. Science 2014,
345 (6195), 437−440.
(20) Shea, M. D.; Mansoor, U. F.; Hopkins, B. A. A Metal-
laphotoredox Method for the Expansion of Benzyl SAR on Electron-
Deficient Amines. Org. Lett. 2020, 22 (3), 1052−1055.
(21) Kanishchev, O. S.; Dolbier, W. R., Jr Ni/Ir-Catalyzed Photoredox
Decarboxylative Coupling of S-Substituted Thiolactic Acids with
10920
https://doi.org/10.1021/acs.joc.1c01309
J. Org. Chem. 2021, 86, 10914−10920