N-Methylation of Self-Immolative Thiocarbamates Provides Insights into the Mechanism of Carbonyl Sulfide Release

Article abstract of DOI:10.1021/acs.joc.0c02778

Hydrogen sulfide (H2S) is an important biomolecule, and self-immolative thiocarbamates have shown great promise as triggerable H2S donors with suitable analogous control compounds; however, thiocarbamates with electron-deficient payloads are less efficient H2S donors. We report here the synthesis and study of a series of N-methylated esterase-triggered thiocarbamates that block the postulated unproductive deprotonation-based pathway for these compounds. The relative reaction profiles for H2S release across a series of electron-rich and electron-poor N-Me aniline payloads are examined experimentally and computationally. We show that thiocarbamate N-methylation does block some side reactivity and increases the H2S release profiles for electron-poor donors. Additionally, we show that isothiocyanate release is not a competitive pathway, and rather that the reduced efficiency of electron-poor donors is likely due to other side reactions.

Full text of DOI:10.1021/acs.joc.0c02778

pubs.acs.org/joc
Article
N‑Methylation of Self-Immolative Thiocarbamates Provides Insights
into the Mechanism of Carbonyl Sulfide Release
Carolyn M. Levinn, Jenna L. Mancuso, Rachel E. Lutz, Haley M. Smith, Christopher H. Hendon,
and Michael D. Pluth*
Cite This: J. Org. Chem. 2021, 86, 5443−5451
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ABSTRACT: Hydrogen sulfide (H2S) is an important biomolecule, and self-
immolative thiocarbamates have shown great promise as triggerable H2S donors
with suitable analogous control compounds; however, thiocarbamates with
electron-deficient payloads are less efficient H2S donors. We report here the
synthesis and study of a series of N-methylated esterase-triggered thiocarbamates
that block the postulated unproductive deprotonation-based pathway for these
compounds. The relative reaction profiles for H2S release across a series of
electron-rich and electron-poor N-Me aniline payloads are examined experimentally and computationally. We show that
thiocarbamate N-methylation does block some side reactivity and increases the H2S release profiles for electron-poor donors.
Additionally, we show that isothiocyanate release is not a competitive pathway, and rather that the reduced efficiency of electron-
poor donors is likely due to other side reactions.
to both external and internal stimuli, including endogenous
levels of peroxide,16,17 bio-orthogonal chemistry,18 en-
zymes,19,20 thiols,21−23 acid,24 nucleophiles,25,26 and light.27−29
An attractive approach to tune the release rates of
thiocarbamate-based donors is to modify the electron donating
or withdrawing nature of the aniline payload. One would
expect that more electron-deficient anilines would favor an
increased rate of self-immolation by stabilizing the charge
build-up on the nitrogen atom in the COS-releasing transition
state.30 In our recent investigation into esterase-triggered
thiocarbamates, however, we failed to observe the expected
correlation between COS/H2S release rates and aniline σp
values. One explanation for this divergence is that electron-
withdrawing aniline payloads would acidify the thiocarbamate
N−H, resulting in potential deprotonation, isothiocyanate
formation, and benzyl alcohol release. This nonproductive
pathway would reduce the efficiency of COS/H2S release
(Figure 1b). Consistent with this hypothesis, Chakrapani and
co-workers invoked this competing deprotonation mechanism
in a similar system studying S-alkyl thiocarbamates with aryl
and benzyl amine payloads.17,31
INTRODUCTION
■
Hydrogen sulfide (H2S) is an important biomolecule that is
involved in cardioprotection from oxidative stress associated
with myocardial infarction and ischemia-reperfusion events1,2
and that has shown promising roles in potential treatments for
neurodegenerative diseases,3,4 including Parkinson’s5 and
Alzheimer’s diseases.6 Many H2S-related investigations, how-
ever, provide conflicting activities, with H2S having been
shown to have both pro-7 and anti-inflammatory,8,9 as well as
both pro-10 and antiapoptotic11,12 effects, depending on the
specific study. These prior results highlight the need for a
better understanding of how H2S is delivered in different
contexts and different tools to enable specific investigations.
This need has led many research groups to develop a broad
array of donor platforms to deliver known quantities of H2S
(or H2S equivalents) at controllable rates and in response to
specific stimuli.13
Rather than use H2S directly, chemists have developed a
variety of strategies to deliver H2S in biological environments.
For example, donor motifs have been developed in which
hydrolysis or thiolysis results in H2S release.13 Alternatively,
other approaches have utilized the intermediate release of
carbonyl sulfide (COS), which is rapidly converted to H2S by
the enzyme carbonic anhydrase (CA) (Figure 1a).14,15 One
common platform within this approach is the use of self-
immolative thiocarbamates that can be triggered by specific
stimuli to release COS. Moreover, these donor motifs provide
access to critical control compounds, including triggerless
control compounds and sulfur-depleted control compounds
that release CO2 rather than COS. Highlighting the diversity of
this platform, prior donors have been developed that respond
To investigate this hypothesis directly, here we report a
simple method for preparation of N-methylated thiocarba-
mates and assess the COS/H2S releasing efficiency of a library
Received: November 19, 2020
Published: April 5, 2021
https://doi.org/10.1021/acs.joc.0c02778
© 2021 American Chemical Society
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Figure 1. (a) Mechanism of COS/H2S release from self-immolative thiocarbamates. (b) Proposed competing breakdown pathways of
thiocarbamates that include self-immolative release of COS for electron-rich substrates (left, blue) and deprotonation to release an isothiocyanate
(red, right) for electron-poor substrates. (c) This work: N-methylation of thiocarbamate blocks the potential deprotonation pathway allowing for
COS-release from electron-poor substrates.
of N−H and N−Me self-immolative thiocarbamates (Figure
1c). Moreover, we provide computational insights into three
possible reaction trajectories, which reveals large thermal
barriers for isothiocyanate formation and supports thiocarba-
mate hydrolysis to thiocarbonic acid as a more likely
alternative route for electron-withdrawing substituents.
RESULTS AND DISCUSSION
■
Many commonly used methods to prepare thiocarbamates
involve the addition of an alcohol or mercaptan into an
isothiocyanate or isocyanate, respectively.30 Our initial
attempts to prepare N-methyl thiocarbamates focused on
direct methylation of the thiocarbamate nitrogen. Although
this method works well for the parent carbamate compounds,
similar approaches with thiocarbamates resulted in undesired
alkylation of the sulfur. We were able to circumvent this
problem by the addition of one equivalent of an N-methylated
aniline into thiocarbonyldiimidazole (TCDI) to produce an
Figure 2. Synthesis and yields of coupling partners and final O-alkyl
N-methyl thiocarbamate COS/H2S donors.
asymmetric mixed thiourea. This useful intermediate coupling
partner could then be further reacted with a benzyl alcohol to
access the desired N−Me O-alkyl thiocarbamates. Moreover,
this mixed thiourea approach provides a versatile platform for
accessing differently functionalized thiocarbamates that are
otherwise difficult to access through standard methods.
Following this protocol, we prepared a suite of N−Me
thiocarbamates with a range of electronically modified
payloads (Figure 2).32
from the thiocarbamates (50 μM) in phosphate-buffered saline
solutions (10 mM PBS, pH 7.4) with 2% DMSO in the
presence of carbonic anhydrase (CA, 50 μg/mL) and porcine
liver esterase (PLE, 5 U/mL) at 25 °C. The methylene blue
aliquots were passed through a 0.2 μm syringe filter prior to
absorbance measurements to remove any precipitated PLE
from the acidic methylene blue solution. On the basis of the
buildup of negative charge on the thiocarbamate in the
proposed COS-release mechanism, as well as prior work by the
With the N-methylated O-alkyl thiocarbamate donors in
hand, the COS/H2S release profiles were measured using the
colorimetric methylene blue assay.33 We measured H2S release
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Chakrapani lab demonstrating an inverse relationship between
N−H pKa and H2S release rate on S-alkyl thiocarbamates,31 we
hypothesized that installing electron-withdrawing substituents
on the payload would lead to faster peaking times and higher
overall amounts of H2S/COS released, with the p-NO2 donors
being the most efficient. Accordingly, what we observed was
that release from electron-rich donors peaked at the lowest
concentrations of H2S, whereas the electron-poor donors
peaked at higher H2S concentrations but with slower overall
peaking times (Figure 3, Figure S42).
Figure 4. H2S release profiles of select O-alkyl N-methyl and N−H
thiocarbamate donors. H2S concentrations were measured using the
methylene blue assay. Each experiment was performed in quad-
ruplicate.
precedes self-immolation TS1 to release a para-quinone
methide (QM) and a thiocarbamate anion intermediate. Our
computational investigations suggested that the water-assisted
COS-extrusion from the thiocarbamate anion intermediate
TS2 is significantly lower than the unassisted pathway. COS-
extrusion through TS2 results in release of the aniline payload,
which is subsequently protonated to yield an overall exergonic
reaction. We note that these final energies do not account for
the additional energy gain from rearomatization of the para-
quinone methide. Alternate path I (red) follows the possible
deprotonation-based reaction pathway, in which the thio-
carbamate N−H is deprotonated, resulting in release of an
isothiocyanate and a benzyl alkoxide, which is subsequently
protonated. Lastly, we investigated alternate path II (blue) that
intercepts the self-immolation pathway at the thiocarbamate
anion. Instead of COS extrusion, protonation of the
thiocarbamate anion to the thioacid and subsequent hydrolysis
would release the same aniline payload, alongside an equivalent
of thiocarbonic acid, which prior reports show can decompose
to release COS and H2O.35
When comparing the energy coordinate diagrams for the
self-immolation pathway (Figure 5 black, N−H (dot) and N−
Me (bar) donors), the relative energies of the first transition
state are very similar (ΔΔG ∼2.6 kcal/mol) for all of the
donors regardless of N-alkylation or payload electronics. The
stabilities of the resultant thiocarbamate anions, however, show
significant differences with the thiocarbamate anion from
HTCM-NO2 being ∼5 kcal/mol more stable than any other
donor investigated. The relative energies over the second
COS-releasing transition state TS2 are much more dispersed,
with the N−Me donor intermediates on average about 3 kcal/
mol higher in energy than their N−H counterparts.
Thiocarbamate methylation was expected to reduce reaction
rates due to mild electron-donation into the formally anionic
pathway, which is reflected in both the experimental (Figure 4)
and computational data (Figure 5b). Additionally, we
hypothesize that the steric bulk of the N-methyl relative to
Figure 3. H2S release profiles of O-alkyl N-methyl thiocarbamate
donors. H2S concentrations were measured using the methylene blue
assay. Each experiment was performed in quadruplicate.
To directly compare the effects of the N-methylation on
COS/H2S release from thiocarbamates, we next measured the
H2S release from p-NO2 and p-Me N−H thiocarbamate
donors. We found that N-methylation significantly increased
the observed H2S release from the p-NO2 donor relative to the
parent N−H as predicted, while MeTCM-Me was significantly
less efficient than the N−H donor (HTCM-Me). Interestingly,
the HTCM-Me donor displayed the fastest initial rate of H2S
release under these conditions, even when compared to the
MeTCM-NO2 donor (Figure 4).
To further probe the energetics of potential competing
pathways for COS/H2S release, we used DFT investigations to
directly compare how electronic modification of the different
substrates influenced alternative release pathways. Using
Gaussian 09,34 we optimized the different ground state and
transition state geometries for the pathways at the B3LYP/6-
311++G(d,p) level of theory. Using this approach, we
investigated the 1,6-self-immolation and COS extrusion
pathway (Figure 5a, black) and also two additional reaction
trajectories. Specifically, these included deprotonation of the
thiocarbamate N−H to release an isothiocyanate (Figure 5a
red, alternate path I), and protonation of the intermediate
thiocarbamate anion formed after self-immolation and
subsequent hydrolysis to form thiocarbonic acid (Figure 5a
blue, alternate path II).
Along the self-immolation/COS-extrusion pathway (Figure
5, black), deprotonation of the phenol to form the phenoxide
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Figure 5. (a) The intended reaction pathway for thiocarbamate scaffolds where R1 = H, Me and R2 = Me, F, OMe, NO2 is shown in black with
alternate paths I and II shown in red/triangles and blue/squares, respectively, that were investigated computationally in this study. (b) Gibbs Free
Energy coordinate diagram comparing the relative energies of each proposed reaction pathway recovered from B3LYP/6-311++G** including the
PCM for water as implemented in Gaussian09.
the N−H has a significant effect on the conformation of the
thiocarbamate, which could influence the orbital overlap
between the thiocarbamate moiety and the aryl ring of the
payload, impacting the rates of COS extrusion.36
likely plays a role in the observed reduced rates of H2S
production. For HTCM-Me, deprotonation at the nitrogen
and oxygen are effectively the same (54.8(6) and 54.9(2) kcal/
mol, respectively) and the transition state for isothiocyanate
formation could not be isolated, but would be expected to be
considerably less stable than when R2 = NO2.
Beyond the predictable slight electronic effects of N-
methylation, comparing the zero-point energy corrected energy
barriers for the rate-determining step of COS-release from the
thiocarbamate anions we see that scaffolds with electron-
donating groups in the R2-position have higher activation
barriers for COS release, whereas donors with electron-
withdrawing groups in the R2 position have lower barriers as
expected. The relative barriers for the rate-determining step
(TS2) for donors in which R2 = NO2 (MeTCM-NO2 and
HTCM-NO2), however, indicate that they should release H2S
much more efficiently than experimentally observed. To
examine whether this reduced production is the result of N−
H acidification, we next investigated deprotonation of the N−
H scaffold following the expected competing pathway to
isothiocyanate formation (alternative path I, Figure 5b black
triangles).
Deprotonation of the N−H in HTCM-NO2 is favorable as
expected, which is supported by the relative stability of the
resulting anion compared with deprotonation of the phenol
trigger, yet the activation barrier for benzyl alcohol release is
over 20 kcal/mol higher than the rate-determining step for
COS release (TS1), indicating that the benzyl alcohol release
pathway is largely inactive. The reversible deprotonation of the
acidified thiocarbamate N−H when R2 = NO2, however, still
On the basis of these parameters, we expect that alternate
path II (Figure 5a, blue, and Figure 5b, black squares), in
which the thiocarbamate anion is protonated and subsequently
hydrolyzed to reveal thiocarbonic acid, is likely a more
favorable competing pathway. Consistent with this idea, prior
reports have indicated that thiocarbonic acid dimer complexes
can decompose to generate two equivalents of COS and
H2O,35 which in this system would be converted to H2S by
CA. Potential energy surface scans performed to identify the
activation barrier for water attack at the thiocarboxylic acid
carbonyl revealed a barrierless transition (Figure S52) to
higher energy zwitterionic intermediates, for which equilibrium
structures could not be found, which is consistent with fast
decomposition. Notably, hydrolysis to complete alternate path
II is exergonic for R2 = NO2 scaffolds (−6.35 kcal/mol for
HTCM-NO2, −7.21 kcal/mol for MeTCM-NO2) but slightly
endergonic when R2 = Me (0.47 kcal/mol for HTCM-Me, 0.42
kcal/mol for MeTCM-Me) (squares and small dashed lines,
Figure 5b). To test this pathway experimentally, we monitored
for H2S release using the methylene blue assay from HTCM-
NO2 in the absence of CA and failed to observe significant H2S
release (Figure S47). These results suggest that if functional,
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syringe filter into disposable 1.5 mL cuvettes. Absorbance values at
670 nm were measured 1 h after addition of reaction aliquot. Each
experiment was performed in quadruplicate unless stated otherwise.
UV/vis spectra were acquired on an Agilent Cary 60 UV/vis
spectrophotometer equipped with a Quantum Northwest TC-1
temperature controller set at 25 0.05 °C.
Establishing the Calibration Curve for the Methylene Blue Assay.
Solutions containing 0.5 mL of methylene blue cocktail and 0.5 mL
PBS (pH 7.4) containing 5% DMSO, 5 U/mL PLE, and 50 μg/mL
CA were freshly prepared in disposable 1.5 mL cuvettes. Under inert
conditions, a 10 mM stock solution of NaSH (Strem Chemicals) in
PBS was prepared and diluted to 1 mM. Immediately after dilution,
varying amounts of the 1 mM NaSH stock was added to 1.0 mL
solutions for final concentrations of 10, 20, 30, 40, 50, and 60 μM.
Solutions were mixed, filtered through a 0.2 μm syringe filter,
incubated at room temperature for 1 h, and shielded from light.
Absorbance values at 670 nm were measured after 1 h.
Computational Methods. Density functional theory (DFT) as
implemented in Gaussian0934 with the hybrid functional B3LYP and
the triple-ζ Pople basis set with diffuse and polarization functions on
all atoms (6-311++G(d,p)) was employed to equilibrate all
intermediate and transition state structures. A superfine grid and
tight convergence criteria were used for all calculations. A self-
consistent reaction field was included with the dielectric constant of
water using the polarizable continuum model in order to simulate the
biological environment. Vibrational analysis was further performed to
recover thermodynamic values, including the zero-point energy
correction, and to ensure that ground state structures each had zero
negative frequencies, while all activated complexes had exactly one
corresponding to the appropriate bond breaking/forming reaction
coordinate.
Synthetic Procedures. General Procedure for the Synthesis of
N-Me Coupling Partners. General Procedure A. The para-
substituted N−Me aniline (1.0 equiv) and TCDI (2.0 equiv) were
dissolved in anhydrous THF (0.15 M solution based on aniline) in a
flame-dried round-bottomed flask equipped with a magnetic stir bar
under an inert N2 atmosphere. The reaction mixture was refluxed at
70 °C in a silicone oil bath overnight, and then the solvent was
removed under reduced pressure. The crude residue was dissolved in
EtOAc, quenched with brine, and extracted with EtOAc (3 × 20 mL).
The combined organic layers were dried over anhydrous MgSO4 and
purified via silica column chromatography (1:1 Hex:EtOAc).
General Procedure B. The para-substituted N−Me aniline (1.0
equiv) and TCDI (1.2 equiv) were dissolved in anhydrous THF (0.1
M solution based on aniline) and cooled to 0 °C in an ice bath under
an inert N2 atmosphere. NaH (1.1 equiv) was added, and the reaction
mixture was allowed to slowly warm to room temperature and stir
overnight. The reaction mixture was quenched with brine, extracted
with EtOAc (3 × 20 mL), and the combined organic layers were dried
over anhydrous MgSO4 and purified via silica column chromatog-
raphy (1:1 Hex:EtOAc).
this pathway is not a major contributor to H2S release over at
least the first few hours of donor activation.
CONCLUSIONS
■
In conclusion, we have designed a platform for the synthesis of
N-alkyl self-immolative thiocarbamate COS donors, which we
have shown to have significantly different rates of H2S release
than the parent N−H analogues. N-Methylation also allows for
access to thiocarbamates with electron deficient payloads,
which were otherwise slow to release H2S from the N−H
congeners. Using computational investigations into the
mechanism of COS release from O-alkyl thiocarbamates, we
show that the isothiocyanate formation pathway is energeti-
cally disfavored. The lower levels of H2S release from
thiocarbamates with electron-withdrawing payloads are likely
due to a combination of side reactions due to the acidity of the
N−H and the reduced electrophilicity of the carbonyl in the
thiocarbamate anion when compared to electron-rich systems.
We anticipate these findings will help to inform researchers in
future H2S donor design and will expand the chemical space
available for thiocarbamate-based COS donors.
EXPERIMENTAL SECTION
■
Synthesis/Spectral Details of Prepared Compounds. Re-
agents were purchased from Sigma-Aldrich, VWR, Acros Organics, or
Tokyo Chemical Industry (TCI) and were used as received.
Spectroscopic grade, inhibitor-free THF was deoxygenated by
sparging with argon followed by passage through a Pure Process
Technologies solvent purification system to remove water. Deuterated
solvents were purchased from Cambridge Isotope Laboratories and
used as received. Silica gel (SiliaFlash F60, Silicycle, 230−400 mesh)
was used for column chromatography. H, 13C{1H}, and 19F NMR
1
spectra were recorded on a Bruker 500 or 600 MHz instrument (as
indicated). Chemical shifts are reported in parts per million relative to
residual protic solvent resonances. Mass spectrometric measurements
were performed by the University of Illinois, Urbana−Champaign MS
facility. All air-free manipulations were performed under an inert
atmosphere using standard Schlenk techniques or an Innovative
Atmospheres N2-filled glovebox. HTCM-NO2, HTCM-F, and
HTCM-Me were prepared as described in the literature, with spectral
data matching those reported previously.30
H2S Detection Materials and Methods. H2S Detection
Materials and Methods. Phosphate buffered saline (PBS) tablets
(1X, CalBioChem) were used to prepare buffered solutions (140 mM
NaCl, 3 mM KCl, 10 mM phosphate, pH 7.4) in deionized water.
Buffer solutions were sparged with nitrogen to remove dissolved
oxygen and stored in an Innovative Atmosphere nitrogen-filled
glovebox. Donor stock solutions (in DMSO) were prepared inside a
nitrogen-filled glovebox immediately before use. PLE stock solutions
(in PBS) were freshly prepared in an N2-filled glovebox immediately
before use. CA stock solutions (in PBS) were freshly prepared in a
nitrogen-filled glovebox immediately before use.
CP-OMe was prepared with 4-methoxy-N-methylaniline and TCDI
according to the general procedure A and purified by column
chromatography (1:1 Hex:EtOAc) as described above. (reddish-
1
brown solid, 856 mg, 95% yield). H NMR (600 MHz, CDCl3) δ
(ppm) 7.69 (t, J = 1.02 Hz, 1H), 6.96 (m, 3H), 6.82 (m, 2H), 6.77
(dd, J = 1.02, 1.61 Hz, 1H), 3.81 (s, 3H), 3.76 (s, 3H). 13C{1H}
NMR (151 MHz, CDCl3) δ (ppm) 178.5, 158.9, 137.9, 137.7, 129.0,
125.7, 119.9, 115.3, 55.5, 47.2. IR (cm−1) 3462, 3147, 3003, 2970,
2362, 1739, 1604, 1584, 1524, 1504, 1472, 1459, 1364, 1312, 1288,
1228, 1217, 1168, 1127, 1104, 1092, 1066, 1036, 1015, 1006, 910.
HRMS m/z [M + H]+ calcd. for [C12H14N3OS]+ 248.0858, found
248.0852.
General Procedure for Measuring H2S Release with the
Methylene Blue Assay (MBA). Scintillation vials containing 20 mL
of 10 mM PBS (pH 7.4) with 2% DMSO were prepared in a nitrogen-
filled glovebox. To these solutions, 100 μL of 10 mg mL−1 CA and 50
μL of a 20 mM DMSO donor stock were added for final
concentrations 50 μg mL−1 and 50 μM, respectively. Immediately
prior to PLE addition, 0.5 mL solutions of methylene blue cocktail
were prepared. The methylene blue cocktail solution contains: 200 μL
of 30 mM FeCl3 in 1.2 M HCl, 200 μL of 20 mM N,N-dimethyl-p-
phenylenediamine in 7.2 M HCl, and 100 μL of 1% (w/v) Zn(OAc)2.
To begin an experiment, 100 μL of 1000 U/mL PLE stock solution
was added for a final concentration of 5 U/mL. At set time points
after the addition of PLE, 500 μL reaction aliquots were added to the
methylene blue cocktail solutions and incubated for 1 h at room
temperature shielded from light, then filtered through a 0.2 μm
CP-Me was prepared with 4-methyl-N-methylaniline and TCDI
according to the general procedure A and purified by column
chromatography (1:1 Hex:EtOAc) as described above. (off-white
1
solid, 378 mg, 99% yield). H NMR (500 MHz, CDCl3) δ (ppm)
7.65 (t, J = 0.94 Hz, 1H), 7.11 (d, J = 8.34 Hz, 2H), 6.98 (t, J = 1.49
Hz, 1H), 6.92 (d, J = 8.34 Hz, 2H), 6.76 (dd, J = 0.94, 1.49 Hz, 1H),
3.81 (s, 3H), 2.30 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ
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(ppm) 178.5, 142.5, 138.3, 137.8, 130.7, 129.0, 124.3, 120.0, 47.0. IR
(cm−1) 3162, 2922, 1738, 1507, 1524, 1481, 1456, 1389, 1364, 1296,
1268, 1255, 1217, 1125, 1108, 1094, 1062, 1013, 912. HRMS m/z [M
+ H]+ calcd. for [C12H14N3S]+ 232.0908, found 232.0903.
heated to 40 °C in a silicone oil bath, and monitored by TLC. Upon
completion, the reaction mixture was quenched with brine, extracted
with EtOAc (3 × 10 mL), the combined organic layers were dried
over anhydrous MgSO4, and the crude product purified by silica gel
column chromatography (10:1 Hexanes:EtOAc). Unreacted coupling
partner was also isolated and purified.
MeTCM-OMe was prepared with CP-OMe and 4-
(hydroxymethyl)phenyl pivalate according to the general procedure
as described above and purified by column chromatography (10:1
Hex:EtOAc) (24 mg, 9% yield, off-white solid). 1H NMR (600 MHz,
DMSO-d6, 60 °C) δ (ppm) 7.36−6.82 (m, 8H), 5.47 (bs, 2H), 3.78
(s, 3H), 3.55 (bs, 3H), 1.31 (s, 9H). 13C{1H} NMR (151 MHz,
DMSO-d6, 60 °C) δ (ppm) 188.4, 176.7, 170.7, 158.7, 150.9, 134.0,
129.0, 129.0, 128.9, 127.4, 121.9, 114.9, 71.9, 60.1, 55.9, 55.3 39.0,
27.2, 21.2, 14.5. IR (cm−1) 2969, 2930, 2359, 1748, 1608, 1509, 1478,
1383, 1277, 1246, 1194, 1164, 1112, 1030, 941. HRMS m/z [M +
H]+ calcd. for [C21H26NO4S]+ 388.1583, found 388.1579.
CP-H was prepared with N-methylaniline and TCDI according to
the general procedure A and purified by column chromatography (1:1
Hex:EtOAc) as described above. (colorless oil, 606 mg, 75% yield).
1H NMR (600 MHz, CDCl3) δ (ppm) 7.69 (t, J = 1.0 Hz, 2H), 7.33
(m, 2H), 7.27 (m, 1H), 7.05 (m, 2H), 6.96 (t, J = 1.48 Hz, 1H), 6.76
(dd, J = 1.0, 1.48 Hz, 1H), 3.84 (s, 3H). 13C{1H} NMR (151 MHz,
CDCl3) δ (ppm) 178.6, 145.0, 137.9, 130.2, 129.1, 128.1, 124.6,
119.9, 46.9. IR (cm−1) 3118, 2913, 1593, 1518, 1491, 1466, 1382,
1359, 1293, 1221, 1177, 1117, 1096, 1071, 1018, 1001, 917. HRMS
m/z [M + H]+ calcd. for [C11H12N3S]+ 218.0752, found 218.0744.
CP-F was prepared with 4-fluoro-N-methylaniline and TCDI
according to the general procedure A and purified by column
chromatography (1:1 Hex:EtOAc) as described above. (pale yellow
solid, 1.04 g, 55% yield). 1H NMR (600 MHz, CDCl3) δ (ppm) 7.69
(t, J = 1.01 Hz, 1H), 7.06−7.01 (m, 4H), 6.95 (t, J = 1.49 Hz, 1H),
6.80 (dd, J = 1.01, 1.49 Hz, 1H), 3.81 (s, 3H). 13C{1H} NMR (151
MeTCM-Me was prepared with CP-Me and 4-(hydroxymethyl)-
phenyl pivalate according to the general procedure as described above
and purified by column chromatography (10:1 Hex:EtOAc) (white
1
1
solid, 62 mg, 22% yield). H NMR (500 MHz, DMSO-d6, 60 °C) δ
MHz, CDCl3) δ (ppm) 178.9, 161.5 (d, C−F, JC−F = 250.4 Hz),
4
(ppm) 7.55−6.83 (m, 8H), 5.48 (s, 2H), 3.54 (bs, 3H), 2.33 (s, 3H),
1.31 (s, 9H). 13C{1H} NMR (151 MHz, DMSO-d6, 60 °C) δ (ppm)
188.2, 176.7, 150.9, 137.2, 133.9, 130.1, 129.0, 122.1, 121.9, 71.9,
55.3, 39.0, 27.4, 27.2, 21.0. IR (cm−1) 3456, 3016, 2970, 2361, 1739,
1435, 1366, 1229, 1217, 1113. HRMS m/z [M + H]+ calcd. for
[C21H26NO3S]+ 372.1633, found 372.1627.
160.7, 141.0 (d, C−F, JC−F = 3.4 Hz), 137.8, 129.3, 126.4 (d, C−F,
2
3JC−F = 8.8 Hz), 119.8, 117.3 (d, C−F, JC−F = 22.9 Hz), 47.0. 19F
NMR (525 MHz, CDCl3) δ (ppm) −111.7 (m). IR (cm−1) 3456,
3016, 2970, 2945, 2362, 2343, 2131, 1739, 1504, 1435, 1365, 1303,
1283, 1228, 1217, 1157, 1095, 1073, 1019, 939, 914. HRMS m/z [M
+ H]+ calcd. for [C11H11N3SF]+ 236.0658, found 236.0651.
MeTCM-H was prepared with CP-H and 4-(hydroxymethyl)-
phenyl pivalate according to the general procedure as described above
and purified by column chromatography (10:1 Hex:EtOAc) (colorless
CP-OCF3 was prepared with 4-trifluoromethoxy-N-methylaniline
and TCDI according to the general procedure A and purified by
column chromatography (1:1 Hex:EtOAc) as described above.
1
1
oil, 50 mg, 19% yield). H NMR (500 MHz, DMSO-d6, 60 °C) δ
(yellow oil, 532 mg, 60% yield). H NMR (600 MHz, CDCl3) δ
(ppm) 7.49−7.20 (m, 7H), 7.04 (d, J = 8.03 Hz, 2H), 5.47 (s, 2H),
3.56 (s, 3H), 1.31 (s, 9H). 13C{1H} NMR (151 MHz, DMSO-d6, 60
°C) δ (ppm) 188.3, 176.7, 150.9, 133.9, 129.6, 129.0, 127.8, 126.6,
121.9, 72.0, 39.0, 27.2. IR (cm−1) 2970, 2933, 2875, 2360, 1748,
1594, 1494, 1462, 1384, 1364, 1277, 1229, 1213, 1189, 1163, 1151,
1112, 1029, 1017, 1005, 994, 944. HRMS m/z [M + H]+ calcd. for
[C20H24NO3S]+ 358.1477, found 358.1476.
(ppm) 7.72 (bs, 1H), 7.18 (d, J = 8.94 Hz, 2H), 7.10 (d, J = 8.94 Hz,
2H), 6.94 (bs, 1H), 6.80 (bs, 1H), 3.82 (s, 3H). 13C{1H} NMR (151
3
MHz, CDCl3) δ (ppm) 178.8, 148.16 (q, C−F, JC−F = 1.6 Hz),
1
143.3, 137.8, 129.5, 126.2, 122.5, 121.1 (q, C−F, JC−F = 257.6 Hz),
119.7, 46.8. 19F NMR (525 MHz, CDCl3) δ (ppm) −58.0 (bs). IR
(cm−1) 3115, 1501, 1468, 1383, 1363, 1249, 1203, 1159, 1118, 1096,
1015, 919. HRMS m/z [M + H]+ calcd. for [C12H11F3N3OS]+
302.0575, found 302.0565.
MeTCM-F was prepared with CP-F and 4-(hydroxymethyl)phenyl
pivalate according to the general procedure as described above and
purified by column chromatography (10:1 Hex:EtOAc) (colorless oil,
51 mg, 21% yield). 1H NMR (500 MHz, DMSO-d6, 60 °C) δ (ppm)
7.47−7.14 (m, 6H), 7.06 (d, J = 7.99 Hz, 2H), 5.48 (s, 2H), 3.54 (s,
3H), 1.31 (s, 9H). 13C{1H} NMR (151 MHz, DMSO-d6, 60 °C) δ
(ppm) 188.5, 176.7, 161.2 (d, C−F, 1JC−F = 244.8 Hz), 151.0, 133.8,
CP-CF3 was prepared with 4-trifluoromethyl-N-methylaniline and
TCDI according to the general procedure B and purified by column
chromatography (1:1 Hex:EtOAc) as described above. (yellow oil,
625 mg, 81% yield). 1H NMR (600 MHz, CDCl3) δ (ppm) 7.69 (d, J
= 1.0 Hz, 1H), 7.60 (d, J = 8.88 Hz, 2H), 7.18 (d, J = 8.88 Hz, 2H),
6.96 (t, J = 1.50 Hz, 1H), 6.80 (dd, J = 1.0, 1.50 Hz, 1H), 3.84 (s,
3H). 13C{1H} NMR (151 MHz, CDCl3) δ (ppm) 178.9, 148.0 (q,
C−F, 4JC−F = 1.3 Hz), 137.7, 129.8 (q, C−F, 2JC−F = 33.3 Hz), 129.7,
2
130.5, 129.8, 129.1, 128.8, 122.1, 122.0, 116.4 (d, C−F, JC−F = 22.6
Hz), 72.1, 55.2, 39.0, 27.2. 19F NMR (565 MHz, DMSO-d6, 60 °C) δ
(ppm) −114.6 (m). IR (cm−1) 3462, 2970, 2362, 1744, 1604, 1507,
1476, 1366, 1276, 1217, 1164, 1108, 1029, 1015, 940. HRMS m/z [M
+ H]+ calcd. for [C20H23NO3FS]+ 376.1383, found 376.1380.
MeTCM-OCF3 was prepared with CP-OCF3 and 4-
(hydroxymethyl)phenyl pivalate according to the general procedure
as described above and purified by column chromatography (10:1
3
1
127.4 (q, C−F, JC−F = 3.8 Hz), 125.0, 123.2 (q, C−F, JC−F = 272.3
Hz), 119.7, 46.6. 19F NMR (565 MHz, CDCl3) δ (ppm) −63.7. IR
(cm−1) 3113, 1614, 1590, 1515, 1466, 1417, 1388, 1361, 1320, 1301,
1285, 1253, 1223, 1165, 1117, 1096, 1062, 1014, 954, 919. HRMS m/
z [M + H]+ calcd. for [C12H11N3F3S]+ 286.0626, found 286.0616.
CP-NO2 was prepared with 4-nitro-N-methylaniline and TCDI
according to the general procedure B and purified by column
chromatography (1:1 Hex:EtOAc) as described above. (40 mg yellow
solid, 26% yield). 1H NMR (600 MHz, CDCl3) δ (ppm) 8.16 (d, J =
8.97 Hz, 2H), 7.67 (t, J = 1.08 Hz, 1H), 7.21 (d, J = 8.97 Hz, 2H),
6.95 (t, J = 1.44 Hz, 1H), 6.80 (dd, J = 1.08, 1.44 Hz, 1H), 3.83 (s,
3H). 13C{1H} NMR (151 MHz, CDCl3) δ (ppm) 178.9, 150.3, 146.2,
137.6, 130.0, 125.6, 125.4, 119.7, 46.4. IR (cm−1) 3460, 3132, 3071,
3016, 2970, 2944, 2360, 2128, 1739, 1607, 1591, 1515, 1487, 1456,
1366, 1304, 1285, 1227, 1217, 1122, 1104, 1073, 1017, 1009, 919.
HRMS m/z [M + H]+ calcd. for [C11H11N4O2S]+ 263.0603, found
263.0604.
1
Hex:EtOAc) (colorless oil, 42 mg, 14% yield). H NMR (500 MHz,
DMSO-d6, 60 °C) δ (ppm) 7.46 (d, J = 9.01 Hz, 2H), 7.40 (m, 2H),
7.30 (bs, 2H), 7.05 (d, J = 9.20 Hz, 2H), 5.49 (s, 2H), 3.56 (s, 3H),
1.31 (s, 9H). 13C{1H} NMR (126 MHz, DMSO-d6, 60 °C) δ (ppm)
188.4, 176.7, 151.0, 147.5, 133.7, 129.2, 129.0 (q, C−F, 1JC−F = 248.6
Hz), 122.1, 121.9, 121.4, 119.7, 72.2, 55.3, 39.0, 27.4. 19F NMR (565
MHz, DMSO-d6, 60 °C) δ (ppm) −56.9 (s). IR (cm−1) 3457, 2970,
2362, 2342, 1737, 1609, 1508, 1479, 1456, 1366, 1257, 1228, 1217,
1146, 1108, 1029, 1017, 939. HRMS m/z [M + H]+ calcd. for
[C21H23NO4F3S]+ 442.1300, found 442.1297.
MeTCM-CF3 was prepared with CP-CF3 and 4-(hydroxymethyl)-
phenyl pivalate according to the general procedure as described above
and purified by column chromatography (10:1 Hex:EtOAc) (colorless
General Procedure for the Synthesis of N-Methyl Thiocarba-
mates. 4-(Hydroxymethyl)phenyl pivalate was prepared according to
the literature procedure.37 4-(Hydroxymethyl)phenyl pivalate (1.0
equiv) and an N−Me coupling partner (5.0 equiv) were dissolved in
anhydrous THF (0.1 M solution) and put under an atmosphere of N2.
DBU (1.2 equiv) was added, and the reaction mixture was stirred,
1
oil, 30 mg, 10% yield). H NMR (600 MHz, DMSO-d6, 60 °C) δ
(ppm) 7.79 (d, J = 8.25 Hz, 2H), 7.57 (d, J = 8.25 Hz, 2H), 7.33 (d, J
= 8.52 Hz, 2H), 7.06 (d, J = 8.52 Hz, 2H), 5.51 (s, 2H), 3.58 (s, 3H),
1.31 (s, 9H). 13C{1H} NMR (126 MHz, DMSO-d6, 60 °C) δ (ppm)
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The Journal of Organic Chemistry
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Article
188.4, 176.7, 151.0, 133.6, 133.6, 129.8, 129.3, 129.1, 127.9, 126.7,
over anhydrous MgSO4, and the solvent removed under a vacuum.
The crude product was purified via silica gel column chromatography
(4:1 Hex:EtOAc) to yield 529 mg (59%) of the F-indoline-CP as a
yellow solid. 1H NMR (500 MHz, CDCl3, 25 °C) δ (ppm) 8.04 (bs,
1H), 7.18 (s, 1H), 7.13 (s, 1H), 6.93 (d, J = 7.74 Hz, 1H), 6.68 (t, J =
8.63 Hz, 1H), 6.08 (bs, 1H), 4.42 (t, J = 7.93 Hz, 2H), 3.16 (t, J =
7.93 Hz, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ (ppm) 171.7,
1
126.7, (q, C−F, JC−F = 246.4 Hz), 122.1 (m, unresolvable C−F
coupling from rotamers), 72.3, 39.0, 27.2. 19F NMR (565 MHz,
DMSO-d6, 60 °C) δ (ppm) −61.0. IR (cm−1) 2972, 2362, 1749,
1514, 1509, 1479, 1380, 1324, 1277, 1197, 1165, 1113, 1067, 1019.
HRMS m/z [M + H]+ calcd. for [C21H23NO3SF3]+ 426.1351, found
426.1343.
1
3
160.3 (d, C−F, JC−F= 246.7 Hz), 137.4 (d, C−F JC−F = 2.8 Hz),
MeTCM-NO2 was prepared with CP-NO2 and 4-(hydroxymethyl)-
phenyl pivalate according to the general procedure as described above
and purified by column chromatography (10:1 Hex:EtOAc) (white
3
136.9 (d, C−F, JC−F= 9.1 Hz), 128.7, 118.9, 116.8, 114.6 (d, C−F,
2
2JC−F = 24.0 Hz), 113.3 (d, C−F, JC−F = 24.0 Hz), 57.6, 27.3. 19F
1
solid, 46 mg, 33% yield). H NMR (600 MHz, DMSO-d6, 60 °C) δ
NMR (471 MHz, CDCl3, 25 °C) δ (ppm) 114.8 (s). HRMS m/z [M
+ H]+ calcd. for [C12H11N3FS]+ 248.0658, found 248.0664.
(ppm) 8.26 (d, J = 8.96 Hz, 2H), 7.64 (d, J = 8.96 Hz, 2H), 7.35 (d, J
= 8.35 Hz, 2H), 7.08 (d, J = 8.35 Hz, 2H), 5.52 (s, 2H), 3.60 (s, 3H),
1.31 (s, 9H). 13C{1H} NMR (126 MHz, DMSO-d6, 60 °C) δ (ppm)
188.4, 176.7, 151.1, 149.9, 146.4, 133.4, 129.4, 128.2, 124.9, 122.0,
72.5, 42.8, 39.0, 27.2. IR (cm−1) 3388, 2974, 2361, 1748, 1607.82,
1595, 1522, 1493, 1475, 1445, 1379, 1343, 1309, 1276, 1195, 1165,
F-Indoline-TCM. To a stirring solution of F-indoline-CP (529 mg,
2.14 mmol, 1.0 equiv) in THF (0.1 M) at 0 °C was added 4-
(hydroxymethyl)phenyl pivalate (89 mg, 0.43 mmol, 0.2 equiv) and
DBU (80 μL, 0.54 mmol, 0.25 equiv). The reaction mixture was
stirred for 3 h while warming to room temperature, quenched with
brine, and extracted with EtOAc. The combined organic layers were
dried over anhydrous MgSO4. The crude mixture was concentrated
and purified via silica column chromatography (8:1 Hex:EtOAc) to
yield F-indoline-TCM as a white solid (29.0 mg, 17% yield). 1H NMR
(600 MHz, DMSO-d6, 60 °C) δ (ppm) 7.62 (bs, 1H), 7.54 (d, J =
7.93 Hz, 2H), 7.17 (bs, 1H), 7.14 (d, J = 7.93 Hz, 2H), 6.96 (bs, 1H),
5.69 (bs, 2H), 4.34 (t, J = 8.30 Hz, 2H), 3.15 (m, 2H), 1.32 (s, 9H).
13C{1H} NMR (151 MHz, DMSO-d6, 60 °C) δ (ppm) 180.0, 176.7,
1112, 1029, 1013. HRMS m/z [M
+
Na]+ calcd. for
[C20H22N2O5SNa]+ 425.1147, found 425.1133.
S-Alkyl CP. N−Me p-toluidine (1.04 mL, 8.25 mmol, 1.0 equiv)
was added dropwise to a stirring solution of CDI (2.68 g, 16.50 mmol,
2.0 equiv) dissolved in anhydrous THF (83 mL, 0.1 M solution)
under an atmosphere of N2. The resulting solution was heated to
reflux in a silicone oil bath overnight. The reaction mixture was cooled
to room temperature, and the solvent was removed under a vacuum.
The remaining residue was dissolved in DCM, washed with water,
dried over anhydrous MgSO4, and concentrated to an off-white solid.
The crude product was taken forward without further purification
1
159.4 (d, C−F, JC−F = 240.0 Hz), 151.2, 137.8, 137.1, 133.6, 130.1,
129.2, 122.2, 118.3, 114.0 (d, C−F, 2JC−F = 25.0 Hz), 113.2 (d, C−F,
2JC−F = 22.3 Hz), 72.2, 54.8, 39.0, 27.2, 26.7. 19F NMR (565 MHz,
DMSO-d6, 60 °C) δ (ppm) −118.5 (bs). HRMS m/z [M + H]+ calcd.
for [C21H23FNO3S]+ 388.1383, found 388.1376.
1
(1.65 g, 92% yield, white solid). H NMR (500 MHz, CDCl3) δ
(ppm) 7.60 (bs, 1H), 7.18 (d, J = 8.14, 2H), 7.01 (d, J = 8.14, 2H),
6.91 (bs, 1H), 6.85 (bs, 1H), 3.47 (s, 3H), 2.35 (s, 3H). 13C{1H}
NMR (125 MHz, CDCl3) δ (ppm) 150.0, 140.2, 138.4, 137.5, 131.0,
128.3, 128.1, 125.7, 118.7, 40.3, 21.1. The unactivated coupling
partner (2.62 g, 12.2 mmol, 1.0 equiv) was dissolved in anhydrous
MeCN (61 mL, 0.2 M solution) and put under an atmosphere of N2.
MeI (3.03 mL, 48.7 mmol, 4.0 equiv) was added dropwise, and the
reaction mixture was heated to reflux in a silicone oil bath with
magnetic stirring overnight. Upon completion, the reaction mixture
was let cool and the solvent removed via rotary evaporation, to afford
the crude product, which was used with no further purification (4.2 g
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02778.
■
sı
NMR spectra, methylene blue data, computational data
(PDF)
1
crude dark reddish-brown solid, 97%). H NMR (500 MHz, CDCl3)
AUTHOR INFORMATION
Corresponding Author
■
δ (ppm) 9.76 (bs, 1H), 7.50 (s, 1H), 7.38 (d, J = 8.19, 2H), 7.26 (d, J
= 8.19, 2H), 7.03 (bs, 1H), 4.13 (s, 3H), 3.53 (s, 3H), 2.4 (s, 3H).
13C{1H} NMR (126 MHz, CDCl3) δ (ppm) 171.1, 145.9, 139.7,
138.4, 137.9, 131.4, 126.4, 123.6, 121.2, 60.4, 53.5, 41.3, 38.2, 21.2,
21.0, 14.2. IR (cm−1) 3438, 3043, 1723, 1642, 1580, 1532, 1509,
1410, 1365, 1304, 1268, 1145, 1109, 1045, 1016, 983, 948. HRMS m/
z [M]+ calcd. for [C13H16N3O]+ 230.1293, found 230.1299.
Michael D. Pluth − Department of Chemistry and
Biochemistry, Materials Science Institute, Knight Campus for
Accelerating Scientific Impact, Institute of Molecular Biology,
University of Oregon, Eugene, Oregon 97403, United States;
orcid.org/0000-0003-3604-653X; Email: pluth@
uoregon.edu
S-Alkyl MeTCM-Me. 4-(Mercaptomethyl)phenyl pivalate (40 mg,
0.18 mmol, 1.0 equiv) was added to a stirring solution of the S-alkyl
CP (70.1 mg, 0.20 mmol, 1.1 equiv) in anhydrous DCM (2 mL, 0.1
M solution). Et3N (30 μL, 0.21 mmol, 1.2 equiv) was added, and the
reaction mixture was stirred at room temperature for 8 h. The crude
reaction mixture was directly concentrated onto silica and purified via
silica gel column chromatography (4:1 Hex:EtOAc) to afford the
Authors
Carolyn M. Levinn − Department of Chemistry and
Biochemistry, Materials Science Institute, Knight Campus for
Accelerating Scientific Impact, Institute of Molecular Biology,
University of Oregon, Eugene, Oregon 97403, United States;
orcid.org/0000-0001-7857-7465
Jenna L. Mancuso − Department of Chemistry and
Biochemistry, Materials Science Institute, Knight Campus for
Accelerating Scientific Impact, Institute of Molecular Biology,
University of Oregon, Eugene, Oregon 97403, United States
Rachel E. Lutz − Department of Chemistry and Biochemistry,
Materials Science Institute, Knight Campus for Accelerating
Scientific Impact, Institute of Molecular Biology, University of
Oregon, Eugene, Oregon 97403, United States
1
product as a white solid (43 mg, 65% yield, white solid). H NMR
(500 MHz, CDCl3, 25 °C) δ (ppm) 7.29 (d, J = 8.52, 2H), 7.19 (d, J
= 8.20, 2H), 7.14 (d, J = 8.20, 2H), 6.94 (d, J = 8.52, 2H), 4.06 (s,
2H), 3.31 (s, 3H), 2.37 (s, 3H), 1.34 (s, 9H). 13C{1H} NMR (125
MHz, CDCl3) δ (ppm) 177.0, 168.4, 150.0, 135.7, 130.1, 130.0,
128.1, 121.4, 39.1, 38.4, 34.9, 27.1, 21.2. IR (cm−1) 3457, 3016, 2970,
2143, 1653, 1506, 1455, 1366, 1277, 1205, 1168, 1115, 1022, 901.
HRMS m/z [M + H]+ calcd. for [C21H26NO3S]+ 372.1633, found
372.1634.
F-Indoline-CP. 5-fluoroindoline (500 mg, 3.65 mmol, 1.0 equiv)
was added to a stirring solution of TCDI (1.30 g, 7.29 mmol, 2.0
equiv) in THF (0.1 M) under an atmosphere of N2. The reaction
mixture was heated at 50 °C in overnight in a silicone oil bath, cooled
to room temperature, quenched with brine, and extracted with
EtOAc. The combined organic layers were washed with brine, dried
Haley M. Smith − Department of Chemistry and Biochemistry,
Materials Science Institute, Knight Campus for Accelerating
Scientific Impact, Institute of Molecular Biology, University of
Oregon, Eugene, Oregon 97403, United States
5449
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The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(15) Levinn, C. M.; Cerda, M. M.; Pluth, M. D. Development and
Application of Carbonyl Sulfide-Based Donors for H2S Delivery. Acc.
Chem. Res. 2019, 52 (9), 2723−2731.
Christopher H. Hendon − Department of Chemistry and
Biochemistry, Materials Science Institute, Knight Campus for
Accelerating Scientific Impact, Institute of Molecular Biology,
University of Oregon, Eugene, Oregon 97403, United States;
orcid.org/0000-0002-7132-768X
(16) Zhao, Y.; Pluth, M. D. Hydrogen Sulfide Donors Activated by
Reactive Oxygen Species. Angew. Chem., Int. Ed. 2016, 55 (47),
14638−14642.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02778
(17) Zhao, Y.; Henthorn, H. A.; Pluth, M. D. Kinetic Insights into
Hydrogen Sulfide Delivery from Caged-Carbonyl Sulfide Isomeric
Donor Platforms. J. Am. Chem. Soc. 2017, 139 (45), 16365−16376.
(18) Steiger, A. K.; Yang, Y.; Royzen, M.; Pluth, M. D. Bio-
orthogonal ″click-and-release” donation of caged carbonyl sulfide
(COS) and hydrogen sulfide (H2S). Chem. Commun. 2017, 53 (8),
1378−1380.
(19) Steiger, A. K.; Marcatti, M.; Szabo, C.; Szczesny, B.; Pluth, M.
D. Inhibition of Mitochondrial Bioenergetics by Esterase-Triggered
COS/H2S Donors. ACS Chem. Biol. 2017, 12 (8), 2117−2123.
(20) Chauhan, P.; Bora, P.; Ravikumar, G.; Jos, S.; Chakrapani, H.
Esterase Activated Carbonyl Sulfide/Hydrogen Sulfide (H2S)
Donors. Org. Lett. 2017, 19 (1), 62−65.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Work described in this manuscript was supported by the NIH
(MDP; R01GM113030) and the NSF/GRFP (CML; DGE-
1309047). We thank Kaylin Fosnacht for assistance with
analysis of different compounds.
(21) Zhao, Y.; Steiger, A. K.; Pluth, M. D. Cysteine-activated
hydrogen sulfide (H2S) delivery through caged carbonyl sulfide
(COS) donor motifs. Chem. Commun. 2018, 54 (39), 4951−4954.
(22) Cerda, M. M.; Mancuso, J. L.; Mullen, E. J.; Hendon, C. H.;
Pluth, M. D. Use of Dithiasuccinoyl-Caged Amines Enables COS/
H2S Release Lacking Electrophilic Byproducts. Chem. - Eur. J. 2020,
26 (24), 5374−5380.
(23) Zhou, S. C.; Mou, Y. J.; Liu, M.; Du, Q.; Ali, B.; Ramprasad, J.;
Qiao, C. H.; Hu, L. F.; Ji, X. Y. Insights into the Mechanism of Thiol-
Triggered COS/H2S Release from N-Dithiasuccinoyl Amines. J. Org.
Chem. 2020, 85 (13), 8352−8359.
(24) Gilbert, A. K.; Zhao, Y.; Otteson, C. E.; Pluth, M. D.
Development of Acid-Mediated H2S/COS Donors That Respond to a
Specific pH Window. J. Org. Chem. 2019, 84 (22), 14469−14475.
(25) Powell, C. R.; Foster, J. C.; Okyere, B.; Theus, M. H.; Matson,
J. B. Therapeutic Delivery of H2S via COS: Small Molecule and
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M.; Matson, J. B. Functional N-Substituted N-Thiocarboxyanhydrides
as Modular Tools for Constructing H2S Donor Conjugates. ACS
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