Xanthates as Thiol Surrogates for Nucleophilic Substitution with Aryl Halides

Article abstract of DOI:10.1002/ejoc.202100647

We herein report an unprecedented xanthate-based protocol for the preparation of aryl-alkyl thioethers. Heating xanthates with aryl halides and namely cesium carbonate in methanol provides the target thioethers in generally good yields within short reaction times. This method allows one to avoid contact with odorous thiols and also to introduce substituents of which the corresponding thiols are virtually unavailable or inconvenient in use.

Full text of DOI:10.1002/ejoc.202100647

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Xanthates as thiol surrogates for nucleophilic substitution with
aryl halides
Authors: Anatolii I. Sokolov, Andrey A. Mikhaylov, Nadezhda S.
Baleeva, and Mikhail S. Baranov
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202100647
Link to VoR: https://doi.org/10.1002/ejoc.202100647
01/2020

10.1002/ejoc.202100647
European Journal of Organic Chemistry
FULL PAPER
Xanthates as thiol surrogates for nucleophilic substitution with
aryl halides
Anatolii I. Sokolov,[a,b] Andrey A. Mikhaylov,[a] Nadezhda S. Baleeva,[a, b] and Mikhail S. Baranov*[a, b]
[a]
Institute of Bioorganic Chemistry, Russian Academy of Sciences
Miklukho-Maklaya 16/10, 117997 Moscow, Russia
Pirogov Russian National Research Medical University
Ostrovitianov 1, 117997 Moscow, Russia
[b]
E-mail: baranovmikes@gmail.com
http://www.ibch.ru/en/structure/groups/heterocyclic
Supporting information for this article is given via a link at the end of the document.
A) Starts from RX and thiurea (by Lu 2014)
Abstract: We herein report an unprecedented xanthate-based
protocol for the preparation of aryl-alkyl thioethers. Heating xanthates
with aryl halides and namely cesium carbonate in methanol provides
the target thioethers in generally good yields within short reaction
times. This method allows one to avoid contact with odorous thiols
and also to introduce substituents of which the corresponding thiols
are virtually unavailable or inconvenient in use.
Selection of a base
for a specific halide is required
R
X
Base
R
S
S
Alkyl halide RX variation is limited
due to a number of side reactions
+
H2N NH2
Ar
TX100/H2O, heat
ArF
B) Starts from ArX and sulfur source (by Ma 2017 and 2019)
R
S
Under air
Suff iciently strong
heating is required
Incompatible with
OH
R
H2N NH2
S
+
140-170 °C
Ar
ArX
many functional groups
or Na2S2O3
Introduction
C) Starts from xanthate (This work)
S
Soft conditions
Combinatorial approach
Being the sixteenth most abundant element in the earth's crust
and eighth most abundant element in the human body, sulfur
significantly contributes to a diversity of organic chemistry. A
number of organosulfur compounds are found naturally and
demonstrate a wide range of biological properties. In this regard,
designing novel approaches to arranging C-S bond in various
organic compounds is a key challenge in the modern organic
synthesis. Formation of a C-S bond in aromatic substrates is
provided by a variety of metal-catalyzed methods,[1] although the
direct nucleophilic substitution with thiols remains important once
the reaction proceeds on an activated substrate. Generally, a thiol
partner needs to be synthesized, which can be achieved by a
number of synthetic approaches to thiols created. Most of them
are associated with the use thioacids,[2] thiourea,[3] and other
related compounds including xanthates and Na2S2O3.[4] As a
drawback, low- and medium molecular weight thiols are toxic, [5]
and notorious for their extremely unpleasant odors, what makes
the search for thiol surrogates an urgent task.
Cs2CO3
R
R
S
S
OEt
Diversity of functionalized
substituents due to prior
odorless xanthate isolation
+
MeOH
70 °C
Ar
ArX
CN
N
Cl
NO2
(HO)2B
Cl
O
N
S
O2
N
SBn
S
Inhibitor of the
Staphylococcus aureus
NorA efflux pump [18]
TRI-1
Inhibition of thioredoxin pathway
in cancer treatment [16]
Antimicobacterial [17]
Scheme 1. Methods for thioether synthesis that do not require isolation of thiols.
Examples of bioactive aryl-thioethers and their derivatives.
In this article, we would like to demonstrate that various xanthates
can also be used for this purpose under much milder conditions.
Although an extra step of xanthate synthesis is thus added, much
greater scope of the reaction partners is expected. Unlike thiourea
derivatives, xanthates can be obtained from a wide variety of
halides (as well mesylates, tosylates, etc[9], including very
inactive ones) by nucleophilic substitution,[10] from aromatic
diazonium salts by ion-radical reaction,[11] from C-H acids and
organometallic reagents by electrophilic xanthylation,[12] or even
by direct C-H activation of alkanes.[13] Moreover, given the
extensively explored by Prof. Samir Zard area of the xanthate
radical addition across the double bond,[4b, 14] virtually any
aliphatic xanthate is now available. Xanthates are almost odorless,
bench-stable and provide thiols under relatively mild basic
conditions.[15]
Thereby, reactions of aromatic nucleophilic substitution without
the isolation of thiols have become more popular. Thiourea is a
general reagent of choice in this case,[6] coupled with aryl halides
and alkyl halides [7] or even alcohols[8](Scheme 1). Such
protocols benefit from one-pot mixing three reagents, being
almost odorless and fulfilling requirements of green chemistry,
despite harsh conditions are required.
In this work, we have shown that, in the case of nucleophilic
substitution in aromatic halides, xanthate can be used as thiol
surrogates in the presence of cesium carbonate in methanol.
1
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10.1002/ejoc.202100647
European Journal of Organic Chemistry
FULL PAPER
S
O
KSCSOEt
1h-k 1o 1q 1r
, , ,
for 1a, 1c-g, 1l-n, 1p
for 1b
for
X = Cl
X = Br
X = I
Results and Discussion
R
RX
O
Acetone, 25oC
S
In the course of work on the preparation of thio derivatives, we
found that heating of the mixture of a xanthates, 2-chloro-3-
nitropyridine and a base in isopropanol leads to formation of a
corresponding aryl-thioethers. Earlier, a similar reaction with
potassium hydroxide in methanol was shown, but it was used only
for intramolecular conversion, only in one example, and its yield
turned out to be very low.[4b] Thus, we studied this transformation
in more detail and showed (Table 1) that the best result can be
achieved when cesium carbonate in methanol is used. Under
optimized conditions, a non-target alkoxy derivative is formed in a
minimal amount, and the yield of the target thioether is maximal.
Probably, good solubility of cesium carbonate in methanol
accounts for effective methoxide formation and subsequent
S
O
S
O
S
S
O
Bn
S
S
S
S
1d
(95%)
1a (98%)
1b (96%)
1c (95%)
Cl
F
Br
1e (91%)
1f (95%)
1g
(94%)
O
S
O
S
O
S
S
S
S
O
1j (97%)
1h
1i
(97%)
(96%)
O
N
O
S
S
O
S
O
O
S
S
S
O2N
1l
1m (95%)
1k
(94%)
O
(87%)
O
xanthate alcoholysis.
Table 1. Optimization of the reaction conditions
S
O
S
O
S
NC
S
S
O
S
BnS
O
NO2
SBn
NO2
NO2
Cl
1a
S
S
O
S
S
O
S
O
NC
1q
S
O
S
S
N
N
S
OMe
1p
(98%)
(96%)
S
N
1o
(88%)
Base, solvent
1n (87%)
2a
3
Cl
Entry
Solvent
iPrOH
EtOH
Time
2 h
Base
K2CO3
K2CO3
K2CO3
Temp.
80 oC
80 oC
70 oC
Resultb
(98%)
O
O
O
1s
1t (93%)
O
S
1
2
3
Conversion<50%
Conversion<50%
2a 65%, 3 20%
2a 60%,
S
O
S
2 h
1r (89%)
S
S
MeOH
2 h
Scheme 2. Synthesis of xanthates.
The reaction of these xanthates with 2-chloro-3-nitropyridine
proceeded in high yields in almost all cases (Scheme 3). Using
this approach, we synthesized a thiomethyl derivative 2b, which
otherwise requires the use of gaseous methylthiol, and
cyanomethyl derivative 2r, for which the corresponding thiol does
not exist at all. Reaction yields are decreased for allyl, metallyl,
caroboxymethyl and cyanomethyl derivatives. Probably, these
substrates underwent certain side reactions under the basic
medium. Due to the similar reason, the yield turned out to be
extremely low in case of propargyl and nitrobenzyl derivatives. In
these cases we were unable to isolate the target products from
the obtained mixture.
4
5
iPrOH
EtOH
2 h
2 h
Cs2CO3
Cs2CO3
80 oC
numerous by-
products
2a 40%,
80 oC
numerous by-
products
6
7
MeOH
MeOH
CH3CN
2 h
24 h
2 h
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
70 oC
25 oC
70 oC
70 oC
70 oC
2a 85%, 3 5%
Conversion<50%
Conversion<10%
Complex mixture
Complex mixture
8
9
CH3CN+water
water
2 h
2 h
10
a Reaction conditions: 1 mmol of 2-chloro-3-nitro-pyridine, 1.2 mmol of 1a, 1.3 mmol of a base
and 3 ml of corresponding solvent. b NMR determined.
Next, we carried out the synthesis of an extended series of
xanthates 1. The synthesis was performed using the classical
approach employing potassium xanthate and halides in acetone.
The yields for such
a transformation were often almost
quantitative (Scheme 2). Isolation of substances did not require
complex column purification. Filtration through a short pad of silica
was sufficient to achieve more than 90% purity, which was
satisfactory for the next stage.
2
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10.1002/ejoc.202100647
European Journal of Organic Chemistry
FULL PAPER
S
O
S
O
R
R
R'
R'
O2N
NO2
Cl
NO2
NO2
Cl
S
S
ArSR
R
S
Cs2CO3, MeOH, 70oC
NO2
Cs2CO3, MeOH, 70oC
Cl
N
Cl
N
N
R'
NO2
SBn
NO2
S
NO2
S
NO2
Bn
NO2
NO2
NO2
O
4a
N
O
N
O
N
S
O
N
CN
N
S
N
S
N
S
N
S
4b
(63%)
(87%)
4o
(52%)
4q (95%)
2a (76%)
2b (70%)
2c
2d
(74%)
(69%)
NO2
S
CN
CN
S
CN
NO2
NO2
NO2
O
O
N
N
SBn
N
N
S
N
S
N
S
N
S
O
4r (44%)
5a
(95%)
5c (78%)
5o (84%)
2g
2e
F
2f (84%)
NO2
Cl
(71%)
Br
(80%)
CF3
S
Cl
Cl
CF3
NO2
NO2
S
O
O
O
N
N
S
N
S
N
SBn
N
S
N
S
N
N
O
6a (~70%)
Br
2j (74%)
6b
7g (65%)
7n (21%)
NO2
2h (77%)
2i (82%)
(71%)
NMR determined yield
NO2
NO2
F3C
NO2
S
NO2
NO2
S
10 (83%)
CN
S
N
S
S
O
N
S
N
Cl
9 (79%)
8 (90%)
2m
2l
(83%)
2n (69%)
(67%)
NO2
NO2
NO2
NO2
SBn
O2N
O2N
Cl
SBn
O2N
CF3
SBn
O
N
S
N
S
N
S
CN
MeOOC
SBn
O
2q
2p
2r (39%)
2o
(49%)
(55%)
11
12
13
14
(43%)
(82%)
(43%)
(72%)
Limitations:
Limitations:
NO2 or COOMe
Too reactive
Give only MeO product
instantly
NO2
S
NO2
Yield < 10%
Complex mixtures
2k
No reaction
Cl
N
F
N
N
S
NO2
R
NO2
Scheme 3. Scope of 2-chloro-3-nitro-pyridine reaction with various xanthates.
The next step, we expanded the scope of the activated aryl
halides, including simple o- and p-chloronitrobenzenes (Scheme
4). We showed that proposed technique can be used for less
active derivatives, but it required prolonged reaction time (up to
40 hours).
NH2
CN
S
O
NH2
COOMe
CN
Cl
S
S
S
N
N
Cs2CO3, MeOH, 70oC
N
15a (88%)
15b
(95%)
R = CH2CN, CH2COOMe
Scheme 4. Scope of various aryl halides reaction.
The limitations of the approach are bound by the active aryl
halides (e.g., dinitrofluorobenzene), which react with methanol
readily before the S-nucleophile is released. In addition, less
reactive 2-chloropyridine cannot be involved in the reaction, since
methanol media cannot maintain sufficient temperature for the
reaction to begin. Meanwhile, the reaction with functionalized
xanthates 1q and 1r does not stop after the nucleophilic
substitution step for 2-chloro-nicotinonitrile. In this case, 3-
aminothieno[2,3-b]pyridines 15 are obtained in good yields.
Although this condition could be regarded as the limitation of the
devised protocol, such substances otherwise are available
through more sophisticated pathways according to literature
procedures and used for the further synthesis of many important
biologically active compounds.[19]
We also have shown that the approach proposed by us can be
used for the synthesis of the above-mentioned (Scheme 1)
antimicobacterial compounds on example of compound 16,[17]
although this specific reaction may require further optimization
(Scheme 5).
CN
S
CN
Cl
S
O
1t
Cl
N
S
N
Cl
Cs2CO3, MeOH, 70oC
16 (22%)
Scheme 5. Scale-up experiments and bio-active compound synthesis
The proposed reaction set-up is almost odorless, except for the
cases of less active substrates, or incomplete reaction when
formation of thiols and disulfides is clearly observed. This
3
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10.1002/ejoc.202100647
European Journal of Organic Chemistry
FULL PAPER
mmol) was added to the solution. The resulting mixture was stirred at room
temperature for 4 hours (in case of allyl, propargyl, and benzyl halides) or
24 hours (in case of alkyl halides). The solvent was evaporated; EtOAc
(100 mL) and water (30 mL) were added. The mixture was shaken untill all
solids dissolved. Water phase was discarded and organic phase was
washed with brine (3x30 mL). The solution was dried over Na2SO4. The
solvents were removed under reduced pressure. The crude product was
dissolved in EtOAc (20 mL) and filtered through a pad of silica gel (approx.
20 mL). The silica gel pad was additionally washed with EtOAc (50 mL).
The solvent was evaporated to afford desired xanthates with 90%+ purity
in almost quantitative yields. This purity was found to be suitable for the
next step. Moreover, deeper purification (column chromatography
engaging weakly polar eluents) leads to considerable losses of the product
and does not always significantly increase the purity.
confirms that the above-described process is likely to proceed via
cesium thiolate formation (Scheme 6).
S
O
R
Cs2CO3
S
O
O
S
Me
MeO
MeOH
+
R
S
-X
-X
ArX
ArX
SNAr
ArOMe
ArSR
Side product
Main product
Scheme 6. Proposed reaction mechanism
Nevertheless, reaction workup consists only of evaporation and
immediate column purification. This technology minimizes
contacts with an unpleasant odor since thiols are in a non-volatile
anionic form all the time.
Finally we performed the scale-up experiment using 2-chloro-3-
nitropyridine and xanthate 1a (Scheme 7, SI). The yields of
Preparation of the xanthates 1a,[20] 1b,[21] 1c,[22] 1d,[13] 1f,[23] 1k,[24]
1n,[25] 1p,[26] 1q,[27] 1r[27] asd 1s,[23] have already been described in
the literature.
reaction even slightly increase upon increase of scale.
(5.1 g, 24 mmol)
BnS
1a
O
NO2
SBn
NO2
S-benzyl O-ethyl carbonodithioate (1a).[20] Light yellowish oil (4.16 g,
98%); 1H NMR (700 MHz, DMSO-d6) δ=7.38 (d, J=7.4 Hz, 2H), 7.33 (t,
J=7.4 Hz, 2H), 7.27 (t, J=7.3 Hz, 1H), 4.63 (q, J=7.3 Hz, 2H), 4.40 (s, 2H),
1.35 (t, J=7.3 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ=213.1, 135.9,
128.9, 128.4, 127.3, 70.2, 39.2, 13.4; HRMS (ESI): m/z calcd for
2a
S
N
N
Cl
Cs2CO3, MeOH, 70oC
(3.2 g, 20 mmol)
3.9 g (80%)
Scheme 7. Scale-up experiment
C
10H13OS2+: 213.0402 [M+H]+; found: 213.0401.
O-ethyl S-methyl carbonodithioate (1b).[21] Light yellowish oil (2.62 g,
96%); 1H NMR (700 MHz, DMSO-d6) δ=4.63 (q, J=7.1 Hz, 2H), 2.55 (s,
3H), 1.36 (t, J=7.1 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ=215.3, 70.0,
18.4, 13.5; HRMS (ESI): m/z calcd for C4H9OS2+: 137.0089 [M+H]+; found:
137.0091.
Conclusion
Thus, in this paper, we proposed a new protocol for the synthesis
of aryl-alkyl thioethers. The novelty of the protocol consists in the
use of S-alkylated xanthates, which acts as the thiol surrogates.
The joint heating of xanthates, arylhalides and caesium carbonate
in methanol leads to the formation of aryl-thioethers in high yield.
This technique allows avoiding contact with unpleasant thiol odors
and also introducing substituents of which the corresponding
thiols are hardly obtainable, gaseous, or do not exist at all.
O-ethyl S-ethyl carbonodithioate (1c).[22] Light yellowish oil (2.85 g,
95%); 1H NMR (700 MHz, DMSO-d6) δ=4.63 (q, J=7.1 Hz, 2H), 3.11 (q,
J=7.4 Hz, 2H), 1.36 (t, J=7.1 Hz, 3H), 1.27 (t, J=7.4 Hz, 3H); 13C NMR (75
MHz, DMSO-d6) δ=214.2, 69.8, 29.4, 13.5, 13.4; HRMS (ESI): m/z calcd
for C5H11OS2+: 151.0246 [M+H]+; found 151.0249.
O-ethyl S-hexyl carbonodithioate (1d). Light yellowish oil (3.92 g, 95%);
1H NMR (700 MHz, DMSO-d6) δ=4.63 (q, J=7.1 Hz, 2H), 3.11 (t, J=7.4 Hz,
2H), 1.65-1.59 (m, 2H), 1.38-1.33 (m, 5H), 1.30-1.23 (m, 4H), 0.86 (q,
Experimental Section
J=7.4 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ=214.3, 69.8, 35.1, 30.7,
General Considerations: Commercially available reagents were used
without additional purification. E. Merck Kieselgel 60 was used for column
chromatography. Thin-layer chromatography (TLC) was performed on
silica gel 60 F254 glass-backed plates (MERCK). Visualization was
performed using UV light (254 or 312 nm) and staining with KMnO4. NMR
spectra were recorded on a 700 MHz Bruker Avance III NMR at 303°K,
Avance III 800 (with a 5-mm CPTXI cryoprobe) and Bruker Fourier 300.
Chemical shifts are reported relative to residue peaks of CDCl3 (7.27 ppm
for 1H and 77.0 ppm for 13C) or DMSO-d6 (2.51 ppm for 1H and 39.5 ppm
for 13C). Melting points were measured on a SMP 30 apparatus without
correction. High-resolution mass spectra (HRMS) spectra were recorded
on AB Sciex TripleTOF® 5600+ System using electrospray ionization (ESI).
The measurements were done in a positive ion mode (interface capillary
voltage – 5500 V); mass range from m/z 50 to m/z 3000; external or
internal calibration was done with ESI Tuning Mix, Agilent. A syringe
injection was used for solutions in acetonitrile, methanol, or water (flow
rate 20 μl/min). Nitrogen was applied as a dry gas; interface temperature
was set at 180°C. Elemental analysis was performed on vario MICRO
Cube (Elementar), these data are presented only for hardly ionisable
compounds, for which HRMS data were insufficient – compounds 9, 10,
12-14. IUPAC compound names were generated using ChemDraw
Software.
+
28.0, 27.9, 21.9, 13.7, 13.4; HRMS (ESI): m/z calcd for C9H19OS2
207.0872 [M+H]+; found: 207.0875.
:
O-ethyl S-4-fluorobenzyl carbonodithioate (1e). Light yellowish oil (4.19
g, 91%); 1H NMR (700 MHz, DMSO-d6) δ=7.45-7.39 (m, 2H), 7.16 (t, J=8.8
Hz, 2H), 4.63 (q, J=7.1 Hz, 2H), 4.39 (s, 2H), 1.36 (t, J=7.1 Hz, 3H); 13C
NMR (75 MHz, DMSO-d6) δ=213.0, 161.4 (d, J=243.6 Hz), 132.2, 130.9
(d, J=8.2 Hz), 115.2 (d, J=21.6 Hz), 70.2, 38.3, 13.4; HRMS (ESI): m/z
calcd for C10H12FOS2+: 231.0308 [M+H]+; found: 231.0307.
O-ethyl S-4-chlorobenzyl carbonodithioate (1f).[23] Light yellowish oil
(4.68 g, 95%); 1H NMR (700 MHz, DMSO-d6) δ=7.42-7.37 (m, 4H), 4.62
(q, J=7.1 Hz, 2H), 4.39 (s, 2H), 1.35 (t, J=7.1 Hz, 3H); 13C NMR (75 MHz,
DMSO-d6) δ=212.8, 135.2, 132.0, 130.7, 128.3, 70.3, 38.3, 13.4; HRMS
(ESI): m/z calcd for C10H12ClOS2+: 247.0013 [M+H]+; found: 247.0009.
O-ethyl S-4-bromobenzyl carbonodithioate (1g). Yellow solid (5.47 g,
94%); M.p 28-29°C; 1H NMR (700 MHz, DMSO-d6) δ=7.52 (d, J=8.4 Hz,
2H), 7.33 (d, J=8.4 Hz, 2H), 4.62 (q, J=7.1 Hz, 2H), 4.37 (s, 2H), 1.34 (t,
J=7.1 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ=212.7, 135.6, 131.2, 131.0,
+
120.5, 70.3, 38.3, 13.4; HRMS (ESI): m/z calcd for C10H12BrOS2
290.9507 [M+H]+; found: 290.9509.
:
General procedure for the synthesis of S-substituted-O-ethyl-
carbonodithioates (xanthates 1): Potassium ethyl xanthate (3.84 g, 24
mmol) was dissolved in acetone (100 mL). A corresponding halide (20
O-ethyl S-3-methoxybenzyl carbonodithioate (1h). Light yellowish oil
(4.65 g, 96%); 1H NMR (700 MHz, DMSO-d6) δ=7.25 (t, J=8.2 Hz, 1H),
4
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10.1002/ejoc.202100647
European Journal of Organic Chemistry
FULL PAPER
6.96-6.92 (m, 2H), 6.85 (brd, J=7.4 Hz, 1H), 4.63 (q, J=7.1 Hz, 2H), 4.37
(s, 2H), 3.74 (s, 3H), 1.36 (t, J=7.1 Hz, 3H); 13C NMR (75 MHz, DMSO-d6)
116.6, 71.3, 20.8, 13.3; HRMS (ESI): m/z calcd for C5H8NOS2+: 162.0042
[M+H]+; found: 162.0045.
δ=213.1, 159.2, 137.3, 129.5, 121.1, 114.5, 112.8, 70.2, 54.9, 39.2, 13.4;
+
HRMS (ESI): m/z calcd for C11H15O2S2
243.0504.
:
243.0508 [M+H]+; found:
Methyl 2-((ethoxycarbonothioyl)thio)acetate (1r).[27] Light yellowish oil
(3.46 g, 89%); 1H NMR (700 MHz, DMSO-d6) δ=4.61 (q, J=7.1 Hz, 2H),
4.06 (s, 2H), 3.67 (s, 3H), 1.34 (t, J=7.1 Hz, 3H); 13C NMR (75 MHz,
DMSO-d6) δ=212.6, 168.1, 70.7, 52.4, 36.9, 13.4; HRMS (ESI): m/z calcd
for C6H11O3S2+: 195.0144 [M+H]+; found: 195.0149.
O-ethyl S-2-methoxybenzyl carbonodithioate (1i). Light yellowish oil
(4.70 g, 97%); 1H NMR (700 MHz, DMSO-d6) δ=7.35 (brd, J=7.5 Hz, 1H),
7.29 (brt, J=8.0 Hz, 1H), 7.02 (d, J=8.0 Hz, 1H), 6.91 (t, J=7.4 Hz, 1H),
4.64 (q, J=7.1 Hz, 2H), 4.33 (s, 2H), 3.81 (s, 3H), 1.37 (t, J=7.1 Hz, 3H);
13C NMR (75 MHz, DMSO-d6) δ=213.7, 157.1, 130.3, 129.2, 123.2, 120.1,
110.8, 70.0, 55.4, 34.6, 13.4; HRMS (ESI): m/z calcd for C11H15O2S2
243.0508 [M+H]+; found: 243.0507.
O-ethyl S-4-methylbenzyl carbonodithioate (1s).[23] Light yellowish
solid (4.44 g, 98%); m.p. 24-26°C; 1H NMR (700 MHz, DMSO-d6) δ=7.25
(d, J=8.0 Hz, 2H), 7.13 (d, J=8.0 Hz, 2H), 4.63 (q, J=7.3 Hz, 2H), 4.35 (s,
2H), 2.27 (s, 3H), 1.36 (t, J=7.3 Hz, 3H); 13C NMR (75 MHz, DMSO-d6)
δ=213.3, 136.6, 132.7, 129.0, 128.8, 70.1, 39.0, 20.6, 13.4; HRMS (ESI):
m/z calcd for C11H15OS2+: 227.0559 [M+H]+; found: 227.0559.
+
:
S-((3,5-dimethylisoxazol-4-yl)methyl) O-ethyl carbonodithioate (1j).
Light yellowish oil (4.49 g, 97%); 1H NMR (700 MHz, DMSO-d6) δ=4.67 (q,
J=7.2 Hz, 2H), 4.22 (s, 2H), 2.39 (s, 3H), 2.19 (s, 3H), 1.36 (t, J=7.1 Hz,
3H); 13C NMR (75 MHz, DMSO-d6) δ=212.8, 166.7, 159.0, 108.4, 70.3,
27.4, 13.5, 10.8, 9.7; HRMS (ESI): m/z calcd for C9H14NO2S2+: 232.0460
[M+H]+; found: 232.0458.
O-ethyl S-3-chlorobenzyl carbonodithioate (1t). Light yellowish oil (4.58
g, 93%); 1H NMR (700 MHz, DMSO-d6) δ=7.46 (brs, 1H), 7.38 – 7.32 (m,
3H), 4.62 (q, J=7.1 Hz, 2H), 4.40 (s, 2H), 1.35 (t, J=7.1 Hz, 3H); 13C NMR
(75 MHz, DMSO-d6) δ=212.8, 139.0, 132.9, 130.3, 128.8, 127.7, 127.3,
70.5, 38.2, 13.5; HRMS (ESI): m/z calcd for C10H12ClOS2+: 247.0013
[M+H]+; found: 247.0002.
S-4-nitrobenzyl O-ethyl carbonodithioate (1k).[24] Yellow solid (4.47 g,
87%); m.p. 61-63°C; 1H NMR (700 MHz, DMSO-d6) δ=8.20 (d, J=8.8 Hz,
2H), 7.67 (d, J=8.8 Hz, 2H), 4.62 (q, J=7.1 Hz, 2H), 4.53 (s, 2H), 1.34 (t,
J=7.1 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ=212.4, 146.6, 144.6, 130.1,
123.5, 70.6, 38.1, 13.4; HRMS (ESI): m/z calcd for C10H12NO3S2
258.0253 [M+H]+; found: 258.0250.
General procedures for the synthesis of compounds 2-15:
A
corresponding 2-chloro-pyridine (2 mmol), cesium carbonate (850 mg, 2.6
mmol), a corresponding xanthate (2.4 mmol) and methanol (6 ml) were
mixed in a screw-capped tube. The mixture was stirred for 1-1.5 hours (for
3-nitro, 3-cyano pyridines and nitrobenzenes) or 10-40 hours (for less
active 3-chloro and 3-trifluoromethyl pyridines) at 70°C in the oil bath.
Reaction progress was monitored by TLC (eluent – EtOAc/hexane, 1:10).
After the complete consumption of starting 2-chloro-pyridine or chloro-
nitrobenzene, the solvent was evaporated and the crude product was
purified by flash column chromatography using gradient elution with a
mixture of hexane/toluene (3:1 to 1:3).
+
;
Methyl 3-(((ethoxycarbonothioyl)thio)methyl)benzoate (1l). Light
yellowish oil (5.08 g, 94%); 1H NMR (700 MHz, DMSO-d6) δ=7.99 (brs, 1H),
7.85 (brd, J=7.8 Hz, 1H), 7.66 (brd, J=7.6 Hz, 1H), 7.49 (t, J=7.6 Hz, 1H),
4.61 (q, J=7.1 Hz, 2H), 4.47 (s, 2H), 3.85 (s, 3H), 1.35 (t, J=7.1 Hz, 3H);
13C NMR (75 MHz, DMSO-d6) δ=212.7, 165.8, 137.1, 133.6, 129.8, 129.6,
128.7, 128.0, 70.3, 51.9, 38.5, 13.3; HRMS (ESI): m/z calcd for
C12H15O3S2+: 271.0457 [M+H]+; found: 271.0457.
Thioesters 2a,[28] 2b,[29] 5c,[30] 6a,[8b] 6b,[31] 7n,[32] 8,[7] 11,[33]
12,[34] as well as aminothieno[2,3-b]pyridines 15a,[35] 15b[19b] and 2-
Methoxy-3-nitropyridine 3[36] have already been prepared in the literature
by other methods.
S-3-cyanobenzyl O-ethyl carbonodithioate (1m). White solid (4.51 g,
95%); m.p. 69-71°C; 1H NMR (700 MHz, DMSO-d6) δ=7.84 (brs, 1H), 7.76-
7.12 (m, 2H), 7.55 (t, J=7.8 Hz, 1H), 4.61 (q, J=7.1 Hz, 2H), 4.44 (s, 2H),
1.34 (t, J=7.1 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ=212.6, 138.3,
133.8, 132.5, 131.1, 129.6, 118.5, 111.4, 70.5, 38.0, 13.4; HRMS (ESI):
m/z calcd for C11H12NOS2+: 238.0355 [M+H]+; found: 238.0350.
2-Methoxy-3-nitropyridine (3, main sideproduct for 2-chloro-3-
nitropyridine).[36] Brownish solid; m.p. 57-59°C (lit - 56°C[36]); 1H NMR
(700 MHz, DMSO-d6) δ=8.51 (dd, J=4.8, 1.7 Hz, 1H), 8.44 (dd, J=7.8, 1.7
Hz, 1H), 7.44 (dd, J=7.8, 4.8 Hz, 1H), 4.03 (s, 3H); 1H NMR (700 MHz,
CDCl3) δ=8.41 (dd, J=4.8, 1.7 Hz, 1H), 8.28 (dd, J=7.8, 1.7 Hz, 1H), 7.06
(dd, J=7.8, 4.8 Hz, 1H), 4.13 (s, 3H); HRMS (ESI): m/z calcd for
C6H7N2O3+: 155.0451 [M+H]+; found: 155.0455.
S-allyl O-ethyl carbonodithioate (1n).[25] Light yellowish oil (2.82 g,
87%); 1H NMR (700 MHz, DMSO-d6) δ=5.58 (ddt, J=17.0, 9.9, 6.9 Hz, 1H),
5.31 (brd, J=17.0 Hz, 1H), 5.17 (brd, J=9.9 Hz, 1H), 4.63 (q, J=7.1 Hz, 2H),
3.81 (brd, J=6.9 Hz, 2H), 1.36 (t, J=7.1 Hz, 3H); 13C NMR (75 MHz, DMSO-
d6) δ=213.2, 132.0, 118.8, 70.1, 37.7, 13.4; HRMS (ESI): m/z calcd for
C6H11OS2+: 163.0246 [M+H]+; found: 163.0245.
2-(Benzylthio)-3-nitropyridine (2a).[28] Yellow solid (420 mg, 85%); m.p.
63-65°C (lit – 66-67°C[28]); 1H NMR (700 MHz, DMSO-d6) δ=8.87 (dd,
J=4.6, 1.7 Hz, 1H), 8.62 (dd, J=8.2, 1.7 Hz, 1H), 7.47 (dd, J=8.2, 4.6 Hz,
1H), 7.44 (brd, J=7.2 Hz, 2H), 7.32 (brt, J=7.4 Hz, 2H), 7.25 (brt, J=7.4 Hz,
1H), 4.49 (s, 2H); 13C NMR (75 MHz, DMSO-d6) δ 155.8, 153.7, 141.4,
136.8, 134.3, 129.2, 128.4, 127.1, 120.0, 34.3; HRMS (ESI): m/z calcd for
C12H11N2O2S+: 247.0536 [M+H]+; found: 247.0536.
O-ethyl S-(2-methylallyl) carbonodithioate (1o). Light yellowish oil (3.10
g, 88%); 1H NMR (700 MHz, DMSO-d6) δ=5.01 (brs, 1H), 4.90 (brs, 1H),
4.62 (q, J=7.1 Hz, 2H), 3.82 (s, 2H), 1.76 (s, 3H), 1.36 (t, J=7.1 Hz, 3H);
13C NMR (75 MHz, DMSO-d6) δ=213.4, 139.3, 114.7, 70.1, 41.8, 21.0,
13.4; HRMS (ESI): m/z calcd for C7H13OS2+: 177.0402 [M+H]+; found:
177.0405.
2-(Methylthio)-3-nitropyridine (2b). Yellow solid (238 mg, 70%); m.p.
102-104°C; 1H NMR (700 MHz, DMSO-d6) δ=8.85 (dd, J=4.6, 1.6 Hz, 1H),
O-ethyl S-prop-2-yn-1-yl carbonodithioate (1p).[26] Light yellowish oil
(3.07 g, 96%); 1H NMR (700 MHz, DMSO-d6) δ=4.66 (q, J=7.1 Hz, 2H),
8.61 (dd, J=8.4, 1.6 Hz, 1H), 7.44 (dd, J=8.4, 4.6 Hz, 1H), 2.55 (s, 3H); 13
C
3.97 (d, J=2.7 Hz, 2H), 3.21 (t, J=2.7 Hz, 1H), 1.37 (t, J=7.1 Hz, 3H); 13
C
NMR (75 MHz, DMSO-d6) δ=156.8, 153.7, 141.8, 134.1, 119.5, 13.8;
HRMS (ESI): m/z calcd for C6H7N2O2S+: 171.0223 [M+H]+; found:
171.0225.
NMR (75 MHz, DMSO-d6) δ=211.7, 78.3, 73.9, 70.5, 23.6, 13.4; HRMS
(ESI): m/z calcd for C6H9OS2+: 161.0089 [M+H]+; found: 161.0091.
S-(cyanomethyl) O-ethyl carbonodithioate (1q).[27] Light yellowish oil
(3.16 g, 98%); 1H NMR (700 MHz, DMSO-d6) δ=4.70 (q, J=7.2 Hz, 2H),
4.26 (s, 2H), 1.40 (t, J=7.2 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ=209.8,
2-(Ethylthio)-3-nitropyridine (2c). Yellow solid (254 mg, 69%); m.p. 61-
63°C; 1H NMR (700 MHz, DMSO-d6) δ=8.83 (dd, J=4.6, 1.5 Hz, 1H), 8.58
(dd, J=8.2, 1.5 Hz, 1H), 7.44 (dd, J=8.2, 4.6 Hz, 1H), 3.20 (q, J=7.3 Hz,
2H), 1.30 (t, J=7.3 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ=156.2, 153.7,
5
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202100647
European Journal of Organic Chemistry
FULL PAPER
141.8, 134.3, 119.6, 24.1, 13.7; HRMS (ESI): m/z calcd for C7H9N2O2S+:
185.0379 [M+H]+; found: 185.0385.
3-(((3-Nitropyridin-2-yl)thio)methyl)benzonitrile (2m). Yellow solid (450
mg, 83%); m.p. 150-152°C; 1H NMR (700 MHz, DMSO-d6) δ=8.86 (dd,
J=4.6, 1.6 Hz, 1H), 8.62 (dd, J=8.2, 1.6 Hz, 1H), 7.91 (brs, J=1.8 Hz, 1H),
7.80 (brd, J=7.9 Hz, 1H), 7.71 (brd, J=7.7 Hz, 1H), 7.52 (t, J=7.7 Hz, 1H),
7.48 (dd, J=8.3, 4.6 Hz, 1H), 4.54 (s, 2H); 13C NMR (75 MHz, DMSO-d6)
δ=155.2, 153.7, 141.5, 139.4, 134.5, 134.2, 132.7, 130.8, 129.5, 120.3,
118.6, 111.3, 33.2; HRMS (ESI): m/z calcd for C13H10N3O2S+: 272.0488
[M+H]+; found: 272.0489.
2-(Hexylthio)-3-nitropyridine (2d). Light yellowish oil (355 mg, 74%); 1H
NMR (700 MHz, DMSO-d6) δ=8.81 (dd, J=4.6, 1.5 Hz, 1H), 8.58 (dd, J=8.2,
1.5 Hz, 1H), 7.43 (dd, J=8.2, 4.6 Hz, 1H), 3.19 (t, J=7.4 Hz, 2H), 1.66-1.61
(m, 2H), 1.44-1.37 (m, 2H), 1.31-1.26 (m, 4H), 0.86 (t, J=7.1 Hz, 3H); 13
C
NMR (75 MHz, DMSO-d6) δ=156.3, 153.6, 141.8, 134.2, 119.5, 30.8, 29.7,
28.1, 21.9, 13.8; HRMS (ESI): m/z calcd for C11H17N2O2S+: 241.1005
[M+H]+; found: 241.1005.
2-(Allylthio)-3-nitropyridine (2n). Yellow solid (271 mg, 69%); m.p. 54-
56°C; 1H NMR (700 MHz, DMSO-d6) δ 8.83 (dd, J=4.6, 1.6 Hz, 1H), 8.60
(dd, J=8.2, 1.6 Hz, 1H), 7.45 (dd, J=8.3, 4.6 Hz, 1H), 5.95 (ddt, J=17.0,
10.0, 6.9 Hz, 1H), 5.34 (dq, J=17.0, 1.5 Hz, 1H), 5.15 – 5.11 (m, 1H), 3.90
(brd, J=6.9 Hz, 2H).13C NMR (75 MHz, DMSO-d6) δ=155.5, 153.6, 141.7,
134.3, 133.2, 119.9, 118.4, 32.6; HRMS (ESI): m/z calcd for C8H9N2O2S+:
197.0379 [M+H]+; found: 197.0381.
2-((4-Fluorobenzyl)thio)-3-nitropyridine (2e). Yellow solid (423 mg,
80%); m.p. 108-110°C; 1H NMR (700 MHz, DMSO-d6) δ=8.87 (dd, J=4.6,
1.5 Hz, 1H), 8.62 (dd, J=8.2, 1.5 Hz, 1H), 7.49-7.45 (m, 3H), 7.13 (t, J=8.8
Hz, 2H), 4.48 (s, 2H); 13C NMR (75 MHz, DMSO-d6) δ=161.3 (d, J=243.5
Hz), 155.7, 153.7, 141.4, 134.4, 133.2 (d, J=3.1 Hz), 131.2 (d, J=8.2 Hz),
120.1, 115.1 (d, J=21.5 Hz), 33.4; HRMS (ESI): m/z calcd for
C12H10FN2O2S+: 265.0442 [M+H]+; found: 265.0443.
2-((2-Methylallyl)thio)-3-nitropyridine (2o). Light yellow oil (231 mg,
55%); 1H NMR (700 MHz, DMSO-d6) δ=8.82 (dd, J=4.6, 1.6 Hz, 1H), 8.60
(dd, J=8.2, 1.6 Hz, 1H), 7.44 (dd, J=8.2, 4.6 Hz, 1H), 5.05 (brs, 1H), 4.89
(brs, 1H), 3.93 (s, 2H), 1.80 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ=155.7,
153.6, 141.9, 140.3, 134.3, 119.9, 114.4, 36.4, 21.5; HRMS (ESI): m/z
calcd for C9H11N2O2S+: 211.0536 [M+H]+; found: 211.0539.
2-((4-Сhlorobenzyl)thio)-3-nitropyridine (2f). Yellow solid (471 mg,
84%); m.p. 95-97°C; 1H NMR (700 MHz, DMSO-d6) δ=8.85 (dd, J=4.6, 1.5
Hz, 1H), 8.61 (dd, J=8.4, 1.5 Hz, 1H), 7.49-7.42 (m, 3H), 7.36 (d, J=8.6 Hz,
2H), 4.48 (s, 2H); 13C NMR (75 MHz, DMSO-d6) δ=155.5, 153.7, 141.5,
136.3, 134.4, 131.7, 131.0, 128.3, 120.2, 33.3; HRMS (ESI): m/z calcd for
C
12H10ClN2O2S+: 281.0146 [M+H]+; found: 281.0144.
2-((3-Nitropyridin-2-yl)thio)acetonitrile (2q). Brown solid (152 mg,
39%); m.p. 104-106°C; 1H NMR (700 MHz, DMSO-d6) δ=8.94 (dd, J=4.6,
1.5 Hz, 1H), 8.72 (dd, J=8.3, 1.6 Hz, 1H), 7.59 (dd, J=8.3, 4.6 Hz, 1H),
4.28 (s, 2H); 13C NMR (75 MHz, DMSO-d6) δ=154.0, 153.1, 141.6, 134.8,
121.2, 118.0, 16.1; HRMS (ESI): m/z calcd for C7H6N3O2S+: 196.0175
[M+H]+; found: 196.0180.
2-((4-Bromobenzyl)thio)-3-nitropyridine (2g). Yellow solid (461 mg,
71%); m.p. 97-99°C; 1H NMR (700 MHz, DMSO-d6) δ=8.85 (dd, J=4.6, 1.5
Hz, 1H), 8.62 (dd, J=8.4, 1.5 Hz, 1H), 7.50 (d, J=8.4 Hz, 2H), 7.46 (dd,
J=8.4, 4.6 Hz, 1H), 7.40 (d, J=8.4 Hz, 2H), 4.48 (s, 2H); 13C NMR (75 MHz,
DMSO-d6) δ=155.5, 153.7, 141.4, 136.7, 134.4, 131.4, 131.2, 120.2, 120.1,
33.4; HRMS (ESI): m/z calcd for C12H10BrN2O2S+: 324.9641 [M+H]+;
found: 324.9644.
Methyl 2-((3-nitropyridin-2-yl)thio)acetate (2r). Orange solid (224 mg,
49%); m.p. 59-61°C; 1H NMR (700 MHz, DMSO-d6) δ=8.77 (dd, J=4.6, 1.6
Hz, 1H), 8.64 (dd, J=8.3, 1.6 Hz, 1H), 7.46 (dd, J=8.3, 4.6 Hz, 1H), 4.08 (s,
2H), 3.64 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ=169.3, 155.0, 153.7,
141.5, 134.5, 120.3, 52.2, 32.6; HRMS (ESI): m/z calcd for C8H9N2O4S+:
229.0278 [M+H]+; found: 229.0281.
2-((3-Methoxybenzyl)thio)-3-nitropyridine (2h). Yellow solid (425 mg,
77%); m.p. 82-84°C; 1H NMR (700 MHz, DMSO-d6) δ=8.87 (dd, J = 4.6,
1.6 Hz, 1H), 8.62 (dd, J = 8.3, 1.6 Hz, 1H), 7.47 (dd, J = 8.3, 4.6 Hz, 1H),
7.23 (t, J = 7.8 Hz, 1H), 7.03 – 6.98 (m, 2H), 6.83 (dd, J = 8.3, 2.5 Hz, 1H),
4.46 (s, 2H), 3.73 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ=159.2, 155.9,
153.7, 141.4, 138.3, 134.3, 129.5, 121.4, 120.0, 114.9, 112.6, 54.9, 34.3;
HRMS (ESI): m/z calcd for C13H13N2O3S+: 277.0641 [M+H]+; found:
277.0641.
2-(Benzylthio)-6-methoxy-3-nitropyridine (4a). Yellow solid (348 mg,
63%); m.p. 103-105°C; 1H NMR (700 MHz, DMSO-d6) δ=8.51 (d, J=9.0 Hz,
1H), 7.44 (brd, J=7.2 Hz, 2H), 7.35 (brt, J=7.6 Hz, 2H), 7.28 (brt, J=7.4 Hz,
1H), 6.78 (d, J=9.0 Hz, 1H), 4.53 (s, 2H), 4.02 (s, 3H); 13C NMR (75 MHz,
DMSO-d6) δ=164.2, 157.6, 137.3, 136.4, 135.5, 129.0, 128.5, 127.2, 106.9,
54.9, 34.8; HRMS (ESI): m/z calcd for C13H13N2O3S+: 277.0641 [M+H]+;
found: 277.0644.
2-((2-Methoxybenzyl)thio)-3-nitropyridine (2i). Yellow solid (453 mg,
82%); m.p. 126-128°C; 1H NMR (700 MHz, DMSO-d6) δ=8.88 (dd, J=4.6,
1.6 Hz, 1H), 8.60 (dd, J=8.3, 1.6 Hz, 1H), 7.45 (dd, J=8.3, 4.6 Hz, 1H),
7.40 (dd, J=7.4, 1.7 Hz, 1H), 7.30 – 7.25 (m, 1H), 7.02 (d, J=8.2 Hz, 1H),
6.89 (t, J=7.4 Hz, 1H), 4.45 (s, 2H), 3.82 (s, 3H); 13C NMR (75 MHz,
DMSO-d6) δ=157.4, 156.5, 153.7, 141.4, 134.3, 130.7, 128.9, 124.0, 120.2,
119.7, 110.9, 55.5, 29.4; HRMS (ESI): m/z calcd for C13H13N2O3S+:
277.0641 [M+H]+; found: 277.0644.
6-Methoxy-2-(methylthio)-3-nitropyridine (4b). Yellow solid (348 mg,
87%); m.p. 134-136°C; 1H NMR (700 MHz, DMSO-d6) δ=8.50 (d, J=9.0 Hz,
1H), 6.75 (d, J=9.0 Hz, 1H), 4.06 (s, 3H), 2.57 (s, 3H); 13C NMR (75 MHz,
DMSO-d6) δ=164.2, 158.7, 137.3, 135.9, 106.4, 54.8, 14.0; HRMS (ESI):
m/z calcd for C7H9N2O3S+: 201.0328 [M+H]+; found: 201.0332.
3,5-Dimethyl-4-(((3-nitropyridin-2-yl)thio)methyl)isoxazole (2j). Yellow
solid (392 mg, 74%); m.p. 123-125°C; 1H NMR (700 MHz, DMSO-d6)
δ=8.88 (dd, J=4.6, 1.6 Hz, 1H), 8.61 (dd, J=8.3, 1.6 Hz, 1H), 7.47 (dd,
J=8.3, 4.6 Hz, 1H), 4.26 (s, 2H), 2.44 (s, 3H), 2.24 (s, 3H); 13C NMR (75
MHz, DMSO-d6) δ=166.7, 159.3, 155.5, 153.5, 141.7, 134.5, 120.1, 109.5,
22.3, 10.9, 9.8; HRMS (ESI): m/z calcd for C11H12N3O3S+: 266.0594
[M+H]+; found: 266.0593.
2-(2-Methylallyl)-6-methoxy-3-nitropyridine (4o). Yellow solid (249 mg,
52%); m.p. 76-78°C; 1H NMR (700 MHz, DMSO-d6) δ=8.49 (d, J=9.0 Hz,
1H), 6.76 (d, J=9.0 Hz, 1H), 5.05 (brs, 1H), 4.93 (brs, 1H), 4.04 (s, 3H),
3.95 (brs, 2H), 1.83 (s, 3H). 13C NMR (75 MHz, DMSO-d6) δ=164.1, 157.5,
140.2, 137.4, 135.9, 114.2, 106.8, 54.8, 36.8, 21.6; HRMS (ESI): m/z calcd
for C10H13N2O3S+: 241.0641 [M+H]+; found: 241.0645.
2-((6-Methoxy-3-nitropyridin-2-yl)thio)acetonitrile (4q). Yellow solid
(426 mg, 95%); m.p. 149-151°C; 1H NMR (700 MHz, DMSO-d6) δ=8.56 (d,
J=9.0 Hz, 1H), 6.89 (d, J=9.0 Hz, 1H), 4.31 (s, 2H), 4.16 (s, 3H). 13C NMR
(75 MHz, DMSO-d6) δ=164.6, 154.9, 137.5, 135.8, 118.2, 108.0, 55.2,
16.5; HRMS (ESI): m/z calcd for C8H8N3O3S+: 226.0281 [M+H]+; found:
226.0280.
Methyl 3-(((3-nitropyridin-2-yl)thio)methyl)benzoate (2l). Yellow solid
(407 mg, 67%); m.p. 96-98°C; 1H NMR (700 MHz, DMSO-d6) δ=8.85 (dd,
J=4.6, 1.6 Hz, 1H), 8.61 (dd, J=8.3, 1.6 Hz, 1H), 8.05 (brs, 1H), 7.83 (brd,
J=7.8 Hz, 1H), 7.73 (brd, J=7.7 Hz, 1H), 7.49 – 7.45 (m, 2H), 4.57 (s, 2H),
3.85 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ=166.0, 155.5, 153.7, 141.5,
138.1, 134.4, 134.1, 129.8, 129.7, 128.8, 127.8, 120.2, 52.1, 33.7; HRMS
(ESI): m/z calcd for C14H13N2O4S+: 305.0591 [M+H]+; found: 305.0594.
6
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10.1002/ejoc.202100647
European Journal of Organic Chemistry
FULL PAPER
Methyl 2-((6-methoxy-3-nitropyridin-2-yl)thio)acetate (4r). Yellow solid
(226 mg, 44%); m.p. 115-117°C; 1H NMR (700 MHz, DMSO-d6) δ=8.51 (d,
J=9.0 Hz, 1H), 6.78 (d, J=9.0 Hz, 1H), 4.11 (s, 2H), 3.96 (s, 3H), 3.65 (s,
3H). 13C NMR (75 MHz, DMSO-d6) δ=169.4, 164.4, 156.8, 137.3, 135.7,
107.3, 54.8, 52.2, 33.0; HRMS (ESI): m/z calcd for C9H11N2O5S+: 259.0383
[M+H]+; found: 259.0385.
(4-methylbenzyl)(2-nitro-4-(trifluoromethyl)phenyl)sulfane (9). Yellow
solid (517 mg, 79%); m.p. 136-138°C; 1H NMR (700 MHz, DMSO-d6)
δ=8.46 (d, J=2.1 Hz, 1H), 8.04 (dd, J=8.6, 2.1 Hz, 1H), 7.94 (d, J=8.6 Hz,
1H), 7.35 (d, J=8.0 Hz, 2H), 7.17 (d, J=7.7 Hz, 2H), 4.42 (s, 2H), 2.29 (s,
3H). 13C NMR (75 MHz, DMSO-d6) δ ppm144.7, 142.3, 137.0, 131.8, 129.9
(q, J=3.9 Hz), 129.3, 129.1, 128.7, 125.3 (q, J=33.7 Hz), 123.1 (q, J
=272.4Hz), 122.9 (q, J=3.7 Hz), 35.8, 20.6; elemental analysis calcd (%)
for C15H12F3NO2S: C 55.04; H 3.70; N 4.28; found C 55.14; H 3.69; N 4.27.
2-(Benzylthio)nicotinonitrile (5a). Yellowish solid (430 mg, 95%); m.p.
72-74°C; 1H NMR (700 MHz, DMSO-d6) δ=8.74 (dd, J=5.0, 1.8 Hz, 1H),
8.22 (dd, J=7.7, 1.8 Hz, 1H), 7.43 (brd, J=6.9 Hz, 2H), 7.36 – 7.29 (m, 3H),
7.25 (brt, J=7.4 Hz, 1H), 4.55 (s, 2H); 13C NMR (75 MHz, DMSO-d6)
δ=160.9, 152.6, 141.7, 137.1, 129.0, 128.4, 127.3, 119.7, 115.5, 106.1,
33.4; HRMS (ESI): m/z calcd for C13H11N2S+: 227.0637 [M+H]+; found:
227.0641.
(2-Chloro-6-nitrophenyl)(4-methylbenzyl)sulfane (10). Yellow solid
(487 mg, 83%); m.p. 83-84°C; 1H NMR (700 MHz, DMSO-d6) δ=7.86 (dd,
J=8.1, 1.3 Hz, 1H), 7.77 (dd, J=8.0, 1.3 Hz, 1H), 7.59 (t, J=8.1 Hz, 1H),
7.04 (d, J=7.8 Hz, 2H), 6.99 (d, J=8.0 Hz, 2H), 4.11 (s, 2H), 2.24 (s, 3H).
13C NMR (75 MHz, DMSO-d6) δ=156.0, 140.5, 136.7, 133.3, 133.0, 131.4,
129.0, 128.7, 125.0, 122.0, 38.8, 20.7; elemental analysis calcd (%) for
C14H12ClNO2S: C 57.24; H 4.12; N 4.77; found C 57.33; H 4.11; N 4.76.
2-(Ethylthio)nicotinonitrile (5c).[30] Yellowish oil (256 mg, 78%); 1H
NMR (700 MHz, DMSO-d6) δ=8.70 (dd, J=4.9, 1.8 Hz, 1H), 8.20 (dd, J=7.7,
1.8 Hz, 1H), 7.30 (dd, J=7.7, 4.9 Hz, 1H), 3.25 (q, J=7.3 Hz, 2H), 1.32 (t,
J=7.3 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ=161.5, 152.7, 141.7, 119.3,
115.6, 106.4, 23.9, 14.4; HRMS (ESI): m/z calcd for C8H9N2S+: 165.0481
[M+H]+; found: 165.0483.
Methyl 4-(benzylthio)-3-nitrobenzoate (11).[33] Yellow solid (497 mg,
82%); m.p. 142-145°C (lit – 138-139°C[33]); 1H NMR (700 MHz, DMSO-
d6) δ=8.63 (d, J=2.0 Hz, 1H), 8.16 (dd, J=8.5, 1.9 Hz, 1H), 7.90 (d, J=8.5
Hz, 1H), 7.47 (d, J=6.9 Hz, 2H), 7.37 (t, J=7.6 Hz, 2H), 7.31 (t, J=7.4 Hz,
1H), 4.45 (s, 2H), 3.90 (s, 3H). 13C NMR (75 MHz, DMSO-d6) δ=164.3,
144.4, 143.0, 134.9, 133.4, 129.3, 128.7, 127.8, 127.7, 126.3, 126.1, 52.6,
36.1; HRMS (ESI): m/z calcd for C15H13NNaO4S+: 326.0457 [M+Na]+;
found: 326.0466.
2-((2-Methylallyl)thio)nicotinonitrile (5o). Yellowish oil (319 mg, 84%);
1H NMR (700 MHz, DMSO-d6) δ=8.70 (dd, J=4.9, 1.8 Hz, 1H), 8.21 (dd,
J=7.8, 1.8 Hz, 1H), 7.32 (dd, J=7.8, 4.9 Hz, 1H), 5.03 (brs, 1H), 4.88 (brs,
1H), 3.98 (brs, 2H), 1.79 (brs, 3H); 13C NMR (75 MHz, DMSO-d6) δ=160.9,
152.6, 141.7, 140.2, 119.7, 115.5, 114.4, 106.6, 35.9, 21.2; HRMS (ESI):
m/z calcd for C10H11N2S+: 191.0637 [M+H]+; found: 191.0638.
Benzyl(4-nitrophenyl)sulfane (12).[34] Yellow solid (211 mg, 43%); m.p.
125-127°C (lit - 126-127°C[34]); 1H NMR (700 MHz, DMSO-d6) δ=8.12 (d,
J=9.0 Hz, 2H), 7.55 (d, J=9.0 Hz, 2H), 7.45 (d, J=7.3 Hz, 2H), 7.33 (t, J=7.7
Hz, 2H), 7.27 (t, J=7.4 Hz, 1H), 4.43 (s, 2H). 13C NMR (75 MHz, DMSO-
d6) δ=147.3, 144.5, 136.1, 128.9, 128.6, 127.4, 126.4, 123.8, 35.1;
elemental analysis calcd (%) for C13H11NO2S: C 63.65; H 4.52; N 5.71;
found C 63.74; H 4.50; N 5.70.
2-(Benzylthio)-3-chloropyridine (6a).[8b] Yellowish oil (~70%,
determined from NMR of 80-90% purity product); 1H NMR (700 MHz,
DMSO-d6) δ=8.49 (dd, J=4.8, 1.3 Hz, 1H), 7.87 (dd, J=7.8, 1.5 Hz, 1H),
7.43 (bd, J=7.4 Hz, 2H), 7.31 (bt, J=7.8 Hz, 2H), 7.25 (bt, J=7.3 Hz, 1H),
7.21 (dd, J=7.8, 4.8 Hz, 1H), 4.46 (s, 2H).
Benzyl(2-chloro-4-nitrophenyl)sulfane (13). Yellow solid (403 mg,
72%); m.p. 105-107°C; 1H NMR (700 MHz, DMSO-d6) δ=8.28 (d, J=2.5 Hz,
1H), 8.15 (dd, J=8.8, 2.5 Hz, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.48 (d, J=7.3
Hz, 2H), 7.37 (t, J=7.6 Hz, 2H), 7.30 (t, J=7.4 Hz, 1H), 4.48 (s, 2H). 13C
NMR (75 MHz, DMSO-d6) δ=146.3, 144.5, 135.2, 129.7, 129.0, 128.7,
127.7, 126.1, 123.9, 122.4, 35.2; elemental analysis calcd (%) for
C13H10ClNO2S: C 55.82; H 3.60; N 5.01; found C 55.93; H 3.59; N 5.00.
2-(Methylthio)-3-chloropyridine (6b).[31] Yellowish oil (225 mg, 71%);
1H NMR (800 MHz, DMSO-d6) δ=8.46 (dd, J=4.7, 1.5 Hz, 1H), 7.84 (dd,
J=7.9, 1.5 Hz, 1H), 7.18 (dd, J=7.9, 4.7 Hz, 1H), 2.52 (s, 3H). 13C NMR
(201 MHz, DMSO-d6) δ=156.6, 147.6, 136.2, 128.1, 120.4, 12.8; HRMS
(ESI): m/z calcd for C6H7ClNS+: 159.9982 [M+H]+; found: 159.9977.
2-((4-Bromobenzyl)thio)-3-(trifluoromethyl)pyridine (7g). Yellowish oil
(451 mg, 65%); 1H NMR (700 MHz, DMSO-d6) δ=8.73 (brd, J=4.8 Hz, 1H),
8.09 (brd, J=7.9 Hz, 1H), 7.49 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H),
7.36 (dd, J=7.8, 4.9 Hz, 1H), 4.52 (s, 2H); 13C NMR (176 MHz, DMSO-d6)
δ=156.0, 152.3, 137.0, 135.2 (q, J=5.2 Hz), 131.2, 131.2, 123.3 (q,
J=273.1 Hz), 121.9 (q, J=32.2 Hz), 120.2, 119.6, 32.5; HRMS (ESI): m/z
calcd for C13H10BrF3NS+: 347.9664 [M+H]+; found: 347.9670.
Benzyl(4-nitro-2-(trifluoromethyl)phenyl)sulfane (14). Yellow solid
(269 mg, 43%); m.p. 89-91°C; 1H NMR (700 MHz, DMSO-d6) δ=8.39 (dd,
J=8.8, 2.6 Hz, 1H), 8.37 (d, J=2.5 Hz, 1H), 7.92 (d, J=8.8 Hz, 1H), 7.47 (d,
J=6.8 Hz, 2H), 7.35 (t, J=7.6 Hz, 2H), 7.29 (t, J=7.4 Hz, 1H), 4.57 (s, 2H).
13C NMR (176 MHz, DMSO-d6) δ=146.2, 144.1, 135.0, 129.0, 128.6, 128.6,
127.7, 126.9, 125.8 (q, J=31.6 Hz), 122.6 (q, J=273.9 Hz), 121.8 (q, J=6.1
Hz), 35.8; elemental analysis calcd (%) for C14H10F3NO2S: C 53.67; H
3.22; N 4.47; found C 53.73; H 3.21; N 4.46.
2-(Allylthio)-3-(trifluoromethyl)pyridine (7n). Yellowish oil (90 mg,
21%); 1H NMR (700 MHz, DMSO-d6) δ=8.71 (brd, J=4.6 Hz, 1H), 8.09 (brd,
J=7.8 Hz, 1H), 7.35 (dd, J=7.8, 4.8 Hz, 1H), 5.93 (ddt, J=16.9, 10.1, 6.8
Hz, 1H), 5.31 (dq, J=17.0, 1.5 Hz, 1H), 5.11 (brd, J=10.0 Hz, 1H), 3.95
(brd, J=6.8 Hz, 2H); 13C NMR (201 MHz, DMSO-d6) δ=156.1, 152.3, 135.2
(q, J=5.2 Hz), 133.4, 122.7 (q, J=274.2 Hz), 122.2 (q, J=32.4 Hz), 119.4,
118.2, 31.9; HRMS (ESI): m/z calcd for C9H9F3NS+: 220.0402 [M+H]+;
found: 220.0402.
3-Aminothieno[2,3-b]pyridine-2-carbonitrile (15a).[35] Orange solid
(308 mg, 88%); m.p. 215-217°C (lit – 218-219°C [35]); 1H NMR (700 MHz,
DMSO-d6) δ=8.71 (dd, J=4.6, 1.6 Hz, 1H), 8.50 (dd, J=8.2, 1.6 Hz, 1H),
7.52 (dd, J=8.2, 4.6 Hz, 1H), 7.31 (s, 2H); 13C NMR (75 MHz, DMSO-d6)
δ=159.6, 150.9, 150.4, 131.3, 124.2, 119.9, 115.7, 71.4; HRMS (ESI): m/z
calcd for C8H6N3S+: 176.0277 [M+H]+; found: 176.0279.
Methyl 3-aminothieno[2,3-b]pyridine-2-carboxylate (15b).[19b] Yellow
solid (396 mg, 95%); m.p. 190-191°C (lit – 191°C [19b]); 1H NMR (700
MHz, DMSO-d6) δ=8.68 (dd, J=4.6, 1.6 Hz, 1H), 8.54 (dd, J=8.1, 1.6 Hz,
1H), 7.46 (dd, J=8.1, 4.6 Hz, 1H), 7.30 (brs, 2H), 3.80 (s, 3H); 13C NMR
(75 MHz, DMSO-d6) δ=164.8, 159.7, 150.7, 147.8, 131.5, 125.6, 119.4,
93.3, 51.4; HRMS (ESI): m/z calcd for C9H9N2O2S+: 209.0379 [M+H]+;
found: 209.0384.
(4-methylbenzyl)(2-nitrophenyl)sulfane (8).[7] Yellow solid (466 mg,
90%); m.p. 101-104°C (lit – 101-103°C[7]); 1H NMR (700 MHz, DMSO-d6)
δ=8.18 (dd, J=8.3, 1.4 Hz, 1H), 7.74 (d, J=8.2 Hz, 1H), 7.70 (t, J=8.3 Hz,
1H), 7.41 – 7.36 (m, 1H), 7.32 (d, J=8.0 Hz, 2H), 7.15 (d, J=7.8 Hz, 2H),
4.32 (s, 2H), 2.28 (s, 3H).13C NMR (75 MHz, DMSO-d6) δ=145.3, 136.7,
136.6, 134.1, 132.4, 129.2, 129.1, 127.6, 125.8, 125.3, 35.8, 20.7; HRMS
(ESI): m/z calcd for C14H13NNaO2S+: 282.0559 [M+Na]+; found: 282.0555.
7
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10.1002/ejoc.202100647
European Journal of Organic Chemistry
FULL PAPER
Waisser, J. Kaustova, V. Buchta, K. Krilova, Eur. J. Med. Chem. 1999, 34, 433-
440.
2-((3-chlorobenzyl)thio)isonicotinonitrile (16). Yellowish solid (115 mg,
22%); m.p. 97-99°C; 1H NMR (700 MHz, DMSO-d6) δ=8.69 (brd, J=5.1 Hz,
1H), 7.88 (brs, 1H), 7.56 (dd, J=5.1, 1.4 Hz, 1H), 7.49 (s, 1H), 7.39 (brd,
J=7.5 Hz, 1H), 7.34 (t, J=7.7 Hz, 1H), 7.31 (dt, J=8.0, 1.6 Hz, 1H), 4.47 (s,
2H); 13C NMR (201 MHz, DMSO-d6) δ=159.7, 150.4, 140.2, 132.9, 130.3,
128.6, 127.6, 127.1, 123.6, 121.2, 119.9, 116.4, 32.5; HRMS (ESI): m/z
calcd for C13H10ClN2S+: 261.0248 [M+H]+; found: 261.0244.
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8
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European Journal of Organic Chemistry
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Entry for the Table of Contents
A new protocol for the synthesis of aryl-alky thioethers based on the use of S-alkylated xantathes, which appear the thiol surrogates,
is proposed. This technique allows to avoid contact with unpleasant thiols odor and allows to introduce substituents for which the
corresponding thiols are hardly obtainable, gaseous, or do not exist at all.
9
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